2- (2-Substituted pyrrolidin-4-yl) thio-carbapenem derivatives

TECHNICAL FIELD
The present invention relates to a novel carbapenem derivative useful as a therapeutic agent for treatment of bacterial infectious diseases in pharmacological field.
BACKGROUND ART
Recently, beta-lacatam antibiotics having a beta-lactam ring in their structurs as in penicillin derivaties have been discovered in the natural world. As the typical example thereof, thienamycin having the following structural formula was first isolated by fermentation of microorganism Streptomyces cattleya (Journal of American. Assoc. Vol. 100, p6491, 1978). ##STR2## Thienamycin=�5R-�5.alpha., 6.alpha.(R*)!!-3-�(2-aminoethyl)-thio!-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo�3.2.0!-hept-2-ene-2-carboxylic acid
According to the result of antimicrobial activity test, has been identified that thienamycin exhibits a broad and potent antimicrobial activity against gram-positive and gram-negative bacteria. Thus, thienamycin was expected as a beta-lactam antibiotic substance having a high clinical utility. However, it has been reported that since thienamycin itself is chemically unstable and can be readily decomposed in vivo by dehydrogenase-1(DHP-I enzyme) present in kidney, when thienamycin is clinically administered, antibacterial activity in vivo exhibits a tendency to reduce and the recovery rate in urine is extremely low (Antimicro. Agent. Chemother. Vol 22, p62, 1982). Thus, in order to prepare the compound having an improved chemical stability while maintaining a good-antibacterial activity of thienamycin numerous thienamycin derivatives have been synthesized. Among such thienamycin derivatives, particularly imipenem, i.e. (5R, 6S, 8R)-3-��2-(formimidoylamino)ethyl!thio!-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo�3.2.0!hept-ene-2-carboxylic acid hydrate which is prepared by formylating an amino group in thienamycin, exhibits antibacterial activity equivalent to, or higher than, that of thienamycin against various bacteria including beta-lactamase producing strains and particularly a potent antibacterial activity against Pseudomonas aeruginosa, which is 2 to 4 times stronger than that of thienamycin and further shows a slightly improved stability in a solution in comparison withy thienamycin. Accordingly, imipenem was developed as a Pharmaceutical medicament which can be practically and clinically utilized (J. Med. Chem. Vol. 22, p1435, 1979). However, since imipenem can be readily decomposed by DHP-I enzyme present in human kidney as like as thienamycin, it cannot be used for treatment of urinary tract infection and further, substances produced by DHP-I enzyme decomposition can induce a serious renal toxicity. Accordingly, imipenem cannot be administered alone and should be administered together with DHP-I enzyme inhibitors such as cilastatin (J. Antimicrob. Chemo. Vol. 12 (Suppl. D) pl (1983)). Moreover, recently a frequent use of imipenem for prophylaxis and treatment of infectious diseases results in remarkable increase of imipenem-resistant Straphylococcus aureus and Pseudomonas aeruginosa strains in clinical field. Imipenem cannot provide a suitable therapeutic effect on diseases caused by such resistant strains.
As a result of an effort to solve such disadvantages, many antibiotics having chemical structure and pharmacological activity similar to imipenem but not having the above-mentioned disadvantages involved in imipenem have been developed. For example they are disclosed in European Patent Nos. 411664A, 272456, 272457, 280771, 341557 and the like. Among these patent specifications, European Patent No. 411664A discloses a carbapenem compound having 2-�2-(aminocarbonyl)vinyl!pyrroldin-4-yl!-thio group at 2-position of a carbapenem basic structure with a specific example of (1R, 5S, 6S)-2-�(2S, 4S)-2-�(E)-2-(aminocarbonyl)vinyl!-pyrrolidin-4-yl-thio!-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid (Bo-2171, compound of Example 3). Such beta-lactam antibiotics generally exhibit a toxic effect selectively only on pathogenic bacteria with substantially no toxic effect on animal cells. Accordingly, they have been broadly and safely used for treatment of infectious diseases caused by bacteria for clinical purpose. However, since these beta-lactam antibiotics do not sufficiently exhibit a satisfactory antibacterial effect on causative microorganisms for incurable infectious disease, such as Staphylococcus aureus and Pseudomonas aeruginosa which are resistant to methicillin, their clinical use is greatly restricted, particularly in immunodeficient patients from which such resistant strains are frequently isolated. Further, although such known antibiotic compounds have a resistance to DHP-I enzyme to some extent, it is not sufficient to the desired extent. Accordingly, the development of antibiotic compounds showing an improved antibacterial activity against such resistant strains has been continuously required. Specifically, the major aspect of development of a novel carbapenem antibiotic compound resides in an increase of resistance against DHP-I enzyme and a reduction of renal toxicity and side effects on central nervous system as well as an increase of antibacterial activity.
DISCLOSURE OF INVENTION
Thus, the present inventors have conducted an extensive study to provide a novel carbapenem compound showing an excellent antibacterial activity and a strong resistance against DHP-I enzyme. As a result, we have found that a novel group of carbapenem compounds having a moiety of the following formula (A) at 2-position of carbapenem structure satisfies the above-mentioned requirement and then completed the present invention: ##STR3## wherein R.sub.3 represents hydrogen or lower alkanimidoyl,
z represents ##STR4## or R.sub.9, X represents O or NH,
R.sub.4 represents amino or heterocyclic amine group, each of which can be unsubstituted or substituted with a group of formula ##STR5## a unsubstituted or substituted heterocyclic group or a lower alkyl group, or represents hydroxy(lower)alkyl or carbamoyloxy(lower)alkyl,
R.sub.5 and R.sub.6 independently of one another represent hydrogen, hydroxy, hydroxy(lower)alkyl, cyano, amino, carbamoyl, carbamoyl(lower)alkyl, cyano(lower)alkyl, mono- or di-(lower)alkylcarbamoyl, carbamoyloxy, ureido, amino (lower)alkyl, carbamoyloxy(lower)alkyl, mono- or di-(lower)alkylcarbamoyl-(lower alkyl, ureido(lower)alkyl, or a group of formula ##STR6## wherein ##STR7## denotes a unsubstituted or substituted 3- to 6-membered heterocyclic group which can contain additional hetero atoms, provided that R.sub.5 and R.sub.6 cannot be hydrogen at the same time,
R.sub.9 represents hydroxy(lower)alkyl or carbamoyloxy, and
m is an integer of 1 to 6, provided that when m is 1 and X is O, R.sub.4 is other than unsubstituted amino(--NH.sub.2).
A compound of formula (I), as defined below, having the partial structure (A) above is a novel compound which was not disclosed in the prior art up to now. It is identified that the compound (I) exhibits a superior antibacterial activity against both of gram-positive bacteria such as Staphylococcus aureus and gram-negative bacteria such as Pseudomonas aeruginosa and further shows a good stability to DHP-I enzyme.
Accordingly, it is an object of the present invention to provide a novel 2-(2-substituted pyrrolidin-4-yl)thio-carbapenem derivative represented by the following general formula (I): ##STR8## and pharmaceutically acceptable salts thereof, in which R.sub.1 represents hydrogen or (lower)alkyl,
R.sub.2 represents hydrogen or anion,
R.sub.3 represents hydrogen or (lower)alkanimidoyl,
Z represents ##STR9## or R.sub.9, X represents O or NH,
R.sub.4 represents amino or heterocyclic amine group, each of which can be unsubstituted or substituted with a group of formula ##STR10## a unsubstituted or substituted heterocyclic group or a lower alkyl group, or represents hydroxy(lower)alkyl or carbamoyloxy(lower)alkyl,
R.sub.5 and R.sub.6 independently of one another represent hydrogen, hydroxy, hydroxy(lower)alkyl, cyano, amino, carbamoyl, carbamoyl(lower)alkyl, cyano(lower)alkyl, mono- or di-(lower)alkylcarbamoyl, carbamoyloxy, ureido, amino (lower)alkyl, carbamoyloxy(lower)alkyl, mono- or di-(lower)alkylcarbamoyl-(lower)alkyl, ureido(lower)alkyl, or a group of formula ##STR11## wherein ##STR12## denotes a unsubstituted or substituted 3- to 6-membered heterocyclic group which can contain additional hetero atoms, provided that R.sub.5 and R.sub.6 cannot be hydrogen at the same time,
R.sub.9 represents hydroxy(lower)alkyl or carbamoyloxy, and
m is an integer of 1 to 6, provided that when m is 1 and X is O, R.sub.4 is other than unsubstituted amino(--NH.sub.2).
Further, it is another object of the present invention to provide a process for preparation of the compound of formula (I): ##STR13## wherein R.sub.1, R.sub.2, R.sub.3, Z and m are defined as above, or salts thereof, which comprises reacting a compound of formula (II): ##STR14## wherein R.sub.1 is as defined above and R.sub.7 represents a carboxy-protecting group, or a reactive derivative at the oxo group thereof or salts thereof with a compound of formula (III): ##STR15## wherein Z and m are as defined above and R.sub.10 represents an imino-protecting group, or salts thereof to obtain an intermediate compound of formula (IV), ##STR16## wherein R.sub.1, R.sub.7, R.sub.10, Z and m are as defined above, or salts thereof and subjecting the resulting compound of formula (IV) or salts thereof to elimination reaction of the carboxy- and imino-protecting groups and, if necessary, reacting the resulting compound of formula (I-b), ##STR17## wherein R.sub.1, R.sub.2 Z and m are as defined above, or salts thereof with a lower alkanimidoylating agent.
It is a further object of the present invention to provide a novel 2-substituted mercaptopyrrolidine compound represented by the following general formula (III), which is an intermediate compound useful in the preparation of the desired compound of formula (I): ##STR18## wherein Z, R.sub.10 and m are as defined above, and a process for preparation thereof.
Further, it is another object of the present invention to provide a pharmaceutical composition containing a novel carbapenem compound of formula (I) as defined above.
BEST MODE FOR CARRYING OUT THE INVENTION
In one aspect, the present invention relates to a novel 2-(2-substituted pyrrolidin-4-yl)thio-carbapenem derivative of the following general formula (I): ##STR19## and pharmaceutically acceptable salts thereof, in which R.sub.1 represents hydrogen or (lower)alkyl,
R.sub.2 represents hydrogen or anion,
R.sub.3 represents hydrogen or (lower)alkanimidoyl,
Z represents ##STR20## or R.sub.9, X represents O or NH,
R.sub.4 represents amino or heterocyclic amine group, each of which can be unsubstituted or substituted with a group of formula ##STR21## a unsubstituted or substituted heterocyclic group or a (lower)alkyl group, or represents hydroxy(lower)alkyl or carbamoyloxy(lower)alkyl,
R.sub.5 and R.sub.6 independently of one another represent hydrogen, hydroxy, hydroxy(lower)alkyl, cyano, amino, carbamoyl, carbamoyl(lower)alkyl, cyano(lower)alkyl, mono- or di-(lower)alkylcarbamoyl, carbamoyloxy, ureido, amino-(lower)alkyl, carbamoyloxy(lower)alkyl, mono- or di-(lower)alkylcarbamoyl(lower)alkyl, ureido(lower)alkyl, or a group of formula ##STR22## wherein ##STR23## denotes a unsubstituted or substituted 3- to 6-membered heterocyclic group which can contain additional hetero atoms, provided that R.sub.5 and R.sub.6 cannot be hydrogen at the same time,
R.sub.9 represents hydroxy(lower)alkyl or carbamoyloxy, and
m is an integer of 1 to 6, provided that when m is 1 and X is O, R.sub.4 is other than unsubstituted amino(--NH.sub.2)
The compound of the present invention has the following basic structure ##STR24##
This basic structure is named 7-oxo-1-azabicyclo�3.2.0!hept-2-ene-2-carboxylic acid. In the present invention, it is named 1-carbapen-2-em-3-carboxylic acid according to the more generally and widely used nomenclature system for convenience. ##STR25##
The compound of formula (I) according to the present invention includes optical isomers due to asymmetric carbon atoms present in 1-, 5-, 6- and 8-position of the carbapenem moiety and side chain bound to 6-position thereof. Among such isomeric compound, the most preferred compound is a compound having trans configuration (5S, 6S) at 5 and 6 positions, R-configuration at 8-position and R-configuration at lower alkyl group (R.sub.1) present on 1-position, i.e. a compound having the whole configuration (1R, 5S, 6S, 8R). ##STR26##
In addition, in a (2-substituted pyrrolidin-4-yl)thio group which is the side chain present on 2-position of the carbapenem structure there may be isomeric compound due to asymmetric carbon atoms present on 2- and 4-positions of pyrrolidine, among which the compound having (2S',4S') or (2R',4R') configuration is most preferable. The compound of formula (I) according to the present invention also includes isomers at pyrrolidine moiety which is the side chain present on 2-position of carbapenem structure.
The desired compound of the present invention also includes a pharmaceutically acceptable salt of the compound of formula (I). Such pharmaceutically acceptable salt may include a base-addition salt such as an inorganic base salt for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. magnesium salt, calcium salt, etc.), etc. or an organic base salt, for example, a salt with an organic base (e.g. triethylamine salt, dicyclohexylamine salt, ethanolamine salt, pyridine salt, picoline salt, etc.); an acid-addition salt such as an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.) or an organic acid addition salt (e.g. formate, acetate, tartrate, benzenesulfonate, etc.); an intermolecular quaternary salt, and the like.
The present invention also provides a process for preparation of 2-(2-substituted pyrrolidin-4-yl)thio-carbapenem derivatives of formula (I) as defined above and salts thereof. The process for preparation of he desired compound pound of formula (I) according to the present invention can be illustrated by the following reaction scheme: ##STR27## In the above reaction scheme, R.sub.1, R.sub.2, R.sub.3, Z and m are as defined above,
R.sub.7 represents a carboxy-protecting group and
R.sub.10 represents an imino-protecting group.
The term "lower alkyl" as used herein is intended to mean straight or branched alkyl having 1 to 6 carbon atoms and may include, for example, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, hexyl, etc. Preferable lower alkyl is methyl, ethyl, propyl or t-butyl, Suitable "carbamoyl(lower)alkyl" may include, for example, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, 1-(carbamoylmethyl)ethyl, 1-carbamoyl-1-methylethyl, carbamoylbutyl, 1,1-dimethyl-2-carbamoylethyl, carbamoylpentyl, carbamoylhexyl, and the like, in which preferable one is carbamoyl-(C.sub.1 -C.sub.4)alkyl and the most preferable one is carbamoylmethyl, carbamoylethyl or carbamoylpropyl. Suitable "lower alkanimidoyl" may include straight or branched lower alkanimidoyl having 1 to 6 carbon atoms such as formimidoyl, acetimidoyl, propionimidoyl, butyrimidoyl, isovalerimidoyl, pentanimidoyl, hexanimidoyl, and the like, in which the most preferable one is formimidoyl or acetimidoyl.
Suitable caboxy-protecting group for R may include a group which can form esterified carboxy. Preferable examples of the ester moiety of an esterified carboxy may include lower alkyl ester such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, etc.; lower alkanoyloxy(lower)alkyl ester which may have suitable substituent(s) such as acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1(or 2)-acetoxyethyl ester, 1(or 2, or 3)-acetoxypropyl ester, 1(or 2, or 3, or 4)-acetoxybutyl ester, 1(or 2)-propionyloxyethyl ester, 1(or 2, or 3)-propionyloxypropyl ester, 1(or 2)-butyryl oxyethyl ester, 1(or 2)-isobutyryloxyethyl ester, 1(or 2)-pivaloyloxy ethyl ester, 1(or 2)-hexanoyloxyethyl ester, isobutyryloxymethyl ester, (2-ethylbutyryl)oxymethyl ester, (3,3-dimethylbutyryl)oxymethyl ester, 1(or 2)-pentanoyloxyethyl ester, etc.; (lower)alkanesulfonyl(lower)alkyl ester; mono-(or di- or tri-)halo(lower)alkyl ester such as 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.; lower alkoxycarbonyloxy(lower)alkyl ester such as methoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc.; phthalidinyl (lower)alkyl ester; (5-lower alkyl-2-oxo-1,3-dioxolan-4-yl) (lower)alkyl ester such as (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxolan-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxolan-4-yl)ethyl ester, etc.; lower alkenyl ester such as vinyl ester, allyl ester, etc.; lower alkynyl ester such as ethynyl ester, propynyl ester, etc.; or aromatic(lower)alkyl ester which may have suitable substituent(s), for example, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenylethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-t-butylbenzyl ester and the like; or aryl ester which may have suitable substituents, for example, phenyl ester, 4-chlorophenyl ester, tosyl ester, t-butylphenyl ester, mesityl ester, cumenyl ester, phthalidyl ester, and the like. Among these ester moieties, particularly preferable one may be substituted aromatic(lower)alkyl ester, most preferably 4-nitrobenzyl or phenyl(C.sub.1 -C.sub.4)alkyl ester.
Suitable imino-protecting group for R.sub.10 may include acyl group such as aliphatic acyl substituted with aromatic or heterocyclic group derived from carboxylic acid, carbonic acid, sulfonic acid or carbamic acid, or carbamoyl, aliphatic acyl, aromatic acyl or heterocyclic acyl. Suitable aliphatic acyl may include saturated or unsaturated acyclic or cyclic acyl groups, for example, lower alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.; (lower)alkylsulfonyl such as mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.; N-alkylcarbamoyl such as methylcarbamoyl, ethylcarbamoyl, etc.; (lower)alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.; (lower)alkenyloxycarbonyl such as vinyloxycarbonyl, allyloxycarbonyl, etc.; (lower)alkenoyl such acryloyl, methacryloyl, crotonoyl, etc.; cyclo(lower)alkylcarbonyl such as cyclopentylcarbonyl, cyclopropylcarbonyl, cyclohexylcarbonyl, etc., and the like. Suitable aromatic acyl may include heterocyclic carbonyl such as furoyl, thienylcarbonyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc. The aliphatic acyl substituted with aromatic group may include aralkanoyl such as phenyl(lower)alkanoyl, for example, phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.; aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl, for example, benzyloxycarbonyl, phenylethyloxycarbonyl, etc.; aryloxyalkanoyl such as phenoxy(lower)alkanoyl for example, phenoxyacetyl, phenoxypropionyl, etc., and the like. The aliphatic acyl substituted with heterocyclic group may include heterocyclic(lower)alkanoyl such as thienylacetyl, imidazolylacetyl, pyridylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl, tec. The above-mentioned acyl groups may have one or more substituent(s) and the preferable example of suitable substituent is as follows: (lower)alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.; halogen such as chlorine, bromine, iodine, fluorine, etc.; (lower)alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.; (lower)alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.; mono-(or di- or tri-)haloalkanoyl such as chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc.; mono-(or di- or tri-)haloalkoxycarbonyl such as chloromethoxycarbonyl, dichloromethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, etc.; or nitro(or halo or lower alkoxy)aryl-oxycarbonyl such as nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl, methoxybenzyloxycarbonyl, etc., and the like. More preferable example of imino-protecting groups as defined above may be (C.sub.2 -C.sub.4)alkenyloxycarbonyl or phenyl(C.sub.1 -C.sub.4)alkoxycarbonyl which may have nitro substituent, and the most preferable one may be allyloxycarbonyl or 4-nitrobenzyloxycarbonyl.
Suitable "lower alkylene" may include, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, propylene, etc., in which more preferable example may be C.sub.1 -C.sub.4 alkylene and the most preferable one may be methylene.
In the definitions of R.sub.5 and R.sub.6 above, ##STR28## denotes a 3- to 6-membered heterocyclic group which may contain additional hetero atoms, preferably nitrogen atom, such as substituted or unsubstituted aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl, in which the preferable substituent may be carbamoyl, (lower)alkyl, hydroxy(lower)alkyl, cyano(lower)alkyl, amino(lower)alkyl, carbamoyloxy(lower)alkyl or amino.
"Substituted or unsubstituted heterocyclic amine" suitable for R.sub.4 preferably means a N-containing heterocyclic group, particularly aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl, which may be unsubstituted or substituted with carbamoyl, (lower)alkyl, hydroxy(lower)alkyl, cyano(lower)alkyl, amino(lower)alkyl, carbamoyloxy(lower)alkyl, ureido(lower)alkyl, carbamoyl(lower)alkyl, or mono or di-(lower)alkylcarbamoyl(lower)alkyl.
Among 2-(2-substituted pyrrolidin-4-yl)thio-carbapenem compounds of formula (I) according to the present invention, the preferable one is the compounds wherein R.sub.1 represents hydrogen or lower alkyl, R.sub.2 represents hydrogen or anion, R.sub.3 represents hydrogen or straight or branched (C.sub.1 -C.sub.6)alkanimidoyl, Z represents ##STR29## or R.sub.9, R.sub.4 represents ##STR30## wherein R.sub.5 and R.sub.6 independently of one another represent hydrogen, hydroxy, hydroxy(lower)alkyl, CN, carbamoyl(lower)alkyl, cyano(lower)alkyl, carbamoyloxy(lower)alkyl, ureido(lower)alkyl or substituted or unsubstituted piperazinyl provided that R.sub.5 and R.sub.6 cannot be hydrogen at the same time, R.sub.9 represents hydroxy(C.sub.1 -C.sub.6)alkyl or carbamoyloxy and m is an integer of 1 to 4.
Particularly preferable compounds of formula (I) according to the present invention are the compounds wherein R.sub.1 represents methyl, R.sub.2 represents hydrogen, R.sub.3 represents hydrogen or acetimidoyl, Z represents ##STR31## or R.sub.9, R.sub.4 represents ##STR32## wherein R.sub.5 and R.sub.6 independently of one another represent hydrogen, hydroxy, hydroxy(C.sub.1 -C.sub.4)alkyl, cyano, cyano(C.sub.1 -C.sub.4)alkyl, carbamoyloxy(C.sub.1 -C.sub.4)alkyl, ureido(C.sub.1 -C.sub.4) alkyl, or piperazinyl optionally mono-substituted with substituent selected from carbamoyl, (C.sub.1 -C.sub.4)alkyl, hydroxy(C.sub.l -C.sub.4)alkyl, cyano(C.sub.1 -C.sub.4)alkyl, amino(C.sub.l -C.sub.4)alkyl, carbamoyloxy(C.sub.1 -C.sub.4)alkyl, ureido(C.sub.1 -C.sub.4)alkyl, carbamoyl(C.sub.1 -C.sub.4)alkyl and mono- or di-(C.sub.1 -C.sub.4)alkylcarbamoyl(C.sub.1 -C.sub.4)alkyl, provided that R.sub.5 and R.sub.6 cannot be hydrogen at the same time, R.sub.9 represents hydroxy(C.sub.1 -C.sub.4)alkyl or carbamoyloxy and m is an integer of 1 to 2.
The following example can be mentioned as the most preferable compound of formula (I) according to the present invention:
(1R,5S,6S)-2-�(2S,4S)-2-{(cyanomethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(cyanomethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3 carboxylic acid,
(1R,5S,6S)-2�(2S,4S)-2{-(aminoethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(carbamoylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(hydroxyethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(carbamoylmethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(cyanoethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R, 5S,6S)-2-�(2S,4S)-2-{(hydroxyethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(carbamoylethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-1-acetimidoyl-2-{(2-carbamoylethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-1-acetimidoyl-2-{(2-carbamoylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1,2-dihydroxyethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1-hydroxy-2-cyanoethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1-hydroxy-2-aminoethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1-hydroxy-2-carbamoylethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-1�(R)-1-hydroxyethyl!-1methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1 2-dihydroxyethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1-hydroxy-2-cyanoethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1-hydroxy-2-carbamoylethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R) 1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1-(hydroxymethyl)-2-hydroxyethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1-(hydroxymethyl)-2-carbamoylethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1-(hydroxymethyl)-2-carbamoylethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1-(carbamoylmethyl)-2-ureidoethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1-(carbamoylmethyl)-2-cyanoethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1-(carbamoylmethyl)-2-aminoethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(2-ureidoethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(N-methylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2{-(N,N-dimethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(1-acetimidoyl-2-(carbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{1-acetimidoyl-2-(N-methylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(N-(2-hydroxyethyl)-piperazinylcarbonyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(N-(2-carbamoyloxyethyl)-piperazinylcarbonyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-(2S,4S)-2-{(N-(2-aminoethyl)-piperazinylcarbonyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(2-hydroxyethyl)mercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(3-hydroxypropyl)mercaptomethyl}-pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{(3-(carbamoyloxy)propyl)mercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(hydroxyethylpiperidinylcarbonylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(aminoethylpiperidinylcarbonylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(methoxyethylpiperidinylcarbonylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(carbamoyloxyethylpiperidinylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(ureidoethylpiperidinylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(methoxymethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(carbamoyloxymethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(ureidomethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(methoxymethyloxymethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(aminomethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(cyanoethylpiperidinylcarbonylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(methylcarbamoyloxymethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-2-{2-(methoxymethyloxyethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-�(2S,4S)-1-formimidoyl-2-{(hydroxyethylcarbonyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid, and
(1R, 5S, 6S)-2-�(2S,4S)-2-{(carbamoylethyl)mercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,
The novel desired compound of formula (I) according to the present invention can be prepared by the processes as illustrated by Processes 1 to 4 above. The processes are explained in detail in the following.
(1) Process 1:
In Process 1 of the method according to the present invention, a carbapenem derivative of formula (II) or a reactive derivative at the oxo group thereof or a salt thereof is reacted with a mercaptopyrrolidine derivative of formula (III) or a salt thereof to prepare a compound of formula (IV) or a salt thereof. In this reaction, the carbapenem derivative of formula (II) can be preferably converted into a reactive derivative of formula (II-a) which is then reacted with the mercaptopyrrolidine derivative of formula (III). Such reactive derivative can be prepared by reacting the compound of formula (II) with an acylating agent as illustrated in the following reaction scheme: ##STR33##
In the above reaction scheme, R.sub.1 and R.sub.7 are as defined above, R.sub.8 represents acyl group-as exemplified for the imino-protecting group R.sub.10 or 0,0-substituted phosphono group derived from, for example, organic phosphoric acid as mentioned below.
Suitable acylating agent which can be used in the above reaction may include conventional ones which can introduce the acyl group as mentioned above into the compound (II). Preferable acylating agents may be organic sulfonic acid, organic phosphoric acid, or its reactive derivative such as acid halide or acid anhydride, for example, arenesulfonyl halide such as benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, etc.; arenesulfonic anhydride such as benzenesulfonic anhydride, p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, etc.; optionally halogen-substituted(lower)alkanesulfonyl halide such as methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethane sulfonyl chloride, etc.; optionally halogen-substituted (lower)alkanesulfonic anhydride such as methanesulfonic anhydride, ethanesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.; di(lower)alkyl phosphorohaloridate such as diethyl phosphorochloridate, etc.; diaryl phosphorohaloridate such as diphenyl phosphorochloridate, etc., and the like, with diphenyl phosphorochloridate being most preferable.
This acylation reaction for converting the compound of formula (II) into the reactive derivative of formula (II-a) is preferably carried out in the presence of a solvent. For this purpose, any conventional organic solvent which does not adversely influence the reaction, for example, acetone, dioxane, acetonitrile, chloroform, dichloromethane, benzene, toluene, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylsulfoxide, N,N-dimethylformamide, pyridine, etc., can be used. Particularly, the most preferable solvent may be acetonitrile or benzene.
When the acylating agent is used in the form of a free acid or its salt in this acylation reaction, the reaction is usually carried out in the presence of a condensing agent. Suitable condensing agent or this purpose may include, for example, carbodiimide compounds such as N,N-diethylcarbodiimide, N,N-diisopropylcarbodiimide, N,N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.; imidazole compounds such as N,N'-carbonyldiimidazole, N,N'-carbonylbis(2-methylimidazole), etc.; keteneimine compounds such as pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, etc.; 1-alkoxy-1-chloroethylene; ethoxyacetylene; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride; phosphorus trichloride; thienyl chloride; oxalyl chloride; a combination of triphenylphosphine with carbon tetrachloride or diazenedicarboxylate; 2-ethyl-7-hydroxybenzeneisoxazolium salt, and the like, with N,N'-carbonyldiimidazole being most preferable. In addition, this acylation reaction may be practiced in the presence of an inorganic or organic base. Suitable bases for this purpose may include hydroxides, carbonates, bicarbonates or alkanoates of an alkali metal such as lithium, sodium, potassium, etc., and an alkaline earth metal such as calcium, magnesium, etc., for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, magnesium carbonate or calcium carbonate; or tri(lower)alkyl amine such as triethylamine, trimethylamine, N,N-diisopropyl-N-ethylamine, etc.; pyridine compounds such as pyridine, picoline, lutidine, etc.; N,N-di(lower)alkylaminopyridine; N-(lower)alkylmorpholine; N,N-di(lower)alkylbenzeneamine, and the like. The most preferable base is N,N-diisopropylethylamine or triethylamine.
The acylation reaction is generally carried out under cooling to warming, for example, at the temperature of -40.degree. C. to 50.degree. C., preferably at the temperature of -20.degree. C. to 20.degree. C. The reaction time is generally in the range of 0.5 to 3 hours, preferably in the range of 1 to 2 hours. In this acylation reaction, 1 to 3 moles, preferably 1 to 1.5 moles, of the base and 1 to 3 moles, preferably 1 to 1.5 moles of the acylating agent are generally used with respect to one mole of the compound of formula (II).
With regard to the compound (II), it is well known that the 3,7-dioxo-1-azabicyclo�3.2.0!heptane ring system of the following formula (II-b) lies in tautomeric relation with the 3-hydroxy-7-oxo-1-azabicyclo�3.2.0!hept-2-one ring system of the following formula (II-c). Accordingly, it should be understood that both of these ring systems are substantially the same. ##STR34##
The compound of formula (II) or the compound of formula (II-a) or salts thereof can be subsequently reacted with the compound of formula (III) or salts thereof to prepare the intermediate compound of formula (IV) or salts thereof. In this reaction, the compound of formula (II-a) produced by the above acylation reaction can be used with or preferably without isolation. The reaction of the compound (II) or (II-a) or salts thereof with the compound (III) or salts thereof can be carried out in a reaction-inert solvent which does not adversely influence the reaction. As an example of such solvent, those solvent given in the explanation of the acylation reaction may be mentioned. The most preferable one may be acetonitrile or benzene. The reaction temperature can be varied within a substantially wide range. Generally, the reaction is carried out under cooling to warming.
(2) Process 2:
In Process 2, the compound (IV) or salts thereof subjected to elimination reaction of the carboxy-protecting group R.sub.7 to prepare the compound (I-a) or salts thereof. The present reaction for removing the carboxy-protecting group is usually carried out by means of a conventional method such as hydrolysis, reduction, and the like.
(i) Hydrolysis
Hydrolysis for removing the carboxy-protecting group is preferably carried out in the presence of an acid or a base.
Suitable acid which can be used in such acid hydrolysis reaction may include an organic acid such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; and an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. When the acidic hydrolysis is carried out using trifluoroacetic acid, the reaction can be accelerated by addition of a cation-trapping agent such as phenol, anisol, etc.
Suitable base for the basic hydrolysis may include an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc.; an alkaline earth metal hydroxide such as magnesium hydroxide, calcium hydroxide, etc.; an alkaline earth metal hydride such as calcium hydride, etc.; an alkali metal hydride such as sodium hydride, etc; an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; an alkali metal carbonate such as sodium carbonate, potassium carbonate, etc.; or an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, etc., and the like.
This hydrolysis reaction is usually carried out in the presence of a solvent which does not adversely influence the reaction such as water, alcohol, for example, methanol, ethanol, etc., tetrahydrofuran, and the like, in which the preferable one may be methanol. When the acid or base used in the hydrolysis is a liquid form, it can be also used as the solvent.
(ii) Reduction
The reduction method which can be used for elimination reaction of the carboxy-protecting group may include reduction by using a combination of a metal such as zinc or zinc amalgam or a salt of chrome compound such as chromous chloride or chromous acetate and an organic or inorganic acid such as acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.; and conventional: catalytic reduction in the presence of a conventional metallic catalyst such as palladium catalyst, for example, spongy palladium, palladium black, palladium oxide., palladium on carbon, palladium hydroxide on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc., nickel catalysts, for example, reduced nickel, nickel oxide, Raney nickel, etc., or patinum catalyst, for example, platinum plate, platinum black, platinum on carbon, colloidal platinum, platinum oxide, etc., and the like. Among those reduction methods, the catalytic reduction using palladium oxide or palladium on carbon is most preferable. In case that the catalytic reduction is applied, the reaction is preferably carried out under neutral condition.
This reduction can be conveniently carried out in a solvent which does not adversely influence the reaction. For this purpose, suitable solvent may include, for example, water, alcohol such as methanol, ethanol, propanol, etc., dioxane, tetrahydrofuran, acetic acid, phosphate buffer, and the like, or a mixture thereof, with the mixed solvent of water and ethanol or water and tetrahydrofuran being most preferable. In this reaction, the preferable reaction temperature is in the range of 0.degree. C. to 30.degree. C., most preferably in the range of 20.degree. C. to 30.degree. C., and the reaction time is generally 0.5 to 4 hours and most preferably 2 to 3 hours. The amount of catalyst used in this reduction is usually 0.01 to 1 moles, preferably 0.01 to 0.5 moles, with respect to one mole of the compound of formula (IV). Hydrogen atmosphere is used in 1 to 4 atmospheric pressure and preferably in 3 to 4atmospheric pressure.
In case that the carboxy-protecting group is allyl group, it can be deprotected by hydrogenolysis in the presence of a palladium compound Suitable palladium compound used in this deprotecting reaction may include palladium on carbon, palladium hydroxide on carbon, palladium chloride, tetrakis(triphenylphospine)palladium (0), bis (dibenzylidenylacetone)palladium(0), di�(1,2-bis(diphenylphosphino)ethane!palladium(0), tetrakis(triphenylphosphite)palladium(0), tetrakis(triethylphosphite)palladium(0). This reaction can preferably be carried out in the presence of a scavenger of allyl group generated in situ. Suitable scavenger which can be used for this purpose may include, for example, amine such as morpholine, N-methylaniline, etc.; an activated methylene compound such as dimedone, benzoylacetate, 2-methyl-3-oxovaleric acid, etc.; a cyanohydrin compound such as .alpha.-tetrahydropyranyloxybenzylcyanide, etc.; lower alkanoic acid such as formic acid, ammonium formate, sodium acetate, etc.; N-hydroxysuccinimide, and the like. This reaction can also be carried out in the presence of a base such as lower alkylamine, for example, butylamine, triethylamine, etc., pyridine, and the like. When palladium-ligand complex is used in this reaction, the reaction can preferably be carried out in the presence of the corresponding ligand, for example, triphenylphosphine, triphenylphosphite, triethylphosphite, and the like. The reaction is usually carried out in a reaction-inert solvent such as water, methanol, ethanol, propanol, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, ethylacetate, etc. The reaction temperature can be varied within a substantially wide range and the reaction is generally carried out under cooling to warming.
The elimination reaction of protecting group can be carried out using a reducing agent appropriately selected depending on the kind of carboxy-protecting group to be eliminated.
(3) Process 3:
In the reaction of Process 3, the compound of formula (I-a) or salts thereof is subjected to elimination reaction of the imino-protecting group(R.sub.10) to prepare the compound of formula (I-b.))or salts thereof. This elimination reaction of the imino-protecting group can generally be carried out by means of a conventional method such as hydrolysis, reduction and the like. The method of hydrolysis and reduction, and the reaction conditions (reaction temperature, solvent, and the like) are substantially the same as those illustrated for elimination reaction of the carboxy-protecting group in Process 2 above. If necessary, the reaction of Process 3 can be directly carried out in the same reaction vessel without isolation of the compound (I-a) produced by Process 2.
The reaction of Process 3 for removing the imino-protection group is carried out in the same manner as the reaction of Process 2 for removing the carboxy-protecting group.
Alternatively, Process 3 can be practiced simultaneously with Process 2 and this case is also included within the score of the present invention.
(4) Process 4:
In Process 4, the compound of formula (I-b) or salts thereof is reacted with lower alkanimidoylating agent to prepare the compound of formula (I) wherein R.sub.3 is lower alkanimidoyl group, i.e. the compound of formula (I-c), or salts thereof.
In this reaction, suitable lower alkanimidoylating agent may be any of conventional ones which can introduce the lower alkanimidoyl group into the compound of formula (I-b). As a specific example of such lower alkanimidoylating agent, the following compounds can be mentioned: lower alkyl(lower)alkanimidate such as methyl formimidate, ethyl formimidate, methyl acetimidate, ethyl acetimidate, ethyl propionimidate, methyl butyrimidate, ethyl isovalerimidate, ethyl pentanimidate, ethyl hexanimidate, etc.; lower alkanimidoyl halide such as formimidoyl chloride, formimidoyl bromide, acetimidoyl chloride, acetimidoyl bromide, propionimidoyl bromide, butyrimidoyl chloride, isovalerimidoyl chloride, pentanimidoyl chloride, hexanimidoyl chloride, etc., and the like, with methyl formimidate or methyl acetimidate being most preferable.
This reaction is usually carried out in a solvent which does not adversely influence the reaction such as tetrahydrofuran, dioxane, water, methanol, ethanol, etc., or a mixture thereof. The most preferable solvent may be a mixed solvent of water and ethanol. The reaction temperature can be varied within a substantially wide range and the reaction is generally carried out under cooling to warming, most preferably at the temperature of -10.degree. C. to 10.degree. C., for the reaction time of 0.5 to 3 hours, more preferably 1 to 1.5 hours.
In the present reaction, the lower alkanimidoylating agent may be used in an amount of 1 to 2 moles, preferably 1 to 1.5 moles and particularly 1.2 moles, with respect to one mole of the compound (I-b).
The reaction can also be carried out in the presence of an inorganic or organic base. Suitable base which can be used in this reaction may be those given in the explanation of the reaction of Process 1. In this reaction, the base is used in an amount sufficient to maintain the pH value of the reaction solution at the weak alkaline level, preferably in the range of pH 8 to 9 and most preferably in the range of pH 8.5 to 8.7.
The compound of formula (I) and salts thereof obtained from the Processes 1 to 4 according to the present invention can be isolated and purified by means of a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, column chromatography, and the like.
Suitable salts of the compounds of formulae (II), (II-a), (III), (IV), (I-a), (I-b) and (I-c), which are used as starting materials and reactants or obtained as reaction products in the Processes 1 to 4 above, may be the same as those specifically exemplified in connection with the salts of the compound of formula (I).
The mercaptopyrrolidine derivative of formula (III), which is used as a reactant in Process 1 above for preparation of the compound (I) according to the present invention, is a novel compound which was never disclosed in the prior art. Accordingly, another object of the present invention is to provide a compound of the following formula (III): ##STR35## or salts thereof, in which R.sub.10 represents an imino-protecting group,
Z represents ##STR36## or R.sub.9, X represents O or NH,
R.sub.4 represents amino or heterocyclic amine group, each of which can be unsubstituted or substituted with a group of formula ##STR37## a unsubstituted or substituted heterocyclic group or a (lower)alkyl group, or represents hydroxy(lower)alkyl or carbamoyloxy(lower)alkyl,
R.sub.5 and R.sub.6 independently of one another represent hydrogen, hydroxy, hydroxy(lower)alkyl, cyano, amino, carbamoyl, carbamoyl(lower)alkyl, cyano(lower)alkyl, mono- or di-(lower)alkylcarbamoyl, carbamoyloxy, ureido, amino(lower)alkyl, carbamoyloxy(lower)alkyl, mono- or di-(lower)alkylcarbamoyl(lower)alkyl, ureido(lower)alkyl, or a group of formula ##STR38## wherein ##STR39## denotes a unsubstituted or substituted 3- to 6-membered heterocyclic group which can contain additional hetero atoms, provided that R.sub.5 and R.sub.6 cannot be hydrogen at the same time,
R.sub.9 represents hydroxy(lower)alkyl or carbamoyloxy, and
m is an integer of 1 to 6, provided that when m is 1 and X is O, R.sub.4 is other than unsubstituted amino(--NH.sub.2)
Further, the present invention provides a process for preparation of the compound of formula (III) and salts thereof. The process for preparation of the compound (III) according to the present invention can be represented by Methods A and B as depicted below. ##STR40##
In the above reaction scheme, R.sub.11 represents a mercapto-protecting group, and R.sub.10, Z and m are as defined above.
Suitable "mercapto-protecting group" for R.sub.11 may include acyl group as mentioned above in connection with the imino-protecting group; ar(lower)alkyl group such as mono- or di- or tri-phenyl(lower)alkyl, for example, benzyl, phenethyl, benzhydryl, trityl, etc.; and the like, in which more preferable example may be C.sub.1 -C.sub.4 alkanoyl, aroyl and triphenyl(C.sub.1 -C.sub.4)alkyl and the most preferable mercapto-protecting group may be acetyl.
Methods A and B for preparing the novel compound of formula (III) and salts thereof are explained in detail in the following.
a) Method A:
In Method A, the compound of formula (V) or a reactive derivative at the hydroxy group thereof or salts thereof can be reacted with the mercaptan derivative of formula (VI) or salts thereof to prepare the derivative of formula (III-a) or salts thereof.
Suitable reactive derivative at the hydroxy group of the compound of formula (V) may include a conventional one such as halides, for example, chloride, bromide, iodide, etc.; sulfonates, for example, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.; and the like, with a sulfonate compound, particularly methanesulfonate being most preferable. In case that the compound of formula (V) is a methanesulfonate derivative, the reaction of Method A can be carried out, for example, by reacting one equivalent weight of the compound of formula (VI) with 1 to 2 equivalent weight, preferably 1.2 equivalent weight, of the methanesulfonate compound of formula (V) and 1 to 2 equivalent weight, preferably 1.2 equivalent weight, of an organic or inorganic base in a halogenated alkane solvent such as dichloromethane, at the temperature of -10.degree. C. to 40.degree. C., more preferably -5.degree. C. to 0.degree. C., or 1 to 3 hours, more preferably 1 to 1.5 hours.
Preferable example of the mercaptan derivative of formula (VI) used as a reactant in the reaction of Method A may be ar(lower)alkanethiol such as mono- or di- or tri-phenyl(lower)alkanethiol, for example, phenylmethanethiol, diphenylmethanethiol, triphenylmethanethiol, etc.; thio(lower)alkanoic-S-acid such as thioacetic-S-acid, etc.; thioarenoic-S-acid such as thiobenzoic-S-acid, etc.; and the like, in which more preferable example may be triphenyl(C.sub.1 -C.sub.4)alkanethiol, thio(C.sub.1 -C.sub.4)alkanoic-S-acid and thio(C.sub.6 -C.sub.10)arenoic-S-acid, and salts thereof. The most preferable mercaptan derivative(VI) may be thioacetic-S-acid or its potassium salt. In case that the compound(VI) is thioacetic-S-acid potassium salt, the reaction of Method A can be carried out in a stoichiometric manner, for example, by reacting one equivalent weight of the compound (V) with 1 to 2 equivalent weight, preferably 1.5 equivalent weight, of potassium thioacetate(VI) in a solvent such as dimethylsulfoxide, hexamethylphosphoramide or N,N-dimethylformamide, preferably in N,N-dimethylformamide, at the temperature in the range of 60.degree. C. to 100.degree. C., more preferably 80.degree. C. to 90.degree. C., for 2 to 5 hours, more preferably 2.5 to 3 hours.
In Method A, when the compound of formula (VI) is ar(lower)alkanethiol, the compound of formula (V) is preferably used in the form of its reactive derivative at the hydroxy group and the reaction can be conveniently carried out in the presence of an inorganic or organic base. Suitable inorganic or organic base used in this reaction may be those exemplified in Process 1 above.
In case that the compound (VI) is thio(lower)alkanoic-S-acid or thioarenoic-S-acid, the reaction of Method A is preferably carried out in the presence of a conventional condensing agent such as a combination of triarylphosphine, for example, triphenylphosphine, etc., and di(lower)alkylazodicarboxylate, for example, diethylazodicarboxylate, etc. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as dichloromethane, methanol, ethanol, propanol, pyridine, N,N-dimethylformamide or tetrahydrofuran, with tetrahydrofuran being most preferable. In such a case, the reaction-of Method A is preferably carried out, for example by reacting one equivalent weight of the compound of formula (V) with 1 to 2 equivalent weight, preferably 1.5 equivalent weight, of thio(lower)alkanoic-S-acid such as thioacetic acid, 1 to 2 equivalent weight, preferably 1.5 equivalent weight, of diethylazodicarboxylate and 1 to 5 equivalent weight, preferably 2 equivalent weight, of triphenylphosphine in tetrahydrofuran solvent at the temperature of -40.degree. C. to 10.degree. C., preferably 0.degree. C. to 5.degree. C., for 2 to 5 hours, preferably 2 to 3 hours.
As a result of the reaction of Method A, the configuration on the carbon atom substituted with the hydroxy group of the compound (V) is inverted in the resulting compound (III-a)
b) Method B:
In Method B, the compound of formula (III-a) or salts thereof obtained from Method A is subjected to elimination reaction of the mercapto-protecting group to prepare the compound of formula (III) or salts thereof.
The elimination reaction of the mercapto-protecting group according to Method B is carried out by means of a conventional method as described below and can be appropriately selected depending on the kind of the mercapto-protecting group to be eliminated. For example, when the protecting group is ar(lower)alkyl group, this protecting group can generally be eliminated by treating with a silver compound such as silver nitrate, silver carbonate, etc. This elimination reaction with silver compound is preferably carried out in the presence of an organic base such as pyridine, etc. The resulting silver salt of the compound of formula (II:) can be converted into its alkali metal salt, if necessary, by treating with alkali metal halide such as sodium iodide, potassium iodide, etc.
Further in case that the mercapto-protecting group is acyl, this protecting group can generally be eliminated by solvolysis such as alcoholysis or hydrolysis using acid or base. Suitable acid and base which can be used in this reaction may be those exemplified in connection with hydrolysis in Process 2 above, in which sodium methoxide and sodium hydroxide is most preferable. This hydrolysis is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol, for example, methanol, ethanol, etc., water, pyridine, N,N-dimethylformamide, etc., or a mixture thereof, in which the most preferable one is methanol or water.
In case that the reaction of Method B is carried out by basic hydrolysis, the reaction is carried out, for example, by using 1 to 2 moles, preferably 1 to 1.5 moles, of a base with respect to one mole of the compound of formula (III-a) in the presence of a solvent such as water, alcohol or tetrahydrofuran, most preferably in methanol solvent, at the temperature of -20.degree. C. to 50.degree. C., most preferably -10.degree. C. to 10.degree. C., for 0.5 to 2 hours, most preferably 0.5 to 1 hour. The reaction is practiced substantially in a stoichiometric manner.
The compound of formula (III) obtained from Methods A and B above can be isolated and purified according to a conventional method, for example, by extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
The novel carbapenem derivative of formula (I) and pharmaceutically acceptable salts thereof according to the present invention exhibit a potent antibacterial activity against various gram-positive and gram-negative bacterial strains and, therefore, has a clinical utility for prophylaxis and treatment of various bacterial infectious diseases. Antibacterial activity of the desired compound (I) of the present invention is demonstrated by the following experiments including in vitro antibacterial activity test.
Test Examples
Test 1: In Vitro Antibacterial Activity Test
The antibacterial activity of the compound (I) of the present invention was determined by measuring the minimal inhibitory concentration(MIC) according to the antibacterial activity test method as described below. The compounds of Examples 1,2,3 and 4 according to the present invention were used as a test compound and imipenem was used as a comparative compound.
The test compounds and comparative compound were gradually diluted in Mueller Hinton Agar(MHA) medium. Test strains as listed in the following table were inoculated into the medium in an amount of 10.sup.6 viable cells/ml and then incubated at 37.degree. C. for 18 hours. Then, MIC value was measured and expressed in terms of .mu.g/ml. The results are shown in the following Table 1.
TABLE 1______________________________________Minimal Inhibitory Concentration of thecompound (I) and imipenem MICs Minimal Inhibitory Concentration (.mu.g/ml) Test compoundTest Imi- Example Example Example Examplestrains penem 1 2 3 4______________________________________Staphylococcus 0.10 0.05 0.05 0.05 0.05aureus SG 511Escherichia 0.78 0.10 0.10 0.10 0.10coli DC 2Escherichia 0.20 0.10 0.05 0.05 0.10coil TEMPseudomonas 0.78 0.10 0.78 0.39 0.10aeruginosa9027Pseudomonas 0.78 0.78 0.78 0.39 0.78aeruginosa1592ESalmonella 0.78 0.20 0.10 0.10 0.20typhimuriumKlebsiella 0.78 0.20 0.10 0.10 0.10aerogenes1522EKlebsiella 0.39 0.20 0.20 0.20 0.20oxytoca 1082EEnterobacter 0.20 0.05 0.05 0.05 0.05cloacae 1321E______________________________________
From the result given in Table 1 above, it can be seen that the compound of formula (I) and pharmaceutically acceptable salts thereof according to the present invention exhibit a considerably superior antibacterial activity in comparison with the known compound in the prior art, imipenem.
Test 2: Stability Test Against kidney Dehydrogenase DHP-I
Each of the novel compounds of Examples 1,2,3 and 4 of the present invention and the comparative compound imipenem was dissolved in 10 mM phosphate buffer and the resulting solution was mixed with dehydrogenase enzyme solution extracted from pig kidney in a ratio of equivalent amounts. The resulting mixture was incubated at 37.degree. C. for 2 hours, during which the decomposition degree of the compound was measured. The result thereof was given in the following Table 2 in terms of percentage of the remaining amount on the basis of the initially added amount of the compound.
TABLE 2______________________________________Stability of the compounds (I) and imipenemon DHP-I enzyme (Unit: %) Time (minute)Test Compound 5 10 20 40 80 120______________________________________Imipenem 99.2 97.9 94.3 87.7 77.0 66.6Compound of Example 1 99.7 99.4 99.1 98.1 97.5 97.2Compound of Example 2 100 99.4 98.6 97.2 96.3 96.3Compound of Example 3 99.7 99.2 98.9 98.0 97.2 97.0Compound of Example 4 100 99.8 99.0 99.8 98.8 98.8______________________________________
From the result given in Table 2 above, it can be seen that the known compound in prior art, imipenem, was composed by about 40% within about 2 hours from the begining of mixing incubation, while the novel compound of formula (I) of the present invention was substantially never decomposed and shows a high stability. Such test result demonstrates that imipenem has a disadvantage in that it should be administered together with an enzyme inhibitor such as Cilastatin, whereas the compound of the present invention shows stably a high antibacterial activity even when it is administered alone.
As can be demonstrated by the results of Tests 1 and 2 above, the carbapenem derivative of formula (I) and pharmaceutically acceptable salts thereof according to the present invention are clinically used for the purpose of prophylaxis and treatment of infectious diseases. For this purpose, the compound of formula (I) and pharmaceutically acceptable salts thereof can be formulated into a pharmaceutically acceptable preparation suitable for administration, together with pharmaceutically acceptable carriers such as solid or liquid excipients. Such pharmaceutical preparation may be in solid or liquid form, for example, tablet, capsule, granule, powder, pill, solution, suspension, syrup, emulsion, and the like. If necessary, the pharmaceutical preparation can additionally contain conventional additives, for example, formulating aid, stabilizer, wetting agent, thickening agent, disintegrator, perfume, pigment, binder, and the like.
The dosage of the compound of formula (I) and pharmaceutically acceptable salts thereof according to the present invention may vary depending on kind and severity of diseases to be treated, age and conditions of the patient, and kind of the compound (I) to be administered. In general, an amount of 100 to 500 mg per day may be administered per one adult patient as a single dose or a multiple-divided dose.
The present invention will be explained by the following Examples and Reference Examples in more detail. However, it should be understood that the present invention is not limited by these examples in any manner.

EXAMPLE 1
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(cyanomethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) 580 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 380 mg of (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(cyanomethylcarbamoyl)methylmercaptomethyl}-4-mercaptopyrrolidine were dissolved in 25 ml of acetonitrile. To the resulting solution was added dropwise 0.25 ml of N,N-diisopropylethylamine under nitrogen atmosphere at -10.degree. C. to -5.degree. C. and then the reaction mixture was stirred overnight at 5.degree. C. The reaction solution was concentrated under reduced pressure. 20 ml of 5% sodium bicarbonate solution was added to the residue and the mixture was extracted with 30 ml of ethylacetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography(eluent: EtOAc:acetone=3:2 v/v) to obtain 760 mg of 4-nitrobenzyl (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(cyanomethylcarbamoyl)methylmercaptomethyl }pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Nujol)cm.sup.-1 : 1755, 1751, 1710, 1653 NMR(CDCl.sub.3) .delta.: 1.27 (3H,d,J=8 Hz), 1.37 (3H,d,J=8 Hz), 1.78-1.90 (1H,m), 2.30-2.80 (7H,m), 3.31-3.76 (4H,m), 5.04-5.54 (6H,m), 7.44-7.50 (2H, dd, J=18 Hz), 7.55-7.65 (4H, d, J=9 Hz), 8.17-8.25 (6H,m)
(2) 690 mg of the compound obtained in the above (1) was dissolved in 10 ml of tetrahydrofuran. To the resulting solution were added 18 ml of 0.1M 4-morpholinopropane sulfonate solution (pH=7.0), 1.8 ml of ethanol and 0.3 g of 10% palladium on carbon and then the mixture was hydrogenated under pressure. After the reaction time of 4 hours, the catalyst was filtered off and the filtrate was washed with 20 ml of dichloromethane. The aqueous layer was separated and purified with polymer chromatography(CHP-20, eluent: 5% THF-H.sub.2 O ). Then, the eluate was lyophilized to obtain 170 mg of the title compound.
Melting Point: 173.degree.-174.5.degree. C. (dec.) IR(KBr)cm.sup.-1 : 1750, 1580, 1390 NMR(D.sub.2 O) .delta.: 1.20 (3H,d,J=8 Hz), 1.28 (3H,d,J=8 Hz), 1.40-2.10 (2H,m), 2.55-3.95 (6H,m)
EXAMPLE 2
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(cyanomethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 480 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 320 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(cyanomethylcarbamoyl)ethylmercaptomethyl}-4-mercapto!pyrrolidine to obtain 580 mg of 4-nitrobenzyl (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(cyanomethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Nujol)cm.sup.-1 : 1780, 1750, 1620 NMR(D.sub.2 O) .delta.: 1.21 (3H,d,J=3 Hz), 1.30 (3H,d,J=8 Hz), 3.02-385 (12H,m), 4.80 (2H, br. s), 5.25 (2H,s), 5.38 (2H, dd, J=18 Hz), 7.58 (2H, d, J=8 Hz), 8.26 (6H,m)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 120 mg of the title compound.
Melting Point: 175.degree.-175.5.degree. C. (dec.) IR(KBr)cm.sup.-1 : 1750, 1580 NMR(D.sub.2 O) .delta.: 1.23 (3H,d,J=7.9 Hz), 1.30 (3H,d,J=6.8 Hz), 1.81 (1H, dd, J=18 Hz, J=8.5 Hz), 2.70-3.34 (5H,m), 3.45-3.85 (3H,m), 4.25-4.27 (2H,m)
EXAMPLE 3
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(hydroxyethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 550 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 410 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(hydroxyethylcarbamoyl)ethylmercaptomethyl}-4-mercapto!pyrrolidine to obtain 420 mg of 4-nitrobenzyl (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(hydroxyethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Nujol)cm.sup.-1 : 3400, 1770-1740, 1710-1680, 1605 NMR(CDCl.sub.3) .delta.: 1.1-1.6 (6H,m), 5.1-5.6 (4H,m), 7.3-7.7 (4H,m), 8.21 (4H, d, J=9 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as the a of Example 1-(2) to obtain 250 mg or the title compound.
Melting Point: 172.degree.-173.degree. C. (dec.) IR(KBr)cm.sup.-1 : 1765-1725, 1590-1550 NMR(D.sub.2 O) .delta.: 1.21 (3H,d,J=8 Hz), 1.28 (3H,d,J=7 Hz), 1.52-2.0 (4H,m), 2.49-2.9 (3H,m)
EXAMPLE 4
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(2-carbamoylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 650 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 350 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(2-carbamoylmethylcarbamoyl)ethylmercaptomethyl}-4-mercapto!pyrrolidine to obtain 450 mg of 4-nitrobenzyl (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(2-carbamoylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-� (R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Nujol)cm.sup.-1 : 1770, 1705, 1610, 1525 NMR(CDCl.sub.3) .delta.: 1.25 (3H,d,J=7.5 Hz), 1.32 (3H,d,J=6 Hz) 3.10-4.83 (3H,m), 4.81 (2m, br. s), 5.24 (2H,s), 5.38 (2H, dd, J=18 Hz), 7.56-7.63 (4H, dd, J=18 Hz), 8.24 (4H, d, J=8 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 120 mg of the title compound.
Melting Point 168.degree.-172.degree. C. (dec.) IR(KBr)cm.sup.-1 : 1755, 1680 NMR(D.sub.2 O) .delta.: 1.21 (3H,d,J=9 Hz), 1.27 (3H,d,J=6 Hz), 1.42-2.03 (2H,m), 2.53-4.36 (10H,m)
EXAMPLE 5
Preparation of (1R,5S,6S)-2-�(2S,4S)-1-acetimidoyl-2-{(2-carbamoylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
120 mg of the compound obtained in Example4-(2), (1R,5S,6S)-2-�(2S,4S)-2-{(2-carbamoylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid was dissolved in 30 ml of distilled water. To the resulting solution was added 1.4 g of ethylacetimidate hydrochloride. Then, the reaction mixture was adjusted to pH 8.4-8.6 by adding 10% aqueous sodium carbonate solution at 0.degree. to 4.degree. C. When the reaction was completed, the reaction mixture was adjusted to pH 6.5 by adding 1N-aqueous hydrochloric acid solution and then washed with the mixture of 50 ml of ethyl acetate and 10 ml of tetrahydrofuran. The organic layer was removed and the aqueous layer was subjected to polymer chromatography (CHP-20, eluent: 5% acetone-H.sub.2 O ). The eluate was lyophilized to obtain 80 mg of the title compound.
IR(KBr)cm.sup.-1 : 1800-1720 NMR(D.sub.2 O) .delta.: 1.27 (6H, t, J=7.4 Hz), 2,30-2.80 (3H,s)
EXAMPLE 6
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(carbamoyl-1-(hydroxy)ethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 580 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 310 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(carbamoyl-1-(hydroxy)ethylcarbamoyl)methylmercaptomethyl}-4-mercapto!pyrrolidine to obtain 620 mg of 4-nitrobenzyl (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(carbamoyl-1-(hydroxy)ethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Neat)cm.sup.-1 : 1765, 1725-1700, 1605 NMR(CDCl.sub.3) .delta.: 1.1-1.7 (6H,m), 5.0-5.6 (4H,m), 7.4-7.8 (4H,m), 8.21 (4H, d, J=8.5 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 170 mg of the title compound.
Melting Point: 176.degree.-177.5.degree. C. (dec.) IR(KBr)cm.sup.-1 : 1765, 1705-1675 NMR(D.sub.2 O) .delta.: 1.21 (3H,d,J=9 Hz) 1.27 (3H,d,J=6 Hz), 1.42-2.03 (2H,m), 2.53-4.36 (10H,m)
EXAMPLE 7
Preparation of (1R, 5S, 6S)-2-�(2S,4S)-2-{(hydroxy-1-(hydroxymethyl)ethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 720 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 310 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(hydroxy-1-(hydroxymethyl)ethylcarbamoyl)methylmercaptomethyl}-4-mercapto!pyrrolidine to obtain 840 mg of 4-nitrobenzyl (1R,55, 6S)-2-�(2S, 4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(hydroxy-1-(hydroxymethyl)ethylcarbamoyl)methylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Nujol)cm.sup.-1 : 1760, 1725-1710, 1705, 1605 NMR(CDCl.sub.3) .delta.: 1.26 (3H,d,J=9 Hz), 1.36 (3H,d,J=6 Hz), 5.15-5.45 (6H,m), 7.40-7.75 (6H,m), 8.25 (6H, d, J=8 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 225 mg of the title compound.
Melting Point: 168.degree.-171.degree. C. (dec.) IR(Nujol)cm.sup.-1 : 1750, 1725-1700, 1580 NMR(D.sub.2 O) .delta.: 1.22 (3H,d,J=7 Hz), 1.28 (3H,d,J=6 Hz), 1.6-1.9 (2H,m), 2.49-2.90 (2H,m)
EXAMPLE 8
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(carbamoyl-1-(hydroxymethyl)ethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 760 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 350 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(carbamoyl-1-(hydroxymethyl)ethylcarbamoyl}-4-mercapto!pyrrolidine to 840 mg of 4-nitrobenzyl (1R,5S,6S)-2-�(2S,4S)-1-(nitrobenzyloxycarbonyl)-2-{(carbamoyl-1-(hydroxymethyl)ethylcarbamoyl)ethylmercaptomethyl}-pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Nujol)cm.sup.-1 : 1765, 1725, 1710, 1690 NMR(CDCl.sub.3) .delta.: 1.23 (3H,d,J=9 Hz), 1.33 (3H,d,J=8 Hz), 4.42-4.56 (2H,m), 4.82-5.5 (10H,m), 7.4-7.70 (4H,m), 8.25. (6H, d, J=8 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 250 mg of the title compound.
Melting Point: 163.degree.-167.degree. C. (dec.) IR(KBr)cm.sup.-1 : 1750, 1725-1710 NMR(D.sub.2 O): .delta.: 1.22 (3H,d,J=7 Hz), 1.28 (3H,d,J=6 Hz), 1.45-2.00 (4H,m), 2.46-2.95 (3H,m), 3.01-3.13 (3H,m)
EXAMPLE 9
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(2-cyano-1-(carbamoylmethyl)ethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the manner as that of Example 1-(1), starting from 820 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 380 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(cyano-1-(carbamoylmethyl)ethylcarbamoyl)ethylmercaptomethyl}-4-mercapto!pyrrolidine to obtain 920 mg of 4-nitrobenzyl(1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2{(cyano-1-(carbamoylmethyl)ethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-(R)-1-hydroxyethyl-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Nujol)cm.sup.-1 : 1765, 1715-1705, 1665 NMR(CDCl.sub.3) .delta.: 1.18 (3H,d,J=9 Hz), 1.26 (3H,d,J=9 Hz), 5.15-5.47 (6H,m), 7.40-7.75 (6H,m), 8.25 (6H, d, J=8 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 270 mg of the title compound.
Melting Point: 163.degree.-164.degree. C. (dec.) IR(Nujol)cm.sup.-1 : 1750, 1725-1705, 1665 NMR(CDCl.sub.3) .delta.: 1.22 (3H,d,J=7 Hz), 1.28 (3H,d,J=6 Hz) 1.60-1.90 (2H,m), 2.50-3.10 (4H,m)
EXAMPLE 10
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(carbamoylethyl)mercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 520 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 270 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2{(carbamoylethyl)mercaptomethyl}-4-mercapto!pyrrolidine to obtain 480 mg of 4-nitrobenzyl (1R,5S, 6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(carbamoylethyl)mercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Nujol)cm.sup.-1 : 1 : 1775-1760, 1690-1660 NMR(CDCl.sub.3) .delta.: 1.26 (3H,d,J=7 Hz), 1.33 (3H,d,J=7 Hz), 1.70-2.15 (2H,m), 2.30-2.80 (2H,m), 4.50-4.83 (4H,m), 7.40-7.65 (4H,m), 8.25 (6H, d, J=8 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 120 mg of the title compound.
Melting Point: 162.degree.-163.degree. C. (dec.) IR (KBr)cm.sup.-1 : 1765, 1715-1690, 1580 NMR(D.sub.2 O) .delta.: 1.27 (3H,d,J=8 Hz), 1.33 (3H,d,J=8 Hz), 2.17-2.50 (4H,m), 2.65-2.95 (2H,m)
EXAMPLE 11
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(hydroxyethyl)mercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 480 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 210 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(hydroxyethyl)-mercaptomethy}-4-mercapto!pyrrolidine to obtain 325 mg of 4-nitrobenzyl(1R, 5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(hydroxyethyl)mercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Neat)cm.sup.-1 : 3400, 1765-1725, 1610-1590 NMR(CDCl.sub.3) .delta.: 1.20-1.80 (6H,m), 5.1-5.6 (4H,m), 7.3-7.70 (4H,m), 8.20 (4H, d, J=8 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 80 mg of the title compound.
Melting Point: 172.degree.-174.degree. C. (dec.) IR(KBr)cm.sup.-1 : 1760-1730, 1595-1775 NMR(D.sub.2 O) .delta.: 1.21 (3H,d,J=8 Hz), 1.28 (3H,d,J=7 Hz) 1.51-2.1 (1H,m), 2.99-2.9 (1H,m)
EXAMPLE 12
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(4-(2-hydroxyethyl)piperazinyl)carbonylethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 720 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 250 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(4-(2-hydroxyethyl)piperazinyl)carbonyethylmercaptomethy}-4-mercapto!pyrrolidine to obtain 870 mg of 4-nitrobenzyl(1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(4-2-hydroxyethyl)piperazinyl)carbonylethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Neat)cm.sup.-1 : 3400, 1760-1750, 1690, 1525 NMR(CDCl.sub.3) .delta.: 1.26 (3H,d,J=6 Hz), 1.33 (3H,d,J=6 Hz), 1.80-2.18 (4H,m), 2.27-2.38 (4H,m), 5.10-5.63 (4H,m), 7.48 (2H, d, J=8 Hz), 7.62 (2H, d, J=8 Hz), 8.16-8.27 (4H, d, J=8 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 210 mg of the title compound.
Melting Point: 168.degree.-170.degree. C. (dec.) IR(KBr)cm.sup.-1 : 3400, 1760-1735, 1600-1580 NMR(D.sub.2 O) .delta.: 1.23 (3H,d,J=8 Hz), 1.28 (3H,d,J=8 Hz), 1.45-1.85 (2H,m), 2.30-2.66 (3H,m), 2.38-3.0 (3H m)
EXAMPLE 13
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(4(2-hydroxyethyl)piperazinylcarbonylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 680 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 290 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{((4-(2-hydroxyethyl)piperazinylcarbonylmethylcarbamoyl)ethylmercaptomethy}-4-mercapto!-pyrrolidine to obtain 580 mg of 4-nitrobenzyl(1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{((4-(2-hydroxyethyl)piperazinylcarbonylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate
IR(Neat)cm.sup.-1 : 3400, 1770, 1705, 1650 NMR(CDCl.sub.3) .delta.: 1.25 (3H,d,J=7.5 Hz), 1.32 (3H,d,J=6 Hz) 2.21-2.38 (2H,m), 3.10-4.83 (4H,m), 4.85 (2H, br. s), 5.24 (2H,s), 7.52 (2H, d, J=8 Hz), 7.65 (2H, d, J=8 Hz), 8.25 (4H, d, J=8 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 90 mg of the title compound.
Melting Point: 180.degree.-182.degree. C. (dec.) IR(KBr)cm.sup.-1 : 3400, 1755, 1680 NMR(D.sub.2 O) .delta.: 1.22 (3H,d,J=8 Hz), 1.30 (3H,d,J=8 Hz), 1.57-2.35 (6H,m), 3.01-3.55 (2H,m)
EXAMPLE 14
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(aminocarbonyloxymethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 420 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 280 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(aminocarbonyloxymethylcarbamoyl)ethylmercaptomethy}-4-mercapto!pyrrolidine to obtain 380 mg of 4-nitrobenzyl(1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(aminocarbonyloxymethylcarbamoyl)ethylmercaptomethyl}-pyrrolidin-4-yl!thio6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Neat)cm.sup.-1 : 3400, 1765, 1725-1715, 1610-1600, 1512, 1360 NMR(CDCl.sub.3) .delta.: 1.1-1.6 (6H,m), 4.25-5.8 (6H,m), 7.4-8.2 (4H,m), 8.15 (4H, d, J=8.5 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 110 mg of the title compound.
Melting Point: >170.degree. C. (dec.) IR(KBr)cm.sup.-1 : 1750, 1700-1690, 1600-1580 NMR(D.sub.2 O) .delta.: 1.23 (3H,d,J=7.0 Hz), 1.29 (3H,d,J=6 Hz), 1.6-2.1 (2H,m), 2.5-3.0 (2H,m)
EXAMPLE 15
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{2-(ureidomethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1) starting from 580 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 275 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{2-(ureidomethylcarbamoyl)ethylmercaptomethy}-4-mercapto!pyrrolidine to obtain 425 mg of 4-nitrobenzyl(1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{2-(ureidomethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Neat)cm.sup.-1 : 3400, 1775, 1710-1690, 1610, 1525-1510, 1350 NMR(CDCl.sub.3) .delta.: 1.25-1.35 (6H,m), 3.05-4.25 (10H,m) 4.80 (2H, br. s), 5.20 (2H,s), 5.40 (2H, dd, J=14 Hz) 7.56 (2H, d, J=8 Hz) 7.68 (2H, d, J=8 Hz), 8.26 (4H, d, J=8 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 90 mg of the title compound.
Melting Point: >175.degree. C. (dec.) IR(KBr)cm.sup.-1 : 1760, 1710, 1650, 1580 NMR(D.sub.2 O) .delta.: 1.21 (3H,d,J=9 Hz), 1.28 (3H,d,J=6 Hz), 1.42-2.10 (4H,m), 2.53-4.36 (14H,m)
EXAMPLE 16
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{2-(aminomethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 620 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 380 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{2-((4-nitrobenzyloxycarbonyl)methylcarbamoyl)ethylmercaptomethyl}-4-mercapto!pyrrolidine to obtain 420 mg of 4-nitrobenzyl (1R,5S,6S)-2-�(2S,4S)-1(p-nitrobenzyloxycarbonyl)-2-{2-((4-nitrobenzyloxycarbonyl)methylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Nujol)cm.sup.-1 : 1765-1700, 1710-1690, 1660-1650, 1530-1510
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 190 mg of the title compound.
Melting Point: >180.degree. C. (dec.) IR(Nujol)cm.sup.-1 : 1760-1750, 1590-1580, 1350 NMR(D.sub.2 O) .delta.: 1.21 (3H,d,J=7 Hz) 1.30 (3H,d,J=7 Hz), 1.40-2.1 (4H,m), 2.55-3.08 (4H,m), 3.12-4.35 (9H,m)
EXAMPLE 17
Preparation of (1R,5S,6S)-2-�(2S,4S)-2-{(2-(methoxymethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
(1) The reaction was carried out in the same manner as that of Example 1-(1), starting from 510 mg of 4-nitrobenzyl-2-diphenoxyphosphoryloxy-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate and 250 mg of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{2-(methoxymethylcarbamoyl)ethylmercaptomethy}-4-mercapto!pyrrolidine to obtain 420 mg of 4-nitrobenzyl (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{2-(methoxymethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
IR(Nujol)cm.sup.-1 : 1750, 1700, 1685, 1516 NMR(CDCl.sub.3) .delta.: 1.28 (3H,d,J=7 Hz), 1.37 (3H,d,J=7 Hz), 1.65-2.10 (3H,m), 2.35-2.85 (2H,m), 2.94 (3H,s), 5.25 (4H,s), 5.40-5.75 (2H,m), 7.56 (2H, d, J=9 Hz), 7.66 (2H, d, J=9 Hz), 8.26 (4H, d, J=9 Hz)
(2) The compound obtained in the above (1) was hydrogenated in the same manner as that of Example 1-(2) to obtain 110 mg of the title compound.
Melting Point:>178.degree. C. (dec.) IR(KBr)cm.sup.-1 : 1760-1750 1590-1580, 1350 NMR(D.sub.2 O) .delta.: 1.22 (3H,d,J=7 Hz), 1.28 (3H,d,J=6 Hz), 1.45-2.10 (4H,m), 2.24-2.95 (2H,m), 3.13 (3H,s)
The compounds of the following Examples 18 to 27 can be prepared in the same manner as that of Example 1 using the corresponding starting materials.
EXAMPLE 18
(1) (1R,5R,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{2-((4-cyanoethylpiperazinyl)carbonylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
IR(Neat)cm.sup.-1 : 3600, 1765, 1710-1685, 1610, 1520 NMR(CDCl.sub.3) .delta.: 1.30-1.38 (6H, dd, J=18 Hz), 2.25-2.83 (7H,m), 3.18-350 (3H,m), 5.20-5.52 (4H,m), 7.56-7.69 (4H,m), 8.28 (4H, d,=9 Hz)
(2) (1R,5S,6S)-2-�(2S,4S)-2-{2-((4-cyanoethylpiperazinyl)carbonylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
UV.sub.max.sup.H.sbsp.2.sup.O : 298.2 nm IR(Nujol)cm.sup.-1 : 1755, 1710, 1585 NMR(D.sub.2 O) .delta.: 1.22 (3H,d,J=6 Hz), 1.31 (3H,d,J=6 Hz), 1.75-2.35 (5H,m)
EXAMPLE 19
(1) (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{2-((4-p-nitrobenzyloxycarbonylaminoethylpiperazinyl)carbonylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
IR(Neat)cm.sup.-1 : 1765-1750, 1710, 1660-1640 1530-1510 NMR(CDCl.sub.3) .delta.: 1.30 (3H,d,J=7 Hz), 1.38 (3H,d,J=7 Hz), 1.75-2.10 (3H,m), 2.80-3.90 (10H,m), 3.90-4.40 (4H,m), 5.20-5.50 (6H,m), 7.55 (4H, d, J=8 Hz), 7.66-8.25 (4H, dd)
(2) (1R,5S,6S)-2-�(2S,4S)-2-{2-((4-aminoethylpiperazinyl)carbonylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
UV.sub.max.sup.H.sbsp.2.sup.O : 297.8 nm IR(Nujol)cm.sup.-1 : 1750, 1590-1580 NMR(D.sub.2 O) .delta.: 1.22 (5H, d, J=7 Hz), 1.30 (3H,d,J=7 Hz), 1.45-1.95 (3H,m), 2.55-3.08 (4H,m), 3.12-4.35 (10H,m)
EXAMPLE 20
(1) (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{2-(4-(2-methoxyethyl)piperazinyl)carbonylmethylcarbamoylethylmercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
IR(Neat)cm.sup.-1 : 1765-1755, 1700, 1685, 1516, 1392 NMR(CDCl.sub.3) .delta.: 1.27 (3H,d,J=7 Hz) 1.34 (3H,d,J=7 Hz), 2.76 (4H,m), 3.30 (3H,s), 5.21 (2H,s), 7.50-7.69 (4H,m), 8.28 (4H, d, J=9 Hz)
(2) (1R,5S,6S)-2-�(2S,4S)-2-{2-(4-(2-methoxyethyl)piperazinyl)carbonylmethylcarbamoylethylmercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
UV.sub.max.sup.H.sbsp.2.sup.O : 298 nm IR(Nujol)cm.sup.-1 : 1745-1750, 1650, 1585, 1380 NMR(D.sub.2 O) .delta.: 1.19 (3H,d,J=7 Hz), 1.27 (3H,d,J=6 Hz), 2.72 (3H,s), 2.79-3.14 (4H,m) 3.30 (3H,s), 4.05-4.20 (4H,m)
EXAMPLE 21
(1) (1R, 5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{2-(4-(2-carbamoyloxyethyl)piperazinylcarbonyl) methylcarbamoylethylmercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
IR(Neat)cm.sup.-1 : 1785, 1740, 1705, 1525, 1348 NMR(CDCl.sub.3) .delta.: 1.35 (3H,d,J=6 Hz), 1.48 (3H,d,J=7 Hz), 1.95-2.05 (2H,m), 2.65-3.40 (3H,m), 5.22 (2H,s), 7.5-7.8 (4H, dd, J=19 Hz), 8.20 (4H, d, J=8 Hz)
(2) (1R,5S,6S)-2-�(2S,4S)-2-{2-(4-(2-carbamoyloxyethyl)piperazinylcarbonyl)methylcarbamoylethylmercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylic acid
UV.sub.max.sup.H.sbsp.2.sup.O : 297.8 nm IR(Nujol)cm.sup.-1 : 1750, 1725-1710, 1600-1580 NMR(D.sub.2 O) .delta.: 1.22 (3H,d,J=7 Hz), 1.28 (3H,d,J=6 Hz), 1.6-1.9 (4H,m), 2.5-2.9 (1H,m)
EXAMPLE 22
(1) (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{2-(4-(2-ureidoethyl)piperazinyl)carbonylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
IR(Nujol)cm.sup.-1 : 1770, 1700, 1610, 1525, 1350 NMR(CDCl.sub.3) .delta.: 1.27 (3H,d,J=7 Hz), 1.32 (3H,d,J=6 Hz), 2.85-3.90 (11H,m), 4.80 (2H, br. s), 5.25 (2H,s), 5.37 (2H, dd, J=18 Hz), 7.56-7.68 (4H, dd, J=18 Hz), 8.26 (4H, d, J=8 Hz)
(2) (1R,5S,6S)-2-�(2S,4S)-2-{2-(4-(2-ureidoethyl)piperazinyl)carbonylmethylcarbamoyl)ethylmercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
UV.sub.max.sup.H.sbsp.2.sup.O : 298.5 nm IR(Nujol)cm.sup.-1 : 1755, 1700, 1650, 1580 NMR(CDCl.sub.3) .delta.: 1.25 (3H,d,J=7 Hz), 1.33 (3H,d,J=6 Hz), 1.42-2.03 (2H,m), 2.53-4.50 (45H,m)
EXAMPLE 23
(1) (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl-2-{(2-methoxymethyloxymethylcarbamoylethyl)mercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
IR(Neat)cm.sup.-1 : 1765-1750, 1700, 1680 NMR(CDCl.sub.3) .delta.: 1.27 (3H,d,J=7 Hz), 1.34 (3H,d,J=7 Hz), 2.25-2.60 (3H,m), 3.35 (3H,s), 5.21 (2H,s), 7.55-7.70 (4H,m), 8.26 (4H, d, J=9 Hz)
(2) (1R,5S,6S)-2-�(2S,4S)-2-{(2-methoxymethyloxymethylcarbamoylethyl)mercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
UV.sub.max.sup.H.sbsp.2.sup.O : 298.7 nm IR(Nujol)cm.sup.-1 : 1750-1745, 1700, 1655, 1580, 1350 NMR(D.sub.2 O) .delta.: 1.20 (3H,d,J=7 Hz), 1.26 (3H,d,J=7 Hz), 2.73 (3H,s), 2.77-3.15 (4H,m), 3.33 (3H,s), 4.10-4.15 (3H,m)
EXAMPLE 24
(1) (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(2-methylcarbamoyloxymethylcarbamoylethyl)mercaptomethyl}pyrrolidin-4-yl)-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
IR(Neat)cm.sup.-1 : 3500-3400, 1765, 1720-1700, 1605 NMR(CDCl.sub.3) .delta.: 1.1-1.8 (6H,m), 5.10-5.75 (4H,m), 7.4-7.8 (4H,m), 8.21 (4H, d, J=8.5 Hz)
(2) (1R,5S,6S)-2-�(2S,4S)-2-{(2-methylcarbamoyloxymethylcarbamoylethyl)mercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
UV.sub.max.sup.H.sbsp.2.sup.O : 297.8 nm IR(Nujol)cm.sup.-1 : 1750 1725-1705, 1580 NMR(D.sub.2 O) .delta.: 1.25 (3H,d,J=7 Hz), 1.28 (3H,d,J=8 Hz), 1.6-1.9 (2H,m), 2.4-2.9 (2H,m)
EXAMPLE 25
(1) (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(2-ureidoethylcarbamoylethyl)mercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
IR(Neat)cm.sup.-1 : 1770-1760, 1710-1705, 1610-1605, 1525 NMR(CDCl.sub.3) .delta.: 1.27 (3H,d,J=7 Hz), 1.33 (3H,d,J=7 Hz), 3.10-3.95 (13H,m), 4.85 (2H, br. s), 5.24 (2H,s), 5.50 (2H, d, J=7 Hz), 7.56-7.68 (4H, dd, J=18 Hz), 8.26 (4H, d, J=8 Hz)
(2) (1R,5S,6S)-2-�(2S,4S)-2-{(2-ureidoethylcarbamoylethyl)mercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
UV.sub.max.sup.H.sbsp.2.sup.O : 298.2 nm IR(Nujol)cm.sup.-1 : 1755, 1650, 1580 NMR(D.sub.2 O) .delta.: 1.20 (3H,d,J=9 Hz), 1.25 (3H,d,J=6 Hz), 1.45-2.10 (4H,m) 2.53-4.35 (14H,m)
EXAMPLE 26
(1) (1R,5S,6S)-2-�(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(2-(p-nitrobenzyloxycarbonyl)aminoethylcarbamoylethyl)mercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
IR(Neat)cm.sup.-1 : 1765-1750, 1710, 1665-1650, 1510 NMR(CDCl.sub.3) .delta.: 1.24 (3H,d,J=7 Hz) 1.36 (3H,d,J=7 Hz) 2.35-2.50 (2H,m), 3.15-3.46 (3H,m), 3.56-4.40 (12H,m), 5.12-5.50 (6H,m), 7.36-7.80 (6H,m), 8.24 (6H, d, J=8 Hz)
(2) (1R,5S,6S)-2-�(2S,4S)-2-{(2-aminoethylcarbamoylethyl)mercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
UV.sub.max.sup.H.sbsp.2.sup.O : 298.5 nm IR(Nujol)cm.sup.-1 : 1770, 1705, 1610, 1525, 1350 NMR(D.sub.2 O) .delta.: 1.25 (3H,d,J=7 Hz), 1.33 (3H,d,J=6 Hz), 1.43-2.15 (4H,m), 2.55-4.25 (14H,m)
EXAMPLE 27
(1) (1R, 5S, 6S)-2-�(2S, 4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(2-methoxymethyloxyethylcarbamoylethyl) mercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
IR(Neat)cm.sup.-1 : 1770-1750, 1710-1700, 1690, 1605, 1520 NMR(CDCl.sub.3) .delta.: 1.28 (3H,d,J=7 Hz), 1.37 (3H d, J=7 Hz), 1.65-2.10 (5H,m), 2.35-2.85 (4H,m), 2.94-3.10 (4H,m), 3.25 (3H,s), 5.40-5.74 (2H,m), 7.56 (2H, d, J=9 Hz), 7.66 (2H, d, J=9 Hz), 8.26 (4H, d, J=9 Hz)
(2) (1R,5S,6S)-2-�(2S,4S)-2-{(2-methoxymethyloxyethylcarbamoylethyl)mercaptomethyl}pyrrolidin-4-yl!-thio-6-�(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid
UV.sub.max.sup.H.sbsp.2.sup.O : 299.0 nm IR(Nujol)cm.sup.-1 : 1760-1750, 1700, 1590-1580, 1380 NMR(D.sub.2 O) .delta. : 1.22 (3H,d,J=7 Hz), 1.28 (3H,d,J=7 Hz), 1.48-2.00 (4H,m), 2.46-2.95 (2H,m), 3.15 (3H,s)
The specific examples of the compound of formula (I) which can be prepared in the same manner as that of Example 1 are listed in the following Table.
__________________________________________________________________________ ##STR41##No R.sub.1 R.sub.2 R.sub.3 R.sub.5 R.sub.6 X m__________________________________________________________________________1 Me H H H CH O 12 Me H H H CN O 13 Me H H H NH.sub.2 O 14 Me H H H CONH.sub.2 O 15 Me H H H CONHCH.sub.3 O 16 Me H H H CON(CH.sub.3).sub.2 O 17 Me H H H OCONH.sub.2 O 18 Me H H H NHCONH.sub.2 O 19 Me H H H CH O 210 Me H H H CN O 211 Me H H H NH.sub.2 O 212 Me H H H CONH.sub.2 O 213 Me H H H CONHCH.sub.3 O 214 Me H H H CON(CH.sub.3).sub.2 O 215 Me H H H OCONH.sub.2 O 216 Me H H H NHCONH.sub.2 O 217 Me H H H CH.sub.2 OH O 118 Me H H H CH.sub.2 CN O 119 Me H H H CH.sub.2 NH.sub.2 O 120 Me H H H ##STR42## O 121 Me H H H ##STR43## O 122 Me H H H ##STR44## O 123 Me H H H ##STR45## O 124 Me H H H ##STR46## O 125 Me H H H CH.sub.2 CN O 226 Me H H H CH.sub.2 OH O 227 Me H H H CH.sub.2 NH.sub.2 O 228 Me H H H CH.sub.2 CONH.sub.2 O 229 Me H H H CH.sub.2 CONHCH.sub.3 O 230 Me H H H CH.sub.2 CON(CH.sub.3).sub.2 O 231 Me H ##STR47## H CH.sub.2 OH O 132 Me H ##STR48## H CH.sub.2 CN O 133 Me H ##STR49## H CH.sub.2 NH.sub.2 O 134 Me H ##STR50## H CH.sub.2 CONH.sub.2 O 135 Me H ##STR51## H CH.sub.2 OCONH.sub.2 O 136 Me H ##STR52## H CH.sub.2 NHCONH.sub.2 O 137 Me H ##STR53## H CH.sub.2 OH O 238 Me H ##STR54## H CH.sub.2 CN O 239 Me H ##STR55## H CH.sub.2 NH.sub.2 O 240 Me H ##STR56## H CH.sub.2 COH.sub.2 O 241 Me H ##STR57## H CH.sub.2 OCONH.sub.2 O 242 Me H ##STR58## H CH.sub.2 NH.sub.2 CONH.sub.2 O 243 Me H ##STR59## H CH.sub.2 OH O 144 Me H ##STR60## H CH.sub.2 CN O 145 Me H ##STR61## H CH.sub.2 NH.sub.2 O 146 Me H ##STR62## H CH.sub.2 CONH.sub.2 O 147 Me H ##STR63## H CH.sub.2 OCONH.sub.2 O 148 Me H ##STR64## H CH.sub.2 NHCONH.sub.2 O 149 Me H ##STR65## H CH.sub.2 OH O 250 Me H ##STR66## H CH.sub.2 CN O 251 Me H ##STR67## H CH.sub.2 NH.sub.2 O 252 Me H ##STR68## H CH.sub.2 CONH.sub.2 O 253 Me H ##STR69## H CH.sub.2 OCONH.sub.2 O 254 Me H ##STR70## H CH.sub.2 CONHCH.sub.3 O 255 Me H ##STR71## H CH.sub.2 NHCONH.sub.2 O 256 Me H H H ##STR72## O 157 Me H H H ##STR73## O 158 Me H H H ##STR74## O 159 Me H H H ##STR75## O 160 Me H H H ##STR76## O 161 Me H H H ##STR77## O 162 Me H H H ##STR78## O 163 Me H H H ##STR79## O 164 Me anion H H ##STR80## O 165 Me H H H ##STR81## O 166 Me H H H ##STR82## O 167 Me H H H ##STR83## O 168 Me H H H ##STR84## O 169 Me H H H ##STR85## O 270 Me H H H ##STR86## O 271 Me H H H ##STR87## O 272 Me H H H ##STR88## O 273 Me H H H ##STR89## O 274 Me H H H ##STR90## O 275 Me H H H ##STR91## O 276 Me H H H ##STR92## O 277 Me anion H H ##STR93## O 278 Me H H H ##STR94## O 279 Me H H H ##STR95## O 280 Me H H H ##STR96## O 281 Me H H H ##STR97## O 282 Me H H H ##STR98## O 183 Me H H H ##STR99## O 184 Me H H H ##STR100## O 185 Me H H H ##STR101## O 186 Me H H H ##STR102## O 187 Me H H H ##STR103## O 188 Me H H H ##STR104## O 189 Me H H H ##STR105## O 190 Me anion H H ##STR106## O 291 Me H H H ##STR107## O 192 Me H H H ##STR108## O 193 Me H H H ##STR109## O 194 Me H H H ##STR110## O 195 Me H H H ##STR111## O 296 Me H H H ##STR112## O 297 Me H H H ##STR113## O 298 Me H H H ##STR114## O 299 Me H H H ##STR115## O 2100 Me H H H ##STR116## O 2101 Me H H H ##STR117## O 2102 Me H H H ##STR118## O 2103 Me H H H ##STR119## O 2104 Me H H H ##STR120## O 2105 Me H H H ##STR121## O 2106 Me H H H ##STR122## O 2107 Me H ##STR123## H CN O 1108 Me H ##STR124## H CN O 2109 Me H ##STR125## H CH.sub.2 CN O 1110 Me N ##STR126## H (CH.sub.2).sub.2 CN O 2111 Me H ##STR127## H (CH.sub.2).sub.2 OH O 1112 Me H ##STR128## H (CH.sub.2).sub.2 OH O 2113 Me H ##STR129## H ##STR130## O 1114 Me H ##STR131## H ##STR132## O 2115 Me H ##STR133## H CN O 1116 Me H ##STR134## H CN O 2117 Me H ##STR135## H (CH.sub.2).sub.2 CN O 1118 Me H ##STR136## H (CH.sub.2).sub.2 OH O 2119 Me H ##STR137## H (CH.sub.2).sub.2 OH O 1120 Me H ##STR138## H (CH.sub.2).sub.2 OH O 2121 Me H ##STR139## H (CH.sub.2).sub.2 NH.sub.2 O 1122 Me H ##STR140## H (CH.sub.2).sub.2 NH.sub.2 O 2123 Me H ##STR141## H (CH.sub.2).sub.2 CONH.sub.2 O 1124 Me H ##STR142## H (CH.sub.2).sub.2 CONH.sub.2 O 2125 Me H H CH CH.sub.2 OH O 1126 Me H H CH CH.sub.2 CN O 1127 Me H H CH CH.sub.2 NH.sub.2 O 1128 Me H H CH CH.sub.2 OCONH.sub.2 O 1129 Me H H CH CH.sub.2 CONH.sub.2 O 1130 Me H H CH CH.sub.2 NHCONH.sub.2 O 1131 Me H H CH ##STR143## O 1132 Me H H CH ##STR144## O 1133 Me H H CH ##STR145## O 1134 Me H H CH ##STR146## O 1135 Me H H CH ##STR147## O 1136 Me H H CH ##STR148## O 1137 Me H H CH ##STR149## O 1138 Me H H CH ##STR150## O 1139 Me anion H CH ##STR151## O 1140 Me H H CH ##STR152## O 1141 Me H H CH ##STR153## O 1142 Me H H CH ##STR154## O 1143 Me H H CH ##STR155## O 1144 Me H H CH ##STR156## O 1145 Me H H CH ##STR157## O 1146 Me H H CH CH.sub.2 OH O 2147 Me H H CH CH.sub.2 CN O 2148 Me H H CH CH.sub.2 NH.sub.2 O 2149 Me H H CH CH.sub.2 CONH.sub.2 O 2150 Me H H CH CH.sub.2 CONHCH.sub.3 O 2151 Me H H CH CH.sub.2 CON(CH.sub.3).sub.2 O 2152 Me H H CH CH.sub.2 OCONH.sub.2 O 2153 Me H H CH CH.sub.2 NHCONH.sub.2 O 2154 Me H H CH ##STR158## O 2155 Me H H CH ##STR159## O 2156 Me H H CH ##STR160## 0 2157 Me H H CH ##STR161## O 2158 Me H H CH ##STR162## O 2159 Me H H CH ##STR163## O 2160 Me H H CH ##STR164## O 2161 Me H H CH ##STR165## O 2162 Me anion H CH ##STR166## O 2163 Me H H CH ##STR167## O 2164 Me H H CH ##STR168## O 2165 Me H H CH ##STR169## O 2166 Me H H CH ##STR170## O 2167 Me H H CH ##STR171## O 2168 Me H H CH ##STR172## O 2169 Me H ##STR173## CH CH.sub.2 OH O 1170 Me H ##STR174## CH CH.sub.2 CN O 1171 Me H ##STR175## CH CH.sub.2 NH.sub.2 O 1172 Me H ##STR176## CH CH.sub.2 CONH.sub.2 O 1173 Me H ##STR177## CH CH.sub.2 OH O 2174 Me H ##STR178## CH CH.sub.2 CN O 2175 Me H ##STR179## CH CH.sub.2 NH.sub.2 O 2176 Me H ##STR180## CH CH.sub.2 CONH.sub.2 O 2177 Me H ##STR181## CH ##STR182## O 2178 Me H ##STR183## CH CH.sub.2 OH O 1179 Me H ##STR184## CH CH.sub.2 CN O 1180 Me H ##STR185## CH CH.sub.2 NH.sub.2 O 1181 Me H ##STR186## CH CH.sub.2 CONH.sub.2 O 1182 Me H ##STR187## CH ##STR188## O 1183 Me H ##STR189## CH CH.sub.2 NH.sub.2 CONH.sub.2 O 1184 Me H ##STR190## CH CH.sub.2 OH O 2185 Me H ##STR191## CH CH.sub.2 CN O 2186 Me H ##STR192## CH CH.sub.2 NH.sub.2 O 2187 Me H ##STR193## CH CH.sub.2 CONH.sub.2 O 2188 Me H ##STR194## CH CH.sub.2 OCONH.sub.2 O 2189 Me H ##STR195## CH CH.sub.2 NHCONH.sub.2 O 2190 Me H H CN CH.sub.2 OH O 1191 Me H H CN CH.sub.2 CN O 1192 Me H H CN CH.sub.2 NH.sub.2 O 1193 Me H H CN CH.sub.2 CONH.sub.2 O 1194 Me H H CN CH.sub.2 CONHCH.sub.3 O 1195 Me H H CN CH.sub.2 CON(CH.sub.3).sub.2 O 1196 Me H H CN CH.sub.2 OCONH.sub.2 O 1197 Me H H CN CH.sub.2 NHCONH.sub.2 O 1198 Me H H CN CH.sub.2 OH O 2199 Me H H CN CH.sub.2 CN O 2200 Me H H CN CH.sub.2 NH.sub.2 O 2201 Me H H CN CH.sub.2 CONH.sub.2 O 2202 Me H H CN CH.sub.2 CON(CH.sub.3).sub.2 O 2203 Me H H CN CH.sub.2 CON(CH.sub.3).sub.2 O 2204 Me H H CN CH.sub.2 NHCONH.sub.2 O 2205 Me H H CN CH.sub.2 OCONH.sub.2 O 2206 Me H H CN ##STR196## O 1207 Me H H CN ##STR197## O 1208 Me H H CN ##STR198## O 1209 Me H H CN ##STR199## O 1210 Me H H CN ##STR200## O 1211 Me H H CN ##STR201## O 1212 Me H H CN ##STR202## O 1213 Me H H CN ##STR203## O 1214 Me anion H CN ##STR204## O 1215 Me H H CN ##STR205## O 1216 Me H H CN ##STR206## O 1217 Me H H CN ##STR207## O 1218 Me H H CN ##STR208## O 1219 Me H H CN ##STR209## O 1220 Me H H CN ##STR210## O 1221 Me H H CN ##STR211## O 2222 Me H H CN ##STR212## O 2223 Me H H CN ##STR213## O 2224 Me H H CN ##STR214## O 2225 Me H H CN ##STR215## O 2226 Me H H CN ##STR216## O 2227 Me H H CN ##STR217## O 2228 Me H H CN ##STR218## O 2229 Me anion H CN ##STR219## O 2230 Me H H CN ##STR220## O 2231 Me H H CN ##STR221## O 2232 Me H H CN ##STR222## O 2233 Me H H CN ##STR223## O 2234 Me H H CN ##STR224## O 2235 Me H H CN ##STR225## O 2236 Me H H CH.sub.2 OH CH.sub.2 OH O 1237 Me H H CH.sub.2 OH CH.sub.2 CN O 1238 Me H H CH.sub.2 OH CH.sub.2 NH.sub.2 O 1239 Me H H CH.sub.2 OH CH.sub.2 OCONH.sub.2 O 1240 Me H H CH.sub.2 OH CH.sub.2 NHCONH.sub.2 O 1241 Me H H CH.sub.2 OH CH.sub.2 CONH.sub.2 O 1242 Me H H CH.sub.2 OH CH.sub.2 CONHCH.sub.3 O 1243 Me H H CH.sub.2 OH CH.sub.2 CON(CH.sub.3).sub.2 O 1244 Me H H CH.sub.2 OH CH.sub.2 OH O 2245 Me H H CH.sub.2 OH CH.sub.2 CN O 2246 Me H H CH.sub.2 OH CH.sub.2 NH.sub.2 O 2247 Me H H CH.sub.2 OH CH.sub.2 OCONH.sub.2 O 2248 Me H H CH.sub.2 OH CH.sub.2 NHCONH.sub.2 O 2249 Me H H CH.sub.2 OH CH.sub.2 CONH.sub.2 O 2250 Me H H CH.sub.2 OH CH.sub.2 CONHCH.sub.3 O 2251 Me H H CH.sub.2 OH CH.sub.2 CON(CH.sub.3).sub.2 O 2252 Me H H CH.sub.2 OH CH.sub.2 CH.sub.2 OH O 1253 Me H H CH.sub.2 OH CH.sub.2 CH.sub.2 CN O 1254 Me H H CH.sub.2 OH CH.sub.2 CH.sub.2 NH.sub.2 O 1255 Me H H CH.sub.2 OH CH.sub.2 CH.sub.2 CONH.sub.2 O 1256 Me H H CH.sub.2 OH CH.sub.2 CH.sub.2 NHCONH.sub.2 O 1257 Me H H CH.sub.2 OH CH.sub.2 CH.sub.2 OCONH.sub.2 O 1258 Me H H CH.sub.2 OH CH.sub.2 CH.sub.2 OH O 2259 Me H H CH.sub.2 OH CH.sub.2 CH.sub.2 CN O 2260 Me H H CH.sub.2 OH CH.sub.2 CH.sub.2 NH.sub.2 O 2261 Me H H CH.sub.2 OH CH.sub.2 CH.sub.2 OCONH.sub.2 O 2262 Me H H CH.sub.2 OH CH.sub.2 CH.sub.2 CONH.sub.2 O 2263 Me H H CH.sub.2 OH CH.sub.2 CH.sub.2 NHCONH.sub.2 O 1264 Me H H CH.sub.2 OH ##STR226## O 1265 Me H H CH.sub.2 OH ##STR227## O 1266 Me H H CH.sub.2 OH ##STR228## O 1267 Me H H CH.sub.2 OH ##STR229## O 1268 Me H H CH.sub.2 OH ##STR230## O 1269 Me H H CH.sub.2 OH ##STR231## O 1270 Me H H CH.sub.2 OH ##STR232## O 1271 Me H H CH.sub.2 OH ##STR233## O 1272 Me anion H CH.sub.2 OH ##STR234## O 1273 Me H H CH.sub.2 OH ##STR235## O 1274 Me H H CH.sub.2 OH ##STR236## O 1275 Me H H CH.sub.2 OH ##STR237## O 1276 Me H H CH.sub.2 OH ##STR238## O 2277 Me H H CH.sub.2 OH ##STR239## O 2278 Me H H CH.sub.2 OH ##STR240## O 2279 Me H H CH.sub.2 OH ##STR241## O 2280 Me H H CH.sub.2 OH ##STR242## O 2281 Me H H CH.sub.2 OH ##STR243## O 2282 Me H H CH.sub.2 OH ##STR244## O 2283 Me H H CH.sub.2 OH ##STR245## O 2284 Me anion H CH.sub.2 OH ##STR246## O 2285 Me H H CH.sub.2 OH ##STR247## O 2286 Me H H CH.sub.2 OH ##STR248## O 2287 Me H H CH.sub.2 OH ##STR249## O 2288 Me H ##STR250## CH.sub.2 OH CH.sub.2 OH O 1289 Me H ##STR251## CH.sub.2 OH CH.sub.2 CN O 1290 Me H ##STR252## CH.sub.2 OH CH.sub.2 NH.sub.2 O 1291 Me H ##STR253## CH.sub.2 OH CH.sub.2 OCONH.sub.2 O 1292 Me H ##STR254## CH.sub.2 OH CH.sub.2 CONH.sub.2 O 1293 Me H ##STR255## CH.sub.2 OH CH.sub.2 NHCONH.sub.2 O 1294 Me H ##STR256## CH.sub.2 OH CH.sub.2 OH O 2295 Me H ##STR257## CH.sub.2 OH CH.sub.2 CN O 2296 Me H ##STR258## CH.sub.2 OH CH.sub.2 NH.sub.2 O 2297 Me H ##STR259## CH.sub.2 OH CH.sub.2 OCONH.sub.2 O 2298 Me H ##STR260## CH.sub.2 OH CH.sub.2 NHCONH.sub.2 O 2299 Me H ##STR261## CH.sub.2 OH CH.sub.2 CONH.sub.2 O 2300 Me H ##STR262## CH.sub.2 OH CH.sub.2 OH O 1301 Me H ##STR263## CH.sub.2 OH CH.sub.2 CN O 1302 Me H ##STR264## CH.sub.2 OH CH.sub.2 NH.sub.2 O 1303 Me H ##STR265## CH.sub.2 OH CH.sub.2 OCONH.sub.2 O 1304 Me H ##STR266## CH.sub.2 OH CH.sub.2 CONH.sub.2 O 1305 Me H ##STR267## CH.sub.2 OH CH.sub.2 NHCONH.sub.2 O 1306 Me H ##STR268## CH.sub.2 OH CH.sub.2 OH O 2307 Me H ##STR269## CH.sub.2 OH CH.sub.2 CN O 2308 Me H ##STR270## CH.sub.2 OH CH.sub.2 NH.sub.2 O 2309 Me H ##STR271## CH.sub.2 OH CH.sub.2 OCONH.sub.2 O 2310 Me H ##STR272## CH.sub.2 OH CH.sub.2 CONH.sub.2 O 2311 Me H ##STR273## CH.sub.2 OH CH.sub.2 NHCONH.sub.2 O 2312 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 OH O 1313 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CN O 1314 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 NH.sub.2 O 1315 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CONH.sub.2 O 1316 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 NHCONH.sub.2 O 1317 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 OCONH.sub.2 O 1318 Me H H CH.sub.2 CONH.sub.2 ##STR274## O 1319 Me H H CH.sub.2 CONH.sub.2 ##STR275## O 1320 Me H H CH.sub.2 CONH.sub.2 ##STR276## O 1321 Me H H CH.sub.2 CONH.sub.2 ##STR277## O 1322 Me H H CH.sub.2 CONH.sub.2 ##STR278## O 1323 Me H H CH.sub.2 CONH.sub.2 ##STR279## O 1324 Me H H CH.sub.2 CONH.sub.2 ##STR280## O 1325 Me H H CH.sub.2 CONH.sub.2 ##STR281## O 1326 Me anion H CH.sub.2 CONH.sub.2 ##STR282## O 1327 Me H H CH.sub.2 CONH.sub.2 ##STR283## O 1328 Me H H CH.sub.2 CONH.sub.2 ##STR284## O 1329 Me H H CH.sub.2 CONH.sub.2 ##STR285## O 1330 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 OH O 1331 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 CN O 1332 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 NH.sub.2 O 1333 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 CONH.sub.2 O 1334 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 OCONH.sub.2 O 1335 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 NHCONH.sub.2 O 1336 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 OH O 2337 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CN O 2338 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 NH.sub.2 O 2339 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 OCONH.sub.2 O 2340 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CONH.sub.2 O 2341 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 NHCONH.sub.2 O 2342 Me H H CH.sub.2 CONH.sub.2 ##STR286## O 2343 Me H H CH.sub.2 CONH.sub.2 ##STR287## O 2344 Me H H CH.sub.2 CONH.sub.2 ##STR288## O 2345 Me H H CH.sub.2 CONH.sub.2 ##STR289## O 2346 Me H H CH.sub.2 CONH.sub.2 ##STR290## O 2347 Me H H CH.sub.2 CONH.sub.2 ##STR291## O 2348 Me H H CH.sub.2 CONH.sub.2 ##STR292## O 2349 Me H H CH.sub.2 CONH.sub.2 ##STR293## O 2350 Me anion H CH.sub.2 CONH.sub.2 ##STR294## O 2351 Me H H CH.sub.2 CONH.sub.2 ##STR295## O 2352 Me H H CH.sub.2 CONH.sub.2 ##STR296## O 2353 Me H H CH.sub.2 CONH.sub.2 ##STR297## O 2354 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 OH O 2355 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 CN O 2356 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 NH.sub.2 O 2357 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 OCONH.sub.2 O 2358 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 NHCONH.sub.2 O 2359 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 CONH.sub.2 O 2360 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 CONHCH.sub.3 O 2361 Me H H CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 CON(CH.sub.3).sub.2 O 2362 Me H ##STR298## CH.sub.2 CONH.sub.2 CH.sub.2 OH O 1363 Me H ##STR299## CH.sub.2 CONH.sub.2 CH.sub.2 NH.sub.2 O 1364 Me H ##STR300## CH.sub.2 CONH.sub.2 CH.sub.2 CN O 1365 Me H ##STR301## CH.sub.2 CONH.sub.2 CH.sub.2 OCONH.sub.2 O 1366 Me H ##STR302## CH.sub.2 CONH.sub.2 CH.sub.2 CONH.sub.2 O 1367 Me H ##STR303## CH.sub.2 CONH.sub.2 CH.sub.2 NHCONH.sub.2 O 1368 Me H ##STR304## CH.sub.2 CONH.sub.2 CH.sub.2 OH O 2369 Me H ##STR305## CH.sub.2 CONH.sub.2 CH.sub.2 NH.sub.2 O 2370 Me H ##STR306## CH.sub.2 CONH.sub.2 CH.sub.2 CN O 2371 Me H ##STR307## CH.sub.2 CONH.sub.2 CH.sub.2 CONH.sub.2 O 2372 Me H ##STR308## CH.sub.2 CONH.sub.2 CH.sub.2 NHCONH.sub.2 O 2373 Me H ##STR309## CH.sub.2 CONH.sub.2 CH.sub.2 OH O 1374 Me H ##STR310## CH.sub.2 CONH.sub.2 CH.sub.2 CN O 1375 Me H ##STR311## CH.sub.2 CONH.sub.2 CH.sub.2 NH.sub.2 O 1376 Me H ##STR312## CH.sub.2 CONH.sub.2 CH.sub.2 OCONH.sub.2 O 1377 Me H ##STR313## CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 NHCONH.sub.2 O 1378 Me H ##STR314## CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 CONH.sub.2 O 1379 Me H ##STR315## CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 CONHCH.sub.3 O 2280 Me H ##STR316## CH.sub.2 CONH.sub.2 CH.sub.2 CH.sub.2 CON(CH.sub.3).sub.2 O 2381 Me H ##STR317## CH.sub.2 CONH.sub.2 CH.sub.2 OH O 2382 Me H ##STR318## CH.sub.2 CONH.sub.2 CH.sub.2 NH.sub.2 O 2383 Me H ##STR319## CH.sub.2 CONH.sub.2 CH.sub.2 CN O 2384 Me H ##STR320## CH.sub.2 CONH.sub.2 CH.sub.2 OCONH.sub.2 O 2385 Me H ##STR321## CH.sub.2 CONH.sub.2 CH.sub.2 CONH.sub.2 O 2__________________________________________________________________________
__________________________________________________________________________ ##STR322##No R.sub.1 R.sub.2 R.sub.3 R.sub.4 X m__________________________________________________________________________386 Me H H NHCH.sub.3 O 1387 Me H H NH.sub.2 O 2388 Me H H NHCH.sub.3 O 2389 Me H H N(CH.sub.3).sub.2 O 1390 Me H H MeNEt O 1391 Me H H MeNiPr O 1392 Me H H EtNiPr O 1393 Me H H N(iPr).sub.2 O 1394 Me H H MeNEt O 2395 Me H H N(Et).sub.2 O 2396 Me H H EtNiPr O 2397 Me H H N(iPr).sub.2 O 2398 Me H ##STR323## N(iPr).sub.2 O 1399 Me H ##STR324## NHCH.sub.3 O 2400 Me H ##STR325## NH.sub.2 O 2401 Me H ##STR326## NHCH.sub.3 O 1402 Me H ##STR327## NH.sub.2 O 2403 Me H ##STR328## NHCH.sub.3 O 2404 Me H H ##STR329## O 1405 Me H H ##STR330## O 1406 Me H H ##STR331## O 1407 Me H H ##STR332## O 1408 Me H H ##STR333## O 1409 Me H H ##STR334## O 1410 Me H H ##STR335## O 2411 Me H H ##STR336## O 2412 Me H H ##STR337## O 2413 Me H H ##STR338## O 2414 Me H H ##STR339## O 2415 Me H H ##STR340## O 2416 Me H ##STR341## ##STR342## O 1417 Me H ##STR343## ##STR344## O 1418 Me H ##STR345## ##STR346## O 2419 Me H ##STR347## ##STR348## O 2420 Me H ##STR349## ##STR350## O 1421 Me H ##STR351## ##STR352## O 1422 Me H ##STR353## ##STR354## O 2423 Me H ##STR355## ##STR356## O 2424 Me H H ##STR357## O 1425 Me H H ##STR358## O 1426 Me H H ##STR359## O 1427 Me H H ##STR360## O 1428 Me H H ##STR361## O 1429 Me H H ##STR362## O 1430 Me H H ##STR363## O 1431 Me H H ##STR364## O 1432 Me H H ##STR365## O 1433 Me H H ##STR366## O 1434 Me H H ##STR367## O 2435 Me H H ##STR368## O 2436 Me H H ##STR369## O 2437 Me H H ##STR370## O 2438 Me H H ##STR371## O 2439 Me H H ##STR372## O 2440 Me H H ##STR373## O 2441 Me H H ##STR374## O 2442 Me H H ##STR375## O 2443 Me H H ##STR376## O 2444 Me H H ##STR377## O 1445 Me H H ##STR378## O 1446 Me H H ##STR379## O 1447 Me H H ##STR380## O 1448 Me H H ##STR381## O 1449 Me H H ##STR382## O 1450 Me H H ##STR383## O 1451 Me H H ##STR384## O 1452 Me H H ##STR385## O 2453 Me H H ##STR386## O 2454 Me H H ##STR387## O 2455 Me H H ##STR388## O 2456 Me H H ##STR389## O 2457 Me H H ##STR390## O 2458 Me H H ##STR391## O 2459 Me H ##STR392## ##STR393## O 1460 Me H ##STR394## ##STR395## O 1461 Me H ##STR396## ##STR397## O 1462 Me H ##STR398## ##STR399## O 1463 Me H ##STR400## ##STR401## O 1464 Me H ##STR402## ##STR403## O 1465 Me H ##STR404## ##STR405## O 1466 Me H ##STR406## ##STR407## O 1467 Me H ##STR408## ##STR409## O 1468 Me H ##STR410## ##STR411## O 1469 Me H ##STR412## ##STR413## O 2470 Me H ##STR414## ##STR415## O 2471 Me H ##STR416## ##STR417## O 2472 Me H ##STR418## ##STR419## O 2473 Me H ##STR420## ##STR421## O 2474 Me H ##STR422## ##STR423## O 2475 Me H ##STR424## ##STR425## O 2476 Me H ##STR426## ##STR427## O 2477 Me H ##STR428## ##STR429## O 2478 Me H ##STR430## ##STR431## O 2479 Me H H NH.sub.2 NH 1480 Me H H NHCH.sub.3 NH 1481 Me H H N(CH.sub.3).sub.2 NH 1482 Me H H MeNEt NH 1483 Me H H N(Et).sub.2 NH 1484 Me H H NH.sub.2 NH 2485 Me H H NHCH.sub.3 NH 2486 Me H H N(CH.sub.3).sub.2 NH 2487 Me H H MeNEt NH 2488 Me H H N(Et).sub.2 NH 2489 Me H H EtNiPr NH 2490 Me H H N(iPr).sub.2 NH 2491 Me H H ##STR432## NH 2492 Me H H ##STR433## NH 2493 Me H H ##STR434## NH 2494 Me H H ##STR435## NH 2495 Me H H ##STR436## NH 2496 Me H H ##STR437## NH 2497 Me H H ##STR438## NH 2498 Me H H ##STR439## NH 2499 Me H H ##STR440## NH 2500 Me H H ##STR441## NH 2501 Me H H ##STR442## NH 2502 Me H H ##STR443## NH 2503 Me H H ##STR444## NH 2504 Me H H ##STR445## NH 2__________________________________________________________________________
______________________________________ ##STR446##No R.sub.1 R.sub.2 R.sub.3 R.sub.9 m______________________________________505 Me H H OH 1506 Me H H OH 2507 Me H H OH 3508 Me H H OH 4509 Me H H OH 5510 Me H H OH 6511 Me H H CH(OH)CH.sub.3 1512 Me H H CH(OH).sub.2 1513 Me H H CH(OH)CH.sub.3 2514 Me H H CH(OH).sub.2 2515 Me H H CH(OH)CH.sub.3 3516 Me H H CH(OH).sub.2 CH.sub.3 3517 Me H H CH(OH)CH.sub.3 4518 Me H H CH(OH).sub.2 4519 Me H ##STR447## OH 1520 Me H ##STR448## OH 2521 Me H ##STR449## OH 3522 Me H ##STR450## OH 4523 Me H ##STR451## OH 5524 Me H ##STR452## OH 1525 Me H ##STR453## OH 2526 Me H ##STR454## OH 3527 Me H ##STR455## OH 4528 Me H H OCONH.sub.2 1529 Me H H OCONH.sub.2 2530 Me H H OCONH.sub.2 3531 Me H H OCONH.sub.2 4532 Me H H OCONH.sub.2 5533 Me H H OCONH.sub.2 6534 Me H ##STR456## OCONH.sub.2 1535 Me H ##STR457## OCONH.sub.2 2536 Me H ##STR458## OCONH.sub.2 3537 Me H ##STR459## OCONH.sub.2 4538 Me H ##STR460## OCONH.sub.2 1539 Me H ##STR461## OCONH.sub.2 2540 Me H ##STR462## OCONH.sub.2 3541 Me H ##STR463## OCONH.sub.2 4______________________________________
______________________________________ ##STR464##No R.sub.1 R.sub.2 R.sub.3 R.sub.4 X m______________________________________542 Me H H CH.sub.2 OH O 1543 Me H H (CH.sub.2).sub.2 OH O 1544 Me H H (CH.sub.2).sub.2 OH O 1545 Me H H (CH.sub.2).sub.2 OH O 1546 Me H H CH.sub.2 CH O 2547 Me H H (CH.sub.2).sub.2 OH O 2548 Me H H (CH.sub.2).sub.3 OH O 2549 Me H H (CH.sub.2).sub.4 OH O 2550 Me H ##STR465## (CH.sub.2).sub.2 OH O 1551 Me H ##STR466## (CH.sub.2).sub.2 OH O 1552 Me H ##STR467## (CH.sub.2).sub.4 OH O 2553 Me H ##STR468## (CH.sub.2).sub.4 OH O 2554 Me H H (CH.sub.2).sub.4 OCH.sub.3 O 1555 Me H H (CH.sub.2).sub.2 OCONH.sub.2 O 1556 Me H H (CH.sub.2).sub.3 OCONH.sub.2 O 1557 Me H H (CH.sub.2).sub.4 OCONH.sub.2 O 1558 Me H H CH.sub.2 OCONH.sub.2 O 2559 Me H H (CH.sub.2).sub.2 OCONH.sub.2 O 2560 Me H H (CH.sub.2).sub.3 OCONH.sub.2 O 2561 Me H H (CH.sub.2).sub.4 OCONH.sub.2 O 2562 Me H ##STR469## (CH.sub.2).sub.2 OCONH.sub.2 O 2563 Me H ##STR470## (CH.sub.2).sub.3 OCONH.sub.2 O 2564 Me H ##STR471## (CH.sub.2).sub.4 OCONH.sub.2 O 2565 Me H ##STR472## (CH.sub.2).sub.2 OCONH.sub.2 O 2566 Me H ##STR473## (CH.sub.2).sub.3 OCONH.sub.2 O 2567 Me H ##STR474## (CH.sub.2).sub.4 OCONH.sub.2 O 2568 H H H CH.sub.2 OH O 1569 H H H (CH.sub.2).sub.2 OH O 1570 H H H (CH.sub.2).sub.3 OH O 1571 H H H (CH.sub.2).sub.4 OH O 1572 H H H (CH.sub.2).sub.2 OH O 2573 H H H (CH.sub.2).sub.2 OH O 2574 H H H (CH.sub.2).sub.3 OH O 2575 H H H (CH.sub.2).sub.4 OH O 2576 H H H (CH.sub.2).sub.2 OCONH.sub.2 O 1577 H H H (CH.sub.2).sub.3 OCONH.sub.2 O 1578 H H H (CH.sub.2).sub.4 OCONH.sub.2 O 1579 H H H (CH.sub.2).sub.2 OCONH.sub.2 O 2580 H H H (CH.sub.2).sub.3 OCONH.sub.2 O 2581 H H H (CH.sub.2).sub.4 OCONH.sub.2 O 2582 H H H NH.sub.2 O 2______________________________________
Reference Example 1
44.6 g of 2-amino-2-methyl-1-propanol, 65 g of diethyl-carbonate and 7 g of potassium carbonate were mixed and stirred while heating at 120.degree. C. to 140.degree. C., and then methanol produced during the reaction was removed with a water-trapping apparatus. The reaction solution was concentrated and then allowed to stand in a refrigerator to obtain a white precipitate. The resulting product was dissolved in ethyl ether and filtered to remove the insoluble materials. The filtrate was concentrated and then allowed to stand under ice-cooling to obtain a white solid which is then filtered and dried to obtain 25.7 g of the desired product 4,4-dimethyl-oxazolidin-2-one.
Melting Point: 52.degree.-53.degree. C. .sup.1 H NMR(DCCl.sub.3) .delta.: 1.35 (s, 6H, 2CH.sub.3), 4.00 (s, 2H, CH.sub.2), 6.70 (bs, 1H, NH.sub.1)
Reference Example 2
11.5 g of the compound prepared in Reference Example 1 was dissolved in 200 ml of anhydrous tetrahydrofuran and the resulting solution was cooled to -50.degree. C. to -60.degree. C. and 70 ml of n-butyl lithium was slowly added thereto under nitrogen atmosphere. At the same temperature 22 g of 2-bromopropionyl bromide was added dropwise thereto under stirring. After stirring for one hour at the same temperature, the reaction mixture was slowly warmed to 0.degree. C. and then stirred for one hour. The reaction mixture was diluted with water and then extracted with ethyl ether. The organic layer was combined, dried and concentrated under reduced pressure to obtain 18 g of the desired product 3-(2-bromopropionyl)-4,4-dimethyl-oxazolidin-2-one.
.sup.1 H NMR(DCCl.sub.3) .delta.: 1.60 (s, 6H, 2CH.sub.3), 1.82 (d, 3H, CH.sub.3), 4.05 (s, 2H, CH.sub.2), 5.80 (q, 1H, CH, CH.sub.3)
Reference Example 3
0.59 g of azetinone and 0.5 g of activated zinc were added to 40 ml of anhydrous tetrahydrofuran. 1.06 g of the compound prepared in Reference Example 2 was added dropwise thereto while heating under reflux and then the reaction mixture was heated for further 30 minutes under reflux. Saturated ammonium chloride solution was added to the mixture to complete the reaction. Ethyl acetate was added to the mixture to extract the reaction product and the extracted organic layers were combined, washed with distilled water, dried and concentrated under reduced pressure to obtain 470 mg of the desired product (3S,4S)-3-(1R-t-butyldimethylsilyloxyethyl)-4-�(1R"-1-carboxyethyl)-2-(4", 4"-dimethyl-2"-oxazolidinoyl)!azetidin-2-one.
Melting Point: 171.degree.-172.degree. C. .sup.1 H NMR(DCCl.sub.3) .delta.: 0.07 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H), 1.19 (d, 3H, J=6 Hz), 1.21 (d, 3H, J=6 Hz), 1.58 (s, 6H), 3.01-3.04 (s, 1H), 3.90-3.95 (m,1H), 4.14-4.23 (m, 2H), 6.00 (s, 1H, NH)
Reference Example 4
5.1 g of the compound prepared in Reference Example 3 was dissolved in 200 ml of tetrahydrofuran and then 3.5 ml of 30% hydrogen peroxide was added thereto. Then, 1N-sodium hydroxide solution was slowly added dropwise to the reaction mixture with stirring at 5.degree. to 10.degree. C. The whole reaction mixture was stirred for 30 minutes at the same temperature, evaporated under reduced pressure to remove tetrahydrofuran solvent and extracted with ethyl acetate. The extract was adjusted to pH 3 to 4 by adding 10% hydrochloric acid solution and evaporated under reduced pressure to remove the solvent to obtain 2.6 g of the white desired product (3S,4S)-3-�(1R-t-butyldimethylsilyloxyethyl)-4-(1R-1-carboxyethyl)!-azetidin-2-one.
Melting Point: 148.5.degree.-151.5.degree. C. .sup.1 H NMR(CDCl.sub.3) .delta.: 0.07-0.08 (s, 6H), 0.89 (s, 9H), 1.19 (d, 3H, J=6 Hz), 1.27 (d, 3H, J=7 Hz), 2.78-2.74 (m, 1H), 3.05 (d, 1H, J=4.4 Hz, 2H), 3.98 (d, 1H, J=4.82 Hz), 4.25-4.17 (m, 2H), 6.50 (s, 1H, NH)
Reference Example 5
0.6 g of the compound prepared in Reference Example 4 was dissolved in 5 ml of anhydrous acetonitrile and the resulting solution was stirred for 30 minutes. Then 2.0 g of magnesium p-nitrobenzylmalonate was added thereto and the mixture was stirred for 18 hours at 65.degree. C. The reaction mixture was evaporated to remove the solvent and the residue was suspended in 50 ml of ethyl acetate and then washed successively with 1N-hydrochloric acid solution, 10% potassium carbonate and saline. After removing the solvent, the residue was purified with column chromatography to obtain 70 mg of the desired product (3S,4S)-3-�(R)-1-(t-butyldimethylsilyloxy)ethyl!-4-�(R)-1-(p-nitrobenzylacetoxy)carboxyethyl!azetidin-2-one.
.sup.1 H NMR(CDCl.sub.3): 0.07 (s, 6H, CH.sub.3 .times.2), 0.9 (s, 9H), 1.10 (d, 3H, CH.sub.3), 1.23 (d, 3H, CH.times.3), 2.29 (dd,1H), 2.92 (m, 1H), 3.66 (s, 2H), 3.96 (dd, 1H), 4.20 (m, 1H), 5.39 (s, 2H), 7.56 and 8.25 (d, 2H, .O slashed.)
Reference Example 6
2.87 g of the compound prepared in Reference Example 5 was dissolved in 30 ml of methanol and 3 ml of 6N-hydrochloric acid solution was added thereto. The reaction mixture was stirred for 2 hours at room temperature and then adjusted to pH 7 to 8 with 0.1N-phosphate buffer and 10% potassium carbonate. After removing the solvent from the reaction mixture, the residue was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified with column chromatography to obtain 1.7 g of the desired product (3S,4S)-3-�(R)-1-(t-butyldimethylsilyloxy)ethyl!-4-�(R)-1-(p-nitrobenzylacetoxy)carboxyethyl!azetidin-2-one.
.sup.1 .sup.1 H NMR(CDCl.sub.3) .delta.: 1.30 (d, 6H), 2.90 (dd, 1H, CH), 2.94 (q, 1H, CH), 3.65-3.70 (ABq, 2H, CH.sub.2), 3.84 (dd, 1H, CH), 4.15 (m, 1H, CH), 7.50 and 8.25 (d, 2H, .O slashed.)
Reference Example 7
0.4 g of the compound prepared in Reference Example 6 was dissolved in 5 ml of anhydrous acetonitrile and to the resulting solution were added 7.4 g of tosyl azide and 0.2 g of triethylamine. The reaction solution was stirred for 2 hours at room temperature and then concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 400 mg of the desired product (3S,4S)-3-�(R)-1-hydroxyethyl!4-�(R)-1-methyl-3-diazo-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl!azetidin-2-one.
.sup.1 H NMR(CDCl.sub.3) .delta.: 1.25 (d, 6H), 2.95 (dd, 1H), 3.77 (q, 1H, CH), 3.86 (dd, 1H, CH), 4.15 (m, 1H, CH), 5.38 (s, 2H, CH.sub.2), 7.55 and 8.30 (d, 2H, .O slashed.)
Reference Example 8
0.4 g of the compound prepared in Reference Example 7 was added to 20 ml of the mixed solvent of anhydrous ethyl acetate and anhydrous hexane and the resulting mixture was heated for one hour under reflux. A catalytic amount of rhodium acetate was added thereto under warming. The reaction mixture was stirred under reflux for one hour and then filtered with diatomaceous earth to remove the solvent to obtain 380 mg of the desired product p-nitrobenzyl-(1R,5S,6S)-2-keto-6-�(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate.
.sup.1 H NMR(CDCl.sub.3) .delta.: 1.23 (d, 3H, .beta.-methyl), 1.40 (d, 3H, CH.sub.3 CHOH), 2.86 (q, 1H, CH), 3.30 (dd, 1H, CH), 4.30 (dd, 1H, CH), 4.36 (q, 1H, CH), 4.78 (s, 1H, CH), 5.28 and 5.42 (ABq, 2H, CH.sub.2), 7.58 and 8.30 (d, 2H, .O slashed.)
Reference Example 9
13.2 g of trans-4-hydroxy-L-proline was dissolved in 111 ml of 2N-sodium hydroxide solution, and 23.76 g of p-nitrobenzyloxycarbonylchloroformate dissolved in 20 ml of methylene chloride was added thereto while stirring under ice-cooling and the mixture was stirred for 2 hours at the same temperature. Then 50 ml of 2N-sodium hydroxide was added to the mixture to separate the layers. The organic layer was removed, and 18.5 g of concentrated sulfuric acid was added to the aqueous layer to precipitate the product. The resulting product was filtered, washed with distilled water and dried to obtain the desired product trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline in the yield of 83%.
Melting Point: 132.degree.-135.degree. C. IR(Nujol)cm.sup.-1 : 3300, 1738, 1660, 1665, 1520
Reference Example 10
120 g of the compound prepared in Reference Example 9 was dissolved in 50 ml of methanol and the resulting solution was added dropwise to 50 ml of tetrahydrofuran. To this mixture was added dropwise 60 ml of ethyl ether solution of diazomethane under nitrogen atmosphere while stirring with ice-cooling and the whole mixture was stirred for 20 hours. The reaction solution was concentrated under reduced pressure to obtain the desired product trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline methyl ester in the yield of 70%.
IR(Neat)cm.sup.-1 : 1748, 1695, 1518, 1438, 1360, 1250, 1175
Reference Example 11
5.18 g of the compound prepared in Reference Example 10, 3.79 g of trimethylamine and 3.77 g of t-butyldimethylsilyl chloride were dissolved in 50 ml of anhydrous dimethylformamide and the resulting solution was stirred for 3 hours at room temperature, diluted with distilled water and then extracted with ethyl acetate. The organic layer was separated and washed successively with distilled water, 1.0N-hydrochloric acid solution and saline, dried and concentrated under reduced pressure to obtain the desired product trans-1-�(p-nitrobenzyloxycarbonyl)-4-(4-(t-butyldi-methylsilyloxy)!-L-proline methyl ester in the yield of 68%.
�.alpha.!.sub.D.sup.19 =-36.20.degree. (C=1.00 CHCl.sub.3) IR(Neat)cm.sup.-1 : 1750, 1710, 1517, 1415, 1355, 1250, 1115 NMR(CDCl.sub.3) .delta.: 0.08 (9H,s), 1.8-2.4 (2H,m), 3.3-3.8 (2H,m), 3.63 (3H,s), 3.72 (3H,s), 5.20 (1H, J=14 Hz), 5.23 (1H,s), 7.42 (2H, d, J=9 Hz), 8.15 (2H, d, J=9 Hz)
Reference Example 12
5.64 g of the compound prepared in Reference Example 11 was dissolved in 60 ml of anhydrous tetrahydrofuran and 1.0 g of sodium borohydride and 3.52 g of calcium chloride were added to the resulting solution. The reaction solution was refluxed under heating for one hour and diluted with distilled water and then extracted with ethyl acetate. The organic layer was separated, washed with distilled water and saline, dried and concentrated under reduced pressure to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(hydroxymethyl)-4-(t-butyldimethylsilyloxy))pyrrolidine in the yield of 75%.
�.alpha.!.sub.D.sup.19 =-40.10.degree. (C=1.00 CHCl.sub.3) IR(Neat)cm.sup.-1 : 1670, 1504, 1420, 1405, 1240, 1100 NMR(CDCl.sub.3) .delta.: 0.07 (6H,s), 0.87 (9H,s), 1.4-2.1 (2H,m), 3.38-3.84 (4H,m), 3.9-4.5 (2H,m), 5.22 (2H,s), 7.47 (2H, d, J=9 Hz), 8.17 (2H, d, J=9 Hz)
Reference Example 13
32.6 g of the compound prepared in Reference Example 12 was dissolved in 64 ml of anhydrous pyridine and 28 g of p-toluenesulfonyl chloride was added to the resulting solution and then the mixture was stirred for 12 hours at room temperature. The reaction solution was diluted with distilled water and then extracted with ethyl acetate. The organic layer was separated, washed with saline, 1.0N hydrochloric acid solution and distilled water, dried and concentrated under reduced pressure to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(p-toluenesulfonyloxymethyl)-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 75%.
IR(Neat)cm.sup.-1 : 1700, 1518, 1342, 1265, 1172, 1090
Reference Example 14
35.8 g of the compound prepared in Reference Example 13 and 19 g of sodium iodide were added to 90 ml of methylethylketone and the mixture was refluxed under heating. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with each of distilled water and saline, dried and concentrated under reduced pressure to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(iodomethyl)-4-(t-butyldimethylsilyloxy)!-pyrrolidine in the yield of 70%.
Melting Point: 88.degree.-92.degree. C. IR(Neat)cm.sup.-1 : 1700, 1512, 1405, 1353, 1248 NMR(CDCl.sub.3) .delta.: 0.07 (6H,s), 0.87 (9H,s), 1.4-2.5 (2H,m), 3.1-3.8 (4H,m), 3.95-4.38 (2H,m), 5.22 (2H,s), 7.5-8.3 (4H, d, J=9 Hz)
Reference Example 15-A
5 g of the compound prepared in Reference Example 14 was dissolved in 50 ml of dimethylformamide, and then 2 g of 3-mercaptopropionate ethyl ester, 1.7 g of calcium iodide and 1.7 g of triethylamine were added to the resulting solution while stirring. The reaction mexture was warmed to 60.degree. C. to 70.degree. C. and allowed to react for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed several times with distilled water and then washed with 1N hydrochloric acid solution and saline, dried and concentrated under reduced pressure to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(ethyloxycarbonylethylthiomethyl)-4-(t-butyldimethylsilyloxy) !pyrrolidine in the yield of 60%.
IR(Neat)cm.sup.-1 : 1745, 1705, 1695, 1510, 1405, 1342 NMR(CDCl.sub.3) .delta.: 0.07 (6H,s), 0.9 (9H,s), 1.55-2.5 (4H,m), 3.0 (3H,s), 3.15-3.8 (4H,m), 3.95-4.25 (4H, m), 5.22 (2H,s), 7.25-8.35 (9H, d, J=9 Hz)
Reference Example 15-B
11 g of the compound prepared in Reference Example 15-A was dissolved in 20 ml of methanol, and 30 ml of 2N-sodium hydroxide solution was added to the resulting solution while stirring under ice-cooling. The reaction mixture was stirred for 30 minutes, adjusted to neutral pH value by adding 1N-acetic acid and then evaporated under reduced pressure to remove the solvent. The residue was extracted with ethyl acetate. The extract was dried, concentrated under reduced pressure and then subjected to column chromatography to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(hydroxycarbonylethylthiomethyl)-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 85%.
IR(Neat)cm.sup.-1 : 3500, 1725, 1690, 1425, 1350 NMR(CDCl.sub.3) .delta.: 0.08 (6H,s), 0.87 (9H,s), 1.45-2.20 (4H,m), 3.10-3.50 (4H,m), 5.22 (2H,s), 7.25-8.5 (4H, d, J=8 Hz)
Reference Example 15-C
4 g of the compound prepared in Reference Example 15-B was dissolved in 40 ml of anhydrous acetonitrile and 1.56 g of carbonyldiimidazole was added to the resulting solution under ice-cooling. The mixture was stirred for 30 minutes and 2.7 g of triethylamine and 1.06 g of glycinamide hydrochloride were added thereto. The whole mixture was stirred for 2 hours under ice-cooling and then for one hour at room temperature. The reaction solution was diluted with ethyl acetate, washed successively with distilled water, 1N-hydrochloric acid solution, 5% sodium bicarbonate solution and saline, dried and then concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexane (1:1) to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(carbamoylmethylcarbamoylethylthiomethyl)-4-(t-butyldimethylsilyloxy)!-pyrrolidine in the yield of 65%.
IR(Neat)cm.sup.-1 : 1725, 1710, 1695, 1515, 1420, 1325 NMR(CDCl.sub.3) .delta.: 0.07 (6H,s), 0.8 (9H,s), 1.25-1.45 (2H,m), 2.25-2.50 (4H,m), 3.95-4.25 (2H,m), 5.25 (2H,s), 7.5-8.5 (4H, d, J=8 Hz)
Reference Example 15-D
2.93 g of the compound prepared in Reference Example 15-C was dissolved in 15 ml of methanol and 2 ml of 6N-hydrochloric acid solution was added to the resulting solution while stirring under ice-cooling. The mixture was stirred for 2 hours at the same temperature. The reaction solution was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was dried and then concentrated under reduced pressure to remove the solvent. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexane (3:1) to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(carbamoylmethylcarbamoylethylthiomethyl)-4-(hydroxy)!pyrrolidine in the yield of 93.3%.
IR(Neat)cm.sup.-1 : 3600, 1720, 1700, 1690, 1510, 1420 NMR(CDCl.sub.3) .delta.: 1.80-2.18 (2H,m), 2.65-3.05 (2H,m), 3.09 (2H,s), 3.30-3.35 (2H,m), 3.85-4.50 (2H,m), 4.96-5.24 (2H, d, J=8 Hz), 7.66-8.26 (4H, d, J=8 Hz)
Reference Example 15-E
2.17 g of the compound prepared in Reference Example 15-D was dissolved in 30 ml of anhydrous dichloromethane and 0.59 of methanesulfonyl chloride and 0.71 g of triethylamine were added to the resulting solution while stirring under ice-cooling. Then, the mixture was stirred for 2 hours at the same temperature. The reaction solution was then washed with distilled water, 1N hydrochloric acid solution and saline, dried and concentrated under reduced pressure to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(carbamoylmethylcarbamoylethylthiomethyl)-4-(mesyloxy)!pyrrolidine in the yield of 66.1%.
IR(Neat)cm.sup.-1 : 1710, 1700, 1690, 1510, 1435, 1350, 1050 NMR(CDCl.sub.3) .delta.: 2.05-2.60 (3H,m), 3.03 (3H,s), 5.25 (2H,s), 7.53 (2H, d, J=8 Hz), 8.25 (2H, d, J=8 Hz)
Reference Example 15-F
To 20 ml of dimethylformamide were added 2 g of the compound prepared in Reference Example 15-E and 0.57 g of potassium thioacetate and then the reaction mixture was stirred for 4 hours at 70.degree. to 80.degree. C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and then washed several times with distilled water, dried and concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(carbamoylmethylcarbamoylethylthiomethyl)-4-(acetylthio)!pyrrolidine in the yield of 65.2%.
IR(Neat)cm.sup.-1 : 1725, 1710, 1690, 1510, 1420, 1350 NMR(CDCl.sub.3) .delta.: 2.40-3.15 (4H,m), 3.25 (3H,s), 3.75-4.50 (4H,m), 5.23 (2H,s), 7.25-8.23 (4H, d, J=8 Hz)
Reference Example 15-G
1.5 g of the compound prepared in Reference Example 15-F was dissolved in 15 ml of methanol and 0.2 g of sodium methoxide was added to the resulting solution while stirring under ice-cooling. The mixture was stirred for 15 minutes at the same temperature. The reaction mixture was added to acetic acid to neutralize and then concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was dried and then concentrated under reduced pressure to obtain the desired product (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-(carbamoylmethylcarbamoylethylthiomethyl)-4-mercaptopyrrolidine in the yield of 85.2%.
IR(Neat)cm.sup.-1 : 1710, 1690, 1510, 1425 NMR(CDCl.sub.3) .delta.: 1.75-1.95 (3H,m), 2.45-2.85 (2H,m), 2.90-3.15 (2H,m), 3.21 (2H,s), 3.25-4.30 (4H,m), 5.24 (2H,s), 7.55-8.27 (4H, d, J=8 Hz)
Reference Example 16-A
The reaction was carried out in the same manner as that of Reference Example 15-A, using 7 g of the compound prepared in Reference Example 14, 1.8 ml of ethylthioglyconate, 2.7 g of calcium iodide and 2.1 ml of triethylamine to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(ethyloxycarbonylmethylthiomethyl)-4-(t-butyldimethylsilyloxy)!-pyrrolidine in the yield of 75%.
IR(Neat)cm.sup.-1 : 1745, 1700, 1690, 1515, 1410 NMR(CDCl.sub.3) .delta.: 0.07 (6H,s), 0.9 (9H,s), 1.50-1.98 (2H,m), 2.02-2.25 (2H,m), 3.0 (3H,s), 3.15-3.8 (2H, m), 3.95-4.25 (4H,m), 5.22 (2H,s), 7.25-8.35 (4H, d, J=8 Hz)
Reference Example 16-B
3 g of the compound prepared in Reference Example 16-A was treated in the same manner as that of Reference Example 15-B to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(hydroxycarbonylmethylthiomethyl)-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 60%.
IR(Neat)cm.sup.-1 : 3600, 1720, 1695, 1520, 1420 NMR(CDCl.sub.3) .delta.: 0.08 (6H,m), 0.85 (9H,s), 1.45-2.20 (2H,m), 3.10-3.45 (4H,m), 5.22 (2H,s), 7.25-8.5 (4H, d, J=8 Hz)
Reference Example 16-C
5 g of the compound prepared in Reference Example 16-B was dissolved in 30 ml of anhydrous acetonitrile solution and 2 g of carbonyldiimidazole was added to the resulting solution while stirring under ice-cooling. After stirring the mixture, 3.0 g of triethylamine and 1.5 g of glycinamide hydrochloride were successively added thereto and the reaction mixture was then treated in the same manner as that of Reference Example 15-C to obtain the desired product (2S, 4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(carbamoylmethylcarbamoylmethylthiomethyl)-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 80%.
IR(Neat)cm.sup.-1 : 1720, 1705, 1695, 1570 NMR(CDCl.sub.3) .delta.: 0.06 (6H; s), 0.86 (9H,s), 1.88-2.22 (2H,m), 3.22 (2H,s), 5.25 (2H,s), 7.53 (2H, d, J=8 Hz), 8.25 (2H, d, J=8 Hz)
Reference Example 16-D
3.2 g of the compound prepared in Reference Example 16-B was treated in the same manner as that of Reference Example 15-C to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(carbamoylmethylcarbamoylmethylthiomethyl)-4-(hydroxy)!pyrrolidine in the yield of 85.2%.
IR(Neat)cm.sup.-1 : 3600, 1715, 1700, 1510, 1400 NMR(CDCl.sub.3) .delta.: 1.80-2.10 (2H,m), 2.65-3.05 (2H,m), 3.09 (2H, s), 3.30-3.55 (2H,m), 3.85-4.50 (2H,m), 4.95-5.24 (2H,s), 7.66-8.26 (4H, d, J=8 Hz)
Reference Example 16-E
2 g of the compound prepared in Reference Example 16-D was dissolved in 30 ml of anhydrous dichloromethane, and 0.75 g of triethylamine and 0.6 g of methanesulfonyl chloride were added to the resulting solution. Then, the reaction mixture was treated in the same manner as that of Reference Example 15-E to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(carbamoylmethylcarbamoylmethylthiomethyl)-4-(mesyloxy)!pyrrolidine in the yield of 72%.
IR(Neat)cm.sup.-1 : 1715, 1700, 1695, 1500, 1410, 1355 NMR(CDCl.sub.3) .delta.: 2.05-2.60 (3H,m), 3.03 (3H,s), 5.25 (2H,s), 7.53-8.25 (4H, d, J=8 Hz)
Reference Example 16-F
1.9 g of the compound prepared in Reference Example 16-E was added to 15 ml of dimethylformamide and 0.5 g of potassium thioacetate and the resulting mixture was treated in the same manner as that of Reference Example 15-E to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(carbamoylmethylcarbamoylmethylthiomethyl)-4-(acetylthio)!pyrrolidine in the yield of 57%.
IR(Neat)cm.sup.-1 : 1725, 1750, 1695, 1500 NMR(CDCl.sub.3) .delta.: 2.40-3.15 (4H,m), 3.21 (3H,s), 3.75-4.50 (5H, m), 5.23 (2H,s), 7.59-8.23 (4H, d, J=8 Hz)
Reference Example 16-G
2.0 g of the compound prepared in Reference Example 16-F was dissolved in 18 ml of methanol and 0.25 g of sodium methoxide was added to the resulting solution while stirring under ice-cooling. The reaction mixture was then treated in the same manner as that of Reference Example 15-G to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(carbamoylmethylcarbamoylmethylthiomethyl)-4-(mercapto)!pyrrolidine in the yield of 78%.
IR(Neat)cm.sup.-1 : 1710, 1695, 1520, 1425, 1350 NMR(CDCl.sub.3) .delta.: 1.75-1.95 (3H,m), 2.45-2.85 (2H,m), 2.90-3.15 (2H,m), 3.21 (2H,s), 3.25-3.50 (2H,m), 3.85-4.30 (2H,m), 5.24 (2H,s), 7.55-8.27 (4H, d, J=8 Hz)
Reference Example 17-A
4 g of the compound prepared in Reference Example 14 was dissolved in 40 ml of anhydrous acetonitrile and 1.56 g of carbonyldiimidazole was added to the resulting solution. After stirring the mixture for 30 minutes, 2.7 g of triethylamine and 2.3 g of aminoacetonitrile hydrochloride were added thereto and the whole mixture was stirred for 2 hours under ice-cooling and then one hour at room temperature. The reaction solution was diluted with ethyl acetate, washed successively with distilled water, 1N-hydrochloric acid solution, 5% sodium bicarbonate solution and saline, dried and then concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexane (2:1) to obtain the desired product (2S,4S)-(1-(p-nitrobenzyloxycarbonyl)-2-(cyanomethylcarbamoylethylthiomethyl)-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 65%.
IR(Neat)cm.sup.-1 : 2250, 1725-1710, 1690-1665 NMR(CDCl.sub.3) .delta.: 0.05 (6H,s), 0.86 (9H,s), 1.80-2.15 (4H,m), 5.25 (2H,s), 7.25-8.21 (4H, d, J=8 Hz)
Reference Example 17-B
3.5 g of the compound prepared in Reference Example 17-A was dissolved in 15 ml of methanol and 2 ml of 6N-hydrochloric acid solution was added to the resulting solution while stirring under ice-cooling. The reaction solution was stirred for 2 hours at the same temperature and concentrated under reduced pressure. The residue was extracted with ethyl acetate and the extract was dried and then concentrated under reduced pressure to remove the solvent. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexane (3:1) to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(cyanomethylcarbamoylethylthiomethyl)-4-(hydroxy)!pyrrolidine in the yield of 87.5%.
IR(Neat)cm.sup.-1 : 2250, 1710, 1695-1675, 1610, 1525 NMR(CDCl.sub.3) .delta.: 1.52-1.95 (2H,m), 2.75-3.50 (2H,m), 4.05-4.75 (4H,m), 5.23 (2H,s), 7.53-8.22 (4H, d, J=8 Hz)
Reference Example 17-C
2.78 g of the compound prepared in Reference Example 17-B was dissolved in 30 ml of anhydrous dichloromethane and 0.62 g of methanesulfonyl chloride and 1.4 g of triethylamine were added to the resulting solution while stirring under ice-cooling. The mixture was stirred for 2 hours at the same temperature. The reaction solution was washed with distilled water, 1N-hydrochloric acid solution and saline, dried and then concentrated under reduced pressure to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(cyanomethylcarbamoylethylthiomethyl)-4-(mesyloxy)!pyrrolidine in the yield of 72.5%.
IR(Neat)cm.sup.-1 : 2250, 1710, 1700, 1690, 1510, 1435, 1350, 1050 NMR(CDCl.sub.3) .delta.: 2.05-2.80 (4H,m), 3.03 (3H,m), 7.53-8.25 (4H, d, J=8 Hz)
Reference Example 17-D
2.8 g of the compound prepared in Reference Example 17-C was added to 20 ml of dimethylformamide and then 0.65 g of potassium thioacetate was added thereto. The reaction mixture was stirred for 4 hours at 70.degree. to 80.degree. C. and then cooled to room temperature, diluted with ethyl acetate, washed several times with distilled water, dried and concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(cyanomethylcarbamoylethylthiomethyl)-4-(acetylthio)!pyrrolidine in the yield of 73.5%.
NMR(CDCl.sub.3) .delta.: 1.75-2.40 (4H,m), 3.25-4.55 (6H,m), 7.85-8.10 (4H, d, J=8 Hz)
Reference Example 17-E
0.9 g of the compound prepared in Reference Example 17-D was dissolved in 15 ml of methanol, and 0.1 g of sodium methoxide was added to the resulting solution while stirring under ice-cooling. The reaction solution was stirred for 15 minutes at the same temperature, neutralized with acetic acid and then concentrated under reduced pressure. The residue was extracted with ethyl acetate and the extract was dried and concentrated under reduced pressure to obtain the desired product (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-(cyanomethylcarbamoylethylthiomethyl)-4-mercaptopyrrolidine in the yield of 63.8%.
IR(Neat)cm.sup.-1 : 1720-1690, 1605, 1530-1515 NMR(CDCl.sub.3) .delta.: 1.65-1.94 (3H,m), 2.45-2.85 (2H,m), 2.90-3.30 (4H,m), 3.25-3.50 (2H,m), 5.24 (2H,s), 7.55-8.24 (4H, d, J=8 Hz)
Reference Example 18-A
6 g of the compound prepared in Reference Example 14 was dissolved in 40 ml of anhydrous acetonitrile and 2.5 g of carbonyldiimidazole was added to the resulting solution while stirring under ice-cooling. After stirring the mixture, 3.5 g of triethylamine and 2.1 g of aminoacetonitrile hydrochloride were successively added thereto. Then, the subsequent reaction was carried out in the same manner as that of Reference Example 15-C to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(cyanomethylcarbamoylmethylthiomethyl)-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 88.5%.
IR(Neat)cm.sup.-1 : 2250, 1735-1710, 1695-1665, 1610 NMR(CDCl.sub.3) .delta.: 0.06 (6H,s), 0.85 (9H,s), 1.75-2.10 (4H,m), 5.25 (2H,s), 7.30-8.56 (4H, d, J=8 Hz)
Reference Example 18-B
2.5 g of the compound prepared in Reference Example 18-A was treated in the same manner as that of Reference Example 15-D to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(cyanomethylcarbamoylmethylthiomethyl)-4-(hydroxy)!pyrrolidine in the yield of 90.8%.
IR(Neat)cm.sup.-1 : 2250, 1745-1710, 1690-1675 NMR(CDCl.sub.3) .delta.: 1.75-2.25 (2H,m), 2.55-3.10 (2H,m), 3.90 (2H,s), 3.30-3.45 (3H,m), 4.95-5.24 (2H,s), 7.66-8.25 (4H, d, J=8 Hz)
Reference Example 18-C
2.5 g of the compound prepared in Reference Example 18-B was dissolved in 30 ml of anhydrous dichloromethane and 0.8 g of methanesulfonyl chloride and 1.0 g of triethylamine were added to the resulting solution while stirring under ice-cooling. The resulting reaction mixture was treated in the same manner as that of Reference Example 15-E to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(cyanomethylcarbamoylmethylthiomethyl)-4-(mesyloxy)!pyrrolidine in the yield of 72%.
IR(Neat)cm.sup.-1 : 2250, 1725-1690, 1660, 1610 NMR(CDCl.sub.3) .delta.: 2.10-2.45 (3H,m), 3.03 (3H,s), 5.25 (2H,s), 7.53-8.25 (4H, d, J=8 Hz)
Reference Example 18-D
2.5 g of the compound prepared in Reference Example 18-C was added to 15 ml of dimethylformamide and 0.8 g of potassium thioacetate and then the reaction mixture was treated in the same manner as that of Reference Example 15-E to obtain the desired product (2S,4S)-(1-(p-nitrobenzyloxycarbonyl)-2-(cyanomethylcarbamoylmethylthiomethyl)-4-(acetylthio)!pyrrolidine in the yield of 63.5%.
IR(Neat)cm.sup.-1 : 2250, 1725, 1750, 1695, 1500 NMR(CDCl.sub.3) .delta.: 2.15-3.00 (4H,m), 3.2 (3H,s), 3.75-4.50 (5H,m), 5.23 (2H,s), 7.59-8.23 (4H, d, J=8 Hz)
Reference Example 18-E
1.8 g of the compound prepared in Reference Example 18-D was dissolved in 18 ml of methanol, and 0.25 g of sodium methoxide was added to the resulting solution while stirring under ice-cooling. The reaction mixture was treated in the same manner as that of Reference Example 15-G to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(cyanomethylcarbamoylmethylthiomethyl)-4-(mercapto)!pyrrolidine in the yield of 65.8%.
IR(Neat)cm.sup.-1 : 2250, 1735-1710, 1695-1675, 1610 NMR(CDCl.sub.3) .delta.: 1.65-1.75 (3H,m), 2.45-2.85 (2H,m), 2.90-3.30 (5H,m), 3.50 (2H,m), 5.24 (2H,s), 7.55-8.27 (4H, d, J=8 Hz)
Reference Example 19-A
52 g of the compound prepared in Reference Example 14 and 18.3 g of potassium thioacetate were added to 50 ml of dimethylformamide and the mixture was warmed to 60.degree. to 75.degree. C. and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with distilled water and extracted with ethyl acetate. The organic layer was washed with distilled water, saline and 5% sodium bicarbonate solution, dried and concentrated under reduced pressure to obtain the desired product (2S,45)-�1-(p-nitrobenzyloxycarbonyl)-2-(acetylthiomethyl)-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 55%.
IR(Neat)cm.sup.-1 : 1710-1700, 1610, 1530 NMR(CDCl.sub.3) .delta.: 0.06 (6H,s), 1.84 (9H,s), 2.35 (3H,s), 5.26(2H,s), 7.54-8.22 (4H, d, J=8 Hz)
Reference Example 19-B
5 g of the compound prepared in Reference Example 19-A was dissolved in 10 ml of methanol and 2 ml of 28% sodium methoxide was added to the resulting solution while stirring under ice-cooling. The mixture was stirred for 15 minutes under nitrogen atmosphere and then 1 g of 2-iodoethanol dissolved in 10 ml of methanol was added dropwise thereto at the same temperature. The reaction mixture was stirred for 4 hours at the same temperature and concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate, washed with distilled water, dried and then concentrated under reduced pressure to remove the solvent to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(hydroxyethylthiomethyl)-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 50%.
IR(Neat)cm.sup.-1 : 1710, 1690-1675, 1610, 1525 NMR(CDCl.sub.3) .delta.: 0.06 (6H,s), 0.86 (9H,s), 1.88-2.22 (2H,m), 3.22 (2H,s), 5.25 (2H,s), 7.53-8.29 (4H, d, J=8 Hz)
Reference Example 19-C
850 mg of the compound prepared in Reference Example 19-B and 1 ml of 6N-hydrochloric acid solution were added to 8 ml of methanol and the mixture was stirred for one hour, diluted with ethyl acetate, washed with distilled water, dried and then concentrated under reduced pressure. The residue was purified with column chromatography to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(acetoxyethylthiomethyl)-4-(hydroxy)!pyrrolidine in the yield of 70%.
IR(CHC.sub.1.sub.3)cm.sup.-1 : 1710, 1610, 1525 NMR(DMSO-d.sub.6) .delta.: 1.80-2.15 (2H,m), 2.65-3.05 (2H,m), 3.09 (2H,s), 3.30-3.55 (2H,m), 5.24 (2H,s), 7.66-8.26 (2H, d, J=8 Hz)
Reference Example 19-D
1.5 g of the compound prepared in Reference Example 19-C, 2.2 g of triphenylphosphine and 5 g of diethylazodicarboxylate were respectively added to 20 ml of anhydrous tetrahydrofuran solution, and the mixture was stirred for 2 hours under ice-cooling. 1.2 g of thiolacetic acid was added to the reaction mixture at the same temperature and the mixture was stirred for 2 hours. The reaction solution was increased to room temperature and then stirred for 20 hours, evaporated under reduced pressure, diluted with ethyl acetate, washed with distilled water, dried and then concentrated under reduced pressure. The residue was purified with column chromatography to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(acetoxyethylthiomethyl)-4-(acetylthio)!pyrrolidine in the yield of 70%.
IR(Neat)cm.sup.-1 : 1745, 1710, 1600, 1510, 1398, 1360, 1098 NMR(CDCl.sub.3) .delta.: 1.75-1.95 (3H,m), 2.45-2.85 (1H,m), 2.90-3.15 (2H,m), 3.21 (2H,s), 3.25-3.50 (2H,m), 3.58-4.30 (2H,m), 5.24 (2H,s), 7.55-8.27 (4H, d, J=8 Hz)
Reference Example 20-A
5 g of the compound prepared in Reference Example 19-A was dissolved in 10 ml of methanol, and 2 ml of 28% sodium methoxide was added to the resulting solution under ice-cooling. The mixture was stirred for 15 minutes under nitrogen atmosphere. To this mixture was added 1 g of 2-iodoethanol dissolved in 10 ml of methanol at the same temperature. The reaction mixture was stirred for 4 hours at the same temperature and concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate, washed with distilled water, dried and concentrated under reduced pressure to remove the solvent to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(hydroxyethylthiomethyl)-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 50%.
IR(Neat)cm.sup.-1 : 3600, 1740, 1690, 1523, 1400, 1345 NMR(CDCl.sub.3) .delta.: 0.06 (6H,s), 0.86 (9H,s), 1.51-2.1 (2H,m), 2.4-2.9 (2H,m), 3.22 (2H,s), 5.25 (2H,s), 7.53-8.25 (4H, d, J=8 Hz)
Reference Example 20-B
1.5 g of the compound prepared in Reference Example 20-A was dissolved in 15 ml of anhydrous pyridine and 0.8 ml of acetic anhydride and 0.3 g of dimethylaminopyridine were added to the resulting solution. The mixture was stirred for one hour at room temperature, diluted with ethyl acetate, washed with distilled water and then concentrated under reduced pressure. The residue was purified with column chromatography to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(acetoxyethylthiomethyl)-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 70%.
IR(Neat)cm.sup.-1 : 1740, 1725-1710, 1690, 1610 NMR(CDCl.sub.3) .delta.: 0.06 (6H,s), 0.8 (9H,s), 1.52-1.95 (2H,m), 2.4-2.65 (2H,m), 3.15-3.35 (3H,s), 5.25 (2H,s), 7.53-8.25 (4H, d, J=8 Hz)
Reference Example 20-C
850 mg of the compound prepared in Reference Example 20-B and 1 ml of 6N-hydrochloric acid solution were added to 8 ml of methanol. The reaction mixture was stirred for one hour at room temperature, diluted with 20 ml of ethyl acetate, washed with distilled water, dried and concentrated under reduced pressure. The residue was purified with column chromatography to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(acetoxyethylthiomethyl)-4-(hydroxy)!pyrrolidine in the yield of 70%.
IR(Neat)cm.sup.-1 : 3600, 1720, 1680, 1510, 1410, 1342, 1225 NMR(CDCl.sub.3) .delta.: 1.52-1.95 (2H,m), 2.75-2.95 (2H,m), 3.35 (3H,s), 4.05-4.75 (2H,m), 5.25 (2H,s), 7.53-8.22 (4H, d, J=8 Hz)
Reference Example 20-D
1.5 g of the compound prepared in Reference Example 20-C, 2.2 g of triphenylphosphine and 5 g of diethylazodicarboxylate were added to 20 ml of anhydrous tetrahydrofuran solution. The mixture was stirred for 2 hours under ice-cooling, and 1.2 g of thiolacetic acid was added thereto at the same temperature. The reaction mixture was increased to room temperature and then stirred for 20 hours, evaporated under reduced pressure, diluted with ethyl acetate, washed with distilled water and then concentrated under reduced pressure. The residue was purified with column chromatography to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-(acetoxyethylthiomethyl)-4-(acetylthio)!-pyrrolidine in the yield of 70%.
IR(Neat)cm.sup.-1 : 1745, 1710, 1600, 1510, 1398, 1360, 1098
Reference Example 20-E
300 mg of the compound prepared in Reference Example 20-D was dissolved in 5 ml of methanol and 2 ml of 1 N sodium hydroxide solution was added to the resulting solution. The mixture was stirred for 20 minutes in nitrogen atmosphere under ice-cooling and then 2 ml of 1N hydrochloric acid solution was added thereto. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with distilled water and saline, dried, and then concentrated under reduced pressure to obtain an oily residue. This oily residue was purified with column chromatography to obtain the desired product (2S,4S)-(1-(p-nitrobenzyloxycarbonyl)-2-(hydroxyethylthiomethyl)-4-(mercapto)!pyrrolidine in the yield of 46%.
IR(Neat)cm.sup.-1 : 3600, 1725, 1680, 1522, 1433, 1410, 1350 NMR(CDCl.sub.3) .delta.: 1.85-2.22 (2H,m), 2.65-3.05 (2H,m), 3.09 (2H,m), 3.30-3.55 (2H,m), 3.85-4.50 (2H,m), 5.24 (2H,s), 7.66-8.26 (4H, d, J=8 Hz)
Reference Example 21-A
4 g of the compound prepared in Reference Example 15-B was dissolved in 50 ml of anhydrous acetonitrile and 1.56 g of carbonyldiimidazole was added to the resulting solution under ice-cooling. The reaction mixture was stirred for 30 minutes and 2.5 g of triethylamine and 2 g of 4-aminoacetyloxyethylpiperazine were added thereto. The whole mixture was stirred for 2 hours under ice-cooling and then for 4 hours at room temperature to complete the reaction. The reaction solution was diluted with ethyl acetate, washed with distilled water, 1N-hydrochloric acid solution, 5% sodium bicarbonate solution and saline, dried and then concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexane (1:3) to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(acetyloxyethylpiperazinylcarbamoyl)ethylmercaptomethyl}-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 68%.
IR(Neat)cm.sup.-1 : 1740, 1710-1690, 1550 NMR(CDCl.sub.3) .delta.: 0.07 (6H,s), 0.8 (9H,s), 1.25-1.55 (4H,m), 2.10-2.50 (4H,m), 5.25 (2H,s), 7.5-8.5 (4H, d, J=8 Hz)
Reference Example 21-B
3.15 g of the compound prepared in Reference Example 21-A was dissolved in 15 ml of methanol, and 1.5 ml of 6N-hydrochloric acid solution was added to the resulting solution while stirring under ice-cooling. The reaction solution was stirred for 2 hours at the same temperature and then concentrated under reduced pressure. The residue was extracted with ethyl acetate, dried and then concentrated under reduced pressure to remove the solvent. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexan (3:1) to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(acetyloxyethylpiperazinyl)carbamoylethylthiomethyl}-4-(hydroxy)!pyrrolidine in the yield of 87.2%.
IR(Neat)cm.sup.-1 : 3600, 1720, 1690, 1420 NMR(CDCl.sub.3) .delta.: 1.80-2.10 (2H,m), 2.65-3.05 (4H,m), 3.90 (2H,s), 3.30-3.35 (2H,m), 4.96-5.29 (2H, d, J=8 Hz), 7.66-8.26 (4H, d, J=8 Hz)
Reference Example 21-C
1.85 g of the compound prepared in Reference Example 21-B was dissolved in 30 ml of anhydrous dichloromethane, and 0.45 g of methanesulfonyl chloride and 0.62 g of triethylamine were added to the resulting solution. The reaction solution was stirred for 2 hours at the same temperature, washed with distilled water, 1N-hydrochloric acid solution and saline, dried and then concentrated under reduced pressure to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(acetyloxypiperazinylcarbamoyl)ethylthiomethyl}-4-(mesyloxy)!pyrrolidine in the yield of 68.5%.
IR(Neat)cm.sup.-1 : 1745, 1710-1695, 1610, 1580 NMR(CDCl.sub.3) .delta.: 2.10-2.55 (4H,m), 3.30-3.33 (3H,m), 5.25 (2H,s), 7.58 (2H, d, J=8 Hz), 8.25 (2H, d, J=8 Hz)
Reference Example 21-D
2 g of the compound prepared in Reference Example 21-C was added to 20 ml of dimethylformamide, and 0.57 g of potassium thioacetate was added thereto. The reaction mixture 4was stirred for 4 hours at 70.degree. to 80.degree. C. and then cooled to room temperature. Then, the mixture was diluted with ethyl acetate, washed several times with distilled water, dried and then concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate to obtain the desired product (2S,4S)-�1-(p-nitrobenzyl-oxycarbonyl)-2-{(acetyloxyethylpiperazinyl)carbamoylethylthiomethyl}-4-(acetylthio)!pyrrolidine in the yield of 65.2%.
IR(Neat)cm.sup.-1 : 1725, 1710, 1690, 1510, 1420, 1350 NMR(CDCl.sub.3) .delta.: 2.55-3.15 (4H,m), 3.25-3.35 (3H,m), 3.75-4.50 (4H,m), 5.23 (2H,s), 7.25-8.55 (4H, d, J=8 Hz)
Reference Example 21-E
2.0 g of the compound prepared in Reference Example 21-D wad dissolved in 15 ml of methanol, and 0.21 g of sodium methoxide was added to the resulting solution while stirring under ice-cooling. The mixture was stirred for 15 minutes at the same temperature and then neutralized with acetic acid. The reaction solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate, dried and concentrated under reduced pressure to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-�(hydroxyethylpiperazinylcarbamoyl)ethylthiomethyl!-4-mercaptopyrrolidine in the yield of 70.1%.
IR(Neat)cm.sup.-1 : 1740, 1690, 1550 NMR(CDCl.sub.3) .delta.: 1.75-1.88 (3H,m), 2.45-2.85 (2H,m), 2.90-3.15 (2H,m), 3.21 (2H,s), 3.25-4.30 (4H,m), 5.24 (2H,s), 7.55-8.27 (4H, d, J=8 Hz)
Reference Example 22-A
3.5 g of the compound prepared in Reference Example 15-B was dissolved in 50 ml of anhydrous acetonitrile, and 1.8 g of carbonyldiimidazole was added to the resulting solution under ice-cooling. The mixture was stirred for 30 minutes and then 21 g of triethylamine and 2.5 g of glycinamide hydrochloride were added thereto. The reaction mixture was stirred for 2 hours under ice-cooling and then 11 hours at room temperature. The reaction solution was diluted with ethyl acetate, washed with distilled water, 1N-hydrochloric acid solution, 5% sodium bicarbonate solution and saline, respectively, dried and then concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate: n-hexane (10:1) to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(hydroxycarbonylmethylcarbamoyl)methylcarbamoylethylthiomethyl}-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 65%.
IR(Neat)cm.sup.-1 : 2250, 1725-1710, 1690-1665 NMR(CDCl.sub.3) .delta.: 0.07 (6H,s), 0.09 (9H,s), 1.27-1.31 (4H,m), 2.25-2.60 (4H,m), 3.95-4.45 (2H,m), 5.25 (2H,s), 7.5-8.25 (4H, d, J=8 Hz)
Reference Example 22-B
4.2 g of the compound prepared in Reference Example 22-A was dissolved in 50 ml of anhydrous acetonitrile solution, and 2.5 g of carbonyldiimidazole was added to the resulting solution under ice-cooling. The mixture was stirred for 30 minutes. To this mixture were added 21 g of triethylamine and 2.06 g of 4-aminohydroxyethylpiperazine, and the whole mixture was stirred for 2 hours under ice-cooling and then 10 hours at room temperature. The reaction solution was diluted with ethyl acetate, washed with distilled water, 1N hydrochloric acid solution, 5% sodium bicarbonate solution and saline, respectively, dried and then concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate to obtain the desired product (2S,4S)-(1-(p-nitrobenzyloxycarbonyl)-2-{(hydroxyethylpiperazinylcarbamoylmethylcarbamoyl)ethylthiomethyl}-4-(t-butyldimethylsilyloxy)!pyrrolidine in the yield of 52%.
IR(Neat)cm.sup.-1 : 1730, 1710, 1680, 1510 NMR(CDCl.sub.3) .delta.: 0.07 (6H,s), 0.09 (9H,s), 1.25-1.65 (4H,m), 2.25-2.45 (4H,m), 3. 01-3.75 (4H,m), 4.15-4.25 (2H,m), 5.25 (2H,s), 7.55-8.52 (4H, d, J=8 Hz)
Reference Example 22-C
To 10 ml of acetic anhydride were added 2.6 g of the compound prepared in Reference Example 22-B and 2.5 g of triethylamine and the mixture was stirred for 5 hours under reflux. The reaction solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1N-hydrochloric acid solution, 5% sodium bicarbonate solution and distilled water, dried and then distilled under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(acetyloxyethylpiperazinylcarbamoylmethylcarbamoyl)ethylthiomethyl}-4-(hydroxy)!pyrrolidine in the yield of 78.2%.
IR(Neat)cm.sup.-1 : 1725, 1710-1690, 1610, 1580 NMR(CDCl.sub.3) .delta.: 0.07 (6H,s), 0.09 (9H,s), 1.25-1.30 (2H,m), 1.85-2.20 (6H,m), 4.15-4.50 (4H,m), 3.77-3.90 (2H,m), 4.55-4.50 (2H,m), 5.24 (2H, d, J=6 Hz), 7.65-8.25 (4H, d, J=8 Hz)
Reference Example 22-D
2.55 g of the compound prepared in Reference Example 22-C was dissolved in 30 ml of anhydrous dichloromethane, and 0.61 g of methanesulfonyl chloride and 0.71 g of triethylamine were added to the resulting solution while stirring under ice-cooling. The mixture was then stirred for 2 hours at the same temperature. The reaction solution was washed with distilled water, 1N hydrochloric acid solution and saline, dried and concentrated under reduced pressure to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(acetyloxypiperazinylcarbamoylmethylcarbamoyl)ethylthiomethyl}-4-(mesyloxy)!pyrrolidine in the yield of 80.5%.
IR(Neat)cm.sup.-1 : 1710, 1690, 1510 NMR(CDCl.sub.3) .delta.: 2.10-2.45 (6H,m), 3.03 (3H,m), 5.25 (2H,s), 7.53-8.24 (4H, d, J=8 Hz)
Reference Example 22-E
To 20 ml of dimethylformamide was added 1.5 g of the compound prepared in Reference Example 22-D and then 0.45 g of potassium thioacetate was added thereto. The reaction mixture was stirred for 4 hours at 70.degree. to 80.degree. C., cooled to room temperature, diluted with ethyl acetate, washed several times with distilled water, dried and then concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(acetyloxyethylpiperazinylcarbamoylmethylcarbamoyl)ethylthiomethyl}-4-(acetylthio)!pyrrolidine in the yield of 65.9%.
IR(Neat)cm.sup.-1 : 1725, 1690, 1420, 1350 NMR(CDCl.sub.3) .delta.: 2.15-3.00 (6H,m), 3.21 (2H,m), 3.75-4.50 (4H,m), 5.23 (2H,s), 7.59-8.23 (4H, d, J=8 Hz)
Reference Example 22-F
2.5 g of the compound prepared in Reference Example 22-E was dissolved in 18 ml of methanol, and 0.31 g of sodium methoxide was added to the resulting solution while stirring under ice-cooling. The reaction mixture was then treated in the same manner as that of Reference Example 15-G to obtain the desired product (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(hydroxyethylpiperazinylcarbamoylmethylcarbamoyl)ethylthiomethyl}-4-(mercapto)!pyrrolidine in the yield of 60.1%.
IR(Neat)cm.sup.-1 : 1710, 1695, 1520, 1425, 1350 NMR(CDCl.sub.3) .delta.: 1.65-1.75 (3H,m), 2.45-2.85 (4H,m), 2.90-3.30 (5H,m), 3.30 (2H,s), 5.24 (2H,s), 7.55-8.25 (4H, d, J=8 Hz)
Reference Example 23-A
10 g of (2S,4S)-�1-(p-nitrobenzyloxycarbonyl)-2-{(2-hydroxymethylcarbamoyl)ethylmercaptomethyl}-4-acetylthiopyrrolidine was dissolved in 30 ml of anhydrous ethyl acetate, and 5 ml of trichloroisocyanate was added dropwise to the resulting solution while stirring with ice-cooling under nitrogen atmosphere. The mixture was continuously stirred for 3 hours under ice-cooling. Then, the reaction solution was diluted with 50 ml of ethyl acetate, washed with aqueous sodium bicarbonate solution, distilled water and saline, respectively, and then dried. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexane (4:1) to obtain the desired product (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-{(2-trichloroacetylaminocarbonyloxymethylcarbamoly)ethymercaptomethyl}-4-acetylthiopyrrolidine in the yield of 52%.
IR(Neat)cm.sup.-1 : 1755-1750, 1725, 1680, 1600, 1400, 1335 NMR(CDCl.sub.3) .delta.: 1.70-1.95 (3H,m), 2.45-2.85 (1H,m), 2.90-3.15 (2H,m), 3.25-3.50 (2H,m), 5.24-5.27 (2H,s), 7.55-8.27 (4H, d, J=8 Hz)
Reference Example 23-B
800 mg of the compound prepared in Reference Example 23-A was dissolved in 5 ml of methanol, and 3 ml of 1N-sodium hydroxide solution was added dropwise to the resulting solution while stirring under ice-cooling. The reaction mixture was stirred for 20 minutes under nitrogen atmosphere, adjusted to the neutral pH value with 1N hydrochloric acid solution, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saline and distilled water, respectively, dried and then concentrated under reduced pressure to obtain an oily residue. The resulting oily residue was subjected to column chromatography eluting with ethyl acetate:n-hexane (5:1) to obtain the desired product (2S,4S)-(1-(p-nitrobenzyloxycarbonyl)-2-{(2-aminocarbonyloxymethylcarbamoyl)ethylmercaptomethyl}-4-mercaptopyrrolidine in the yield of 65%.
IR(Nujol)cm.sup.-1 : 1715, 1603, 1512, 1393, 1360 NMR(CDCl.sub.3) .delta.: 1.65-1.95 (3H,m), 2.45-2.95 (2H,m), 3.01-3.20 (3H,m), 3.25-3.50 (2H,m), 3.84-4.30 (2H,m), 5.24 (2H,s), 7.55-8.27 (4H, d, J=8 Hz)
Reference Example 24-A
To 21 ml of anhydrous N,N-dimethylformamide were added 2 g of (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-{(2-iodomethylcarbamoyl)ethylmercaptomethyl}-4-acetylthiopyrrolidine and 1.2 g of potassium phthalimide. The mixture was stirred for 6 hours at 90.degree. to 95.degree. C. The reaction solution was diluted with 50 ml of distilled water and then extracted three times with 50 ml of ethyl acetate in each time. The organic layers were combined, washed with saline and distilled water, respectively, dried and then concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexane (2:1) to obtain the desired product (2S,4R)-2-(p-nitrobenzyloxycarbonyl)-2-{(2-phthalimidoylmethylcarbamoyl)ethylmercaptomethyl}-4-acetylthiopyrrolidine in the yield of 72%.
IR(Neat)cm.sup.-1 : 1775, 1720, 1605, 1522, 1346, 1275 NMR(CDCl.sub.3) .delta.: 2.28 (3H,s), 2.77 (3H,s), 5.18 (2H,s), 7.46 (2H, d, J=8 Hz), 8.16 (2H, d, J=8 Hz)
Reference Example 24-B
To 20 ml of anhydrous ethanol were added 2.5 g of the compound prepared in Reference Example 24-A and 2.3 g of hydrazine hydrate. The reaction mixture was stirred for about one hour under reflux and then cooled to room temperature. The mixture was filtered to remove the insoluble solid materials and then the filtrate was concentrated. The residue was dissolved in 30 ml of anhydrous tetrahydrofuran, and 2.1 g of trichloroacetylisocyanate was added to the resulting solution while stirring under ice-cooling. The mixture was stirred for 3 hours and then evaporated under reduced pressure to remove the reaction solvent. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexan (3:1) to obtain the desired product (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-{(2-trichloroacetylaminocarbonylaminomethylcarbamoyl)ethylmercaptomethyl}-4-acetylthiopyrrolidine in the yield of 58%.
IR(Neat)cm.sup.-1 : 1710, 1600, 1517, 1440, 1270
Reference Example 24-C
860 mg of the compound prepared in Reference Example 24-B was dissolved in 10 ml of anhydrous methanol, and 1.48 ml of 1N-sodium hydroxide solution was added dropwise to the resulting solution while stirring under ice-cooling. The reaction mixture was stirred for 2 hours at room temperature, neutralized with 1.5 ml of 1N-hydrochloric acid solution, and then concentrated under reduced pressure. The residue was diluted with 60 ml of ethyl acetate, washed with distilled water and then concentrated again under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexane (1:1) to obtain the desired product (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-{(2-aminocarbonylaminomethylcarbamoyl)ethylmercaptomethyl}-4-mercaptopyrrolidine in the yield of 55%.
IR(Neat)cm.sup.-1 : 1710, 1665, 1590, 1510, 1425 NMR(CDCl.sub.3) .delta.: 1.75-1.95 (3H,m), 2.45-2.8 (1H,m), 2.90-3.15 (2H,m), 3.21 (2H,s), 3.25-3.50 (2H,m), 3.84-4.30 (2H,m), 5.24 (2H,m), 7.55-8.27 (4H,d,J=8 Hz)
Reference Example 25-A
To 25 ml of anhydrous ethanol was added 1.05 g of the compound prepared in Reference Example 24-A. Then, 15 ml of saturated ammonia-methanol solution in anhydrous methanol was added thereto. The reaction mixture was stirred for 8 hours under reflux and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saline and distilled water, respectively, and then concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexane (3:1) to obtain the desired product (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-{(2-aminomethylcarbamoyl)ethylmercaptomethyl}-4-acetylmercaptopyrrolidine in the yield of 82%.
IR(Neat)cm.sup.-1 : 1715, 1603, 1512, 1400-1390 NMR(CDCl.sub.3) .delta.: 2.28-2.68 (1H,m), 3.03-3.70 (8H,m), 3.80-4.24 (2H,m), 5.16 (2H,s), 7.49-8.17 (4H,d,J=8 Hz)
Reference Example 25-B
To 15 ml of anhydrous methylene chloride was added 610 mg of the compound prepared in Reference Example 25-A. While stirring under ice-cooling, 500 mg of p-nitrobenzyloxy carbonylchloroformate and 400 mg of triethylamine were added to the mixture. The reaction mixture was stirred for 2 hours and then diluted with 30 ml of methylene chloride, washed with 1N-hydrochloric acid solution, 10% sodium carbonate solution and distilled water, respectively, dried and then concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexane (4:1) to obtain the desired product (2S, 4R)-1-(p-nitrobenzyloxycarbonyl)-2-{(2-nitrobenzyloxycarbonylaminomethylcarbamoyl)ethylmercaptomethyl}-4-acetylthiopyrrolidine in the yield of 75%.
IR(Neat)cm.sup.-1 : 1760, 1715, 1690, 1550, 1480 NMR(CDCl.sub.3) .delta.: 2.40-3.10 (5H,m), 3.15-3.60 (2H,m), 5.15-5.35 (4H,m), 7.35-7.70 (7H,m), 7.75-8.15 (2H,m), 8.22 (4H, br. J=8 Hz)
Reference Example 25-C
710 mg of the compound prepared in Reference Example 25-B was dissolved in 10 ml of anhydrous methanol and this reaction mixture was treated in the same manner as that of Reference Example 24-C to obtain the desired product (2S, 4R)-1-(p-nitrobenzyloxycarbonyl)-2-{(4-nitrobenzyloxycarbonylaminomethylcarbamoyl)ethylmercaptomethyl}-4-mercaptopyrrolidine in the yield of 55%.
IR(Neat)cm.sup.-1 : 1710-1700, 1610, 1530-1520, 1350 NMR(CDCl.sub.3) .delta.: 1.60-2.00 (2H,m), 2.30-3.65 (8H,m), 3.80-4.35 (2H,m), 5.20 (4H,s), 7.50-7.55 (4H,d,J=8 Hz), 8.21 (4H,d,J=8 Hz)
Reference Example 26-A
1.3 g of (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-{(2-hydroxymethylcarbamoyl)ethylmercaptomethyl}-4-acetylthiopyrrolidine was added to 30 ml of anhydrous methylene chloride. To this reaction mixture were added 2 ml of a solution of diazomethane dissolved in ethyl ether and a catalytic amount of boron trifluoride-etherate complex while stirring under ice-cooling, and then the whole mixture was stirred for 30 minutes. The reaction solution was washed with saline and filtered to remove the insoluble solid materials. The filtrate was washed with aqueous sodium bicarbonate solution, saline and distilled water, respectively. The organic layer was separated and concentrated under reduced pressure. The residue was subjected to column chromatography eluting with ethyl acetate:n-hexane (10:1) to obtain the desired product (2S,4R)-1-�(p-nitrobenzyloxycarbonyl)-2-{(methoxymethylcarbamoyl)ethylmercaptomethyl}-4-acetylmercaptopyrrolidine in the yield of 62%.
IR(Neat)cm.sup.-1 : 1710, 1690, 1685, 1520, 1390 NMR(CDCl.sub.3) .delta.: 2.46-2.95 (2H,m), 3.15 (3H,s), 3.85-4.15 (3H,m) 5.16 (2H,s), 7.49-8.17 (4H, br. J=8 Hz)
Reference Example 26-B
910 mg of the compound prepared in Reference Example 26-A was added to 15 ml of anhydrous methanol, and the reaction mixture was treated in the same manner as that of Reference Example 24-C to obtain the desired product (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-{(methoxymethylcarbamoyl)ethylmercaptomethyl}-4-mercaptopyrrolidine in the yield of 50%.
IR(Neat)cm.sup.-1 : 1710-1700, 1690-1680, 1550-1540, 1390 NMR(CDCl.sub.3) .delta.: 1.60-2.05 (2H,m), 2.33-3.10 (2H,m), 3.15 (3H,s), 3.30-3.80 (5H,m), 3.85-4.33 (2H,m), 5.24 (2H,s), 7.56-8.26 (2H,d,J=8 Hz)

Number	Date	Country
1992/24838	Dec 1992	KRX
1993/09017	May 1993	KRX
1993/12009	Jun 1993	KRX

Number	Date	Country
0 182 213	May 1986	EPX
0 243 686	Nov 1987	EPX
0 280 771	Sep 1988	EPX
657 853	Aug 1982	CHX

2- (2-Substituted pyrrolidin-4-yl) thio-carbapenem derivatives

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