Claims
- 1. A method of preparing dehydropenicillins of the formula ##STR17## wherein X is an aminic group which may be substituted with at least one member selected from the group consisting of aralkyl and acyl and R is a carboxyl group or a salt, an amide, an ester, or thioester thereof comprising:
- (a) irradiating a compound of the formula ##STR18## or of the formula ##STR19## wherein R.sup.1 is selected from the group consisting of alkyl, aryl, and aralkyl and X and R are the same as defined above, in the presence of an inert gas and in an inert anhydrous oxygen-free solvent selected from aromatic solvents and acetonitrile at a temperature of from -10.degree. C. to 40.degree. C.; and
- (b) treating said irradiated compound with triethylamine in the presence of a halogen-substituted aliphatic solvent or an aromatic solvent at a temperature of -10.degree. C.+40.degree. C.
- 2. A method of preparing dehydropenicillins of the formula ##STR20## wherein X is an aminic group which may be substituted with at least one member selected from the group consisting of aralkyl and acyl and R is a carboxyl group or a salt, an amide, an ester, or thioester thereof comprising:
- (a) irradiating a compound of the formula ##STR21## wherein R.sup.1 is selected from the group consisting of alkyl, aryl, and aralkyl and X and R are the same as defined above, in the presence of an inert gas and in an inert anhydrous oxygen-free solvent selected from aromatic solvents and acetonitrile at a temperature of from -10.degree. C. to 40.degree. C.; and
- (b) treating said irradiated compound with a Bronsted or Lewis acid in the presence of an aliphatic or aromatic solvent.
- 3. The method of claim 2 wherein said Bronsted or Lewis acid is silica gel.
- 4. A method of preparing dehydropenicillins of the formula ##STR22## wherein X is an aminic group which may be substituted with at least one member selected from the group consisting of aralkyl and acyl and R is a carboxyl group or a salt, an amide, an ester, or thioester thereof comprising:
- (a) irradiating a compound of the formula ##STR23## wherein R.sup.1 is selected from the group consisting of alkyl, aryl, and aralkyl and X and R are the same as defined above, in the presence of an inert gas and in an inert anhydrous oxygen-free solvent selected from aromatic solvent and acetonitrile at a temperature of from -10.degree. C. to 40.degree. C.; and
- (b) heating said irradiated compound to a temperature between about 50.degree. and 150.degree. C. in the presence of an aliphatic or aromatic solvent.
- 5. The method of claim 1, 2 or 4 wherein R is selected from a carboxylic ester or thioester of an alkyl, aralkyl or aryl group and X is selected from benzylamino, triphenylmethylamino, phenylacetamido, phenoxyacetamido, or phthalimido.
- 6. The method of claim 1, 2 or 4 wherein said inert gas is nitrogen.
- 7. The method of claim 1 wherein said halogen substituted aliphatic solvent is methylene chloride.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 20451 A/76 |
Feb 1976 |
ITX |
|
Parent Case Info
This is a divisional application of Ser. No. 949,546 filed Oct. 10, 1978 now abandoned which is a divisional application of Ser. No. 769,527 filed Feb. 17, 1977 now U.S. Pat. No. 4,133,807 and which claims the priority of Italian Patent Application No. 20457 A/76 filed on Feb. 23, 1976.
This invention relates to 5,6-dehydropenicillins ("dehyd-ropenicillins") and to a method for their preparation.
Dehydropenicillins are a novel class of penicillin derivatives which are characterized by the presence of an unsaturation in the beta-lactamic ring structure and which belong to the class of the 2-azetine-4-ones of which only a few members were known heretofore no one of which was bicyclic.
The structure of the dehydropenicillins is illustrated by the general formula: ##STR1## in which X is an aminic group, also monosubstituted or disubstituted whereas R is a carboxyl group or a salt, an amide, an ester or a thioester thereof.
Specifically, the group R can be a carboxylic ester or thioester of an alkyl (for example methyl, ethyl, propyl, butyl), of an aralkyl (for example benzyl or substituted benzyl), of an aryl (for example phenyl or substituted phenyl) or a 2,2,2-trichloroethyl ester or thioester of a carboxylic acid.
The selection of an ester the clevage of which is carried out under blad conditions (for example a benzyl ester or a 2,2,2-trichloroethyl ester) should be preferred in the case in which it is desired to prepare from esters of the general formula (I) the corresponding free carboxylic acids from which, in their turn, it is possible to prepare other carboxyl derivatives with procedures which are within the purview of anyone skilled in the art.
Specifically, the group R can also be a mono- or dialkyl (such as mono- or diethylamide), mono- or diaralkyl (for example mono- or dibenzylamide), or mono- or diaryl (such as mono- or diphenylamide) carboxylamide.
Both the basic salts to the carboxyl group and the acidic salts to the aminic group of the dehydropenicillins of the general formula (I) can be prepared with methods known to anyone skilled in the art from the corresponding precursors.
In the general formula (I) particular examples of substituted aminic groups such as X are aralkylaminic groups (such as benzylamino, triphenylmethylamino), or acylaminic groups (such as those present in natural penicillins or cephalosporins, such as phenylacetamido or phenoxylacetamido).
A particular example of the aminic group X (disubstituted) is represented by the phthalimido group.
According to the present invention, the preparation of such compounds is carried out, as shown in the pattern I, by irradiation of substituted 4-acylmethylthio-2-azetidinones of the type II or IIa to give, through a photochemical reaction of the Norris II type, the corresponding 4-thioxo-2-azetidinone derivative of the kind III or IIIa which, by the subsequent basic treatment (in the case of III also acidic or merely a heat-treatment) gives rise to the formation of the dehydropenicillin I. ##STR2##
In the above reported pattern I, X and R have the same meaning as reported above and R' is an alkyl, aryl or aralkyl radical.
It should be noted that in the synthesis shown in the pattern I the nature of the groups X, or R of the starting compound II or IIa must not necessarily be that of the final product I as expected, inasmuch as it is also possible to effect, with conventional methods, a modification of such groups at the level of the intermediate III or IIIa, or after the cyclization of such intermediate to I.
It is to be noted, moreover, that for such a synthesis, it is possible to use starting compounds II or IIa, both in the cis or the trans form relative to the substituents on the C.sub.3 and the C.sub.4 of the lactamic ring.
The derivatives I such as obtained with the method shown in the pattern I are optically inactive cheiral products which can be split into their enantiomers by conventional procedures as known to anyone skilled in the art.
An interesting aspect of the method according to the present invention, of which it is otherwise an integral part, is the fact that the precursors of the dehydropenicillins, compounds III and IIIa of the pattern I, are novel products: as a matter of fact no example of any 4-thioxo-2-azetidinone has been reported by the literature.
The starting compounds II and IIa of this synthesis are, on the contrary, a class of known products and can be prepared starting from derivatives of natural penicillins or by total synthesis, more detailedly:
Lastly, the compounds II in which R' is an aryl, X is an R"NH group (in which R" is an aralkyl) and R a COOR"' group (wherein R"' is an alkyl, an aralkyl or an aryl) (V) can also be prepared with an original method which must thus also be considered as an integral part of the present invention, and is more direct than those indicated above, such method being shown in the pattern II (wherein Y=halogen and Ar=aryl), by reacting 6-aralkylaminopenicillates (IV, wherein R" and R"' have the same meanings given above) with halomethyl aryl ketones in the presence of a strong base. ##STR3##
Also from the compounds, V, with conventional procedures known to anyone skilled in the art, it is possible to prepare, in their turn, the other derivatives II with R'=aryl as already cited above.
More exactly, for the preparation of the dehydropenicillins I according to the present invention, the starting product II or IIa is subjected to the irradiation of an ultraviolet lamp, preferably of the kind with an average mercury pressure and equipped with a filter, preferably a Pyrex or Corex filter.
The reaction is carried out in an atmosphere of an inert gas (for example nitrogen) in an inert solvent (such as an aromatic solvent or in acetonitrile), in anhydrous and oxygen-free and at a temperature in the range from -10.degree. C. and +40.degree. C. (preferably at room temperature) to give the derivative III or IIIa with generally high yields.
The intermediate III or IIIa is then treated in an anhydrous inert solvent (such as a halogen-aliphatic solvent or an aromatic solvent) with a quantity which can also be catalytic (when III or IIIa is a neutral molecule) of an organic base (preferably triethylamine) at a temperature in the range from -10.degree. C. to +40.degree. C. (preferably at room temperature) to give, with generally high yields, the dehydropenicillin I.
As an alternative, the cyclization of III to I can be carried out in an inert anhydrous solvent (such as an aliphatic or aromatic solvent, also with a Bronsted or a Lewis acid, preferably silica gel, or in a neutral environment by merely heating to a temperature between 50.degree. C. and 150.degree. C.
More detailedly, as regards the preparation of the starting produces of the kind V according to the method of the present invention, the compounds IV is reacted with a halomethyl aryl ketone (preferably bromo- or iodomethyl aryl ketone) in an inert anhydrous solvent (such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or mixtures of the latter with ter-butyl alcohol, but preferably with tetrahydrofuran alone) in the presence of a strong base which is capable of cleaving the thiazolidine ring of IV but incapable of cleaving the lactam ring of IV or V (such as an alkali metal hydride such as sodium hydride, or the alkali metal salt of a tertiary alcohol, preferably potassium ter-butylate), at a temperature comprised between -80.degree. C. and +30.degree. C. (preferably at -40.degree. C.).
Derivatives of the type IV which are particularly suitable as the starting compounds for the preparation of the compounds V according to the pattern II are those in which R" is a triphenylmethyl group and this both from the point of view of the yield of the reaction as itself and the ease with which such a group can be removed from the product V to give the free amine from which it is possible to prepare, according to the conventional procedures, other aminic derivatives.
The importance of the dehydropenicillins I and of the 4-thioxo-2-azetidinones III and IIIa which are the subject-matter of the present invention lies in that these compounds are useful intermediates for the preparation of other derivatives of the penicillins and cephalosporins having a pharmaceutical interest.
In addition, a few of the dehydropenicillins I are endowed with a bland antibacterial activity.
The present invention is illustrated by the following examples which are not to be construed in any wise as limitation to the invention itself.
US Referenced Citations (3)
Foreign Referenced Citations (6)
| Number |
Date |
Country |
| 2138320 |
Jul 1971 |
DEX |
| 2204105 |
Jan 1972 |
DEX |
| 2254632 |
Jul 1973 |
DEX |
| 720207 |
Jan 1972 |
ZAX |
| 1368234 |
Sep 1974 |
GBX |
| 1409801 |
Oct 1975 |
GBX |
Non-Patent Literature Citations (2)
| Entry |
| Justus Liebigs, Annalen der Chemie, 1974, Heft 9, pp. 1361 & 1937. |
| Yoshimote et al., Tetrahedron Letters, No. 43, pp.4387-4390 (1972). |
Divisions (2)
|
Number |
Date |
Country |
| Parent |
949546 |
Oct 1978 |
|
| Parent |
769527 |
Feb 1977 |
|
Patent Grant
4288366
