Amino acid-n-carboxy anhydrides hvaing substituent at nitrogen

TECHNICAL FIELD

[0001] This invention relates to activated amino acid derivatives which are important intermediates useful in many fields led by the fields of pharmaceuticals and agrochemicals. The present invention is also concerned with novel amino acid N-carboxyanhydrides each of which has a substituent of the N-acyl type on a nitrogen atom thereof, and also with a process for the production of diamides, which makes use of the amino acid N-carboxyanhydrides, requires fewer steps and is economical.

BACKGROUND ART

[0002] Amino acids are available rather readily at low prices and have diverse structures and asymmetric carbon atoms, so that they have been widely used for many years as raw materials or the like for a variety of optically active compounds led by peptides. In particular, production technology of peptides, which uses amino acids as raw materials, has been one of important basic technologies for many years in many fields led by the fields of pharmaceuticals and agrochemicals. Keeping in step with the advance of molecular biology in recent years, the importance of peptides tends to increase progressively. There is, accordingly, an outstanding demand for an economical production process of peptides, which is suited for industrial practice on large scale.

[0003] The principle of peptide production resides a reaction in which a carboxyl group of an amino acid and an amino group of an amine derivative, which may be an amino acid, are subjected to dehydrating condensation to form an amide bond. In practice, however, a free amino acid becomes an ampholytic ion, forms an internal salt and is stabilized, so that the above-mentioned reaction does not occur spontaneously. Even if the reaction should proceed, high-yield production of a specific target product cannot be expected because the amino groups contained in the respective reactants are free and many dipeptides, diketopiperazine derivatives and the like are hence byproduced.

[0004] To obtain the target peptide with good yield, functional groups other than those needed have to be masked beforehand to prevent occurrence of undesired reactions. In the case of a methyl ester or the like, its reaction velocity is low and impractical so that a carboxyl component must be activated suitably. A protecting group used as a mask not only plays a role to prevent a side reaction but also has an effect to reduce the polarity of the amino acid and to render it more readily soluble in an organic solvent.

[0005] Examples of the protecting group can include urethane-type protecting groups such as tert-butoxycarbonyl (Boc) group and benzyloxycarbonyl (Z) group, alkyl-type protecting groups such as trityl group, and acyl-type protecting groups such as formyl group, tosyl group, acetyl group and benzoyl group. In these protecting groups, urethane-type protecting groups can hardly induce racemization [Jiro Yajima, Yuki Gosei Kyokai Shi (Journal of Synthetic Organic Chemistry, Japan), 29, 27 (1971); Noboru Yanaihara, Pharmacia, 7, 721 (1972)], but acyl-type and alkyl-type protecting groups are accompanied by a drawback that they tend to induce racemization. Further, alkyl-type protecting groups do not fully mask the basicity of an amino group so that the amino group may still be subjected to further acylation. With a trityl group, no second acylation can take place owing to its steric hindrance. Conversely, this steric hindrance makes it difficult to achieve introduction itself of a trityl group, and further, it is not easy to conduct a condensation reaction between a trityl-protected amino acid with and a trityl-protected amine.

[0006] A synthesis process which includes introduction of protecting groups requires protecting and deprotecting steps, each of which requires a costly reagent, and also purification steps after the protecting and deprotecting groups, respectively. This synthesis process, therefore, results in multi-step production, leading to an increase in cost.

[0007] If it is difficult to allow a condensation reaction to proceed easily between an amino acid and an amine, there are processes in each of which a carboxyl group of an amino acid derivative with a protected amino group is activated by an electron-attracting substituent to facilitate its nucleophilic attack on the carbon atom of a carbonyl group of the amine. Illustrative of these processes are the acid chloride process in which an activated amino acid is derived using PCl5, PCl3 or thionyl chloride, the azidation process in which an activated amino acid is derived from an amino acid ester or the like via a hydrazide, the mixed acid anhydride process in which an activated amino acid is derived from a protected amino acid and another acid, and the crosslinking process making use of a conventional condensing agent such as N,N′-dicyclohexylcarbodiimide (DCC) or 1,1-carbonyl-diimidazole (hereinafter abbreviated as “CDI”). However, the acid chloride process involves a problem that many side reactions occur, the azidation process is accompanied by a problem that the derivation into an azide is very cumbersome, and the mixed acid anhydride process has a problem that disproportionation tends to occur when the temperature rises (“Peptide Synthesis” written by Nobuo Izumiya et al.). The process making use of a condensing agent is also accompanied by some drawbacks. In the case of DCC, for example, an acylisourea which is an intermediate formed by a reaction between a carboxyl group and DCC may undergo an intermolecular rearrangement in the presence of a base to form an acylurea, thereby lowering the yield of the target product or making it difficult to separate the acylurea from the target product. Further, DCC dehydrates the co-amide of asparagine or glutamine to form a nitrile. On the other hand, CDI is an expensive reagent, and the crosslinking process making use of CDI is not considered to be an economical production process of peptides.

[0008] As described above, many peptide production processes have been studied. To be industrially stable production technology or low-cost production technology, however, these processes have to be considered to be still insufficient.

[0009] On the other hand, amino acid N-carboxyanhydrides (referred to as “NCAs” when abbreviated) which have been studied as active amino acids readily react with most free amines. Primary merits of NCAs include that they themselves are effective acylating agents (“Peptides”, 9, 83) and that they permit more economical production through fewer steps than the commonly-employed crosslinking process making use of a condensing agent such as N,N-dicyclohexylcarbodiimide or 1,1-carbonyldiimidazole or the N-hydroxysuccinimide ester crosslinking process. In addition, these amino acid NCAs do not develop the problem of racemization or the like of amino acids under reaction conditions commonly employed for the production of peptides. NCAs have, therefore, been expected for many years to serve as important intermediates for the synthesis of peptides [Pheiol Chem., 147, 91 (1926)].

[0010] The peptide synthesis which uses an N-unsubstituted NCA as a production intermediate and has been known well for many years, however, involves many problems in that side reactions such as a polymerization reaction are always hardly controllable and the reactivity and stability differ depending on the kinds of the reactants. This peptide synthesis, therefore, has not been considered as a common peptide production process although its potential utility has been recognized. With a view to solving these problems, numerous improvements have been made. For example, Bailey et al. reported an illustrative condensation reaction between L-alanine-NCA and glycine under low temperature (−40° C.) conditions in an organic solvent [J. Chem. Soc., 8461 (1950)]. Further, Robert G. D. et al. reported illustrative production of a dipeptide under 0 to 5° C. conditions in an aqueous solution (around pH 10) by using L-phenylalaline-NCA [J. Am. Chem. Soc., 88, 3163 (1966)]. In addition, Thomas J. B. et al. reported potential industrial utility of a condensation reaction making use of L-alanine-NCA and L-proline [J. Org. Chem., 53, 836 (1988)].

[0011] Despite these efforts, however, N-unsubstituted NCAs are very limited in conditions optimal for the prevention of a polymerization reaction and racemization reaction as side reactions and are not suited from the industrial viewpoint.

[0012] Accordingly, efforts have been made in attempts to solve problems in polymerization control and the like by introducing a substituent of the N-alkyl or N-sulfenyl type onto a nitrogen atom of an NCA. Reported in patents and other technical publications include, for example, N-methyl-NCA, N-ethyl-NCA, N-nitrophenylsulfenyl-NCA [Kricheldorf et al., Angew. Chem. Acta 85, (1978) 86], N-xanthyl-NCA [Halstroem and Kovacs et al., Acta Chemica Scandvnavia, Ser. B, 1986, BYO(6), 462; U.S. Pat. No. 4,267,344], and N-trityl-NCA (Block and Cox et al., “Peptides, Proc. of the 5th Europ. Symp., Oxford, September 1962, Pergramon Press 1963, Compiled by G. T. Young, page 84”. However, production processes of these compounds themselves lack general applicability, and effects of these compounds for polymerization control and the like are not sufficient. These compounds, therefore, have not lead to solution of the fundamental problems.

[0013] In 1980's, it was attempted to control the reactivity of an NCA by introducing a trimethylsilyl group onto the nitrogen atom of the NCA. This control was practiced with glycine-NCA (Bayer AG, DE 1768871). This approach indicated possibility of suppressing a polymerization reaction which was considered to be one of serious side reactions, but involves a problem in stability and a problem of an increase in production cost, and its application to other amino acids has not been made since then. The idea of introducing a substituent onto a nitrogen atom was subsequently applied by Palomo C. et al. to a condensation reaction between a non-natural amino acid and an amine by using a NCA in which a nitrogen atom is protected by a benzyl group [Chem. Commun., 7, 691 (1997); Tetrahedron Lett., 38(17), 3093 (1997)]. However, these processes are also accompanied by problems in that the target NCA cannot be produced economically due to the need for many steps for its synthesis and a limitation is imposed on amino acids which can be synthesized.

[0014] In recent years, N-substituted NCAs with substituents of the urethane type as substituents on nitrogen atoms were reported. Firstly, Kricheldolf et al. reported a process for the production of N-methoxycarbonylglycine-NCA and N-ethoxycarbonylglycine-NCA [Macromol. Chem., 178, 905 (1977)]. Then, Fuller et al. reported production of N-urethane-substituted NCA and N-urethane-substituted thiocarboxylic acid anhydride from amino acids other than glycine (Bioresearch Inc., JP 2875834 B). They admirably solved the problem of polymerization control or the like by using these N-urethane-substituted NCAs. They, however, used costly N-urethane groups as amino-protecting groups, thereby failing to make good use of the merit of NCAs that amide compounds can be produced through fewer steps at low cost without using protecting groups. Further, they did not conduct any study on N-substituted NCAs other than N-urethane-substituted NCAs and made no mention about N-acyl-substituted NCAs.

[0015] An N-acyl-substituted NCA, on the other hand, is expected to provide a short and economical process for forming an amino acid into a derivative thereof because use of a target amide structure as a substituent in NCA prevents side reactions such as polymerization and obviates protection and deprotection. For example, a reaction with a desired amine has possibility of synthesizing a diamide compound at low cost without steps such as bonding and elimination of a protecting group to and from an amino group.

[0016] Only an extremely limited number of reports have, however, been made on the synthesis of N-acyl-substituted NCAs. Moreover, none of these synthesis processes are equipped with general applicability. For example, Kricheldolf et al. reported 3-(3,5-dinitrobenzoyl)-4,4-dimethyl-2,5-oxazolinedinedione in the article referred to in the above [Macromol. Chem., 178, 905 (1977)]. This is the only example reported by them concerning N-acyl-substituted NCAs. In addition, the amino acid employed in their report is di-substituted at the a-position and contains no asymmetric carbon atom, and their report does not disclose any N-acyl-substituted NCA with other acyl group. Accordingly, their process is poor in wide applicability.

[0017] N-(3-oxobutanoyl)-substituted NCAs, on the other hand, are reported in JP 48-86886 A. The substituent on the nitrogen atom is, however, limited only to an N-(3-oxobutanoyl) group introduced using a diketene in their production process, so that this process cannot introduce acyl groups which are widely used. Concerning the compounds represented by the formula (2) and the formula (3), respectively, no synthesis process is disclosed [M. Wakselman et al., Amino Acids, 7, 67-77 (1994); Reibel Leonard et al., Bull. Soc. Chim. Fr., 3, 1025-319 (1972)]. These articles disclose only the structures of such compounds, and therefore, no synthesis is feasible following the articles.

[0018] As described above, many of conventional reports are directed to alkyl- or urethane-substituted NCAs, and production and use of N-acyl-substituted NCAs are still considered to be very difficult or impossible although they are expected to have high utility [“Peptides, Proc. of the 5th Europ. Symp., Oxford, September 1962”, Pergamon Press 1963, Compiled by G. T. Young, Pages 84-87; Yonezawa et al., “Yuki Gosei Kagaku (Synthetic Organic Chemistry)”, 47(9), 782-794 (1989)].

[0019] In short, N-acyl-substituted NCAs and various amino acid derivatives produced by amidation reactions making use of these NCAs are expected to find utility as useful compounds or production processes in many fields led by the fields of pharmaceuticals and agrochemicals. Nonetheless, neither commonly applicable production process of N-acyl-substituted NCAs nor widely applicable, industrially-excellent peptide production process making use of these NCAs were known practically to date.

DISCLOSURE OF THE INVENTION

[0020] Objects of the present invention is to provide a novel amino acid N-carboxyanhydride with an N-acyl substituent on a nitrogen atom thereof, which is considered to be an important intermediate extremely useful in many fields led by the fields of pharmaceuticals and agrochemicals but cannot be obtained by the conventional production techniques, and its production process, and a production process of a diamide compound, which owing to use of the N-carboxyanhydride, does not develop problems such as racemization, includes fewer steps and is economical.

[0021] The present inventors have proceeded with an extensive investigation to achieve the above-described objects. As a result, they have succeeded in obtaining a novel amino acid N-carboxyanhydride with an N-acyl substituent on a nitrogen atom thereof and based on use of the compound, have also found a novel amidation reaction which does not develop problems such as racemization, leading to the completion of the present invention.

[0022] Described specifically, an amino acid N-carboxy-anhydride with a substituent on a nitrogen atom thereof according to the present invention has a structure represented by the following formula (1):

[0023] wherein R1 and R2 each independently represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, or a substituted or unsubstituted heterocyclic alkyl group.

[0024] Examples of the invention compound represented by the formula (1) can include the following compounds:

[0025] 1. Among compounds represented by the formula (1), those falling within neither the following category A nor the following category B:

[0026] A. Compounds of the formula (1) in which R2is a 2-oxopropyl group; and

[0027] B. Compounds of the following formulas (2) and (3):

[0028] 2. Compounds of the formula (1) in which R2 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted aralkyl group.

[0029] 3. Compounds of the formula (1) in which R2 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted aralkyl group, with a proviso that the compounds falling within the above category A or B are excluded.

[0030] 4. Compounds of the formula (1) in which R2 is a substituted or unsubstituted aryl group.

[0031] 5. Compounds of the formula (1) in which R2 is a substituted or unsubstituted aryl group, with a proviso that the compounds falling within the above category B are excluded.

[0032] 6. Compounds of the formula (1) in which R2 is a substituted or unsubstituted heterocycle or a substituted or unsubstituted heterocyclic alkyl group.

[0033] 7. Compounds of the formula (1) in which R1 is a side chain on an α-carbon atom of a protected or unprotected amino acid.

[0034] 8. Compounds having any one of the structures described above under items 1-6, in which R1 is a side chain on an α-carbon atom of a protected or unprotected amino acid.

[0035] A process according to the present invention for the production of the compound represented by the formula (1), in a first aspect thereof, comprises reacting, in an inert diluent and in the presence of a condensing agent, an amino acid N-carboxyanhydride represented by the following formula (4):

[0036] wherein R1 has the same meaning as defined in claim 1 with a compound represented by the following formula (5):

[0037] wherein R2 has the same meaning as defined in claim 1.

[0038] The process according to the present invention for the production of the compound represented by the formula (1), in a second aspect thereof, comprises reacting, in an inert diluent and in the presence of an amine base, an amino acid N-carboxyanhydride represented by the following formula (4):

[0039] wherein R1 has the same meaning as defined in claim 1 with a compound represented by the following formula (6):

[0040] wherein R2 has the same meaning as defined in claim 1 and Y represents a halogen atom.

[0041] A process according to the present invention for the production of an amide derivative represented by the following formula (8):

[0042] wherein R1 and R2 have the same meanings as defined above, and R3 and R4 each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, or a substituted or unsubstituted heterocyclic alkyl group, which comprises a step of reacting a compound represented by the formula (1), for example, any one of the compounds exemplified above under items 1-8 with an amine derivative represented by the following formula (7):

[0043] wherein R3 and R4 have the same meanings as defined above.

[0044] The process according to the present invention for the production of the compound represented by the formula (8), in another aspect thereof, comprises a step of reacting a compound represented by the formula (1), for example, any one of the compounds exemplified above under items 1-8 with an unprotected or protected amino acid.

BEST MODES FOR CARRYING OUT THE INVENTION

[0045] The compounds according to the present invention will next be described in further detail.

[0046] The term “substituted or unsubstituted alkyl group” represented by R1, R2, R3 and R4 in the formulas (1), (4), (5), (6), (7) and (8) means an alkyl group which may be substituted at one or more desired parts thereof. Examples of the alkyl group can include methyl, ethyl, methoxyethyl, phenoxymethyl, benzyloxymethyl, methylthiomethyl, phenylthiomethyl, fluorenylmethyl, fluoroethyl, n-propyl, chloropropyl, isopropyl, n-butyl, (substituted amino)-n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0047] The term “substituted or unsubstituted cycloalkyl group” means a cycloalkyl group which may be substituted at one or more desired parts thereof. Examples of the cycloalkyl group can include cyclopropyl, cyclobutyl, cyclopentyl, ethoxycyclopentyl, cyclohexyl, tert-butoxycyclohexyl, benzyloxycyclohexyl, nitrocyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0048] The term “substituted or unsubstituted aralkyl group” means an aralkyl group which may be substituted at one or more desired parts thereof. Examples of the aralkyl group can include benzyl, 2-phenylethyl, 3-phenylpropyl, cinnamyl, naphthylmethyl, 3-chlorobenzyl, 4-aminobenzyl, 2-nitrobenzyl, 4-methoxybenzyl, 3,4-dihydroxybenzyl, and 3,4-dimethoxybenzyl.

[0049] The term “substituted or unsubstituted aryl group” means an aryl group which may be substituted at one or more desired parts thereof. Examples of the aryl group can include phenyl, tolyl, bromophenyl, methoxyphenyl, ethylphenyl, propylphenyl, nitrophenyl, amidophenyl, fluorenyl, naphthyl, hydroxynaphthyl, anthracenyl, phenanthrenyl, and benzophenanthrenyl.

[0050] The term “substituted or unsubstituted heterocycle” means a heterocycle which may be substituted at one or more desired parts thereof. Examples of the heterocycle can include tetrahydropyranyl, tetrahydrofuranyl, alkyltetrahydrofuranyl, tetrahydrothienyl, methylsulfonyltetrahydrothienyl, pyridyl, pyrazyl, pyrimidyl, thienyl, hydroxypyridyl, imidazolyl, thiazolyl, pyrazolyl, pyrazolonyl, isoxazolyl, isothiazyl, pyrrolyl, furanyl, naphthylidinyl, quinolyl, sulfamoylquinolyl, and sydononyl.

[0051] The term “substituted or unsubstituted heterocyclic alkyl group” means a heterocyclic alkyl group which may be substituted at one or more desired parts thereof. Examples of the heterocyclic alkyl group can include 3-pyridylmethyl, 4-pyridylmethyl, 6-methoxy-3-pyridylmethyl, 3-quinolylmethyl, N-methyl-4-imidazolemethyl, 2-amino-4-thiazolemethyl, and morpholinomethyl.

[0052] The term “side chain on an α-carbon atom of a protected or unprotected amino acid” means a side chain on an α-carbon atom of an amino acid such as alanine or valine, leucine, isoleucine, tert-leucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, hydroxylysine, arginine, cysteine, cystine, methionine, phenylalanine, tyrosine, tryptophan, histidine, homoserine or ornithine, for example. Representative examples of the side chain can include those represented by the following formulas (9) to (29):

[0053] The above-described side chains may be protected with protecting groups by methods, both of which are known commonly to those having ordinary skill in the art, as desired. For example, they may be protected using a commonly-employed, amino-protecting group, thiol-protecting group or carboxy-protecting group.

[0054] Illustrative inert diluents, which are usable in the first and second aspects of the process according to the present invention for the production of the compound represented by the formula (1), are chlorine-containing organic solvents such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane and tetrachloroethane; esters such as methyl acetate, ethyl acetate and butyl acetate; ethers such as diethyl ether, diphenyl ether, dioxane and tetrahydrofuran; and hexane, liquid sulfur dioxide, carbon disulfide, benzene, toluene, xylene, nitromethane, nitrobenzene, acetonitrile, dimethylformamide, dimethylacetamide, and 1,3-dimethyl-2-imidazolidinone. They can be used either singly or in combination as needed.

[0055] Examples of the condensing agent can include thionyl chloride, thionyl bromide, N,N-dicyclohexylcarbodiimide, and 1,1-carbonyldiimidazole. They can be used either singly or in combination as needed.

[0056] Examples of the halogen atom represented by Y in the formula (6) can include a chlorine atom, bromine atom and iodine atom.

[0057] Illustrative of the amine base are trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, lutidine, N,N-dimethylaniline, N,N-dimethyl-toluidine, 4-dimethylaminopyridine, N-methylmorpholine, diazabicycloundecene, and 1,8-bis(dimethylamino)-naphthalene.

[0058] Examples of the protected or unprotected amino acid usable as an amine in the production process of the compound of the formula (8) can include alanine, valine, leucine, isoleucine, tert-leucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, hydroxylysine, arginine, cysteine, cystine, methionine, phenylalanine, tyrosine, tryptophan, histidine, homoserine, and ornithine. They can be used either singly or in combination as needed.

[0059] When the invention derivative represented by the formula (1) contains one or more asymmetric carbon atoms, the derivative may exist in the form of a specific stereoisomer or in the form of a mixture of stereoisomers including a racemic form.

[0060] Compounds encompassed by the formula (1) will be exemplified in Table 1 to Table 46, although they shall by no means restrict the compound according to the present invention. Incidentally, “Ph” in the tables means “a phenyl group” or “a phenylene group”.

1TABLE 1

Compound No.R2Compound No.R21001CH31045

1002CH2CH31046

1003(CH2)2CH31047

1004CH(CH3)21048

1005(CH2)3CH31049

1006CH2CH(CH3)21050

1007CH(CH3)CH2CH31051

1008C(CH3)31052

1009(CH2)4CH31053

1010(CH2)5CH31054

1011(CH2)6CH31055

1012(CH2)7CH31056

1013(CH2)8CH31057

1014cyclopropyl1058

1015cyclobutyl1059

1016cyclohexyl1060

1017Ph1061

1018PhCH21062

1019Ph(CH2)21020Ph(CH2)31021PhO(CH2)21022PhCH2OCH2CH21023PhCH2O(C═O)CH2CH21024o-CH3Ph1025m-CH3Ph1026p-CH3Ph10272,4-(CH3)2Ph10283,5-(CH3)2Ph10292,4,6-(CH3)3Ph1030p-CH3OPh1031p-CH3CH2OPh1032p-CH3(CH2)2OPh1033p-FPh1034p-ClPh1035p-BrPh1036p-IPh1037p-PhOPh1038p-PhCH2OPh1039p-NO2Ph1040p-CNPh1041p-CH3SO2Ph1042

1043

1044

[0061]

2

TABLE 2

Compound No.
R2
Compound No.
R2

2001
CH3
2045

2002
CH2CH3
2046

2003
(CH2)2CH3
2047

2004
CH(CH3)2
2048

2005
(CH2)3CH3
2049

2006
CH2CH(CH3)2
2050

2007
CH(CH3)CH2CH3
2051

2008
C(CH3)3
2052

2009
(CH2)4CH3
2053

2020
(CH2)5CH3
2054

2011
(CH2)6CH3
2055

2012
(CH2)7CH3
2056

2013
(CH2)8CH3
2057

2014
cyclopropyl
2058

2015
cyclobutyl
2059

2016
cyclohexyl
2060

2017
Ph
2061

2018
PhCH2
2062

2019
Ph(CH2)2

2020
Ph(CH2)3

2021
PhO(CH2)2

2022
PhCH2OCH2CH2

2023
PhCH2O(C═O)CH2CH2

2024
o-CH3Ph

2025
m-CH3Ph

2026
p-CH3Ph

2027
2,4-(CH3)2Ph

2028
3,5-(CH3)2Ph

2029
2,4,6-(CH3)3Ph

2030
p-CH3OPh

2031
p-CH3CH2OPh

2032
p-CH3(CH2)2OPh

2033
p-FPh

2034
p-ClPh

2035
p-BrPh

2036
p-IPh

2037
p-PhOPh

2038
p-PhCH2OPh

2039
p-NO2Ph

2040
p-CNPh

2041
p-CH3SO2Ph

2042

2043

2044

[0062]

3

TABLE 3

Compound No.
R2
Compound No.
R2

3001
CH3
3045

3002
CH2CH3
3046

3003
(CH2)2CH3
3047

3004
CH(CH3)2
3048

3005
(CH2)3CH3
3049

3006
CH2CH(CH3)2
3050

3007
CH(CH3)CH2CH3
3051

3008
C(CH3)3
3052

3009
(CH2)4CH3
3053

3030
(CH2)5CH3
3054

3011
(CH2)6CH3
3055

3012
(CH2)7CH3
3056

3013
(CH2)8CH3
3057

3014
cyclopropyl
3058

3015
cyclobutyl
3059

3016
cyclohexyl
3060

3017
Ph
3061

3018
PhCH2
3062

3019
Ph(CH2)2

3020
Ph(CH2)3

3021
PhO(CH2)2

3022
PhCH2OCH2CH2

3023
PhCH2O(C═O)CH2CH2

3024
o-CH3Ph

3025
m-CH3Ph

3026
p-CH3Ph

3027
2,4-(CH3)2Ph

3028
3,5-(CH3)2Ph

3029
2,4,6-(CH3)3Ph

3030
p-CH3OPh

3031
p-CH3CH2OPh

3032
p-CH3(CH2)2OPh

3033
p-FPh

3034
p-ClPh

3035
p-BrPh

3036
p-IPh

3037
p-PhOPh

3038
p-PhCH2OPh

3039
p-NO2Ph

3040
p-CNPh

3041
p-CH3SO2Ph

3042

3043

3044

[0063]

4

TABLE 4

Compound No.
R2
Compound No.
R2

4001
CH3
4045

4002
CH2CH3
4046

4003
(CH2)2CH3
4047

4004
CH(CH3)2
4048

4005
(CH2)3CH3
4049

4006
CH2CH(CH3)2
4050

4007
CH(CH3)CH2CH3
4051

4008
C(CH3)3
4052

4009
(CH2)4CH3
4053

4040
(CH2)5CH3
4054

4011
(CH2)6CH3
4055

4012
(CH2)7CH3
4056

4013
(CH2)8CH3
4057

4014
cyclopropyl
4058

4015
cyclobutyl
4059

4016
cyclohexyl
4060

4017
Ph
4061

4018
PhCH2
4062

4019
Ph(CH2)2

4020
Ph(CH2)3

4021
PhO(CH2)2

4022
PhCH2OCH2CH2

4023
PhCH2O(C═O)CH2CH2

4024
o-CH3Ph

4025
m-CH3Ph

4026
p-CH3Ph

4027
2,4-(CH3)2Ph

4028
3,5-(CH3)2Ph

4029
2,4,6-(CH3)3Ph

4030
p-CH3OPh

4031
p-CH3CH2OPh

4032
p-CH3(CH2)2OPh

4033
p-FPh

4034
p-ClPh

4035
p-BrPh

4036
p-IPh

4037
p-PhOPh

4038
p-PhCH2OPh

4039
p-NO2Ph

4040
p-CNPh

4041
p-CH3SO2Ph

4042

4043

4044

[0064]

5

TABLE 5

100

Compound No.
R2
Compound No.
R2

5001
CH3
5045

101

5002
CH2CH3
5046

102

5003
(CH2)2CH3
5047

103

5004
CH(CH3)2
5048

104

5005
(CH2)3CH3
5049

105

5006
CH2CH(CH3)2
5050

106

5007
CH(CH3)CH2CH3
5051

107

5008
C(CH3)3
5052

108

5009
(CH2)4CH3
5053

109

5050
(CH2)5CH3
5054

110

5011
(CH2)6CH3
5055

111

5012
(CH2)7CH3
5056

112

5013
(CH2)8CH3
5057

113

5014
cyclopropyl
5058

114

5015
cyclobutyl
5059

115

5016
cyclohexyl
5060

116

5017
Ph
5061

117

5018
PhCH2
5062

118

5019
Ph(CH2)2

5020
Ph(CH2)3

5021
PhO(CH2)2

5022
PhCH2OCH2CH2

5023
PhCH2O(C═O)CH2CH2

5024
o-CH3Ph

5025
m-CH3Ph

5026
p-CH3Ph

5027
2,4-(CH3)2Ph

5028
3,5-(CH3)2Ph

5029
2,4,6-(CH3)3Ph

5030
p-CH3OPh

5031
p-CH3CH2OPh

5032
p-CH3(CH2)2OPh

5033
p-FPh

5034
p-ClPh

5035
p-BrPh

5036
p-IPh

5037
p-PhOPh

5038
p-PhCH2OPh

5039
p-NO2Ph

5040
p-CNPh

5041
p-CH3SO2Ph

5042

119

5043

120

5044

121

[0065]

6

TABLE 6

122

Compound No.
R2
Compound No.
R2

6001
CH3
6045

123

6002
CH2CH3
6046

124

6003
(CH2)2CH3
6047

125

6004
CH(CH3)2
6048

126

6005
(CH2)3CH3
6049

127

6006
CH2CH(CH3)2
6050

128

6007
CH(CH3)CH2CH3
6051

129

6008
C(CH3)3
6052

130

6009
(CH2)4CH3
6053

131

6060
(CH2)5CH3
6054

132

6011
(CH2)6CH3
6055

133

6012
(CH2)7CH3
6056

134

6013
(CH2)8CH3
6057

135

6014
cyclopropyl
6058

136

6015
cyclobutyl
6059

137

6016
cyclohexyl
6060

138

6017
Ph
6061

139

6018
PhCH2
6062

140

6019
Ph(CH2)2

6020
Ph(CH2)3

6021
PhO(CH2)2

6022
PhCH2OCH2CH2

6023
PhCH2O(C═O)CH2CH2

6024
o-CH3Ph

6025
m-CH3Ph

6026
p-CH3Ph

6027
2,4-(CH3)2Ph

6028
3,5-(CH3)2Ph

6029
2,4,6-(CH3)3Ph

6030
p-CH3OPh

6031
p-CH3CH2OPh

6032
p-CH3(CH2)2OPh

6033
p-FPh

6034
p-ClPh

6035
p-BrPh

6036
p-IPh

6037
p-PhOPh

6038
p-PhCH2OPh

6039
p-NO2Ph

6040
p-CNPh

6041
p-CH3SO2Ph

6042

141

6043

142

6044

143

[0066]

7

TABLE 7

144

Compound No.
R2
Compound No.
R2

7001
CH3
7045

145

7002
CH2CH3
7046

146

7003
(CH2)2CH3
7047

147

7004
CH(CH3)2
7048

148

7005
(CH2)3CH3
7049

149

7006
CH2CH(CH3)2
7050

150

7007
CH(CH3)CH2CH3
7051

151

7008
C(CH3)3
7052

152

7009
(CH2)4CH3
7053

153

7070
(CH2)5CH3
7054

154

7011
(CH2)6CH3
7055

155

7012
(CH2)7CH3
7056

156

7013
(CH2)8CH3
7057

157

7014
cyclopropyl
7058

158

7015
cyclobutyl
7059

159

7016
cyclohexyl
7060

160

7017
Ph
7061

161

7018
PhCH2
7062

162

7019
Ph(CH2)2

7020
Ph(CH2)3

7021
PhO(CH2)2

7022
PhCH2OCH2CH2

7023
PhCH2O(C═O)CH2CH2

7024
o-CH3Ph

7025
m-CH3Ph

7026
p-CH3Ph

7027
2,4-(CH3)2Ph

7028
3,5-(CH3)2Ph

7029
2,4,6-(CH3)3Ph

7030
p-CH3OPh

7031
p-CH3CH2OPh

7032
p-CH3(CH2)2OPh

7033
p-FPh

7034
p-ClPh

7035
p-BrPh

7036
p-IPh

7037
p-PhOPh

7038
p-PhCH2OPh

7039
p-NO2Ph

7040
p-CNPh

7041
p-CH3SO2Ph

7042

163

7043

164

7044

165

[0067]

8

TABLE 8

166

Compound No.
R2
Compound No.
R2

8001
CH3
8045

167

8002
CH2CH3
8046

168

8003
(CH2)2CH3
8047

169

8004
CH(CH3)2
8048

170

8005
(CH2)3CH3
8049

171

8006
CH2CH(CH3)2
8050

172

8007
CH(CH3)CH2CH3
8051

173

8008
C(CH3)3
8052

174

8009
(CH2)4CH3
8053

175

8080
(CH2)5CH3
8054

176

8011
(CH2)6CH3
8055

177

8012
(CH2)7CH3
8056

178

8013
(CH2)8CH3
8057

179

8014
cyclopropyl
8058

180

8015
cyclobutyl
8059

181

8016
cyclohexyl
8060

182

8017
Ph
8061

183

8018
PhCH2
8062

184

8019
Ph(CH2)2

8020
Ph(CH2)3

8021
PhO(CH2)2

8022
PhCH2OCH2CH2

8023
PhCH2O(C═O)CH2CH2

8024
o-CH3Ph

8025
m-CH3Ph

8026
p-CH3Ph

8027
2,4-(CH3)2Ph

8028
3,5-(CH3)2Ph

8029
2,4,6-(CH3)3Ph

8030
p-CH3OPh

8031
p-CH3CH2OPh

8032
p-CH3(CH2)2OPh

8033
p-FPh

8034
p-ClPh

8035
p-BrPh

8036
p-IPh

8037
p-PhOPh

8038
p-PhCH2OPh

8039
p-NO2Ph

8040
p-CNPh

8041
p-CH3SO2Ph

8042

185

8043

186

8044

187

[0068]

9

TABLE 9

188

Compound No.
R2
Compound No.
R2

9001
CH3
9045

189

9002
CH2CH3
9046

190

9003
(CH2)2CH3
9047

191

9004
CH(CH3)2
9048

192

9005
(CH2)3CH3
9049

193

9006
CH2CH(CH3)2
9050

194

9007
CH(CH3)CH2CH3
9051

195

9008
C(CH3)3
9052

196

9009
(CH2)4CH3
9053

197

9090
(CH2)5CH3
9054

198

9011
(CH2)6CH3
9055

199

9012
(CH2)7CH3
9056

200

9013
(CH2)8CH3
9057

201

9014
cyclopropyl
9058

202

9015
cyclobutyl
9059

203

9016
cyclohexyl
9060

204

9017
Ph
9061

205

9018
PhCH2
9062

206

9019
Ph(CH2)2

9020
Ph(CH2)3

9021
PhO(CH2)2

9022
PhCH2OCH2CH2

9023
PhCH2O(C═O)CH2CH2

9024
o-CH3Ph

9025
m-CH3Ph

9026
p-CH3Ph

9027
2,4-(CH3)2Ph

9028
3,5-(CH3)2Ph

9029
2,4,6-(CH3)3Ph

9030
p-CH3OPh

9031
p-CH3CH2OPh

9032
p-CH3(CH2)2OPh

9033
p-FPh

9034
p-ClPh

9035
p-BrPh

9036
p-IPh

9037
p-PhOPh

9038
p-PhCH2OPh

9039
p-NO2Ph

9040
p-CNPh

9041
p-CH3SO2Ph

9042

207

9043

208

9044

209

[0069]

10

TABLE 10

210

Compound No.
R2
Compound No.
R2

10001
CH3
10045

211

10002
CH2CH3
10046

212

10003
(CH2)2CH3
10047

213

10004
CH(CH3)2
10048

214

10005
(CH2)3CH3
10049

215

10006
CH2CH(CH3)2
10050

216

10007
CH(CH3)CH2CH3
10051

217

10008
C(CH3)3
10052

218

10009
(CH2)4CH3
10053

219

10010
(CH2)5CH3
10054

220

10011
(CH2)6CH3
10055

221

10012
(CH2)7CH3
10056

222

10013
(CH2)8CH3
10057

223

10014
cyclopropyl
10058

224

10015
cyclobutyl
10059

225

10016
cyclohexyl
10060

226

10017
Ph
10061

227

10018
PhCH2
10062

228

10019
Ph(CH2)2

10020
Ph(CH2)3

10021
PhO(CH2)2

10022
PhCH2OCH2CH2

10023
PhCH2O(C═O)CH2CH2

10024
o-CH3Ph

10025
m-CH3Ph

10026
p-CH3Ph

10027
2,4-(CH3)2Ph

10028
3,5-(CH3)2Ph

10029
2,4,6-(CH3)3Ph

10030
p-CH3OPh

10031
p-CH3CH2OPh

10032
p-CH3(CH2)2OPh

10033
p-FPh

10034
p-ClPh

10035
p-BrPh

10036
p-IPh

10037
p-PhOPh

10038
p-PhCH2OPh

10039
p-NO2Ph

10040
p-CNPh

10041
p-CH3SO2Ph

10042

229

10043

230

10044

231

[0070]

11

TABLE 11

232

Compound No.
R2

11001
CH3

11002
CH2CH3

11003
(CH2)2CH3

11004
CH(CH3)2

11005
(CH2)3CH3

11006
CH2CH(CH3)2

11007
CH(CH3)CH2CH3

11008
C(CH3)3

11009
(CH2)4CH3

11010
(CH2)5CH3

11011
(CH2)6CH3

11012
(CH2)7CH3

11013
(CH2)8CH3

11014
cyclopropyl

11015
cyclobutyl

11016
cyclohexyl

11017
Ph

11018
PhCH2

11019
Ph(CH2)2

11020
Ph(CH2)3

11021
PhO(CH2)2

11022
PhCH2OCH2CH2

11023
PhCH2O(C═O)CH2CH2

11024
o-CH3Ph

11025
m-CH3Ph

11026
p-CH3Ph

11027
2,4-(CH3)2Ph

11028
3,5-(CH3)2Ph

11029
2,4,6-(CH3)3Ph

11030
p-CH3OPh

11031
p-CH3CH2OPh

11032
p-CH3(CH2)2OPh

11033
p-FPh

11034
p-ClPh

11035
p-BrPh

11036
p-IPh

11037
p-PhOPh

11038
p-PhCH2OPh

11039
p-NO2Ph

11040
p-CNPh

11041
p-CH3SO2Ph

11042

233

11043

234

11044

235

11045

236

11046

237

11047

238

11048

239

11049

240

11050

241

11051

242

11052

243

11053

244

11054

245

11055

246

11056

247

11057

248

11058

249

11059

250

11060

251

11061

252

11062

253

[0071]

12

TABLE 12

254

Compound No.
R2

12001
CH3

12002
CH2CH3

12003
(CH2)2CH3

12004
CH(CH3)2

12005
(CH2)3CH3

12006
CH2CH(CH3)2

12007
CH(CH3)CH2CH3

12008
C(CH3)3

12009
(CH2)4CH3

12010
(CH2)5CH3

12011
(CH2)6CH3

12012
(CH2)7CH3

12013
(CH2)8CH3

12014
cyclopropyl

12015
cyclobutyl

12016
cyclohexyl

12017
Ph

12018
PhCH2

12019
Ph(CH2)2

12020
Ph(CH2)3

12021
PhO(CH2)2

12022
PhCH2OCH2CH2

12023
PhCH2O(C═O)CH2CH2

12024
o-CH3Ph

12025
m-CH3Ph

12026
p-CH3Ph

12027
2,4-(CH3)2Ph

12028
3,5-(CH3)2Ph

12029
2,4,6-(CH3)3Ph

12030
p-CH3OPh

12031
p-CH3CH2OPh

12032
p-CH3(CH2)2OPh

12033
p-FPh

12034
p-ClPh

12035
p-BrPh

12036
p-IPh

12037
p-PhOPh

12038
p-PhCH2OPh

12039
p-NO2Ph

12040
p-CNPh

12041
p-CH3SO2Ph

12042

255

12043

256

12044

257

12045

258

12046

259

12047

260

12048

261

12049

262

12050

263

12051

264

12052

265

12053

266

12054

267

12055

268

12056

269

12057

270

12058

271

12059

272

12060

273

12061

274

12062

275

[0072]

13

TABLE 13

276

Compound No.
R2

13001
CH3

13002
CH2CH3

13003
(CH2)2CH3

13004
CH(CH3)2

13005
(CH2)3CH3

13006
CH2CH(CH3)2

13007
CH(CH3)CH2CH3

13008
C(CH3)3

13009
(CH2)4CH3

13010
(CH2)5CH3

13011
(CH2)6CH3

13012
(CH2)7CH3

13013
(CH2)8CH3

13014
cyclopropyl

13015
cyclobutyl

13016
cyclohexyl

13017
Ph

13018
PhCH2

13019
Ph(CH2)2

13020
Ph(CH2)3

13021
PhO(CH2)2

13022
PhCH2OCH2CH2

13023
PhCH2O(C═O)CH2CH2

13024
o-CH3Ph

13025
m-CH3Ph

13026
p-CH3Ph

13027
2,4-(CH3)2Ph

13028
3,5-(CH3)2Ph

13029
2,4,6-(CH3)3Ph

13030
p-CH3OPh

13031
p-CH3CH2OPh

13032
p-CH3(CH2)2OPh

13033
p-FPh

13034
p-ClPh

13035
p-BrPh

13036
p-IPh

13037
p-PhOPh

13038
p-PhCH2OPh

13039
p-NO2Ph

13040
p-CNPh

13041
p-CH3SO2Ph

13042

277

13043

278

13044

279

13045

280

13046

281

13047

282

13048

283

13049

284

13050

285

13051

286

13052

287

13053

288

13054

289

13055

290

13056

291

13057

292

13058

293

13059

294

13060

295

13061

296

13062

297

[0073]

14

TABLE 14

298

Compound No.
R2

14001
CH3

14002
CH2CH3

14003
(CH2)2CH3

14004
CH(CH3)2

14005
(CH2)3CH3

14006
CH2CH(CH3)2

14007
CH(CH3)CH2CH3

14008
C(CH3)3

14009
(CH2)4CH3

14010
(CH2)5CH3

14011
(CH2)6CH3

14012
(CH2)7CH3

14013
(CH2)8CH3

14014
cyclopropyl

14015
cyclobutyl

14016
cyclohexyl

14017
Ph

14018
PhCH2

14019
Ph(CH2)2

14020
Ph(CH2)3

14021
PhO(CH2)2

14022
PhCH2OCH2CH2

14023
PhCH2O(C═O)CH2CH2

14024
o-CH3Ph

14025
m-CH3Ph

14026
p-CH3Ph

14027
2,4-(CH3)2Ph

14028
3,5-(CH3)2Ph

14029
2,4,6-(CH3)3Ph

14030
p-CH3OPh

14031
p-CH3CH2OPh

14032
p-CH3(CH2)2OPh

14033
p-FPh

14034
p-ClPh

14035
p-BrPh

14036
p-IPh

14037
p-PhOPh

14038
p-PhCH2OPh

14039
p-NO2Ph

14040
p-CNPh

14041
p-CH3SO2Ph

14042

299

14043

300

14044

301

14045

302

14046

303

14047

304

14048

305

14049

306

14050

307

14051

308

14052

309

14053

310

14054

311

14055

312

14056

313

14057

314

14058

315

14059

316

14060

317

14061

318

14062

319

[0074]

15

TABLE 15

320

Compound No.
R2

15001
CH3

15002
CH2CH3

15003
(CH2)2CH3

15004
CH(CH3)2

15005
(CH2)3CH3

15006
CH2CH(CH3)2

15007
CH(CH3)CH2CH3

15008
C(CH3)3

15009
(CH2)4CH3

15010
(CH2)5CH3

15011
(CH2)6CH3

15012
(CH2)7CH3

15013
(CH2)8CH3

15014
cyclopropyl

15015
cyclobutyl

15016
cyclohexyl

15017
Ph

15018
PhCH2

15019
Ph(CH2)2

15020
Ph(CH2)3

15021
PhO(CH2)2

15022
PhCH2OCH2CH2

15023
PhCH2O(C═O)CH2CH2

15024
o-CH3Ph

15025
m-CH3Ph

15026
p-CH3Ph

15027
2,4-(CH3)2Ph

15028
3,5-(CH3)2Ph

15029
2,4,6-(CH3)3Ph

15030
p-CH3OPh

15031
p-CH3CH2OPh

15032
p-CH3(CH2)2OPh

15033
p-FPh

15034
p-ClPh

15035
p-BrPh

15036
p-IPh

15037
p-PhOPh

15038
p-PhCH2OPh

15039
p-NO2Ph

15040
p-CNPh

15041
p-CH3SO2Ph

15042

321

15043

322

15044

323

15045

324

15046

325

15047

326

15048

327

15049

328

15050

329

15051

330

15052

331

15053

332

15054

333

15055

334

15056

335

15057

336

15058

337

15059

338

15060

339

15061

340

15062

341

[0075]

16

TABLE 16

342

Compound No.
R2

16001
CH3

16002
CH2CH3

16003
(CH2)2CH3

16004
CH(CH3)2

16005
(CH2)3CH3

16006
CH2CH(CH3)2

16007
CH(CH3)CH2CH3

16008
C(CH3)3

16009
(CH2)4CH3

16010
(CH2)5CH3

16011
(CH2)6CH3

16012
(CH2)7CH3

16013
(CH2)8CH3

16014
cyclopropyl

16015
cyclobutyl

16016
cyclohexyl

16017
Ph

16018
PhCH2

16019
Ph(CH2)2

16020
Ph(CH2)3

16021
PhO(CH2)2

16022
PhCH2OCH2CH2

16023
PhCH2O(C═O)CH2CH2

16024
o-CH3Ph

16025
m-CH3Ph

16026
p-CH3Ph

16027
2,4-(CH3)2Ph

16028
3,5-(CH3)2Ph

16029
2,4,6-(CH3)3Ph

16030
p-CH3OPh

16031
p-CH3CH2OPh

16032
p-CH3(CH2)2OPh

16033
p-FPh

16034
p-ClPh

16035
p-BrPh

16036
p-IPh

16037
p-PhOPh

16038
p-PhCH2OPh

16039
p-NO2Ph

16040
p-CNPh

16041
p-CH3SO2Ph

16042

343

16043

344

16044

345

16045

346

16046

347

16047

348

16048

349

16049

350

16050

351

16051

352

16052

353

16053

354

16054

355

16055

356

16056

357

16057

358

16058

359

16059

360

16060

361

16061

362

16062

363

[0076]

17

TABLE 17

364

Compound No.
R2

17001
CH3

17002
CH2CH3

17003
(CH2)2CH3

17004
CH(CH3)2

17005
(CH2)3CH3

17006
CH2CH(CH3)2

17007
CH(CH3)CH2CH3

17008
C(CH3)3

17009
(CH2)4CH3

17010
(CH2)5CH3

17011
(CH2)6CH3

17012
(CH2)7CH3

17013
(CH2)8CH3

17014
cyclopropyl

17015
cyclobutyl

17016
cyclohexyl

17017
Ph

17018
PhCH2

17019
Ph(CH2)2

17020
Ph(CH2)3

17021
PhO(CH2)2

17022
PhCH2OCH2CH2

17023
PhCH2O(C═O)CH2CH2

17024
o-CH3Ph

17025
m-CH3Ph

17026
p-CH3Ph

17027
2,4-(CH3)2Ph

17028
3,5-(CH3)2Ph

17029
2,4,6-(CH3)3Ph

17030
p-CH3OPh

17031
p-CH3CH2OPh

17032
p-CH3(CH2)2OPh

17033
p-FPh

17034
p-ClPh

17035
p-BrPh

17036
p-IPh

17037
p-PhOPh

17038
p-PhCH2OPh

17039
p-NO2Ph

17040
p-CNPh

17041
p-CH3SO2Ph

17042

365

17043

366

17044

367

17045

368

17046

369

17047

370

17048

371

17049

372

17050

373

17051

374

17052

375

17053

376

17054

377

17055

378

17056

379

17057

380

17058

381

17059

382

17060

383

17061

384

17062

385

[0077]

18

TABLE 18

386

Compound No.
R2

18001
CH3

18002
CH2CH3

18003
(CH2)2CH3

18004
CH(CH3)2

18005
(CH2)3CH3

18006
CH2CH(CH3)2

18007
CH(CH3)CH2CH3

18008
C(CH3)3

18009
(CH2)4CH3

18010
(CH2)5CH3

18011
(CH2)6CH3

18012
(CH2)7CH3

18013
(CH2)8CH3

18014
cyclopropyl

18015
cyclobutyl

18016
cyclohexyl

18017
Ph

18018
PhCH2

18019
Ph(CH2)2

18020
Ph(CH2)3

18021
PhO(CH2)2

18022
PhCH2OCH2CH2

18023
PhCH2O(C═O)CH2CH2

18024
o-CH3Ph

18025
m-CH3Ph

18026
p-CH3Ph

18027
2,4-(CH3)2Ph

18028
3,5-(CH3)2Ph

18029
2,4,6-(CH3)3Ph

18030
p-CH3OPh

18031
p-CH3CH2OPh

18032
p-CH3(CH2)2OPh

18033
p-FPh

18034
p-ClPh

18035
p-BrPh

18036
p-IPh

18037
p-PhOPh

18038
p-PhCH2OPh

18039
p-NO2Ph

18040
p-CNPh

18041
p-CH3SO2Ph

18042

387

18043

388

18044

389

18045

390

18046

391

18047

392

18048

393

18049

394

18050

395

18051

396

18052

397

18053

398

18054

399

18055

400

18056

401

18057

402

18058

403

18059

404

18060

405

18061

406

18062

407

[0078]

19

TABLE 19

408

Compound No.
R2

19001
CH3

19002
CH2CH3

19003
(CH2)2CH3

19004
CH(CH3)2

19005
(CH2)3CH3

19006
CH2CH(CH3)2

19007
CH(CH3)CH2CH3

19008
C(CH3)3

19009
(CH2)4CH3

19010
(CH2)5CH3

19011
(CH2)6CH3

19012
(CH2)7CH3

19013
(CH2)8CH3

19014
cyclopropyl

19015
cyclobutyl

19016
cyclohexyl

19017
Ph

19018
PhCH2

19019
Ph(CH2)2

19020
Ph(CH2)3

19021
PhO(CH2)2

19022
PhCH2OCH2CH2

19023
PhCH2O(C═O)CH2CH2

19024
o-CH3Ph

19025
m-CH3Ph

19026
p-CH3Ph

19027
2,4-(CH3)2Ph

19028
3,5-(CH3)2Ph

19029
2,4,6-(CH3)3Ph

19030
p-CH3OPh

19031
p-CH3CH2OPh

19032
p-CH3(CH2)2OPh

19033
p-FPh

19034
p-ClPh

19035
p-BrPh

19036
p-IPh

19037
p-PhOPh

19038
p-PhCH2OPh

19039
p-NO2Ph

19040
p-CNPh

19041
p-CH3SO2Ph

19042

409

19043

410

19044

411

19045

412

19046

413

19047

414

19048

415

19049

416

19050

417

19051

418

19052

419

19053

420

19054

421

19055

422

19056

423

19057

424

19058

425

19059

426

19060

427

19061

428

19062

429

[0079]

20

TABLE 20

430

Compound No.
R2

20001
CH3

20002
CH2CH3

20003
(CH2)2CH3

20004
CH(CH3)2

20005
(CH2)3CH3

20006
CH2CH(CH3)2

20007
CH(CH3)CH2CH3

20008
C(CH3)3

20009
(CH2)4CH3

20010
(CH2)5CH3

20011
(CH2)6CH3

20012
(CH2)7CH3

20013
(CH2)8CH3

20014
cyclopropyl

20015
cyclobutyl

20016
cyclohexyl

20017
Ph

20018
PhCH2

20019
Ph(CH2)2

20020
Ph(CH2)3

20021
PhO(CH2)2

20022
PhCH2OCH2CH2

20023
PhCH2O(C═O)CH2CH2

20024
o-CH3Ph

20025
m-CH3Ph

20026
p-CH3Ph

20027
2,4-(CH3)2Ph

20028
3,5-(CH3)2Ph

20029
2,4,6-(CH3)3Ph

20030
p-CH3OPh

20031
p-CH3CH2OPh

20032
p-CH3(CH2)2OPh

20033
p-FPh

20034
p-ClPh

20035
p-BrPh

20036
p-IPh

20037
p-PhOPh

20038
p-PhCH2OPh

20039
p-NO2Ph

20040
p-CNPh

20041
p-CH3SO2Ph

20042

431

20043

432

20044

433

20045

434

20046

435

20047

436

20048

437

20049

438

20050

439

20051

440

20052

441

20053

442

20054

443

20055

444

20056

445

20057

446

20058

447

20059

448

20060

449

20061

450

20062

451

[0080]

21

TABLE 21

452

Compound No.
R2

21001
CH3

21002
CH2CH3

21003
(CH2)2CH3

21004
CH(CH3)2

21005
(CH2)3CH3

21006
CH2CH(CH3)2

21007
CH(CH3)CH2CH3

21008
C(CH3)3

21009
(CH2)4CH3

21010
(CH2)5CH3

21011
(CH2)6CH3

21012
(CH2)7CH3

21013
(CH2)8CH3

21014
cyclopropyl

21015
cyclobutyl

21016
cyclohexyl

21017
Ph

21018
PhCH2

21019
Ph(CH2)2

21020
Ph(CH2)3

21021
PhO(CH2)2

21022
PhCH2OCH2CH2

21023
PhCH2O(C═O)CH2CH2

21024
o-CH3Ph

21025
m-CH3Ph

21026
p-CH3Ph

21027
2,4-(CH3)2Ph

21028
3,5-(CH3)2Ph

21029
2,4,6-(CH3)3Ph

21030
p-CH3OPh

21031
p-CH3CH2OPh

21032
p-CH3(CH2)2OPh

21033
p-FPh

21034
p-ClPh

21035
p-BrPh

21036
p-IPh

21037
p-PhOPh

21038
p-PhCH2OPh

21039
p-NO2Ph

21040
p-CNPh

21041
p-CH3SO2Ph

21042

453

21043

454

21044

455

21045

456

21046

457

21047

458

21048

459

21049

460

21050

461

21051

462

21052

463

21053

464

21054

465

21055

466

21056

467

21057

468

21058

469

21059

470

21060

471

21061

472

21062

473

[0081]

22

TABLE 22

474

Compound No.
R2

22001
CH3

22002
CH2CH3

22003
(CH2)2CH3

22004
CH(CH3)2

22005
(CH2)3CH3

22006
CH2CH(CH3)2

22007
CH(CH3)CH2CH3

22008
C(CH3)3

22009
(CH2)4CH3

22010
(CH2)5CH3

22011
(CH2)6CH3

22012
(CH2)7CH3

22013
(CH2)8CH3

22014
cyclopropyl

22015
cyclobutyl

22016
cyclohexyl

22017
Ph

22018
PhCH2

22019
Ph(CH2)2

22020
Ph(CH2)3

22021
PhO(CH2)2

22022
PhCH2OCH2CH2

22023
PhCH2O(C═O)CH2CH2

22024
o-CH3Ph

22025
m-CH3Ph

22026
p-CH3Ph

22027
2,4-(CH3)2Ph

22028
3,5-(CH3)2Ph

22029
2,4,6-(CH3)3Ph

22030
p-CH3OPh

22031
p-CH3CH2OPh

22032
p-CH3(CH2)2OPh

22033
p-FPh

22034
p-ClPh

22035
p-BrPh

22036
p-IPh

22037
p-PhOPh

22038
p-PhCH2OPh

22039
p-NO2Ph

22040
p-CNPh

22041
p-CH3SO2Ph

22042

475

22043

476

22044

477

22045

478

22046

479

22047

480

22048

481

22049

482

22050

483

22051

484

22052

485

22053

486

22054

487

22055

488

22056

489

22057

490

22058

491

22059

492

22060

493

22061

494

22062

495

[0082]

23

TABLE 23

496

Compound No.
R2

23001
CH3

23002
CH2CH3

23003
(CH2)2CH3

23004
CH(CH3)2

23005
(CH2)3CH3

23006
CH2CH(CH3)2

23007
CH(CH3)CH2CH3

23008
C(CH3)3

23009
(CH2)4CH3

23010
(CH2)5CH3

23011
(CH2)6CH3

23012
(CH2)7CH3

23013
(CH2)8CH3

23014
cyclopropyl

23015
cyclobutyl

23016
cyclohexyl

23017
Ph

23018
PhCH2

23019
Ph(CH2)2

23020
Ph(CH2)3

23021
PhO(CH2)2

23022
PhCH2OCH2CH2

23023
PhCH2O(C═O)CH2CH2

23024
o-CH3Ph

23025
m-CH3Ph

23026
p-CH3Ph

23027
2,4-(CH3)2Ph

23028
3,5-(CH3)2Ph

23029
2,4,6-(CH3)3Ph

23030
p-CH3OPh

23031
p-CH3CH2OPh

23032
p-CH3(CH2)2OPh

23033
p-FPh

23034
p-ClPh

23035
p-BrPh

23036
p-IPh

23037
p-PhOPh

23038
p-PhCH2OPh

23039
p-NO2Ph

23040
p-CNPh

23041
p-CH3SO2Ph

23042

497

23043

498

23044

499

23045

500

23046

501

23047

502

23048

503

23049

504

23050

505

23051

506

23052

507

23053

508

23054

509

23055

510

23056

511

23057

512

23058

513

23059

514

23060

515

23061

516

23062

517

[0083]

24

TABLE 24

518

Compound No.
R2

24001
CH3

24002
CH2CH3

24003
(CH2)2CH3

24004
CH(CH3)2

24005
(CH2)3CH3

24006
CH2CH(CH3)2

24007
CH(CH3)CH2CH3

24008
C(CH3)3

24009
(CH2)4CH3

24010
(CH2)5CH3

24011
(CH2)6CH3

24012
(CH2)7CH3

24013
(CH2)8CH3

24014
cyclopropyl

24015
cyclobutyl

24016
cyclohexyl

24017
Ph

24018
PhCH2

24019
Ph(CH2)2

24020
Ph(CH2)3

24021
PhO(CH2)2

24022
PhCH2OCH2CH2

24023
PhCH2O(C═O)CH2CH2

24024
o-CH3Ph

24025
m-CH3Ph

24026
p-CH3Ph

24027
2,4-(CH3)2Ph

24028
3,5-(CH3)2Ph

24029
2,4,6-(CH3)3Ph

24030
p-CH3OPh

24031
p-CH3CH2OPh

24032
p-CH3(CH2)2OPh

24033
p-FPh

24034
p-ClPh

24035
p-BrPh

24036
p-IPh

24037
p-PhOPh

24038
p-PhCH2OPh

24039
p-NO2Ph

24040
p-CNPh

24041
p-CH3SO2Ph

24042

519

24043

520

24044

521

24045

522

24046

523

24047

524

24048

525

24049

526

24050

527

24051

528

24052

529

24053

530

24054

531

24055

532

24056

533

24057

534

24058

535

24059

536

24060

537

24061

538

24062

539

[0084]

25

TABLE 25

540

Compound No.
R2

25001
CH3

25002
CH2CH3

25003
(CH2)2CH3

25004
CH(CH3)2

25005
(CH2)3CH3

25006
CH2CH(CH3)2

25007
CH(CH3)CH2CH3

25008
C(CH3)3

25009
(CH2)4CH3

25010
(CH2)5CH3

25011
(CH2)6CH3

25012
(CH2)7CH3

25013
(CH2)8CH3

25014
cyclopropyl

25015
cyclobutyl

25016
cyclohexyl

25017
Ph

25018
PhCH2

25019
Ph(CH2)2

25020
Ph(CH2)3

25021
PhO(CH2)2

25022
PhCH2OCH2CH2

25023
PhCH2O(C═O)CH2CH2

25024
o-CH3Ph

25025
m-CH3Ph

25026
p-CH3Ph

25027
2,4-(CH3)2Ph

25028
3,5-(CH3)2Ph

25029
2,4,6-(CH3)3Ph

25030
p-CH3OPh

25031
p-CH3CH2OPh

25032
p-CH3(CH2)2OPh

25033
p-FPh

25034
p-ClPh

25035
p-BrPh

25036
p-IPh

25037
p-PhOPh

25038
p-PhCH2OPh

25039
p-NO2Ph

25040
p-CNPh

25041
p-CH3SO2Ph

25042

541

25043

542

25044

543

25045

544

25046

545

25047

546

25048

547

25049

548

25050

549

25051

550

25052

551

25053

552

25054

553

25055

554

25056

555

25057

556

25058

557

25059

558

25060

559

25061

560

25062

561

[0085]

26

TABLE 26

562

Compound No.
R2

26001
CH3

26002
CH2CH3

26003
(CH2)2CH3

26004
CH(CH3)2

26005
(CH2)3CH3

26006
CH2CH(CH3)2

26007
CH(CH3)CH2CH3

26008
C(CH3)3

26009
(CH2)4CH3

26010
(CH2)5CH3

26011
(CH2)6CH3

26012
(CH2)7CH3

26013
(CH2)8CH3

26014
cyclopropyl

26015
cyclobutyl

26016
cyclohexyl

26017
Ph

26018
PhCH2

26019
Ph(CH2)2

26020
Ph(CH2)3

26021
PhO(CH2)2

26022
PhCH2OCH2CH2

26023
PhCH2O(C═O)CH2CH2

26024
o-CH3Ph

26025
m-CH3Ph

26026
p-CH3Ph

26027
2,4-(CH3)2Ph

26028
3,5-(CH3)2Ph

26029
2,4,6-(CH3)3Ph

26030
p-CH3OPh

26031
p-CH3CH2OPh

26032
p-CH3(CH2)2OPh

26033
p-FPh

26034
p-ClPh

26035
p-BrPh

26036
p-IPh

26037
p-PhOPh

26038
p-PhCH2OPh

26039
p-NO2Ph

26040
p-CNPh

26041
p-CH3SO2Ph

26042

563

26043

564

26044

565

26045

566

26046

567

26047

568

26048

569

26049

570

26050

571

26051

572

26052

573

26053

574

26054

575

26055

576

26056

577

26057

578

26058

579

26059

580

26060

581

26061

582

26062

583

[0086]

27

TABLE 27

584

Compound No.
R2

27001
CH3

27002
CH2CH3

27003
(CH2)2CH3

27004
CH(CH3)2

27005
(CH2)3CH3

27006
CH2CH(CH3)2

27007
CH(CH3)CH2CH3

27008
C(CH3)3

27009
(CH2)4CH3

27010
(CH2)5CH3

27011
(CH2)6CH3

27012
(CH2)7CH3

27013
(CH2)8CH3

27014
cyclopropyl

27015
cyclobutyl

27016
cyclohexyl

27017
Ph

27018
PhCH2

27019
Ph(CH2)2

27020
Ph(CH2)3

27021
PhO(CH2)2

27022
PhCH2OCH2CH2

27023
PhCH2O(C═O)CH2CH2

27024
o-CH3Ph

27025
m-CH3Ph

27026
p-CH3Ph

27027
2,4-(CH3)2Ph

27028
3,5-(CH3)2Ph

27029
2,4,6-(CH3)3Ph

27030
p-CH3OPh

27031
p-CH3CH2OPh

27032
p-CH3(CH2)2OPh

27033
p-FPh

27034
p-ClPh

27035
p-BrPh

27036
p-IPh

27037
p-PhOPh

27038
p-PhCH2OPh

27039
p-NO2Ph

27040
p-CNPh

27041
p-CH3SO2Ph

27042

585

27043

586

27044

587

27045

588

27046

589

27047

590

27048

591

27049

592

27050

593

27051

594

27052

595

27053

596

27054

597

27055

598

27056

599

27057

600

27058

601

27059

602

27060

603

27061

604

27062

605

[0087]

28

TABLE 28

606

Compound No.
R2

28001
CH3

28002
CH2CH3

28003
(CH2)2CH3

28004
CH(CH3)2

28005
(CH2)3CH3

28006
CH2CH(CH3)2

28007
CH(CH3)CH2CH3

28008
C(CH3)3

28009
(CH2)4CH3

28010
(CH2)5CH3

28011
(CH2)6CH3

28012
(CH2)7CH3

28013
(CH2)8CH3

28014
cyclopropyl

28015
cyclobutyl

28016
cyclohexyl

28017
Ph

28018
PhCH2

28019
Ph(CH2)2

28020
Ph(CH2)3

28021
PhO(CH2)2

28022
PhCH2OCH2CH2

28023
PhCH2O(C═O)CH2CH2

28024
o-CH3Ph

28025
m-CH3Ph

28026
p-CH3Ph

28027
2,4-(CH3)2Ph

28028
3,5-(CH3)2Ph

28029
2,4,6-(CH3)3Ph

28030
p-CH3OPh

28031
p-CH3CH2OPh

28032
p-CH3(CH2)2OPh

28033
p-FPh

28034
p-ClPh

28035
p-BrPh

28036
p-IPh

28037
p-PhOPh

28038
p-PhCH2OPh

28039
p-NO2Ph

28040
p-CNPh

28041
p-CH3SO2Ph

28042

607

28043

608

28044

609

28045

610

28046

611

28047

612

28048

613

28049

614

28050

615

28051

616

28052

617

28053

618

28054

619

28055

620

28056

621

28057

622

28058

623

28059

624

28060

625

28061

626

28062

627

[0088]

29

TABLE 29

628

Compound No.
R2

29001
CH3

29002
CH2CH3

29003
(CH2)2CH3

29004
CH(CH3)2

29005
(CH2)3CH3

29006
CH2CH(CH3)2

29007
CH(CH3)CH2CH3

29008
C(CH3)3

29009
(CH2)4CH3

29010
(CH2)5CH3

29011
(CH2)6CH3

29012
(CH2)7CH3

29013
(CH2)8CH3

29014
cyclopropyl

29015
cyclobutyl

29016
cyclohexyl

29017
Ph

29018
PhCH2

29019
Ph(CH2)2

29020
Ph(CH2)3

29021
PhO(CH2)2

29022
PhCH2OCH2CH2

29023
PhCH2O(C═O)CH2CH2

29024
o-CH3Ph

29025
m-CH3Ph

29026
p-CH3Ph

29027
2,4-(CH3)2Ph

29028
3,5-(CH3)2Ph

29029
2,4,6-(CH3)3Ph

29030
p-CH3OPh

29031
p-CH3CH2OPh

29032
p-CH3(CH2)2OPh

29033
p-FPh

29034
p-ClPh

29035
p-BrPh

29036
p-IPh

29037
p-PhOPh

29038
p-PhCH2OPh

29039
p-NO2Ph

29040
p-CNPh

29041
p-CH3SO2Ph

29042

629

29043

630

29044

631

29045

632

29046

633

29047

634

29048

635

29049

636

29050

637

29051

638

29052

639

29053

640

29054

641

29055

642

29056

643

29057

644

29058

645

29059

646

29060

647

29061

648

29062

649

[0089]

30

TABLE 30

650

Compound No.
R2

30001
CH3

30002
CH2CH3

30003
(CH2)2CH3

30004
CH(CH3)2

30005
(CH2)3CH3

30006
CH2CH(CH3)2

30007
CH(CH3)CH2CH3

30008
C(CH3)3

30009
(CH2)4CH3

30010
(CH2)5CH3

30011
(CH2)6CH3

30012
(CH2)7CH3

30013
(CH2)8CH3

30014
cyclopropyl

30015
cyclobutyl

30016
cyclohexyl

30017
Ph

30018
PhCH2

30019
Ph(CH2)2

30020
Ph(CH2)3

30021
PhO(CH2)2

30022
PhCH2OCH2CH2

30023
PhCH2O(C═O)CH2CH2

30024
o-CH3Ph

30025
m-CH3Ph

30026
p-CH3Ph

30027
2,4-(CH3)2Ph

30028
3,5-(CH3)2Ph

30029
2,4,6-(CH3)3Ph

30030
p-CH3OPh

30031
p-CH3CH2OPh

30032
p-CH3(CH2)2OPh

30033
p-FPh

30034
p-ClPh

30035
p-BrPh

30036
p-IPh

30037
p-PhOPh

30038
p-PhCH2OPh

30039
p-NO2Ph

30040
p-CNPh

30041
p-CH3SO2Ph

30042

651

30043

652

30044

653

30045

654

30046

655

30047

656

30048

657

30049

658

30050

659

30051

660

30052

661

30053

662

30054

663

30055

664

30056

665

30057

666

30058

667

30059

668

30060

669

30061

670

30062

671

[0090]

31

TABLE 31

672

Compound No.
R2

31001
CH3

31002
CH2CH3

31003
(CH2)2CH3

31004
CH(CH3)2

31005
(CH2)3CH3

31006
CH2CH(CH3)2

31007
CH(CH3)CH2CH3

31008
C(CH3)3

31009
(CH2)4CH3

31010
(CH2)5CH3

31011
(CH2)6CH3

31012
(CH2)7CH3

31013
(CH2)8CH3

31014
cyclopropyl

31015
cyclobutyl

31016
cyclohexyl

31017
Ph

31018
PhCH2

31019
Ph(CH2)2

31020
Ph(CH2)3

31021
PhO(CH2)2

31022
PhCH2OCH2CH2

31023
PhCH2O(C═O)CH2CH2

31024
o-CH3Ph

31025
m-CH3Ph

31026
p-CH3Ph

31027
2,4-(CH3)2Ph

31028
3,5-(CH3)2Ph

31029
2,4,6-(CH3)3Ph

31030
p-CH3OPh

31031
p-CH3CH2OPh

31032
p-CH3(CH2)2OPh

31033
p-FPh

31034
p-ClPh

31035
p-BrPh

31036
p-IPh

31037
p-PhOPh

31038
p-PhCH2OPh

31039
p-NO2Ph

31040
p-CNPh

31041
p-CH3SO2Ph

31042

673

31043

674

31044

675

31045

676

31046

677

31047

678

31048

679

31049

680

31050

681

31051

682

31052

683

31053

684

31054

685

31055

686

31056

687

31057

688

31058

689

31059

690

31060

691

31061

692

31062

693

[0091]

32

TABLE 32

694

Compound No.
R2

32001
CH3

32002
CH2CH3

32003
(CH2)2CH3

32004
CH(CH3)2

32005
(CH2)3CH3

32006
CH2CH(CH3)2

32007
CH(CH3)CH2CH3

32008
C(CH3)3

32009
(CH2)4CH3

32010
(CH2)5CH3

32011
(CH2)6CH3

32012
(CH2)7CH3

32013
(CH2)8CH3

32014
cyclopropyl

32015
cyclobutyl

32016
cyclohexyl

32017
Ph

32018
PhCH2

32019
Ph(CH2)2

32020
Ph(CH2)3

32021
PhO(CH2)2

32022
PhCH2OCH2CH2

32023
PhCH2O(C═O)CH2CH2

32024
o-CH3Ph

32025
m-CH3Ph

32026
p-CH3Ph

32027
2,4-(CH3)2Ph

32028
3,5-(CH3)2Ph

32029
2,4,6-(CH3)3Ph

32030
p-CH3OPh

32031
p-CH3CH2OPh

32032
p-CH3(CH2)2OPh

32033
p-FPh

32034
p-ClPh

32035
p-BrPh

32036
p-IPh

32037
p-PhOPh

32038
p-PhCH2OPh

32039
p-NO2Ph

32040
p-CNPh

32041
p-CH3SO2Ph

32042

695

32043

696

32044

697

32045

698

32046

699

32047

700

32048

701

32049

702

32050

703

32051

704

32052

705

32053

706

32054

707

32055

708

32056

709

32057

710

32058

711

32059

712

32060

713

32061

714

32062

715

[0092]

33

TABLE 33

716

Compound No.
R2

33001
CH3

33002
CH2CH3

33003
(CH2)2CH3

33004
CH(CH3)2

33005
(CH2)3CH3

33006
CH2CH(CH3)2

33007
CH(CH3)CH2CH3

33008
C(CH3)3

33009
(CH2)4CH3

33010
(CH2)5CH3

33011
(CH2)6CH3

33012
(CH2)7CH3

33013
(CH2)8CH3

33014
cyclopropyl

33015
cyclobutyl

33016
cyclohexyl

33017
Ph

33018
PhCH2

33019
Ph(CH2)2

33020
Ph(CH2)3

33021
PhO(CH2)2

33022
PhCH2OCH2CH2

33023
PhCH2O(C═O)CH2CH2

33024
o-CH3Ph

33025
m-CH3Ph

33026
p-CH3Ph

33027
2,4-(CH3)2Ph

33028
3,5-(CH3)2Ph

33029
2,4,6-(CH3)3Ph

33030
p-CH3OPh

33031
p-CH3CH2OPh

33032
p-CH3(CH2)2OPh

33033
p-FPh

33034
p-ClPh

33035
p-BrPh

33036
p-IPh

33037
p-PhOPh

33038
p-PhCH2OPh

33039
p-NO2Ph

33040
p-CNPh

33041
p-CH3SO2Ph

33042

717

33043

718

33044

719

33045

720

33046

721

33047

722

33048

723

33049

724

33050

725

33051

726

33052

727

33053

728

33054

729

33055

730

33056

731

33057

732

33058

733

33059

734

33060

735

33061

736

33062

737

[0093]

34

TABLE 34

738

Compound No.
R2

34001
CH3

34002
CH2CH3

34003
(CH2)2CH3

34004
CH(CH3)2

34005
(CH2)3CH3

34006
CH2CH(CH3)2

34007
CH(CH3)CH2CH3

34008
C(CH3)3

34009
(CH2)4CH3

34010
(CH2)5CH3

34011
(CH2)6CH3

34012
(CH2)7CH3

34013
(CH2)8CH3

34014
cyclopropyl

34015
cyclobutyl

34016
cyclohexyl

34017
Ph

34018
PhCH2

34019
Ph(CH2)2

34020
Ph(CH2)3

34021
PhO(CH2)2

34022
PhCH2OCH2CH2

34023
PhCH2O(C═O)CH2CH2

34024
o-CH3Ph

34025
m-CH3Ph

34026
p-CH3Ph

34027
2,4-(CH3)2Ph

34028
3,5-(CH3)2Ph

34029
2,4,6-(CH3)3Ph

34030
p-CH3OPh

34031
p-CH3CH2OPh

34032
p-CH3(CH2)2OPh

34033
p-FPh

34034
p-ClPh

34035
p-BrPh

34036
p-IPh

34037
p-PhOPh

34038
p-PhCH2OPh

34039
p-NO2Ph

34040
p-CNPh

34041
p-CH3SO2Ph

34042

739

34043

740

34044

741

34045

742

34046

743

34047

744

34048

745

34049

746

34050

747

34051

748

34052

749

34053

750

34054

751

34055

752

34056

753

34057

754

34058

755

34059

756

34060

757

34061

758

34062

759

[0094]

35

TABLE 35

760

Compound No.
R2

35001
CH3

35002
CH2CH3

35003
(CH2)2CH3

35004
CH(CH3)2

35005
(CH2)3CH3

35006
CH2CH(CH3)2

35007
CH(CH3)CH2CH3

35008
C(CH3)3

35009
(CH2)4CH3

35010
(CH2)5CH3

35011
(CH2)6CH3

35012
(CH2)7CH3

35013
(CH2)8CH3

35014
cyclopropyl

35015
cyclobutyl

35016
cyclohexyl

35017
Ph

35018
PhCH2

35019
Ph(CH2)2

35020
Ph(CH2)3

35021
PhO(CH2)2

35022
PhCH2OCH2CH2

35023
PhCH2O(C═O)CH2CH2

35024
o-CH3Ph

35025
m-CH3Ph

35026
p-CH3Ph

35027
2,4-(CH3)2Ph

35028
3,5-(CH3)2Ph

35029
2,4,6-(CH3)3Ph

35030
p-CH3OPh

35031
p-CH3CH2OPh

35032
p-CH3(CH2)2OPh

35033
p-FPh

35034
p-ClPh

35035
p-BrPh

35036
p-IPh

35037
p-PhOPh

35038
p-PhCH2OPh

35039
p-NO2Ph

35040
p-CNPh

35041
p-CH3SO2Ph

35042

761

35043

762

35044

763

35045

764

35046

765

35047

766

35048

767

35049

768

350350

769

35051

770

35052

771

35053

772

35054

773

35055

774

35056

775

35057

776

35058

777

35059

778

35060

779

35061

780

35062

781

[0095]

36

TABLE 36

782

Compound No.
R2

36001
CH3

36002
CH2CH3

36003
(CH2)2CH3

36004
CH(CH3)2

36005
(CH2)3CH3

36006
CH2CH(CH3)2

36007
CH(CH3)CH2CH3

36008
C(CH3)3

36009
(CH2)4CH3

36010
(CH2)5CH3

36011
(CH2)6CH3

36012
(CH2)7CH3

36013
(CH2)8CH3

36014
cyclopropyl

36015
cyclobutyl

36016
cyclohexyl

36017
Ph

36018
PhCH2

36019
Ph(CH2)2

36020
Ph(CH2)3

36021
PhO(CH2)2

36022
PhCH2OCH2CH2

36023
PhCH2O(C═O)CH2CH2

36024
o-CH3Ph

36025
m-CH3Ph

36026
p-CH3Ph

36027
2,4-(CH3)2Ph

36028
3,5-(CH3)2Ph

36029
2,4,6-(CH3)3Ph

36030
p-CH3OPh

36031
p-CH3CH2OPh

36032
p-CH3(CH2)2OPh

36033
p-FPh

36034
p-ClPh

36035
p-BrPh

36036
p-IPh

36037
p-PhOPh

36038
p-PhCH2OPh

36039
p-NO2Ph

36040
p-CNPh

36041
p-CH3SO2Ph

36042

783

36043

784

36044

785

36045

786

36046

787

36047

788

36048

789

36049

790

360350

791

36051

792

36052

793

36053

794

36054

795

36055

796

36056

797

36057

798

36058

799

36059

800

360360

801

36061

802

36062

803

[0096]

37

TABLE 37

804

Compound No.
R2

37001
CH3

37002
CH2CH3

37003
(CH2)2CH3

37004
CH(CH3)2

37005
(CH2)3CH3

37006
CH2CH(CH3)2

37007
CH(CH3)CH2CH3

37008
C(CH3)3

37009
(CH2)4CH3

37010
(CH2)5CH3

37011
(CH2)6CH3

37012
(CH2)7CH3

37013
(CH2)8CH3

37014
cyclopropyl

37015
cyclobutyl

37016
cyclohexyl

37017
Ph

37018
PhCH2

37019
Ph(CH2)2

37020
Ph(CH2)3

37021
PhO(CH2)2

37022
PhCH2OCH2CH2

37023
PhCH2O(C═O)CH2CH2

37024
o-CH3Ph

37025
m-CH3Ph

37026
p-CH3Ph

37027
2,4-(CH3)2Ph

37028
3,5-(CH3)2Ph

37029
2,4,6-(CH3)3Ph

37030
p-CH3OPh

37031
p-CH3CH2OPh

37032
p-CH3(CH2)2OPh

37033
p-FPh

37034
p-ClPh

37035
p-BrPh

37036
p-IPh

37037
p-PhOPh

37038
p-PhCH2OPh

37039
p-NO2Ph

37040
p-CNPh

37041
p-CH3SO2Ph

37042

805

37043

806

37044

807

37045

808

37046

809

37047

810

37048

811

37049

812

370350

813

37051

814

37052

815

37053

816

37054

817

37055

818

37056

819

37057

820

37058

821

37059

822

370360

823

37061

824

37062

825

[0097]

38

TABLE 38

826

Compound No.
R2

38001
CH3

38002
CH2CH3

38003
(CH2)2CH3

38004
CH(CH3)2

38005
(CH2)3CH3

38006
CH2CH(CH3)2

38007
CH(CH3)CH2CH3

38008
C(CH3)3

38009
(CH2)4CH3

38010
(CH2)5CH3

38011
(CH2)6CH3

38012
(CH2)7CH3

38013
(CH2)8CH3

38014
cyclopropyl

38015
cyclobutyl

38016
cyclohexyl

38017
Ph

38018
PhCH2

38019
Ph(CH2)2

38020
Ph(CH2)3

38021
PhO(CH2)2

38022
PhCH2OCH2CH2

38023
PhCH2O(C═O)CH2CH2

38024
o-CH3Ph

38025
m-CH3Ph

38026
p-CH3Ph

38027
2,4-(CH3)2Ph

38028
3,5-(CH3)2Ph

38029
2,4,6-(CH3)3Ph

38030
p-CH3OPh

38031
p-CH3CH2OPh

38032
p-CH3(CH2)2OPh

38033
p-FPh

38034
p-ClPh

38035
p-BrPh

38036
p-IPh

38037
p-PhOPh

38038
p-PhCH2OPh

38039
p-NO2Ph

38040
p-CNPh

38041
p-CH3SO2Ph

38042

827

38043

828

38044

829

38045

830

38046

831

38047

832

38048

833

38049

834

380350

835

38051

836

38052

837

38053

838

38054

839

38055

840

38056

841

38057

842

38058

843

38059

844

380360

845

38061

846

38062

847

[0098]

39

TABLE 39

848

Compound No.
R2

39001
CH3

39002
CH2CH3

39003
(CH2)2CH3

39004
CH(CH3)2

39005
(CH2)3CH3

39006
CH2CH(CH3)2

39007
CH(CH3)CH2CH3

39008
C(CH3)3

39009
(CH2)4CH3

39010
(CH2)5CH3

39011
(CH2)6CH3

39012
(CH2)7CH3

39013
(CH2)8CH3

39014
cyclopropyl

39015
cyclobutyl

39016
cyclohexyl

39017
Ph

39018
PhCH2

39019
Ph(CH2)2

39020
Ph(CH2)3

39021
PhO(CH2)2

39022
PhCH2OCH2CH2

39023
PhCH2O(C═O)CH2CH2

39024
o-CH3Ph

39025
m-CH3Ph

39026
p-CH3Ph

39027
2,4-(CH3)2Ph

39028
3,5-(CH3)2Ph

39029
2,4,6-(CH3)3Ph

39030
p-CH3OPh

39031
p-CH3CH2OPh

39032
p-CH3(CH2)2OPh

39033
p-FPh

39034
p-ClPh

39035
p-BrPh

39036
p-IPh

39037
p-PhOPh

39038
p-PhCH2OPh

39039
p-NO2Ph

39040
p-CNPh

39041
p-CH3SO2Ph

39042

849

39043

850

39044

851

39045

852

39046

853

39047

854

39048

855

39049

856

390350

857

39051

858

39052

859

39053

860

39054

861

39055

862

39056

863

39057

864

39058

865

39059

866

390360

867

39061

868

39062

869

[0099]

40

TABLE 40

870

Compound No.
R2

40001
CH3

40002
CH2CH3

40003
(CH2)2CH3

40004
CH(CH3)2

40005
(CH2)3CH3

40006
CH2CH(CH3)2

40007
CH(CH3)CH2CH3

40008
C(CH3)3

40009
(CH2)4CH3

40010
(CH2)5CH3

40011
(CH2)6CH3

40012
(CH2)7CH3

40013
(CH2)8CH3

40014
cyclopropyl

40015
cyclobutyl

40016
cyclohexyl

40017
Ph

40018
PhCH2

40019
Ph(CH2)2

40020
Ph(CH2)3

40021
PhO(CH2)2

40022
PhCH2OCH2CH2

40023
PhCH2O(C═O)CH2CH2

40024
o-CH3Ph

40025
m-CH3Ph

40026
p-CH3Ph

40027
2,4-(CH3)2Ph

40028
3,5-(CH3)2Ph

40029
2,4,6-(CH3)3Ph

40030
p-CH3OPh

40031
p-CH3CH2OPh

40032
p-CH3(CH2)2OPh

40033
p-FPh

40034
p-ClPh

40035
p-BrPh

40036
p-IPh

40037
p-PhOPh

40038
p-PhCH2OPh

40039
p-NO2Ph

40040
p-CNPh

40041
p-CH3SO2Ph

40042

871

40043

872

40044

873

40045

874

40046

875

40047

876

40048

877

40049

878

40050

879

40051

880

40052

881

40053

882

40054

883

40055

884

40056

885

40057

886

40058

887

40059

888

400360

889

40061

890

40062

891

[0100]

41

TABLE 41

892

Compound No.
R2
Compound No.
R2

41001
CH3
41045

893

41002
CH2CH3
41046

894

41003
(CH2)2CH3
41047

895

41004
CH(CH3)2
41048

896

41005
(CH2)3CH3
41049

897

41006
CH2CH(CH3)2
41050

898

41007
CH(CH3)CH2CH3
41051

899

41008
C(CH3)3
41052

900

41009
(CH2)4CH3
41053

901

41010
(CH2)5CH3
41054

902

41011
(CH2)6CH3
41055

903

41012
(CH2)7CH3
41056

904

41013
(CH2)8CH3
41057

905

41014
cyclopropyl
41058

906

41015
cyclobutyl
41059

907

41016
cyclohexyl
41060

908

41017
Ph
41061

909

41018
PhCH2
41062

910

41019
Ph(CH2)2

41020
Ph(CH2)3

41021
PhO(CH2)2

41022
PhCH2OCH2CH2

41023
PhCH2O(C═O)CH2CH2

41024
o-CH3Ph

41025
m-CH3Ph

41026
p-CH3Ph

41027
2,4-(CH3)2Ph

41028
3,5-(CH3)2Ph

41029
2,4,6(CH3)3Ph

41030
p-CH3OPh

41031
p-CH3CH2OPh

41032
p-CH3(CH2)2OPh

41033
p-FPh

41034
p-ClPh

41035
p-BrPh

41036
p-IPh

41037
p-PhOPh

41038
p-PhCH2OPh

41039
p-NO2Ph

41040
p-CNPh

41041
p-CH3SO2Ph

41042

911

41043

912

41044

913

[0101]

42

TABLE 42

914

Compound No.
R2
Compound No.
R2

42001
CH3
42045

915

42002
CH2CH3
42046

916

42003
(CH2)2CH3
42047

917

42004
CH(CH3)2
42048

918

42005
(CH2)3CH3
42049

919

42006
CH2CH(CH3)2
42050

920

42007
CH(CH3)CH2CH3
42051

921

42008
C(CH3)3
42052

922

42009
(CH2)4CH3
42053

923

42010
(CH2)5CH3
42054

924

42011
(CH2)6CH3
42055

925

42012
(CH2)7CH3
42056

926

42013
(CH2)8CH3
42057

927

42014
cyclopropyl
42058

928

42015
cyclobutyl
42059

929

42016
cyclohexyl
42060

930

42017
Ph
42061

931

42018
PhCH2
42062

932

42019
Ph(CH2)2

42020
Ph(CH2)3

42021
PhO(CH2)2

42022
PhCH2OCH2CH2

42023
PhCH2O(C═O)CH2CH2

42024
o-CH3Ph

42025
m-CH3Ph

42026
p-CH3Ph

42027
2,4-(CH3)2Ph

42028
3,5-(CH3)2Ph

42029
2,4,6(CH3)3Ph

42030
p-CH3OPh

42031
p-CH3CH2OPh

42032
p-CH3(CH2)2OPh

42033
p-FPh

42034
p-ClPh

42035
p-BrPh

42036
p-IPh

42037
p-PhOPh

42038
p-PhCH2OPh

42039
p-NO2Ph

42040
p-CNPh

42041
p-CH3SO2Ph

42042

933

42043

934

42044

935

[0102]

43

TABLE 43

936

Compound No.
R2
Compound No.
R2

43001
CH3
43045

937

43002
CH2CH3
43046

938

43003
(CH2)2CH3
43047

939

43004
CH(CH3)2
43048

940

43005
(CH2)3CH3
43049

941

43006
CH2CH(CH3)2
43050

942

43007
CH(CH3)CH2CH3
43051

943

43008
C(CH3)3
43052

944

43009
(CH2)4CH3
43053

945

43010
(CH2)5CH3
43054

946

43011
(CH2)6CH3
43055

947

43012
(CH2)7CH3
43056

948

43013
(CH2)8CH3
43057

949

43014
cyclopropyl
43058

950

43015
cyclobutyl
43059

951

43016
cyclohexyl
43060

952

43017
Ph
43061

953

43018
PhCH2
43062

954

43019
Ph(CH2)2

43020
Ph(CH2)3

43021
PhO(CH2)2

43022
PhCH2OCH2CH2

43023
PhCH2O(C═O)CH2CH2

43024
o-CH3Ph

43025
m-CH3Ph

43026
p-CH3Ph

43027
2,4-(CH3)2Ph

43028
3,5-(CH3)2Ph

43029
2,4,6(CH3)3Ph

43030
p-CH3OPh

43031
p-CH3CH2OPh

43032
p-CH3(CH2)2OPh

43033
p-FPh

43034
p-ClPh

43035
p-BrPh

43036
p-IPh

43037
p-PhOPh

43038
p-PhCH2OPh

43039
p-NO2Ph

43040
p-CNPh

43041
p-CH3SO2Ph

43042

955

43043

956

43044

957

[0103]

44

TABLE 44

958

Compound No.
R2
Compound No.
R2

44001
CH3
44045

959

44002
CH2CH3
44046

960

44003
(CH2)2CH3
44047

961

44004
CH(CH3)2
44048

962

44005
(CH2)3CH3
44049

963

44006
CH2CH(CH3)2
44050

964

44007
CH(CH3)CH2CH3
44051

965

44008
C(CH3)3
44052

966

44009
(CH2)4CH3
44053

967

44010
(CH2)5CH3
44054

968

44011
(CH2)6CH3
44055

969

44012
(CH2)7CH3
44056

970

44013
(CH2)8CH3
44057

971

44014
cyclopropyl
44058

972

44015
cyclobutyl
44059

973

44016
cyclohexyl
44060

974

44017
Ph
44061

975

44018
PhCH2
44062

976

44019
Ph(CH2)2

44020
Ph(CH2)3

44021
PhO(CH2)2

44022
PhCH2OCH2CH2

44023
PhCH2O(C═O)CH2CH2

44024
o-CH3Ph

44025
m-CH3Ph

44026
p-CH3Ph

44027
2,4-(CH3)2Ph

44028
3,5-(CH3)2Ph

44029
2,4,6(CH3)3Ph

44030
p-CH3OPh

44031
p-CH3CH2OPh

44032
p-CH3(CH2)2OPh

44033
p-FPh

44034
p-ClPh

44035
p-BrPh

44036
p-IPh

44037
p-PhOPh

44038
p-PhCH2OPh

44039
p-NO2Ph

44040
p-CNPh

44041
p-CH3SO2Ph

44042

977

44043

978

44044

979

[0104]

45

TABLE 45

980

Compound No.
R2
Compound No.
R2

45001
CH3
45045

981

45002
CH2CH3
45046

982

45003
(CH2)2CH3
45047

983

45004
CH(CH3)2
45048

984

45005
(CH2)3CH3
45049

985

45006
CH2CH(CH3)2
45050

986

45007
CH(CH3)CH2CH3
45051

987

45008
C(CH3)3
45052

988

45009
(CH2)4CH3
45053

989

45010
(CH2)5CH3
45054

990

45011
(CH2)6CH3
45055

991

45012
(CH2)7CH3
45056

992

45013
(CH2)8CH3
45057

993

45014
cyclopropyl
45058

994

45015
cyclobutyl
45059

995

45016
cyclohexyl
45060

996

45017
Ph
45061

997

45018
PhCH2
45062

998

45019
Ph(CH2)2

45020
Ph(CH2)3

45021
PhO(CH2)2

45022
PhCH2OCH2CH2

45023
PhCH2O(C═O)CH2CH2

45024
o-CH3Ph

45025
m-CH3Ph

45026
p-CH3Ph

45027
2,4-(CH3)2Ph

45028
3,5-(CH3)2Ph

45029
2,4,6(CH3)3Ph

45030
p-CH3OPh

45031
p-CH3CH2OPh

45032
p-CH3(CH2)2OPh

45033
p-FPh

45034
p-ClPh

45035
p-BrPh

45036
p-IPh

45037
p-PhOPh

45038
p-PhCH2OPh

45039
p-NO2Ph

45040
p-CNPh

45041
p-CH3SO2Ph

45042

999

45043

1000

45044

1001

[0105]

46

TABLE 46

1002

Compound No.
R2
Compound No.
R2

46001
CH3
46045

1003

46002
CH2CH3
46046

1004

46003
(CH2)2CH3
46047

1005

46004
CH(CH3)2
46048

1006

46005
(CH2)3CH3
46049

1007

46006
CH2CH(CH3)2
46050

1008

46007
CH(CH3)CH2CH3
46051

1009

46008
C(CH3)3
46052

1010

46009
(CH2)4CH3
46053

1011

46010
(CH2)5CH3
46054

1012

46011
(CH2)6CH3
46055

1013

46012
(CH2)7CH3
46056

1014

46013
(CH2)8CH3
46057

1015

46014
cyclopropyl
46058

1016

46015
cyclobutyl
46059

1017

46016
cyclohexyl
46060

1018

46017
Ph
46061

1019

46018
PhCH2
46062

1020

46019
Ph(CH2)2

46020
Ph(CH2)3

46021
PhO(CH2)2

46022
PhCH2OCH2CH2

46023
PhCH2O(C═O)CH2CH2

46024
o-CH3Ph

46025
m-CH3Ph

46026
p-CH3Ph

46027
2,4-(CH3)2Ph

46028
3,5-(CH3)2Ph

46029
2,4,6(CH3)3Ph

46030
p-CH3OPh

46031
p-CH3CH2OPh

46032
p-CH3(CH2)2OPh

46033
p-FPh

46034
p-ClPh

46035
p-BrPh

46036
p-IPh

46037
p-PhOPh

46038
p-PhCH2OPh

46039
p-NO2Ph

46040
p-CNPh

46041
p-CH3SO2Ph

46042

1021

46043

1022

46044

1023

[0106] The compound numbers described in the above tables correspond to the compound numbers to be described in Examples.

[0107] A description will hereinafter be made about certain representative production processes according to the present invention.

[0108] [Production process of an amino acid N-carboxyanhydride with a substituent on a nitrogen atom thereof, which is represented by the formula (1)]

[0109] The compound represented by the formula (1) can be produced by reacting an amino acid N-carboxyanhydride, which is represented by the formula (4), with a compound of the formula (5) or (6).

[0110] Incidentally, the amino acid N-carboxyanhydride represented by the formula (4), which is used as a raw material in the production of the invention compound represented by the formula (1), can be produced by reacting the corresponding available amino acid with phosgene or by causing phosphorus trichloride, thionyl chloride or the like on an amino acid with a nitrogen atom thereof protected by urethane.

[0111] Further, the compound represented by the formula (5) or (6) is readily available from the market or by synthesis in a known manner.

[0112] The reaction temperature may range from −78 to 200° C., preferably from −50 to 50° C. The reaction time, on the other hand, may range from several minutes to 72 hours, preferably from several minutes to 24 hours.

[0113] [Production process of an amide derivative represented by the formula (8)]

[0114] The amidation reaction according to the present invention can be practiced by dissolving an N-substituted NCA in an inert diluent (for example, ethyl acetate) and then cooling the resulting solution under stirring. As an alternative, the reaction can be conducted in the absence of an inert diluent. Next, a solution of a desired amine (including a protected or unprotected amino acid) in an inert solvent (for example, ethyl acetate) is charged dropwise. This charging of the amine into a reaction system may also be conducted in the absence of an inert diluent. To the mixture so obtained, a base (for example, N-methylmorpholine, 4-dimethylaminopyridine or the like) is added. The base can promote a condensation reaction and can eliminate carbonic acid produced during the reaction, although it is not absolutely necessary to add the base.

[0115] Per mole of the N-substituted NCA, the desired amine may be used in an amount of from 1 to 20 equivalents, preferably from 1 to 5 equivalents, and the base, when to be added, may be used in an amount of from 0.1 to 20 equivalents, preferably from 0.1 to 5 equivalents.

[0116] When the inert diluent is used, the concentration of the N-substituted NCA may range from 0.01 to 50 mol/L, with a range of from 0.05 to 20 mol/L being preferred.

[0117] The reaction temperature may range from −78 to 200° C., preferably from −50 to 50° C. The reaction time, on the other hand, may range from several minutes to 72 hours, preferably from several minutes to 24 hours.

[0118] The amide derivative so completed can be purified by washing it with an aqueous acidic solution (for example, an aqueous solution of hydrochloric acid or an aqueous solution of potassium hydrogensulfate) to remove the unreacted amine, by washing it with an aqueous alkaline solution (for example, an aqueous solution of sodium hydroxide or an aqueous solution of sodium hydrogencarbonate) to eliminate byproducts formed by decomposition or the like, or by an operation such as recrystallization making use of an appropriate solvent. The amide derivative obtained by this purification is extremely uniform, and practically requires no further purification. As the concurrent formation of byproducts is very limited, the amide derivative is formed with extremely high yield and its purification is easy.

[0119] A description will next be described about racemization of an amino acid N-carboxyanhydride with a substituent of the acyl type on a nitrogen atom thereof as described herein. This compound can be readily converted into its corresponding diastereomer compound (diamide compound) by conducting a reaction with an optically active compound. It is possible to confirm racemization of the resulting diastereomer compound, because the surplus rate of the diastereomer can be easily determined by analyzing the compound, for example, by high-performance liquid chromatography, nuclear magnetic resonance spectroscopy or the like. The compounds and production processes described herein have been ascertained to be free of the problem of racemization because each of the compounds can be obtained in the form of a single diastereomer compound (diamide compound) alone by conducting the reaction under appropriate conditions.

[0120] Incidentally, the amine substituted by R3 and R4, which is represented by the formula (7) and is used as a raw material in the production of the invention compound represented by the formula (8), is readily available from the market or by synthesis in a known manner.

EXAMPLES

[0121] Examples and Referential Examples of the present invention will hereinafter be described. It should, however, be borne in mind that the present invention is by no means limited by them.

Example 1

Synthesis of (S)-3-benzoyl-4-methyl-2,5-oxazolidinedione (L-N-benzoylalaline-NCA)

[0122]

1024

[0123] (S)-4-Methyl-2,5-oxazolidinedione (L-alanine-NCA) (230 mg, 2.0 mmol) was dissolved in ethyl acetate (23 mL), followed by the addition of benzoyl chloride (365 mg, 2.6 mmol) under ice cooling. Further, a solution of 4-dimethylaminopyridine (318 mg, 2.6 mmol) in ethyl acetate (11 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 3 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in a mixed solvent consisting of ethyl acetate (5 mL) and hexane (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound as white crystals (351 mg, 80%).

[0124] Melting point: 104.2-105.1° C.(dec.)

[0125]

1
H-N.M.R.(CDCl3, 400 MHz) δ 1.74(3H, d, J=6.8 Hz), 5.13(1H, q, J=6.8 Hz), 7.44-7.54(2H, m), 7.61-7.65(1H, m), 7.72-7.75(2H, m).

[0126] IR(KBr)νmax 3379, 3074, 2991, 1865, 1822, 1698 cm−1

Example 2

Synthesis of (S)-3-benzoyl-4-methyl-2,5-oxazolidinedione (L-N-benzoylalaline-NCA) (Compound No. 1017)

[0127] 4-Dimethylaminopyridine (61 mg, 0.5 mmol) and N-methylmorpholine (152 mg, 1.5 mmol) were dissolved in ethyl acetate (15 mL), followed by the addition of (S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (230 mg, 2.0 mmol) under ice cooling. Further, a solution of benzoyl chloride (281 mg, 2.0 mmol) in ethyl acetate (7 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in a mixed solvent consisting of ethyl acetate (5 mL) and hexane (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound as white crystals (324 mg, 74%).

Example 3

Synthesis of (S)-3-benzoyl-4-isopropyl-2,5-oxazolidinedione (L-N-benzoylvaline-NCA)

[0128]

1025

[0129] Benzoyl chloride (295 mg, 2.1 mmol) was dissolved in ethyl acetate (21 mL), followed by the addition of (S)-4-isopropyl-2,5-oxazolidinedione (L-valine-NCA) (286 mg, 2.0 mmol) under ice cooling. Further, a solution of 4-dimethylaminopyridine (257 mg, 2.1 mmol) in ethyl acetate (11 mL) was added dropwise under ice cooling over 20 minutes. The resulting mixture was allowed to rise as was in temperature from 09. After the mixture was stirred at room temperature for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in a mixed solvent consisting of ethyl acetate (5 mL) and hexane (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound as white crystals (351 mg, 80%).

[0130] Melting point: 124.8-125.9° C. (dec.) 1H-N.M.R.(CDCl3, 400 MHz) δ 1.09(3H, d, J=6.8 Hz), 1.26(3H, d, J=7.1 Hz), 2.51(1H, m), 5.09(1H, d, J=3.7 Hz), 7.47-7.52(2H, m), 7.62-7.66(1H, m), 7.74-7.77(2H, m).

[0131] IR(KBr)νmax 2969, 2937, 2879, 1862, 1816, 1694 cm−1

Example 4

Synthesis of (S)-3-benzoyl-4-tert-butyl-2,5-oxazolidinedione (L-N-benzoyl-tert-leucine-NCA) (Compound No. 9017)

[0132]

1026

[0133] In a similar manner as in Example 3, the title compound was obtained as white crystals (341 mg, 65%) by using benzoyl chloride (295 mg, 2.1 mmol), (S)-4-tert-butyl-2,5-oxazolidinedione (L-tert-leucine-NCA)(314 mg, 2.0 mmol), 4-dimethylaminopyridine (257 mg, 2.1 mmol) and ethyl acetate (32 mL).

[0134] Melting point: 127.8-128.9° C.(dec.)

[0135]

1
H-N.M.R.(CDCl3, 400 MHz) δ 1.15(9H, s), 5.10(1H, s), 7.52(2H, t, J=8.1 Hz), 7.67(1H,t, J=7.3 Hz), 7.86(2H, dd,J=1.2,8.3 Hz).

[0136] IR(KBr)νmax 2983, 2963, 2876, 1860, 1808, 1704 cm−1

Example 5

Synthesis of (S)-3-benzoyl-4-phenyl-2,5-oxazolidinedione (L-N-benzoylphenylalanine-NCA) (Compound No. 35017)

[0137]

1027

[0138] In a similar manner as in Example 3, the title compound was obtained as white crystals (476 mg, 81%) by using benzoyl chloride (295 mg, 2.1 mmol), (S)-4-phenyl-2,5-oxazolidinedione (L-phenylalanine-NCA)(382 mg, 2.0 mmol), 4-dimethylaminopyridine (257 mg, 2.1 mmol) and ethyl acetate (32 mL).

[0139] Melting point: 125.8-126.4° C. (dec.)

[0140]

1
H-N.M.R.(CDCl3, 400 MHz) δ 3.50(1H, d, J=2.9 Hz), 3.51(1H, d, J=5.6 Hz), 5.36(1H, dd, J=2.9, 5.6 Hz), 7.09-7.11(2H, m), 7.31-7.36(3H, m), 7.39-7.45(4H, m), 7.57-7.60(1H, m).

[0141] IR(KBr)νmax 3070, 3031, 1867, 1786, 1708 cm−1

Example 6

Synthesis of (S)-3-benzoyl-4-benzyloxy-carbonylethyl-2,5-oxazolidinedione (L-N-benzoyl-O-benzylglutamic acid-NCA) (Compound No. 17017)

[0142]

1028

[0143] In a similar manner as in Example 3, the title compound was obtained as white crystals (573 mg, 78%) by using benzoyl chloride (295 mg, 2.1 mmol), (S)-4-benzyloxycarbonylethyl-2,5-oxazolidinedione (L-N-benzoyl-O-benzylglutamic acid-NCA)(527 mg, 2.0 mmol), 4-dimethylaminopyridine (257 mg, 2.1 mmol) and ethyl acetate (32 mL).

[0144] Melting point: 94.5-94.9° C. (dec.)

[0145]

1
H-N.M.R.(CDCl3, 400 MHz) δ 2.47-2.50(2H, m), 2.53-2.63(2H, m), 5.09(1H, d, J=12.0 Hz), 5.14(1H, d, J=12.2 Hz), 5.21(1H, t, J=5.5 Hz), 7.32-7.39(5H, m), 7.43-7.47(2H, m), 7.61(1H, t, J=7.6 Hz), 7.69(2H, dd, J=1.2, 8.1 Hz). IR(KBr)νmax 3258, 3065, 2964, 1869, 1805, 1731, 1701 cm−1

Example 7

Synthesis of (S)-3-(p-methylbenzoyl)-4-methyl-2,5-oxazolidinedione (L-N-(p-methylbenzoyl)-alanine-NCA) (Compound No. 1026)

[0146]

1029

[0147] p-Methylbenzoyl chloride (309 mg, 2.0 mmol) was dissolved in ethyl acetate (5 mL), followed by the addition of (S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (230 mg, 2.0 mmol) under ice cooling. Further, a solution of 4-dimethylaminopyridine (244 mg, 2.0 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in a mixed solvent consisting of ethyl acetate (5 mL) and hexane (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound (152 mg, 33%) as a colorless clear syrup.

[0148]

1
H-N.M.R.(CDCl3, 400 MHz) δ 1.72(3H, d, J=7.1 Hz), 2.44(3H, s), 5.14(1H, q, J=7.1 Hz), 7.29(2H, d, J=8.1 Hz), 7.65(2H, d, J=8.3 Hz).

[0149] IR(KBr)νmax 3278, 2998, 2942, 1853, 1835, 1694 cm−1

Example 8

Synthesis of (S)-3-(p-bromobenzoyl)-4-methyl-2,5-oxazolidinedione (L-N-(p-bromobenzoyl)-alanine-NCA) (Compound No. 1035)

[0150]

1030

[0151] In a similar manner as in Example 7, the title compound (238 mg, 40%) was obtained as a colorless clear syrup by using p-bromobenzoyl chloride (439 mg, 2.0 mmol), (S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA)(230 mg, 2.0 mmol), 4-dimethylaminopyridine (244 mg, 2.0 mmol) and ethyl acetate (15 mL).

[0152]

1
H-N.M .R.(CDCl3, 400 MHz) δ 1.74(3H, d, J=6.8 Hz), 5.13(1H, q, J=6.8 Hz), 7.61(2H, d, J=2.3 Hz), 7.63(2H, d, J=2.3 Hz).

[0153] IR(KBr)νmax 3350, 2998, 2942, 1855, 1840, 1698 cm−1

Example 9

Synthesis of (S)-3-acetyl-4-methyl-2,5-oxazolidinedione (L-N-acetylalanine-NCA) (Compound No. 1001)

[0154]

1031

[0155] (S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of acetyl chloride (306 mg, 3.9 mmol) under ice cooling. Further, a solution of N-methyl-morpholine (394 mg, 3.9 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in chloroform (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound (350 mg, 74%) as a colorless clear syrup.

[0156]

1
H-N.M.R.(CDCl3, 400 MHz) δ 1.69(3H, d, J=6.9 Hz), 2.59(3H, s), 4.80(1H, q, J=6.9 Hz).

[0157] IR(neat)νmax 3405, 2945, 1864, 1794, 1720 cm−1

Example 10

Synthesis of (S)-3-acetyl-4-methyl-2,5-oxazolidinedione (L-N-acetylalanine-NCA) (Compound No. 1001)

[0158] (S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of acetyl chloride (306 mg, 3.9 mmol) under ice cooling. Further, a solution of 4-dimethyl-aminopyridine (476 mg, 3.9 mmol) in ethyl acetate (15 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in ethyl acetate (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound (118 mg, 25%) as a colorless clear syrup.

Example 11

Synthesis of (S)-3-decanoyl-4-methyl-2,5-oxazolidinedione (L-N-decanoylalanine-NCA) (Compound No. 1013)

[0159]

1032

[0160] (S)-4-methyl-2, 5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of decanoyl chloride (744 mg, 3.9 mmol) under ice cooling. Further, a solution of N-methylmorpholine (394 mg, 3.9 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes, and the resulting mixture was then stirred at the same temperature for 2 hours, the reaction mixture was treated in a similar manner as in Synthesis Process 5 of Example 8 to afford the title compound (525 mg, 65%) as a colorless clear syrup. A portion of the thus-obtained syrup was recrystallized from hexane to obtain white crystals (280 mg).

[0161] Melting point: 61-63° C.

[0162]

1
H-N.M.R.(CDCl3, 400 MHz) δ 0.88(3H, t, J=6.9 Hz), 1.27(12H, bs), 1.68(3H, d, J=7.3 Hz), 1.73-1.60(2H, m), 2.93(2H, t, J=7.6 Hz), 4.81(1H, q, J=7.3 Hz).

[0163] IR(KBr)νmax 2926, 2857, 1868, 1801, 1715 cm−1

Example 12

Synthesis of (S)-3-(3-phenylpropanoyl)-4-methyl-2,5-oxazolidinedione (L-N-(3-phenylpropanoyl)-alanine-NCA) (Compound No. 1019)

[0164]

1033

[0165] (S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of 3-phenylpropanoyl chloride (658 mg, 3.9 mmol) under ice cooling. Further, a solution of N-methyl-morpholine (394 mg, 3.9 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes, and the resulting mixture was then stirred at the same temperature for 2 hours. The reaction mixture was treated in a similar manner as in Synthesis Process 5 of Example 8 to afford the title compound (408 mg, 55%) as a colorless clear syrup.

[0166]

1
H-N.M.R.(CDCl3, 400 MHz) δ 1.64(3H, d, J=6.8 Hz), 3.03-2.99(2H, m), 3.29-3.19(2H, m), 4.78(1H, q, J=6.8 Hz), 7.32-7.18(5H, m).

[0167] IR(neat)νmax 3405, 2910, 2850, 1860, 1803, 1720 cm−1

Example 13

Synthesis of N-benzoyl-L-alanyl-L-phenylalanine methyl ester (Compound No. 30)

[0168]

1034

[0169] L-Phenylalanine methyl ester hydrochloride (518 mg, 2.4 mmol) was suspended in tetrahydrofuran (12 mL), and at 0° C., N-methylmorpholine (242 mg, 2.4 mmol) was added, followed by stirring for 20 minutes. (S)-3-Benzoyl-4-methyl-2,5-oxazolidinedione (N-benzoyl-L-alanine-NCA (438 mg, 2 mmol) was added as crystals at 0° C. After the resulting mixture was stirred for 15 minutes, the mixture was allowed to rise in temperature to room temperature, at which the mixture was stirred for 15 minutes. The reaction mixture was poured into 1 N hydrochloric acid (25 mL), followed by extraction with ethyl acetate (25 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The resulting white solid was washed with hexane-ethyl acetate to afford the title compound (462 mg, 65%) as white crystals.

[0170] Melting point: 134-135° C.

[0171]

1
H-N.M.R.(CDCl3, 400 MHz) δ 1.45(3H, d, J=7.0 Hz), 3.05(1H, dd, J=13.9, 6.8 Hz), 3.16(1H, dd, J=13.9, 5.6 Hz), 3.74(3H, s,), 4.71(1H, quintet, J=7.0 Hz), 4.88-4.85(1H, m), 6.78-6.74(2H, m), 7.16-7.06(5H, m), 7.53-7.42(3H, m), 7.77(2H, d, J=7.0 Hz).

[0172] IR(KBr)νmax 3298, 3062, 3025, 2976, 2932, 1741, 1661, 1630, 1536, 1451 cm−1

Example 14

Synthesis of N-benzoyl-L-alanine-(S)-1-(p-tolyl)ethylamide (Compound No. 31)

[0173]

1035

[0174] (S)-3-Benzoyl-4-methyl-2,5-oxazolidinedione (N-benzoyl-L-alanine-NCA) (110 mg, 0.50 mmol) was dissolved in ethyl acetate (2.5 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (68 mg, 0.50 mmol) in ethyl acetate (2.5 mL) at 0° C. A solution of N-methylmorpholine (61 mg, 0.6 mmol) in ethyl acetate (3.0 mL) was then added, followed by stirring for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (149 mg, 97%) as white crystals.

[0175] Melting point: 158.6-160.1° C.

[0176]

1
H-N.M.R.(CDCl3, 400 MHz) δ 1.46(3H, d, J=7.2 Hz), 1.48(3H, d, J=6.8 Hz), 2.33(3H, s), 4.80 (1H, quintet, J=7.1 Hz), 5.06(1H, quintet, J=7.1 Hz), 7.15(2H, d, J=8.1 Hz), 7.25(2H, d, J=8.1 Hz), 7.40-7.43(1H, m), 7.43(2H, d, J=7.6 Hz), 7.79(2H, d, J=7.6 Hz).

[0177] IR(KBr)ν max 3308, 2978, 2935, 1660, 1639, 1603, 1580, 1527, 1490 cm−1

Example 15

Synthesis of N-benzoyl-L-valine-(S)-1-(p-tolyl)ethylamide (Compound No. 32)

[0178]

1036

[0179] (S)-3-Benzoyl-4-isopropyl-2,5-oxazolidinedione (N-benzoyl-L-valine-NCA) (100 mg, 0.40 mmol) was dissolved in ethyl acetate (2.0 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (55 mg, 0.40 mmol) and N-methylmorpholine (61 mg, 0.60 mmol) in ethyl acetate (2.0 mL) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (134 mg, 98%) as white crystals.

[0180] Melting point: 214.4-215.3° C.

[0181]

1
H-N.M.R.(CDCl3, 400 MHz) δ 0.95(3H, d, J=6.6 Hz), 0.96(3H, d, J=6.8 Hz), 1.42(3H, d, J=6.8 Hz), 2.13-2.21(1H, m), 2.33(3H, s), 4.53(1H, dd, J=8.5, 7.3 Hz), 5.06(1H, quintet, J=7.3 Hz), 6.70(1H, brd, J=7.8 Hz), 6.98(1H, brd, J=8.8 Hz), 7.14(2H, d, J=7.8 Hz), 7.21(2H, d, J=8.3 Hz), 7.41(2H, t, J=8.1 Hz), 7.50(1H, t, J=7.5 Hz), 7.79(2H, dd, J=8.1, 1.5 Hz).

[0182] IR(KBr)νmax 3284, 3059, 2970, 2927, 2871, 1654, 1633, 1579, 1541, 1490 cm−1

Example 16

Synthesis of N-benzoyl-L-tert-leucine-(S)-1-(p-tolyl)ethylamide (Compound No. 33)

[0183]

1037

[0184] (S)-3-Benzoyl-4-tert-butyl-2,5-oxazolidinedione (N-benzoyl-L-tert-leucine-NCA)(100 mg, 0.38 mmol) was dissolved in ethyl acetate (2.0 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (52 mg, 0.38 mmol) in ethyl acetate (2.0 mL) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (66 mg, 49%) as white crystals.

[0185] Melting point: 144.0-144.8° C.

[0186]

1
H-N.M.R.(CDCl3, 400 MHz) δ 1.00(9H, s), 1.43(3H, d, J=6.8 Hz), 2.34(3H, s), 4.51(1H, d, J=9.3 Hz), 5.07(1H, quintet, J=7.3 Hz), 6.38(1H, brd, J=7.6 Hz), 6.96(1H, brd, J=7.0 Hz), 7.14(2H, d, J=7.8 Hz), 7.21(2H, d, J=8.1 Hz), 7.43(2H, t, J=7.8 Hz), 7.51(1H, t, J=7.3 Hz), 7.79(2H, dd, J=8.3, 1.2 Hz).

[0187] IR(KBr)νmax 3274, 3065, 2968, 2872, 1636, 1579, 1525 cm−1

Example 17

Synthesis of N-benzoyl-L-phenylalanine-(S)-1-(p-tolyl)ethylamide (Compound No. 34)

[0188]

1038

[0189] (S)-3-Benzoyl-benzoyl-2,5-oxazolidinedione (N-benzoyl-L-phenylalanine-NCA)(100 mg, 0.34 mmol) was dissolved in ethyl acetate (2.0 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (46 mg, 0.34 mmol) in ethyl acetate (2.0 mL) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (110 mg, 84%) as white crystals.

[0190] Melting point: 214.2-214.9° C.

[0191]

1
H-N.M.R.(CDCl3, 400 MHz) δ 1.38(3H, d, J=7.1 Hz), 2.34(3H, s,), 3.05(1H, dd, J=13.4, 8.5 Hz), 3.20(1H, dd, J=13.4, 5.6 Hz), 4.82(1H, dt, J=8.3, 5.6 Hz), 4.99(1H, quintet, J=7.2 Hz), 6.03(1H, brd, J=7.8 Hz), 6.96(1H, brd, J=5.9 Hz), 6.98(1H, d, J=8.1 Hz), 7.09(1H, d, J=7.8 Hz), 7.14-7.17(1H, m), 7.18(4H, m), 7.42(2H, dt, J=7.8, 1.2 Hz), 7.50(1H, t, J=7.3 Hz), 7.74(2H, dd, J=8.3, 1.2 Hz).

[0192] IR(KBr)νmax 3289, 3063, 3030, 2974, 2926, 1653, 1632, 1604, 1579, 1541 cm−1

Example 18

Synthesis of N-benzoyl-O-benzyl-L-glutamic acid-(S)-1-(p-tolyl)ethylamide (Compound No. 35)

[0193]

1039

[0194] (S)-3-Benzoyl-4-benzyloxycarbonylethyl-2,5-oxazolidinedione (L-N-benzoyl-O-benzylglutamic acid-NCA)(100 mg, 0.27 mmol) was dissolved in ethyl acetate (2.0 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (37 mg, 0.27 mmol) and N-methylmorpholine (28 mg, 0.27 mmol) in ethyl acetate (2.0 mL) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (106 mg, 85%) as white crystals.

[0195] Melting point: 123.4-124.9° C.

[0196]

1
H-N.M.R.(CDCl3, 400 MHz) δ 1.43(3H, d, J=7.1 Hz), 2.04-2.23(2H, m), 2.32(3H, s), 2.34-2.67(2H, m), 4.69-4.74(1H, m), 5.00-5.07(1H, m), 5.10(2H, s), 6.85-6.94(1H, m), 7.12(2H, d, J=8.2 Hz), 7.19(2H, d, J=8.2 Hz), 7.29-7.36(6H, m), 7.40-7.45(2H, m), 7.49-7.52(1H, m), 7.80(2H, dd, J=8.3, 1.2 Hz).

[0197] IR(KBr)νmax 3289, 3060, 3032, 2974, 2931, 1726, 1630, 1579, 1534 cm−1

Example 19

Synthesis of N-acetyl-L-alanine-(S)-1-(p-tolyl)ethylamide (Compound No. 36)

[0198]

1040

[0199] (S)-3-Acetyl-4-methyl-2,5-oxazolidinedione (N-acetyl-L-alanine-NCA)(424 mg, 2.7 mmol) was dissolved in ethyl acetate (10 mL), followed by the addition of (S)-1-(p-tolyl)ethylamine (406 mg, 3 mmol) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (25 mL), followed by extraction with ethyl acetate (25 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the resulting white solid was washed with hexane-ethyl acetate to afford the title compound (380 mg, 57%) as white crystals.

[0200] Melting point: 201-203° C.

[0201]

1
H-N.M.R.(CDCl3, 400 MHz) δ 1.32(3H, d, J=7.9 Hz), 1.44(3H, d, J=7.9 Hz), 1.98(3H, s), 2.32(3H, s), 4.54(1H, quintet, J=7.9 Hz), 5.01(1H, quintet, J=7.9 Hz), 6.48(1H, brd, J=7.9 Hz), 6.88(1H, brd, J=7.9 Hz), 7.20-7.10(4H, m).

[0202] IR(KBr)νmax 3292, 1633, 1546, 1444 cm−1

Example 20

Synthesis of N-decanoyl-L-alanyl-L-phenylalanine methyl ester (Compound No. 37)

[0203]

1041

[0204] L-Phenylalanine methyl ester hydrochloride (259 mg, 1.2 mmol) was suspended in tetrahydrofuran (6 mL), followed by the addition of N-methylmorpholine (121 mg, 1.2 mmol) at 0° C. The resulting mixture was stirred for 20 minutes. (S)-3-Decanoyl-4-methyl-2,5-oxazolidinedione (N-decanoyl-L-alanine-NCA) (270 mg, 1 mmol) was added as crystals at 0° C., followed by stirring for 5 minutes. The mixture was allowed to rise in temperature to room temperature, at which the mixture was stirred for 30 minutes. The reaction mixture was treated in a similar manner as in Example 19 to afford the title compound (289 mg, 71%) as white crystals.

[0205] Melting point: 120-122° C.

[0206]

1
H-N.M.R.(CDCl3, 400 MHz) δ 0.88(3H, t, J=6.8 Hz), 1.30-1.25(12H, m), 1.32(3H, d, J=7.1 Hz), 1.61-1.58(2H, m), 2.15(2H, t, J=7.8 Hz), 3.06(1H, dd, J=6.6, 13.9 Hz), 3.14(1H, dd, J=5.6, 13.9 Hz), 3.72(3H, s), 4.50-4.44(1H, m), 4.85-4.80(1H, m), 6.00(1H, brd, J=7.8 Hz), 6.57(1H, brd, J=7.8 Hz), 7.11-7.09(2H, m), 7.30-7.23(3H, m).

[0207] IR(KBr)νmax 3298, 3061, 2923, 2852, 1750, 1644, 1541, 1453 cm−1

Example 21

Synthesis of N-decanoyl-L-alanine-(S)-1-(p-tolyl)ethylamide (Compound No. 38)

[0208]

1042

[0209] (S)-3-Decanoyl-4-methyl-2,5-oxazolidinedione (N-decanoyl-L-alanine-NCA) (100 mg, 0.37 mmol) was dissolved in tetrahydrofuran (3 mL), and at 0° C., (S)-1-(p-tolyl)ethylamine (49 mg, 0.36 mmol) and N-methylmorpholine (37 mg, 0.36 mmol) were added, followed by stirring for 30 minutes. The reaction mixture was treated in a similar manner as in Example 19 to afford the title compound (103 mg, 77%) as white crystals.

[0210] Melting point: 153-154° C.

[0211]

1
H-N.M.R.(CDCl3, 400 MHz) δ 0.88(3H, t, J=6.8 Hz), 1.33-1.20(12H, m), 1.33(3H, d, J=6.8 Hz), 1.44(3H, d, J=6.8 Hz), 1.71-1.59(2H, m), 2.18(2H, t, J=7.2 Hz), 2.33(3H, s), 4.53(1H, quintet, J=6.8 Hz), 5.02(1H, quintet, J=6.8 Hz), 6.28(1H, brs), 6.84(1H, brs), 7.13(2H, d, J=8.1 Hz), 7.20(2H, d, J=8.1 Hz).

[0212] IR(KBr)νmax 3297, 2920, 2852, 1638, 1556, 1452 cm−1

Example 22

Synthesis of N-decanoyl-L-alaninebutylamide (Compound No. 39)

[0213]

1043

[0214] (S)-3-Decanoyl-4-methyl-2,5-oxazolidinedione (N-decanoyl-L-alanine-NCA) (270 mg, 1 mmol) was dissolved in tetrahydrofuran (6 mL), and at 0° C., butylamine (146 mg, 2 mmol) was added, followed by stirring for 30 minutes. The reaction mixture was treated in a similar manner as in Example 19 to afford the title compound (217 mg, 73%) as white crystals.

[0215] Melting point: 128-130° C.

[0216]

1
H-N.M.R.(CDCl3, 400 MHz) δ 0.88(3H, t, J=6.8 Hz), 0.92(3H, t, J=7.3 Hz), 1.36-1.26(14H, m), 1.36(3H, d, J=7.6 Hz), 1.52-1.45(2H, m), 1.63-1.57(2H, m), 2.23-2.15(2H, m), 3.27-3.21(2H, m), 4.51(1H, quintet, J=7.6 Hz), 6.34(1H, brd, J=7.6 Hz), 6.61(1H, brs).

[0217] IR(KBr)νmax 3295, 3096, 2959, 2925, 2853, 1634, 1545, 1468 cm−1

Example 23

Synthesis of N-decanoyl-L-alaninemorpholino-amide (Compound No. 40)

[0218]

1044

[0219] (S)-3-Decanoyl-4-methyl-2,5-oxazolidinedione (N-decanoyl-L-alanine-NCA) (100 mg, 0.37 mmol) was dissolved in tetrahydrofuran (3 mL), and at 0° C., morpholine (52 mg, 0.6 mmol) was added, followed by stirring for 30 minutes. The reaction mixture was treated in a similar manner as in Example 19 to afford the title compound (112 mg, 97%) as a colorless clear syrup.

[0220]

1
H-N.M.R.(CDCl3, 400 MHz) δ 0.88(3H, t, J=6.9 Hz), 1.32-1.19(12H, m), 1.31(3H, d, J=7.8 Hz), 1.64-1.59(2H, m), 2.20(2H, t, J=7.6 Hz), 3.61-3.47(4H, m), 3.73-3.66(4H, m), 4.89(1H, quintet, J=7.8 Hz), 6.60-6.55(1H, m).

[0221] IR(neat)νmax 3308, 2926, 2856, 1637, 1535, 1466 cm−1

INDUSTRIAL APPLICABILITY

[0222] The invention compounds represented by the formula (1) readily react with nucleophilic reagents such as free amines, and use of these compounds permits high-yield, mass and low-cost production of amino acid derivatives, optically active compounds, peptides, polypeptides or the like without racemization. The novel compounds and novel production processes according to the present invention, therefore, are extremely useful and are expected to find themselves as industrially-excellent compounds and processes in many fields led by the fields of pharmaceuticals and agrochemicals.

Amino acid-n-carboxy anhydrides hvaing substituent at nitrogen

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