Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-03-20
2002-01-15
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S039000, C562S444000, C562S449000, C562S450000
Reexamination Certificate
active
06339170
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for producing optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-amino acid ester. The present invention is useful for producing optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester.
2. Description of the Related Art
(S)-N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester with an inhibitory action against angiotensin converting enzyme is useful as therapeutic agents of deteriorated cardiovascular system, hypertension, cardiac function impairment and liver function impairment. Alternatively, the (R) form thereof with an inhibitory action of enkepharinase is useful as analgesic, antidiarrheic, and antacid (JP-A-2-161 and JP-A-8-59606). Methods for producing optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester having been known so far include a method comprising optically resolving racemic 2-acetylthiomethyl-3-phenylpropionic acid by using ephedrine and subjecting one of the resulting products to condensation with glycine benzyl ester and N, N′-dicyclohexylcarbodiimide (JP-A-8-59606). According to the method, however, the efficiency of the optical resolution of 2-acetylthiomethyl-3-phenylpropionic acid with ephedrine is so low that the method is not practical. Furthermore, the method generates such an enormous volume of sulfur-containing wastes that the method cannot be said to be an industrially advantageous method.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a method for producing optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-amino acid ester, particularly optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester, in an inexpensive manner suitable for industrial production.
The present inventors have made investigations so as to overcome the problems. Consequently, the inventors have found a method for producing N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-amino acid ester, the method comprising subjecting optically active 2-hydroxymethyl-3-phenylpropionic acid and an amino acid ester to condensation to subsequently convert the hydroxyl group into an elimination group, and substituting the elimination group with an acetylthio group. Thus, the invention has been achieved.
More specifically, the invention relates to a method for producing an optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-amino acid ester, represented by the general formula (IV):
wherein R
1
represents hydrogen, an amino acid side chain or a protected amino acid side chain; R
2
represents a linear or branched C
1
to C
18
alkyl group, or a benzyl group which may or may not have a substituent; AcS represents an acetylthio group; and * represents an optically active carbon atom, the method comprising subjecting optically active 2-hydroxymethyl-3-phenylpropionic acid, represented by the general formula (I):
wherein * represents an optically active carbon atom, to reaction with an amino acid ester or a salt thereof for conversion into optically active N-(2-hydroxymethyl-1-oxo-3-phenylpropyl)-amino acid ester, represented by the general formula (II):
wherein R
1
and R
2
independently represent the same as described above and * represents an optically active carbon atom; activating the hydroxyl group of the hydroxymethyl group at the 2-position for conversion into optically active N-acylamino acid ester, represented by the general formula (III):
wherein R
1
and R
2
independently represent the same as described above; X represents chlorine, bromine, iodine, a linear, branched or cyclic C
1
-C
6
alkylsulfonyloxy group which may or may not have a substituent, or a C
6
-C
18
arylsulfonyloxy group; and * represents an optically active carbon atom; and further subjecting the resulting optically active N-acylamino acid ester to reaction with a thioacetate salt or thioacetic acid in the presence of a base.
The present invention is particularly useful for producing optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester. More specifically, the invention relates to a method for producing optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester, represented by the general formula (IV):
wherein R
1
represents hydrogen; R
2
represents a benzyl group; AcS represents an acetylthio group; and * represents an optically active carbon atom, the method comprising subjecting optically active 2-hydroxymethyl-3-phenylpropionic acid, represented by the general formula (I):
wherein * represents an optically active carbon atom, to reaction with glycine benzyl ester or a salt thereof for conversion into optically active N-(2-hydroxymethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester, represented by the general formula (II):
wherein R
1
represents hydrogen; R
2
represents benzyl group; and * represents an optically active carbon atom; activating the hydroxymethyl group at the 2-position for conversion into optically active N-acylglycine benzyl ester, represented by the general formula (III):
wherein X represents chlorine, bromine, iodine, a linear, branched or cyclic C
1
-C
6
alkylsulfonyloxy group which may or may not have a substituent, or a C
6
-C
18
arylsulfonyloxy group; R
1
represents hydrogen; R
2
represents a benzyl group; and * represents an optically active carbon atom; and further subjecting the resulting N-acylglycine benzyl ester to reaction with a thioacetate salt or thioacetic acid in the presence of a base.
According to the invention, the optically active carbon atom can be in the S configuration or in the R configuration.
Additionally, significant intermediates according to the method, namely the optically active N-(2-hydroxymethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester represented by the general formula (II) and the optically active N-acyl-glycine benzyl ester represented by the general formula (III) are also encompassed within the scope of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The optically active 2-hydroxymethyl-3-phenylpropionic acid (I) for use as a raw material in accordance with the invention, can be prepared by optically resolving racemic 2-hydroxymethyl-3-phenylpropionic acid by using an optically active amine such as (1R,2S)-(+)-cis-1-amino-2-indanol (JP97-270680).
The amino acid in the amino acid ester or a salt thereof for use as the raw material in accordance with the invention includes glycine, phenylglycine, alanine, glutamine, asparagine, valine, leucine, isoleucine, proline, methionine, serine, threonine, phenylalanine, naphtylalanine, tyrosine, 3,4-dihydroxyphenylalanine, tryptophan, histidine, glutamic acid, aspartic acid, lysine, and arginine. These amino acids may satisfactorily have substituents at the side chains thereof. Examples of substituents include C
1
-C
6
alkyl groups, C
1
-C
6
alkoxy groups, a halogen group and a nitro group. Furthermore, any reactive functional group within the side chains is preferably protected with protective groups for use in peptide synthesis, for example ester-type protective groups such as methyl ester, ethyl ester, and benzyl ester for carboxyl group; acyl groups such as formyl group, acetyl group, trifluoroacetyl group, benzoyl group, t-butyloxycarbonyl group and benzyloxycarbonyl group for amino group; and ether-type protective groups such as benzyl ether and t-butyl ether and ester-type protective groups such as acetyl or benzoyl for hydroxyl group.
In the amino acid ester, &agr;-carboxyl group has been esterified preliminarily. The ester includes for example methyl ester, ethyl ester and benzyl ester. The ester may optionally have substituents. Examples of substituents include C
1
-C
6
alkyl groups, C
1
-C
6
alkoxy groups, a halogen group and a nitro group. Because the &agr;-carboxyl group of the amino acid in the final compound, namely N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester as one of the objective compounds of the invention, is prepared in the form of benzyl ester, the am
Hamada Takayuki
Izawa Kunisuke
Suzuki Takayuki
Ajinomoto Co. Inc.
Killos Paul J.
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