Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-10-06
2001-05-29
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S021000
Reexamination Certificate
active
06239308
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to &agr;-hydroxy-&bgr;-aminocarboxylic acid derivatives which are important as the ingredients constituting inhibitors for enzymes, such as HIV protease and renin, or constituting some carcinostatics. In particular, the compounds of the present invention are important constituents of the HIV protease inhibitor KNI-272 (see Chem. Pharm. Bull., 40, 2251 (1992)), the renin inhibitor KRI-1314 (see J. Med. Chem., 33, 2707 (1990)), the carcinostatic Bestatin (see Biochem. Pharmacol., 32, 1051 (1983)), and the carcinostatic Taxol (see Bull. Cancer, 80, 326 (1993)); comprising, as the constitutive ingredients, (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid, (2R,3S)-3-amino-2-hydroxy-4-cyclohexylbutyric acid, (2S,3R)-3-amino-2-hydroxy-4-phenylbutyric acid, and (2R,3S)-phenylisoserine.
2. Discussion of the Background
Conventional methods for producing the above-mentioned compounds are known and rely on, the corresponding &agr;-amino acids as starting materials. The methods comprise preparing N-protected &agr;-aminoaldehydes from the starting acids, reacting them with prussic acid derivatives to give cyanohydrin intermediates and hydrolyzing them at the cyano group to obtain the intended compounds (see U.S. Pat. No. 4,599,198; Iizuka et al., J. Med. Chem., 33, 2707 (1990); M. T. Reets et al., Tetrahedron Lett., 29, 3295 (1988)). However, since these methods are defective because they require an oxidation-reduction step, they use toxic cyano derivatives and they produce, as intermediates, N-protected &agr;-aminoaldehydes which are unstable in quantity production. Accordingly, they are not suitable for the production of large quantities of the compounds.
Another method is also known which comprises reacting a N-protected &agr;-aminoaldehyde with nitromethane through an aldol reaction in the presence of an asymmetric catalyst, followed by hydrolyzing the resulting compound with an acid to obtain the intended product (see EP-657415). However, this method is also unsuitable for large-scale production of the product, since the intermediate &agr;-aminoaldehyde is unstable and the asymmetric catalyst to be used is expensive.
Still another method is known which comprises reacting an N-protected &agr;-aminocarboxylic acid chloride to be derived from the corresponding &agr;-amino acid with trimethylsilyl cyanide to give an &agr;-oxonitrile, then converting it into an &agr;-ketocarboxylate and thereafter reducing it to obtain the intended product (see EP-543343). However, this method is also unsuitable to large-scale production of the product, since it uses such an expensive and toxic cyano compound.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide an industrial method for producing &agr;-hydroxy-&bgr;-aminocarboxylic acids and their esters.
The present inventors have now found a method for stereoselectively producing &agr;-hydroxy-&bgr;-aminocarboxylic acids and their esters, which comprises reacting a &bgr;-ketosulfoxide that is easily obtained from an N-protected aminocarboxylate, with an acid to give an &agr;-keto-hemimercaptal, then acylating it to give an &agr;-keto-hemimercaptal-carboxylate, and thereafter rearranging it in the presence of a base.
DETAILED DESCRIPTION OF THE EMBODIMENTS
Specifically, the present invention is a method for producing &agr;-acyloxy-thioesters of the formula (II):
wherein R
1
represents hydrogen, an unsubstituted or substituted linear, branched or cyclic alkanoyl group having from 2 to 18 carbon atoms; an unsubstituted or substituted linear, branched or cyclic alkoxycarbonyl group having from 2 to 18 carbon atoms (such as t-butoxy carbonyl); an aralkyloxycarbonyl group having from 7 to 18 carbon atoms (such as benzyloxycarbonyl); or an unsubstituted or substituted benzyl group, or represents, together with R
1
, a residue of a dibasic acid having from 8 to 18 carbon atoms;
R
2
represents a hydrogen atom or an optionally-substituted benzyl group, or represents, together with R
1′
, a residue of a dibasic acid having from 8 to 18 carbon atoms;
R
3
represents an unsubstituted or substituted, linear, branched or cyclic alkyl group having from 1 to 18 carbon atoms (such as cyclohexylmethyl or isobutyl), an aralkyl group having from 7 to 18 carbon atoms (such as phenyl); or an aryl group having from 6 to 18 carbon atoms (such as benzyl);
R
4
represents an unsubstituted or substituted, linear, branched or cyclic alkanoyl group having from 2 to 18 carbon atoms (such as acetyl), or an arylcarbonyl group having from 7 to 18 carbon atoms (such as benzoyl); and
R
5
represents an alkyl group having 1 or 2 carbon atoms (such as methyl), an aryl group having from 6 to 18 carbon atoms, or an aralkyl group having from 7 to 18 carbon atoms,
which comprises rearranging, in the presence of a base, an &agr;-keto-hemimercaptal-carboxylate of a general formula (I):
wherein R
5
, R
2
, R
3
, R
4
and R
5
have the same meanings as above.
Compounds the formula (I) can be obtained by
(i) reacting an N-protected &agr;-aminocarboxylate of the formula (III):
wherein R
1
, R
2
and R
3
have the same meanings as above; and R
6
represents a linear or branched alkyl group having from 1 to 5 carbon atoms, an aryl group having from 6 to 18 carbon atoms, or an aralkyl group having from 7 to 18 carbon atoms,
with a carbanion of a general formula (IV):
wherein R
5
has the same meaning as above, to obtain a &bgr;-ketosulfoxide of the formula (V):
wherein R
1
, R
2
, R
3
and R
5
have the same meanings as above,
(ii) then reacting the sulfoxide with an acid to obtain an &agr;-ketohemimercaptal of a general formula (VI):
wherein R
1
, R
2
, R
3
and R
5
have the same meanings as above, and thereafter
(iii) acylating the hemimercaptal.
N-protected a-aminocarboxylates (III) which are used in the present invention can be derived from &agr;-aminocarboxylic acids according to conventional means used in ordinary peptide synthesis. The &agr;-aminocarboxylic acids may be naturally-existing amino acids or synthetic amino acids. Their esters are represented by the following structural formula:
wherein R
3
represents an unsubstituted or substituted, linear, branched or cyclic alkyl group having from 1 to 18 carbon atoms, an aralkyl group having from 7 to 18 carbon atoms, or an aryl group having from 6 to 18 carbon atoms. Suitable examples include benzyl, cyclohexyl-methyl, phenyl, isopropyl, isobutyl and sec-butyl groups. Suitable amino acid moieties include, for example, phenylalanine, cyclohexylalanine, phenylglycine, valine, leucine and isoleucine.
R
1
and R
2
in the N-protected &agr;-aminocarboxylates (III) are amino-protecting groups or are the protected condition of the esters. The protecting groups are not specifically defined but may be any ones that are used in ordinary peptide synthesis. For example, R
1
may be an unsubstituted or substituted, linear, branched or cyclic alkanoyl group having from 2 to 18 carbon atoms, an unsubstituted or substituted, linear, branched or cyclic alkoxycarbonyl group having from 2 to 18 carbon atoms, an aralkyloxycarbonyl group having from 7 to 18 carbon atoms, or an unsubstituted or substituted benzyl group, or may be, together with R
2
, a residue of a dibasic acid having from 8 to 18 carbon atoms R
2
may be a hydrogen atom or an unsubstituted or substituted benzyl group, or may be, together with R
2
, a residue of a dibasic acid having from 8 to 18 carbon atoms. Namely, R
1
and R
2
each are independently a hydrogen atom or an amino-protecting group, or they form, as combined, a bifunctional, amino-protecting group. The amino-protecting group includes, for example, so-called, urethane-type protecting groups such as a benzyloxycarbonyl group and a t-butyloxycarbonyl group; acyl-type protecting groups such as an acetyl group and a benzoyl group; and a benzyl-type protecting groups such as a benzyl group and a dibenzyl group. One example of the bifunctional amino-protecting group is a phthaloyl group.
R
6
in the N-protected
Honda Yutaka
Izawa Kunisuke
Suzuki Takayuki
Ajinomoto Co. Inc.
D'Souza A M
Lambkin Deborah C.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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