Process for the asymmetric synthesis of S-acyl derivatives of 2-

Details Process for the asymmetric synthesis of S-acyl derivatives of 2- Process for the asymmetric synthesis of S-acyl derivatives of 2-

1997-11-26

2000-01-11

Barts, Samuel

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

562418, 562426, 435106, 435128, 435130, C07C32100, C12P 1304

Patent

active

060138297

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a process for the enantioselective synthesis of S-acyl derivatives of 2-mercaptomethyl-3-phenylpropanoic acid and to their use in the asymmetric synthesis of N-(mercaptoacyl)-amino acid derivatives. More specifically, the present invention relates to a novel process for the synthesis of optically pure derivatives of general formula (I): ##STR2## in which: R.sub.1 represents a linear or branched aliphatic acyl radical or an aromatic acyl radical.
The derivatives of formula (I) obtained according to the process of the invention are useful in particular for the synthesis of optically active N-(mercaptoacyl)amino acid derivatives of formula (II): ##STR3## in which: R.sub.1 represents a hydrogen atom, a linear or branched aliphatic acyl radical or an aromatic acyl radical; or a lower phenylalkylene group; hydroxyalkylene group; a phenyl group; a lower phenylalkylene group; a lower hydroxyphenylalkylene group; a lower aminoalkylene group; a lower guanidinoalkylene group; a lower mercaptoalkylene group; a lower alkyl lower thioalkylene group; a lower imidazolylalkylene group; a lower indolylalkylene group; a lower carbamylalkylene group; a lower carboxyalkylene group; n ranges from 0 to 10.
The expression lower alkyl group is understood to refer to alkyl groups having linear or branched chains containing from 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms.
The expression lower alkylene group is understood to refer to alkylene groups containing from 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms.
The preferred compounds of formula (II) are the compounds corresponding to formulae (III) and (IV) below: ##STR4## or benzyl N--(R)-[2-acetylthiomethyl-1-oxo-3-phenylpropyl]glycinate; ##STR5## or benzyl N--(S)-[2-acetylthiomethyl-1-oxo-3-phenylpropyl]glycinate, for which the process of the present invention may be applied more particularly.
The compounds of formula (II) have advantageous pharmacological properties. In particular, they exert an inhibitory activity on certain enzymes, such as neutral endopeptidase (EC 3.4.24.11) and the angiotensin conversion enzyme (EC 3.4.15.1). The administration of the compounds of formula (II) thus makes it possible to reduce or eliminate the activity of these enzymes, which are respectively responsible for the inactivation of encephalins, of atrial natriuretic factor, and for the conversion of angiotensin I into angiotensin II. In therapeutic treatment, these compounds exert antisecretory, intestinal or antihypertensive activities and are used in the treatment of chronic cardiac insufficiency. Furthermore, such compounds may also be used in the treatment of osteoporosis (WO 94/21242).
The compounds of formula (II) and, more particularly, the compounds of formulae (III) and (IV), their preparation and their therapeutic use have been described in French patent No. 2,623,498.
The compounds of formula (I) may be used for the preparation of the compounds of formula (II).
The compounds of formula (I) comprise a so-called asymmetric carbon which may have two configurations, R or S. They thus exist in the form of two enantiomers, which may be denoted by (I R) and (I S), according to the configuration of this asymmetric carbon: ##STR6##
No process of asymmetric synthesis of the derivatives of formula (I) has been described to date.
European patent No. EP 318,377 is known, in which the two enantiomers (I R) and (I S) of the acid of general formula (I) are obtained by separation of the racemic mixture using a chiral amine. However, this method of resolution makes it possible to obtain only a maximum of fifty (50) per cent of the desired enantiomer.
The aim of the present invention is to provide a process for the preparation of S-acyl derivatives of 2-mercaptomethyl-3-phenylpropanoic acid, in optically pure form.
Another aim of the invention is also to provide such a process which does not have the drawback of an optical separation as mentioned above.
The aim of the invention is also to provide a process for the preparation of optically active N-(m

REFERENCES:
Mori et al, "Preparation . . . Key Step", Liebigs Ann. Chem., No. 10, 1989 pp. 957962, XP 000611532.
Atsuumi et al, "An Efficient . . . Reaction", Tetrahedron Letters, vol. 31, No. 11, 1990, pp. 1601-1604, XP 002020256.
Strijiveen et al, "Evidence . . . Reagent", Recueil de Travaux Chimiques des Pays-Bas, vol. 106, No. 10, 1987, pp. 539-542 XP 000196631.
Caron et al, "Sequential . . . Cepacia", vol. 4, No. 9, 1993, pp. 1995-2000, XP000611535.

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