Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1999-04-22
2000-01-04
Geist, Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560152, 562557, C07C32104
Patent
active
060111704
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a process for producing a cysteine derivative of the following general formula (III) (hereinafter referred to as cysteine derivative (III)). ##STR3## (wherein R.sup.1 represents an amino-protecting group; R.sup.0 represents hydrogen or, taken together with R.sup.1, represents an amino-protecting group; R.sup.2 represents a carboxy-protecting group; R.sup.3 represents an alkyl group of 1 to 7 carbon atoms, an aryl group of 6 to 10 carbon atoms, or an aralkyl group of 7 to 10 carbon atoms.)
The cysteine derivative (III) which can be provided by the present invention is a compound of importance as a starting material for intermediates of an HIV-protease inhibitor and, according to WO 96/23756 and EP 604185A1, for instance, is of value as a starting material for the reaction according to the following schema. ##STR4##
BACKGROUND ART
For the production of the above cysteine derivative (III), there is already known the technology by which an R.sup.3 -S group is introduced into a compound whose amino and carboxyl groups have been protected, for example the process which comprises transforming the hydroxyl group of a serine derivative Into a leaving group and then conducting a substitution reaction [Tetrahedron Letters, 28, 6069 (1987), ibid, 34, 6607 (1993), and EP 604185A1].
However, this technology involves transformation of the hydroxyl group of a serine derivative into a sulfonyloxy group and a subsequent substitution reaction with the sodium salt of a thiol in anhydrous N,N-dimethylformamide. None of the available literature refer to the impurity by-produced in the reaction, but our investigation revealed that, in this reaction, there is a problem that the sodium salt of thiol or its derivatives, which acts as a base, causes abstraction of the carbonyl .alpha.-hydrogen and subsequent E2 elimination in competition with the objective substitution reaction to give the dehydroalanine derivative of the following general formula (IV) [hereinafter referred to as dehydroalanine derivative (IV)], with the result that the yield of the objective compound is decreased.
We also found that, when the objective cysteine derivative (III) is an optically active compound, a Michael addition of the thiol to the dehydroalanine derivative (IV) so produced may further cause the objective cysteine derivative (III) to reduce the optical purity thereof. ##STR5##
In the above reaction scheme, R.sup.1, R.sup.2, and R.sup.3 are as defined above; X represents a leaving group.
Furthermore, as a production method of the thiol salt for use in the reaction, a method using sodium hydride or potassium hydride under anhydrous conditions have been used but, from the standpoint of handling, the method cannot be said to be suitable for industrial application.
Under the circumstances, the present invention has for its object to provide a process for producing a cysteine derivative, which is economical, high in production efficiency even in a commercial operation, and especially insuring a high optical purity of the objective compound.
SUMMARY OF THE INVENTION
The present invention is essentially directed to a method of producing a cysteine derivative which comprises reacting an amino acid derivative of the following general formula (I): ##STR6## (wherein R.sup.0, R.sup.1, R.sup.2 and X are as defined hereinbefore) with a thiol compound of the following general formula (II): in the presence of a base and water to give a cysteine derivative (III).
DETAILED DISCLOSURE OF THE INVENTION
The present invention is now described in detail.
In accordance with the invention, an amino acid derivative of the above general formula (I) [hereinafter referred to as amino acid derivative (I)] is reacted with a thiol compound of the above general formula (II) [hereinafter referred to as thiol compound (II)] to provide said cysteine derivative (III).
As defined above, said R.sup.1 represents an amino-protecting group. If there is an effect that the amino group can be masked against the intended substitution re
REFERENCES:
patent: 5516936 (1996-05-01), Phillips et al.
Liebigs Ann. Chem., (6), 1988, p5010505, Wulff et al., `Uber die Darstellung von N-(Arylmethylen)dehydroalanin-methylestern sowie ihre Eignung als Bausteine in der Aminosauresynthese.`.
Database Casereact, An. No. 109:23350, Wulff et al., `Synthesis of N-(Arnymethylene)dehydroalanine methyl esters and their application as building blocks in the synthsis of amino acids.` Liebigs Ann. Chem., (1988), (6), p501-505 (abstract).
J. Org. Chem., 1990, 55, p3998-4006, Hermkens et al., `Intramolecular Pictet-Spengler Reaction of N-Alkoxytryptamines. 3. Stereoselective Synthesis of (-)-Debromoeudistomin L and (-)-O-Methyldebromoeudistomin E and Their Stereoisomers.`.
Kondo Takeshi
Manabe Hajime
Murao Hiroshi
Nishiyama Akira
Ueda Yasuyoshi
Davis Brian J.
Geist Gary
Kaneka Corporation
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