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Method for Producing Alpha-substituted Cysteine or Salt Thereof or Synthetic Intermediate of Alpha-substituted Cysteine

a technology of alpha-substituted cysteine and synthetic intermediate, which is applied in the field of producing alpha-substituted cysteine or salt thereof or synthetic intermediate of alpha-substituted cysteine, can solve the problems of low production efficiency, inconvenient industrial production method, and difficult removal of metal salt generated during reaction, etc., to achieve stable, industrial-scale production of -substituted cysteine, simple, quick and safe production

Inactive Publication Date: 2018-09-06
API CORP (JP)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0051]According to the production method of the present invention, an α-substituted cysteine or a salt thereof can be simply, quickly, and safely produced using an easily available and inexpensive material, and stable, industrial-scale production of the α-substituted cysteine or the salt thereof can be achieved.

Problems solved by technology

In the method described in Patent Document 2, a long reaction time is required for each of the steps of hydrolysis, decarbamoylation, and sulfur atom deprotection of hydantoin, so that the production efficiency is low.
In this method, very low temperature conditions are required, and sodium metal, which is highly ignitable, needs to be used, so that the method is not suitable for industrial production.
Moreover, since the deprotected α-methyl-D-cysteine is a compound whose extraction with an organic solvent is difficult, removal of the metal salt generated during the reaction is difficult.
However, since the operation of conversion of the (R)-monoester to the (S)-monoester is laborious, the method is not suitable for industrial production.
Thus, the optical purity is insufficient for providing an intermediate for production of a pharmaceutical.

Method used

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  • Method for Producing Alpha-substituted Cysteine or Salt Thereof or Synthetic Intermediate of Alpha-substituted Cysteine
  • Method for Producing Alpha-substituted Cysteine or Salt Thereof or Synthetic Intermediate of Alpha-substituted Cysteine
  • Method for Producing Alpha-substituted Cysteine or Salt Thereof or Synthetic Intermediate of Alpha-substituted Cysteine

Examples

Experimental program
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Effect test

example 1

[Example 1] Step (viii): Production of tert-Butylthiomethanol

[0423]Under nitrogen gas flow, 240 g (2.66 mol) of tert-butyl mercaptan and 216 g (2.66 mol) of formalin (37 wt %) were placed in a 1-L reactor at room temperature, and the resulting mixture was stirred. After allowing the reaction to proceed at 60° C. for 9 hours, separation extraction was carried out by adding 160 g of cyclohexane while keeping the reactor at a temperature within the range of 50° C. to 60° C., followed by removing the aqueous phase. Thereafter, cyclohexane was removed by concentrating the cyclohexane layer under reduced pressure. The resulting crude tert-butylthiomethanol was subjected to distillation under reduced pressure at 70° C. / 2.0 kPa to obtain 208 g (1.73 mmol; yield, 65.0%) of tert-butylthiomethanol. As a result of GC analysis under , its purity was found to be 99% by area. The measurement results obtained were as follows.

[0424]1H-NMR (400 MHz, CDCl3) δ 1.41 (9H, s), 2.11 (1H, t, J=6.4 Hz), 4.83...

example 2

[Example 2] Step (ix): Production of tert-Butylthiochloromethane

[0425]Under nitrogen gas flow, 190 g (1.58 mol) of tert-butylthiomethanol produced in Example 1 and 1.44 kg of cyclohexane were placed in a 3-L reactor at room temperature. To the resulting mixture, 150 g (1.90 mol) of pyridine was added while the inner temperature was kept at 0° C. To the mixture, 226 g (1.89 mol) of thionyl chloride was then added dropwise while the inner temperature was kept at −2° C. to 6° C. After stirring the resulting mixture at a temperature within the range of −4° C. to 0° C. for 1 hour, 380 g of cyclohexane was added thereto, and the precipitated salt was removed by filtration. Cyclohexane was removed by concentrating the obtained filtrate by distillation, and the resulting crude tert-butylthiochloromethane was subjected to distillation under reduced pressure at 57° C. / 3.0 kPa to obtain 140 g (1.01 mol; yield, 63.9%) of tert-butylthiochloromethane. As a result of GC analysis under , its purity...

example 3

[Example 3] Step (x): Production of Diethyl 2-[(tert-Butylthio)methyl]-2-methylmalonate

[0427]Under nitrogen gas flow, 107 g (0.953 mol) of potassium-tert-butoxide and 790 g of tetrahydrofuran were placed in a 3-L reactor. To the resulting mixture, 158 g (0.907 mol) of diethyl methylmalonate was added dropwise at an inner temperature within the range of 18° C. to 26° C. for 30 minutes. After stirring the resulting mixture for 30 minutes, 132 g (0.953 mol) of tert-butylthiochloromethane produced in Example 2 was added dropwise thereto for 1 hour while the inner temperature was kept within the range of 18° C. to 26° C. After stirring the resulting mixture for 3 hours, 395 g of toluene and 395 g (0.229 mol) of 2 wt % hydrochloric acid were added thereto, followed by stirring the resulting mixture for 30 minutes. The aqueous layer was then removed by separation. Subsequently, an operation of adding 395 g of water to the toluene layer, stirring the resulting mixture for 1 hour, and then r...

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Abstract

According to the present invention, it becomes possible to perform a process for converting into an α-substituted cysteine represented by general formula (1) or a salt thereof at low cost and on an industrial scale by employing a process that is routed through a compound represented by general formula (3) to a compound represented by general formula (6). Particularly, by employing a process that is routed through a compound represented by general formula (7-2), it becomes possible to detach a tert-butyl protection group in a simple manner and to produce the compound represented by general formula (1) with high purity. Furthermore, by employing a process that is routed through tert-butylthiomethanol or a process that is routed through a compound represented by general formula (9), it becomes possible to produce a compound represented by general formula (2) without generating bischloromethylether that is an oncogenic substance. In the production of an α-substituted-D-cysteine or a salt thereof, it becomes possible to perform a process for converting the compound represented by general formula (2) into a compound represented by general formula (3S) in one step by allowing an enzyme or the like to act on the compound represented by general formula (2).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This is a continuation of U.S. application Ser. No. 14 / 888,576, which is the U.S. national phase of PCT / JP2014 / 062115 filed May 1, 2014, based on JP 2013-097172 filed May 2, 2013, the entire respective disclosures of which are incorporated herein by reference.TECHNICAL FIELD[0002]The present invention relates to a method for producing an α-substituted cysteine or a salt thereof, which is useful as an intermediate for pharmaceuticals and the like, or an intermediate for synthesis of an α-substituted cysteine.BACKGROUND ART[0003]Among α-substituted cysteines, optically active α-substituted cysteines are especially useful as intermediates for pharmaceuticals. Various methods are conventionally known as methods for producing α-substituted cysteines and salts thereof (for example, Patent Document 1).[0004]However, the conventional methods have been impractical since stable production in an industrial scale has been difficult because of, for ex...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07C319/06C07C323/60C07C323/52C07C323/58C07C319/20C07C319/14C12P13/12C07D277/14C07C319/02C07C323/12C07C323/03
CPCC07C323/60C07C319/14C12P13/12C07D277/14C07C319/06C07C323/58C07C319/20C07C323/52C07C319/02C07C323/12C07C323/03
Inventor ASUMA, YUUKIUEHARA, HISATOSHIMAEDA, TOMOKOSAITO, YASUYOMIYAKE, RYOMAKAWABATA, HIROSHI
Owner API CORP (JP)
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