GB2140009A - Process for producing S-carboxymethylcysteine - Google Patents

Process for producing S-carboxymethylcysteine Download PDF

Info

Publication number
GB2140009A
GB2140009A GB08409851A GB8409851A GB2140009A GB 2140009 A GB2140009 A GB 2140009A GB 08409851 A GB08409851 A GB 08409851A GB 8409851 A GB8409851 A GB 8409851A GB 2140009 A GB2140009 A GB 2140009A
Authority
GB
United Kingdom
Prior art keywords
reaction
carboxymethylcysteine
beta
chloroalanine
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
GB08409851A
Other versions
GB2140009B (en
Inventor
Kazuo Nakayasu
Jun Tanaka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Resonac Holdings Corp
Original Assignee
Showa Denko KK
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Showa Denko KK filed Critical Showa Denko KK
Publication of GB2140009A publication Critical patent/GB2140009A/en
Application granted granted Critical
Publication of GB2140009B publication Critical patent/GB2140009B/en
Expired legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A process for producing S-carboxymethylcysteine, which comprises reacting beta-chloroalanine with thioglycollic acid in an aqueous solution containing an alkali at a pH of 10 to 13 to form S-carboxymethylcysteine, acidifying the reaction mixture, and separating the resulting precipitate.

Description

SPECIFICATION Process for producing S-carboxymethylcysteine This invention relates to a novel process for producing S-carboxymethylcysteine.
More specifically, this invention relates to a process for producing S-carboxymethylcysteine, which comprises reacting beta-chloroalanine with thioglycollic acid in an aqueous solution at a pH of 10 to 13 to form S-carboxymethylcysteine, thereafter acidifying the reaction mixture, and separating the resulting precipitate.
S-carboxymethylcysteine is a derivative of cysteine, a sulfur-containing amino acid, and is useful as a medicine, for example.
In the prior art, S-carboxymethylcysteine is produced by reacting cysteine and chloroacetic acid in an alkaline medium [J. Org. Chem., 16,749-753 (1951)]. Cysteine, a starting material in this process, is generally obtained by hydrolyzing a keratincontaining natural material such as hair with an acid, and chemically or electrolytically reducing the resulting cystine. Suitable natural materials which can be used in this process are scarce, and this scarcity naturally limits the amount of cysteine that can be produced. Various methods have been attempted, on the other hand, to obtain cysteine by chemical synthesis.They include, for example, (1) the hydrolysis of thiazoline-4-carbonitrile with an acid (Japanese Laid-Open Patent Publication No.46918/ 1983), (2) the action of an enzyme on 2-aminothiazoline-4-carboxylic acid (Japanese Laid-Open Patent Publication No. 72883/1977), (3) the hydrolysis of S-sulfocysteine with an acid (Japanese Laid-Open Patent Publication No. 164669/1980), and (4) the acid cleavage of mono(aminocarboxyethyl) trithiocar bonate. Cysteine obtained by these methods, however, are by no means inexpensive partly be cause of the long reaction steps required, and are not entirely suitable as a material for S-carboxy methylcysteine.
It is an object of this invention therefore to provide an industrial process for producing S-carboxy methylcysteine.
According to this invention, this object is achieved by a process for producing S-carboxymethyl cysteine, which comprises reacting beta-chloroalanine with thioglycollic acid in an aqueous solution containing an alkali at a pH of 10 to 13, thereafter acidifying the reaction mixture (preferably to a pH of 2 to 4), and separating the resulting precipitate.
This process is an industrially advantageous pro cess for producing S-carboxymethylcysteine be cause beta-chloroalanine is a material commercially available at low cost and the operation is very simple.
The beta-chloroalanine used as a starting material in the process of this invention can be easily produced by hydrolyzing alpha-amino-beta chloropropionitrile with an acid, or aziridine-2 carboxylic acid with an acid. For example, it can be produced by reacting monochloroacetaldehyde with ammonium bisulfite, reacting the resulting adduct with ammonia, reacting the resulting alpha-aminobeta-chloroethanesulfonic acid with hydrocyanic acid, and heating the resulting alpha-amino-betachloropropionitrile with an acid such as hydrochloric acid or sulfuric acid at a high temperature.
There is no particular limitation on the alkali to be present in the reaction system for obtaining the desired pH during the reaction of beta-chloroalanine with thioglycollic acid. Examples of the alkali include ammonia, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide.
The reaction is usually carried out in aqueous solution, but, if desired, a water-miscible organic solvent such as methanol and ethanol may be used in combination with water.
In mixing the reaction materials, it is preferred to add beta-chloroalanine to a mixture of thioglycollic acid and the alkali, or the alkali to a mixture of thioglycollic acid and beta-chloroalanine. Mixing of beta-chloroalanine with the alkali in the absence of thioglycollic acid is undesirable because it will induce decomposition of beta-chloroalanine.
The amount of the alkali to be present in the reaction system is usually 2 to 20 times the amount of beta-chloroalanine, and thus, the pH of the reaction solution is maintained at 10 to 13, preferably 11 to 12. When the reaction solution is alkaline but below pH 10, a sufficient rate of reaction cannot be obtained. On the other hand, when the pH is higherthan 13, a sufficient rate of reaction can be obtained, but the yield of S-carboxymethylcysteine is reduced. When the alkali is a strong one such as sodium hydroxide and the mole ratio of it to beta-chloroalanine is made high, the pH becomes higherthan 13, and the yield of the desired product is lowered as stated above. Hence, care is necessary in this regard. When ammonia is used as the alkali, the pH never exceeds 13, and its amount is not limited.
Completion of the reaction usually requires a temperature of 10 to 50 C and a period of 2 to 50 hours, preferably a temperature of 15 to 250C and a period of 20 to 40 hours. The reaction time can be shortened by raising the reaction temperature. But higher temperatures are undesirable because they lead to the decomposition of the starting betachloroalanine. The course of the reaction can be monitored by analysis, for example, by liquid chromatography using an RI detector. The end point of the reaction can be determined by the vanishing of the starting beta-chloroanaline.
The resulting S-carboxymethylcysteine contained in the reaction mixture is precipitated by adjusting the pH of the reaction mixture to 2 to 4 with a suitable acid such as hydrochloric acid or sulfuric acid. The precipitated S-carboxymethylcysteine can be separated and recovered easily by ordinary means such as centrifugal separation.
The following non-limitative Examples illustrate the present invention specifically.
Example 1 A three-necked flask equipped with a thermometer and a magnetic stirrer was set in a constanttemperature vessel kept at 200C, and charged with 14.9 g ofthioglycollic acid and 110 g of 25% aqueous ammonia and further with 10 g of betachloroalanine. They were reacted at 20"C for 20 hours. The pH of the reaction solution during the reaction was 12.0-11.5. Analysis of the reaction solution by liquid chromatography showed that 13.5 g of S-carboxymethylcysteine was formed. This amount corresponded to a yield of 92% based on beta-chloroalanine. The reaction solution was heated under reduced pressure to remove the excess of ammonia, and hydrochloric acid was added to adjust its pH to 3.0.The resulting precipitate was separated by filtration, and subjected to infrared absorption spectroscopic analysis and elemental analysis. The data obtained agreed with those of an authentic sample of S-carboxymethylcysteine.
Example 2 A three-necked flask equipped with a thermometer and a magnetic stirrer was set in a constanttemperature vessel kept at 20"C, and charged with 34.6 g of water, 10 g of beta-chloroalanine and 14.9 g of thioglycollic acid, and further with a 40% aqueous solution of sodium hydroxide (total 40.5 g). They were reacted at 20"C for 20 hours. The pH of the reaction solution during the reaction was 11.5-11.0.
Analysis of the reaction solution by liquid chroma tography showed that 13.0 g of S-carboxymethyl cysteine was formed. This amount corresponded to a yield of 90% based on betachloroalanine.
chloroalanine.
Comparative Example I Athree-necked flask equipped with a thermometer and a magnetic stirrer was set in a constant temperature vessel kept at 20 C, and charged with 34.6 g of water, 10 g of beta-choroalanine and 14.9 g of thioglycollic acid, and further with a 40% aqueous solution of sodium hydroxide to adjust the pH of the reaction solution to 9. The reaction solution was reacted at 20"C for 20 hours. Analysis of the reaction mixture by liquid chromatography showed that 2.7 g of S-carboxymethylcysteine was formed. This amount corresponded to a yield of 19% based on beta-chloroalanine.
Comparative Example 2 Athree-necked flask equipped with a thermometer and a magnetic stirrer was set in a constanttemperature vessel kept at 20"C, and charged with 34.6 g of water, 10 g of beta-chloroalanine and 14.9 g of thioglycollic acid, and further with a 40% aqueous solution of sodium hydroxide to adjust the pH of the reaction solution to 14. The reaction solution was reacted at 20"C for 2 hours. Analysis of the reaction mixture by liquid chromatography showed that 3.3 g of S-carboxymethylcysteine was formed. This amount corresponded to a yield of 23% based on beta-chloralanine. The percent residue of beta chloroalanine was 3%.
Example 3 Athree-necked flask equipped with a thermometer and a magnetic stirrer was set in a constanttemperature vessel kept at 20"C, and charged with 14.9 g of thioglycollic acid and 60 g of 25% aqueous ammonia and further with 10 g of betachloroalanine. They were reacted at 20"C for 20 hours. The pH of the reaction solution during the reaction was 10.5-10.0. Analysis of the reaction solution by liquid chromatography showed that 10.1 g of S-carboxymethylcysteine was formed. This amount corresponded to a yield of 70% based on beta-chloroalanine.
Example 4 A three-necked flask equipped with a thermometer and a magnetic stirrer was set in a constanttemperature vessel kept at 20"C, and charged with 34.6 g of water, 10 g of beta-chloroalanine and 14.9 g of thioglycollic acid, and further with a 40% aqueous solution of sodium hydroxide (total 42.2 g). They were reacted at 20"C for 20 hours. The pH of the reaction solution during the reaction was 13.0-12.7.
Analysis of the reaction solution by liquid chromatography showed that 12.6 g of S-carboxymethylcysteine was formed. This amount correspond to a yield of 87% basd on betachloroalanine.

Claims (6)

1. A process for producing S-carboxymethylcysteine, which comprises reacting beta-chloroalanine with thioglycollic acid in an aqueous solution containing an alkali at a pH of 10 to 13 to form S-carboxymethylcysteine, thereafter acidifying the reaction mixture, and separating the resulting precipitate.
2. A process according to claim 1 wherein the reaction is carried out at a temperature of 10 to 50"C.
3. A process according to claim 1 or 2 wherein the alkali is ammonia, an alkali metal hydroxide or an alkaline earth metal hydroxide.
4. A process according to claim 1,2 or 3 wherein the reaction is initiated by adding beta-chloroalanine to a mixture of thioglycollic acid and the alkali.
5. A process according to claim 1,2 or 3 wherein the reaction is initiated by adding the alkali to a mixture of thioglycollic acid and beta-chloroalanine.
6. A process according to claim 1 substantially as described with reference to any one of the Examples.
GB08409851A 1983-04-18 1984-04-16 Process for producing s-carboxymethylcysteine Expired GB2140009B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP58066922A JPS59193867A (en) 1983-04-18 1983-04-18 Preparation of s-carboxymethyl cysteine

Publications (2)

Publication Number Publication Date
GB2140009A true GB2140009A (en) 1984-11-21
GB2140009B GB2140009B (en) 1987-03-04

Family

ID=13329951

Family Applications (1)

Application Number Title Priority Date Filing Date
GB08409851A Expired GB2140009B (en) 1983-04-18 1984-04-16 Process for producing s-carboxymethylcysteine

Country Status (5)

Country Link
JP (1) JPS59193867A (en)
DE (1) DE3413880A1 (en)
FR (1) FR2544310B1 (en)
GB (1) GB2140009B (en)
IT (1) IT1176088B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02138670U (en) * 1989-04-25 1990-11-20

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2955036A (en) * 1958-04-25 1960-10-04 Gen Aniline & Film Corp Fog reduction in photographic silver halide emulsions
JPS58187198A (en) * 1982-04-27 1983-11-01 Showa Denko Kk Preparation of s-carboxymethyl-l-cysteine

Also Published As

Publication number Publication date
IT8420608A1 (en) 1985-10-18
GB2140009B (en) 1987-03-04
JPS59193867A (en) 1984-11-02
JPS6121454B2 (en) 1986-05-27
FR2544310A1 (en) 1984-10-19
DE3413880C2 (en) 1989-09-14
IT1176088B (en) 1987-08-12
DE3413880A1 (en) 1984-10-31
IT8420608A0 (en) 1984-04-18
FR2544310B1 (en) 1987-02-27

Similar Documents

Publication Publication Date Title
JP2941287B2 (en) Process for producing trisodium salt of 2,4,6-trimercapto-S-triazine-9-hydrate
KR940002979B1 (en) Process for the preparation of iminodiacetonitrile and imino-acetic acid
US4230869A (en) Process for preparing 5-(4-hydroxyphenyl)hydantoin
GB2140009A (en) Process for producing S-carboxymethylcysteine
JPH07291921A (en) Production of 3-mercaptopropionitrile and 3-mercaptopropionic acid
JP3003287B2 (en) Method for producing sodium N-alkylaminoethanesulfonate
US4515985A (en) Preparation of chlorinated phenoxyalkanoic acids
CN100364963C (en) Preparation of O-substituted hydroxylamines
US5256818A (en) Method for making β-mercaptopropionic acid
JPS60258158A (en) Preparation of cysteine derivative
JPS60258161A (en) Preparation of cysteine derivative
JP2855871B2 (en) Method for producing thiomalic acid
JPS636545B2 (en)
US3617297A (en) Process for the production of dl-methionine composition
US4549028A (en) Process for the preparation of hydantoin precursor of phenylalanine
KR800001550B1 (en) Preparing process for 5-(4-hyroxy phenyl)hydantoins
CA1297888C (en) Process for preparing bis (ethoxythiocarbonyl)sulfide
US2734917A (en) Method of preparing atrolactamide
JPH0412265B2 (en)
JPS59130246A (en) Production of beta-hydroxy-aminoacid
KR810000879B1 (en) Process for preparing diaceton-2-keto-l-gulonic acid
JPS5929655A (en) Preparation of beta-mercaptopropionic acid
RU2047601C1 (en) Method of synthesis of thioglycolic acid salts as aqueous solutions
JPH09263576A (en) Production of beta-mercaptopropionic acid
JPS5950662B2 (en) Production method of γ-amino-β-hydroxybutyric acid

Legal Events

Date Code Title Description
PE20 Patent expired after termination of 20 years

Effective date: 20040415