GB2140009A - Process for producing S-carboxymethylcysteine - Google Patents
Process for producing S-carboxymethylcysteine Download PDFInfo
- 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
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- 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.)
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- 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
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- 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.
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)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02138670U (en) * | 1989-04-25 | 1990-11-20 |
Family Cites Families (2)
| 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 |
-
1983
- 1983-04-18 JP JP58066922A patent/JPS59193867A/en active Granted
-
1984
- 1984-04-12 DE DE3413880A patent/DE3413880A1/en active Granted
- 1984-04-16 GB GB08409851A patent/GB2140009B/en not_active Expired
- 1984-04-18 IT IT20608/84A patent/IT1176088B/en active
- 1984-04-18 FR FR8406133A patent/FR2544310B1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6121454B2 (en) | 1986-05-27 |
| GB2140009B (en) | 1987-03-04 |
| IT1176088B (en) | 1987-08-12 |
| DE3413880C2 (en) | 1989-09-14 |
| IT8420608A0 (en) | 1984-04-18 |
| DE3413880A1 (en) | 1984-10-31 |
| IT8420608A1 (en) | 1985-10-18 |
| FR2544310A1 (en) | 1984-10-19 |
| JPS59193867A (en) | 1984-11-02 |
| FR2544310B1 (en) | 1987-02-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PE20 | Patent expired after termination of 20 years |
Effective date: 20040415 |