WO1990014335A1 - Process for the n-monoacylation of cysteine - Google Patents
Process for the n-monoacylation of cysteine Download PDFInfo
- Publication number
- WO1990014335A1 WO1990014335A1 PCT/SE1990/000322 SE9000322W WO9014335A1 WO 1990014335 A1 WO1990014335 A1 WO 1990014335A1 SE 9000322 W SE9000322 W SE 9000322W WO 9014335 A1 WO9014335 A1 WO 9014335A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cysteine
- process according
- acid halide
- chloride
- alkali carbonate
- Prior art date
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Classifications
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- 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
- C07C319/12—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols by reactions not involving the formation of mercapto groups
Definitions
- the present invention relates to an improved and simplified process for the selective N-monoacylation of cysteine.
- N-acylderivatives of L-cysteine typified by N-acetyl-L-cysteine and N-isobutyryl-L-cysteine have unique mucolytic properties and are of value for treatment of respiratory diseases.
- N-monoacylated-L-cysteine is a straight forward process
- several problems occur, i.a. to avoid the formation of N,S-diacylated compounds resp. to eliminate free acid formed by using acid anhydride.
- the object of the present invention is to provide an improved and simplified method for obtaining N-monoacylated-L-cysteine by acylation of L-cysteine with one chemical equivalent of acid halide R-CO-X, wherein R is CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) 3 CH 3 or CH 2 CH(CH 3 ) 2 and X prefereably is CI, without racemization of the starting material or by reaction of N,S-diacylated-L- cysteine
- the starting material L-cysteine
- the starting material is acylated with one chemical equivalent of acid halide, i.e.
- N,S-diacylated-L-cysteine and one chemical equivalent of L-cysteine in water containing alkali carbonate or a suitable mixture of water containing alkali carbonate and any reaction stable organic solvent will result in N-monoacylated-L-cysteine.
- alkali carbonate preferably potassium carbonate
- water as a buffer, giving the desired pH of about 7.1 about 10 in the reaction mixture, prefereably 8 - 9.5.
- N-monoacylated-L-cysteine After the reaction is completed, pH is reduced momentarily down to below 4, and prefereably below 2 by the addition of a strong acid, such as cone, hydrochloric acid.
- a strong acid such as cone, hydrochloric acid.
- the N-monoacylated-L-cysteine then crystallizes, eventually after cooling of the reaction mixture and/or the addition of petroleumether and/or after evaporation of part of the organic solvent and then the crystals may be filtered off and dried.
- the monoacylation is performed in water buffered with alkali carbonate, prefereably sodium or potassium carbonate, or in a mixture of water and an against acid halide non-reactive organic solvent.
- Suitable solvents to be used in mixture with water are alkyl chlorides such as methylene chloride, lower aliphatic cyclic ethers such as tetrahydrofuran, alkylethers such as tert . - butylmetyleter, alkylacetates such as etyl-, propyl- and butylacetat, alkylketons, alkylesters.
- alkyl chlorides such as methylene chloride
- lower aliphatic cyclic ethers such as tetrahydrofuran
- alkylethers such as tert . - butylmetyleter
- alkylacetates such as etyl-, propyl- and butylacetat, alkylketons, alkylesters.
- Potassium carbonate 180 g is dissolved in water (500 ml). Methylene chloride (500 ml) is added and the mixture is cooled to -8°C. Isobutyryl chloride (87 g, 0.82 mol) is added followed by the addition of L-cysteine (100 g, 0.82 mol). The temperature is adjusted to 20 - 25°C and after 2 hours at this temperature hydrochloric acid cone. (150 ml) is added to pH ⁇ 1. The heavy methylene chloride phase containing the product is separated. N- isobutyryl-L-cysteine is crystallized by addition of petroleumether (500 ml), filtered off and dried at 50°C in vacuum.
- N,S-diisobutyrylcysteine is dissolved in a mixture of 200 ml water, 200 ml methylene chloride and 56.7 g potassium carbonate. 38.0 g L-cysteine is added at room temperature. After 1 hour hydrochloric acid cone. (75 ml) is added to a pH of 0.54. The water phase is discharged. N-isobutyrylcysteine is crystallized by addition of petroleumether (40 - 65°), the crystals are filtered off and dried.
- Tert.-butylmetyleter 80 ml is added to a mixture of water (115 ml), potassium carbonate (37.5 g) and L-cysteine (20.2 g) and the temperature is adjusted to 8°C.
- Isobutyryl chloride (17.8 g) is added dropwise and the reaction mixture is heated to 25°C. pH of the mixture is 9.5. After 1 hour at 25°C, hydrochloric acid cone. (35 ml) is added to pH 0.5. The reaction mixture is cooled whereby the product crystallizes. The crystals are filtered of f and dried.
- Example 5 Butylacetate (80 ml) is added to a mixture of water (115 ml), potassium carbonate (37.5 g) and L-cysteine (20.2 g) and the temperature is adjusted to 4°C. Isobutyryl chloride (17.8 g) is added dropwise and the reaction mixture is heated to 25°C. pH of the mixture is 9.5. After 1 hour at 25°C hydrochloric acid cone. (35 ml) is added to pH 0.53. The water phase is discharged. 14 % of the organic phase is evaporated, the reaction mixture is cooled, and the product crystallizes. Petroleumether (40 - 65°) is added, the crystals are filtered off at 2°C and dried.
Abstract
An improved and simplified process for the selective N-monacylation of cysteine according to which L-cysteine is acylated with an acid halide in water containing more than one chemical equivalent of alkali carbonate, based on L-cysteine, within the temperature range of up to about 45°C. Water containing alkali carbonate might be used in mixture with any against acid halide non-reactive organic solvent, whereby the process might be performed within the temperature range of about -15° to 45°C.
Description
Process for the N-monoacylation of cysteine
Technical field
The present invention relates to an improved and simplified process for the selective N-monoacylation of cysteine.
Prior art
N-acylderivatives of L-cysteine typified by N-acetyl-L-cysteine and N-isobutyryl-L-cysteine have unique mucolytic properties and are of value for treatment of respiratory diseases.
Various methods of synthesis of N-monoacylated-L-cysteine have been described in the literature, e.g. US-A-3 184 505, which discloses a process for the N-monoacylation of cysteine using alkanoic acid anhydrides having up to 12 carbon atoms.
Although in principle synthesis of N-monoacylated-L-cysteine is a straight forward process, in practice several problems occur, i.a. to avoid the formation of N,S-diacylated compounds resp. to eliminate free acid formed by using acid anhydride.
Disclosure of the invention The object of the present invention is to provide an improved and simplified method for obtaining N-monoacylated-L-cysteine
by acylation of L-cysteine with one chemical equivalent of acid halide R-CO-X, wherein R is CH2CH3, CH(CH3)2, C(CH3)3, (CH2) 3CH3 or CH2CH(CH3)2 and X prefereably is CI, without racemization of the starting material or by reaction of N,S-diacylated-L- cysteine
propyonyl chloride, isobutyryl chloride, pivaloyl chloride, pentyryl chloride or isopentyryl chloride in water containing more than one chemical equivalent, based on the L-cysteine, of alkali carbonate in the temperature range of up to about 45°C,
and within the pH range about 7.1 to about 10, resulting in the formation of N-monoacylated-L-cysteine.
The same result is obtained when performing the acylation with one chemical equivalent of acid halide in a suitable mixture of water containing alkali carbonate and any against acid halide non-reactive organic solvent miscible or non-miscible with water in the temperature range of about -15°C to 45°C and within the pH range of about 7.1 - about 10.
N,S-diacylated-L-cysteine and one chemical equivalent of L-cysteine in water containing alkali carbonate or a suitable mixture of water containing alkali carbonate and any reaction stable organic solvent will result in N-monoacylated-L-cysteine.
One critical aspect of the invention is the use of alkali carbonate, preferably potassium carbonate, in water as a buffer, giving the desired pH of about 7.1 about 10 in the reaction mixture, prefereably 8 - 9.5.
After the reaction is completed, pH is reduced momentarily down to below 4, and prefereably below 2 by the addition of a strong acid, such as cone, hydrochloric acid. The N-monoacylated-L-cysteine then crystallizes, eventually after cooling of the reaction mixture and/or the addition of petroleumether and/or after evaporation of part of the organic solvent and then the crystals may be filtered off and dried.
The monoacylation is performed in water buffered with alkali carbonate, prefereably sodium or potassium carbonate, or in a mixture of water and an against acid halide non-reactive organic solvent. Suitable solvents to be used in mixture with water are alkyl chlorides such as methylene chloride, lower aliphatic cyclic ethers such as tetrahydrofuran, alkylethers such as tert . - butylmetyleter, alkylacetates such as etyl-, propyl- and butylacetat, alkylketons, alkylesters.
The invention will be further explained below by working examples illustrating the synthesis of N-isobutyryl-L-cysteine.
Example 1
Potassium carbonate (180 g) is dissolved in water (500 ml). Methylene chloride (500 ml) is added and the mixture is cooled to -8°C. Isobutyryl chloride (87 g, 0.82 mol) is added followed by the addition of L-cysteine (100 g, 0.82 mol). The temperature is adjusted to 20 - 25°C and after 2 hours at this temperature hydrochloric acid cone. (150 ml) is added to pH < 1. The heavy methylene chloride phase containing the product is separated. N- isobutyryl-L-cysteine is crystallized by addition of petroleumether (500 ml), filtered off and dried at 50°C in vacuum.
Yield: 129 g (84 %). Purity HPLC:, 99.5 %.
Example 2
Potassium carbonate (134 g, 0.96 mol) and L-cysteine (72 g, 0.6 mol) are dissolved in water (360 ml). The temperature is adjusted to 10°C and isobutyryl chloride (63.6 g, 0.6 mol) is added slowly. The temprature is then adjusted to 24°C and after 2 hours at this temperature ethyl acetate (200 ml) is added. Hydrochloric acid cone. (120 ml) is added to pH < 1 and the heavy water phase is discharged. N-isobutyryl-L-cysteine is crystallized by addition of petroleumether (400 ml), filtered off and dried at 50°C in vacuum.
Yield: 96 g (84 %). Purity HPLC: 98.5 %. Example 3
82.3 g N,S-diisobutyrylcysteine is dissolved in a mixture of 200 ml water, 200 ml methylene chloride and 56.7 g potassium carbonate. 38.0 g L-cysteine is added at room temperature. After 1 hour hydrochloric acid cone. (75 ml) is added to a pH of 0.54.
The water phase is discharged. N-isobutyrylcysteine is crystallized by addition of petroleumether (40 - 65°), the crystals are filtered off and dried.
Yield: 96.2 g (80 %). Purity HPLC: 98.1 %.
Example 4
Tert.-butylmetyleter (80 ml) is added to a mixture of water (115 ml), potassium carbonate (37.5 g) and L-cysteine (20.2 g) and the temperature is adjusted to 8°C. Isobutyryl chloride (17.8 g) is added dropwise and the reaction mixture is heated to 25°C. pH of the mixture is 9.5. After 1 hour at 25°C, hydrochloric acid cone. (35 ml) is added to pH 0.5. The reaction mixture is cooled whereby the product crystallizes. The crystals are filtered of f and dried.
Yield: 30.2 g (94.7 %). Purity HPLC: 97.3 %.
Example 5 Butylacetate (80 ml) is added to a mixture of water (115 ml), potassium carbonate (37.5 g) and L-cysteine (20.2 g) and the temperature is adjusted to 4°C. Isobutyryl chloride (17.8 g) is added dropwise and the reaction mixture is heated to 25°C. pH of the mixture is 9.5. After 1 hour at 25°C hydrochloric acid cone. (35 ml) is added to pH 0.53. The water phase is discharged. 14 % of the organic phase is evaporated, the reaction mixture is cooled, and the product crystallizes. Petroleumether (40 - 65°) is added, the crystals are filtered off at 2°C and dried.
Yield: 24.8 g (75 %). Purity HPLC: 98.6 %
Claims
1. Process for the selective N-monoacylation of cysteine, c h a r a c t e r i s e d in that L-cysteine is acylated with an acid halide in water containing more than one chemical equivalent, based on L-cysteine, of alkali carbonate within the temperature range of up to about 45°C.
2. Process according to claim 1, c h a r a c t e r i s e d in that the acylation is performed in a suitable mixture of water containing alkali carbonate and any against acid halide non- reactive organic solvent miscible or non-miscible with water within the temperature range of -15° to 45°C.
3. Process according to claim 1,or 2, c h a r a c t e r i s e d in that L-cysteine is acylated with one chemical equivalent of acid halide.
4. Process according to claim 1 or 2, c h a r a c t e r i s e d in that L-cysteine is acylated with an excess of acid halide resulting in the formation of N,S-diacylated-L-cysteine, and in that one chemical equivalent, based on the N,S-diacyla- ted-L-cysteine, of L-cysteine is added in water containing alkali carbonate or a suitable mixture of water containing alkali carbonate and any against acid halide non-reactive organic solvent, resulting in the formation of N-monoacylated-L-cysteine, which is crystallized, whereupon the crystals are recovered by filtration and dried.
5. Process according to any of claims 1 - 4, c h a r a c-t e r i s e d in that the acid halide is propyonyl chloride, isobutyryl chloride, pivaloyl chloride, pentyryl chloride or isopen- tyryl chloride.
6. Process according to any of claims 2 - 5, c h a r a c t e r i s e d in that the solvent used in mixture with water is chosen from the group of alkyl chlorides such as methylene chloride, lower aliphatic cyclic ethers such as tetrahydrofuran, alkylethers such as tert.-butylmetyleter, alkylacetates such asetyl-, propyl- and butylacetat, alkylketons, alkylethers.
7. Process according to any of the preceeding claims, c h a r a c t e r i s e d in that the alkali carbonate is potassium carbonate.
8. Process according to any of the preceeding claims, c h a r a c t e r i s-e d in that N-monoacylated-L-cysteine is recovered in crystal form after the completion of the reaction by reducing pH to below 4, and/or cooling and/or evaporation of part of the organic solvent and/or adding of petroleumether, filtering off and drying of the crystals.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8901766 | 1989-05-17 | ||
| SE8901766-9 | 1989-05-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1990014335A1 true WO1990014335A1 (en) | 1990-11-29 |
Family
ID=20375973
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE1990/000322 WO1990014335A1 (en) | 1989-05-17 | 1990-05-15 | Process for the n-monoacylation of cysteine |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0472634A1 (en) |
| AU (1) | AU5678290A (en) |
| WO (1) | WO1990014335A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1197637A (en) * | 1956-07-21 | 1959-12-02 | Rech S Et Propagande Scient | Process for the production of cysteine ester derivatives and novel derivatives which can be prepared by this process |
| GB954268A (en) * | 1962-02-26 | 1964-04-02 | Mead Johnson & Co | Decongestant compositions comprising n-acylated sulphydryl compounds |
| US4093740A (en) * | 1973-02-16 | 1978-06-06 | Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessier | Fodder for ruminants |
| EP0304778A1 (en) * | 1987-08-21 | 1989-03-01 | Degussa Aktiengesellschaft | Process for the production of N-acylated mercapto-alpha-amino acids |
| EP0317540A1 (en) * | 1987-11-19 | 1989-05-24 | Aktiebolaget Draco | Cysteine derivatives, processes for their preparation and their use |
-
1990
- 1990-05-15 AU AU56782/90A patent/AU5678290A/en not_active Abandoned
- 1990-05-15 EP EP19900908715 patent/EP0472634A1/en not_active Withdrawn
- 1990-05-15 WO PCT/SE1990/000322 patent/WO1990014335A1/en not_active Application Discontinuation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1197637A (en) * | 1956-07-21 | 1959-12-02 | Rech S Et Propagande Scient | Process for the production of cysteine ester derivatives and novel derivatives which can be prepared by this process |
| GB954268A (en) * | 1962-02-26 | 1964-04-02 | Mead Johnson & Co | Decongestant compositions comprising n-acylated sulphydryl compounds |
| US4093740A (en) * | 1973-02-16 | 1978-06-06 | Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessier | Fodder for ruminants |
| EP0304778A1 (en) * | 1987-08-21 | 1989-03-01 | Degussa Aktiengesellschaft | Process for the production of N-acylated mercapto-alpha-amino acids |
| EP0317540A1 (en) * | 1987-11-19 | 1989-05-24 | Aktiebolaget Draco | Cysteine derivatives, processes for their preparation and their use |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0472634A1 (en) | 1992-03-04 |
| AU5678290A (en) | 1990-12-18 |
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