GB2262282A - Process for preparing n-acylated proline derivatives - Google Patents
Process for preparing n-acylated proline derivatives Download PDFInfo
- Publication number
- GB2262282A GB2262282A GB9204428A GB9204428A GB2262282A GB 2262282 A GB2262282 A GB 2262282A GB 9204428 A GB9204428 A GB 9204428A GB 9204428 A GB9204428 A GB 9204428A GB 2262282 A GB2262282 A GB 2262282A
- Authority
- GB
- United Kingdom
- Prior art keywords
- pyrrolidine
- carboxylic acid
- thiol group
- reaction
- methyl propionyl
- 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
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a novel process for preparing captopril of the formula <IMAGE> characterized by reacting thiol group-introducing agent obtained from reaction of carbon disulfide and alkali metal hydroxide in an aqueous solution, with 1-[3-bromo-(2S)-methyl propionyl]-pyrrolidine-(2S)-carboxylic acid of the formula <IMAGE> and then subjecting the resulting intermediate compound to acid treatment and reduction treatment to provide 1-[3-mercapto-(2S)-methyl propionyl]-pyrrolidine-(2S)carboxylic acid (1).
Description
SPECIFICATION 1. Title of Invention
Process for preparing pyrrolidine carboxylic
acid derivatives 2. Detailed Description of Invention
The present invention relates to a novel process for preparing pyrrolidine carboxylic acid derivatives, particularly 1-[3mercapto-(2S)-methyl propionyl]-pyrrolidine-(2S)-carboxylic acid of the formula (I)
The compound (I) acts on the inhibition of angiotensin-converting enzyme and is widely used as an antihypertensive agent. A process for preparing the compound is disclosed in U. S.Patent
No. 4,046,889 which corresponds to Japanese Laid-open Patent
No. (sho)52-116457. Furthermore, Japanese Laid-open Patent
Nos. (sho)56-100760, (sho)56-125363 and (sho)56-86152 disclose the processes which comprise reacting thiol group-introducing agent such as Na2S203, NH4SH or NaSH, etc., using l-[3-halo- methyl propionyl]-pyrrolidine carboxylic acid as starting material. However, they are not suitable for the industrial production, because the aforementioned processes have the drawbacks that there may occur many side reactions and the yield is not very high.
The present inventors have extensively studied on thiol group-introducing agents and discovered an industrially useful process in which the desired compound of high yield and purity is obtained by reacting carbon disulfide with alkali metal hydroxide in the presense of an aqueous solution to provide thiol group-introducing agent and then reacting the resulting agent with 1-[3-bromo-methylpropionyl]-pyrrolidine carboxylic acid or its salt.
More specifically, the present invention provides a novel process for preparing pyrrolidine carboxylic acid derivative characterized by reacting thiol group-introducing agent obtained from reaction of carbon disulfide and alkali metal hydroxide in an aqueous solution, with l-[3-bromo-methyl propionyl]-pyrrolidine-carboxylic acid and then subjecting the resulting intermediate compound to acid treatment and reduction treatment to provide l-[3-mercapto-methyl propionyl]-pyrrolidine-carboxylic acid.
The thiol group-introducing agent used in the present process is obtained by reacting carbon disulfide with alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in the presence of a water soluble organic solvent or an acqueous solution. This reaction agent is not structurally identified, but is presumed as having an activity of introducing a thiol group.
Thiol group-introducing agent employed in the present process is reacted in an excess amount of about 1,0 to about 8 moles of alkali metal hydroxide to 1 mole of carbon disulfide and the reaction is carried out by first dissolving alkali metal hydroxide in an aqueous solution, adding carbon disulfide thereto and then heating the reaction solution at a temperature between about 15"C and 10"C while stirring. The reaction time depends on the heating temperature and is commonly 0.1 to 48 hours. If unreacted carbon disulfide remains after reaction, it may be used by allowing to fractionation or concentration. In light of industrial view point, water layer may be used as a reaction agent as it is.
For the preparation of the object compound (I) , l-[3-bromo (2S)-methyl propionyl)-pyrrolidine- (25) -carboxylic acid of the formula (II)
may be used as l-[3-bromo-methyl propionyl]-pyrrolidine carboxylic acid.
The bromo derivative and the thiol group-introducing agent are reacted in a stoichiometric mole, but the reaction is preferably carried out in an excessive amount of thiol groupintroducing agent. The reaction is carried out by dissolving the bromo derivative and adding thiol group-introducing agent while stirring. The reaction temperature is preferably about Oe C to 100"C. The reaction time depends on the reaction temperature, etc., but is commonly within the range of 0.5 to 48 hours.
After completion of the reaction, the reaction solution is subjected to subsequent treatment. The subsequent treatment comprises essentially acid treatment and reduction treatment, specifically washing the reaction solution with water insoluble organic solvent such as methylene chloride, chloroform and the like, and then subjecting the water layer to acid treatment.
The acid treatment is carried out by subjecting the water layer to hydrolysis at a PH value ranging from 0.1 to 4.0 by using organic or inorganic acid. Then the acid treatment solution is salted out, and extracted with water insoluble organic solvent and thereafter the solvent is isolated from the extract. The intermediate compound thus isolated is subjected to reduction treatment. The acid treatment solution to be reduced may be used as it is, but it is preferable to carry out the aforementioned extraction so as to increase the purity.
The reduction treatment is carried out by using a conventional reduction agent such as zinc powder, inorganic acid and the like. Hydrogen may also be used under normal pressure. After reduction treatment, the product is extracted, and dried with organic solvent according to conventional method and then allowed to remove the solvent. The residue is crystallized with ethyl acetate and n-hexane. The water solvent may also be used. The desired compound may be obtained in high yield of more than 90% based on purity. The present process may provide the desired compound in a high yield by using cheap starting materials. Thus the process is industrially very useful and economical.
The following examples illustrate the details of this invention. However, it should be understood that they are not intended thereby to limit the scope of the present invention.
Example 1 (a) Preparation of thiol group-introducing agent
To 58.13g of sodium hydroxide dissolved in 700ml of distilled water was added 105g of carbon disulfide. The solution was stirred at a temperature between 400 C and 45"C for 4 hours and then cooled to a room temperature. The water layer is removed to obtain thiol group-introducing agent.
(b) Preparation of l-[3-mercapto- (2S)-methyl propionyl] -pyrrolidine-(2S)-carboxylic acid
16.3g of l-[3-bromo-(2S)-methyl propionyl]-pyrrolidine-(2S)carboxylic acid hydrate was added to 32ml of distilled water.
A solution of 2.45g of sodium hydroxide dissolved in 13.3ml of distilled water was added thereto. Then thiol group-introducing agent (a) was added at a temperature of below 10"C, stirred at 85"C for 5 hours and cooled to room temperature. The reaction mixture was washed with 60ml of methylene chloride, cooled to below 50C, adjusted to a PH value of 1.0 by using 17.5% hydrochloric acid, stirred for 22 hours, extracted 3 times with 600 ml of methylene chloride and concentrated under reduced pressure. Thereafter, 164g of 1N His04 and 1.07g of zine powder were added and stirred overnight. 32g of sodium chloride was added, extracted 3 times with 60ml of methylene chloride, dryed over anhydrous sodium sulfate, filtered with celite, concentrated and recrystallized with ethyl acetate and n-hexane to obtain 11.82g of crystals (yield : 94.11%).
[α]25: -127.7 Melting Point : 1030 - 105" C
HPLC : 96.74 %
Example 2 (a) Preparation of thiol group-introducing agent
The thiol group-introducing agent was obtained by carrying out the procedure described in Example 1 except that 11.85g of sodium hydroxide, lOOml of distilled water and 15g of carbon disufide were used.
(b) Preparation of 1-[3-mercapto-(2S)-methyl propionyl]
-pyrrolidine-(2S)-carboxylic acid
11.61g of crystals (yield : 92.45%) was obtained by carrying out the procedure described in Example 1 except that 70g of sodium chloride was used.
[ ot ]25: -126.2 Melting Point : 103 -106 C
HPLC : 97.569Ó Example 3 (a) Preparation of thiol group-introducing agent
30.9g of sodium hydroxide was dissolved in 200ml of distilled water and then 43g of carbon disulfide was added thereto.
The reaction solution was stirred for 5 hours at a temperature between 400 C and 45 C and cooled to room temperture. The water layer was isolated by using separatory funnel to obtain thiol group-introducing agent.
(b) Preparation of 1-[3-mercapto-(2S)-methyl propionyl]
-pyrrolidine-(2S)-carboxylic acid
To 16.3g of 1-[3-bromo-(2S)-methyl propionyl)-pyrrolidine- (2S)-carboxylic acid hydrate was added 32ml of distilled water.
2.45g of sodium hydroxide dissolved in 13.3ml of distilled water was further added, cooled to below 10"C and thereafter thiol group-introducing agent (a) was added and maintained overnight.
The reaction mixture was washed with 60ml of methylene chloride, adjusted to a PH value of 1.0 by adding 17.5% hydrochloric acid, stirred for 22 hours, extracted 3 times with 60ml of methylene cholride by adding 300g of sodium chloride and concentrated under reduced pressure. Then, 168g of 1N H2SO4and 1.5g of zinc powder were added and stirred for 5 hours. 35g of sodium chloride was further added and dissolved, extracted 3 times with 60ml of methylene chloride, concentrated under reduced pressure and then recrystallized with ethyl acetate and n-hexane. The precipitate was filtered and dried to obtain 11.96g of white crystals (yield : 95.22%).
[ ffi ]25: -1280 Melting Point : 103 C - 106 C HPLC : 98.0%
Example 4 (a) Preparation of thiol group-introducing agent
To 71.lg of sodium hydroxide dissolved in 600ml of distilled water was added 129g carbon disulfide. The solution was maintained at a temperature between 40"C and 45"C for 5 hours and cooled to room temperature. The water layer was isolated by using separatory funnel to obtain thiol group-introducing agent.
(b) Preparation of l-[3-mercapto-(2S)-methyl propionyl]
-pyrrolidine-(2S)-carboxylic acid
To 48.9g of l-[3-bromo-(2S)-methyl propionyl]-pyrrolidine (2S)-carboxylic acid hydrate was added 100ml of distilled water and then 7.36g of.sodium hydroxide dissolved in 40ml of distilled water was added and cooled to a temperature of 10 C.
Thiol group-introducing agent was added, maintained at room temperature overnight, washed with 200ml of methylene chloride, adjusted to a PH value of 1.0 by using 17.5% hydrochloric acid, stirred for 3 hours, and then allowed to dissolve 900g of sodium chloride. The reaction mixture was extracted 3 times with 200ml of methylene chloride and concentrated under reduced pressure, thereafter 500g of 1N-H2S04 and 4.5g of zinc powder were added, stirred and allowed to dissolve 105g of sodium chloride. The residue was extracted 3 times with 200ml of methylene chloride, concentrated, crystallized with ethyl acetate and n-hexane, filtered and dried to obtain 35.91g of white crystals (yield : 95.29%).
[ Ob ]25: -128.3 Melting Point : 104C - 106oC HPLC : 9 Example 5 (a) Preparation of thiol group-introducing agent
8.g of sodium hydroxide was added to 75ml of distilled
water and then 11.5g of carbon disulfide was further added
and heated under reflux for 4 hours. After cooling to
room temperature, the remaining carbon disulfide was iso
lated and removed.
(b) Preparation of 1-[3-mercapto-(2S)-methyl propionyl]
-pyrrolidine-(2S)-carboxylic acid
3.0g of sodium hydroxide dissolved in 70ml of distilled
water and then 20g of 1-(3-bromo-(2S)-methyl propionyl]
pyrrolidine-(2S)-carboxylic acid hydrate was added and
reacted with thiol group-introducing agent (a). After
stirring at a temperature between 40"C and 45 C for a day,
the reaction mixture was cooled to room temperature and
washed with methylene chloride. After hydrolyzing with
conc.hydrochloric acid, 1.Og of zinc powder was added and
allowed to reduction. Then 30g of sodium hydroxide was
further added, extracted 3 times with 80ml of methylene
chloride, dried over magnesium sulfate, filtered and con
centrated. The residue was crystallized with ethyl ace
tate and n-hexane to obtain the desired compound in yield simiiar to that of the Example 1.
Claims (4)
1. A novel process for preparing pyrrolidine carboxylic acid
derivative of the formula
characterized by reacting thiol group-introducing agent obtained from reaction of carbon disulfide and alkali metal hydroxide in an aqueous solution, with l-[3-bromo-(2S)-methyl propionyl]-pyrrolidine-2(S)-carboxylic acid of the formula
and then subjecting the resulting intermediate compound to
acid treatment and reduction treatment to provide 1-[3 mercapto-(2S) -methyl propionyl]-pyrrolidine-(2S) -carboxylic acid (I).
2. The process of claim 1 wherein the alkali metal hydroxide is
strong base such as sodium hydroxide and potassium hydroxide.
3. The process of claim 1 wherein the temperature in the prepa
ration reaction of the thiol group-introducing agent is
between 15"C and 100'C.
4. A process for preparing the pyrrolidine carboxylic acid
derivative of formula I given in claim 1, substantially as
described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019910019709A KR940005014B1 (en) | 1991-11-07 | 1991-11-07 | Process for producting pyrrolidine derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB9204428D0 GB9204428D0 (en) | 1992-04-15 |
| GB2262282A true GB2262282A (en) | 1993-06-16 |
| GB2262282B GB2262282B (en) | 1995-08-23 |
Family
ID=19322380
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9204428A Expired - Fee Related GB2262282B (en) | 1991-11-07 | 1992-02-27 | Process for preparing pyrrolidine carboxylic acid derivatives |
Country Status (6)
| Country | Link |
|---|---|
| KR (1) | KR940005014B1 (en) |
| CN (1) | CN1031752C (en) |
| GB (1) | GB2262282B (en) |
| IT (1) | IT1255497B (en) |
| MY (1) | MY108145A (en) |
| PH (1) | PH30239A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103086940B (en) * | 2011-10-28 | 2014-07-09 | 华中药业股份有限公司 | Synthetic method of 1-(3-mercapto-2-D-methyl propionyl)-L-proline |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2066252A (en) * | 1979-12-29 | 1981-07-08 | Egyt Gyogyszervegyeszeti Gyar | Process for the preparation of 1-(3-mercapto-/2s/-methylpropionyl)-pyrrolidine-/2s/-carboxylic acid |
| EP0084380A1 (en) * | 1982-01-20 | 1983-07-27 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Process for the preparation of optically active thiol compounds |
| GB2168978A (en) * | 1984-12-19 | 1986-07-02 | Boryung Pharm | Process for preparing pyrrolidine derivatives |
| GB2170806A (en) * | 1985-02-11 | 1986-08-13 | Boryung Pharm | N-(b-mercapto-iso-butyryl)proline, derivatives and a process for their preparation |
-
1991
- 1991-11-07 KR KR1019910019709A patent/KR940005014B1/en not_active IP Right Cessation
-
1992
- 1992-02-21 PH PH43962A patent/PH30239A/en unknown
- 1992-02-27 MY MYPI92000323A patent/MY108145A/en unknown
- 1992-02-27 GB GB9204428A patent/GB2262282B/en not_active Expired - Fee Related
- 1992-02-28 CN CN92101241A patent/CN1031752C/en not_active Expired - Fee Related
- 1992-09-18 IT ITMI922157A patent/IT1255497B/en active IP Right Grant
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2066252A (en) * | 1979-12-29 | 1981-07-08 | Egyt Gyogyszervegyeszeti Gyar | Process for the preparation of 1-(3-mercapto-/2s/-methylpropionyl)-pyrrolidine-/2s/-carboxylic acid |
| EP0084380A1 (en) * | 1982-01-20 | 1983-07-27 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Process for the preparation of optically active thiol compounds |
| GB2168978A (en) * | 1984-12-19 | 1986-07-02 | Boryung Pharm | Process for preparing pyrrolidine derivatives |
| GB2170806A (en) * | 1985-02-11 | 1986-08-13 | Boryung Pharm | N-(b-mercapto-iso-butyryl)proline, derivatives and a process for their preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1255497B (en) | 1995-11-09 |
| CN1072175A (en) | 1993-05-19 |
| ITMI922157A0 (en) | 1992-09-18 |
| PH30239A (en) | 1997-02-05 |
| KR930009995A (en) | 1993-06-21 |
| KR940005014B1 (en) | 1994-06-09 |
| ITMI922157A1 (en) | 1994-03-18 |
| GB9204428D0 (en) | 1992-04-15 |
| GB2262282B (en) | 1995-08-23 |
| CN1031752C (en) | 1996-05-08 |
| MY108145A (en) | 1996-08-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20070227 |