CN1072175A - The preparation method of pyrrolidine carboxylic acid derivatives - Google Patents
The preparation method of pyrrolidine carboxylic acid derivatives Download PDFInfo
- Publication number
- CN1072175A CN1072175A CN92101241A CN92101241A CN1072175A CN 1072175 A CN1072175 A CN 1072175A CN 92101241 A CN92101241 A CN 92101241A CN 92101241 A CN92101241 A CN 92101241A CN 1072175 A CN1072175 A CN 1072175A
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- Prior art keywords
- carboxylic acid
- methylpropionyl
- thiol group
- agent
- preparation
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- 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
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- 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 novel method of preparation formula (I) pyrrolidine carboxylic acid derivatives; it is characterized in that dithiocarbonic anhydride and alkali metal hydroxide are reacted 1-[3-bromo-(2S)-methylpropionyl that the thiol group that obtains is introduced agent and formula (II) in the aqueous solution] tetramethyleneimine-(2S)-carboxylic acid reacts; again the intermediate that obtains is carried out acid treatment and reduction is handled, just can obtain 1-[3-sulfydryl-(2S)-methylpropionyl] tetramethyleneimine-(2S)-carboxylic acid (I).
Description
The present invention relates to the preparation of 1-(3-sulfydryl-(2S)-the methylpropionyl)-tetramethyleneimine of the novel preparation method of pyrrolidine carboxylic acid derivatives, particularly formula I-(2S)-carboxylic acid derivative
Compound (I) has been widely used as hypotensive agent as the effect that suppresses angiotensin converting enzyme.The method for preparing this compound has been disclosed in U.S.P.046889(corresponding to open (Sho) 52-116457 of Japanese Patent).In addition, Japanese Patent open (Sho) 56-100760, (Sho) 56-125363 and (Sho) 56-86152 disclose and comprised that the reacting thiourea alcohol radical introduces agent such as Na
2S
2O
3, NH
4The method of SH or NaSH etc., they with 1-(3-halogen-methylpropionyl)-pyrrolidine carboxylic acid as starting raw material.But above-mentioned each method has possibility and the not too high shortcoming of productive rate that produces various side reactions, and therefore, they also are not suitable for industrial production.
The present inventor is through introducing the further investigation of agent to thiol group; found in industrial suitable method; can obtain high yield and highly purified required compound; this method is to act on dithiocarbonic anhydride with alkali metal hydroxide to introduce agent so that thiol group to be provided in the aqueous solution, uses 1-(3-bromo-methylpropionyl) pyrrolidine carboxylic acid or its salt and resulting thiol group to introduce the agent reaction then.
More particularly; the invention provides the novel method of preparation pyrrolidine carboxylic acid derivatives; the feature of this method is dithiocarbonic anhydride and alkali metal hydroxide to be reacted in the aqueous solution thiol group that obtains is introduced agent and 1-(3-bromo-methylpropionyl) pyrrolidine carboxylic acid reacts; then with resulting midbody compound acid treatment; handle through reduction again, obtain 1-(3-sulfydryl-methyl-prop 5 acyl groups) pyrrolidine carboxylic acid.
It is that alkali metal hydroxide and the dithiocarbonic anhydride reaction with sodium hydroxide or potassium hydroxide and so on obtains in the presence of the water-miscible organic solvent or the aqueous solution that the used thiol group of the present invention is introduced agent.The structure of this reagent is not determined as yet, but can be supposed that it has the activity of introducing thiol group.
The thiol group introducing agent that the inventive method adopted is that alkali metal hydroxide/1 mole of carbon disulfide with about 8 molar excess of about 1.0-is reacted, what react is with the water-soluble solution of alkali metal hydroxide elder generation, to wherein adding dithiocarbonic anhydride, then under agitation in 15 °-10 ℃ temperature reacting by heating solution.Reaction times is depended on Heating temperature, normally 0.1-48 hour, has unreacted dithiocarbonic anhydride to retain after reacting, available fractionation or concentrated being used.Send from the viewpoint of industry, can former water layer as reagent.
Be preparation purpose compound (I), can be with 1-(3-bromo-(2S)-methylpropionyl) tetramethyleneimine of formula II-(2S)-carboxylic acid as 1-(3-bromo-methylpropionyl) pyrrolidine carboxylic acid.
Bromo derivative and thiol group are introduced agent and are reacted with stoichiometric mole number, carry out with excessive mercaptan introducing agent but react best.What react is to dissolve bromo derivative earlier, and adding mercaptan is introduced agent under stirring again.Preferably about 0-100 ℃ of temperature of reaction.Reaction times is depended on temperature of reaction etc., but normally in 0.5-48 hour scope.
After reacting completely, reaction soln is carried out aftertreatment, aftertreatment mainly is that acid treatment and reduction are handled, and concrete grammar is with water-insoluble organic solvents such as washing reaction solution such as methylene dichloride, chloroform, again water layer is carried out acid treatment.
Acid treatment is water layer to be hydrolyzed under the condition of pH0.1-4.0 with organic or inorganic acid.Then acid treating solution is saltoutd, the water insoluble solvent extracts again, isolates solvent from extract.The intermediate compound that obtains after the separation reduces processing.The reductive acid treating solution can be used original solution, but preferably carries out above-mentioned leaching process, to increase its purity.The processing of reducing is with common reductive agent, as zinc powder, mineral acid etc., also can reduce with hydrogen under normal pressure.After reduction was handled, product removed and desolvates through extracting and use the ordinary method dry solvent.Resistates carries out crystallization with ethyl acetate and normal hexane.Water solvent also is operable.Based on its purity, can obtain the required compound of productive rate greater than 90% high yield.Because the inventive method uses cheap raw material can obtain the required compound of high yield, thus this method industrial be very useful, and be economical.
The following examples will the present invention is described in detail, but scope of the present invention is limited.
Example 1
(a) thiol group is introduced the preparation of agent
105g dithiocarbonic anhydride is added the solution of 58.13g sodium hydroxide in 700ml distilled water, between 40-50 ℃ temperature,, be chilled to room temperature then this solution stirring 4 hours.After removing water layer, obtain thiol group and introduce agent.
(b) preparation of 1-(3-sulfydryl-(2S)-methylpropionyl) tetramethyleneimine-(2S)-carboxylic acid.
16.3g hydration 1-(3-bromo-(2S)-methylpropionyl) tetramethyleneimine-(2S)-carboxylic acid is added in the 32ml distilled water.To wherein adding the solution of 2.45g sodium hydroxide in 13.3ml distilled water.Add thiol group under 10 ℃ the temperature and introduce agent (a) being lower than then, stirred 5 hours down, be cooled to room temperature in 85 ℃.With 60ml washed with dichloromethane reaction mixture, be cooled to below 5 ℃, with 17.5%HCl the pH value is transferred to 1.0, stirred 22 hours, with 600ml dichloromethane extraction 3 times, concentrating under reduced pressure.After this, add 164g 1N H
2SO
4Spend the night with 1.07g zinc powder and stirring.Add 32g sodium-chlor,, use anhydrous sodium sulfate drying with 60ml dichloromethane extraction 3 times, diatomite filtration, concentrated, recrystallization in ethyl acetate and normal hexane obtains crystal 11.82g(productive rate: 94.11%).
〔α〕
25D：-127.7°
Fusing point: 103-105 ℃
HPLC：96.74%
Example 2
(a) thiol group is introduced the preparation of agent
Produce thiol group by example 1 described step and introduce agent, but use 11.85g sodium hydroxide, 100ml distilled water and 15g dithiocarbonic anhydride.
(b) preparation of 1-(3-sulfydryl-(2S)-methylpropionyl) tetramethyleneimine-(2S)-carboxylic acid.
Press example 1 described step, but use 70g sodium-chlor, make crystal 11.61g(productive rate: 92.45%).
〔α〕
25D：-126.2°
Fusing point: 103-105 ℃
HPLC：97.56%
Example 3
(a) thiol group is introduced the preparation of agent
30.9g sodium hydroxide is dissolved in the 200ml distilled water, to wherein adding 43g dithiocarbonic anhydride.This reaction soln stirred 5 hours between 40-45 ℃ temperature, was cooled to room temperature then.Divide water-yielding stratum to produce thiol group with separating funnel and introduce agent.
(b) preparation of 1-(3-sulfydryl-(2S)-methylpropionyl) tetramethyleneimine-(2S)-carboxylic acid.
32ml distilled water is added 16.3g hydration 1-(3-bromo-(2S)-methylpropionyl) tetramethyleneimine-(2S)-carboxylic acid, add the solution of 2.45g sodium hydroxide in 13.3ml distilled water again, be cooled to below 10 ℃.Add thiol group then and introduce agent (a), placement is spent the night.Reaction mixture 60ml washed with dichloromethane transfers to 1.0 with 17.5%HCl with the pH value, stirs 22 hours.Add 300g sodium-chlor, use 60ml dichloromethane extraction 3 times, concentrating under reduced pressure.Add 168g 1N H then
2SO
4With the 1.5g zinc powder, stirred 5 hours.Continue to add 35g sodium-chlor, make it dissolving, use 60ml dichloromethane extraction 3 times, concentrating under reduced pressure is with ethyl acetate and normal hexane recrystallization.Leach precipitation, drying obtains white crystal 11.96g(productive rate: 95.22%).
〔α〕
25D：-128°
Fusing point: 103-105 ℃
HPLC：98.0%
Example 4
(a) thiol group is introduced the preparation of agent
129g dithiocarbonic anhydride is added the solution of 71.1g sodium hydroxide in 600ml distilled water, and this solution kept 5 hours between 40-50 ℃.Be cooled to room temperature.Divide water-yielding stratum with separating funnel, make thiol group and introduce agent.
(b) preparation of 1-(3-sulfydryl-(2S)-methylpropionyl) tetramethyleneimine-(2S)-carboxylic acid.
100ml distilled water is added 48.9g hydration 1-(3-bromo-(2S)-methylpropionyl) tetramethyleneimine-(2S)-carboxylic acid, add the solution of 7.36g sodium hydroxide in 40ml distilled water again, be cooled to 10 ℃.Add thiol group and introduce agent, under room temperature, keep spending the night.Use the 200ml washed with dichloromethane, the pH value is transferred to 1.0, stirred 2 hours, again in wherein dissolving 900g sodium-chlor with 17.5%HCl.With 200ml dichloromethane extraction reaction mixture 3 times, concentrating under reduced pressure.Add 500ml 1N H then
2SO
4With the 4.5g zinc powder, stir, dissolve 105g sodium-chlor therein.Resistates 200ml dichloromethane extraction 3 times concentrate, and with ethyl acetate and normal hexane crystallization, filter, and drying obtains white crystal 35.91g(productive rate: 95.29%).
〔α〕
25D：-128.3°
Fusing point: 104-106 ℃
HPLC：98.88%
Example 5
(a) thiol group is introduced the preparation of agent
8.8g sodium hydroxide is added in the 75ml distilled water, add 11.5g dithiocarbonic anhydride again, reflux 4 hours.After being cooled to room temperature, separating and remove remaining dithiocarbonic anhydride.
(b) preparation of 1-(3-sulfydryl-(2S)-methylpropionyl) tetramethyleneimine-(2S)-carboxylic acid.
3.0g sodium hydroxide is dissolved in 70ml distilled water, adds 20g hydration 1-(3-bromo-(2S)-methylpropionyl) pyridine alkane-(2S)-carboxylic acid again and introduce agent (a) with thiol group and react.After stirring one day between 40-50 ℃, reaction mixture is cooled to room temperature, use washed with dichloromethane.Behind concentrated hydrochloric acid hydrolysis, add the 1.0g zinc powder and make its reduction.After this add 30g sodium hydroxide again, use 80ml dichloromethane extraction 3 times,, filter, concentrate with dried over mgso.Residuum crystallization in ethyl acetate and normal hexane obtains needed compound, and its productive rate is similar to person in the example 1.
Claims (3)
1, the novel method of preparation formula I pyrrolidine carboxylic acid derivatives,
It is characterized in that dithiocarbonic anhydride and alkali metal hydroxide are reacted 1-[3-bromo-(2S)-methylpropionyl that the thiol group that obtains is introduced agent and formula II in the aqueous solution] tetramethyleneimine-(2S)-carboxylic acid reacts,
Then the midbody compound that obtains is carried out acid treatment and reduction is handled, obtains 1-[3-sulfydryl-(2S)-methylpropionyl] tetramethyleneimine-(2S)-carboxylic acid (I).
2, the process of claim 1 wherein that alkali metal hydroxide is the highly basic of sodium hydroxide, potassium hydroxide and so on.
3, the process of claim 1 wherein that the temperature that thiol group is introduced the agent preparation feedback is between 15 ℃-100 ℃.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR91-19709 | 1991-11-07 | ||
| KR1019910019709A KR940005014B1 (en) | 1991-11-07 | 1991-11-07 | Process for producting pyrrolidine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1072175A true CN1072175A (en) | 1993-05-19 |
| CN1031752C CN1031752C (en) | 1996-05-08 |
Family
ID=19322380
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92101241A Expired - Fee Related CN1031752C (en) | 1991-11-07 | 1992-02-28 | 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) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103086940A (en) * | 2011-10-28 | 2013-05-08 | 华中药业股份有限公司 | Synthetic method of 1-(3-mercapto-2-D-methyl propionyl)-L-proline |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU184082B (en) * | 1979-12-29 | 1984-06-28 | Egyt Gyogyszervegyeszeti Gyar | Process for preparing 1-3-/3mercapto-/2s/-methyl-propinyl/-pyrrolidine-/2s/-carboxylic acid |
| JPS58124764A (en) * | 1982-01-20 | 1983-07-25 | Kanegafuchi Chem Ind Co Ltd | Production of optically active thiol |
| KR870001570B1 (en) * | 1984-12-19 | 1987-09-04 | 보령제약 주식회사 | Preparing process for pyrolidine derivatives |
| KR870001569B1 (en) * | 1985-02-11 | 1987-09-04 | 보령제약 주식회사 | Preparing process for pyrolidine derivatives |
-
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
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103086940A (en) * | 2011-10-28 | 2013-05-08 | 华中药业股份有限公司 | Synthetic method of 1-(3-mercapto-2-D-methyl propionyl)-L-proline |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1255497B (en) | 1995-11-09 |
| GB2262282B (en) | 1995-08-23 |
| PH30239A (en) | 1997-02-05 |
| GB2262282A (en) | 1993-06-16 |
| CN1031752C (en) | 1996-05-08 |
| KR940005014B1 (en) | 1994-06-09 |
| KR930009995A (en) | 1993-06-21 |
| GB9204428D0 (en) | 1992-04-15 |
| MY108145A (en) | 1996-08-30 |
| ITMI922157A1 (en) | 1994-03-18 |
| ITMI922157A0 (en) | 1992-09-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C15 | Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993) | ||
| OR01 | Other related matters | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 19960508 |