CN100436417C - Resolution method of optically active amlodipine - Google Patents
Resolution method of optically active amlodipine Download PDFInfo
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- CN100436417C CN100436417C CNB2006100769353A CN200610076935A CN100436417C CN 100436417 C CN100436417 C CN 100436417C CN B2006100769353 A CNB2006100769353 A CN B2006100769353A CN 200610076935 A CN200610076935 A CN 200610076935A CN 100436417 C CN100436417 C CN 100436417C
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Abstract
The present invention relates to chemical method of resolving despinner Amlodipine into (S)-(-)-Amlodipine and (R)-(+)-Amlodipine. The resolving agent is L-tartaric acid or D-tartaric acid; and the solvent is methyl ethyl sulfoxide or mixed solvent containing methyl ethyl sulfoxide. The present invention has greatly shortened reaction period and no special requirement on the water content in the solvent, and is especially suitable for large scale production.
Description
Technical field
The present invention relates to a kind of chemical process that splits (S)-(-)-amlodipine and (R)-(+)-amlodipine by the raceme amlodipine.
Technical background
Amlodipine is a calcium ion antagonist, clinical hypertension and the stable angina pectoris of being used for the treatment of.The amlodipine of using clinically is mainly raceme at present, according to Arrowsmiith, and J.E.; Etal.J.Med.Chem (1986) 29; 1696-1702 report, its pharmacologically active main component is (S)-(-)-amlodipine, its calcium ion antagonistic activity approximately is 1000 times of (R)-(+)-amlodipine, 2 times of raceme; Young, J.W., WO93/10779 report use (S)-(-)-amlodipine and can reduce side effects such as acro-edema, headache, dizziness with respect to using racemic amlodipine.Therefore adopt (S)-(-)-amlodipine treatment hypertension and stable angina pectoris to have good market outlook.Another enantiomorph (R)-(+)-amlodipine has the atherosclerotic activity of treatment.
The amlodipine chemical structural formula is as follows:
The method for preparing the amlodipine enantiomorph mainly is to split racemic amlodipine.The WO95/25722 patent of Pfizer provides one to be resolving agent with D or L-tartrate; dimethyl sulfoxide (DMSO) is a solvent; directly split the method that amlodipine obtains the amlodipine enantiomorph; its weak point is a long reaction time; need reaction overnight; water content to solvent has strict demand; the dimethyl sulfoxide (DMSO) water content was at 0.25% o'clock in embodiment 11; the product E value is 96.8%; water content was at 0.5% o'clock; the product E value is 87.7%; illustrate that thus water content is big to the E value influence of product in the dimethyl sulfoxide (DMSO), need the water content in the control solvent system, and want strict control moisture content in process of production; at first to control the moisture content of initiator; wherein the removal of dimethyl sulfoxide (DMSO) moisture content is complicated, only could realize under the rectifying condition, thereby cause processing step loaded down with trivial details; equipment cost strengthens, and is not suitable for large-scale production.
Summary of the invention
The present invention make every effort to seek a kind of by racemic amlodipine preparation (S)-(-)-amlodipine and (R)-(+)-industrialized preparing process of amlodipine.
It is as follows that the present invention splits (S)-(-)-amlodipine method: racemic amlodipine and D-(-)-tartrate are dissolved in the first and second basic sulfoxides respectively or contain in the mixed solvent of the first and second basic sulfoxides, stir, mix, precipitation, continue to stir 0.5～5 hour, separate, wherein throw out is the solvate of (S)-(-)-amlodipine and D-(-)-tartrate and the first and second basic sulfoxides generations, with lower alcohol refining solvent thing, add methylene dichloride, with the sodium hydroxide solution neutralization, obtain (S)-(-)-amlodipine.
It is as follows that the present invention splits (R)-(+)-amlodipine method: racemic amlodipine and L-(+)-tartrate are dissolved in the first and second basic sulfoxides respectively or contain in the mixed solvent of the first and second basic sulfoxides, stir, mix, precipitation, continue to stir 0.5～5 hour, separate, wherein throw out is the solvate of (R)-(+)-amlodipine and L-(+)-tartrate and the first and second basic sulfoxides generations, with lower alcohol refining solvent thing, add methylene dichloride, with the sodium hydroxide solution neutralization, obtain (R)-(+)-amlodipine.
The first and second basic sulfoxides make with following method:
This chemical equation:
CH
3SCH
2CH
3+H
2O
2→CH
3SOCH
2CH
3+H
2O
Under the ice bath the first and second basic thioethers are dissolved in acetone, drip hydrogen peroxide, temperature of reaction is controlled at below 40 ℃, and 25-35 ℃ is incubated 6 hours, and excessive first and second thioethers, acetone and water are removed in 60 ℃ of underpressure distillation, get product, water content 5.2%, yield 90%.Gas chromatographic purity 99.2%.
The gained first and second basic sulfoxides are added calcium oxide, be warmed up to 70 degree, dry 5 hours, drop to the room temperature after-filtration, filtrate decompression is filtered, and vacuum distilling obtains fraction, and yield is 81%, and moisture content is 0.4%, gas chromatographic purity 99.3%.
The mixed solvent of the first and second basic sulfoxides is made up of the first and second basic sulfoxides and solubility promoter.
Solubility promoter is selected from methyl alcohol, ethanol, propyl carbinol, acetone, butanone, 2 pentanone, ether, methyl ethyl ether, ethyl acetate, ethyl formate, N, dinethylformamide, methylene dichloride or chloroform.
Racemic amlodipine and D-(-)-tartaric mol ratio is 1: 0.25～0.8, preferred molar ratio 1: 0.5.
Racemic amlodipine and L-(+)-tartaric mol ratio is 1: 0.25～0.8, preferred molar ratio 1: 0.5.
Lower alcohol solvent is selected from ethanol, methyl alcohol or Virahol.
According to the hydrogen nuclear magnetic resonance spectrum analysis, the composition of solvate is (S)-(-)-amlodipine, D-(-)-tartrate, the first and second basic sulfoxides.
Amlodipine enantiomorph detection method:
Measure optical purity by chiral column HPLC, adopt Ultron ES-OVM chiral column, ovomucoid-15cm; Flow velocity-1ml/min; Measure wavelength-360nm; Moving phase 0.02mol/L Sodium phosphate dibasic (PH7): acetonitrile=80: 20.Sample dissolution is at acetonitrile: water, 50: 50,0.2mg/ml solution.
The mixed solvent that the present invention uses the first and second basic sulfoxides or the first and second basic sulfoxides solvent that splits the reaction times is shortened greatly, and the moisture content of solvent for use is not had particular requirement, so the present invention is fit to scale production very much.
Embodiment
The preparation of embodiment one first and second basic sulfoxide
1. get four-hole 1000ml reaction flask (band thermometer, prolong), add acetone 350ml, first ethyl ether 2mol earlier, reaction flask is placed in the ice bath, be added dropwise to hydrogen peroxide 1.98mol (concentration is 31%), answer temperature to be controlled at below 40 degree, add the back and between the 25-35 degree, be incubated 6 hours, 60 degree vacuum decompressions are removed excessive first and second thioethers, acetone and water again, get product 176 grams, water content is 5.2%, yield 91%.Gas chromatographic purity 99.2%.
2. get the said products 80 grams (water content 5.2%), add calcium oxide 60 grams, be warmed up to 70 degree, dry 5 hours, drop to the room temperature after-filtration, filtrate decompression is filtered, and vacuum distilling obtains fraction 62 grams, yield is 81%, and moisture content is 0.4%., gas chromatographic purity 99.3%.
The preparation of embodiment two (S)-(-)-amlodipine
It is in 0.4% the first and second basic sulfoxides (being made by embodiment one) that 5 gram (0.012mol) amlodipines are dissolved in the 40ml water content, add that to be dissolved with 1.0 gram (0.006mol) D-(-)-tartaric 40ml water content be 0.5% the first and second basic sulfoxide solution, stirring at room reaction 1 hour, separate out precipitation, filter, use the 15ml washing with acetone, 50 ℃ of vacuum 4 hours, solvate 2.40 grams formed of (S)-(-)-amlodipine, D-(-)-tartrate, first and second basic sulfoxide three components.
With dried above-mentioned solvate 2.40 grams, add methylene dichloride 35ml, 2N sodium hydroxide solution 18ml, stirring reaction 30 minutes leaves standstill, and tells organic layer, add an amount of dried over anhydrous sodium carbonate, filter, with a small amount of washed with dichloromethane filter cake, filtrate decompression is concentrated, add an amount of normal hexane, stirred crystallization is filtered, vacuum-drying 4 hours gets (S)-(-)-amlodipine 1.53 grams.Utilizing chiral column HPLC to measure its enantiomeric excess value (ee) is 99.0%, and total recovery is 61.2%.
The preparation of embodiment three (S)-(-)-amlodipine
Use the not dry first and second basic sulfoxides among the embodiment one, water content 5.2%, other is with embodiment two, obtain solvate 2.35 grams of (S)-(-)-amlodipine, D-(-)-tartrate, the first and second basic sulfoxide three components compositions, finally obtain (S)-(-)-amlodipine 1.49 grams, it is 98.5% that chiral column HPLC measures its enantiomeric excess value (ee), and total recovery is 59.6%.
The preparation of embodiment four (S)-(-)-amlodipine
Implementation method is with embodiment two, and solvent is changed to the solubility promoter in the following table and the mixed solvent of the first and second basic sulfoxides.
| Solubility promoter | Mixed solvent is formed (V Solubility promoter∶V Total solvent)％ | (S)-(-)-amlodipine ee% |
| Water | 15 | 98.1 |
| Propyl carbinol | 4 | 98.0 |
| Methyl acetate | 3 | 96.3 |
| Trichloromethane | 2 | 97.6 |
| 2-butanone | 2 | 97.8 |
| DMSO | 30 | 98.8 |
The preparation of embodiment five (R)-(+)-amlodipine
It is in 0.4% the first and second basic sulfoxides (being made by embodiment one) that 5 gram (0.012mol) amlodipines are dissolved in the 40ml water content, add that to be dissolved with 1.0 gram (0.006mol) L-(+)-tartaric 40ml water content be 0.4% the first and second basic sulfoxide solution, stirring at room reaction 1 hour, separate out precipitation, filter, use the 15ml washing with acetone, 50 ℃ of vacuum 4 hours, solvate product 2.20 grams formed of (R)-(+)-amlodipine, L-(+)-tartrate, first and second basic sulfoxide three components.
With dried above-mentioned solvate 2.20 grams, add methylene dichloride 35ml, 2N sodium hydroxide solution 18ml, stirring reaction 30 minutes leaves standstill, and tells organic layer, add an amount of dried over anhydrous sodium carbonate, filter, with a small amount of washed with dichloromethane filter cake, filtrate decompression is concentrated, add an amount of normal hexane, stirred crystallization is filtered, vacuum-drying 4 hours gets (R)-(+)-amlodipine 1.40 grams.Utilizing chiral column HPLC to measure its enantiomeric excess value (ee) is 99.0%, and total recovery is 56%.
Claims (10)
1, the preparation method of a kind of (S)-(-)-amlodipine, it is characterized in that racemic amlodipine and D-(-)-tartrate being dissolved in the first and second basic sulfoxides respectively or containing in the mixed solvent of the first and second basic sulfoxides, stir, mix, precipitation, continue to stir 0.5～5 hour, separate, wherein throw out is the solvate of (S)-(-)-amlodipine and D-(-)-tartrate and the first and second basic sulfoxides generations, with ethanol, methyl alcohol or Virahol refining solvent thing, add methylene dichloride,, obtain (S)-(-)-amlodipine with the sodium hydroxide solution neutralization.
2, (S)-(-) according to claim 1-amlodipine preparation method is characterized in that the mixed solvent of the first and second basic sulfoxides is made up of the first and second basic sulfoxides and solubility promoter.
3, the preparation method of (S)-(-) according to claim 2-amlodipine, it is characterized in that solubility promoter is selected from methyl alcohol, ethanol, propyl carbinol, acetone, butanone, 2 pentanone, ether, methyl ethyl ether, ethyl acetate, ethyl formate, N, dinethylformamide, methylene dichloride or chloroform.
4, the preparation method of (S)-(-) according to claim 1-amlodipine is characterized in that racemic amlodipine and D-(-)-tartaric mol ratio is 1: 0.25～0.8.
5, the preparation method of (S)-(-) according to claim 4-amlodipine is characterized in that racemic amlodipine and D-(-)-tartaric mol ratio is 1: 0.5.
6, the preparation method of a kind of (R)-(+)-amlodipine, it is characterized in that racemic amlodipine and L-(+)-tartrate being dissolved in the first and second basic sulfoxides respectively or containing in the mixed solvent of the first and second basic sulfoxides, stir, mix, precipitation, continue to stir 0.5～5 hour, separate, wherein throw out is the solvate of (R)-(+)-amlodipine and L-(+)-tartrate and the first and second basic sulfoxides generations, with ethanol, methyl alcohol or Virahol refining solvent thing, add methylene dichloride,, obtain (R)-(+)-amlodipine with the sodium hydroxide solution neutralization.
7, the preparation method of (R)-(+) according to claim 6-amlodipine is characterized in that the mixed solvent of the first and second basic sulfoxides is made up of the first and second basic sulfoxides and solubility promoter.
8, the preparation method of (R)-(+) according to claim 7-amlodipine, it is characterized in that solubility promoter is selected from methyl alcohol, ethanol, propyl carbinol, acetone, butanone, 2 pentanone, ether, methyl ethyl ether, ethyl acetate, ethyl formate, N, dinethylformamide, methylene dichloride or chloroform.
9, the preparation method of (R)-(+) according to claim 6-amlodipine is characterized in that racemic amlodipine and L-(+)-tartaric mol ratio is 1: 0.25～0.8.
10, the preparation method of (R)-(+) according to claim 6-amlodipine is characterized in that racemic amlodipine and L-(+)-tartaric mol ratio is 1: 0.5.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1144523A (en) * | 1994-03-24 | 1997-03-05 | 辉瑞研究与发展公司 | Separation of enantiomers of amlodiping via their diastereomeric tartrates |
| CN1267669A (en) * | 2000-02-21 | 2000-09-27 | 张喜田 | Separation of Amlodipine antimer |
| CN1608051A (en) * | 2001-10-24 | 2005-04-20 | 塞普拉科有限公司 | Method of resolving amlodipine racemate |
| CN1609102A (en) * | 2003-12-05 | 2005-04-27 | 石家庄制药集团欧意药业有限公司 | Optically active amlodipine resolving process |
| CN1681786A (en) * | 2002-09-11 | 2005-10-12 | 韩林制药株式会社 | Processes for the preparation of s-(-)-amlodipine |
-
2006
- 2006-04-11 CN CNB2006100769353A patent/CN100436417C/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1144523A (en) * | 1994-03-24 | 1997-03-05 | 辉瑞研究与发展公司 | Separation of enantiomers of amlodiping via their diastereomeric tartrates |
| US5750707A (en) * | 1994-03-24 | 1998-05-12 | Pfizer Inc. | Separation of the enantiomers of amlodipine via their diastereomeric tartrates |
| CN1267669A (en) * | 2000-02-21 | 2000-09-27 | 张喜田 | Separation of Amlodipine antimer |
| CN1608051A (en) * | 2001-10-24 | 2005-04-20 | 塞普拉科有限公司 | Method of resolving amlodipine racemate |
| CN1681786A (en) * | 2002-09-11 | 2005-10-12 | 韩林制药株式会社 | Processes for the preparation of s-(-)-amlodipine |
| CN1609102A (en) * | 2003-12-05 | 2005-04-27 | 石家庄制药集团欧意药业有限公司 | Optically active amlodipine resolving process |
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Owner name: SHIJIAZHUANG PHARMACEUTICAL GROUP OUYI PHARMA CO., Effective date: 20130509 |
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Effective date of registration: 20130509 Address after: 050035 No. 226 the Yellow River Avenue, Shijiazhuang hi tech Development Zone, Hebei Patentee after: Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. of CSPC Group Patentee after: Shijiazhuang Pharmaceutical Group Ouyi Pharma Co., Ltd. Address before: 050035 No. 226 the Yellow River Avenue, Shijiazhuang hi tech Development Zone, Hebei Patentee before: Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. of CSPC Group |