CN101863899B - Method for improving resolution yield of clopidogrel camphorsulfonate - Google Patents
Method for improving resolution yield of clopidogrel camphorsulfonate Download PDFInfo
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- CN101863899B CN101863899B CN 201010204576 CN201010204576A CN101863899B CN 101863899 B CN101863899 B CN 101863899B CN 201010204576 CN201010204576 CN 201010204576 CN 201010204576 A CN201010204576 A CN 201010204576A CN 101863899 B CN101863899 B CN 101863899B
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- clopidogrel
- camphorsulfonate
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Abstract
The invention discloses a synthesis method capable of improving the yield of dextro-clopidogrel camphorsulfonate. In the method, racemate of clopidogrel is used as a raw material, the dextro-clopidogrel camphorsulfonate is obtained by repeatedly performing the steps of resolution with the resolving agent, crystallization, vacuum filtration and drying, and the obtained dextro-clopidogrel camphorsulfonate is dissociated by a dissociating agent to obtain the dextro-clopidogrel camphorsulfonate with a yield of over 90 percent. The enantiomer of the clopidogrel dextroisomer product obtained by the method is less than 0.1 percent, and the ee value of the clopidogrel dextroisomer product obtained by the method is over 99.5 percent. Compared with other methods, the method has the advantage of simple operation.
Description
Technical field
The present invention relates to a kind of improvement of clopidogrel method for splitting, relate in particular to a kind of synthetic method that improves dextrorotation clopidogrel camphorsulfonate yield.
Background technology
Clopidogrel is a kind of platelet suppressant drug, succeeded in developing in 1986 by France match Norfin, Inc, clinical application is its vitriol, clopidogrel optionally suppresses adenosine diphosphate (ADP) (ADP) and its combination of platelet receptor and the activation of the glycoprotein GPIIIb/IIIa mixture of the ADP mediation of secondary, but so anticoagulant, clopidogrel must could suppress hematoblastic gathering through bio-transformation, except ADP, clopidogrel can also by blocking the amplification of the platelet activation that is caused by the ADP that discharges, suppress the platelet aggregation of other agonist induction.Clopidogrel works by irreversibly modifying platelet ADP receptor.Its chemical formula is as follows:
Synthetic method about clopidogrel, the synthetic method of clopidogrel principal constituent has been described by Sanofic companies in 1985 at patent US4529596, in succession split out the clopidogrel dextrorotatory isomer with excellent (ee value＞99.8%) anti-platelet aggregation activity with camphorsulfonic acid again in French Patent FR2612929, European patent EP 281459, Japanese Patent JP64562, its route is as follows:
The weak point of present method is this committed step of chiral separation, the yield of target product only has (in the dextrorotatory form in the racemic modification) about 45%, affected its competitive power, on the basis of aforesaid method, continue to have optimized resolution process among the patent WO2005104663, can obtain the resolution yield more than 70%, but its another enantiomer is in the HPLC detected result, and obviously too high, quality can not be guaranteed.
Sanofic company in 1993 has developed o-chlorobenzaldehyde and sodium cyanide and azanol reaction and has generated 2-amino-2-(2-chloro-phenyl-) acetic acid, react with 2-(2-thienyl) ethyl-4-methylbenzenesulfonate after the esterification, then carry out chiral separation, later stage is optimized around this technique again, and the method that exploitation makes new advances in the US Patent No. 6180793 of calendar year 2001, namely use the reaction of 2-(2-thienyl) ethamine and o-chlorobenzaldehyde and sodium cyanide to generate 2-(2-thienyl) ethylamino--2-(2-chloro-phenyl-) acetonitrile, then reaction generates 2-(2-thienyl) ethylamino--2-(2-chloro-phenyl-) ethanamide in the methanol solution of hydrogenchloride, in the methanol solution of sulfuric acid, generate again 2-(2-thienyl) ethylamino--2-(2-chloro-phenyl-) methyl acetate, split with camphorsulfonic acid again, but the first condensation again technique of cyclization has all related to this poisonous reagent of sodium cyanide, and significant discomfort is closed in long-range suitability for industrialized production.
Summary of the invention
In order to solve the shortcoming that the clopidogrel resolution yield is low in the prior art, splitting step is complicated, the invention provides a kind of method that improves resolution yield of clopidogrel camphorsulfonate, splitting step is improved, resolution yield is increased to more than 90%, its enantiomer is less than 0.1%, and practicality simple to operate is compared with additive method, has had very significantly advantage.
The invention discloses a kind of method that improves resolution yield of clopidogrel camphorsulfonate, may further comprise the steps:
Step 1: the ratio of clopidogrel racemic modification with mass volume ratio 1g: 5mL is dissolved in the mixed solvent of acetone and methylene dichloride, add and the equimolar resolving agent of clopidogrel racemic modification, under 15 ℃ of-20 ℃ of temperature, stirred 12-24 hour, crystallization, suction filtration, drying obtain dextrorotation clopidogrel camphorsulfonate and mother liquor;
Step 2: the mother liquor that obtains in the step 1 was stirred 4-12 hour under-5 ℃～10 ℃ temperature, suction filtration, drying obtains clopidogrel camphorsulfonate DL body, getting the dextrorotation clopidogrel camphorsulfonate that an amount of step 1 obtains joins in the clopidogrel camphorsulfonate DL body, keep mol ratio left-handed: dextrorotation=1: 1, then the mixture of dextrorotation clopidogrel camphorsulfonate and the clopidogrel camphorsulfonate DL body ratio with mass volume ratio 1g: 5mL is dissolved in the mixed solvent of acetone and methylene dichloride, under 15 ℃ of-20 ℃ of temperature, stirred 12～24 hours, crystallization, suction filtration, dry dextrorotation clopidogrel camphorsulfonate and the mother liquor of getting;
Step 3: the mother liquor that obtains in the step 2 was stirred 4-12 hour under-5 ℃～10 ℃ temperature, suction filtration, drying obtains clopidogrel camphorsulfonate DL body, getting the dextrorotation clopidogrel camphorsulfonate that an amount of step 1 obtains joins in the clopidogrel camphorsulfonate DL body, keep mol ratio left-handed: dextrorotation=1: 1, then the mixture of dextrorotation clopidogrel camphorsulfonate and the clopidogrel camphorsulfonate DL body ratio with mass volume ratio 1g: 5mL is dissolved in the mixed solvent of acetone and methylene dichloride, under 15 ℃ of-20 ℃ of temperature, stirred 12～24 hours, crystallization, suction filtration, the dry dextrorotation clopidogrel camphorsulfonate that gets, mother liquor reclaims;
Step 4: the dextrorotation clopidogrel camphorsulfonate that step 1 step 2 step 3 is obtained passes through dissociating of the agent of dissociating, and obtains the clopidogrel dextrorotatory isomer of the anti-platelet aggregation activity of ee value＞99.8%.
Resolving agent is levo-camphor-10-sulfonic acid in the described step 1; Acetone in the described step 1 step 2 step 3 mixed solvent: the methylene chloride volume ratio is 1: 5～10; The agent of dissociating in the described step 4 is yellow soda ash, salt of wormwood or sodium bicarbonate.
Beneficial effect:
1, the present invention is take Plavix raceme as starting raw material, and l-camphor sulfonic acid is resolving agent, and the mode by physics is added, circulated and splits is increased to more than 90% resolution yield.
2, the target product enantiomer that obtains of the present invention is less than 0.1%, ee value＞99.5%.
3, the present invention compares with additive method, and is simple to operate.
Description of drawings
Fig. 1 is for improving the process flow sheet of resolution yield of clopidogrel camphorsulfonate method
Wherein L is operating process, ratio according to two kinds of isomer in the clopidogrel camphorsulfonate DL body is carried out, left-handed when wherein: dextrorotation＞1: 1, can be by adding an amount of dextrorotation clopidogrel camphorsulfonate, make wherein left-handed: dextrorotation=1: 1.
Embodiment:
What the present invention described is as starting material take Plavix raceme, take levo-camphor-10-sulfonic acid as resolving agent, with the dissolving of acetone and methylene dichloride mixed solvent, split out the ee value greater than 99.5% clopidogrel dextrorotatory form, yield reaches the method more than 90%, and the principal reaction formula is:
Embodiment 1:
Step 1: get clopidogrel racemic modification 90g (0.28mol) and be dissolved among methylene dichloride/acetone mixed solvent (volume ratio is 1/10) 450ml, add levo-camphor-10-sulfonic acid 64.5g (0.28mol), stirring and dissolving, stirring and crystallizing is 12 hours between 15-20 ℃, suction filtration (mother liquor continues to use in step 2), dry that target product dextrorotation clopidogrel camphorsulfonate B is 46.5g, ee value＞99.8%.
Step 2: with 5～10 ℃ of mother liquor control temperature in the step 1, stirred 4 hours, suction filtration, dry that clopidogrel camphorsulfonate C is 64g, getting 4.1g dextrorotation clopidogrel camphorsulfonate B joins among the C, and adding methylene dichloride/acetone mixed solvent (volume ratio is 1/10) 340ml, heating makes its dissolving, stirring and crystallizing, stirring and crystallizing is 12 hours between 15-20 ℃ of the temperature of control, then through suction filtration (mother liquor continues to use in step 3), dry that dextrorotation clopidogrel camphorsulfonate B ' is 20.7g, ee value＞99.9%.
Step 3: with 5～10 ℃ of mother liquor control temperature in the step 2, stirred 4 hours, suction filtration, dry that clopidogrel camphorsulfonate C ' is 27.2g, getting 2.2g dextrorotation clopidogrel camphorsulfonate B joins among the C ', and adding methylene dichloride/acetone mixed solvent (volume ratio is 1/10) 147ml, heating for dissolving, stirred 12 hours at 15-20 ℃, system through suction filtration (mother liquor reclaim camphorsulfonic acid and solvent), dryly must get dextrorotation clopidogrel camphorsulfonate B and " be 7.8g, ee value＞99.9%.
" weight is also removed the B that uses in the step 2, three, and gross weight is 71.8g, and yield is 86.7% for comprehensive B, B ', B.
Embodiment 2:
Step 1: get clopidogrel racemic modification 180g (0.56mol) and be dissolved among methylene dichloride/acetone mixed solvent (volume ratio is 1/10) 900ml, add levo-camphor-10-sulfonic acid 129g (0.56mol), stirring and dissolving, stirring and crystallizing is 12 hours between 15-20 ℃, suction filtration (mother liquor continues to use in step 2), dry that target product dextrorotation clopidogrel camphorsulfonate solid B is 95g, ee value＞99.8%.
Step 2: with 0～5 ℃ of mother liquor control temperature in the step 1, stirred 4 hours, suction filtration, dry that clopidogrel camphorsulfonate C is 130g, getting 8g dextrorotation clopidogrel camphorsulfonate B joins among the C, and adding methylene dichloride/acetone mixed solvent (volume ratio is 1/10) 690ml, heating for dissolving, 15-20 ℃ of stirring and crystallizing 18 hours, then through suction filtration (mother liquor continues to use in step 3), dry that dextrorotation clopidogrel camphorsulfonate solid B ' is 44.1g, ee value＞99.8%.
Step 3: with 0～5 ℃ of mother liquor control temperature in the step 2, stirred 4 hours, suction filtration, dry that clopidogrel camphorsulfonate C ' is 56.9g, getting 4.7g dextrorotation clopidogrel camphorsulfonate B joins among the C ', and adding methylene dichloride/acetone mixed solvent (volume ratio is 1/10) 308ml, heating for dissolving, 15-20 ℃ was stirred 18 hours, system through suction filtration (the recyclable camphorsulfonic acid of mother liquor and solvent), dryly must get dextrorotation clopidogrel camphorsulfonate solid B and " be 16.8g, ee value＞99.8%.
" weight is also removed the B that uses in the step 2, three, and gross weight is 143.2g, and yield is 92.2% for comprehensive B, B ', B.
Embodiment 3:
Step 1: get clopidogrel racemic modification 180g (0.56mol) and be dissolved among methylene dichloride/acetone mixed solvent (volume ratio is 1/10) 900ml, add levo-camphor-10-sulfonic acid 129g (0.56mol), stirring and dissolving, stirring and crystallizing is 18 hours between 15-20 ℃, suction filtration (mother liquor continues to use in step 2), dry that target product dextrorotation clopidogrel camphorsulfonate B is 95.6g, ee value＞99.8%.
Step 2: with 0～5 ℃ of mother liquor control temperature in the step 1, stirred 8 hours, suction filtration, dry that clopidogrel camphorsulfonate C is 141g, getting 10g dextrorotation clopidogrel camphorsulfonate B joins among the C, and adding methylene dichloride/acetone mixed solvent (volume ratio is 1/10) 755ml, heating makes its dissolving, stirring and crystallizing, stirring and crystallizing is 18 hours between 15-20 ℃ of the temperature of control, then through suction filtration (mother liquor continues to use in step 3), dry that dextrorotation clopidogrel camphorsulfonate solid B ' is 48.6g, ee value＞99.8%.
Step 3: with 0～5 ℃ of mother liquor control temperature in the step 2, stirred 8 hours, suction filtration, dry that clopidogrel camphorsulfonate C ' is 60.5g, getting 6g dextrorotation clopidogrel camphorsulfonate B joins among the C ', and adding methylene dichloride/acetone mixed solvent (volume ratio is 1/10) 328ml, heating for dissolving, 15-20 ℃ was stirred 18 hours, system through suction filtration (mother liquor reclaim camphorsulfonic acid and solvent), dryly must get dextrorotation clopidogrel camphorsulfonate solid B and " be 19g, ee value＞99.8%.
" weight is also removed the B that uses in the step 2, three, and gross weight is 147.2g, and yield is 94.9% for comprehensive B, B ', B.
Embodiment 4:
Step 1: get clopidogrel racemic modification 90g (0.28mol) and be dissolved among methylene dichloride/acetone mixed solvent (volume ratio is 1/8) 450ml, add levo-camphor-10-sulfonic acid 64.5g (0.28mol), stirring and dissolving, stirring and crystallizing is 18 hours between 15-20 ℃, suction filtration (mother liquor continues to use in step 2), dry that target product dextrorotation clopidogrel camphorsulfonate B is 47.5g, ee value＞99.8%.
Step 2: with 0～5 ℃ of mother liquor control temperature in the step 1, stirred 12 hours, suction filtration, dry that clopidogrel camphorsulfonate C is 66g, getting 4g dextrorotation clopidogrel camphorsulfonate B joins among the C, and adding methylene dichloride/acetone mixed solvent (volume ratio is 1/8) 350ml, heating makes its dissolving, stirring and crystallizing, stirring and crystallizing is 18 hours between 15-20 ℃ of the temperature of control, then through suction filtration (mother liquor continues to use in step 3), dry that dextrorotation clopidogrel camphorsulfonate B ' is 21.8g, ee value＞99.9%.
Step 3: with 0～5 ℃ of mother liquor control temperature in the step 2, stirred 12 hours, suction filtration, dry that clopidogrel camphorsulfonate C ' is 28.3g, getting 2.3g dextrorotation clopidogrel camphorsulfonate B joins among the C ', and adding methylene dichloride/acetone mixed solvent (volume ratio is 1/8) 152ml, heating for dissolving, stirred 24 hours at 15-20 ℃, system through suction filtration (mother liquor reclaim camphorsulfonic acid and solvent), dryly must get dextrorotation clopidogrel camphorsulfonate B and " be 8.8g, ee value＞99.9%.
" weight is also removed the B that uses in the step 2, three, and gross weight is 71.8g, and yield is 90.5% for comprehensive B, B ', B.
Embodiment 5:
Step 1: get clopidogrel racemic modification 180g (0.56mol) and be dissolved among methylene dichloride/acetone mixed solvent (volume ratio is 1/5) 900ml, add levo-camphor-10-sulfonic acid 129g (0.56mol), stirring and dissolving, stirring and crystallizing is 12 hours between 15-20 ℃, suction filtration (mother liquor continues to use in step 2), dry that target product dextrorotation clopidogrel camphorsulfonate solid B is 95.7g, ee value＞99.8%.
Step 2: with mother liquor control temperature-5～0 in the step 1 ℃, stirred 4 hours, suction filtration, dry that clopidogrel camphorsulfonate C is 131g, getting 8g dextrorotation clopidogrel camphorsulfonate B joins among the C, and adding methylene dichloride/acetone mixed solvent (volume ratio is 1/5) 700ml, heating for dissolving, 15-20 ℃ of stirring and crystallizing 24 hours, then through suction filtration (mother liquor continues to use in step 3), dry that dextrorotation clopidogrel camphorsulfonate solid B ' is 44.8g, ee value＞99.8%.
Step 3: with mother liquor control temperature-5～0 in the step 2 ℃, stirred 4 hours, suction filtration, dry that clopidogrel camphorsulfonate C ' is 57.7g, getting 4.8g dextrorotation clopidogrel camphorsulfonate B joins among the C ', and adding methylene dichloride/acetone mixed solvent (volume ratio is 1/5) 310ml, heating for dissolving, 15-20 ℃ was stirred 24 hours, system through suction filtration (the recyclable camphorsulfonic acid of mother liquor and solvent), dryly must get dextrorotation clopidogrel camphorsulfonate solid B and " be 17.4g, ee value＞99.8%.
" weight is also removed the B that uses in the step 2, three, and gross weight is 145.3g, and yield is 93.6% for comprehensive B, B ', B.
Embodiment 6:
Step 1: get clopidogrel racemic modification 180g (0.56mol) and be dissolved among methylene dichloride/acetone mixed solvent (volume ratio is 1/5) 900ml, add levo-camphor-10-sulfonic acid 129g (0.56mol), stirring and dissolving, stirring and crystallizing is 24 hours between 15-20 ℃, suction filtration (mother liquor continues to use in step 2), dry that target product dextrorotation clopidogrel camphorsulfonate B is 94.3g, ee value＞99.8%.
Step 2: with mother liquor control temperature-5～0 in the step 1 ℃, stirred 8 hours, suction filtration, dry that clopidogrel camphorsulfonate C is 138g, getting 9g dextrorotation clopidogrel camphorsulfonate B joins among the C, and adding methylene dichloride/acetone mixed solvent (volume ratio is 1/5) 735ml, heating makes its dissolving, stirring and crystallizing, stirring and crystallizing is 24 hours between 15-20 ℃ of the temperature of control, then through suction filtration (mother liquor continues to use in step 3), dry that dextrorotation clopidogrel camphorsulfonate solid B ' is 46.7g, ee value＞99.8%.
Step 3: with mother liquor control temperature-5～0 in the step 2 ℃, stirred 8 hours, suction filtration, dry that clopidogrel camphorsulfonate C ' is 59.2g, getting 5g dextrorotation clopidogrel camphorsulfonate B joins among the C ', and adding methylene dichloride/acetone mixed solvent (volume ratio is 1/5) 320ml, heating for dissolving, 15-20 ℃ was stirred 24 hours, system through suction filtration (mother liquor reclaim camphorsulfonic acid and solvent), dryly must get dextrorotation clopidogrel camphorsulfonate solid B and " be 19.6g, ee value＞99.8%.
" weight is also removed the B that uses in the step 2, three, and gross weight is 146.6g, and yield is 94.5% for comprehensive B, B ', B.
Above said content only is the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical solution of the present invention is carried out, all belongs to category of the present invention.
Claims (1)
1. a method that improves resolution yield of clopidogrel camphorsulfonate is characterized in that, may further comprise the steps:
Step 1: the clopidogrel racemic modification is dissolved in the acetone and the mixed solvent of methylene dichloride of volume ratio as 1: 5～10 take the ratio of mass volume ratio 1g: 5mL, add and the equimolar resolving agent levo-camphor of clopidogrel racemic modification-10-sulfonic acid anhydride, under 15 ℃ of-20 ℃ of temperature, stirred 12-24 hour, crystallization, suction filtration, drying obtain dextrorotation clopidogrel camphorsulfonate and mother liquor;
Step 2: the mother liquor that obtains in the step 1 was stirred 4-12 hour under-5 ℃～10 ℃ temperature, suction filtration, drying obtains clopidogrel camphorsulfonate DL body, getting the dextrorotation clopidogrel camphorsulfonate that an amount of step 1 obtains joins in the clopidogrel camphorsulfonate DL body, keep mol ratio left-handed: dextrorotation=1: 1, then the mixture of dextrorotation clopidogrel camphorsulfonate and clopidogrel camphorsulfonate DL body is dissolved in the acetone and the mixed solvent of methylene dichloride of volume ratio as 1: 5～10 take the ratio of mass volume ratio 1g: 5mL, under 15 ℃ of-20 ℃ of temperature, stirred 12～24 hours, crystallization, suction filtration, dry dextrorotation clopidogrel camphorsulfonate and the mother liquor of getting;
Step 3: the mother liquor that obtains in the step 2 was stirred 4-12 hour under-5 ℃～10 ℃ temperature, suction filtration, drying obtains clopidogrel camphorsulfonate DL body, getting the dextrorotation clopidogrel camphorsulfonate that an amount of step 1 obtains joins in the clopidogrel camphorsulfonate DL body, keep mol ratio left-handed: dextrorotation=1: 1, then the mixture of dextrorotation clopidogrel camphorsulfonate and clopidogrel camphorsulfonate DL body is dissolved in the acetone and the mixed solvent of methylene dichloride of volume ratio as 1: 5～10 take the ratio of mass volume ratio 1g: 5mL, under 15 ℃ of-20 ℃ of temperature, stirred 12～24 hours, crystallization, suction filtration, the dry dextrorotation clopidogrel camphorsulfonate that gets, mother liquor reclaims;
Step 4: the dextrorotation clopidogrel camphorsulfonate that step 1 step 2 step 3 is obtained passes through dissociating of the agent of dissociating, and obtains the clopidogrel dextrorotatory isomer of the anti-platelet aggregation activity of ee value＞99.8%.
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| CN101463038A (en) * | 2009-01-14 | 2009-06-24 | 天津市中央药业有限公司 | Production method of (-)-(R)- clopidogrel (-)-(R)-camphorsulfonate racemisation |
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| CN101463038A (en) * | 2009-01-14 | 2009-06-24 | 天津市中央药业有限公司 | Production method of (-)-(R)- clopidogrel (-)-(R)-camphorsulfonate racemisation |
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Denomination of invention: A method for improving the resolution yield of clopidogrel Camphor Sulfonate Effective date of registration: 20201223 Granted publication date: 20130320 Pledgee: NANTONG CHANGYOO PHARMATECH Co.,Ltd. Pledgor: CHANGZHOU PHARMACEUTICAL FACTORY Co.,Ltd. Registration number: Y2020980009788 |
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