CN101787032A - Novel method for preparing clopidogrel and slat thereof - Google Patents
Novel method for preparing clopidogrel and slat thereof Download PDFInfo
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- CN101787032A CN101787032A CN200910234695A CN200910234695A CN101787032A CN 101787032 A CN101787032 A CN 101787032A CN 200910234695 A CN200910234695 A CN 200910234695A CN 200910234695 A CN200910234695 A CN 200910234695A CN 101787032 A CN101787032 A CN 101787032A
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Abstract
The invention discloses a novel method for preparing a clopidogrel compound, which comprises the following steps: taking a compound shown in Formula (II) as a raw material, obtaining a compound shown in Formula (III) through optical resolution, obtaining a compound shown in Formula (IV) through substitution reaction of the compound shown in Formula (III), further obtaining a compound shown in Formula (V) by acetifying the compound shown in Formula (IV) to be salt, obtaining the final product, i.e. the lopidogrel compound shown in Formula (VI), through Mannich cyclization, and then generating salt by mixing the compound shown in Formula (VI) and sulfuric acid for reaction to obtain the target product (I). The method of the invention for preparing the clopidogrel compound has the advantages of readily available raw materials, low price, mild reaction condition, simple operation and high total yield, and is a novel integrated synthesis method applicable for industrial production of clopidogrel.
Description
Technical field
The present invention relates to the chemical pharmaceutical technical field, specifically, is a kind of preparation method of new clopidogrel.
Background technology
Clopidogrel is a kind of antiplatelet condensing agent medicine by French Sai Nuofei drugmaker (Sanofi) development, it is a kind of anticoagulant, suppress adenosine diphosphate (ADP) (ADP) and its combining and the activation of the glycoprotein GPIIb/IIIa mixture that the ADP of secondary mediates of platelet receptor by selectivity, clopidogrel can also suppress the platelet aggregation of other agonist induction by blocking the amplification that is discharged the platelet activation that causes by ADP simultaneously.Clopidogrel has two kinds of configurations, wherein have only (S)-clopidogrel to demonstrate platelet aggregation and suppress active, and (R)-clopidogrel be do not have active, and (R)-tolerance of clopidogrel is 1/40 of (S)-clopidogrel.At present, the common drug kind that is used for anti-platelet aggregation is few, is no more than 10.Clopidogrel has now become one of standard medication of anti-platelet aggregation, its sales volume at U.S.'s medical market ranked second after coming Simvastatin in 2005, big and medium-sized cities in China, clopidogrel also replaces some anti-platelet aggregation medications in the past rapidly and ranks the first place, and therefore developing highly purified (S)-clopidogrel has very vast market prospect.
The existing both at home and abroad existing many reports of the development technology of clopidogrel mainly concentrate on following several routes:
With alpha-halo acetate and 4,5,6,7-tetramethylene sulfide also [3,2-C] pyridine is a starting raw material, through splitting, becomes ester, replaces and makes clopidogrel base.
The main drawback of this route is an initiator 4,5,6, and 7-tetramethylene sulfide also [3,2-C] pyridine prepares difficulty of purification ratio, has a strong impact on the yield and the purity of back product.
This route is with o-chlorobenzaldehyde, and 2 thiophene ethyl amine and sodium cyanide are starting raw material, and through condensation, hydrolysis becomes ester, closes ring and obtains clopidogrel base.
The main drawback of this route is that one of initiator is a sodium cyanide, is unfavorable for suitability for industrialized production, and after the step of optical resolution relatively leans on, has a strong impact on productive rate.
This route is an initiator with (R)-o-Chloromelic acid,, is converted into (R)-sulphonate acetogenin again through esterification, and at last again with 4,5,6,7-tetramethylene sulfide also [3,2-C] pyridine reaction makes (S)-clopidogrel.The same with route a, this route has also used 4,5,6, and the 7-tetramethylene sulfide is [3,2-C] pyridine also, and (R)-and o-Chloromelic acid costs an arm and a leg, and is unfavorable for industrialization production.
In addition, the synthetic route below patent WO98/39322 has also reported:
Above route exists reaction complicated, the problem that overall yield and purity are on the low side.
Summary of the invention
The object of the invention is to provide a kind of clopidogrel synthetic method of simple and practical economy newly, this method reaction conditions gentleness, easy and simple to handle, and raw material cheaply is easy to get, end product purity height, and the total recovery height is suitable for suitability for industrialized production.
The objective of the invention is to be achieved through the following technical solutions:
1, at first split o-chlorobenzene glycine with the D-camphorsulfonic acid, water as solvent, the salify temperature is 40-70 ℃, the reaction churning time is 0.5-1.5 hour.
2, finish the back and promptly get (S)-(+)-o-chlorobenzene glycine (III) with alkaline purification.Mother liquor concentrates the back and reclaims (R)-(+)-o-chlorobenzene glycine and D-camphorsulfonic acid with alkaline purification.
3, will go up (S)-o-chlorobenzene glycine of obtaining of step joins in the solvent, as acetonitrile, carry out condensation with 2-thiophene ethanol derivative in the presence of alkali, aftertreatment feeds hydrochloric acid gas and obtains intermediate (S)-(+)-α-(2-thiophene ethylamino)-(2-chloro-phenyl-) acetic acid hydrochloride (IV).
4, upward going on foot the intermediate (IV) that obtains joins in the methyl alcohol, ice bath adds the thionyl chloride of 2.0eq down, be heated to 30-45 ℃ of reaction 12 hours, reaction finishes concentrated (S)-(+)-α-(2-thiophene ethylamino)-(2-chloro-phenyl-) the methyl acetate hydrochloride (V) that obtains in back.
5, intermediate (V) is carried out Mannich pass ring in water or acids solvent and obtain clopidogrel base (VI).
6, clopidogrel base is obtained final product bisulfate clopidogrel (I) with the sulfuric acid salify in suitable solvent.
The present invention splits o-chlorobenzene glycine with the D-camphorsulfonic acid, and recyclable camphorsulfonic acid is simple after aftertreatment, reclaims the raw material that obtains with the currently known methods racemization simultaneously, can drop into reaction again.O-chlorobenzene glycine and 2-thiophene ethanol derivatives reaction prepare intermediate (IV) and are the committed step of this route, add hydrochloric acid gas salify in the last handling process, have obviously improved yield and purity.
In sum, the present invention's preparation (S)-clopidogrel has following advantage:
1, the selected raw material of preparation method of the present invention can directly cheaply have been bought from market, and reactions steps is few, and the yield height provides cost savings greatly.
2, the present invention adopts starting raw material is split, invalid corresponding body carries out racemization under highly basic, has solved in the prior art problem that the ester run into when ester split the invalid corresponding body of back racemization is hydrolyzed.
3, preparation method of the present invention directly prepares intermediate (IV) with 2-thiophene ethanol derivatives reaction in the intact back of splitting step, has obviously improved the transformation efficiency and the optical purity of reacting.
4, all intermediates of the present invention all are easy to purifying, have saved a lot of loaded down with trivial details purge processes in the prior art, have improved production efficiency.
Embodiment
Be that concrete embodiment is given an example below, so that technical scheme of the present invention is described further; But it should be considered as scope restriction of the present invention.
Embodiment 1:(S)-(+)-preparation of o-chlorobenzene glycine (III)
In the 250mL single port reaction that magnetic agitation is housed, the o-chlorobenzene glycine that adds 10.0g (0.0539mol) DL, and 13.8g (0.0595mol) D-camphorsulfonic acid, and then add 100mL water, be heated to 65 ℃ of dissolvings, insulated and stirred is reduced to 45 ℃ of filtrations after 0.5 hour.Filtrate is reduced to-10 ℃ and was placed 6 hours, filters, and filter cake washs with Virahol (15mL * 2).Mother liquor is concentrated into 50mL, and-10 ℃ of crystallizations are once more filtered, and the washing back merges the gained white solid, gets product 9.8g, purity 99%, e.e=95% after the drying.This solid is joined in the 30mL water again, be heated to dissolving, freezing and crystallizing filters, and uses the 10mL water washing, and drying gets refined products 9.0g, purity 99.5%, e.e=99%.Merge mother liquor twice, be concentrated into dried, impure (R)-(+)-o-chlorobenzene glycine camsilate.
Above-mentioned (S)-(+) that obtains-o-chlorobenzene glycine camsilate is joined in the 100mL Virahol, add the 2.0g sodium bicarbonate then, be heated to 60 ℃ of reaction 2h.Be cooled to-10 ℃ and spend the night, filter, filter cake gets product 4.0g with anhydrous diethyl ether 20mL washing after the drying.Content 99.5%,
[α]
25 D=+115.8 (c=1, methyl alcohol).Mother liquor contains D-camphorsulfonic acid sodium salt, keeps somewhere standby.
Above-mentioned (R)-(+) that obtains-o-chlorobenzene glycine camsilate by handling with quadrat method, is got impure (R)-(+)-o-chlorobenzene glycine and the mother liquor that contains D-camphorsulfonic acid sodium salt.(R)-(+)-o-chlorobenzene glycine is added in the 15mL water, add the 2.0g dissolution of sodium hydroxide, be heated to 85 ℃ of reactions and spend the night.PH to 5-6 is regulated with hydrochloric acid in cooling back, be cooled to 0 ℃ stir filtered in two hours the o-chlorobenzene glycine 5.0g of racemization.
Merge the above-mentioned mother liquor that contains D-camphorsulfonic acid sodium salt that obtains for twice, be concentrated into the dried D-of obtaining camphorsulfonic acid sodium salt, add concentrated hydrochloric acid to solid with less water dissolving back and fully separate out, filter, filter cake washs with small amount of acetone, after the drying D-camphorsulfonic acid 8.2g,
[α]
25 D＝+21.8。
Embodiment 2:(S)-(+)-preparation of α-(2-thiophene ethylamino)-(2-chloro-phenyl-) acetic acid hydrochloride (IV)
Get (S)-(+)-o-chlorobenzene glycine 18.6g (0.1mol), join in the three mouthfuls of reaction flasks of 250mL that have magnetic agitation, add the dissolving of 100mL anhydrous acetonitrile again, add 21g (0.25mol) sodium bicarbonate and 42g (0.15mol) α-thiophene ethanol p-toluenesulfonic esters then, start and stir, be warming up to 80 ℃ of reactions 48 hours.Filter, filtrate concentrate oily matter; Filter cake washs with ethyl acetate (50mL * 3).With the oily matter that obtains before this washings acetic acid ethyl dissolution, stir fast down and fed hydrogen chloride gas 20 minutes, there are a large amount of white solids to separate out, stop to feed ℃ insulation of hydrogen chloride gas postcooling to 0 and filtered in 2 hours, filter cake washs with a small amount of ether.Mother liquor is concentrated into 75mL and refrigerates the crystallization of spending the night, and obtains product behind the filtration washing once more, merges product, 45 ℃ of dryings of vacuum.White solid 30g, this solid is joined the 60mL ethyl acetate: in the solution of ether=1: 1, being warming up to the insulation that refluxes and slowly cooling to 0 ℃ after 1 hour, be incubated filtration in 4 hours again, filter cake washs with ether, heavy 25.6g after the product vacuum-drying, content 98.5%.
Embodiment 3: the preparation of α-thiophene ethanol p-toluenesulfonic esters (VII)
Get α-thiophene ethanol 12.7g (0.1mol) and put in the 250mL single port reaction that has magnetic agitation, add 25mL methylene dichloride and 21mL (0.15mol) triethylamine, be cooled to 0 ℃.Other gets 21g (0.12mol) tosic acid and is added in the 40mL methylene dichloride, and this solution is slowly splashed in the reaction flask.Rise to 35 ℃ of reactions 5 hours after drip finishing, TLC detects and adds 0.9g sodium bicarbonate and 20mL water after α-thiophene ethanol disappears, restir 1 hour, TLC detects unnecessary Tosyl chloride hydrolysis and finishes postcooling to room temperature, add 30mL water again, stirred 10 minutes, behind the separatory organic phase again the water saturated aqueous common salt each the washing once.The organic phase anhydrous sodium sulfate drying concentrates, and obtains tawny solid 26.8g after the cooling, content 99%.
Embodiment 4:(S)-(+)-preparation of α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate hydrochloride (V)
(S)-(+)-α-(2-thiophene ethylamino)-(2-chloro-phenyl-) acetic acid hydrochloride (IV) 4.0g (0.012mol) that gets above-mentioned preparation joins in the 50mL single port reaction flask that has magnetic agitation, and then adding 30mL anhydrous methanol, be cooled to 0 ℃, splash into 1.7mL (0.023nol) thionyl chloride, rise to stirring at room 1 hour after drip finishing, be warming up to 40 ℃ of reactions 12 hours then.TLC detects raw material reaction and finishes postcooling to room temperature, is concentrated into driedly, adds 10mL EA and stirs 0.5 hour, filter product 3.8g, yield: 90%; Purity: 99%.
Embodiment 5:(S)-preparation of clopidogrel base (VI)
With the above-mentioned 10g that obtains (0.029mol) intermediate (V) join be warming up in 60mL 37% formaldehyde solution 60 ℃ the reaction 2 hours, the TLC detection reaction finishes postcooling to room temperature, add sodium bicarbonate and regulate pH to 7-8, add ethyl acetate 50mL extraction again, water again with ethyl acetate 30mL extraction once behind the separatory, use the saturated common salt water washing behind the combined ethyl acetate, use anhydrous sodium sulphate again
Drying concentrates and obtains light yellow oil (S)-clopidogrel base (VI) 8.5g, content 99%.e.e＝98％。
Embodiment 6:(S)-preparation of clopidogrel base (VI)
Get (S)-(+)-α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate hydrochloride (V) 10g (0.029mol), join in 50mL ethyl acetate and the 30mL water, stir fast, slowly add sodium bicarbonate again and regulate pH to 8-9, separatory, water extracts once with ethyl acetate 20mL, combined ethyl acetate, with using anhydrous sodium sulfate drying after the saturated common salt water washing again, concentrate 8.8g oily matter.
Other gets Paraformaldehyde 96 1.0g, joins in the 50mL anhydrous formic acid.Be heated to 60 ℃ of dissolvings, join after the cooling in the appeal oily matter, be heated to 45 ℃ and react to intermediate (V) and disappear.Reaction finishes the back and concentrates, and residue 50mL acetic acid ethyl dissolution adds 40mL water again, stirs separatory after 10 minutes, and water extracts once with ethyl acetate 20mL again.With saturated aqueous common salt 30mL washing, use anhydrous sodium sulfate drying again behind the combined ethyl acetate, concentrate, get yellow oil 9.1g, content 95%, e.e=98%.
Embodiment 7: the preparation of bisulfate clopidogrel (I)
Get the clopidogrel base 10g of above-mentioned preparation, join in the 20mL acetone, be cooled to 5-10 ℃, with the 10mL acetone solution 1.7mL vitriol oil, slowly be added drop-wise in the clopidogrel base acetone soln in addition, a complete back insulation rises to 10-15 ℃ after 0.5 hour and leaves standstill crystallization, 12 hours after-filtration, filter cake is with cooling off washing with acetone on a small quantity, and drying gets white solid 9.5g.Fusing point 195-198 ℃.[α]
25 D=56 ° (c=1, methyl alcohol); Content 99.5%.
Embodiment 8: the preparation of bisulfate clopidogrel (I)
Get the clopidogrel base 10g of above-mentioned preparation, join in the 30mL ethyl acetate, be cooled to 5-10 ℃, with the 10mL acetic acid ethyl dissolution 1.7mL vitriol oil, slowly be added drop-wise in the clopidogrel base acetone soln in addition, stir fast, drip finishing the back insulation rises to 10-15 ℃ and stirs and filtered in 2 hours after 0.5 hour
Filter cake washs with a small amount of cooling ethyl acetate, and drying gets white solid 11.5g.Fusing point 189-192 ℃.[α]
25 D=55.8 ° (c=1, methyl alcohol); Content 99.5%.
The above specific embodiment of lifting is directly perceived to describe for example of the present invention, and its those skilled in the art can make amendment based on this or replenish but can not depart from the range of definition of appended claims of the present invention.
Claims (9)
1. novel method for preparing clopidogrel, this method may further comprise the steps:
(1) the o-chlorobenzene glycine racemic modification of structural formula for (II) joined in the solvent, add the D-camphorsulfonic acid then, heating for dissolving is filtered, crystallisation by cooling under the ice bath, mother liquor concentrates crystallization once again, obtain compound (S)-(+)-o-chlorobenzene glycine of structural formula with alkaline purification again after the filtration, reclaim the D-camphorsulfonic acid simultaneously for (III).Mother liquor is concentrated into dried, drops into reaction after the racemization again.
(2) be that compound (S)-(+)-o-chlorobenzene glycine of (III) and the compound that structural formula (VII) is heat in solvent with structural formula, basic cpd is the acid binding agent reaction.After finishing, reaction makes structural formula (IV) compound (S)-(+)-α-(2-thiophene ethylamino)-(2-chloro-phenyl-) acetic acid hydrochloride with the salt acid treatment crystallization of laying equal stress on again.X=OTs in the compound (VII), I, Br.
(3) (S)-(+)-α-(2-thiophene ethylamino)-(2-chloro-phenyl-) acetic acid hydrochloride is joined and dissolves in the methyl alcohol, ice bath adds thionyl chloride down, be warming up to 25-60 ℃ then and react, reaction finishes condensing crystal and makes (S)-(+)-α-(2-thiophene ethylamino)-(2-chloro-phenyl-) methyl acetate hydrochloride (V) compound.
(4) (S)-(+)-α-(2-thiophene ethylamino)-(2-chloro-phenyl-) methyl acetate hydrochloride (V) and formaldehyde solution or Paraformaldehyde 96 being heated to 35-75 ℃ in solvent reacts and makes product (S)-clopidogrel base (VI).
(5) with (S)-clopidogrel base (VI) in suitable solvent with the sulfuric acid salify, obtain bisulfate clopidogrel (I).
2. clopidogrel preparation method according to claim 1 is characterized in that:
Selected solvent is a water among the step a, acetone or methyl alcohol one or more, preferably water, the mol ratio of o-chlorobenzene glycine and D-camphorsulfonic acid is 1: 1.2, used alkali is yellow soda ash or sodium bicarbonate.
3. clopidogrel preparation method according to claim 1 is characterized in that:
Used alkali is sodium bicarbonate among the step b, yellow soda ash, SODIUM PHOSPHATE, MONOBASIC, salt of wormwood, saleratus, ammoniacal liquor, triethylamine, DBU, pyridine.Be preferably sodium bicarbonate.
4. clopidogrel preparation method according to claim 1 is characterized in that:
Solvent for use is an acetonitrile among the step b, ethanol, and DMF, methylene dichloride is preferably acetonitrile, and solvent and formula (IV) weight ratio is 4-10: 1, the reaction Heating temperature is 60-85 ℃.
5. clopidogrel preparation method according to claim 1 is characterized in that:
Compound used therefor among the step b (VII) is a 2-thiophene ethanol p-toluenesulfonic esters, 2-(2-bromotrifluoromethane) thiophene or 2-(2-iodine ethyl) thiophene.
6. clopidogrel preparation method according to claim 1 is characterized in that:
The product recrystallization solvent is an ethyl acetate among the step b, methyl acetate, and ethyl formate, methyl alcohol, ethanol, acetone, one or more in the ether are preferably ethyl acetate and ether.
7. clopidogrel preparation method according to claim 1 is characterized in that:
The mol ratio of (S)-(+)-α among the step c-(2-thiophene ethylamino)-(2-chloro-phenyl-) acetic acid hydrochloride and thionyl chloride is 1: 1-1: 3, and temperature of reaction is 15-60 ℃, is preferably 30-35 ℃.
8. clopidogrel preparation method according to claim 1 is characterized in that:
Used formaldehyde or Paraformaldehyde 96 concentration are 30%-40% in the steps d, and solvent for use is a water, glacial acetic acid, formic acid.
9. SR-25990C preparation method according to claim 1 is characterized in that:
Solvent for use is a ketone among the step e, and the ester class is preferably acetone.Temperature is controlled at 5-45 ℃, is preferably 10-15 ℃.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103467486A (en) * | 2013-09-10 | 2013-12-25 | 宁夏康亚药业有限公司 | Preparation method of clopidogrel disulfate compound |
| CN106866617A (en) * | 2017-01-22 | 2017-06-20 | 山西恒强化工有限公司 | A kind of synthetic method of the thiophene ethyl ester of p-methyl benzenesulfonic acid 2 |
| CN107523594A (en) * | 2017-03-29 | 2017-12-29 | 武汉茵茂特生物技术有限公司 | The synthetic method of clopidogrel and its sulfate |
| CN110804063A (en) * | 2019-11-14 | 2020-02-18 | 天方药业有限公司 | Synthetic method of high-purity clopidogrel |
-
2009
- 2009-11-27 CN CN200910234695A patent/CN101787032A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103467486A (en) * | 2013-09-10 | 2013-12-25 | 宁夏康亚药业有限公司 | Preparation method of clopidogrel disulfate compound |
| CN103467486B (en) * | 2013-09-10 | 2016-04-13 | 宁夏康亚药业有限公司 | A kind of preparation method of clopidogrel disulfate compound |
| CN106866617A (en) * | 2017-01-22 | 2017-06-20 | 山西恒强化工有限公司 | A kind of synthetic method of the thiophene ethyl ester of p-methyl benzenesulfonic acid 2 |
| CN107523594A (en) * | 2017-03-29 | 2017-12-29 | 武汉茵茂特生物技术有限公司 | The synthetic method of clopidogrel and its sulfate |
| CN110804063A (en) * | 2019-11-14 | 2020-02-18 | 天方药业有限公司 | Synthetic method of high-purity clopidogrel |
| CN110804063B (en) * | 2019-11-14 | 2021-01-05 | 天方药业有限公司 | Synthesis method of clopidogrel |
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