CN104370935B - A kind of preparation method of bisulfate clopidogrel - Google Patents
A kind of preparation method of bisulfate clopidogrel Download PDFInfo
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- CN104370935B CN104370935B CN201410478320.8A CN201410478320A CN104370935B CN 104370935 B CN104370935 B CN 104370935B CN 201410478320 A CN201410478320 A CN 201410478320A CN 104370935 B CN104370935 B CN 104370935B
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- GKTWGGQPFAXNFI-HNNXBMFYSA-N COC([C@H](c(cccc1)c1Cl)N(CC1)Cc2c1[s]cc2)=O Chemical compound COC([C@H](c(cccc1)c1Cl)N(CC1)Cc2c1[s]cc2)=O GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 2
- OGUWOLDNYOTRBO-UHFFFAOYSA-N C(CNC1)c2c1cc[s]2 Chemical compound C(CNC1)c2c1cc[s]2 OGUWOLDNYOTRBO-UHFFFAOYSA-N 0.000 description 1
- HMBUCZUZRQQJQD-UHFFFAOYSA-N COC(C(c1ccccc1Cl)Br)=O Chemical compound COC(C(c1ccccc1Cl)Br)=O HMBUCZUZRQQJQD-UHFFFAOYSA-N 0.000 description 1
- BRAWSKJPUOPQIK-UHFFFAOYSA-N Cc1cc(CN(CC2)C(C(OC)=O)c(cccc3)c3Cl)c2[s]1 Chemical compound Cc1cc(CN(CC2)C(C(OC)=O)c(cccc3)c3Cl)c2[s]1 BRAWSKJPUOPQIK-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The present invention relates to a kind of preparation method of bisulfate clopidogrel, it is using 2 thiophene aldehydes as basic initiation material, it is set to occur condensation reaction with O-chlorobenzene glycine methyl ester, generate corresponding imine intermediate, imine intermediate is reduced to corresponding secondary amine intermediate with itrile group sodium borohydride with sodium borohydride or directly again, then this secondary amine intermediate obtains clopidogrel with formaldehyde reaction cyclization, and target compound bisulfate clopidogrel is obtained after being acidified through sulfuric acid.Synthetic route provided by the present invention is short, and the reaction being related to is classical organic reaction, and reaction condition is gentle, easy to operate, and total recovery is high, and cost is low, is suitable for industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, it is related to a kind of preparation method of bisulfate clopidogrel.
Background technology
Bisulfate clopidogrel, chemical name (S)-(+)-α-(2- chlorphenyls) -6,7- dihydro-thiophenes simultaneously [3,2-c] pyridine -5
(4H) acetate hydrogensulfate is French Sai Nuofei (sanofic) companies in the blood platelet of new generation of research and development in 1986
Agglutination inhibitor, trade name Plavix, structural formula：
Bisulfate clopidogrel is a kind of new thienopyridine analog derivative, and it passes through selectivity and blood platelet table
The adp receptor of face polyadenylation enzyme coupling is combined and the irreversible hematoblastic aggregation of suppression, can reduce the shape of thrombus in blood vessel
Into being clinically used for preventing miocardial infarction, apoplexy or have the atherosclerosis of peripheral arterial disease history patient, join with aspirin
Close, for Non-ST elevation acute coronary artery syndrome patient.
A large amount of clinical trials show that bisulfate clopidogrel has the advantages that notable drug effect, safety and tolerance are strong, has
Good market prospects.
Synthesis on bisulfate clopidogrel in the prior art has that synthetic route is long, and total recovery is low, and cost is high, difficult
To carry out the shortcoming of industrialized production.Following three kinds of methods are summed up：
Method one：Split Method after first synthesizing：
D.Aubert et al. by 4,5,6,7- thiophanes simultaneously [3,2-c] pyridine and α-chloro- 2- chlorophenyl acetates in carbon
Reacted in the presence of sour potassium and tetrahydrofuran, generate racemic clopidogrel, then carry out chiral resolution, route synthesis racemic
The yield of clopidogrel be only 45%.Subsequent M.B.Sisteron and J.R.Toulouse is improved (such as to above-mentioned route
Shown in lower reaction equation), replace α-chloro- 2- chlorophenyl acetates to be reacted with α-bromo- 2- chlorophenyl acetates, although yield has
Improved, but final step carries out chiral resolution, and the yield of target product is only half.
Method two：First condensation and then cyclization are split again：
M.D.Lhum and J.R.Toulouse o-chlorobenzaldehydes and Cymag and azanol reaction generation alpha-amido -2- chlorobenzenes
Acetic acid, reacts with p-methyl benzenesulfonic acid thiophene -2- ethyl esters after esterification, then carries out chiral resolution, the condensation reaction time of the route
Up to 40 hours, yield was only 50%.Another route is to generate α-bromo- 2- chlorobenzene second by o-chloromandelic acid and bromination phosphorus reaction
Acid, reacts with thiophene ethamine, finally splits and obtain the chiral intermediate again after esterification.B.Castro et al. is reported the above method
In alpha-amido -2- chlorophenyl acetates first split, then with thiophene -2- glycidic acids sodium and cyaniding sodium borohydride in second
Reaction generates the intermediate under the catalysis of acid.The route agents useful for same cyaniding sodium borohydride is difficult to obtain, and influences it to industrialize.
M.Bakonyi etc. reports 2 thiophene ethyl amine and o-chlorobenzaldehyde and Cymag reaction generation 2- (2 thiophene ethyl amine base) (2- chlorine
Phenyl) acetonitrile, then with hydrogen chloride and methanol reaction generation 2- (2 thiophene ethyl amine base) (2- chlorphenyls) acetamide, then use sulfuric acid
Methanol solution be hydrolyzed to thiophene ethamine base chlorophenylacetic acid methyl esters, split with (+)-camphor -10- sulfonic acid or (+)-tartaric acid
The intermediate.But yield only has 50% or so, and split obtain intermediate purity it is not high, so can not in industrialized production
Using this route.
Method three：First split and synthesize afterwards：
A.Bousquet et al. is split (as above shown in reaction equation), esterification first using o-chloromandelic acid as raw material
Afterwards with benzene sulfonyl chloride react, generation with strong leaving group chiral intermediate, then with 4,5,6,7- thiophanes simultaneously [3,
2-c] bimolecular nucleophilic subsititution occurs in the presence of potassium carbonate for pyridine, configuration reversal generation clopidogrel.The route sulphur
Acylated yield is only 45%, and the final step reaction time is partially long, more than 20 hours.The use of dichloromethane is solvent, heats back
Stream temperature is limited to, and route is longer.
The content of the invention
The purpose of the present invention provides a kind of preparation of bisulfate clopidogrel aiming at above-mentioned the deficiencies in the prior art
Method, this method synthetic route is short, and the reaction being related to is classical organic reaction, and reaction condition is gentle, easy to operate, total recovery
Height, is suitable for industrialized production.
The present invention realizes that the technical scheme that above-mentioned purpose is used is：A kind of preparation method of bisulfate clopidogrel, institute
The method of stating comprises the following steps：
1) 2- thiophene aldehydes are added in reaction bulb with S- O-chlorobenzene glycine methyl esters, add organic solvent and catalysis
Agent, heating stirring back flow reaction, reaction temperature is 40-110 DEG C, and TLC detection reactions are cooled to 20-30 DEG C after terminating, add with
The isometric water of organic solvent, stratification after stirring, organic layer anhydrous sodium sulfate drying, filtering, filtrate decompression is evaporated
To solid imine intermediate crude product, the crude product obtains sterling imine intermediate with ethyl alcohol recrystallization；2- thiophene aldehydes used with
The mol ratio of S- O-chlorobenzene glycine methyl esters is the quality of 1: 1,2- thiophene aldehydes and the ratio of volume of organic solvent is 1: 8,
Catalyst amount is the 3%~5% of 2- thiophene aldehyde quality；
2) by step 1) in imine intermediate and organic solvent be added in new reaction bulb, add reducing agent,
Then stirring reaction adds methanol and reaction is quenched, solvent is distilled off, add ethyl acetate molten to terminating at a temperature of 20-30 DEG C
Solution, water washing, dry filter distill secondary amine intermediate is standby；Imine intermediate wherein used and the mol ratio of reducing agent are 1:
1, the ratio of the quality of imine intermediate and the volume of organic solvent is 1: 6~8, and the consumption of ethyl acetate is imine intermediate body
Long-pending 6-8 times is measured, and the consumption of water is 0.5 times of amount of ethyl acetate volume；
3) take step 2) gained secondary amine intermediate be dissolved in organic solvent, the organic solvent solution for obtaining secondary amine intermediate is standby
With paraformaldehyde and the concentrated sulfuric acid that into the vacant reaction bulb newly taken, input concentration is 30%-40% are cooled to 0-5 DEG C, then
20-30 DEG C of stirring is warming up to after the organic solvent solution of secondary amine intermediate, completion of dropping are proportionally added dropwise for 1: 3.5 (W: V)
Reaction to TLC detection reactions terminate, and reaction adds the 3-4 times of water measured after terminating, stir stratification, and water layer is measured with 6-8 times again
Solvent washing, merge organic layer, washed once with saturated sodium bicarbonate solution, then with anhydrous sodium sulfate drying, filtering, filtrate
It is evaporated to obtain clopidogrel free alkali；The mass ratio of secondary amine intermediate and paraformaldehyde used is 1: 7, and the quality of the concentrated sulfuric acid is many
The 10% of polyformaldehyde quality；
4) by step 3) in gained clopidogrel free alkali and the 5-7 times of organic solvent measured be added in reaction bulb, drop
Temperature is added dropwise after the solvent solution of the concentrated sulfuric acid of 0.2 times of amount, completion of dropping to 0-10 DEG C, is continued in the case where maintaining the temperature at 0-10 DEG C
Stirring reaction 2h, then filtration drying obtain bisulfate clopidogrel.
The step 1) in used catalyst be derived from ammonium chloride or ammonium acetate any one.
The step 1) in used organic solvent be derived from toluene, chloroform or dichloromethane any one.
The step 2) in used reducing agent be derived from any one of sodium borohydride, potassium borohydride or itrile group sodium borohydride
Kind.
The step 2) in used organic solvent be derived from tetrahydrofuran, acetonitrile, DMF it is any one
Kind.
The step 3) in used organic solvent be derived from dichloromethane, chloroform or ethyl acetate any one.
The step 4) in used organic solvent be derived from ethyl acetate or acetone any one.
The step 4) in the organic solvent solution of the concentrated sulfuric acid be the concentrated sulfuric acid and ethyl acetate or acetone volume ratio are 1:
3.5 mixture.
The beneficial effect that the present invention is brought using such scheme is：
First, preparation method synthetic route of the invention is short, and raw material is easy to get；
Second, the reaction in preparation method of the invention is classical organic chemical reactionses, and reaction easily occurs, reaction condition
It is gentle easy to operate, superhigh temperature or ultralow temperature or other conditions that are complicated and being difficult to are had no, are conducive to Product industrialization to produce；
3rd, three-step reaction yield is all higher in preparation method of the invention, and total recovery can reach more than 75%, make product
Cost be greatly lowered, the increase of potential economic benefit；
4th, solvent and reagent in preparation method of the invention used in three-step reaction are all to common are chemical machine examination
Agent, can reduce cost with recovery；Used in experimentation without special, poisonous and harmful reagent, do not produce toxic waste, profit
In environmental protection.
Embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This：
Embodiment 1：
A kind of preparation method of bisulfate clopidogrel of the present invention comprises the following steps：
1) 2- thiophene aldehyde 12.6g and S- O-chlorobenzene glycine methyl ester 20.0g are weighed, tri- mouthfuls of reaction bulbs of 250mL are added to
In, organic solvent toluene 100mL and catalyst acetic acid ammonium 0.4g are added, heating stirring back flow reaction, reaction temperature is 110
℃.TLC tracking and monitorings, display raw material is disappeared, and reaction solution is cooled into 25 DEG C, adds 100mL water, stratification after stirring, first
Benzene layer anhydrous sodium sulfate drying.Then filter, filtrate decompression, which is evaporated, obtains solid imine intermediate crude product, the crude product is used
Ethyl alcohol recrystallization obtains sterling imine intermediate 28.7g, yield 93.2%.
2) step 1 is taken) gained imine intermediate 15.4g added in tri- mouthfuls of reaction bulbs of 100mL, adds tetrahydrofuran 50mL
The reducing agent itrile group sodium borohydride 3.15g that the mol ratio of stirring and dissolving, addition and imine intermediate is 1: 1,25 DEG C of stirring reactions,
Until TLC shows that imines disappears, add methanol 5mL and reaction is quenched.Rotary evaporation removes tetrahydrofuran, and residue adds acetic acid second
Ester 100mL dissolves, then 50mL water washings, ethyl acetate layer anhydrous sodium sulfate drying, filtering, and rotary evaporation, which is evaporated, obtains secondary amine
Intermediate 14.9g, yield 96.1%；
3) weigh step 2) gained secondary amine intermediate 14.5g be dissolved in 50mL dichloromethane obtain secondary amine intermediate solvent it is molten
Liquid is standby；Paraformaldehyde 100mL and concentrated sulfuric acid 10mL, stirring and dissolving of the concentration for 35% are added in reaction bulb, 3 DEG C of left sides are cooled to
The right side, 25 DEG C or so stirring reactions are risen to after the solvent solution of secondary amine intermediate, completion of dropping is added dropwise.When TLC shows that raw material disappears
Afterwards, water 50mL is added into reaction solution, stratification is stirred, the water layer after layering is extracted with dichloromethane 100mL, is merged organic
Layer, washed once, anhydrous sodium sulfate drying with saturated sodium bicarbonate solution, filter, and filtrate is evaporated to obtain clopidogrel free alkali
14.0g, yield 93.3%.
4) weigh step 3) gained clopidogrel free alkali 14.0g be dissolved in 70mL ethyl acetate, be cooled to 5 DEG C or so,
It is added dropwise after the ethyl acetate solution (the 2.8mL concentrated sulfuric acids are dissolved in 10mL ethyl acetate) of the concentrated sulfuric acid, completion of dropping and is being kept for 5 DEG C or so
Continue stirring 2 hours, then filtration drying obtains bisulfate clopidogrel 17.5g, yield 95.7%.
Embodiment 2：
A kind of preparation method of bisulfate clopidogrel of the present invention comprises the following steps：
1) 2- thiophene aldehyde 12.6g and S- O-chlorobenzene glycine methyl ester 20.0g are weighed, tri- mouthfuls of reaction bulbs of 250mL are added to
In, solvent chloroform 100mL and catalyst ammonium chloride 0.6g are added, heating stirring backflow, reaction temperature is 60 DEG C, TLC tracking
Monitoring, display raw material is disappeared, and reaction solution is cooled into 20 DEG C, adds 100mL water, stratification after stirring, and chloroform layer is with anhydrous
Sodium sulphate is dried.Then filter, filtrate decompression, which is evaporated, obtains solid imine intermediate crude product, the crude product ethyl alcohol recrystallization
Obtain sterling imine intermediate 27.9g, yield 90.6%.
2) step 1 is taken) gained imine intermediate 15.4g added in tri- mouthfuls of reaction bulbs of 100mL, adds acetonitrile 50mL stirrings
Dissolving, adds reducing agent sodium borohydride 1.90g, and 20 DEG C of stirring reactions, until TLC shows that imine intermediate disappears, add methanol
Reaction is quenched in 5mL.Rotary evaporation removes solvent acetonitrile, and residue adds ethyl acetate 100mL dissolvings, then 50mL water washings,
Ethyl acetate layer anhydrous sodium sulfate drying, filtering, rotary evaporation, which is evaporated, obtains secondary amine intermediate 14.7g, yield 94.8%.
3) weigh step 2) gained secondary amine intermediate 14.5g be dissolved in 50mL chloroforms, obtain the chloroformic solution of secondary amine intermediate
It is standby, the paraformaldehyde 100mL and concentrated sulfuric acid 10mL that concentration is 30%, stirring and dissolving, drop are added in vacant reaction bulb to newly taking
Temperature rises to 20 DEG C or so stirring reactions to 0 DEG C after the chloroformic solution of secondary amine intermediate, completion of dropping is added dropwise.When TLC shows raw material
After disappearance, water 50mL, layering, water layer chloroform 100mL extractions are added into reaction solution.Merge organic layer, saturated sodium bicarbonate is molten
Liquid washed once, anhydrous sodium sulfate drying, and filtering, filtrate is evaporated to obtain clopidogrel free alkali 14.3g, yield 95.3%.
4) above-mentioned clopidogrel free alkali 14.0g is dissolved in 70mL ethyl acetate, is cooled to 0 DEG C or so, dense sulphur is added dropwise
In 0 DEG C or so continuation of keeping temperature after the ethyl acetate solution (the 2.8mL concentrated sulfuric acids are dissolved in 10mL ethyl acetate) of acid, completion of dropping
Stirring 2 hours, then filtration drying obtain bisulfate clopidogrel 17.3g, yield 94.6%.
Embodiment 3：
A kind of preparation method of bisulfate clopidogrel of the present invention comprises the following steps：
1) 2- thiophene aldehyde 12.6g and S- O-chlorobenzene glycine methyl ester 20.0g are weighed, tri- mouthfuls of reaction bulbs of 250mL are added to
In, methylene chloride 100mL and catalyst acetic acid ammonium 0.4g are added, heating stirring backflow, reaction temperature is 40 DEG C, TLC
Tracking and monitoring, display raw material is disappeared, and reaction solution is cooled into 30 DEG C, adds 100mL water, stratification after stirring, dichloromethane
Layer anhydrous sodium sulfate drying.Then filter, filtrate decompression, which is evaporated, obtains solid imine intermediate crude product, the crude product second
Alcohol recrystallizes to obtain sterling imine intermediate 28.8g, yield 93.5%.
2) step 1 is weighed) gained imine intermediate 15.4g added in tri- mouthfuls of reaction bulbs of 100mL, adds N, N- dimethyl
Formamide 50mL stirring and dissolvings, add reducing agent potassium borohydride 2.7g, 30 DEG C of stirring reactions, until TLC shows imine intermediate
Disappear, add methanol 5mL and reaction is quenched.Rotary evaporation removes solvent DMF, and residue adds ethyl acetate
100mL is dissolved, then 50mL water washings, ethyl acetate layer anhydrous sodium sulfate drying, filtering, and rotary evaporation, which is evaporated, to be obtained in secondary amine
Mesosome 14.5g, yield 93.5%.
3) weigh step 2) gained secondary amine intermediate 14.5g be dissolved in 50mL ethyl acetate, obtain the acetic acid of secondary amine intermediate
Ethyl ester solution for standby, the paraformaldehyde 100mL and concentrated sulfuric acid 10mL that concentration is 40%, stirring are added to newly taking in vacant reaction bulb
Dissolving, is cooled to 5 DEG C, and 30 DEG C of stirring reactions are risen to after the ethyl acetate solution of secondary amine intermediate, completion of dropping is added dropwise.Work as TLC
After showing that raw material disappears, water 50mL, layering, the aqueous layer with ethyl acetate 100mL extractions after layering are added into reaction solution.Merge
Organic layer, saturated sodium bicarbonate solution washed once, anhydrous sodium sulfate drying, and filtering, filtrate is evaporated to obtain clopidogrel free alkali
14.2g, yield 94.6%；
4) above-mentioned clopidogrel free alkali 14.0g is dissolved in 70mL acetone, is cooled to 10 DEG C or so, the concentrated sulfuric acid is added dropwise
Stirred 2 hours in 10 DEG C or so continuation of keeping temperature after acetone soln (the 2.8mL concentrated sulfuric acids are dissolved in 10mL acetone), completion of dropping,
Then filtration drying obtains bisulfate clopidogrel 17.6g, yield 96.2%.
Claims (8)
1. a kind of preparation method of bisulfate clopidogrel, it is characterised in that：It the described method comprises the following steps：
1）2- thiophene aldehydes are added in reaction bulb with S- O-chlorobenzene glycine methyl esters, add organic solvent and catalyst, plus
Thermal agitation back flow reaction, reaction temperature is 40-110 DEG C, and TLC detection reactions are cooled to 20-30 DEG C after terminating, add with it is organic molten
The isometric water of agent, stratification after stirring, organic layer anhydrous sodium sulfate drying, filtering, filtrate decompression, which is evaporated, obtains solid
Imine intermediate crude product, the crude product obtains sterling imine intermediate with ethyl alcohol recrystallization；2- thiophene aldehydes used and the adjacent chlorine of S-
The mol ratio of Phenylglycine methyl ester is 1:The ratio of the quality of 1,2- thiophene aldehyde and the volume of organic solvent is 1:8, catalyst
Consumption is the 3% ~ 5% of 2- thiophene aldehyde quality；
2）By step 1）In imine intermediate and organic solvent be added in new reaction bulb, reducing agent is added, in 20-30
Then stirring reaction adds methanol and reaction is quenched, solvent is distilled off to terminating at a temperature of DEG C, adds ethyl acetate dissolving, water
Washing, dry filter distill secondary amine intermediate is standby；Imine intermediate wherein used and the mol ratio of reducing agent are 1:1, it is sub-
The ratio of the quality of amine intermediate and the volume of organic solvent is 1:6 ~ 8, the consumption of ethyl acetate is imine intermediate volume
6-8 times is measured, and the consumption of water is 0.5 times of amount of ethyl acetate volume；
3）Weigh step 2）Gained secondary amine intermediate is dissolved in organic solvent, the quality of the secondary amine intermediate weighed with it is organic molten
The ratio of agent volume is 1:3.5, the organic solvent solution for obtaining secondary amine intermediate is standby；Put into the vacant reaction bulb newly taken
Concentration is 30%-40% paraformaldehyde and the concentrated sulfuric acid, is cooled to 0-5 DEG C, and the organic solvent solution of secondary amine intermediate is then added dropwise,
It is warming up to 20-30 DEG C of stirring reaction to TLC detection reactions after completion of dropping to terminate, reaction adds the 3-4 times of water measured after terminating, stir
Stratification is mixed, water layer is washed with the 6-8 times of solvent measured again, merge organic layer, washed once with saturated sodium bicarbonate solution, then
With anhydrous sodium sulfate drying, filtering, filtrate is evaporated to obtain clopidogrel free alkali；The quality of secondary amine intermediate and paraformaldehyde used
Ratio is 1:7, the quality of the concentrated sulfuric acid is the 10% of paraformaldehyde quality；
4）By step 3）The organic solvent that the clopidogrel free alkali of middle gained and 5-7 times are measured is added in reaction bulb, is cooled to
0-10 DEG C, it is added dropwise after the organic solvent solution of the concentrated sulfuric acid of 0.2 times of amount, completion of dropping, then maintains the temperature at continuation at 0-10 DEG C
Stirring reaction 2h, then filtration drying obtain bisulfate clopidogrel.
2. the preparation method of bisulfate clopidogrel according to claim 1, it is characterised in that：The step 1）In it is used
Catalyst be derived from ammonium chloride or ammonium acetate any one.
3. the preparation method of bisulfate clopidogrel according to claim 1 or 2, it is characterised in that：The step 1）In
Organic solvent used is derived from any one of toluene, chloroform or dichloromethane.
4. the preparation method of bisulfate clopidogrel according to claim 1, it is characterised in that：The step 2）In it is used
Reducing agent be derived from sodium borohydride, potassium borohydride or sodium cyanoborohydride any one.
5. the preparation method of bisulfate clopidogrel according to claim 4, it is characterised in that：The step 2）In it is used
Organic solvent be derived from tetrahydrofuran, acetonitrile, N,N-dimethylformamide any one.
6. the preparation method of bisulfate clopidogrel according to claim 5, it is characterised in that：The step 3）In it is used
To organic solvent be derived from dichloromethane, chloroform or ethyl acetate any one.
7. the preparation method of bisulfate clopidogrel according to claim 5, it is characterised in that：The step 4）In it is used
To organic solvent be derived from ethyl acetate or acetone any one.
8. the preparation method of bisulfate clopidogrel according to claim 1, it is characterised in that：The step 4）In it is dense
The organic solvent solution of sulfuric acid is the concentrated sulfuric acid and ethyl acetate or acetone volume ratio are 1:3.5 mixture.
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| CN110862372B (en) * | 2019-12-03 | 2024-01-12 | 江西川奇药业有限公司 | Synthesis of clopidogrel intermediate (S) -2- (2-thiophenoethylamine) - (2-chlorophenyl) -methyl acetate |
| CN111440139A (en) * | 2020-05-27 | 2020-07-24 | 廊坊市泽康医药科技有限公司 | Preparation method of clopidogrel sulfonate impurity |
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