CN101333223A - Method for preparing clopidogrel and salts thereof - Google Patents
Method for preparing clopidogrel and salts thereof Download PDFInfo
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Abstract
The invention provides a preparation method for clopidogrel and the salts of clopidogrel, belonging to the field of medical and chemical technology. The invention solves the problems of more reaction steps, long technical route, high cost and low purity of the existing preparation method for clopidogrel. The preparation method for clopidogrel comprises the following steps: a. synchronous resolution and racemization; b. preparation of (plus) alpha-(2 - thiophene triethylamine yl) -2 - (2 - chlorophenyl) methyl acetate; c. preparation of target product clopidogrel through cyclization reaction. The clopidogrel can generate medicinal salt with acids in a solvent. The preparation method for clopidogrel and the salts of clopidogrel has simple technology, easy operation, lower costs and higher product purity.
Description
Technical field
The present invention relates to the preparation method of PID agent and antithrombotic drug agent, in particular, the preparation method who relates to clopidogrel [(S)-α-(2-chloro-phenyl-)-6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-methyl acetate also] and pharmacologically acceptable salt thereof; Belong to medicine and chemical technology field.
Background technology
Clopidogrel (Clopidogrel), chemical name (S)-α-(2-chloro-phenyl-)-6,7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-methyl acetate, English name methyl (+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5 (4H)-acetate, (I) is as follows for structural formula.
It is an anticoagulant, irreversibly suppress hematoblastic gathering by optionally combining with platelet surface adenylate cyclase link coupled adp receptor, can reduce thrombosis in the blood vessel, because its action intensity and tolerance height and side effect is less are having positive effect so substitute acetylsalicylic acid (Aspirin) and ticlopidine (Ticlopidine) gradually aspect the inhibition thrombosis.
Because clopidogrel is the good antithrombotic new drug of a kind of curative effect, has vast market prospect, has caused the extensive attention of each the world of medicine, have the preparation method's of a lot of relevant clopidogrels report at present.
By analysis-by-synthesis, as can be seen, the emphasis of clopidogrel preparation all concentrates on the following aspects: 1, select because of all multifactor operational paths of facing of consideration raw material.2, split the selection of target and method for splitting.3, the selection of the racemization method of invalid enantiomer.
It is to be that the compound of a and the compound of structural formula b are starting raw material with the structural formula as Chinese patent application (CN1972950A), elder generation is that the optically active amino alcohol of c replaces the leavings group y in the formula (a) with the structural formula, react the target product of system again with formula (b), though the effective enantiomer of the product that this method is made and the specific energy of invalid enantiomer reach 3: 1 or are higher, one step resolution yield height, but this method reactions steps is many, and operational path is long, and cost is higher.
(x is a halogen, and y is a leavings group)
Chinese patent application (02803998.X) is that d and structural formula are that the compound of e is that raw material makes clopidogrel with the structural formula, though this method steps is less, operational path is short; But cost of material is higher, and structural formula is that the molten point of compound of d is lower, and the purification of target product is difficulty relatively, has a strong impact on the purity of target product.
(x is a halogen)
Summary of the invention
The present invention is directed to the defective that prior art exists, provide a kind of raw material cheap and easy to get, technology is simple, and is easy to operate, and cost is lower, the preparation method of the clopidogrel that product purity is higher.
The objective of the invention is to realize by following technical proposal: a kind of preparation method of clopidogrel, this method may further comprise the steps:
A. structural formula is dissolved in the solvent for racemic modification (soil) O-chlorobenzene glycine methyl ester of (II), adds racemization agent and resolving agent, being that 70 ℃～110 ℃ condition is following in temperature splits the limit racemization, makes (+) O-chlorobenzene glycine methyl ester enantiomer;
B. (+) O-chlorobenzene glycine methyl ester enantiomer and structural formula being put in the solvent for the α-thiophene ethanol p-toluenesulfonic esters of (III), is to react under 60 ℃～100 ℃ the condition to make (+) α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate of structural formula for (IV) in temperature as acid binding agent with basic cpd;
C. with formula (IV) and hydrochloric acid reaction production (IV) hydrochloride, be to carry out cyclization with the formaldehyde or the Paraformaldehyde 96 aqueous solution under 40 ℃～80 ℃ the condition with formula (IV) hydrochloride in temperature, after adding the organic solvent stirring then, behind alkaline compound accent pH value to 7～8, make the target product clopidogrel of structural formula for (I);
Fractionation is the committed step in the clopidogrel preparation process, the raw material of fractionation earlier that has, the intermediate of fractionation earlier that has, the then fractionation final product that has; The effect of the final product that the time period difference that splits obtains is also different, as splitting the processing that raw material can be simplified subsequent technique earlier, and the plant factor height, the auxiliary material consumption is less, but has part material or the intermediate product might be by racemization; The racemization that splits the residual invalid enantiomer in back also is another committed step in the clopidogrel preparation process, because racemization directly has influence on the height that splits efficient.
The present invention is according to the mechanism about in acidic medium racemization of Neuberger to the improvement of Dakin racemization mechanism.The mechanism that this racemization proposes relates to imines (Schiff alkali) and sloughs proton from the alpha-carbon of protonated imines, produces a stable zwitter-ion, and its chemical equation is as follows:
The racemization of invalid corresponding isomer (-) o-chlorobenzene glycine ester is consistent with the racemization mechanism of Dakin, it is the minimizing of negative charge on electronegative increase of R and the hydroxy-acid group, accelerated the racemic speed of invalid corresponding isomer, and the racemization speed of ester is faster than acid, so can reach a large amount of racemizations.
Fractionation racemization of the present invention is carried out synchronously, and wherein racemic modification (soil) O-chlorobenzene glycine methyl ester with formula (II) joins in the solvent, adds the racemization agent then, be warming up to 75 ℃～80 ℃, drop into (+) resolving agent, be incubated 5～10 hours, be preferably 7～9 hours after the cooling filtration.Filtrate is warming up to 85 ℃～110 ℃, is incubated 0.5～2 hour, invalid enantiomer and then is repeated above-mentioned steps and splits by racemization in the residue, thereby has realized synchronous fractionation racemization.
Racemic modification of the present invention (soil) O-chlorobenzene glycine methyl ester can directly be buied from the market, also can adopt existing common technology to prepare, can also make by following method, concrete process is: be raw material with the o-chlorobenzene glycine, with strong acid is catalyzer, carries out esterification and make racemic modification (soil) O-chlorobenzene glycine methyl ester in methanol solvate.Wherein the used solvent of esterification is a methyl alcohol, and product yield is improved.The mol ratio of methyl alcohol and o-chlorobenzene glycine is 5～20: 1, is preferably 10～15: 1. catalyzer is strong acid such as sulfuric acid, hydrochloric acid, chlorsulfonic acid, sulfur oxychloride, is preferably sulfuric acid.The mol ratio of o-chlorobenzene glycine and strong acid is 0.1～1.0: 1, and preferred molar ratio is 0.3～0.6: 1.Entire reaction course keeps reflux state, and return time is 10～30 hours, and the preferred time is 18～22 hours.After reacting end, steam and remove methyl alcohol, being neutralized to pH value with aqueous sodium hydroxide solution is about 8.5, and chloroform extraction obtains racemic modification (soil) O-chlorobenzene glycine methyl ester behind washing, drying, precipitation.
In the preparation method of above-mentioned clopidogrel, solvent described in the step a is one or more in methylene dichloride, ethylene dichloride, methyl alcohol, Virahol, acetone, butanone, acetonitrile, the water, described resolving agent is a kind of in (+) tartrate enantiomer, (+) camphorsulfonic acid enantiomer, described racemization agent is aldehyde and organic acid mixture, and both mol ratios are 1: 2～5.The preferred resolution solvent of the present invention is an acetonitrile, and preferred resolving agent is (+) tartrate enantiomer, and wherein the mol ratio of (+) tartrate enantiomer and racemic modification (soil) O-chlorobenzene glycine methyl ester is 0.5～2.0: 1, is preferably 0.8～1.2: 1; Splitting temperature is 75～80 ℃, and the fractionation time is 5～10 hours, and preferably the fractionation time is 7～9 hours; Described aldehyde is formaldehyde, acetaldehyde, butyraldehyde, phenyl aldehyde, salicylic aldehyde etc., is preferably salicylic aldehyde, and described organic acid is formic acid, acetate, oxalic acid etc., is preferably acetate; Aldehyde and organic acid mol ratio are 1: 2～5, are preferably 1: 3.Solvent and organic acid weight ratio are 1: 1. racemization temperature is 85～110 ℃, is preferably 90～100 ℃, and the racemization time is 0.5～2 hour, is preferably 1 hour.
In the preparation method of above-mentioned clopidogrel, the synthetic method of the formula described in the step b (III) is: selecting thiophene ethanol and Tosyl chloride is raw material, putting into then in the solvent with the basic cpd is that acid binding agent carries out esterification, and reactant obtains formula (III) behind washing, recrystallization.The above-mentioned solvent that adopts is polarity or non-polar solvent, as toluene, methylene dichloride, ethylene dichloride, chloroform, tetracol phenixin, sherwood oil, hexanaphthene etc., is preferably methylene dichloride.Described basic cpd is mineral alkali such as yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, dipotassium hydrogen phosphate etc.; Organic bases is methylamine, triethylamine, pyridine etc., is preferably triethylamine.Wherein the mol ratio of thiophene ethanol and Tosyl chloride is 1.0: 1.0～3.0; Be preferably 1.0: 1.5.The mol ratio of acid binding agent and thiophene ethanol is 1.0～3.0: 1.0; Be preferably 2.0: 1.0.Temperature of reaction is 20～50 ℃, and the reaction times is 1～10 hour.Reactant obtains product α-thiophene ethanol p-toluenesulfonic esters behind neutralization, washing, precipitation and recrystallization.
In the preparation method of above-mentioned clopidogrel, the solvent when (+) O-chlorobenzene glycine methyl ester enantiomer and structural formula react for the α-thiophene ethanol p-toluenesulfonic esters of (III) among the step b is an acetonitrile, and the weight ratio of acetonitrile and formula (III) is 2～4: 1.Described basic cpd is a kind of in yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, Sodium phosphate dibasic, the dipotassium hydrogen phosphate.Temperature of reaction is 60 ℃～100 ℃, is preferably 75 ℃～85 ℃.Reaction times is 50～100 hours, and the preferred reaction time is 60～80 hours.Reactant washes with water after steaming desolventizes, and ethyl acetate extraction adds hydrochloric acid and saltouts, and obtains the hydrochloride of formula IV.
In the preparation method of above-mentioned clopidogrel, the concentration of the formaldehyde described in the step c or the Paraformaldehyde 96 aqueous solution is 30%～45%, and described organic solvent is a kind of in methyl alcohol, ethanol, methylene dichloride, ethylene dichloride, methyl-formiate, the ethyl acetate.Be preferably methylene dichloride, it is 37% formalin that methylating agent is preferably concentration, and temperature of reaction is preferably 50～60 ℃, and the reaction times is 0.5～2.0 hour.
Because clopidogrel just can be used in the medicine of preparation treatment thrombus disease after only making salt.So another object of the present invention is to provide the preparation method of clopidogrel pharmacologically acceptable salt.
A kind of preparation method of clopidogrel salt, this method may further comprise the steps:
A. choose clopidogrel as method for preparing;
B. with clopidogrel and acid salify in solvent; Described acid is a kind of in sulfuric acid, hydrochloric acid, alkyl sulfide sulfonic acid, naphthene sulfonic acid, acetate, phenylformic acid, toxilic acid, citric acid, tartrate, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, the tosic acid, and described organic solvent is a kind of in ethyl acetate, the acetone.
Clopidogrel with in the alkaline compound and after, tell organic phase, through washing, decolouring, steam to desolventize and wait processing, obtain clopidogrel base oily matter, use again sour in solvent salify, obtain pharmaceutically useful clopidogrel salt.
As preferably, the clopidogrel salt that step B makes is clopidogrel hydrochloride or clopidogrel sulfate.
The reaction equation of clopidogrel preparation of the present invention is as follows:
In sum, the preparation method of clopidogrel of the present invention and pharmacologically acceptable salt thereof has the following advantages:
1, the raw material sources of preparation method's employing of the present invention are abundant, cheap and easy to get, and processing condition relax, and avoid using poisonous and hazardous chemical, yield height, the demand of suitability for mass industrialized production as far as possible.
2, preparation method of the present invention adopts α-thiophene ethanol p-toluenesulfonic esters as raw material, it has overcome the low melting point solid material 4 of available technology adopting, 5,6, and the 7-tetrahydrochysene (2,3-e) thienopyridine, be difficult to obtain pure product, have influence on the defective of the finished product clopidogrel quality, also overcome and selected in the prior art that 2-(2-thiophene)-monobromoethane is a raw material for use, in reaction, generate the defective that hydrogen bromide causes environmental pollution; Preparation method of the present invention also provides the preparation method of a kind of α-thiophene ethanol p-toluenesulfonic esters simultaneously, this method product yield and purity height, and the clopidogrel quality of preparation is better.
3, preparation method of the present invention adopts the mode that fractionation and racemization are carried out synchronously, it has solved in the prior art under alkaline substance existence conditions such as sodium hydroxide, potassium hydroxide, and the ester group after the racemization is hydrolyzed easily, also needs esterification again, product yield is lower, the defective that processing step is loaded down with trivial details.
Embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail; But the present invention is not limited to these embodiment.
Embodiment 1
Add methyl alcohol 400g in reaction flask, o-chlorobenzene glycine 193g under agitation drips vitriol oil 220g in material, dripped off in about 0.5～1.0 hour, is heated to backflow, insulation back flow reaction 20 hours.After reaction finishes, steam and remove methyl alcohol, when interior temperature reaches 85 ℃, reduce to room temperature after, drop into 400g trash ice and 800g chloroform, stir dropping sodium accent pH value to 8.5 down, standing demix, water layer is incorporated chloroform layer into the chloroform extraction secondary, and chloroform layer washes secondary with water, adds anhydrous magnesium sulfate drying.With the underpressure distillation of exsiccant chloroform layer, go out until no chloroform, make red oil O-chlorobenzene glycine methyl ester (II), 165g, content 97.2%.
In another reaction flask, drop into the 800g acetonitrile, the O-chlorobenzene glycine methyl ester of the above-mentioned preparation of 165g, 70g acetate and 50g salicylic aldehyde are warming up to 75 ℃, drop into 103g (+) tartrate, insulated and stirred 8 hours.Reduce to room temperature, filter.Filter cake is cooled to 0 ℃ of filtration with the recrystallizing methanol of 2.5 times of weight, gets (+) O-chlorobenzene glycine methyl ester tartrate 123g of white crystal shape, [α] D/20=85 °.The acetonitrile mother liquor is warming up to 90 ℃, is incubated 1 hour, be cooled to 75 ℃, drop into 60g (+) tartrate, repeat above-mentioned splitting step, obtain (+) O-chlorobenzene glycine methyl ester tartrate 75g. mother liquor and can continue to reuse, also can give over to down to criticize and apply mechanically.
Drop into thiophene ethanol 128g, methylene dichloride 800g in another reaction flask, Tosyl chloride 226g under agitation drips triethylamine 200g, controlled temperature about 30 ℃, insulation reaction 6 hours.Drop into water 200g in reaction solution, concentrated hydrochloric acid 100g stirred 1 hour, and standing demix is told dichloromethane layer and added the 200g washing once with the 20g concentrated hydrochloric acid, washes once with clear water again, uses the 10g anhydrous magnesium sulfate drying.Behind the filtering sal epsom, remove methylene dichloride under reduced pressure, residue is molten clear with 200g methyl alcohol, and crystallization is separated out in cooling, is cooled to below 0 ℃ to filter, and filter cake is white solid α-thiophene ethanol p-toluenesulfonic esters (III), content 99.1%, yield 93%.
In another reaction flask, drop into methylene dichloride 1000g, water 350g, (+) O-chlorobenzene glycine methyl ester tartrate 140g, gradation drops into sodium bicarbonate 84g, stirs 1 hour, left standstill 0.5 hour, branch vibration layer, dichloromethane layer washes with water, adds anhydrous magnesium sulfate drying, behind the elimination sal epsom, remove methylene dichloride under reduced pressure.Add acetonitrile 300g in the residue, stirs molten clear after, adding α-thiophene ethanol p-toluenesulfonic esters 124g, sodium bicarbonate 100g, be warming up to backflow (about 80 ℃) reaction 70 hours, remove acetonitrile under reduced pressure, reduce to room temperature then, add ethyl acetate 800g, water 300g stirred 1 hour, left standstill separatory, the ethyl acetate layer saturated aqueous common salt, anhydrous magnesium sulfate drying.The ethyl acetate solution of elimination anhydrous magnesium sulfate stirs adding concentrated hydrochloric acid 84g down, and growing the grain 3 hours is cooled to 0 ℃, filters, and gets white solid (+) α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate (IV) hydrochloride crude product 130g.With the mixed solvent (methyl alcohol 18% of the above-mentioned crude product that makes with 4 times of weight, acetonitrile 82%) 60 ℃ of insulation 4 hours, slowly be cooled to 0 ℃, filter, obtain (+) α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate hydrochloride highly finished product, oven dry back white crystals body 118g, [α] D/20=110 °, content are 99.7%.
With purified (+) α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate hydrochloride 17.5g adding 85ml concentration is 37% formalin, reaction is 1 hour about 75 ℃, after reaction finishes, in reaction solution, add 170ml water and 350ml methylene dichloride, stir under the room temperature, transferring the pH value of solution with sodium bicarbonate is 8.0.Standing demix, dichloromethane layer washes with water, and concentrating under reduced pressure gets 16.5g oily matter clopidogrel (I).
With 250ml acetone diluted oily matter clopidogrel, add the 4.5g vitriol oil, stir and separate out crystallization.Filter, obtain the clopidogrel sulfate 13.5g of white crystals after the filter cake oven dry.Mp is 189～190 ℃, [α] D/20=53.4 °.
Embodiment 2
The preparation process of O-chlorobenzene glycine methyl ester (II) repeats no more with embodiment 1.
In reaction flask, drop into the 500g butanone, the O-chlorobenzene glycine methyl ester of the above-mentioned preparation of 165g, 140g oxalic acid and 50g salicylic aldehyde are warming up to 80 ℃, drop into 148g (+) tartrate, insulated and stirred 6 hours.Reduce to room temperature, filter.Filter cake is cooled to 0 ℃ of filtration with the recrystallizing methanol of 2.5 times of weight, gets (+) O-chlorobenzene glycine methyl ester tartrate 125g of white crystal shape, [α] D/20=85 °.The butanone mother liquor is warming up to 100 ℃, is incubated 0.5 hour, be cooled to 80 ℃, drop into 72g (+) tartrate, repeat above-mentioned splitting step, obtain (+) O-chlorobenzene glycine methyl ester tartrate 74g. mother liquor and can continue to reuse, also can give over to down to criticize and apply mechanically.
In another reaction flask, drop into thiophene ethanol 64g, pyridine 100g, be cooled to after stirring evenly below 0 ℃, slowly 114g powdery Tosyl chloride is dropped in batches, after throwing is finished, continue reaction 5 hours.Drop into 300g water and 150g concentrated hydrochloric acid in reaction solution, the 200g ethyl acetate stirs separatory after 1 hour, and organic layer is with 15g hydrochloric acid and 100g water washing, again with clear water washing, anhydrous magnesium sulfate drying.Behind the elimination sal epsom, remove ethyl acetate under reduced pressure, the residue recrystallizing methanol is being filtered below 0 ℃, gets white filter cake, and vacuum-drying gets α-thiophene ethanol p-toluenesulfonic esters (III) 126g, content 99.0%, yield 90%.
In another reaction flask, drop into ethylene dichloride 1200g, water 400g, (+) O-chlorobenzene glycine methyl ester tartrate 150g, gradation drops into yellow soda ash 106g, stirs 1 hour, left standstill 0.5 hour, branch vibration layer, the ethylene dichloride layer washes with water, adds anhydrous magnesium sulfate drying, behind the elimination sal epsom, remove ethylene dichloride under reduced pressure.Add acetonitrile 350g in the residue, stirs molten clear after, adding α-thiophene ethanol p-toluenesulfonic esters 136g, yellow soda ash 106g, be warming up to backflow (about 90 ℃) reaction 60 hours, remove acetonitrile under reduced pressure, reduce to room temperature then, add ethyl acetate 800g, water 300g stirred 1 hour, left standstill separatory, the ethyl acetate layer saturated aqueous common salt, anhydrous magnesium sulfate drying.The ethyl acetate solution of elimination anhydrous magnesium sulfate stirs adding concentrated hydrochloric acid 84g down, and growing the grain 3 hours is cooled to 0 ℃, filters, and gets white solid (+) α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate (IV) hydrochloride crude product.With the mixed solvent (methyl alcohol 18% of the above-mentioned crude product that makes with 4 times of weight, acetonitrile 82%) 60 ℃ of insulation 4 hours, slowly be cooled to 0 ℃, filter, obtain (+) α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate hydrochloride highly finished product, the oven dry back is the white crystals body, and [α] D/20=110 °, content are 99.5%.
With purified (+) α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate hydrochloride 35g adding 170ml concentration is 37% formalin, reaction is 1.5 hours about 60 ℃, after reaction finishes, in reaction solution, add 340ml water and 700ml ethyl acetate, stir under the room temperature, transferring the pH value of solution with sodium bicarbonate is 7.5.Standing demix, ethyl acetate layer washes with water, and concentrating under reduced pressure gets 32g oily matter clopidogrel (I).
With 500ml ethyl acetate dilution oily matter clopidogrel, add the 6g concentrated hydrochloric acid, stir and separate out crystallization.Filter, obtain the clopidogrel hydrochloride 25g of white crystals after the filter cake oven dry.Mp is 189～190 ℃, [α] D/20=53.4 °.
Embodiment 3
The preparation process of O-chlorobenzene glycine methyl ester (II) repeats no more with embodiment 1.
In reaction flask, drop into 400g acetone, the O-chlorobenzene glycine methyl ester of the above-mentioned preparation of 165g, 80g formic acid and 60g salicylic aldehyde are warming up to 75 ℃, drop into 103g (+) tartrate, insulated and stirred 10 hours.Reduce to room temperature, filter.Filter cake is cooled to 0 ℃ of filtration with the recrystallizing methanol of 2.5 times of weight, gets (+) O-chlorobenzene glycine methyl ester tartrate 126g of white crystal shape, [α] D/20=85 °.The acetone mother liquor is warming up to 110 ℃, is incubated 0.5 hour, be cooled to 75 ℃, drop into 50g (+) tartrate, repeat above-mentioned splitting step, obtain (+) O-chlorobenzene glycine methyl ester tartrate 72g. mother liquor and can continue to reuse, also can give over to down to criticize and apply mechanically.
Drop into thiophene ethanol 128g, ethylene dichloride 850g in another reaction flask, Tosyl chloride 226g under agitation drips methylamine 180g, controlled temperature about 40 ℃, insulation reaction 4 hours.Drop into water 200g in reaction solution, concentrated hydrochloric acid 100g stirred 1 hour, and standing demix is told the ethylene dichloride layer and added the 200g washing once with the 20g concentrated hydrochloric acid, washes once with clear water again, uses the 10g anhydrous magnesium sulfate drying.Behind the filtering sal epsom, remove ethylene dichloride under reduced pressure, residue is molten clear with 200g methyl alcohol, and crystallization is separated out in cooling, is cooled to below 0 ℃ to filter, and filter cake is white solid α-thiophene ethanol p-toluenesulfonic esters (III), content 99.5%, yield 92%.
In another reaction flask, drop into methylene dichloride 1000g, water 350g, (+) O-chlorobenzene glycine methyl ester tartrate 140g, gradation drops into saleratus 100g, stirs 1 hour, left standstill 0.5 hour, branch vibration layer, dichloromethane layer washes with water, adds anhydrous magnesium sulfate drying, behind the elimination sal epsom, remove methylene dichloride under reduced pressure.Add acetonitrile 350g in the residue, stirs molten clear after, adding α-thiophene ethanol p-toluenesulfonic esters 135g, saleratus 100g, be warming up to backflow (about 70 ℃) reaction 50 hours, remove acetonitrile under reduced pressure, reduce to room temperature then, add ethyl acetate 800g, water 300g stirred 1 hour, left standstill separatory, the ethyl acetate layer saturated aqueous common salt, anhydrous magnesium sulfate drying.The ethyl acetate solution of elimination anhydrous magnesium sulfate stirs adding concentrated hydrochloric acid 84g down, and growing the grain 3 hours is cooled to 0 ℃, filters, and gets white solid (+) α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate (IV) hydrochloride crude product 135g.With the mixed solvent (methyl alcohol 18% of the above-mentioned crude product that makes with 5 times of weight, acetonitrile 82%) 60 ℃ of insulation 4 hours, slowly be cooled to 0 ℃, filter, obtain (+) α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate hydrochloride highly finished product, oven dry back white crystals body 122g, [α] D/20=110 °, content are 99.5%.
With purified (+) α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate hydrochloride 17.5g adding 100ml concentration is 35% the Paraformaldehyde 96 aqueous solution, reaction is 2 hours about 50 ℃, after reaction finishes, in reaction solution, add 180ml water and 320ml ethylene dichloride, stir under the room temperature, transferring the pH value of solution with yellow soda ash is 7.0.Standing demix, the ethylene dichloride layer washes with water, and concentrating under reduced pressure gets 16g oily matter clopidogrel (I).
With 300ml acetone diluted oily matter clopidogrel, add the 4.5g vitriol oil, stir and separate out crystallization.Filter, obtain the clopidogrel sulfate 13.2g of white crystals after the filter cake oven dry.Mp is 189～190 ℃, [α] D/20=53.4 °.
Specific embodiment described in the present invention only is that the present invention's spirit is illustrated.The technician of the technical field of the invention can make various modifications or replenishes or adopt similar mode to substitute described specific embodiment, but can't depart from spirit of the present invention or surmount the defined scope of appended claims.
Although the present invention has been made detailed explanation and has quoted some specific embodiments as proof, to those skilled in the art, only otherwise leave that the spirit and scope of the present invention can be done various variations or correction is obvious.
Claims (8)
1, a kind of preparation method of clopidogrel, this method may further comprise the steps:
A. structural formula is dissolved in the solvent for racemic modification (soil) O-chlorobenzene glycine methyl ester of (II), adds racemization agent and resolving agent, being that the condition of 70 ℃～11O ℃ is following in temperature splits the limit racemization, makes (+) O-chlorobenzene glycine methyl ester enantiomer;
B. (+) O-chlorobenzene glycine methyl ester enantiomer and structural formula being put in the solvent for the α-thiophene ethanol p-toluenesulfonic esters of (III), is to react under 60 ℃～100 ℃ the condition to make (+) α-(2 thiophene ethyl amine base)-2-(2-chlorobenzene) methyl acetate of structural formula for (IV) in temperature as acid binding agent with basic cpd;
C. with formula (IV) and hydrochloric acid reaction production (IV) hydrochloride, be to carry out cyclization with the formaldehyde or the Paraformaldehyde 96 aqueous solution under 40 ℃～80 ℃ the condition with formula (IV) hydrochloride in temperature, after adding the organic solvent stirring then, behind alkaline compound accent pH value to 7～8, make the target product clopidogrel of structural formula for (I);
2, the preparation method of clopidogrel according to claim 1, it is characterized in that: the solvent described in the step a is one or more in methylene dichloride, ethylene dichloride, methyl alcohol, Virahol, acetone, butanone, acetonitrile, the water, described resolving agent is a kind of in (+) tartrate enantiomer, (+) camphorsulfonic acid enantiomer, described racemization agent is aldehyde and organic acid mixture, and both mol ratios are 1: 2～5.
3, the preparation method of clopidogrel according to claim 1, it is characterized in that: the synthetic method of the formula described in the step b (III) is: selecting thiophene ethanol and Tosyl chloride is raw material, putting into then in the solvent with the basic cpd is that acid binding agent carries out esterification, and reactant obtains formula (III) behind washing, recrystallization.
4, the preparation method of clopidogrel according to claim 1, it is characterized in that: the solvent when (+) O-chlorobenzene glycine methyl ester enantiomer and formula (III) are reacted among the step b is that described solvent is an acetonitrile, and the weight ratio of acetonitrile and formula (III) is 2～4: 1.
5, the preparation method of clopidogrel according to claim 1 is characterized in that: (+) O-chlorobenzene glycine methyl ester enantiomer and formula (III) described basic cpd of when reaction is a kind of in yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, Sodium phosphate dibasic, the dipotassium hydrogen phosphate among the step b.
6, the preparation method of clopidogrel according to claim 1, it is characterized in that: the concentration of the formaldehyde described in the step c or the Paraformaldehyde 96 aqueous solution is 30%～45%, and described organic solvent is a kind of in methyl alcohol, ethanol, methylene dichloride, ethylene dichloride, methyl-formiate, the ethyl acetate.
7, a kind of preparation method of clopidogrel salt is characterized in that: this method may further comprise the steps:
A. choose clopidogrel as method preparation as described in the claim 1～6 any;
B. with above-mentioned clopidogrel and acid salify in solvent; Described acid is a kind of in sulfuric acid, hydrochloric acid, alkyl sulfide sulfonic acid, naphthene sulfonic acid, acetate, phenylformic acid, toxilic acid, citric acid, tartrate, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, the tosic acid, and described organic solvent is a kind of in ethyl acetate, the acetone.
8, the preparation method of clopidogrel salt according to claim 7 is characterized in that: the clopidogrel salt that step B makes is clopidogrel hydrochloride or clopidogrel sulfate.
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