CN102924474A - Preparation method of crystal form I of clopidogrel hydrogen sulfate - Google Patents
Preparation method of crystal form I of clopidogrel hydrogen sulfate Download PDFInfo
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- CN102924474A CN102924474A CN201210444685XA CN201210444685A CN102924474A CN 102924474 A CN102924474 A CN 102924474A CN 201210444685X A CN201210444685X A CN 201210444685XA CN 201210444685 A CN201210444685 A CN 201210444685A CN 102924474 A CN102924474 A CN 102924474A
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- HGIZTSALXNCHQO-UHFFFAOYSA-N COC(C(c1ccccc1Cl)N(CC1)CC2=C1S(C[U]C)C=C2)=O Chemical compound COC(C(c1ccccc1Cl)N(CC1)CC2=C1S(C[U]C)C=C2)=O HGIZTSALXNCHQO-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a preparation method of a crystal form I of clopidogrel hydrogen sulfate. The preparation method comprises the following steps of (1) dropwise adding concentrated sulfuric acid or 2-methyltetrahydrofuran solution of the concentrated sulfuric acid into 2-methyltetrahydrofuran solution of clopidogrel free base to obtain mixed solution, wherein the temperature of the mixed solution is controlled to range from -10 DEG C to 5 DEG C when the dropwise adding is performed; and (2) heating the mixed solution to the temperature of 10-35 DEG C, performing crystal precipitation with stirring, separating precipitated crystals, and drying the precipitated crystals to obtain the crystal form I of the clopidogrel hydrogen sulfate. The preparation method is simple, easy to implement, good in reproducibility and suitable for industrial production. The prepared crystal form I of the clopidogrel hydrogen sulfate has the advantages of being high in crystal form purity and high-performance liquid chromatography (HPLC) purity, low in cost, good in stability, high in solvent recovery, environment-friendly and the like.
Description
Technical field
The present invention relates to pharmaceutical chemistry crystallization technique field, in particular to a kind of preparation method of SR-25990C crystalline form I.
Background technology
SR-25990C is French a kind of platelet aggregation inhibitor of matching Norfin, Inc's exploitation, is used for preventing and treating clinically the circulation disorder of the heart, brain and other arteries that cause because of the high state of aggregation of thrombocyte.Be applicable to apoplexy, the myocardial infarction of in the recent period outbreak and made a definite diagnosis the patient of peripheral arterial disease, can reduce the generation of atherosclerotic event.Compare with other antiplatelet drugs, SR-25990C has the advantages such as curative effect is strong, security good, tolerance is good, for many years rank whole world best-selling drugs prostatitis always.
The molecular structural formula of SR-25990C is as follows:
EP0281459A has described SR-25990C and preparation method thereof at first, but does not mention crystal formation.WO99065915A1 discloses two kinds of medicinal crystal-forms---crystalline form I and the crystal form II of SR-25990C.Crystalline form I is metastable-state crystal, has higher solubleness and bioavailability.Crystal form II is the thermodynamic stability crystal formation, but solubleness and bioavailability are poorer than crystalline form I.
Preparation method about the SR-25990C crystalline form I has been reported.Adopt the technique of mixed solvent system, weak point is complicated operation, and the solvent recuperation cost is high, is unfavorable for industrialization production, and adopts the technique of single solvent also to have different defectives.
WO99065915A1 discloses acetone can form crystalline form I or crystal form II as solvent, but industrialization production is not suitable for adopting acetone, because crystalline form I irreversibly changes crystal form II easily in the unsettled solvent acetone of its heat power.
WO03051362A1 discloses a kind of preparation method of crystalline form I: amorphous clopidogrel hydrogen sulfate is suspended in a kind of ether keeps more than 1 hour preferred C
2-8Ether, more preferably ether, t-butyl methyl ether.The starting raw material of this invention is amorphous clopidogrel hydrogen sulfate, and by SR-25990C being dissolved in methyl alcohol or the ethanol, removal of solvent under reduced pressure is collected oily matter or foam and obtained among the embodiment.Process with ether afterwards, obtain crystalline form I or crystalline form I and unformed mixture, the purity of gained crystalline form I is not mentioned in this invention.This preparation method's complicated operation, poor reproducibility is difficult to industrialization control, and ether and t-butyl methyl ether are volatile, inflammable noxious solvent.
WO2004020443 discloses clopidogrel free alkali and vitriol oil salify in a kind of solvent, isolates the SR-25990C crystalline form I, and solvent is selected from C
1-5Alcohol or they and C
1-4The ester that carboxylic acid forms, the purity of gained crystalline form I can only be controlled at 98%.WO2005100364 discloses with ether, ethyl formate, ethyl acetate, methyl acetate, isopropyl ether, methylene dichloride can prepare crystalline form I as solvent, uses the product yield of ethyl formate or ethyl acetate or isopropyl ether to only have 50%～64% among the embodiment.Experiment is found,, forms easily dope in the salification process and adheres on the agitator as solvent with ethyl acetate, and dope is difficult to scatter under the low temperature, if crystal conversion easily occurs again long-time the stirring.Butylacetate is the volatility noxious solvent, affects central nervous system.
CN1903859A uses expensive five-carbon ketone or six-carbon ketone as the solvent for preparing crystalline form I.
WO2008093357A2 discloses industrialized scale and has prepared improving one's methods of crystalline form I, and solvent for use is selected from methyl aceto acetate, methyl acetoacetate, 4-chloroethyl methyl aceto acetate, 3-nitro Propionylacetic acid ethyl ester, propyl lactate, ethyl lactate, cyclopentyl methyl ether, dipropylene glycol, dibutylene glycol ether, propyl group methylcyclohexane, butyl methyl cellosolve, propyl group ethyl cellosolve, butyl ethyl cellosolve.These solvents are of little use, and boiling point is high, and residual solvent is difficult for removing, and affects quality product.
CN101805354A discloses a kind of preparation method of SR-25990C crystalline form I, comprising: clopidogrel free alkali is dissolved in the tetrahydrofuran (THF), adds the vitriol oil at-14 ℃ ~ 0 ℃; With mixture reaction after 1 ~ 2 hour, be warming up to 20 ℃ ~ 40 ℃ and continue reaction crystal is fully separated out, obtain crystal after, filter, with the tetrahydrofuran (THF) washing leaching cake, drain, vacuum-drying, obtain crystalline form I.The yield of the method only has 73 ~ 80%, and production cost is higher.The tetrahydrofuran (THF) boiling point is lower, and solvent recovering rate is low, and discharge amount of exhaust gas is large, and three wastes processing cost is high, is not suitable for industrialization production.
Obviously, all there are different defectives in the preparation method of known SR-25990C crystalline form I, can not satisfy obtain high purity stable crystal form, simple process reliable, have cost advantage, be fit to the requirements at the higher level of industrialization production, environmental protection.
Summary of the invention
The object of the invention is to: for existing SR-25990C crystalline form I preparation method's various deficiencies, provide a kind of new preparation method of suitable industrialization.The characteristics of the method be 2-methyltetrahydrofuran take environmental protection as solvent, clopidogrel free alkali and vitriol oil salt-forming reaction obtain highly purified SR-25990C crystalline form I, product impurity is few, has cost advantage, excellent storage stability, environmental friendliness.
The inventor finds that through a large amount of solvent screenings the 2-methyltetrahydrofuran is a kind of good organic solvent, is fit to very much the preparation of SR-25990C crystalline form I.The 2-methyltetrahydrofuran has good solubility to clopidogrel free alkali, solubleness to SR-25990C is moderate, between acetone and ethyl acetate, the speed of separating out of SR-25990C crystalline form I is moderate in the salt-forming reaction, and product crystal formation purity is high, and impurity is few.Neither can make SR-25990C be difficult to separate out as acetone, the prolongation of crystallization time is so that the easier formation crystal form II of SR-25990C; Can not dissolve hardly SR-25990C as ethyl acetate yet, cause salify crystallization excessive velocities, easily wrap assorted clopidogrel free alkali in the crystal of formation, product purity is not high, poor stability.
The 2-methyltetrahydrofuran is the 4th kind solvent of environmental protection, and its LD50 is 5720mg/kg, and the LD50 of ethyl acetate is 5620mg/kg, and the LD50 of tetrahydrofuran (THF) is 1650mg/kg, and is so the toxicity of 2-methyltetrahydrofuran is little, little to operator ' s health harm.
The salt-forming reaction of SR-25990C crystalline form I can not consume solvent, and it is necessary to carry out solvent recuperation during industrialization is produced.With respect to 66 ℃ of the boiling points of tetrahydrofuran (THF), the moderate boiling point of 2-methyltetrahydrofuran is 80 ℃; The easier recovery of 2-methyltetrahydrofuran, the rate of recovery is high, and exhaust gas emission is few, and is more friendly to environment.
Based on above-mentioned discovery, the inventor has finished the present invention.
The present invention can be achieved through the following technical solutions:
A kind of preparation method of SR-25990C crystalline form I, described preparation method may further comprise the steps:
(1) the 2-methyltetrahydrofuran solution that drips the vitriol oil or the vitriol oil in the 2-methyltetrahydrofuran solution of clopidogrel free alkali obtains mixing solutions; The temperature of described mixing solutions is controlled at-10 ℃ ~ 5 ℃ during dropping;
(2) above-mentioned mixing solutions is warming up to 10 ℃ ~ 35 ℃, stirring and crystallizing, then with the crystal separation of separating out, drying obtains described SR-25990C crystalline form I.
In the step (1), the 2-methyltetrahydrofuran solution of described clopidogrel free alkali is to obtain by clopidogrel free alkali is dissolved in the 2-methyltetrahydrofuran.For example, at room temperature stir and clopidogrel free alkali can be dissolved in the 2-methyltetrahydrofuran.
Preferably, in the step (1), in the described mixing solutions, the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran is less than or equal to 15:100.If easily mix oily matter in the SR-25990C crystalline form I that the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran greater than 15:100, is then separated out.Further preferably, the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran is less than or equal to 12:100; 3 ~ 10:100 more preferably.When solvent load was excessive, SR-25990C was difficult to separate out, and caused yield on the low side, and caused solvent load large, and plant factor is low, and cost increases.
Preferably, in the step (1), the temperature of described mixing solutions is controlled at-5 ℃ ~ 0 ℃ during dropping; The massfraction of the described vitriol oil is 94% ~ 98%; In the described mixing solutions, the mol ratio of the described vitriol oil and described clopidogrel free alkali is 0.95 ~ 1.1:1.
More preferably, in the step (1), the massfraction of the described vitriol oil is 98%; In the described mixing solutions, the mol ratio of the described vitriol oil and described clopidogrel free alkali is 0.95 ~ 1.0:1.
Preferably, the time for adding of the 2-methyltetrahydrofuran solution of the described vitriol oil or the vitriol oil is 1 ~ 5 hour.
Preferably, after the 2-methyltetrahydrofuran solution that drips the vitriol oil or the vitriol oil in the 2-methyltetrahydrofuran solution of clopidogrel free alkali obtains mixing solutions (dropwising), selectively, with described mixing solutions insulation 0 ~ 1 hour.
Preferably, in the step (2), described recrystallization temperature is 15 ℃ ~ 25 ℃; The described crystallization time is 5 ~ 20 hours, is preferably 10 ~ 15 hours.
In the step (2), can isolate by means commonly known in the art the SR-25990C crystalline form I, for example filter.Consider that from the industrialization angle moisture in the filtration procedure in the SR-25990C crystalline form I absorbing air causes the part dissolution of crystals, filter cake surface thickness affect quality product, and preferably, the press filtration of described separation employing nitrogen is carried out.More preferably, with 2-methyltetrahydrofuran washing leaching cake, number of times is 1 ~ 2 time.
In the step (2), dry SR-25990C crystalline form I by means commonly known in the art, for example vacuum-drying is specifically as follows 20 ~ 50 ℃ of lower vacuum-dryings 5 ~ 24 hours.
Preferably, in the step (1), be added with the crystal seed of SR-25990C crystalline form I in the 2-methyltetrahydrofuran solution of described clopidogrel free alkali; And the consumption of the crystal seed of described SR-25990C crystalline form I is 1.0% ~ 2.5% of described clopidogrel free alkali weight.This step can improve crystallization velocity.It will be understood by those skilled in the art that not add crystal seed the effect that can obtain equally.
Preferably, method of the present invention further comprises: the SR-25990C crystalline form I that step (2) is obtained is pulled an oar in acetone in-15 ℃ ~-5 ℃, and beating time is 20 ~ 60 minutes; The weight ratio of the volume of described acetone and described SR-25990C crystalline form I is 5 ~ 10ml:1g; Then separate and drying.Separation after the making beating is with dry identical with drying operation with separating of step (2).This making beating step does not affect the product crystal formation, can further remove residual 2-methyltetrahydrofuran and sulfuric acid, makes the product package stability obtain further to improve.
More preferably, the preparation method of SR-25990C crystalline form I of the present invention is specially:
(1) mass percent according to described clopidogrel free alkali and described 2-methyltetrahydrofuran is that 3 ~ 10:100 is dissolved in clopidogrel free alkali in the 2-methyltetrahydrofuran solution in stirring at room, system temperature is down to-5 ℃ ~ 0 ℃; Then drip massfraction and be 98% the vitriol oil and obtain mixing solutions; The mol ratio of the described vitriol oil and described clopidogrel free alkali is 0.95 ~ 1.0:1;
(2) above-mentioned mixing solutions is warming up to 15 ℃ ~ 25 ℃, stirring and crystallizing 10 ~ 15 hours, then the crystal by adopting nitrogen press filtration of separating out is separated and with 2-methyltetrahydrofuran washing leaching cake 1 ~ 2 time, 20 ~ 50 ℃ of lower vacuum-drying 5 ~ 24 hours obtains the SR-25990C crystalline form I; This SR-25990C crystalline form I is pulled an oar in acetone in-15 ℃ ~-5 ℃, and beating time is 20 ~ 60 minutes; The weight ratio of the volume of described acetone and described SR-25990C crystalline form I is 5 ~ 10ml:1g; Then separate and drying, namely get described SR-25990C crystalline form I.
It will be understood by those skilled in the art that above-mentioned each step of the present invention, all fully carrying out under the agitation condition.
Compared with prior art, the preparation method of SR-25990C crystalline form I of the present invention has following advantage:
The SR-25990C crystalline form I of preparation method's preparation of the present invention, HPLC purity reaches more than 99.5%, and crystal formation purity is high, does not contain the crystal form II of trace, and product stability is good.Yield reaches more than 93%, has cost advantage.Simple for process, favorable reproducibility is fit to industrialization production.Adopting the 2-methyltetrahydrofuran of environmental protection low toxicity is solvent, the personnel health is endangered little, and solvent recovering rate is high, environmental friendliness.
Description of drawings
Fig. 1 is the X-ray powder diffraction (XRD) that the SR-25990C crystalline form I of embodiment 8 preparations is measured with detection method 1.
Fig. 2 is the X-ray powder diffraction (XRD) that the SR-25990C crystalline form I of embodiment 8 preparations is measured with detection method 2.
Fig. 3 is dsc (DSC) curve of the SR-25990C crystalline form I of embodiment 8 preparations.
Embodiment
To help further to understand the present invention by following embodiment, but be not used in restriction content of the present invention.
Starting material and reagent in the embodiment of the invention are the commercially available prod.
The correlation detection of product of the present invention is as follows:
Related substances (Related substances) detects
Detecting instrument: Agilent 1260 high performance liquid chromatographs
Detection method: the SR-25990C quality standard of 7.2 editions records of European Pharmacopoeia.
The X-ray powder diffraction collection of illustrative plates is measured:
Detecting instrument: Bruker D8Advance XRD
Detection method 1: use Cu-K α radiation, 3.0 °～40.0 ° of scanning angles, 0.02 ° of scanning step, 0.5 second/step of sweep velocity.
Detection method 2: use Cu-K α radiation, 11.0 °～14.0 ° of scanning angles, 0.02 ° of scanning step, 35 seconds/step of sweep velocity.
Dsc (DSC) is analyzed:
Detecting instrument: TA Q200DSC
Detection method: 10 ℃/min of heat-up rate is warming up to 200 ℃
In the 1000mL four-hole boiling flask, add the 32.1g(0.10 mole) clopidogrel free alkali, the 214g2-methyltetrahydrofuran, stirring and dissolving under the room temperature, system cools to-10 ℃, drip the 9.5g98% vitriol oil (0.095 mole), then system is warmed up to 10 ℃, insulated and stirred crystallization 20 hours, at normal temperatures vacuum-drying of nitrogen press filtration, filter cake 3 hours is warmed up to 45 ℃ of vacuum-dryings 10 hours again, obtain 39.3g SR-25990C crystalline form I, molar yield 93.8%, HPLC content 99.6%, all single assorted HPLC content are less than 0.1%.
Embodiment 2
In the 500mL four-hole boiling flask, add the 32.1g(0.10 mole) clopidogrel free alkali, the 270g2-methyltetrahydrofuran, stirring and dissolving, system temperature control-5 ℃, drip the 9.8g98% vitriol oil (0.098 mole), after dropwising system is warmed up to 20 ℃, insulated and stirred crystallization 12 hours, the nitrogen press filtration, filter cake washs with the 100mL2-methyltetrahydrofuran, the nitrogen press filtration, filter cake obtains 39.9g SR-25990C crystalline form I, molar yield 95.0% 40 ℃ of vacuum-dryings 10 hours, HPLC content 99.8%, all single assorted HPLC content are less than 0.1%.
In the 500mL four-hole boiling flask, add the 32.1g(0.10 mole) clopidogrel free alkali, 321g2-methyltetrahydrofuran, stirring and dissolving, 0 ℃ of system temperature control, drip the 9.8g98% vitriol oil (0.098 mole), after dropwising system is warmed up to 25 ℃, insulated and stirred crystallization 10 hours, the nitrogen press filtration, filter cake obtains 40.6g SR-25990C crystalline form I, molar yield 96.7% 40 ℃ of vacuum-dryings 10 hours, HPLC content 99.8%, all single assorted HPLC content are less than 0.1%.
In the 2000mL four-hole boiling flask, add 32.1g (0.10 mole) clopidogrel free alkali, the 1070g2-methyltetrahydrofuran, stirring and dissolving, 0 ℃ of system temperature control, add 0.64g SR-25990C crystal formation I crystal seed, then drip the 9.8g98% vitriol oil (0.098 mole), time for adding 1 hour is warmed up to 25 ℃ with system after dropwising, insulated and stirred crystallization 10 hours, the nitrogen press filtration, filter cake obtains 40.3g SR-25990C crystalline form I 40 ℃ of vacuum-dryings 10 hours, molar yield 94.7% behind the deduction crystal seed, HPLC purity 99.8%, all single assorted HPLC are less than 0.1%.In the 500mL four-hole boiling flask, add again 340mL acetone, be cooled to-10 ℃, add the above-mentioned 40.3g SR-25990C crystalline form I that makes, started stirring to pulp 30 minutes, nitrogen press filtration, filter cake obtain 39.2g SR-25990C crystalline form I 45 ℃ of vacuum-dryings 10 hours, HPLC content 99.8%, all single assorted HPLC content are less than 0.1%.
Embodiment 5
In the 1000mL four-hole boiling flask, add the 32.1g(0.10 mole) clopidogrel free alkali, the 430g2-methyltetrahydrofuran, stirring and dissolving, system cools to 5 ℃, add 0.32g SR-25990C crystal formation I crystal seed, then drip the 10g98% vitriol oil (0.10 mole), then system is warmed up to 15 ℃, insulated and stirred crystallization 15 hours, filter, filter cake is drained with the washing of 100mL2-methyltetrahydrofuran, filter cake dry 1 hour at normal-temperature vacuum, be warmed up to again 40 ℃ of vacuum-dryings 15 hours, obtain 39.9g SR-25990C crystalline form I, molar yield 94.3% behind the deduction crystal seed, HPLC content 99.7%, all single assorted HPLC content are less than 0.1%.
Embodiment 6
In the 500mL four-hole boiling flask, add the 32.1g(0.10 mole) clopidogrel free alkali, the 250g2-methyltetrahydrofuran, stirring and dissolving, system cools to-10 ℃, drip the 11g98% vitriol oil (0.11 mole), then system is warmed up to 35 ℃, insulated and stirred crystallization 5 hours filters, filter cake washs with the 100mL2-methyltetrahydrofuran, drain, at normal temperatures vacuum-drying of filter cake 3 hours is warmed up to 45 ℃ of vacuum-dryings 10 hours again, obtain 39.1g SR-25990C crystalline form I, molar yield 93.1%, HPLC content 99.6%, all single assorted HPLC content are less than 0.1%.
Embodiment 7
In the 500mL four-hole boiling flask, add the 32.1g(0.10 mole) clopidogrel free alkali, the 340g2-methyltetrahydrofuran, stirring and dissolving, system temperature control-5 ℃, add 0.8g SR-25990C crystal formation I crystal seed, then drip the 10g94% vitriol oil (0.096 mole), after dropwising system is warmed up to 20 ℃, insulated and stirred crystallization 12 hours, the nitrogen press filtration, filter cake is drained with the washing of 100mL2-methyltetrahydrofuran, and filter cake was 40 ℃ of vacuum-dryings 10 hours, obtain 40.6g SR-25990C crystalline form I, molar yield 95.0% behind the deduction crystal seed, HPLC content 99.8%, all single assorted HPLC content are less than 0.1%.
Embodiment 8
In the 500mL four-hole boiling flask, add the 32.1g(0.10 mole) clopidogrel free alkali, the 340g2-methyltetrahydrofuran, stirring and dissolving, system temperature control-5 ℃, drip the solution that the 10g98% vitriol oil (0.10 mole) is diluted in the 40g2-methyltetrahydrofuran, after dropwising system is warmed up to 20 ℃, insulated and stirred crystallization 12 hours, the nitrogen press filtration, filter cake washs with the 100mL2-methyltetrahydrofuran, the nitrogen press filtration, filter cake obtains 40.7g SR-25990C crystalline form I, molar yield 96.9% 40 ℃ of vacuum-dryings 10 hours, HPLC content 99.8%, all single assorted HPLC content are less than 0.1%.See Fig. 1 with the X-ray powder diffraction (XRD) that detection method 1 is measured.See Fig. 2 with the X-ray powder diffraction (XRD) that detection method 2 is measured.Dsc (DSC) curve is seen Fig. 3.
Embodiment 9
In the 500mL four-hole boiling flask, add the 32.1g(0.10 mole) clopidogrel free alkali, the 340g2-methyltetrahydrofuran, stirring and dissolving, system temperature control-5 ℃, add 0.5g SR-25990C crystal formation I crystal seed, then drip the solution that the 10g98% vitriol oil (0.10 mole) is diluted in the 40g2-methyltetrahydrofuran, after dropwising system is warmed up to 15 ℃, insulated and stirred crystallization 15 hours, the nitrogen press filtration, filter cake washs with the 100mL2-methyltetrahydrofuran, the nitrogen press filtration, filter cake obtains 41.2g SR-25990C crystalline form I 40 ℃ of vacuum-dryings 10 hours, molar yield 96.9% behind the deduction crystal seed.HPLC purity 99.8%, all single assorted HPLC are less than 0.1%.In the 500mL four-hole boiling flask, add again 300mL acetone, be cooled to-5 ℃, add the above-mentioned 40.7g SR-25990C crystalline form I that makes, started stirring to pulp 20 minutes, nitrogen press filtration, filter cake obtain 39.1g SR-25990C crystalline form I 45 ℃ of vacuum-dryings 10 hours, HPLC content 99.8%, all single assorted HPLC content are less than 0.1%.
Embodiment 10
In the 100L reactor, add the 3.21kg(10 mole) clopidogrel free alkali, 34kg2-methyltetrahydrofuran, stirring and dissolving, 0 ℃ of system temperature control, drip the 1kg98% vitriol oil (10 moles), after dropwising system is warmed up to 20 ℃, insulated and stirred crystallization 12 hours, the nitrogen press filtration, filter cake obtains 4.07kg SR-25990C crystalline form I, molar yield 96.9% 40 ℃ of vacuum-dryings 10 hours, HPLC content 99.7%, all single assorted HPLC content are less than 0.1%.
Embodiment 11
In the 100L reactor, add the 3.21kg(10 mole) clopidogrel free alkali, the 34kg2-methyltetrahydrofuran, stirring and dissolving, 0 ℃ of system temperature control, drip the 1kg98% vitriol oil (10 moles), time for adding 2 hours is warmed up to 20 ℃ with system after dropwising, insulated and stirred crystallization 12 hours, the nitrogen press filtration, filter cake washs with the 10L2-methyltetrahydrofuran, the nitrogen press filtration, and filter cake was 40 ℃ of vacuum-dryings 12 hours, obtain 4.04kg SR-25990C crystalline form I, molar yield 96.2%, HPLC purity 99.7%, all single assorted HPLC are less than 0.1%.In the 100L reactor, add again 40L acetone, be cooled to-15 ℃, add the above-mentioned 4.04kg SR-25990C crystalline form I that makes, started stirring to pulp 1 hour, the nitrogen press filtration, filter cake obtains 3.92kg SR-25990C crystalline form I 45 ℃ of lower vacuum-dryings 10 hours, HPLC content 99.8%, all single assorted HPLC content are less than 0.1%.
Embodiment 12
In the 500L reactor, add the 19.3kg(60 mole) clopidogrel free alkali, the 215kg2-methyltetrahydrofuran, stirring and dissolving, 0 ℃ of system temperature control, drip the 6.0kg98% vitriol oil (60 moles), time for adding 4 hours, after dropwising system is warmed up to 20 ℃, insulated and stirred crystallization 15 hours, the nitrogen press filtration, filter cake was 40 ℃ of vacuum-dryings 10 hours, obtain 24.3kg SR-25990C crystalline form I, molar yield 96.4%, HPLC content 99.8%, all single assorted HPLC content are less than 0.1%.
The sample for preparing among above-mentioned other embodiment has and embodiment 8 same or analogous X-ray powder diffraction and dsc curve (not shown).What illustrate that these embodiment prepare is the material identical with embodiment 8, is the SR-25990C crystalline form I.
Related substances (Related substances) detected result: the SR-25990C crystalline form I of all embodiment preparations of the present invention, HPLC content reaches more than 99.5%, and all single assorted HPLC content are less than 0.1%.
X-ray powder diffraction collection of illustrative plates detected result: detection method 1 result shows that the SR-25990C of all embodiment preparations of the present invention all has the obvious characteristic peak of crystalline form I, is the SR-25990C crystalline form I.Detection method 2 is further to carrying out fine scanning in ° scope of 2 θ=11 ~ 14, the situation that detects according to 11.5 °, 13.8 ° characteristic peaks of 12.8 ° of characteristic peaks of crystal form II, crystalline form I, can whether contain crystal form II in the judgement sample, thereby judge the crystal formation purity of crystal formation I.Detection method 2 results show that all embodiment samples all do not detect crystal form II, are crystalline form I, illustrate that the present invention has obtained highly purified SR-25990C crystalline form I.
Dsc (DSC) detected result: the sample of all embodiment preparations of the present invention has an endotherm(ic)peak, about 184 ℃ between 170 ℃ ~ 190 ℃.
It will be understood by those skilled in the art that under the instruction of this specification sheets, can make some modifications or variation to the present invention.These modifications and variations also should be within claim limited range of the present invention.
Claims (9)
1. the preparation method of a SR-25990C crystalline form I is characterized in that, described preparation method may further comprise the steps:
(1) the 2-methyltetrahydrofuran solution that drips the vitriol oil or the vitriol oil in the 2-methyltetrahydrofuran solution of clopidogrel free alkali obtains mixing solutions; The temperature of described mixing solutions is controlled at-10 ℃ ~ 5 ℃ during dropping;
(2) above-mentioned mixing solutions is warming up to 10 ℃ ~ 35 ℃, stirring and crystallizing, then with the crystal separation of separating out, drying obtains described SR-25990C crystalline form I.
2. the preparation method of SR-25990C crystalline form I according to claim 1 is characterized in that, in the step (1), in the described mixing solutions, the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran is less than or equal to 15:100; Preferably less than or equal to 12:100; 3 ~ 10:100 more preferably.
3. the preparation method of SR-25990C crystalline form I according to claim 1 and 2 is characterized in that, in the step (1), the temperature of described mixing solutions is controlled at-5 ℃ ~ 0 ℃ during dropping; The massfraction of the described vitriol oil is 94% ~ 98%; In the described mixing solutions, the mol ratio of the described vitriol oil and described clopidogrel free alkali is 0.95 ~ 1.1:1.
4. want the preparation method of 3 described SR-25990C crystalline form Is according to right, it is characterized in that, in the step (1), the massfraction of the described vitriol oil is 98%; In the described mixing solutions, the mol ratio of the described vitriol oil and described clopidogrel free alkali is 0.95 ~ 1.0:1.
5. the preparation method of each described SR-25990C crystalline form I is characterized in that according to claim 1 ~ 4, and in the step (2), described recrystallization temperature is 15 ℃ ~ 25 ℃; The described crystallization time is 5 ~ 20 hours, is preferably 10 ~ 15 hours.
6. the preparation method of SR-25990C crystalline form I according to claim 5 is characterized in that, described separation adopts the nitrogen press filtration to carry out.
7. the preparation method of SR-25990C crystalline form I according to claim 6 is characterized in that, in the step (1), is added with the crystal seed of SR-25990C crystalline form I in the 2-methyltetrahydrofuran solution of described clopidogrel free alkali; And the consumption of the crystal seed of described SR-25990C crystalline form I is 1.0% ~ 2.5% of described clopidogrel free alkali weight.
8. the preparation method of each described SR-25990C crystalline form I according to claim 1 ~ 7, it is characterized in that, further comprise: the SR-25990C crystalline form I that step (2) is obtained is pulled an oar in acetone in-15 ℃ ~-5 ℃, and beating time is 20 ~ 60 minutes; The weight ratio of the volume of described acetone and described SR-25990C crystalline form I is 5 ~ 10ml:1g; Then separate and drying.
9. the preparation method of a SR-25990C crystalline form I is characterized in that, described preparation method is:
(1) mass percent according to described clopidogrel free alkali and described 2-methyltetrahydrofuran is that 3 ~ 10:100 is dissolved in clopidogrel free alkali in the 2-methyltetrahydrofuran solution in stirring at room, system temperature is down to-5 ℃ ~ 0 ℃; Then drip massfraction and be 98% the vitriol oil and obtain mixing solutions; The mol ratio of the described vitriol oil and described clopidogrel free alkali is 0.95 ~ 1.0:1;
(2) above-mentioned mixing solutions is warming up to 15 ℃ ~ 25 ℃, stirring and crystallizing 10 ~ 15 hours, then the crystal by adopting nitrogen press filtration of separating out is separated and with 2-methyltetrahydrofuran washing leaching cake 1 ~ 2 time, 20 ~ 50 ℃ of lower vacuum-drying 5 ~ 24 hours obtains the SR-25990C crystalline form I; This SR-25990C crystalline form I is pulled an oar in acetone in-15 ℃ ~-5 ℃, and beating time is 20 ~ 60 minutes; The weight ratio of the volume of described acetone and described SR-25990C crystalline form I is 5 ~ 10ml:1g; Then separate and drying, namely get described SR-25990C crystalline form I.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408567A (en) * | 2013-07-18 | 2013-11-27 | 浙江普洛医药科技有限公司 | Method for preparing crystalline form I of clopidogrel bisulfate |
| CN103923100A (en) * | 2014-04-03 | 2014-07-16 | 浙江华海药业股份有限公司 | Method for refining clopidogrel hydrogen sulfate |
| CN104211714A (en) * | 2014-08-14 | 2014-12-17 | 广东东阳光药业有限公司 | Preparation method of platelet aggregation inhibitor |
| CN107337683A (en) * | 2017-08-16 | 2017-11-10 | 中荣凯特（北京）生物科技有限公司 | A kind of crystal formation II of thienopyridine analog derivative disulfate and its preparation method and application |
| CN107383056A (en) * | 2017-08-16 | 2017-11-24 | 中荣凯特（北京）生物科技有限公司 | A kind of crystal formation III of thienopyridine analog derivative disulfate and its preparation method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005100364A1 (en) * | 2004-04-19 | 2005-10-27 | Krka, Tovarna Zdravil, D.D. Novo Mesto | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form i |
| WO2008093357A2 (en) * | 2007-01-29 | 2008-08-07 | Ipca Laboratories Limited | Process for preparation of crystalline clopidogrel hydrogen sulphate form i |
| CN101805354A (en) * | 2010-04-16 | 2010-08-18 | 中山大学 | Preparation method of I type clopidogrel hydrogen sulfate |
-
2012
- 2012-11-08 CN CN201210444685.XA patent/CN102924474B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005100364A1 (en) * | 2004-04-19 | 2005-10-27 | Krka, Tovarna Zdravil, D.D. Novo Mesto | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form i |
| WO2008093357A2 (en) * | 2007-01-29 | 2008-08-07 | Ipca Laboratories Limited | Process for preparation of crystalline clopidogrel hydrogen sulphate form i |
| CN101805354A (en) * | 2010-04-16 | 2010-08-18 | 中山大学 | Preparation method of I type clopidogrel hydrogen sulfate |
Non-Patent Citations (1)
| Title |
|---|
| 潘仙华，等: "Ⅰ型氯吡格雷硫酸氢盐的合成及晶型转换", 《精细化工》, vol. 23, no. 12, 31 December 2006 (2006-12-31), pages 1221 - 1226 * |
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| CN103408567B (en) * | 2013-07-18 | 2016-12-28 | 浙江普洛医药科技有限公司 | A kind of method preparing crystalline form I of clopidogrel bisulfate |
| CN103923100A (en) * | 2014-04-03 | 2014-07-16 | 浙江华海药业股份有限公司 | Method for refining clopidogrel hydrogen sulfate |
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| CN107337683B (en) * | 2017-08-16 | 2019-08-16 | 中荣凯特（北京）生物科技有限公司 | A kind of crystal form II of thienopyridine analog derivative disulfate and its preparation method and application |
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