CN102924474B - 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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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 crystal form I of clopidogrel hydrogen sulfate.
Background technology
SR-25990C is a kind of platelet aggregation inhibitor of match Norfin, Inc of France exploitation, the circulation disorder of the heart, brain and other arteries that cause because of thrombocyte height state of aggregation for prevention and therapy clinically.Be applicable to the apoplexy of in the recent period outbreak, myocardial infarction and made a definite diagnosis the patient of peripheral arterial disease, the generation of atherosclerotic event can be reduced.Compared with other antiplatelet drugs, SR-25990C has the advantages such as curative effect is strong, security good, tolerance is good, for many years always rank the whole world best-selling drugs prostatitis.
The molecular structural formula of SR-25990C is as follows:
EP0281459A describes 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 thermodynamic stability crystal formation, but solubleness and bioavailability poorer than crystalline form I.
Preparation method about crystal form I of clopidogrel hydrogen sulfate has been reported.Adopt the technique of mixed solvent system, weak point is complicated operation, and solvent recuperation cost is high, is unfavorable for that industrialization is produced, and adopts the technique of single solvent also to there is different defects.
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 easily irreversibly changes crystal form II in the solvent acetone of its heat power instability.
WO03051362A1 discloses a kind of preparation method of crystalline form I: be suspended in by amorphous clopidogrel hydrogen sulfate in a kind of ether and keep 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 ethanol in embodiment, removal of solvent under reduced pressure, collects oily matter or foam and obtain.Use ether process 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 and controls, and ether and t-butyl methyl ether is volatile, inflammable noxious solvent.
WO2004020443 discloses clopidogrel free alkali and vitriol oil salify in a kind of solvent, and isolate crystal form I of clopidogrel hydrogen sulfate, solvent is selected from C
1-5alcohol or they and C
1-4the ester that carboxylic acid is formed, the purity of gained crystalline form I can only control 98%.WO2005100364 discloses and can prepare crystalline form I with ether, ethyl formate, ethyl acetate, methyl acetate, isopropyl ether, methylene dichloride as solvent, uses the product yield of ethyl formate or ethyl acetate or isopropyl ether to only have 50% ~ 64% in embodiment.Experiment finds, using ethyl acetate as solvent, easily form dope in salification process and adhere on agitator, under low temperature, dope is difficult to scatter, and stirs easily crystal conversion occurs again if long-time.Butylacetate is volatility noxious solvent, affects central nervous system.
CN1903859A uses expensive five-carbon ketone or six-carbon ketone as the solvent preparing crystalline form I.
WO2008093357A2 discloses industrialized scale and prepares 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, hydroxypropyl methyl cellosolve, butyl methyl cellosolve, ethyl cellosolve, butyl ethyl cellosolve.These solvents are of little use, and boiling point is high, and residual solvent not easily removes, and affect quality product.
CN101805354A discloses a kind of preparation method of crystal form I of clopidogrel hydrogen sulfate, comprising: be dissolved in by clopidogrel free alkali in tetrahydrofuran (THF), adds the vitriol oil at-14 DEG C ~ 0 DEG C; By mixture reaction after 1 ~ 2 hour, be warming up to 20 DEG C ~ 40 DEG C continue reactions crystal is fully separated out, after obtaining crystal, filter, with 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.Tetrahydrofuran (THF) boiling point is lower, and solvent recovering rate is low, and discharge amount of exhaust gas is large, and three-protection design cost is high, is not suitable for industrialization and produces.
Obviously, all there is different defect in the preparation method of known crystal form I of clopidogrel hydrogen sulfate, can not meet and obtain the requirements at the higher level that high purity stable crystal form, simple process are reliable, have cost advantage, be applicable to industrialization production, environmental protection.
Summary of the invention
The object of the invention is to: for the various deficiencies of existing crystal form I of clopidogrel hydrogen sulfate preparation method, provide a kind of new preparation method of applicable industrialization.The feature of the method is with the 2-methyltetrahydrofuran of environmental protection for solvent, and clopidogrel free alkali and vitriol oil salt-forming reaction, obtain highly purified crystal form I of clopidogrel hydrogen sulfate, product impurity is few, there is cost advantage, excellent storage stability, environmental friendliness.
The present inventor, through a large amount of solvent screenings, finds that 2-methyltetrahydrofuran is a kind of excellent organic solvent, is applicable to very much the preparation of crystal form I of clopidogrel hydrogen sulfate.2-methyltetrahydrofuran has good solubility to clopidogrel free alkali, moderate to the solubleness of SR-25990C, between acetone and ethyl acetate, in salt-forming reaction, the speed of separating out of crystal form I of clopidogrel hydrogen sulfate is moderate, and product crystal form purity is high, and impurity is few.Both SR-25990C can not have been made as acetone to be difficult to separate out, and the prolongation of crystallization time makes SR-25990C more easily form crystal form II; Can not dissolve hardly SR-25990C as ethyl acetate, cause salify crystallization excessive velocities, easily wrap assorted clopidogrel free alkali in the crystal of formation, product purity is not high, poor stability yet.
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, so the toxicity of 2-methyltetrahydrofuran is little, little to operator ' s health harm.
The salt-forming reaction of crystal form I of clopidogrel hydrogen sulfate can not consume solvent, and solvent recuperation is carried out in industrialization in producing necessary.Relative to the boiling point 66 DEG C of tetrahydrofuran (THF), the moderate boiling point of 2-methyltetrahydrofuran is 80 DEG C; 2-methyltetrahydrofuran more easily reclaims, and the rate of recovery is high, and exhaust gas emission is few, more friendly to environment.
Based on above-mentioned discovery, the present inventor completes the present invention.
The present invention can be achieved through the following technical solutions:
A preparation method for crystal form I of clopidogrel hydrogen sulfate, described preparation method comprises the following steps:
(1) the 2-methyltetrahydrofuran solution dripping the vitriol oil or the vitriol oil in the 2-methyltetrahydrofuran solution of clopidogrel free alkali obtains mixing solutions; During dropping, the temperature of described mixing solutions controls at-10 DEG C ~ 5 DEG C;
(2) above-mentioned mixing solutions is warming up to 10 DEG C ~ 35 DEG C, stirring and crystallizing, the crystal separation then will separated out, dry, obtain described crystal form I of clopidogrel hydrogen sulfate.
In step (1), the 2-methyltetrahydrofuran solution of described clopidogrel free alkali obtains by being dissolved in 2-methyltetrahydrofuran by clopidogrel free alkali.Such as, at room temperature stir and clopidogrel free alkali can be dissolved in 2-methyltetrahydrofuran.
Preferably, in step (1), in described mixing solutions, the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran is less than or equal to 15:100.If the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran is greater than 15:100, then easily mix oily matter in the crystal form I of clopidogrel hydrogen sulfate separated out.Further preferably, the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran is less than or equal to 12:100; Be more preferably 3 ~ 10:100.When solvent load is excessive, SR-25990C is difficult to separate out, and causes yield on the low side, and causes solvent load large, and plant factor is low, and cost increases.
Preferably, in step (1), during dropping, the temperature of described mixing solutions controls at-5 DEG C ~ 0 DEG C; The massfraction of the described vitriol oil is 94% ~ 98%; In 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 step (1), the massfraction of the described vitriol oil is 98%; In 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 dripping the vitriol oil or the vitriol oil in the 2-methyltetrahydrofuran solution of clopidogrel free alkali obtains mixing solutions (dropwising), selectively, by described mixing solutions insulation 0 ~ 1 hour.
Preferably, in step (2), described recrystallization temperature is 15 DEG C ~ 25 DEG C; The described crystallization time is 5 ~ 20 hours, is preferably 10 ~ 15 hours.
In step (2), crystal form I of clopidogrel hydrogen sulfate can be isolated by means commonly known in the art, such as, filter.Consider from industrialization angle, in filtration procedure, crystal form I of clopidogrel hydrogen sulfate absorbs the moisture in air, causes partial crystals to dissolve, and filter cake surface thickness, affects quality product, and preferably, described separation adopts nitrogen press filtration to carry out.More preferably, with 2-methyltetrahydrofuran washing leaching cake, number of times is 1 ~ 2 time.
In step (2), can dry crystal form I of clopidogrel hydrogen sulfate, such as vacuum-drying by means commonly known in the art, vacuum-drying 5 ~ 24 hours at being specifically as follows 20 ~ 50 DEG C.
Preferably, in step (1), in the 2-methyltetrahydrofuran solution of described clopidogrel free alkali, be added with the crystal seed of crystal form I of clopidogrel hydrogen sulfate; And the consumption of the crystal seed of described crystal form I of clopidogrel hydrogen sulfate 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 and do not add crystal seed, the effect that can obtain equally.
Preferably, method of the present invention comprises further: the crystal form I of clopidogrel hydrogen sulfate that step (2) obtains pulled an oar in acetone in-15 DEG C ~-5 DEG C, and beating time is 20 ~ 60 minutes; The volume of described acetone and the weight ratio of described crystal form I of clopidogrel hydrogen sulfate are 5 ~ 10ml:1g; Then carry out being separated and drying.Separation after making beating is identical with drying operation with being separated of step (2) with drying.This mashing step does not affect product crystal formation, can remove residual 2-methyltetrahydrofuran and sulfuric acid further, product package stability is obtained and improves further.
More preferably, the preparation method of crystal form I of clopidogrel hydrogen sulfate of the present invention is specially:
(1) be that clopidogrel free alkali is dissolved in 2-methyltetrahydrofuran solution in stirring at room temperature by 3 ~ 10:100 according to the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran, system temperature be down to-5 DEG C ~ 0 DEG C; Then drip massfraction be 98% the vitriol oil 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 DEG C ~ 25 DEG C, stirring and crystallizing 10 ~ 15 hours, then adopt nitrogen press filtration carry out being separated and use 2-methyltetrahydrofuran washing leaching cake 1 ~ 2 time in the crystal of precipitation, at 20 ~ 50 DEG C, vacuum-drying 5 ~ 24 hours, obtains crystal form I of clopidogrel hydrogen sulfate; This crystal form I of clopidogrel hydrogen sulfate pulled an oar in acetone in-15 DEG C ~-5 DEG C, beating time is 20 ~ 60 minutes; The volume of described acetone and the weight ratio of described crystal form I of clopidogrel hydrogen sulfate are 5 ~ 10ml:1g; Then be separated and drying, obtain described crystal form I of clopidogrel hydrogen sulfate.
It will be understood by those skilled in the art that the present invention's each step above-mentioned, all carry out under abundant agitation condition.
Compared with prior art, preparation method's tool of crystal form I of clopidogrel hydrogen sulfate of the present invention has the following advantages:
Crystal form I of clopidogrel hydrogen sulfate prepared by preparation method of the present invention, HPLC purity reaches more than 99.5%, and crystal form purity is high, and not containing the crystal form II of trace, product stability is good.Yield reaches more than 93%, has cost advantage.Simple for process, favorable reproducibility, is applicable to industrialization and produces.The 2-methyltetrahydrofuran adopting environmental protection low toxicity is solvent, and endanger little to personnel health, solvent recovering rate is high, environmental friendliness.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction (XRD) of crystal form I of clopidogrel hydrogen sulfate detection method 1 mensuration prepared by embodiment 8.
Fig. 2 is the X-ray powder diffraction (XRD) of crystal form I of clopidogrel hydrogen sulfate detection method 2 mensuration prepared by embodiment 8.
Fig. 3 is dsc (DSC) curve of crystal form I of clopidogrel hydrogen sulfate prepared by embodiment 8.
Embodiment
To contribute to understanding the present invention further by following embodiment, but be not used in restriction content of the present invention.
Starting material in the embodiment of the present invention and reagent are 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 chromatograph
Detection method: the SR-25990C quality standard that European Pharmacopoeia 7.2 editions is recorded.
x-ray powder diffraction pattern measures:
Detecting instrument: Bruker D8Advance XRD
Detection method 1: use Cu-K α radiation, scanning angle 3.0 ° ~ 40.0 °, scanning step 0.02 °, sweep velocity 0.5 second/step.
Detection method 2: use Cu-K α radiation, scanning angle 11.0 ° ~ 14.0 °, scanning step 0.02 °, sweep velocity 35 seconds/step.
dsc (DSC) is analyzed:
Detecting instrument: TA Q200DSC
Detection method: heat-up rate 10 DEG C/min, is warming up to 200 DEG C
Embodiment 1
32.1g(0.10 mole is added in 1000mL four-hole boiling flask) clopidogrel free alkali, 214g2-methyltetrahydrofuran, stirred at ambient temperature dissolves, system cools to-10 DEG C, drip the 9.5g98% vitriol oil (0.095 mole), then system is warmed up to 10 DEG C, insulated and stirred crystallization 20 hours, nitrogen press filtration, filter cake vacuum-drying at normal temperatures 3 hours, then be warmed up to 45 DEG C of vacuum-dryings 10 hours, obtain 39.3g crystal form I of clopidogrel hydrogen sulfate, molar yield 93.8%, HPLC content 99.6%, all lists HPLC content of mixing is less than 0.1%.
Embodiment 2
32.1g(0.10 mole is added in 500mL four-hole boiling flask) clopidogrel free alkali, 270g2-methyltetrahydrofuran, stirring and dissolving, system temperature control-5 DEG C, drip the 9.8g98% vitriol oil (0.098 mole), after dropwising, system is warmed up to 20 DEG C, insulated and stirred crystallization 12 hours, nitrogen press filtration, filter cake 100mL2-methyltetrahydrofuran washs, nitrogen press filtration, filter cake, 40 DEG C of vacuum-dryings 10 hours, obtains 39.9g crystal form I of clopidogrel hydrogen sulfate, molar yield 95.0%, HPLC content 99.8%, all lists HPLC content of mixing is less than 0.1%.
Embodiment 3
32.1g(0.10 mole is added in 500mL four-hole boiling flask) clopidogrel free alkali, 321g2-methyltetrahydrofuran, stirring and dissolving, system temperature control 0 DEG C, drip the 9.8g98% vitriol oil (0.098 mole), after dropwising, system is warmed up to 25 DEG C, insulated and stirred crystallization 10 hours, nitrogen press filtration, filter cake, 40 DEG C of vacuum-dryings 10 hours, obtains 40.6g crystal form I of clopidogrel hydrogen sulfate, molar yield 96.7%, HPLC content 99.8%, all lists HPLC content of mixing is less than 0.1%.
Embodiment 4
32.1g (0.10 mole) clopidogrel free alkali is added in 2000mL four-hole boiling flask, 1070g2-methyltetrahydrofuran, stirring and dissolving, system temperature control 0 DEG C, add 0.64g SR-25990C crystal formation I crystal seed, then the 9.8g98% vitriol oil (0.098 mole) is dripped, time for adding 1 hour, after dropwising, system is warmed up to 25 DEG C, insulated and stirred crystallization 10 hours, nitrogen press filtration, filter cake was 40 DEG C of vacuum-dryings 10 hours, obtain 40.3g crystal form I of clopidogrel hydrogen sulfate, molar yield 94.7% after deduction crystal seed, HPLC purity 99.8%, all lists HPLC that mixes is less than 0.1%.340mL acetone is added again in 500mL four-hole boiling flask, be cooled to-10 DEG C, add above-mentioned obtained 40.3g crystal form I of clopidogrel hydrogen sulfate, start stirring to pulp 30 minutes, nitrogen press filtration, filter cake, 45 DEG C of vacuum-dryings 10 hours, obtains 39.2g crystal form I of clopidogrel hydrogen sulfate, HPLC content 99.8%, all lists HPLC content of mixing is less than 0.1%.
Embodiment 5
32.1g(0.10 mole is added in 1000mL four-hole boiling flask) clopidogrel free alkali, 430g2-methyltetrahydrofuran, stirring and dissolving, system cools to 5 DEG C, add 0.32g SR-25990C crystal formation I crystal seed, then the 10g98% vitriol oil (0.10 mole) is dripped, then system is warmed up to 15 DEG C, insulated and stirred crystallization 15 hours, filter, filter cake 100mL2-methyltetrahydrofuran washs, drain, filter cake was normal-temperature vacuum drying 1 hour, be warmed up to 40 DEG C of vacuum-dryings 15 hours again, obtain 39.9g crystal form I of clopidogrel hydrogen sulfate, molar yield 94.3% after deduction crystal seed, HPLC content 99.7%, all lists HPLC content of mixing is less than 0.1%.
Embodiment 6
32.1g(0.10 mole is added in 500mL four-hole boiling flask) clopidogrel free alkali, 250g2-methyltetrahydrofuran, stirring and dissolving, system cools to-10 DEG C, drip the 11g98% vitriol oil (0.11 mole), then system is warmed up to 35 DEG C, insulated and stirred crystallization 5 hours, filter, filter cake 100mL2-methyltetrahydrofuran washs, drain, filter cake vacuum-drying at normal temperatures 3 hours, be warmed up to 45 DEG C of vacuum-dryings 10 hours again, obtain 39.1g crystal form I of clopidogrel hydrogen sulfate, molar yield 93.1%, HPLC content 99.6%, all lists HPLC content of mixing is less than 0.1%.
Embodiment 7
32.1g(0.10 mole is added in 500mL four-hole boiling flask) clopidogrel free alkali, 340g2-methyltetrahydrofuran, stirring and dissolving, system temperature control-5 DEG C, add 0.8g SR-25990C crystal formation I crystal seed, then the 10g94% vitriol oil (0.096 mole) is dripped, after dropwising, system is warmed up to 20 DEG C, insulated and stirred crystallization 12 hours, nitrogen press filtration, filter cake 100mL2-methyltetrahydrofuran washs, drain, filter cake was 40 DEG C of vacuum-dryings 10 hours, obtain 40.6g crystal form I of clopidogrel hydrogen sulfate, molar yield 95.0% after deduction crystal seed, HPLC content 99.8%, all lists HPLC content of mixing is less than 0.1%.
Embodiment 8
32.1g(0.10 mole is added in 500mL four-hole boiling flask) clopidogrel free alkali, 340g2-methyltetrahydrofuran, stirring and dissolving, system temperature control-5 DEG C, drip the solution that the 10g98% vitriol oil (0.10 mole) is diluted in 40g2-methyltetrahydrofuran, after dropwising, system is warmed up to 20 DEG C, insulated and stirred crystallization 12 hours, nitrogen press filtration, filter cake 100mL2-methyltetrahydrofuran washs, nitrogen press filtration, filter cake was 40 DEG C of vacuum-dryings 10 hours, obtain 40.7g crystal form I of clopidogrel hydrogen sulfate, molar yield 96.9%, HPLC content 99.8%, all lists HPLC content of mixing is less than 0.1%.Fig. 1 is seen by the X-ray powder diffraction (XRD) that detection method 1 measures.Fig. 2 is seen by the X-ray powder diffraction (XRD) that detection method 2 measures.Dsc (DSC) curve is shown in Fig. 3.
Embodiment 9
32.1g(0.10 mole is added in 500mL four-hole boiling flask) clopidogrel free alkali, 340g2-methyltetrahydrofuran, stirring and dissolving, system temperature control-5 DEG C, add 0.5g SR-25990C crystal formation I crystal seed, then the solution that the 10g98% vitriol oil (0.10 mole) is diluted in 40g2-methyltetrahydrofuran is dripped, after dropwising, system is warmed up to 15 DEG C, insulated and stirred crystallization 15 hours, nitrogen press filtration, filter cake 100mL2-methyltetrahydrofuran washs, nitrogen press filtration, filter cake was 40 DEG C of vacuum-dryings 10 hours, obtain 41.2g crystal form I of clopidogrel hydrogen sulfate, molar yield 96.9% after deduction crystal seed.HPLC purity 99.8%, all lists HPLC that mixes is less than 0.1%.300mL acetone is added again in 500mL four-hole boiling flask, be cooled to-5 DEG C, add above-mentioned obtained 40.7g crystal form I of clopidogrel hydrogen sulfate, start stirring to pulp 20 minutes, nitrogen press filtration, filter cake, 45 DEG C of vacuum-dryings 10 hours, obtains 39.1g crystal form I of clopidogrel hydrogen sulfate, HPLC content 99.8%, all lists HPLC content of mixing is less than 0.1%.
Embodiment 10
3.21kg(10 mole is added in 100L reactor) clopidogrel free alkali, 34kg2-methyltetrahydrofuran, stirring and dissolving, system temperature control 0 DEG C, drip the 1kg98% vitriol oil (10 moles), after dropwising, system is warmed up to 20 DEG C, insulated and stirred crystallization 12 hours, nitrogen press filtration, filter cake, 40 DEG C of vacuum-dryings 10 hours, obtains 4.07kg crystal form I of clopidogrel hydrogen sulfate, molar yield 96.9%, HPLC content 99.7%, all lists HPLC content of mixing is less than 0.1%.
Embodiment 11
3.21kg(10 mole is added in 100L reactor) clopidogrel free alkali, 34kg2-methyltetrahydrofuran, stirring and dissolving, system temperature control 0 DEG C, drip the 1kg98% vitriol oil (10 moles), time for adding 2 hours, is warmed up to 20 DEG C by system after dropwising, insulated and stirred crystallization 12 hours, nitrogen press filtration, filter cake 10L2-methyltetrahydrofuran washing, nitrogen press filtration, filter cake was 40 DEG C of vacuum-dryings 12 hours, obtain 4.04kg crystal form I of clopidogrel hydrogen sulfate, molar yield 96.2%, HPLC purity 99.7%, all lists HPLC that mixes is less than 0.1%.40L acetone is added again in 100L reactor, be cooled to-15 DEG C, add above-mentioned obtained 4.04kg crystal form I of clopidogrel hydrogen sulfate, start stirring to pulp 1 hour, nitrogen press filtration, filter cake vacuum-drying 10 hours at 45 DEG C, obtains 3.92kg crystal form I of clopidogrel hydrogen sulfate, HPLC content 99.8%, all lists HPLC content of mixing is less than 0.1%.
Embodiment 12
19.3kg(60 mole is added in 500L reactor) clopidogrel free alkali, 215kg2-methyltetrahydrofuran, stirring and dissolving, system temperature control 0 DEG C, drip the 6.0kg98% vitriol oil (60 moles), time for adding 4 hours, after dropwising, system is warmed up to 20 DEG C, insulated and stirred crystallization 15 hours, nitrogen press filtration, filter cake was 40 DEG C of vacuum-dryings 10 hours, obtain 24.3kg crystal form I of clopidogrel hydrogen sulfate, molar yield 96.4%, HPLC content 99.8%, all lists HPLC content of mixing is less than 0.1%.
The sample prepared in other embodiment above-mentioned has same or analogous X-ray powder diffraction and dsc curve (not shown) with embodiment 8.What illustrate that these embodiments prepare is the material identical with embodiment 8, is crystal form I of clopidogrel hydrogen sulfate.
Related substances (Related substances) detected result: crystal form I of clopidogrel hydrogen sulfate prepared by all embodiments of the present invention, HPLC content reaches more than 99.5%, and all lists HPLC content of mixing is less than 0.1%.
X-ray powder diffraction pattern detected result: detection method 1 result shows, and SR-25990C prepared by all embodiments of the present invention all has the obvious characteristic peak of crystalline form I, is crystal form I of clopidogrel hydrogen sulfate.Detection method 2 carries out fine scanning within the scope of 2 θ=11 ~ 14 ° further, according to 12.8 ° of characteristic peaks of crystal form II, 11.5 °, 13.8 ° characteristic peaks of crystalline form I detect situation, whether can contain crystal form II in judgement sample, thus judge the crystal form purity of crystal formation I.Detection method 2 result shows, and all embodiment samples all do not detect crystal form II, are crystalline form I, illustrate and present invention obtains highly purified crystal form I of clopidogrel hydrogen sulfate.
Dsc (DSC) detected result: sample prepared by all embodiments of the present invention has an endotherm(ic)peak between 170 DEG C ~ 190 DEG C, about 184 DEG C.
It will be understood by those skilled in the art that under the instruction of this specification sheets, some amendments or change can be made to the present invention.These modifications and variations also should within the scope of the claims in the present invention.
Claims (12)
1. a preparation method for crystal form I of clopidogrel hydrogen sulfate, is characterized in that, described preparation method comprises the following steps:
(1) the 2-methyltetrahydrofuran solution dripping the vitriol oil or the vitriol oil in the 2-methyltetrahydrofuran solution of clopidogrel free alkali obtains mixing solutions; During dropping, the temperature of described mixing solutions controls at-10 DEG C ~ 5 DEG C;
(2) above-mentioned mixing solutions is warming up to 10 DEG C ~ 35 DEG C, stirring and crystallizing, the crystal separation then will separated out, dry, obtain described crystal form I of clopidogrel hydrogen sulfate.
2. the preparation method of crystal form I of clopidogrel hydrogen sulfate according to claim 1, it is characterized in that, in step (1), in described mixing solutions, the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran is less than or equal to 15:100.
3. the preparation method of crystal form I of clopidogrel hydrogen sulfate according to claim 2, is characterized in that, the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran is less than or equal to 12:100.
4. the preparation method of crystal form I of clopidogrel hydrogen sulfate according to claim 3, is characterized in that, the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran is less than or equal to 3 ~ 10:100.
5. the preparation method of the crystal form I of clopidogrel hydrogen sulfate according to any one of Claims 1 to 4, is characterized in that, in step (1), during dropping, the temperature of described mixing solutions controls at-5 DEG C ~ 0 DEG C; The massfraction of the described vitriol oil is 94% ~ 98%; In described mixing solutions, the mol ratio of the described vitriol oil and described clopidogrel free alkali is 0.95 ~ 1.1:1.
6. want the preparation method of the crystal form I of clopidogrel hydrogen sulfate described in 5 according to right, it is characterized in that, in step (1), the massfraction of the described vitriol oil is 98%; In described mixing solutions, the mol ratio of the described vitriol oil and described clopidogrel free alkali is 0.95 ~ 1.0:1.
7. the preparation method of the crystal form I of clopidogrel hydrogen sulfate according to any one of Claims 1 to 4, is characterized in that, in step (2), described recrystallization temperature is 15 DEG C ~ 25 DEG C; The described crystallization time is 5 ~ 20 hours.
8. the preparation method of crystal form I of clopidogrel hydrogen sulfate according to claim 7, is characterized in that, the described crystallization time is 10 ~ 15 hours.
9. the preparation method of crystal form I of clopidogrel hydrogen sulfate according to claim 7, is characterized in that, described separation adopts nitrogen press filtration to carry out.
10. the preparation method of crystal form I of clopidogrel hydrogen sulfate according to claim 9, it is characterized in that, in step (1), in the 2-methyltetrahydrofuran solution of described clopidogrel free alkali, be added with the crystal seed of crystal form I of clopidogrel hydrogen sulfate; And the consumption of the crystal seed of described crystal form I of clopidogrel hydrogen sulfate is 1.0% ~ 2.5% of described clopidogrel free alkali weight.
The preparation method of 11. crystal form I of clopidogrel hydrogen sulfate according to any one of Claims 1 to 4, it is characterized in that, comprise further: the crystal form I of clopidogrel hydrogen sulfate that step (2) obtains pulled an oar in acetone in-15 DEG C ~-5 DEG C, beating time is 20 ~ 60 minutes; The volume of described acetone and the weight ratio of described crystal form I of clopidogrel hydrogen sulfate are 5 ~ 10ml:1g; Then carry out being separated and drying.
The preparation method of 12. 1 kinds of crystal form I of clopidogrel hydrogen sulfate, is characterized in that, described preparation method is:
(1) be that clopidogrel free alkali is dissolved in 2-methyltetrahydrofuran solution in stirring at room temperature by 3 ~ 10:100 according to the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran, system temperature be down to-5 DEG C ~ 0 DEG C; Then drip massfraction be 98% the vitriol oil 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 DEG C ~ 25 DEG C, stirring and crystallizing 10 ~ 15 hours, then nitrogen press filtration is adopted to carry out being separated and use 2-methyltetrahydrofuran washing leaching cake 1 ~ 2 time in the crystal of precipitation, at 20 ~ 50 DEG C, vacuum-drying 5 ~ 24 hours, obtains crystal form I of clopidogrel hydrogen sulfate; This crystal form I of clopidogrel hydrogen sulfate pulled an oar in acetone in-15 DEG C ~-5 DEG C, beating time is 20 ~ 60 minutes; The volume of described acetone and the weight ratio of described crystal form I of clopidogrel hydrogen sulfate are 5 ~ 10ml:1g; Then be separated and drying, obtain described crystal form I of clopidogrel hydrogen sulfate.
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| CN103923100B (en) * | 2014-04-03 | 2019-05-14 | 浙江华海药业股份有限公司 | A kind of refining methd of bisulfate clopidogrel |
| CN104211714B (en) * | 2014-08-14 | 2016-09-14 | 广东东阳光药业有限公司 | A kind of preparation method of anticoagulant |
| 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 |
| 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 |
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
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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》.2006,第23卷(第12期),第1221-1226页. * |
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