CN101045731A - S-type clopidogrel and preparation method of its salt - Google Patents
S-type clopidogrel and preparation method of its salt Download PDFInfo
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- CN101045731A CN101045731A CN 200610062880 CN200610062880A CN101045731A CN 101045731 A CN101045731 A CN 101045731A CN 200610062880 CN200610062880 CN 200610062880 CN 200610062880 A CN200610062880 A CN 200610062880A CN 101045731 A CN101045731 A CN 101045731A
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Abstract
This invention relates to a preparation method of S - type clopidogrel and its medicinal salt. It includes four steps :( 1) Split racemic Alpha - (2 - thiofuran ethylamino) - Alpha - (2 - chlorphenyl) methyl acetate (II) or its salt to obtain (+) - II and (-) - II or its salt. (2) Racemize (-)- II or its salt to obtain racemic substance II. (3) Repeat first and second step. (4) Adopt (+) - II obtained from first step to prepare S - type clopidogrel and its corresponding salt. This invention use concentrated sulfuric acid to substitute chlorine sulfoxide, reduce toxicant side effect and erosion of equipment.
Description
Technical field:
The present invention relates to a kind of preparation method of compound, especially prepare the method for S-type clopidogrel and pharmacologically acceptable salt thereof.
Background technology:
Clopidogrel [S (+)-2-(2-chloro-phenyl-)-2-(4,5,6,7-tetramethylene sulfide [3,2-c] and pyridine-5) methyl acetate] (hereinafter to be referred as material I or I), structural formula is as follows:
Clopidogrel is a kind of anticoagulant, optionally suppresses adenosine diphosphate (ADP) (ADP) and its combining and the activation of the glycoprotein GPIIb/IIIa mixture of the ADP of secondary mediation of acceptor, but therefore anticoagulant.Clopidogrel is developed jointly by Japanese first pharmacy and French celo phenanthrene (Sanofi) company the earliest, goes on the market in the U.S. in 1998.
European patent EP 281459 has specifically described the preparation of SR-25990C dextrorotatory isomer, and it has excellent platelet aggregation inhibitory activity, and the activity of levoisomer is lower, and tolerance is poor.The preparation method at first is dissolved in clopidogrel acetone and L-10-camphorsulfonic acid, the salifiable crystallization of shape.Recrystallization in acetone again obtains the product of optically uniform, with saturated NaHCO
3Discharge the dextrorotatory isomer of this salt.Again with it with ice-cooled acetone solution, add the vitriol oil up to forming precipitation.Precipitation is separated after filtration, washs, and obtains the white crystal of SR-25990C.Its specific rotation is+55.1 ° of (c=1.891/CH
3OH).
Patent WO04/013147 has reported the clopidogrel that splits racemization with (-)-camphorsulfonic acid, and the racemization of R-type clopidogrel isomer.But this piece patent is not mentioned α-(the 2 thiophene ethyl amine base)-α-fractionation of (2-chloro-phenyl-) methyl acetate (hereinafter to be referred as material II or II) or the utilization again of its isomer yet.The crystallization of clopidogrel bisulfate polycrystalline state makes by the optical activity form neutralization reaction of clopidogrel.
Patent US5204469 has reported the method for preparing α-(2 thiophene ethyl amine base)-α-(2-chloro-phenyl-) methyl acetate with alpha-amino group (2-chloro-phenyl-) methyl acetate (III) and 2-(2-thienyl) alcohol derivative (IV).Patent adopts (+)-tartrate to split, the tartrate that obtains need be in Virahol four recrystallizations, could finally obtain dextral II-tartrate.But this piece patent does not provide any method that isomer mixture in the mother liquor or any their derivative is transformed into material II.
Patent WO2004/108665 has reported the material II that a kind of method is transformed into racemization with isomer or the derivative of material II, again the dextrorotatory isomer of cycles prepare material II again.At first, add the yellow soda ash neutralization, regulate pH hydrochloride water and the methylene dichloride dissolving successively of material II.With the organic phase concentrating under reduced pressure, product is dissolved in the Virahol, adds the crystallization that L-(+)-tartrate obtains (S) II-tartrate.With reacted mother solution concentrating under reduced pressure, resistates with dissolve with methanol after, handle continuously with sodium methylate at 65-70 ℃.Then in 5-10 ℃ of methanol solution, use the salt acid treatment, N, the catalysis of N-methyl-sulphoxide adds sulfur oxychloride in the time of 5-15 ℃, be warming up to 30-35 ℃ then, continues to stir, and obtains the crystal of the hydrochloride of racemization material II after the concentrated hydrochloric acid acidifying.Simultaneously, (S)-II separates from tartrate with the form of hydrochloride.It is concentrated to circle round in 55 ℃ of formaldehyde, obtains the crystal of clopidogrel.Clopidogrel is obtained the bisulfate of clopidogrel with vitriolization in acetone soln.
This piece patent proposed a kind of can be with the isomer of reaction intermediate material II or derivative cyclic utilization method again, but also there are some defectives in this method: 1, need the numerous and diverse heating and cooling process of experience, required time is long, total overall reaction needed finish in 30-36 hour, energy consumption is big, the cost height.2, in the racemization process, the resistates of mother liquor and the methanol solution of sodium methylate are wanted 2-3 hour 65-70 ℃ of reaction, severe reaction conditions, and the many colors of the impurity in products of gained are dark, influence the quality of the finished product clopidogrel.3, easily produce a large amount of hydrochloric acid and sulfur dioxide gas in the process of using sulfur oxychloride esterification racemization, corrosion reacting kettle is poisoned bigger.
Summary of the invention:
The object of the present invention is to provide a kind of route simple, save cost, save time, cut down the consumption of energy, improve product purity, reduce the method for preparing S-type clopidogrel and pharmacologically acceptable salt thereof of toxic side effect.
The objective of the invention is to adopt following technical scheme to realize:
The method for preparing S-type clopidogrel provided by the invention comprises the steps:
1) racemic α-(2 thiophene ethyl amine base)-α-(2-chloro-phenyl-) methyl acetate (II) hydrochloride is dissolved in the water, add methylene dichloride, stir and use sodium bicarbonate down or/and saleratus is regulated pH7-8, separatory, merge organic phase, wash with water, evaporated under reduced pressure after organic phase usefulness anhydrous sodium sulphate after the washing and/or the anhydrous potassium sulfate drying gets oily matter;
2) oily matter with the step 1) gained dissolves with Virahol, add L-tartrate, stirring is warming up to 45-55 ℃, be incubated half an hour, add crystal seed when being cooled to 30-40 ℃ naturally, spend the night in stirring at normal temperature, be cooled to 15-20 ℃ and stirred 4 hours, dry (+) II-L-tartrate that gets of solid filtering and washing;
3) with step 2) mother liquor evaporated under reduced pressure after the fractionation of gained gets resistates, and resistates is handled according to step 1), and the product after the processing dissolves with anhydrous methanol, and ice bath drips sodium methoxide solution down, and being warming up to stirring at normal temperature naturally spends the night;
4) with the mixing solutions of step 3) gained, ice bath drips the vitriol oil, back flow reaction 6 hours, reacting liquor while hot is poured in the frozen water, adds methylene dichloride, according to step 1) handle product, this product acetic acid ethyl dissolution, ice bath drip concentrated hydrochloric acid salify, solid suction filtration down, wash after drying with cold ethyl acetate, get (±) II-hydrochloride;
5) repeating step 1) to step 4);
6) with step 2) (+) II-L-tartrate after the fractionation of gained dissolves with Virahol, and cooling is separated out, filtering and washing, dry purified (+) II-L-tartrate;
7) (+) II-L--tartrate with the step 6) gained further makes S-type clopidogrel.
In the production process of reality, adopt usual manner that (+) II-L--tartrate is made S-type clopidogrel, for example: (+) II-L--tartrate is added entry and methylene dichloride successively, stir down and transfer pH to 7-8, water layer washed with dichloromethane behind the separatory with sodium bicarbonate, merge organic phase, evaporated under reduced pressure solvent after the dried over sodium sulfate gets colorless oil, mixes with 37% formalin, after the acidifying, be heated to 70-80 ℃, reacted 2 hours, be cooled to 0-5 ℃, reaction solution is poured in the frozen water, use dichloromethane extraction, the combined dichloromethane layer washs with sodium hydrogen carbonate solution, again washing, solvent evaporated after the dried over sodium sulfate gets S-type clopidogrel.
The specific rotation of (+) II-L-tartrate that makes in step 3) in addition is: [α]
20=+90 °～+ 91 ° (c=1.000/CH
3OH).
The present invention provides a kind of preparation method of S-type clopidogrel salt simultaneously, makes S-type clopidogrel by the method for preparing S-type clopidogrel, again with above-mentioned S-type clopidogrel and sour A salify.Wherein sour A is a vitriol, hydrochloride, hydrobromate, alkyl sulfide sulfonate, naphthalenesulfonate, acetate, benzoate, fumarate, maleate, Citrate trianion, tartrate, 2,5-resorcylic acid salt, mesylate, esilate, benzene sulfonate, lauryl sulfonate, Dobesilate and tosilate etc.
In the production process of reality, clopidogrel salt adopts usual manner to make, for example: with S-type clopidogrel acetone solution, ice bath drips sour A, drip off the back and kept ice bath 2-3 hour, remove the ice bath warming-in-water, stir and slowly separate out crystal to 25-35 ℃, stirring is spent the night, the dry clopidogrel salt that gets of filtering and washing.
Wherein clopidogrel salt is preferably I type clopidogrel sulfate.
Beneficial effect of the present invention comprises:
1, split process of the present invention has been avoided numerous and diverse heating and cooling process, and omnidistance only the need once lowered the temperature, easy and simple to handle saving time, and cost is low.For example: split process earlier will be 65-70 ℃ of salify 2 hours in the prior art, stir at normal temperatures after 18-20 hour and in 3-4 hour, reduce the temperature to 0-5 ℃ again, stir after 1-2 hour, in 2 hours, temperature is risen to 15-20 ℃ again, stirred 3-4 hour, numerous and diverse heating and cooling process like this, the operational condition harshness, wayward in actual production process.And the present invention only need be 50 ℃ of salifies 0.5 hour, after stirring at normal temperature 18-20 hour, once cool to 20 ℃ of stirrings and got final product discharging, easy and simple to handle saving time in actual production process in 3-4 hour, can save nearly 1/3 operating time and human cost and the closely energy consumption of half.
2, improved the racemization process of prior art, the temperature the when resistates of mother liquor is handled with sodium methylate and methyl alcohol is controlled in the room temperature, and the product foreign matter content of gained is few, of light color.For example: prior art is controlled at 65-70 ℃ of reaction 2-3 hour with the temperature of sodium methylate and methanol solution in the racemization process, and the impurity in products average content of this method gained is 3.4%, and color is dark, influences the quality of the finished product clopidogrel.And the present invention only need spend the night under 20-25 ℃ in reaction, and the average foreign matter content of the product of gained is 1.2%, obviously is less than the former, and product is of light color simultaneously, the purity height.Its reason be raw material when the highly basic sodium methylate exists, side reaction increases under the hot conditions, makes the content of foreign pigment increase, and cause the color burn of product, and side reaction reduces under the cold condition, the quality product height.
3, adopt the vitriol oil to replace sulfur oxychloride as esterifying reagent, easy and simple to handle, no obnoxious flavour produces.Following reaction easily takes place in sulfur oxychloride in actual production, as follows:
As can be seen, sulfur oxychloride easily produces a large amount of hydrochloric acid and sulfur dioxide gas from reaction, etching apparatus, and it is healthy to influence the workman, therefore needs vent gas treatment, increases cost.And adopt the vitriol oil as esterifying reagent, and no obnoxious flavour produces in the reaction, and the sulfuric acid of gained is reusable edible also, reduces the cost.Reaction process is as follows:
CH
3OH+H
2SO
4→CH
3OSO
3H+H
2O
4, compared with prior art, the improved economic benefit of the present invention is as follows:
Table 1 process modification scheme cost analysis table
| Prior art | The present invention | ||
| Synthesis phase | Vent gas treatment | ||
| Man-hour (h) | 36.00 | 5.00 | 25.00 |
| Operation number (individual) | 5.00 | 2.00 | 5.00 |
| Labor hour (h) | 180.00 | 10.00 | 125.00 |
| Per hour artificial | 10.00 | 10.00 | 10.00 |
| Cost of labor | 1800.00 | 100.00 | 1250.00 |
| Original value of the equipment | 45000.00 | 10000.00 | 45000.00 |
| Remanent value of equipment | 4500.00 | 1000.00 | 4500.00 |
| Period of depreciation | 10.00 | 5.00 | 5.00 |
| Depreciable cost | 16.88 | 5.21 | 23.44 |
| Per hour power consumption | 25.00 | 5.00 | 25.00 |
| Energy consumption cost | 900.00 | 25.00 | 625.00 |
| Expenses of environmental protection | 125 | ||
| Amount to | 2716.88 | 255.21 | 1898.44 |
Through my company's production practice, half a year, accumulative total was produced 42 times, saved more than 45,000 yuan of Renminbi of cost approximately, had saved tail gas treatment process, was more conducive to environmental protection than prior art, had obtained good social benefit.
Description of drawings:
Fig. 1 is the mass spectrum of the I type Clopidogrel Hydrogensulfate of example 1 preparation
Fig. 2 is the nmr spectrum of the I type Clopidogrel Hydrogensulfate hydrogen atom of example 1 preparation
Fig. 3 is the nmr spectrum of the I type Clopidogrel Hydrogensulfate carbon atom of example 1 preparation
Fig. 4 is the infrared spectrum of the I type Clopidogrel Hydrogensulfate carbon atom of example 1 preparation
Fig. 5 is the X-diffraction spectrogram of the I type Clopidogrel Hydrogensulfate carbon atom of example 1 preparation
Embodiment:
Take by weighing the hydrochloride of α-(2 thiophene ethyl amine base)-α-(2-chloro-phenyl-) ritalin of 14g (0.040mol) racemization, add 30mL water and 90mL methylene dichloride, stir down and transfer pH to 7 with sodium bicarbonate, discard water layer behind the separatory, dichloromethane layer is washed 3 times with 30mL, evaporated under reduced pressure solvent after the dried over sodium sulfate gets oily matter 12g (0.039mol).
With oily matter with the dissolving of 150mL Virahol after, add 4.9g (0.033mol) L-tartrate, 50 ℃ are stirred insulation 0.5 hour, add crystal seed when being cooled to 35 ℃ naturally, spend the night, be cooled to 20 ℃ and stirred 4 hours in stirring at normal temperature, dry product, the specific rotation: [α] of getting of solid filtering and washing
20=+88 °～+ 89 °.Take by weighing (+) II-L-tartrate after 50g splits, add 65 ℃ of stirring and dissolving of 200mL Virahol, the cooling nature is separated out, and 20 ℃ are stirred filtering and washing after 2 hours, dry 39.4g purified (+) II-L-tartrate, the specific rotation: [α] of getting
20=+90 °～+ 91 °.
50 ℃ of evaporated under reduced pressure of mother liquor after splitting are got resistates 100g, add 200mL water and 200mL methylene dichloride, stir down and transfer pH to 7 with sodium bicarbonate, water layer is carried secondary again with methylene dichloride behind the separatory, combined dichloromethane layer washing three times, evaporated under reduced pressure solvent after the dried over sodium sulfate gets oily matter 60g.With the dissolving of 120mL anhydrous methanol, ice bath drips 10.5g sodium methylate/120mL methanol solution down, removes ice bath, rises to stirring at normal temperature naturally and spends the night.
The mixed solution ice bath is dripped the 80mL vitriol oil, back flow reaction 6 hours, reacting liquor while hot is poured in the frozen water, add methylene dichloride, stir down and transfer pH to 7 with sodium bicarbonate, water layer is carried secondary again with methylene dichloride behind the separatory, merge organic phase washing three times, anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent adds four times of amount acetic acid ethyl dissolutions, ice bath drips the concentrated hydrochloric acid salify down, the solid suction filtration is washed after drying with cold ethyl acetate, gets (±) II-hydrochloride.
Repeat above step.
Take by weighing the condenses tartrate 50g after the fractionation, add 200ml water and 200ml methylene dichloride, stir down and transfer pH to 7-8 with sodium bicarbonate, water layer is carried twice with methylene dichloride again behind the separatory, combined dichloromethane layer washing three times, evaporated under reduced pressure solvent after the dried over sodium sulfate gets colorless oil 36g.Get colorless oil, mix with the 100ml37% formalin, add the 30ml hydrochloric acid soln, be heated to 70-80 ℃, reacted 2 hours, be cooled to 0-5 ℃, reaction solution is poured in the frozen water, use dichloromethane extraction, the combined dichloromethane layer washs with sodium hydrogen carbonate solution, washing again, solvent evaporated after the dried over sodium sulfate gets 36gS-type clopidogrel.Gained base acetone solution, ice bath drip the vitriol oil, drip off the back and keep ice bath two hours, remove ice bath warming-in-water to 30 ℃, stir and slowly separate out crystal, and stirring is spent the night, filtering and washing dry 29g I type Clopidogrel Hydrogensulfate.
Claims (6)
1, the preparation method of a kind of S-type clopidogrel (I) is characterized in that may further comprise the steps:
1) racemic α-(2 thiophene ethyl amine base)-α-(2-chloro-phenyl-) methyl acetate (II) hydrochloride is dissolved in the water, adds methylene dichloride, stir and use sodium bicarbonate down or/and saleratus is regulated pH 7-8, separatory merges organic phase, washes with water; Evaporated under reduced pressure after organic phase usefulness anhydrous sodium sulphate after the washing and/or the anhydrous potassium sulfate drying gets oily matter;
2) oily matter with the step 1) gained dissolves with Virahol, add L-tartrate, stirring is warming up to 45-55 ℃, be incubated half an hour, add crystal seed when being cooled to 30-40 ℃ naturally, spend the night in stirring at normal temperature, be cooled to 15-20 ℃ and stirred 4 hours, dry (+) II-L-tartrate that gets of solid filtering and washing;
3) with step 2) mother liquor evaporated under reduced pressure after the fractionation of gained gets resistates, and resistates is handled according to step 1), and the product after the processing dissolves with anhydrous methanol, and ice bath drips sodium methoxide solution down, and being warming up to stirring at normal temperature naturally spends the night;
4) with the mixing solutions of step 3) gained, ice bath drips the vitriol oil, back flow reaction 6 hours, reacting liquor while hot is poured in the frozen water, adds methylene dichloride, according to step 1) handle product, this product acetic acid ethyl dissolution, ice bath drip concentrated hydrochloric acid salify, solid suction filtration down, wash after drying with cold ethyl acetate, get (±) II-hydrochloride;
5) repeating step 1) to step 4);
6) with step 2) (+) II-L-tartrate after the fractionation of gained dissolves with Virahol, and cooling is separated out, filtering and washing, dry purified (+) II-L-tartrate;
7) (+) II-L-tartrate with the step 6) gained further makes S-type clopidogrel.
2, a kind of preparation method of S-type clopidogrel salt is characterized in that: by preparing S-type clopidogrel as step 1) in the claim 1 to the described method of step 7), again with above-mentioned S-type clopidogrel and sour A salify.Wherein sour A comprises vitriol, hydrochloride, hydrobromate, alkyl sulfide sulfonate, naphthalenesulfonate, acetate, benzoate, fumarate, maleate, Citrate trianion, tartrate, 2,5-resorcylic acid salt, mesylate, esilate, benzene sulfonate, lauryl sulfonate, Dobesilate and tosilate.
3, preparation method as claimed in claim 1, it is characterized in that, described step 2) after adding L-tartrate in, stirring is warming up to 50 ℃, be incubated half an hour, add crystal seed when being cooled to 35 ℃ naturally, spend the night in stirring at normal temperature, be cooled to 20 ℃ and stirred 4 hours, dry (+) II-L-tartrate that gets of solid filtering and washing.
4, preparation method as claimed in claim 1 is characterized in that, described step 2) in (+) II-L-tartrate of making, specific rotation: [α]
20=+88 °～+ 89 ° (c=1.000/CH
3OH).
5, preparation method as claimed in claim 1 is characterized in that, (+) II-L-tartrate that makes in the described step 3), specific rotation: [α]
20=+90 °～+ 91 ° (c=1.000/CH
3OH).
6, preparation method as claimed in claim 2 is characterized in that, the clopidogrel sulfate that makes is an I type Clopidogrel Hydrogensulfate.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101591346A (en) * | 2009-07-03 | 2009-12-02 | 北京华禧联合科技发展有限公司 | The new synthetic method of related substance B of clopidogrel bisulfate |
| CN101774914A (en) * | 2010-01-28 | 2010-07-14 | 天津市中央药业有限公司 | Method for synthesizing methyl alpha-bromo-2-chlorophenylacetate |
| CN103483356A (en) * | 2013-09-30 | 2014-01-01 | 浙江美诺华药物化学有限公司 | Method for preparing sulfate or hydrochloride of (S)-clopidogrel |
| CN104610275A (en) * | 2015-02-06 | 2015-05-13 | 符健 | 2,5-dyhydroxyl clopidogrel besylate and preparation method thereof |
| US20170037054A1 (en) * | 2014-12-31 | 2017-02-09 | Shenzhen Salubris Pharmaceuticals Co., Ltd | Method For Preparing Spherical Clopidogrel Hydrogen Sulfate Polymorph I |
-
2006
- 2006-09-29 CN CN 200610062880 patent/CN101045731A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101591346A (en) * | 2009-07-03 | 2009-12-02 | 北京华禧联合科技发展有限公司 | The new synthetic method of related substance B of clopidogrel bisulfate |
| CN101591346B (en) * | 2009-07-03 | 2014-10-29 | 北京华禧联合科技发展有限公司 | Novel method for synthesizing related substance B of clopidogrel bisulfate |
| CN101774914A (en) * | 2010-01-28 | 2010-07-14 | 天津市中央药业有限公司 | Method for synthesizing methyl alpha-bromo-2-chlorophenylacetate |
| CN101774914B (en) * | 2010-01-28 | 2012-11-21 | 天津市中央药业有限公司 | Method for synthesizing methyl alpha-bromo-2-chlorophenylacetate |
| CN103483356A (en) * | 2013-09-30 | 2014-01-01 | 浙江美诺华药物化学有限公司 | Method for preparing sulfate or hydrochloride of (S)-clopidogrel |
| CN103483356B (en) * | 2013-09-30 | 2016-01-13 | 浙江美诺华药物化学有限公司 | A kind of vitriol of (S)-clopidogrel or the preparation method of hydrochloride |
| US20170037054A1 (en) * | 2014-12-31 | 2017-02-09 | Shenzhen Salubris Pharmaceuticals Co., Ltd | Method For Preparing Spherical Clopidogrel Hydrogen Sulfate Polymorph I |
| US9815848B2 (en) * | 2014-12-31 | 2017-11-14 | Tianjin University | Method for preparing spherical Clopidogrel Hydrogen Sulfate polymorph I |
| CN104610275A (en) * | 2015-02-06 | 2015-05-13 | 符健 | 2,5-dyhydroxyl clopidogrel besylate and preparation method thereof |
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Open date: 20071003 |