CN110776519B - Preparation method of clopidogrel hydrogen sulfate crystal form II - Google Patents
Preparation method of clopidogrel hydrogen sulfate crystal form II Download PDFInfo
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- CN110776519B CN110776519B CN202010001297.9A CN202010001297A CN110776519B CN 110776519 B CN110776519 B CN 110776519B CN 202010001297 A CN202010001297 A CN 202010001297A CN 110776519 B CN110776519 B CN 110776519B
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
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Abstract
The invention discloses a preparation method of a crystal form II of clopidogrel hydrogen sulfate, which comprises the steps of preparing (+) o-chlorobenzene glycine methyl ester, preparing (+) α - (2-thiophene ethylamino) - α - (2-chlorphenyl) methyl acetate hydrochloride, preparing (+) clopidogrel free alkali, preparing (+) clopidogrel camphorsulfonic acid double salt, hydrolyzing the (+) clopidogrel camphorsulfonic acid double salt and preparing clopidogrel hydrogen sulfate.
Description
Technical Field
The invention relates to a preparation method of a crystal form II of clopidogrel hydrogen sulfate, belonging to the technical field of chemical crystallization of medicines.
Background
Clopidogrel bisulfate is an antiplatelet aggregation-type drug developed in 1986 by the company of Sanlfi-Aventis, France, which irreversibly inhibits platelet aggregation by selectively binding to ADP receptors coupled to platelet surface adenylate cyclase, reducing thrombosis in blood vessels. The medicine has obvious clinical curative effect, less side effect and high tolerance, gradually replaces aspirin, and becomes a first-line medicine for treating thrombotic diseases. The product was first marketed in the united states and united kingdom in 1998 and entered china in 2001. Currently, main manufacturers of clopidogrel bisulfate preparation products in China include Xenofoil (Hangzhou) pharmaceutical Co., Ltd, Shenzhen Xin Li Tai pharmaceutical Co., Ltd, and Lepu pharmaceutical Co., Ltd.
The existing literature has a plurality of methods for preparing clopidogrel bisulfate, most of the methods have complex reaction and harsh reaction conditions, and are not beneficial to large-batch production. Chinese patent CN104370935B relates to a preparation method of clopidogrel hydrogen sulfate, which takes 2-thiopheneacetaldehyde as a basic starting material to perform condensation reaction with o-chlorophenyl glycine methyl ester to generate a corresponding imine intermediate, then reduces the imine intermediate into a corresponding secondary amine intermediate by using sodium borohydride or directly using sodium cyanoborohydride, and then the secondary amine intermediate reacts with formaldehyde to close the ring to obtain clopidogrel, and the target compound clopidogrel hydrogen sulfate is obtained after sulfuric acid acidification.
Chinese patent application CN 107383055A relates to a synthesis method of clopidogrel hydrogen sulfate, which takes o-chloroacetic acid and 4,5,6,7 tetrahydrothiophene [3,2-c ] as raw materials and comprises the following steps: (1) preparing acylation reaction; (2) carrying out bromination reaction; (3) performing esterification reaction; (4) preparing a clopidogrel base crude product; (5) purifying clopidogrel alkali; (6) splitting a racemate; (7) preparing clopidogrel hydrogen sulfate.
International patent application WO2003/051362 reports a process for preparing clopidogrel hydrogen sulfate using acetone as a solvent, which requires low temperature and is not conducive to energy saving and consumption reduction.
Chinese patent CN101643476B reports a preparation method of clopidogrel hydrogen sulfate crystal form II, which is to dissolve clopidogrel hydrogen sulfate crystal form I in lower alcohol, and then add an anti-solvent to obtain crystal form II.
Again, some of the synthetic methods reported in the patent are not ideal in terms of the content of impurities involved. Three known impurities requiring clopidogrel control are specified in the U.S. USP standards, namely impurity A (CAS No.:144750-42-5), impurity B (CAS No.:144750-52-7), and impurity C (CAS No.: 120202-71-3). Wherein A is a hydrolysis product of clopidogrel, B is an isomer, and the impurity C is mainly an optical enantiomer of dextrorotatory clopidogrel hydrogen sulfate. The FDA stipulates that the three impurities can not exceed 0.1% of the HPLC integral area, mainly because the three related impurities A, B and C all have certain influence on the drug effect of clopidogrel hydrogen sulfate, the content of the clopidogrel hydrogen sulfate needs to be controlled.
In view of the current situation that the existing process for preparing clopidogrel hydrogen sulfate is complex, the reaction conditions are harsh and not beneficial to large-scale production, and the impurity content of the product obtained by the preparation method of the crystal form II of clopidogrel hydrogen sulfate is high, a new preparation method needs to be developed, and the crystal form II of clopidogrel hydrogen sulfate with high purity can be obtained by adopting simple and easily obtained materials and using mild reaction conditions.
Disclosure of Invention
The invention provides a preparation method of a crystal form II of clopidogrel hydrogen sulfate, which aims to solve the problems of complex process, harsh reaction conditions and high impurity content of clopidogrel hydrogen sulfate, reduce the cost investment, prepare a high-purity crystal form II of clopidogrel hydrogen sulfate at one time and ensure that the reaction process is safe and environment-friendly.
The invention relates to a preparation method of a crystal form II of clopidogrel hydrogen sulfate, which comprises the following steps:
s1, carrying out hydrolysis reaction on (+) o-chlorophenyl glycine methyl ester tartrate to obtain (+) o-chlorophenyl glycine methyl ester;
s2, adding acetonitrile and inorganic base, mixing with (+) o-chlorophenyl glycine methyl ester, stirring at 20-30 ℃, adding 2- (2-thienyl) ethanol p-toluenesulfonate, heating to 48-52 ℃, carrying out heat preservation reaction, centrifuging after the reaction is finished, adjusting the pH of a mother solution to 3-5, stirring, centrifuging, and drying the obtained solid at 50-60 ℃ to obtain (+) α - (2-thiophene ethylamino) - α - (2-chlorophenyl) acetic acid methyl ester hydrochloride;
s3, mixing the (+) α - (2-thiophene ethylamino) - α - (2-chlorphenyl) methyl acetate hydrochloride with formaldehyde, heating, keeping the temperature for complete reaction, cooling, adding inorganic base, water and dichloromethane, stirring, separating, extracting, and combining organic layers to obtain (+) clopidogrel free alkali;
s4, racemizing and splitting the (+) clopidogrel free alkali to obtain (+) clopidogrel camphorsulfonic acid double salt;
s5, hydrolyzing the (+) clopidogrel camphorsulfonic acid double salt to obtain (+) clopidogrel free alkali I;
s6, mixing the (+) clopidogrel free alkali I with acetone, filtering, cooling the filtrate, adding equimolar concentrated sulfuric acid, stirring, centrifuging, and drying to obtain the clopidogrel hydrogen sulfate crystal form II.
According to the preparation method of the clopidogrel bisulfate crystal form II, in the step S1, an extracting agent, water and inorganic alkali are stirred and dissolved to be clear, (+) o-chlorophenyl glycine methyl ester tartrate is added, liquid separation is carried out after complete reaction, a water layer is extracted by the extracting agent, organic layers are combined, drying is carried out by a drying agent, centrifugation is carried out, filtrate is taken, and the extracting agent is recovered under reduced pressure, so that (+) o-chlorophenyl glycine methyl ester is obtained.
According to the preparation method of the clopidogrel bisulfate crystal form II, in the step S2, the molar ratio of the inorganic base to the (+) o-chlorophenyl glycine methyl ester is 2-2.5: 1.
According to the preparation method of the clopidogrel bisulfate crystal form II, in the step S3, the mixing ratio of methyl (+) α - (2-thiophene ethylamino) - α - (2-chlorophenyl) acetate hydrochloride to formaldehyde is 1: 4-6 in terms of weight ratio.
According to the preparation method of the clopidogrel bisulfate crystal form II, in the step S3, the (+) α - (2-thiophene ethylamino) - α - (2-chlorphenyl) methyl acetate hydrochloride and formaldehyde are mixed and then heated, wherein the heating temperature is 35-45 ℃.
According to the preparation method of the clopidogrel bisulfate crystal form II, in the step of S4, (+) clopidogrel free alkali, acetone and levo-camphorsulfonic acid are mixed, stirred and centrifuged to obtain (+) clopidogrel camphorsulfonic acid double salt.
According to the preparation method of the clopidogrel hydrogen sulfate crystal form II, in the step S5, water, inorganic base, (+) clopidogrel camphorsulfonic acid double salt and dichloromethane are mixed, stirred and separated, a water layer is extracted by dichloromethane, and is kept stand for separating, and an organic layer is combined to recover the dichloromethane under reduced pressure, so that (+) clopidogrel free base I is obtained.
According to the preparation method of the clopidogrel bisulfate crystal form II, the concentrated sulfuric acid is added in the step S6, and then the mixture is stirred at the temperature of 0-10 ℃.
According to the preparation method of the clopidogrel bisulfate crystal form II, in the step S6, the stirring time is 8-20 hours.
According to the preparation method of the crystal form II of clopidogrel bisulfate, the stirring time is 12 hours in the step of S6.
According to the preparation method of the crystal form II of clopidogrel hydrogen sulfate, the inorganic base is selected from dipotassium hydrogen phosphate, sodium sulfate, sodium carbonate, potassium carbonate or disodium hydrogen phosphate in the step of S6.
Drawings
Fig. 1 is an X-ray powder diffraction pattern of clopidogrel bisulfate crystal form II of the present invention measured using Cu-K α radiation.
Figure 2 is an X-ray powder diffraction pattern of clopidogrel bisulfate crystal form II control measured using Cu-K α radiation.
Fig. 3 is a differential thermal scanning analysis DSC chart of clopidogrel hydrogen sulfate crystal form II of the present invention.
FIG. 4 is a DSC (differential thermal scanning analysis) spectrogram of a clopidogrel hydrogen sulfate crystal form II reference substance.
Fig. 5 is a TGA spectrum of clopidogrel bisulfate crystalline form II of the present invention.
Figure 6 is a TGA profile of clopidogrel bisulfate crystalline form II control.
Detailed Description
The term "crystalline form II" herein means that the clopidogrel bisulfate compound exists in a specific crystalline form II state in the crystal structure. The difference of physicochemical properties of different crystal forms can be reflected in the aspects of storage stability, compressibility, density, dissolution speed and the like. Differences in solubility or dissolution rate, in extreme cases, can cause the drug to be ineffective or even toxic.
Different crystal forms may provide different physicochemical properties, such as melting point. The onset temperature of the melting point was determined from the point of significant change in DSC baseline as measured by TA analysis software. Melting points can also be determined by other techniques, other instruments, or other test conditions. Therefore, the melting point data herein is not necessarily an absolute value. One skilled in the art will appreciate that the precise value of the melting point will be affected by the purity of the compound, the amount of sample, the rate of heating, and the particle size.
Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized by prior art means, with instrument errors depending on the test conditions of the instrument, sample preparation and sample purity. For example, it is well known that X-ray diffraction patterns typically vary with instrument conditions, so the order of intensity of peaks is usually not considered. In addition, experimental errors in peak angles are typically 5% or less, and errors in these angles should typically be taken into account. Thus, it will be appreciated that the measured X-ray diffraction patterns of the presently claimed crystalline forms need not be in complete agreement with the corresponding X-ray diffraction patterns set forth herein. Any crystalline form having a pattern substantially the same as or similar to the pattern given herein is contemplated as falling within the scope of the present application. One skilled in the art can compare the profiles listed herein with the profile of an unknown crystalline form to determine whether the two profiles reflect the same or different crystalline forms.
The crystalline forms of the drug can be obtained generally by: including, but not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolventization, fast volatilization, fast temperature reduction, slow temperature reduction, vapor diffusion, and sublimation. The crystalline forms can be detected, discovered, and classified by X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TG), single crystal X-ray diffraction, vibrational spectroscopy, solid state NMR, infrared spectroscopy, raman spectroscopy, dissolution rate determination, solubility, hygroscopicity, and the like.
The instrument used for detecting the XRPD spectrogram is a Y-2000X-ray diffractometer. The samples were tested at room temperature and the sample to be tested was placed on a plexiglass slide. The detection conditions were as follows, angle range: 30 KV; 20 mA; speed: 0.05 deg/sec. Unless otherwise specified, the samples were tested without grinding.
The instrument used for detecting the DSC spectrogram is a NETZSCH DSC-204 type differential thermal analyzer. A sample of 1 to 10 mg is usually placed in an uncapped aluminum crucible (unless otherwise specified), and N is dried at a temperature rise rate of 10K/min at 50mL/min2The sample was raised from room temperature to 200 ℃ under the protection of (1), and the heat change of the sample during the temperature rise was recorded.
The instrument used for detecting the TG spectrogram in the invention is NETZSCH TG-209. Usually, 5-15mg of sample is placed in a platinum crucible, and N is dried at a heating rate of 10K/min at 50mL/min by a sectional high-resolution detection mode2The sample was raised from room temperature to 930 ℃ while recording the thermal change of the sample during the temperature rise.
The invention provides a preparation method of a crystal form II of clopidogrel hydrogen sulfate, which comprises the following steps:
s1 preparation of (+) o-chlorophenyl glycine methyl ester
Adding an extracting agent, water and an inorganic base into a reaction vessel, stirring and dissolving, adding (+) o-chlorophenyl glycine methyl ester tartrate, separating liquid after complete reaction, and extracting a water layer by using the extracting agent. Combining organic layers, drying by using a drying agent, centrifuging, taking filtrate, decompressing and recovering an extracting agent to obtain (+) o-chlorophenyl glycine methyl ester, wherein the reaction process is as follows:
in certain embodiments of the present invention, the inorganic base is selected from dipotassium hydrogen phosphate, sodium sulfate, sodium carbonate, potassium carbonate, or disodium hydrogen phosphate. The inorganic base is used as an acid-binding agent in the preparation method of the crystal form II of clopidogrel hydrogen sulfate, and mainly absorbs H in the reaction step+。
In certain embodiments of the invention, the extractant does not participate in the reaction, is used primarily to extract the organic layer, and can be any low boiling organic solvent that is immiscible with water, that is capable of extractive delamination and is easily recovered, including, but not limited to, tetrahydrofuran, dichloromethane, ethyl acetate, or benzene, with dichloromethane being preferred for the present invention.
S2 preparation of (+) α - (2-thiophene ethylamino) - α - (2-chlorophenyl) acetic acid methyl ester hydrochloride
In certain embodiments of the invention, the molar ratio of the inorganic base to the (+) o-chlorophenyl glycine methyl ester is 2 to 2.5: 1.
In some embodiments of the invention, hydrochloric acid is used to adjust the pH value of the centrifuged mother liquor to 3-5, within the pH range, not only can an acidic environment required for crystallization be ensured, but also reference can be made to the amount of added acid, so that a large amount of added acid is not harmful to environmental protection, and the (+) α - (2-thiophene ethylamino) - α - (2-chlorophenyl) methyl acetate is promoted to carry out salt formation reaction.
Meanwhile, in the step, each temperature range is accurately limited, the temperature is too low, the reaction is incomplete, the reaction time is greatly prolonged, and the risk of generating byproducts is generated; too high a temperature also increases impurities.
S3 preparation of (+) clopidogrel free base
In certain embodiments of the invention, the mixing ratio of the (+) α - (2-thiophene ethylamino) - α - (2-chlorophenyl) acetic acid methyl ester hydrochloride to the formaldehyde is 1: 4-6 by weight ratio, in the step, the formaldehyde is a solvent and a reactant, the feeding is too little, the reaction is incomplete, and the feeding is too much, so that the material waste is caused.
In certain embodiments of the present invention, the (+) α - (2-thiophene ethylamino) - α - (2-chlorophenyl) acetic acid methyl ester hydrochloride is mixed with the formaldehyde and then heated, wherein the heating temperature is 35 to 45 ℃.
S4 preparation of (+) clopidogrel camphorsulfonic acid double salt
Adding (+) clopidogrel free alkali, acetone and levo-camphorsulfonic acid into a reaction container, mixing, stirring and centrifuging to obtain (+) clopidogrel camphorsulfonic acid double salt.
In certain embodiments of the invention, the (+) clopidogrel free base is racemized and resolved in acetone by using levocamphorsulfonic acid, and the mixing ratio of the (+) clopidogrel free base to the acetone to the levocamphorsulfonic acid is 1: 4-8: 0.5-1 in parts by weight.
In the above scheme, acetone is the solvent; the levo-camphorsulfonic acid is one of reactants, if the material amount is reduced, the yield of the camphorsulfonic acid double salt is reduced, and part (+) clopidogrel free alkali can not be fully salified and is taken away with acetone mother liquor.
S5. (+) clopidogrel camphorsulfonic acid double salt hydrolysis
Adding water, inorganic base, (+) clopidogrel camphorsulfonic acid double salt and dichloromethane into a reaction container, mixing, stirring, separating, extracting the water layer with dichloromethane, standing, separating, combining the organic layers, and recovering dichloromethane under reduced pressure to obtain (+) clopidogrel free base I.
In certain embodiments of the inventionThe (+) clopidogrel camphorsulfonic acid double salt comprises dichloromethane and inorganic base = 1: 2: 0.5 in parts by weight. In this step, an inorganic base is used as a reactant, which is mainly to neutralize the levocamphorsulfonic acid, which is generally capable of receiving H, in this step+The weak acid alkali salt of (a) may be selected from dipotassium hydrogen phosphate, sodium sulfate, sodium carbonate, potassium carbonate, or disodium hydrogen phosphate. If the inorganic alkali feeding amount is reduced, the yield of the clopidogrel free alkali I is reduced, and part of clopidogrel camphorsulfonic acid double salt is taken away along with the water layer.
S3 (+) α - (2-thiophene ethylamino) - α - (2-chlorophenyl) methyl acetate hydrochloride and formaldehyde are subjected to cyclization reaction, and then inorganic base is added for hydrolysis to improve purity, S5 (+) clopidogrel camphorsulfonic acid double salt hydrolysis is racemization resolution, has the function of purification and the function of reducing enantiomer, and can reduce the content of enantiomer to be less than 0.1% of HPLC integral area.
S6 preparation of clopidogrel hydrogen sulfate
In certain embodiments of the present invention, the ratio of (+) clopidogrel free base I to acetone is 1: 5 to 6 by weight.
In some embodiments of the invention, the concentrated sulfuric acid is added and stirred at a temperature of 0-10 ℃ for 8-20 hours, preferably 12 hours.
In certain embodiments of the present invention, the drying temperature is 75 to 85 ℃.
In certain embodiments of the invention, the drying time is not less than 18 hours. Too short time for drying the solvent can cause the residual of the detected solvent to exceed the standard; the time is properly prolonged, and the influence on the product is not great because the product does not contain crystal water.
By adopting the crystallization condition in the step, the clopidogrel bisulfate crystal form II with high content can be easily obtained.
Compared with the prior art, the preparation method of the clopidogrel hydrogen sulfate crystal form II optimizes the synthesis process of clopidogrel hydrogen sulfate, selects cheap and easily available materials, adopts mild reaction conditions, and produces a high-purity product safely and environmentally. The reaction principle adopted by the invention is easy to control, and the product with lower impurity content and lower enantiomer content can be obtained at one time.
Examples
For better understanding of the above technical solutions, the following detailed descriptions will be made with reference to the drawings and specific embodiments of the specification, but the present invention is not limited to these specific embodiments.
Example 1
Adding 300ml of dichloromethane, 160ml of water and 80g of sodium carbonate into a three-neck flask, stirring to dissolve, adding 140g of (+) o-chlorophenyl glycine methyl ester tartrate, separating liquid after complete reaction, extracting a water layer with 50ml of dichloromethane for three times, combining organic layers, drying with anhydrous sodium sulfate, centrifuging, taking filtrate, and recovering dichloromethane under reduced pressure to obtain (+) o-chlorophenyl glycine methyl ester.
Adding 600ml of acetonitrile and 140g of dipotassium phosphate into a three-neck flask, mixing with (+) o-chlorophenyl glycine methyl ester obtained in the previous step, stirring for 1 hour at 20 ℃, adding 170g of 2- (2-thienyl) ethanol p-toluenesulfonate, heating to 48 ℃, keeping the temperature for reaction, centrifuging after the reaction is finished, collecting mother liquor into a reaction container, adding a proper amount of hydrochloric acid while stirring until the pH value is 4, stirring for 4 hours, centrifuging, and drying the obtained solid at 50 ℃ to obtain (+) α - (2-thiophene ethylamino) - α - (2-chlorophenyl) acetic acid methyl ester hydrochloride.
Adding the (+) α - (2-thiophene ethylamino) - α - (2-chlorphenyl) methyl acetate hydrochloride obtained in the previous step and 4 times of formaldehyde by weight into a three-neck flask, heating to 35 ℃, keeping the temperature for complete reaction, cooling to room temperature, adding 0.5 times of sodium sulfate by weight, 1 time of purified water by weight and 6.5 times of dichloromethane by weight, stirring, separating, extracting a water layer twice by using dichloromethane, combining organic layers, and recovering the dichloromethane under reduced pressure to obtain (+) clopidogrel free alkali.
Adding (+) clopidogrel free alkali, 5 times of acetone and 0.65 time of levo-camphorsulfonic acid into a three-neck flask, stirring for 24 hours, and centrifuging to obtain (+) clopidogrel camphorsulfonic acid double salt.
Adding 2 times of water, 0.5 time of sodium carbonate, (+) clopidogrel camphorsulfonic acid double salt and 2 times of dichloromethane into a three-neck flask, stirring, separating, extracting an aqueous layer twice by using dichloromethane, standing, separating, combining organic layers, and recovering the dichloromethane under reduced pressure to obtain (+) clopidogrel free alkali.
Adding (+) clopidogrel free alkali and acetone with the weight 5 times of that of the (+) clopidogrel free alkali into a three-neck flask, filtering, cooling filtrate, adding equimolar concentrated sulfuric acid, keeping the temperature at 0 ℃ and stirring for 12 hours, centrifuging, and drying at 75 ℃ for 18 hours to obtain a clopidogrel hydrogen sulfate crystal form II which is a white powdery solid.
An X-ray powder diffraction pattern of the crystal form II of clopidogrel bisulfate obtained in example 1 is shown in a figure 1 by using Cu-K α ray measurement, and the data of the data are shown in a table 1 in detail.
TABLE 1 XRD data for clopidogrel hydrogen sulfate form II
From the spectrum of fig. 1 and the data of table 1, it can be seen that the X-ray powder diffraction 2 θ ° diffraction angle position has a peak intensity ratio of 100 at 21.7 and secondly has intensity peaks at 23.0 and 24.8.
The sample was subjected to differential thermal analysis, and DSC results showed that the sample had a definite phase transition point at 177.5 ℃, and the results are shown in FIG. 3.
The TG analysis of this sample showed that the sample had almost no weight loss at 100 ℃ and only 1% weight loss at 192.3 ℃, indicating that the sample contained no adsorbed water, and the results are shown in fig. 5.
Comparative example 1
The control in FIG. 2 was provided by the national institute for food and drug testing.
The comparative sample obtained in comparative example 1 was measured using Cu-K α radiation to obtain an X-ray powder diffraction pattern as shown in fig. 2, and the data thereof are shown in table 2.
TABLE 2 XRD data for clopidogrel hydrogen sulfate form II
From the spectrum of fig. 2 and the data of table 2, it can be seen that the X-ray powder diffraction 2 θ ° diffraction angle position has a peak intensity ratio of 100 at 21.5 and secondly has intensity peaks at 22.9 and 24.6.
The sample was subjected to differential thermal analysis, and the DSC result showed that the sample also had a definite phase transition point at 177.5 ℃ as in the sample of example 1, and the result is shown in FIG. 4.
The TG analysis of this sample revealed that the sample had almost no weight loss at 100 ℃ and only 1% weight loss at 192.3 ℃ as in the sample of example 1, indicating that the sample contained no adsorbed water, and the results are shown in fig. 6.
It can be seen that the spectra and data of the sample of example 1 obtained according to the preparation method of the present invention are substantially identical to those of the sample of comparative example 1.
Example 2
Adding 300ml of dichloromethane, 160ml of water and 80g of sodium carbonate into a three-neck flask, stirring to dissolve, adding 140g of (+) o-chlorophenyl glycine methyl ester tartrate, separating liquid after complete reaction, extracting a water layer with 50ml of dichloromethane for three times, combining organic layers, drying with anhydrous sodium sulfate, centrifuging, taking filtrate, and recovering dichloromethane under reduced pressure to obtain (+) o-chlorophenyl glycine methyl ester.
Adding 600ml of acetonitrile and 140g of dipotassium phosphate into a three-neck flask, mixing with (+) o-chlorophenyl glycine methyl ester obtained in the previous step, stirring for 1 hour at 30 ℃, adding 170g of 2- (2-thienyl) ethanol p-toluenesulfonate, heating to 52 ℃, keeping the temperature, reacting, centrifuging after the reaction is finished, collecting mother liquor into a reaction container, adding a proper amount of hydrochloric acid while stirring until the pH value is 4, stirring for 4 hours, centrifuging, and drying the obtained solid at 60 ℃ to obtain (+) α - (2-thiophene ethylamino) - α - (2-chlorophenyl) methyl acetate hydrochloride.
Adding the (+) α - (2-thiophene ethylamino) - α - (2-chlorphenyl) methyl acetate hydrochloride obtained in the previous step and 6 times of formaldehyde by weight into a three-neck flask, heating to 45 ℃, keeping the temperature for complete reaction, cooling to room temperature, adding 0.5 times of sodium sulfate by weight, 1 time of purified water by weight and 6.5 times of dichloromethane by weight, stirring, separating, extracting a water layer twice by using dichloromethane, combining organic layers, and recovering the dichloromethane under reduced pressure to obtain (+) clopidogrel free alkali.
Adding (+) clopidogrel free alkali, 5 times of acetone and 0.65 time of levo-camphorsulfonic acid into a three-neck flask, stirring for 24 hours, and centrifuging to obtain (+) clopidogrel camphorsulfonic acid double salt.
Adding 2 times of water, 0.5 time of sodium carbonate, (+) clopidogrel camphorsulfonic acid double salt and 2 times of dichloromethane into a three-neck flask, stirring, separating, extracting an aqueous layer twice by using dichloromethane, standing, separating, combining organic layers, and recovering the dichloromethane under reduced pressure to obtain (+) clopidogrel free alkali.
Adding (+) clopidogrel free alkali and acetone with the weight 5 times of that of the (+) clopidogrel free alkali into a three-neck flask, filtering, cooling filtrate, adding equimolar concentrated sulfuric acid, keeping the temperature at 10 ℃, stirring for 12 hours, centrifuging, and drying at 85 ℃ for 20 hours to obtain a clopidogrel hydrogen sulfate crystal form II which is a white powdery solid.
Comparative example 2
Adding 300ml of dichloromethane, 160ml of water and 80g of sodium carbonate into a three-neck flask, stirring to dissolve, adding 140g of (+) o-chlorophenyl glycine methyl ester tartrate, separating liquid after complete reaction, extracting a water layer with 50ml of dichloromethane for three times, combining organic layers, drying with anhydrous sodium sulfate, centrifuging, taking filtrate, and recovering dichloromethane under reduced pressure to obtain (+) o-chlorophenyl glycine methyl ester.
Adding 600ml of acetonitrile and 140g of dipotassium phosphate into a three-neck flask, mixing with (+) o-chlorophenyl glycine methyl ester obtained in the previous step, stirring for 1 hour at 30 ℃, adding 170g of 2- (2-thienyl) ethanol p-toluenesulfonate, heating to 52 ℃, keeping the temperature, reacting, centrifuging after the reaction is finished, collecting mother liquor into a reaction container, adding a proper amount of hydrochloric acid while stirring until the pH value is 4, stirring for 4 hours, centrifuging, and drying the obtained solid at 60 ℃ to obtain (+) α - (2-thiophene ethylamino) - α - (2-chlorophenyl) methyl acetate hydrochloride.
Adding the (+) α - (2-thiophene ethylamino) - α - (2-chlorphenyl) methyl acetate hydrochloride obtained in the previous step and 6 times of formaldehyde by weight into a three-neck flask, heating to 45 ℃, keeping the temperature for complete reaction, cooling to room temperature, adding 0.5 times of sodium sulfate by weight, 1 time of purified water by weight and 6.5 times of dichloromethane by weight, stirring, separating, extracting a water layer twice by using dichloromethane, combining organic layers, and recovering the dichloromethane under reduced pressure to obtain (+) clopidogrel free alkali.
Adding (+) clopidogrel free alkali, 5 times of acetone and 0.65 time of levo-camphorsulfonic acid into a three-neck flask, stirring for 24 hours, and centrifuging to obtain (+) clopidogrel camphorsulfonic acid double salt.
Adding 2 times of water, 0.5 time of sodium carbonate, (+) clopidogrel camphorsulfonic acid double salt and 2 times of dichloromethane into a three-neck flask, stirring, separating, extracting an aqueous layer twice by using dichloromethane, standing, separating, combining organic layers, and recovering the dichloromethane under reduced pressure to obtain (+) clopidogrel free alkali.
Adding (+) clopidogrel free alkali and acetone with the weight 5 times of that of the (+) clopidogrel free alkali into a three-neck flask, filtering, cooling filtrate, adding equimolar concentrated sulfuric acid, keeping the temperature at 20 ℃, stirring for 12 hours, centrifuging, and drying at 85 ℃ for 20 hours to obtain a clopidogrel hydrogen sulfate crystal form II which is a tan powdery solid.
Stability test
Stability examination was performed on clopidogrel hydrogen sulfate crystal form II prepared in example 1, and the results are shown in table 3:
TABLE 3 Long-term stability study data for clopidogrel hydrogen sulfate drug substance
Wherein impurity I is impurity A; impurity II is an impurity; monohetero refers to the largest unknown impurity other than the known impurities.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention. It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (7)
1. A preparation method of crystal form II of clopidogrel hydrogen sulfate comprises the following steps:
s1, carrying out hydrolysis reaction on (+) o-chlorophenyl glycine methyl ester tartrate to obtain (+) o-chlorophenyl glycine methyl ester;
s2, adding acetonitrile and inorganic base, mixing with (+) o-chlorophenyl glycine methyl ester, stirring at 20-30 ℃, adding 2- (2-thienyl) ethanol p-toluenesulfonate, heating to 48-52 ℃, carrying out heat preservation reaction, centrifuging after the reaction is finished, adjusting the pH of a mother solution to 3-5, stirring, centrifuging, and drying the obtained solid at 50-60 ℃ to obtain (+) α - (2-thiophene ethylamino) - α - (2-chlorophenyl) acetic acid methyl ester hydrochloride;
s3, mixing the (+) α - (2-thiophene ethylamino) - α - (2-chlorphenyl) methyl acetate hydrochloride with formaldehyde, heating, keeping the temperature for complete reaction, cooling, adding inorganic base, water and dichloromethane, stirring, separating, extracting, and combining organic layers to obtain (+) clopidogrel free alkali;
s4, racemizing and splitting the (+) clopidogrel free alkali to obtain (+) clopidogrel camphorsulfonic acid double salt;
s5, hydrolyzing the (+) clopidogrel camphorsulfonic acid double salt to obtain (+) clopidogrel free alkali I;
s6, mixing the (+) clopidogrel free alkali I with acetone, filtering, cooling the filtrate, adding equimolar concentrated sulfuric acid, stirring, centrifuging, and drying to obtain a clopidogrel hydrogen sulfate crystal form II; wherein the mixing ratio of the (+) clopidogrel free alkali I to the acetone is 1: 5-6 in terms of weight ratio; adding the concentrated sulfuric acid, and then keeping the temperature and stirring at 0-10 ℃; the stirring time is 8-20 hours.
2. The method for preparing clopidogrel bisulfate crystal form II according to claim 1, wherein in the step S1, an extracting agent, water and an inorganic base are stirred to be dissolved clearly, (+) o-chlorophenyl glycine methyl ester tartrate is added, liquid separation is carried out after the reaction is completed, an aqueous layer is extracted by the extracting agent, organic layers are combined, drying is carried out by a drying agent, centrifugation is carried out, filtrate is taken, and the extracting agent is recovered under reduced pressure, so as to obtain (+) o-chlorophenyl glycine methyl ester.
3. The method for preparing clopidogrel bisulfate crystal form II according to claim 1, wherein in the S2 step, the molar ratio of the inorganic base to the (+) o-chlorophenyl glycine methyl ester is 2-2.5: 1.
4. The method for preparing clopidogrel bisulfate crystal form II according to claim 1, wherein in the S3 step, the mixing ratio of the (+) α - (2-thienylethylamino) - α - (2-chlorophenyl) acetic acid methyl ester hydrochloride to the formaldehyde is 1: 4-6 by weight.
5. The method for preparing clopidogrel bisulfate crystal form II according to claim 1, wherein in the S3 step, the (+) α - (2-thienylethylamino) - α - (2-chlorophenyl) acetic acid methyl ester hydrochloride is mixed with the formaldehyde and then heated, and the heating temperature is 35 to 45 ℃.
6. The process for the preparation of clopidogrel hydrogen sulfate crystalline form II according to claim 1, wherein the stirring time is 12 hours in the S6 step.
7. The process for the preparation of clopidogrel hydrogen sulfate crystalline form II according to any one of claims 1 to 6, wherein the inorganic base is selected from the group consisting of dipotassium hydrogen phosphate, sodium sulfate, sodium carbonate, potassium carbonate, and disodium hydrogen phosphate.
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Denomination of invention: A preparation method of clopidogrel bisulfate crystal form II Effective date of registration: 20221213 Granted publication date: 20200526 Pledgee: China Construction Bank Corporation Liuyang sub branch Pledgor: HUNAN DINUO PHARMACEUTICAL Co.,Ltd. Registration number: Y2022980026992 |
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