CN112341475A - Preparation method of clopidogrel hydrogen sulfate - Google Patents
Preparation method of clopidogrel hydrogen sulfate Download PDFInfo
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Abstract
The invention relates to a preparation method of clopidogrel hydrogen sulfate, which comprises the following steps: reacting (S) -o-chlorophenyl glycine methyl ester with 1,1,1,3,3, 3-hexamethyldisilazane to obtain trimethylsilyl-protected (S) -o-chlorophenyl glycine methyl ester; adding 2- (2-bromoethyl) thiophene in the presence of acetonitrile, ultrafine potassium carbonate powder and (S) -o-chlorophenyl glycine methyl ester protected by trimethylsilyl, evaporating acetonitrile in batches, adding water and methyl acetate for extraction to obtain a methyl acetate solution of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate, dropwise adding concentrated hydrochloric acid, pulping, cooling to obtain (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride, mixing the hydrochloride with a formaldehyde aqueous solution for reaction, and reacting with concentrated sulfuric acid to obtain clopidogrel hydrogen sulfate. The method can obtain high-purity (S) -2-thiophene ethylamino-2-chlorphenyl methyl acetate hydrochloride and clopidogrel hydrogen sulfate with high efficiency and high yield, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of clopidogrel hydrogen sulfate, belonging to the technical field of chemical synthesis.
Background
Clopidogrel is a platelet aggregation inhibitor, is a new generation anticoagulant drug developed by combining penoxsulam and beumei, can selectively inhibit the combination of ADP and platelet receptors, thereby inhibiting the aggregation and activation of platelets, and is clinically applied to the treatment of acute coronary syndrome, thrombotic complications and the like of atherosclerosis. On 17 d 11/1997, the U.S. Food and Drug Administration (FDA) approved boliv of the company cenoft-antenta for post-myocardial infarction, post-stroke, and confirmed peripheral arterial disease. In 1999, the American Heart institute and American Heart Association guidelines for AMI suggest that hard substitution of ticlopidine is recommended for patients with aspirin allergy or poor drug resistance due to the wide safety margin of clopidogrel. In 2002, 10 months, the american heart society and american heart association published a combination of clopidogrel and aspirin for treatment of unstable angina or non-Q-wave myocardial infarction.
In the prior art, the synthesis route of clopidogrel hydrogen sulfate is as follows:
route 1(CN 104370935):
the synthetic route of the route is short, the total yield is high, but sodium cyanoborohydride is used in the reaction process, and neurotoxic borane gas is generated in the post-treatment process, so that potential safety hazards exist.
Route 2(CN103980288, CN 101333223):
the route 2 has no potential safety hazard, is limited by the highest yield of the chiral resolution of 50 percent, has low total yield of the reaction route and high synthesis cost, uses materials with genotoxicity in the reaction, and improves the research difficulty of the product impurity spectrum. The synthesis reaction time of the key intermediate A is long, and dialkylated impurities and optical isomer impurities are generated, so that the reaction yield of the step is low.
Route 3(CN 10352457):
the method has the advantages of short route, simple operation and no greater potential safety hazard in the production process, but the target product is obtained after the SN1 reaction process in the last step and the manual turnover, the optical purity of the product is low, in addition, the reaction in the last step has great steric hindrance and low reaction activity and conversion rate, and the method provides a challenge for controlling related substances of the final product.
Route 4(Indian Pat2009KO 01373):
the penultimate reaction activity of the route is low, which leads to a serious decrease in the yield of the whole route, and the chiral resolution is carried out in the last step, which is a challenge to the impurity control of the final product.
Route 5 Organic Process Research & Development,13(6), 1195-; 2009
The process has long route and low yield, adopts a chiral induction mode to generate a new chiral center, and has low optical purity.
Route 6, J.Chem.Chem.Chem.17 (3), 163-165; 2007
The process adopts a mode of hand-type resolution to obtain an intermediate containing a hand-type center, so that the yield of the whole process is low, and a large amount of waste containing a hand-type resolving agent is generated. When the key intermediate A is prepared, the reaction time is long, more dialkylated impurity impurities and optical isomers are generated, the yield of the whole route is low, and the optical impurity content of the product is high.
Route 7 CN101121720
The route uses a method of hand type resolution to obtain a precursor with a target product hand type center, and then the precursor is subjected to nucleophilic substitution reaction, reduction reaction and cyclization reaction of amine and bromide to obtain clopidogrel.
Route 8 WO9918110
The synthetic route of the route is short, no potential safety hazard exists, however, the reaction is completed in the last step of reaction through SN1 reaction process to generate the target compound, but practical experiments show that the ee value of the hand form body obtained through hand form turning in SN1 process is lower than the expected value.
Route 9 WO9851682
The route uses a highly toxic chemical sodium cyanide, so that serious potential safety hazards exist; the process of chiral resolution leads to low overall route yields and generates large amounts of waste containing camphorsulfonic or tartaric acids as key intermediates.
Route 10 EP0099802, US4529596
In the route 10, the key intermediate A is prepared in a long reaction time, more optical isomers are generated, more amino dialkylated impurities are generated, and the prepared A is low in purity and low in yield. The optical isomer content of A is high, so that the optical isomer in the final product is large, and the chiral product or the chiral intermediate in the route is obtained by chiral resolution, so that the yield of the whole route is limited.
By comprehensively analyzing the synthetic routes, the reported preparation method of clopidogrel has the following problems:
1) dialkylated impurities are generated in the synthesis of the key intermediate (S) -2-thiophene ethylamino-2-chlorphenyl methyl acetate, so that the reaction selectivity and the yield are low.
One molecule of (S) -o-chlorophenyl glycine methyl ester and one molecule of 2- (2-thienyl) halide or sulfonate are firstly reacted to generate (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate, if more 2- (2-thienyl) halide or sulfonate exists in the reaction system, the reaction system is continuously alkylated with NH in the molecule of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate to generate dialkylated impurities, and the generation of dialkylated impurities cannot be avoided. Therefore, the invention is invented to reduce or even avoid the formation of dialkylated impurities.
2) The synthesis of the key intermediate (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride needs to use inorganic weak base, the reaction is heterogeneous, and the reaction time is long. Therefore, the invention is invented and created for shortening the reaction time.
3) The method for hand-type resolution obtains a hand-type product, has low yield and generates more waste containing the hand-type resolving agent.
4) The 2- (2-thienyl) sulfonate participates in the reaction to prepare clopidogrel hydrogen sulfate, so that the risk of introducing toxic impurities of sulfonate genes in the preparation process is increased.
Aiming at the defects of the method, the invention aims to provide a method for preparing high-purity (S) -2-thiophene ethylamino-2-chlorphenyl methyl acetate hydrochloride and further preparing high-purity clopidogrel hydrogen sulfate, and the method has the advantages of easily available raw materials, simple process, low production cost, good product quality, less generated waste and environmental friendliness.
Disclosure of Invention
The invention provides a preparation method of clopidogrel hydrogen sulfate, aiming at the defects of long preparation reaction time, low product purity, high optical impurity content, low synthesis yield of clopidogrel hydrogen sulfate, high cost, poor product quality, more generated wastes, serious pollution, high cost and the like of an intermediate (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride existing in the prior art.
The technical scheme for solving the technical problems is as follows: a method for preparing clopidogrel hydrogen sulfate (as shown in the following formula 1),
structural formula 1:
the preparation method comprises the following steps:
(1) in the presence of an organic solvent, mixing (S) -o-chlorophenyl glycine methyl ester with 1,1,1,3,3, 3-hexamethyldisilazane, and reacting at the temperature of 25-80 ℃ for 8-16 hours under normal pressure to obtain trimethylsilyl-protected (S) -o-chlorophenyl glycine methyl ester (shown as the following structural formula 2);
structural formula 2:
(2) adding 2- (2-bromoethyl) thiophene in batches in the presence of acetonitrile, ultrafine potassium carbonate powder and trimethylsilyl-protected (S) -o-chlorophenyl glycine methyl ester, reacting at the temperature of 70-80 ℃ for 8-16 hours at normal pressure, and evaporating part of acetonitrile at normal pressure every 4-6 hours to obtain a reaction solution, wherein in the reaction, the (S) -2-thiophene ethylamino-2-chlorophenyl acetic acid methyl ester can be generated at high conversion rate and high selectivity, the proportion of converting the trimethylsilyl-protected (S) -o-chlorophenyl glycine methyl ester into the S) -2-thiophene ethylamino-2-chlorophenyl acetic acid methyl ester is more than 96%, and the proportion of converting the trimethylsilyl-protected (S) -o-chlorophenyl glycine methyl ester into dialkylated impurities is less than 0.5%;
(3) evaporating the solvent from the reaction solution obtained in the step (2) at-0.08 to-0.09 Mp, adding water and methyl acetate for extraction, washing with water to obtain a methyl acetate solution of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate, dropwise adding concentrated hydrochloric acid at controlled temperature until the system is acidic, separating out a white solid, filtering, leaching a filter cake with methyl acetate, and drying the filter cake at 50 to 60 ℃ to obtain a crude product of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride;
(4) mixing the crude (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride with an organic solvent, pulping at 61-71 ℃, cooling to 6-10 ℃, carrying out suction filtration, drying a filter cake to obtain (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride (shown as a structural formula 3), mixing and reacting the (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride with a formaldehyde aqueous solution, and reacting with concentrated sulfuric acid to prepare clopidogrel hydrogen sulfate.
Structural formula 3:
preferably, the organic solvent is one of acetonitrile, dichloromethane, dichloroethane and chloroform.
Preferably, in the step (1), the molar ratio of the S) -o-chlorophenylglycine methyl ester to the 1,1,1,3,3, 3-hexamethyldisilazane is 1.0: 0.5 to 0.8.
Preferably, in the step (2), the molar ratio of the trimethylsilyl-protected (S) -o-chlorophenyl glycine methyl ester, the ultrafine powdered potassium carbonate and the 2- (2-bromoethyl) thiophene is 1.0: 1.1-1.5: 1.01-1.05; the mass ratio of the trimethylsilyl-protected (S) -o-chlorophenyl glycine methyl ester to the acetonitrile is 1: 10-13.
Preferably, in the step (2), the mass ratio of the amount of part of acetonitrile distilled out at normal pressure every 4 to 6 hours to the (S) -o-chlorophenyl glycine methyl ester protected by trimethylsilyl is 2 to 3: 1; the 2- (2-bromoethyl) thiophene added in batches is added in 2-4 batches.
Preferably, the mass ratio of the addition amount of the methyl acetate and water for extraction to the trimethylsilyl-protected (S) -o-chlorophenylglycine methyl ester is 5-8: 4-6: 1.
preferably, in the step (3), the temperature of the hydrochloric acid is controlled to be 6-19 ℃, the concentrated hydrochloric acid is dripped until the system is acidic, namely the pH of the system is 1-5, and the concentrated hydrochloric acid is an HCl aqueous solution with the mass fraction of 30-38%.
More preferably, in the step (3), the temperature of the hydrochloric acid dropwise added under controlled temperature is 10-15 ℃, the dropwise adding of concentrated hydrochloric acid until the system is acidic means that the pH of the system is 1-2, and the concentrated hydrochloric acid is an HCl aqueous solution with the mass fraction of 35-38%.
Preferably, in step (4), the organic solvent is one or more of acetonitrile, ethyl acetate, methanol, ethanol or isopropanol.
More preferably, in step (4), the organic solvent is acetonitrile or a mixture of acetonitrile and ethanol. .
The invention has the beneficial effects that:
1) according to the invention, after amino in (S) -o-chlorophenyl glycine methyl ester molecules in the prior art is protected by trimethylsilyl, when the amino continues to react with 2- (2-bromoethyl) thiophene, dialkylated impurities are greatly reduced, the reaction selectivity is improved, the reaction yield is improved, and the trimethylsilyl protective group is simultaneously removed in the subsequent reaction of dropwise adding hydrochloric acid without special treatment;
2) compared with the prior art, the method of adding 2- (2-bromoethyl) thiophene in batches can ensure that (S) -o-chlorophenyl glycine methyl ester protected by trimethylsilyl is in a large excess state in a reaction system in a longer time compared with 2- (2-bromoethyl) thiophene, thereby reducing the generation of dialkylated impurities to the maximum extent;
3) the method of evaporating partial reaction solvent in batches can improve the reaction concentration of the substrate in the reaction liquid, and the improvement of the concentration of the reaction substrate is beneficial to improving the reaction rate and pushing the reaction balance to move rightwards, so that the substrate is promoted to be converted more, and the purposes of improving the conversion rate and reducing the reaction time are achieved;
4) the superfine potassium carbonate powder is used, so that the acid binding effect can be improved, and the generation of optical isomeric impurities can be reduced; meanwhile, the (S) -2-thiophene ethylamino-2-chlorphenyl methyl acetate hydrochloride is pulped and refined by the selected organic system, so that optical isomers can be further removed, and the optical purity of the product is improved.
In conclusion, the method can obtain high-purity (S) -2-thienylethylamino-2-chlorophenylacetic acid methyl ester hydrochloride and further prepare the high-purity clopidogrel hydrogen sulfate.
Drawings
FIG. 1 is a 1H-NMR chart of methyl (S) -2-thienylethylamino-2-chlorophenylacetate hydrochloride prepared in example 1;
FIG. 2 is a 13C-NMR chart of methyl (S) -2-thienylethylamino-2-chlorophenylacetate hydrochloride prepared in example 1;
FIG. 3 is a 1H-NMR chart of clopidogrel hydrogen sulfate prepared in example 1;
FIG. 4 is a 13C-NMR chart of clopidogrel hydrogen sulfate prepared in example 1.
Detailed Description
The present invention will be described in detail with reference to the following embodiments in order to make the aforementioned objects, features and advantages of the invention more comprehensible. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Example 1
(1) Synthesis of trimethylsilyl protected (S) -o-chlorophenylglycine methyl ester
56.1g (0.3477moL) of 1,1,1,3,3, 3-hexamethyldisilazane (HMDS for short), 138.4g (0.6954moL) of (S) -o-chlorophenyl glycine methyl ester and 348.9g of dichloroethane are added into a reactor, the mixture is heated to 60-80 ℃, the temperature is kept for reaction for 8-16 h, after the reaction is finished, the HMDS is evaporated under reduced pressure (60-80 ℃, minus 0.06 MPa-minus 0.1MPa), 200.1g of light yellow liquid (200.2 g of theoretical yield) is obtained, the yield is 100.0%, and the GC purity is 94.0%.
(2) Synthesis of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride
A three-neck flask, 40.1g (0.1393mol) of trimethylsilyl protected (S) -o-chlorophenylglycine methyl ester, 21.2g (0.1532mol) of ultrafine potassium carbonate powder and 401g of acetonitrile are sequentially added into a reaction flask, 29.1g (0.1407mol) of 2- (2-bromoethyl) thiophene are added in batches, the mixture is heated at 70-80 ℃, the system is refluxed and thermally insulated for reaction, part of acetonitrile is evaporated every 4 hours, after the reaction is carried out for 8-16 hours, the reaction conversion rate reaches 96 percent, and the reaction is stoppedHeating and slowly cooling, taking reaction liquid for testing, wherein the dialkylated impurities are 0.4 percent, and the content of optical isomers is 1.5 percent. T isInner partTransferring the reaction solution into a single-mouth bottle at 50-57 ℃, evaporating to remove the solvent at-0.08 MPa to-0.09 MPa and 50-70 ℃, adding 160g of water and 201g of methyl acetate for extraction, washing with water to obtain a methyl acetate solution of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate, dropwise adding concentrated hydrochloric acid at a controlled temperature until the system is acidic, separating out a white-like solid, filtering, leaching a filter cake with methyl acetate, and drying the filter cake at 50-60 ℃ to obtain 48.0g of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride crude product (the theoretical yield is 48.2g), the HPLC purity is 98.5%, and the optical isomer content is 0.4%. 48.0g of (S) -2-thiophene ethylamino-2-chlorphenyl methyl acetate hydrochloride crude product, 179g of acetonitrile and 13.5g of ethanol are mixed, the mixture is pulped at 50-60 ℃ for more than 1 hour, the temperature is reduced to 6-10 ℃, the mixture is kept for more than 1 hour, the filter cake is filtered and dried at 50-60 ℃ to obtain 46.5g of white solid, the yield is 96.4%, the HPLC purity is 99.91%, the optical isomer content is 0.1%, the dialkylated impurity content is 0.04%, the structure of the white solid is confirmed, 1H-NMR is shown in figure 1, and 13C-NMR data is shown in figure 2, namely (S) -2-thiophene ethylamino-2-chlorphenyl methyl acetate hydrochloride.
(3) Preparation of clopidogrel hydrogen sulfate
Reference is made to the process in US 4529596: 40.0g (0.1155mol) (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride and 93.7g formaldehyde aqueous solution are mixed, reaction is carried out for 12 hours to 19 hours at 36 ℃ to 44 ℃, 11.9g potassium bicarbonate is added in batches, quenching reaction is carried out, 200g dichloromethane is used for extraction, after water washing, solvent is evaporated out to obtain clopidogrel, the clopidogrel is dissolved in 200g acetone, at 6 ℃ to 24 ℃, 37.2g concentrated sulfuric acid is added dropwise, after dropwise addition, the temperature is raised to 36 ℃ to 41 ℃, stirring is carried out for 5 hours to 6 hours, products are separated out, suction filtration, leaching and drying are carried out to obtain white solid, the HPLC purity is 99.95%, the optical isomer content is 0.05%, the structure is confirmed, 1H-NMR is shown in figure 3, and the 13C-NMR data is shown in figure 4, namely the clopidogrel.
Example 2
(1) Synthesis of trimethylsilyl protected (S) -o-chlorophenylglycine methyl ester
67.3g (0.4171moL) of 1,1,1,3,3, 3-hexamethyldisilazane (HMDS for short), 138.4g (0.6954moL) of (S) -o-chlorophenyl glycine methyl ester and 348.9g of dichloroethane are added into a reactor, heated to 60-80 ℃, and reacted for 8-16 hours under heat preservation, after the reaction is finished, the HMDS is evaporated under reduced pressure (60-80 ℃ and-0.06 MPa-0.1 MPa) to obtain 200.2g of light yellow liquid (200.2 g of theoretical yield), the yield is 100.0%, and the GC purity is 97.0%.
(2) Synthesis of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride
A three-neck flask, 40.1g (0.1393mol) of trimethylsilyl protected (S) -o-chlorophenylglycine methyl ester, 25.0g (0.1811mol) of superfine potassium carbonate and 461g of acetonitrile are sequentially added into a reaction flask, 29.7g (0.1435mol) of 2- (2-bromoethyl) thiophene are added in batches, the temperature is between 70 and 80 ℃, the system is heated under reflux and heat preservation, part of acetonitrile is evaporated out every 4 hours, after the reaction is carried out for 8 to 16 hours, the reaction conversion rate reaches 97 percent, the heating is stopped, the temperature is slowly reduced, reaction liquid is taken for testing, the dialkylated impurity is 0.2 percent, and the optical isomer content is 1.0 percent. T isInner partTransferring the reaction solution into a single-mouth bottle at 50-57 ℃, evaporating to remove the solvent at-0.08-0.09 MPa and 50-70 ℃, adding 200g of water and 240g of methyl acetate for extraction, washing with water to obtain a methyl acetate solution of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate, dropwise adding concentrated hydrochloric acid at a controlled temperature until the system is acidic, separating out a white-like solid, filtering, leaching a filter cake with methyl acetate, and drying the filter cake at 50-60 ℃ to obtain 47.6g of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride crude product (the theoretical yield is 48.2 g). 47.6g of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride crude product is mixed with 179g of acetonitrile and 13.5g of ethanol, the mixture is pulped for more than 1 hour at 50-60 ℃, cooled to 6-10 ℃, kept warm for more than 1 hour, filtered, and the filter cake is dried at 50-60 ℃ to obtain 46.0g of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride, the yield is 95.4%, the HPLC purity is 99.96%, the optical isomer content is 0.07%, and the dialkylated impurity content is 0.02%.
(3) Preparation of clopidogrel hydrogen sulfate
Reference is made to the process in US 4529596: 40.0g (0.1155mol) of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride is mixed with 117.1g of formaldehyde aqueous solution, the mixture reacts for 12 hours to 19 hours at the temperature of 36 ℃ to 44 ℃, 11.9g of potassium bicarbonate is added in batches to quench the reaction, 200g of dichloromethane is extracted, after washing, the solvent is evaporated out to obtain clopidogrel, the clopidogrel is dissolved in 200g of acetone and at the temperature of 6 ℃ to 24 ℃, 37.2g of concentrated sulfuric acid is added dropwise after the addition, the temperature is raised to 36 ℃ to 41 ℃, the stirring is carried out for 5 hours to 6 hours, the product is separated out, and the product is filtered, leached, dried and prepared into clopidogrel hydrogen sulfate, wherein the HPLC purity of the obtained clopidogrel hydrogen sulfate is 99.96 percent, and the content of.
Example 3
(1) Synthesis of trimethylsilyl protected (S) -o-chlorophenylglycine methyl ester
89.8g (0.5563moL) of 1,1,1,3,3, 3-hexamethyldisilazane (HMDS for short), 138.4g (0.6954moL) of (S) -o-chlorophenyl glycine methyl ester and 348.9g of dichloroethane are added into a reactor, the mixture is heated to 60-80 ℃, the temperature is kept for reaction for 8-16 h, after the reaction is finished, the HMDS is evaporated out by reducing the pressure (60-80 ℃, minus 0.06-minus 0.1MPa) to obtain 200.0g of light yellow liquid (the theoretical yield is 200.2g), the yield is 99.9%, and the GC purity is 96.0%.
Synthesis of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride
A three-neck flask, 40.1g (0.1393mol) of trimethylsilyl protected (S) -o-chlorophenylglycine methyl ester, 28.9g (0.2090mol) of ultrafine potassium carbonate and 521.3g of acetonitrile are sequentially added into the reaction flask, 29.1g (0.1407mol) of 2- (2-bromoethyl) thiophene is added in batches, the reaction is carried out at 70-80 ℃, the system is refluxed and kept warm, part of acetonitrile is evaporated every 4 hours, after the reaction is carried out for 8-16 hours, the reaction conversion rate reaches 98%, the heating is stopped, the temperature is slowly reduced, and a reaction solution is taken for testing, wherein the dialkylated impurities are 0.46%, and the optical isomer content is 1.8%. Transferring the reaction solution into a single-mouth bottle at 50-57 ℃, evaporating to remove the solvent at-0.08 to-0.09 MPa and 50-70 ℃, adding 160g of water and 201g of methyl acetate for extraction, washing with water to obtain a methyl acetate solution of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate, dropwise adding concentrated hydrochloric acid at a controlled temperature until the system is acidic, separating out a white-like solid, filtering, leaching a filter cake with methyl acetate, and drying the filter cake at 50-60 ℃ to obtain 48.2g of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride crude product (the theoretical yield is 48.2 g). 48.2g of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride crude product, 179g of acetonitrile and 13.5g of ethanol are mixed, the mixture is pulped at 50-60 ℃ for more than 1 hour, the temperature is reduced to 6-10 ℃, the temperature is kept for more than 1 hour, the mixture is filtered, and filter cakes are dried at 50-60 ℃ to obtain 47.5g of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride, the yield is 98.5%, the HPLC purity is 99.91%, the optical isomer content is 0.12%, and the dialkylated impurity content is 0.048%.
3) Preparation of clopidogrel hydrogen sulfate
Reference is made to the process in US 4529596: 40.0g (0.1155mol) of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride is mixed with 140.6g of formaldehyde aqueous solution, the mixture reacts for 12 hours to 19 hours at the temperature of 36 ℃ to 44 ℃, 11.9g of potassium bicarbonate is added in batches to quench the reaction, 200g of dichloromethane is extracted, after washing, the solvent is evaporated out to obtain clopidogrel, the clopidogrel is dissolved in 200g of acetone and at the temperature of 6 ℃ to 24 ℃, 37.2g of concentrated sulfuric acid is added dropwise after the addition, the temperature is raised to 36 ℃ to 41 ℃, the stirring is carried out for 5 hours to 6 hours, the product is separated out, and the product is filtered, leached, dried and prepared into clopidogrel hydrogen sulfate, wherein the HPLC purity of the obtained clopidogrel hydrogen sulfate is 99.93 percent, and the content of.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The preparation method of clopidogrel hydrogen sulfate is characterized by comprising the following steps of:
(1) in the presence of an organic solvent, mixing (S) -o-chlorophenyl glycine methyl ester with 1,1,1,3,3, 3-hexamethyldisilazane, and reacting at the temperature of 25-80 ℃ for 8-16 hours under normal pressure to obtain trimethylsilyl-protected (S) -o-chlorophenyl glycine methyl ester;
(2) adding 2- (2-bromoethyl) thiophene in batches in the presence of acetonitrile, ultrafine potassium carbonate and (S) -o-chlorophenyl glycine methyl ester protected by trimethylsilyl, reacting at the temperature of 70-80 ℃ for 8-16 hours under normal pressure, and evaporating part of acetonitrile at normal pressure every 4-6 hours to obtain reaction liquid;
(3) evaporating the solvent from the reaction solution obtained in the step (2) at-0.08 to-0.09 Mp, adding water and methyl acetate for extraction, washing with water to obtain a methyl acetate solution of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate, dropwise adding concentrated hydrochloric acid at controlled temperature until the system is acidic, separating out a white solid, filtering, leaching a filter cake with methyl acetate, and drying the filter cake at 50 to 60 ℃ to obtain a crude product of (S) -2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride;
(4) mixing the crude (S) -2-thiophene ethylamino-2-chlorphenyl methyl acetate hydrochloride with an organic solvent, pulping at 61-71 ℃, cooling to 6-10 ℃, carrying out suction filtration, drying a filter cake to obtain (S) -2-thiophene ethylamino-2-chlorphenyl methyl acetate hydrochloride, mixing the (S) -2-thiophene ethylamino-2-chlorphenyl methyl acetate hydrochloride with a formaldehyde water solution for reaction, and reacting with concentrated sulfuric acid to prepare clopidogrel hydrogen sulfate.
2. The method for preparing clopidogrel bisulfate according to claim 1, wherein the organic solvent is one of acetonitrile, dichloromethane, dichloroethane and chloroform in the step (1).
3. The method for preparing clopidogrel bisulfate according to claim 1, wherein in the step (1), the molar ratio of the S) -o-chlorophenyl glycine methyl ester to 1,1,1,3,3, 3-hexamethyldisilazane is 1.0: 0.5 to 0.8.
4. The method for preparing clopidogrel bisulfate according to claim 1, wherein in the step (2), the molar ratio of trimethylsilyl-protected (S) -o-chlorophenyl glycine methyl ester, ultrafine powdered potassium carbonate and 2- (2-bromoethyl) thiophene is 1.0: 1.1-1.5: 1.01-1.05; the mass ratio of the trimethylsilyl-protected (S) -o-chlorophenyl glycine methyl ester to the acetonitrile is 1: 10-13.
5. The method for preparing clopidogrel bisulfate according to claim 1, wherein in the step (2), the mass ratio of the amount of part of acetonitrile distilled out at normal pressure every 4 to 6 hours to the trimethylsilyl-protected (S) -o-chlorophenyl glycine methyl ester is 2 to 3: 1; the 2- (2-bromoethyl) thiophene added in batches is added in 2-4 batches.
6. The method for preparing clopidogrel bisulfate according to claim 1, wherein in the step (3), the mass ratio of the added amount of the methyl acetate and water for extraction to the trimethylsilyl-protected (S) -o-chlorophenyl glycine methyl ester is 5-8: 4-6: 1.
7. the method for preparing clopidogrel bisulfate according to claim 1, wherein in the step (3), the temperature for dripping hydrochloric acid is controlled to be 6-19 ℃, the dripping of concentrated hydrochloric acid until the system is acidic means that the pH of the system is 1-5, and the concentrated hydrochloric acid is an HCl aqueous solution with the mass fraction of 30-38%.
8. The method for preparing clopidogrel bisulfate according to claim 7, wherein in the step (3), the temperature for dripping hydrochloric acid is controlled to be 10-15 ℃, the dripping of concentrated hydrochloric acid until the system is acidic means that the pH of the system is 1-2, and the concentrated hydrochloric acid is an HCl aqueous solution with the mass fraction of 35-38%.
9. The method for preparing clopidogrel bisulfate according to claim 1, wherein in the step (4), the organic solvent is one or more of acetonitrile, ethyl acetate, methanol, ethanol or isopropanol.
10. The method for preparing clopidogrel bisulfate according to claim 1, wherein the organic solvent is acetonitrile or a mixture of acetonitrile and ethanol in the step (4).
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