Recovery process of dextro-camphorsulfonic acid and application of recovery process in preparation of dextro-camphorsulfonic acid clopidogrel

Abstract

The invention discloses a recovery process of dextro-camphorsulfonic acid and application of the recovery process in preparation of dextro-camphorsulfonic acid clopidogrel, and relates to the technical field of dextro-camphorsulfonic acid. When the clopidogrel hydrogen sulfate is produced, the dextro-camphorsulfonic acid in the dextro-camphorsulfonic acid clopidogrel mother liquor and the dextro-camphorsulfonic acid clopidogrel extraction water phase generated in the process is recycled and is applied to preparation of the dextro-camphorsulfonic acid clopidogrel, so that the content of COD (Chemical Oxygen Demand) in the wastewater is reduced; the pollution to the environment is reduced, and the production cost of an enterprise is reduced.

Description

Technical Field

[0001] The invention relates to the technical field of dextrorotatory camphorsulfonic acid, and in particular to a recovery process of dextrorotatory camphorsulfonic acid and application thereof in the preparation of dextrorotatory camphorsulfonic acid clopidogrel. Background Art

[0002] D-(+)-10-Camphorsulfonic acid is an important organic compound with optical activity. It is mainly used as a chiral isomer drug resolution agent. D-(+)-10-Camphorsulfonic acid can be obtained by bromination and sulfonation of natural camphor, or by induced crystallization resolution from racemic camphorsulfonic acid. D-(+)-10-Camphorsulfonic acid is mainly used as a pharmaceutical intermediate or isomer product resolution, especially in the synthesis and resolution of chiral drugs.

[0003] Clopidogrel is an important platelet inhibitor, mainly used to prevent myocardial infarction, stroke and peripheral arterial disease. It inhibits platelet aggregation by selectively inhibiting the binding of adenosine diphosphate (ADP) to platelet receptors. Clopidogrel must undergo biotransformation to work. Clopidogrel (D-camphorsulfonate) is a key intermediate in the synthesis of clopidogrel and has excellent antiplatelet aggregation activity.

[0004] In the production process of clopidogrel hydrogen sulfate, the high-boiling product obtained after acetone is concentrated and recovered from the mother liquor of clopidogrel hydrogen sulfate is reacted with sodium hydroxide to obtain free base, which is then reacted with sulfuric acid to obtain crude clopidogrel hydrogen sulfate; the crude clopidogrel hydrogen sulfate is reacted with sodium bicarbonate to obtain free base, which is then reacted with dextrorotatory camphorsulfonic acid to obtain dextrorotatory camphorsulfonic acid clopidogrel crystal liquid, which is centrifuged to obtain dextrorotatory camphorsulfonic acid clopidogrel wet product and dextrorotatory camphorsulfonic acid clopidogrel mother liquor. Then, the dextrorotatory camphorsulfonic acid clopidogrel wet product is dried to obtain a dry product, which is then reacted with sodium bicarbonate, then extracted with dichloromethane and washed with water, and the extraction and stratification are performed to obtain dextrorotatory camphorsulfonic acid clopidogrel extraction aqueous phase and organic phase, which are then reacted with sulfuric acid to obtain the clopidogrel hydrogen sulfate product.

[0005] Therefore, it is necessary to further treat the clopidogrel camphorsulfonate mother liquor and the clopidogrel camphorsulfonate extraction aqueous phase produced in the above production process to recycle the clopidogrel camphorsulfonic acid therein to reduce the COD content in the wastewater, reduce pollution to the environment, and reduce manufacturing costs. Summary of the invention

[0006] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art, provide a recovery process of dextrorotatory camphorsulfonic acid and an application thereof in the preparation of dextrorotatory camphorsulfonic acid clopidogrel, recover dextrorotatory camphorsulfonic acid from dextrorotatory camphorsulfonic acid clopidogrel mother liquor and dextrorotatory camphorsulfonic acid clopidogrel extraction aqueous phase, recycle it, reduce the COD content in wastewater, reduce pollution to the environment, and reduce the manufacturing cost of the enterprise.

[0007] The technical solution of the present invention is: On the one hand, the present invention provides a process for recovering dextrorotatory camphorsulfonic acid, including a process for recovering dextrorotatory camphorsulfonic acid in a dextrorotatory clopidogrel camphorsulfonic acid mother liquor and a process for recovering dextrorotatory camphorsulfonic acid in a dextrorotatory clopidogrel camphorsulfonic acid extraction aqueous phase; The process for recovering dextrorotatory camphorsulfonic acid from the dextrorotatory clopidogrel camphorsulfonic acid mother liquor comprises the following steps: (1) concentrating and evaporating the clopidogrel camphorsulfonate mother liquor to dryness to obtain a solid material; (2) Dissolve the solid material in dichloromethane, keep stirring at 5-10°C for 0.5-1h, and then adjust the pH of the resulting solution to 6.5-7.5; (3) The temperature is lowered to room temperature, and after the solution is separated into layers, dichloromethane is added to the aqueous phase after separation for extraction; (4) Concentrating and evaporating the extracted aqueous phase; (5) Add ethyl acetate and sulfuric acid, wash with ethyl acetate, then heat to 60-70°C and stir for 0.5-1h; (6) filtration, crystallization at room temperature, centrifugation, washing with ethyl acetate, secondary crystallization and secondary centrifugation; (7) drying the solid obtained by the secondary centrifugation at 15-20° C. and vacuum degree >-0.08 MPa for 1-2 h, and then drying at 30-40° C. and vacuum degree >0.08 MPa for 6-8 h to obtain recovered dextrorotatory camphorsulfonic acid; The process for recovering dextrorotatory camphorsulfonic acid in the aqueous phase of clopidogrel dextrorotatory camphorsulfonic acid extraction comprises the following steps: 1) Concentrating and evaporating the aqueous phase extracted from clopidogrel camphorsulfonate; 2) Add ethyl acetate and sulfuric acid, wash with ethyl acetate, then heat to 60-70°C, keep warm and stir for 0.5-1h; 3) Filter by pressure, wash with ethyl acetate, crystallize at room temperature, centrifuge, crystallize a second time, and centrifuge a second time; 4) The solid obtained by the secondary centrifugation is dried at 15-20° C. and vacuum degree >0.08 MPa for 1-2 h, and then dried at 30-40° C. and vacuum degree >0.08 MPa for 6-8 h to obtain recovered dextrorotatory camphorsulfonic acid.

[0008] Preferably, in step (1), during concentration and evaporation, the vacuum degree is greater than 0.08 MPa and the temperature is 30-40°C.

[0009] Preferably, in step (2), the mass ratio of dichloromethane to dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is (5.5-6):1; the pH of the resulting solution is adjusted by an aqueous sodium bicarbonate solution, wherein the mass ratio of sodium bicarbonate to dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is (0.42-0.48):1, and the mass ratio of water to dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is (3.6-4):1.

[0010] Preferably, in step (3), the mass ratio of dichloromethane to dextrorotatory camphorsulfonic acid in the dextrorotatory clopidogrel camphorsulfonic acid mother liquor is (2.2-2.6):1; in step (4), during concentration and evaporation to dryness, the vacuum degree is >0.08 MPa, and the temperature rises to 60-70°C.

[0011] Preferably, in step (5), the mass ratio of ethyl acetate added for the first time to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is (4-6):1, the mass ratio of sulfuric acid to ethyl acetate added for the first time is 0.1:(0.8-1), and the mass ratio of ethyl acetate used for washing to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is (0.25-0.3):1; in step (6), the mass ratio of ethyl acetate used for washing to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is (0.25-0.3):1.

[0012] Preferably, in step 1), during concentration and evaporation, the vacuum degree is greater than 0.08 MPa and the temperature rises to 45-55°C.

[0013] Preferably, in step 2), the mass ratio of ethyl acetate added for the first time to the dextrorotatory camphorsulfonic acid in the aqueous phase extracted with clopidogrel camphorsulfonic acid is (3.6-4):1, the mass ratio of sulfuric acid to ethyl acetate added for the first time is (0.1-0.12):1, and the mass ratio of ethyl acetate used for washing to the dextrorotatory camphorsulfonic acid in the aqueous phase extracted with clopidogrel camphorsulfonic acid is (0.25-0.3):1; in step 3), the mass ratio of ethyl acetate used for washing to the dextrorotatory camphorsulfonic acid in the aqueous phase extracted with clopidogrel camphorsulfonic acid is (0.25-0.3):1.

[0014] On the other hand, the present invention provides the use of dextrorotatory camphorsulfonic acid recovered by the above-mentioned dextrorotatory camphorsulfonic acid recovery process in the preparation of clopidogrel dextrorotatory camphorsulfonic acid, comprising the following steps: S1: dissolve the crude clopidogrel hydrogen sulfate in dichloromethane, cool the resulting solution to 5-10°C, and stir for 0.5-1h; S2 adjusts the pH of the resulting solution to 6.2-6.5, stirs at 10-15°C for 1-2h, and retests to ensure that the pH is 6.2-6.5; S3: transferring the solution obtained in step S2 to a separatory funnel, allowing it to stand for stratification, and retaining the lower organic phase; adding dichloromethane to the upper aqueous phase, stirring and allowing it to stand for 20-30 minutes, and retaining the lower organic phase after stratification; adding dichloromethane to the upper aqueous phase, stirring and allowing it to stand for 20-30 minutes, and retaining the lower organic phase after stratification; S4 Combine the organic phases in step S3 in a separatory funnel, wash with water, stir and let stand for 20-30 minutes, and retain the lower organic phase after separation; wash the lower organic phase with water, stir and let stand for 1-2 hours, and retain the lower organic phase after separation; S5: transferring the organic phase in step S4 to a volumetric flask and concentrating under reduced pressure, controlling the temperature to be less than 35°C and the pressure to be less than -0.08MPa, and concentrating under reduced pressure until the liquid adheres to the wall and flows out; adding acetone, and concentrating under reduced pressure again, controlling the temperature to be less than 35°C and the pressure to be less than -0.08MPa, and concentrating under reduced pressure until the liquid adheres to the wall and flows out; S6 Add acetone and stir; S7 adds acetone, activated carbon and anhydrous sodium sulfate, controls the temperature to 20-30°C, stirs for 1-2h and then filters; S8: Take the filtrate, add the dextrorotatory camphorsulfonic acid recovered by the above dextrorotatory camphorsulfonic acid recovery process at 20-25°C, stir for 0.5-1h, cool to 6-8°C, crystallize for 5-7h and then centrifuge; S9 vacuum degree>0.08MPa, cold blow for 1-2h, heat to 35-40℃, dry for 6-8h to obtain dextrorotatory clopidogrel camphorsulfonate.

[0015] Preferably, in step S1, the mass ratio of dichloromethane to the crude clopidogrel hydrogen sulfate is (5.5-6):1; in step S3, the mass ratio of dichloromethane added twice to the crude clopidogrel hydrogen sulfate is (2-2.5):1 respectively; in step S4, the mass ratio of water used for the two washings to the crude clopidogrel hydrogen sulfate is (3-4):1 respectively; in step S5, the mass ratio of acetone to the crude clopidogrel hydrogen sulfate is (0.4-0.6):1; in step S6, the mass ratio of acetone to the crude clopidogrel hydrogen sulfate is (0.8-1):1.

[0016] Preferably, in step S7, the mass ratio of acetone to the free alkali in the solution obtained in step S6 is (2.5-2.8):1; the mass ratio of activated carbon to the free alkali in the solution obtained in step S6 is (0.01-0.015):1; the mass ratio of anhydrous sodium sulfate to the free alkali in the solution obtained in step S6 is (0.08-0.1):1; in step S8, the mass ratio of dextrorotatory camphorsulfonic acid to the free alkali in the solution obtained in step S6 is (0.56-0.58):1.

[0017] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention recovers dextrorotatory camphorsulfonic acid from the dextrorotatory camphorsulfonic acid clopidogrel mother liquor and the dextrorotatory camphorsulfonic acid clopidogrel extraction aqueous phase produced in the process of clopidogrel hydrogen sulfate production, and recycles it, thereby reducing the COD content in the wastewater, reducing pollution to the environment, and reducing the manufacturing cost of the enterprise.

[0018] 2. The present invention uses a cheap and easily available solvent, mild reaction conditions, and a simple production process operation to recover the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid clopidogrel mother liquor and the dextrorotatory camphorsulfonic acid clopidogrel extraction aqueous phase, and obtains the recovered dextrorotatory camphorsulfonic acid with a quality equivalent to that of fresh dextrorotatory camphorsulfonic acid. In addition, the present invention also uses the recovered dextrorotatory camphorsulfonic acid to produce dextrorotatory camphorsulfonic acid clopidogrel, and the obtained dextrorotatory camphorsulfonic acid clopidogrel has a quality equivalent to that of dextrorotatory camphorsulfonic acid produced using fresh dextrorotatory camphorsulfonic acid. DETAILED DESCRIPTION

[0019] In order to enable persons skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention.

[0020] In the present invention, the mass calculation formula of dextrorotatory camphorsulfonic acid in dextrorotatory clopidogrel camphorsulfonic acid mother solution is: m=(m0-m1)÷554.12×232.2, wherein m0 is the mass of dextrorotatory camphorsulfonic acid input, g; m1 is the mass of dextrorotatory clopidogrel camphorsulfonic acid dry product obtained, g.

[0021] The mass calculation formula of dextrorotatory camphorsulfonic acid in the aqueous phase extracted with dextrorotatory clopidogrel camphorsulfonate is: m'= m1÷554.12×232.2, where m1 is the mass of the dextrorotatory clopidogrel camphorsulfonate dry product obtained above, g.

[0022] Example 1 The recovery process of dextrorotatory camphorsulfonic acid in this embodiment includes a recovery process of dextrorotatory camphorsulfonic acid in clopidogrel dextrorotatory camphorsulfonic acid mother liquor and a recovery process of dextrorotatory camphorsulfonic acid in clopidogrel dextrorotatory camphorsulfonic acid extraction water phase; The process for recovering dextrorotatory camphorsulfonic acid from the dextrorotatory clopidogrel camphorsulfonic acid mother liquor comprises the following steps: (1) Add clopidogrel camphorsulfonate mother liquor into a reaction kettle, control the vacuum degree to be greater than 0.08 MPa, the temperature to be 33° C., and concentrate until no liquid flows out of the sight glass to obtain a solid material; (2) Cooling to 7°C, dissolving the solid material with dichloromethane, starting stirring, maintaining the temperature and stirring for 45 minutes, and then adjusting the pH of the resulting solution to 7; wherein the mass ratio of dichloromethane to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor of clopidogrel dextrorotatory camphorsulfonic acid is 5.8:1; adjusting the pH of the resulting solution with an aqueous sodium bicarbonate solution, wherein the mass ratio of sodium bicarbonate to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor of clopidogrel dextrorotatory camphorsulfonic acid is 0.46:1, and the mass ratio of water to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor of clopidogrel dextrorotatory camphorsulfonic acid is 3.8:1; (3) The temperature was lowered to room temperature. After the solution was separated into layers, the lower organic phase was released, and dichloromethane was recovered. Dichloromethane was added to the upper aqueous phase for extraction. The mass ratio of dichloromethane to dextrorotatory camphorsulfonic acid in the dextrorotatory clopidogrel camphorsulfonic acid mother solution was 2.5:1. (4) Transfer the extracted aqueous phase to another reactor, control the vacuum degree to >0.08 MPa, raise the temperature to 65°C, and concentrate until no liquid flows out; (5) adding ethyl acetate and sulfuric acid, wherein the mass ratio of ethyl acetate to the dextrorotatory camphorsulfonic acid in the dextrorotatory clopidogrel camphorsulfonic acid mother liquor is 5:1, the rate of sulfuric acid addition is controlled at 2 kg / min, and the mass ratio of sulfuric acid to ethyl acetate is 0.1:0.9; washing with ethyl acetate, wherein the mass ratio of ethyl acetate to the dextrorotatory camphorsulfonic acid in the dextrorotatory clopidogrel camphorsulfonic acid mother liquor is 0.28:1, and then heating to 65° C. and stirring at this temperature for 30 min; (6) Press into another reactor through a bag filter, crystallize at room temperature for 1 hour, turn on centrifugal nitrogen, control the pressure to 0.1 MPa, replace for 3 minutes, put the liquid in the reactor into a centrifuge in batches, add ethyl acetate for washing in the last centrifugation, combine and centrifuge, and centrifuge until no liquid flows out; transfer the centrifuged mother liquor back to the reactor, stir and crystallize at room temperature for 3 hours, put the liquid in the reactor into a centrifuge in batches, and centrifuge until no liquid flows out; wherein, the mass ratio of ethyl acetate used for washing to dextrorotatory camphorsulfonic acid in the dextrorotatory clopidogrel camphorsulfonic acid mother liquor is 0.28:1; (7) The solid obtained by centrifugation is placed in a double-cone rotary vacuum dryer, the hot water tank is heated to 17°C, the vacuum degree is controlled to be greater than -0.08MPa, and the drying is performed for 1.5 hours, and the vacuum degree is recorded every hour; the vacuum degree is controlled to be greater than 0.08MPa, the hot water tank is heated to 35°C, and the drying is performed for 7 hours, and the temperature and vacuum degree are recorded every hour; after the drying is completed, the vacuum valve is closed, and the vent valve is opened to obtain the recovered dextrorotatory camphorsulfonic acid.

[0023] The process for recovering dextrorotatory camphorsulfonic acid in the aqueous phase of clopidogrel dextrorotatory camphorsulfonic acid extraction comprises the following steps: 1) Transfer the aqueous phase extracted from clopidogrel camphorsulfonate to a reactor, set the vacuum degree to >0.08 MPa, raise the temperature to 33°C, and then raise the temperature to 52°C after the system is stable, and concentrate until no liquid flows out; 2) Add ethyl acetate and sulfuric acid, the mass ratio of ethyl acetate to clopidogrel camphorsulfonic acid in the aqueous phase extracted with 3.8:1, and the mass ratio of sulfuric acid to ethyl acetate is 0.11:1; then wash with ethyl acetate, the mass ratio of ethyl acetate to clopidogrel camphorsulfonic acid in the aqueous phase extracted with 0.28:1; then heat to 65°C, keep warm and stir for 45 minutes; 3) filtration, washing with ethyl acetate, crystallization at room temperature for 2.5 hours, centrifugation, secondary crystallization of the centrifuge solution and secondary centrifugation; wherein the mass ratio of ethyl acetate used for washing to dextrorotatory camphorsulfonic acid in the aqueous phase extracted with clopidogrel dextrorotatory camphorsulfonic acid is 0.28:1; 4) The solid obtained by the secondary centrifugation was dried at 17°C and vacuum > 0.08 MPa for 1.5 h, and then dried at 35°C and vacuum > 0.08 MPa for 6 h to obtain recovered dextrorotatory camphorsulfonic acid.

[0024] The dextrorotatory camphorsulfonic acid recovered from the dextrorotatory clopidogrel camphorsulfonic acid mother liquor and the dextrorotatory camphorsulfonic acid recovered from the dextrorotatory clopidogrel camphorsulfonic acid extraction aqueous phase were tested respectively, and the test results are shown in Table 1: Table 1 Detection results of dextrorotatory camphorsulfonic acid recovered from the mother liquor of dextrorotatory camphorsulfonic acid clopidogrel and dextrorotatory camphorsulfonic acid recovered from the aqueous phase extracted from dextrorotatory camphorsulfonic acid clopidogrel

[0025] As can be seen from Table 1, except for the higher sulfate content of the D-camphorsulfonic acid recovered in this example compared with fresh D-camphorsulfonic acid, the appearance, purity, loss on drying, specific rotation, melting point, iron ion content and moisture content of the D-camphorsulfonic acid recovered in this example all meet the standards of fresh D-camphorsulfonic acid.

[0026] The method for preparing clopidogrel (D-camphorsulfonate) by using the D-camphorsulfonic acid recovered above comprises the following steps: S1: Dissolve 30 g of crude clopidogrel hydrogen sulfate in 174 g of dichloromethane, cool the resulting solution to 7 °C, and stir for 30 min; S2 adjusts the pH of the resulting solution to 6.3 by using a sodium bicarbonate aqueous solution (the mass of sodium bicarbonate is 13.8 g and the mass of water is 114 g), stirs at 10°C for 2 h, and retests to ensure that the pH is 6.3; S3: Transfer the solution obtained in step S2 to a separatory funnel, let it stand for 25 minutes to separate the layers, and retain the lower organic phase; add 75g of dichloromethane to the upper aqueous phase, stir for 10 minutes, let it stand for 25 minutes, and retain the lower organic phase after separation; then add 75g of dichloromethane to the upper aqueous phase, stir for 10 minutes, let it stand for 25 minutes, and retain the lower organic phase after separation; S4 Combine the organic phases in step S3 in a separatory funnel, wash with 120 g of water, stir for 10 min, let stand for 25 min, and retain the lower organic phase after separation; wash the lower organic phase with 120 g of water, stir for 10 min, let stand for 1.5 h, and retain the lower organic phase after separation; S5: The organic phase in step S4 is transferred to a volumetric flask and concentrated under reduced pressure, the temperature is controlled to be less than 35°C, the pressure is ≤-0.08MPa, and the liquid is concentrated under reduced pressure until it flows out in a linear manner; 15g of acetone is added, and the phase is concentrated under reduced pressure again, the temperature is controlled to be less than 35°C, the pressure is ≤-0.08MPa, and the liquid is concentrated under reduced pressure until it flows out in a linear manner; S6 added 30g of acetone and stirred, and the free base in the resulting solution was 19g; S7 added 49.4g acetone, 0.247g activated carbon, 1.71g anhydrous sodium sulfate, controlled the temperature at 25°C, stirred for 1.5h and filtered; S8 Take the filtrate, add 10.83 g of dextrorotatory camphorsulfonic acid recovered in step (7) or step 4) at 22°C, stir for 45 minutes, cool to 7°C, crystallize for 6 hours and then centrifuge; S9 vacuum degree>0.08MPa, cold blow for 1h, heat to 37℃, dry for 7h to obtain dextrorotatory clopidogrel camphorsulfonate.

[0027] The dextrorotatory clopidogrel camphorsulfonate prepared in this example was tested, and the test results are shown in Table 2: Table 2 Test results of clopidogrel camphorsulfonate

[0028] As can be seen from Table 2, the isomer content and impurity content of clopidogrel camphorsulfonate prepared by using the dextrorotatory camphorsulfonic acid recovered in this example both reach the standard of clopidogrel camphorsulfonate prepared by fresh dextrorotatory camphorsulfonic acid.

[0029] Example 2 The recovery process of dextrorotatory camphorsulfonic acid in this embodiment includes a recovery process of dextrorotatory camphorsulfonic acid in clopidogrel dextrorotatory camphorsulfonic acid mother liquor and a recovery process of dextrorotatory camphorsulfonic acid in clopidogrel dextrorotatory camphorsulfonic acid extraction water phase; The process for recovering dextrorotatory camphorsulfonic acid from the dextrorotatory clopidogrel camphorsulfonic acid mother liquor comprises the following steps: (1) Add clopidogrel camphorsulfonate mother liquor into a reaction kettle, control the vacuum degree to be greater than 0.08 MPa, the temperature to be 30° C., and concentrate until no liquid flows out of the sight glass to obtain a solid material; (2) Cooling to 5°C, dissolving the solid material with dichloromethane, starting stirring, and maintaining the temperature with stirring for 30 minutes, and then adjusting the pH of the resulting solution to 7; wherein the mass ratio of dichloromethane to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor of clopidogrel dextrorotatory camphorsulfonic acid is 5.5:1; adjusting the pH of the resulting solution with an aqueous sodium bicarbonate solution, wherein the mass ratio of sodium bicarbonate to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor of clopidogrel dextrorotatory camphorsulfonic acid is 0.42:1, and the mass ratio of water to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor of clopidogrel dextrorotatory camphorsulfonic acid is 3.6:1; (3) The temperature was lowered to room temperature. After the solution was separated into layers, the lower organic phase was released, and dichloromethane was recovered. Dichloromethane was added to the upper aqueous phase for extraction. The mass ratio of dichloromethane to dextrorotatory camphorsulfonic acid in the dextrorotatory clopidogrel camphorsulfonic acid mother solution was 2.2:1. (4) Transfer the extracted aqueous phase to another reactor, control the vacuum degree to >0.08 MPa, raise the temperature to 60°C, and concentrate until no liquid flows out; (5) adding ethyl acetate and sulfuric acid, wherein the mass ratio of ethyl acetate to the dextrorotatory camphorsulfonic acid in the dextrorotatory clopidogrel camphorsulfonic acid mother liquor is 4:1, the rate of sulfuric acid addition is controlled at 2 kg / min, and the mass ratio of sulfuric acid to ethyl acetate is 0.1:0.8; washing with ethyl acetate, wherein the mass ratio of ethyl acetate to the dextrorotatory camphorsulfonic acid in the dextrorotatory clopidogrel camphorsulfonic acid mother liquor is 0.25:1, and then heating to 60° C. and stirring at this temperature for 30 min; (6) Press into another reactor through a bag filter, crystallize at room temperature for 1 hour, turn on centrifugal nitrogen, control the pressure to 0.1 MPa, replace for 3 minutes, put the liquid in the reactor into a centrifuge in batches, add ethyl acetate for washing in the last centrifugation, combine and centrifuge, and centrifuge until no liquid flows out; transfer the centrifuged mother liquor back to the reactor, stir and crystallize at room temperature for 3 hours, put the liquid in the reactor into a centrifuge in batches, and centrifuge until no liquid flows out; wherein, the mass ratio of ethyl acetate used for washing to dextrorotatory camphorsulfonic acid in the dextrorotatory clopidogrel camphorsulfonic acid mother liquor is 0.25:1; (7) The solid obtained by centrifugation is placed in a double-cone rotary vacuum dryer, the hot water tank is heated to 15°C, the vacuum degree is controlled to be greater than -0.08MPa, and the drying is performed for 1 hour, and the vacuum degree is recorded once every hour; the vacuum degree is controlled to be greater than 0.08MPa, the hot water tank is heated to 30°C, and the drying is performed for 6 hours, and the temperature and vacuum degree are recorded once every hour; after the drying is completed, the vacuum valve is closed, and the vent valve is opened to obtain the recovered dextrorotatory camphorsulfonic acid.

[0030] The process for recovering dextrorotatory camphorsulfonic acid in the aqueous phase of clopidogrel dextrorotatory camphorsulfonic acid extraction comprises the following steps: 1) Transfer the aqueous phase extracted from clopidogrel camphorsulfonate to a reactor, set the vacuum degree to >0.08 MPa, raise the temperature to 33°C, and then raise the temperature to 45°C after the system is stable, and concentrate until no liquid flows out; 2) Add ethyl acetate and sulfuric acid, the mass ratio of ethyl acetate to clopidogrel camphorsulfonic acid in the aqueous phase extracted with 3.6:1, and the mass ratio of sulfuric acid to ethyl acetate is 0.1:1; then wash with ethyl acetate, the mass ratio of ethyl acetate to clopidogrel camphorsulfonic acid in the aqueous phase extracted with 0.25:1; then heat to 60°C, keep warm and stir for 30 minutes; 3) filtration, washing with ethyl acetate, crystallization at room temperature for 2 hours, centrifugation, secondary crystallization of the centrifuge solution and secondary centrifugation; wherein the mass ratio of ethyl acetate used for washing to dextrorotatory camphorsulfonic acid in the aqueous phase extracted with clopidogrel dextrorotatory camphorsulfonic acid is 0.25:1; 4) The solid obtained by the secondary centrifugation was dried at 15°C and vacuum > 0.08 MPa for 1 h, and then dried at 35°C and vacuum > 0.08 MPa for 6 h to obtain recovered dextrorotatory camphorsulfonic acid.

[0031] The dextrorotatory camphorsulfonic acid recovered from the dextrorotatory clopidogrel camphorsulfonic acid mother liquor and the dextrorotatory camphorsulfonic acid recovered from the dextrorotatory clopidogrel camphorsulfonic acid extraction aqueous phase were tested respectively, and the test results are shown in Table 3: Table 3 Detection results of dextrorotatory camphorsulfonic acid recovered from the mother liquor of dextrorotatory camphorsulfonic acid clopidogrel and dextrorotatory camphorsulfonic acid recovered from the aqueous phase extracted from dextrorotatory camphorsulfonic acid clopidogrel

[0032] As can be seen from Table 3, the sulfate content, appearance, purity, loss on drying, specific rotation, melting point, iron ion content and moisture content of the dextrorotatory camphorsulfonic acid recovered from the dextrorotatory camphorsulfonic acid clopidogrel mother liquor of this embodiment all reached the standards of fresh dextrorotatory camphorsulfonic acid; and the dextrorotatory camphorsulfonic acid recovered from the dextrorotatory camphorsulfonic acid clopidogrel extraction aqueous phase, except that the sulfate content was higher than that of fresh dextrorotatory camphorsulfonic acid, the appearance, purity, loss on drying, specific rotation, melting point, iron ion content and moisture content all reached the standards of fresh dextrorotatory camphorsulfonic acid.

[0033] The method for preparing clopidogrel (D-camphorsulfonate) by using the D-camphorsulfonic acid recovered above comprises the following steps: S1: Dissolve 30 g of crude clopidogrel hydrogen sulfate in 165 g of dichloromethane, cool the resulting solution to 5 °C, and stir for 30 min; S2 adjusts the pH of the resulting solution to 6.2 by using a sodium bicarbonate aqueous solution (in the sodium bicarbonate aqueous solution, the mass of sodium bicarbonate is 12.6 g and the mass of water is 108 g), stirs at 12°C for 1 hour, and repeats the measurement to ensure that the pH is 6.2; S3: Transfer the solution obtained in step S2 to a separatory funnel, let it stand for 20 minutes to separate the layers, and retain the lower organic phase; add 66g of dichloromethane to the upper aqueous phase, stir for 10 minutes, let it stand for 20 minutes, and retain the lower organic phase after separation; then add 66g of dichloromethane to the upper aqueous phase, stir for 10 minutes, let it stand for 20 minutes, and retain the lower organic phase after separation; S4 Combine the organic phases in step S3 in a separatory funnel, wash with 90 g of water, stir for 10 min, let stand for 20 min, and retain the lower organic phase after separation; wash the lower organic phase with 90 g of water, stir for 10 min, let stand for 1 h, and retain the lower organic phase after separation; S5: The organic phase in step S4 is transferred to a volumetric flask and concentrated under reduced pressure, the temperature is controlled to be less than 35°C, the pressure is ≤-0.08MPa, and the liquid is concentrated under reduced pressure until it flows out in a linear manner; 12g of acetone is added, and the phase is concentrated under reduced pressure again, the temperature is controlled to be less than 35°C, the pressure is ≤-0.08MPa, and the liquid is concentrated under reduced pressure until it flows out in a linear manner; S6 added 24g of acetone and stirred, and the free base in the resulting solution was 20g; Add 5g acetone to S7, then add 0.2g activated carbon and 1.6g anhydrous sodium sulfate, control the temperature to 20℃, stir for 2h and filter; S8 Take the filtrate, add 11.2 g of dextrorotatory camphorsulfonic acid recovered in step (7) or step 4) at 20°C, stir for 30 min, cool to 6°C, crystallize for 7 h and then centrifuge; S9 vacuum degree>0.08MPa, cold blow for 1h, heat to 35℃, dry for 8h to obtain dextrorotatory clopidogrel camphorsulfonate.

[0034] The dextrorotatory clopidogrel camphorsulfonate prepared in this example was tested, and the test results are shown in Table 4: Table 4 Test results of clopidogrel camphorsulfonate

[0035] As can be seen from Table 4, the isomer content and impurity content of clopidogrel camphorsulfonate prepared by using the dextrorotatory camphorsulfonic acid recovered in this example both reach the standard of clopidogrel camphorsulfonate prepared by fresh dextrorotatory camphorsulfonic acid.

[0036] Example 3 The recovery process of dextrorotatory camphorsulfonic acid in this embodiment includes a recovery process of dextrorotatory camphorsulfonic acid in clopidogrel dextrorotatory camphorsulfonic acid mother liquor and a recovery process of dextrorotatory camphorsulfonic acid in clopidogrel dextrorotatory camphorsulfonic acid extraction water phase; The process for recovering dextrorotatory camphorsulfonic acid from the dextrorotatory clopidogrel camphorsulfonic acid mother liquor comprises the following steps: (1) Add clopidogrel camphorsulfonate mother liquor into a reaction kettle, control the vacuum degree to be greater than 0.08 MPa, the temperature to be 40° C., and concentrate until no liquid flows out of the sight glass to obtain a solid material; (2) Cooling to 10°C, dissolving the solid material with dichloromethane, starting stirring, and stirring for 1 hour, and then adjusting the pH of the resulting solution to 7.5; wherein the mass ratio of dichloromethane to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor of clopidogrel dextrorotatory camphorsulfonic acid is 6:1; adjusting the pH of the resulting solution with an aqueous sodium bicarbonate solution, wherein the mass ratio of sodium bicarbonate to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor of clopidogrel dextrorotatory camphorsulfonic acid is 0.48:1, and the mass ratio of water to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor of clopidogrel dextrorotatory camphorsulfonic acid is 4:1; (3) The temperature was lowered to room temperature. After the solution was separated into layers, the lower organic phase was released, and dichloromethane was recovered. Dichloromethane was added to the upper aqueous phase for extraction. The mass ratio of dichloromethane to dextrorotatory camphorsulfonic acid in the dextrorotatory clopidogrel camphorsulfonic acid mother solution was 2.6:1. (4) Transfer the extracted aqueous phase to another reactor, control the vacuum degree to >0.08 MPa, raise the temperature to 70°C, and concentrate until no liquid flows out; (5) adding ethyl acetate and sulfuric acid, wherein the mass ratio of ethyl acetate to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is 6:1, the rate of sulfuric acid addition is controlled at 2 kg / min, and the mass ratio of sulfuric acid to ethyl acetate is 0.1:1; washing with ethyl acetate, wherein the mass ratio of ethyl acetate to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is 0.3:1, and then heating to 70°C and stirring at this temperature for 1 hour; (6) Press into another reactor through a bag filter, crystallize at room temperature for 1 hour, turn on centrifugal nitrogen, control the pressure to 0.1 MPa, replace for 3 minutes, put the liquid in the reactor into a centrifuge in batches, add ethyl acetate for washing in the last centrifugation, combine and centrifuge, and centrifuge until no liquid flows out; transfer the centrifuged mother liquor back to the reactor, stir and crystallize at room temperature for 3 hours, put the liquid in the reactor into a centrifuge in batches, and centrifuge until no liquid flows out; wherein, the mass ratio of ethyl acetate used for washing to dextrorotatory camphorsulfonic acid in the dextrorotatory clopidogrel camphorsulfonic acid mother liquor is 0.3:1; (7) The solid obtained by centrifugation is placed in a double-cone rotary vacuum dryer, the hot water tank is heated to 20°C, the vacuum degree is controlled to be greater than -0.08MPa, and the drying is performed for 2 hours, and the vacuum degree is recorded once every hour; the vacuum degree is controlled to be greater than 0.08MPa, the hot water tank is heated to 40°C, and the drying is performed for 8 hours, and the temperature and vacuum degree are recorded once every hour; after the drying is completed, the vacuum valve is closed, and the vent valve is opened to obtain the recovered dextrorotatory camphorsulfonic acid.

[0037] The process for recovering dextrorotatory camphorsulfonic acid in the aqueous phase of clopidogrel dextrorotatory camphorsulfonic acid extraction comprises the following steps: 1) Transfer the aqueous phase extracted from clopidogrel camphorsulfonate to a reaction kettle, set the vacuum degree to >0.08MPa, raise the temperature to 33°C, and then raise the temperature to 55°C after the system is stable, and concentrate until no liquid flows out; 2) Add ethyl acetate and sulfuric acid, the mass ratio of ethyl acetate to clopidogrel camphorsulfonic acid in the aqueous phase extracted was 4:1, and the mass ratio of sulfuric acid to ethyl acetate was 0.12:1; then wash with ethyl acetate, the mass ratio of ethyl acetate to clopidogrel camphorsulfonic acid in the aqueous phase extracted was 0.3:1; then heat to 70°C, keep warm and stir for 1h; 3) filtration, washing with ethyl acetate, crystallization at room temperature for 3 hours, centrifugation, secondary crystallization of the centrifuge solution and secondary centrifugation; wherein the mass ratio of ethyl acetate used for washing to dextrorotatory camphorsulfonic acid in the aqueous phase extracted with clopidogrel dextrorotatory camphorsulfonic acid is 0.3:1; 4) The solid obtained by the secondary centrifugation was dried at 20°C and vacuum > 0.08 MPa for 2 h, and then dried at 40°C and vacuum > 0.08 MPa for 8 h to obtain recovered dextrorotatory camphorsulfonic acid.

[0038] The dextrorotatory camphorsulfonic acid recovered from the dextrorotatory clopidogrel camphorsulfonic acid mother liquor and the dextrorotatory camphorsulfonic acid recovered from the dextrorotatory clopidogrel camphorsulfonic acid extraction aqueous phase were tested respectively, and the test results are shown in Table 5: Table 5 Detection results of dextrorotatory camphorsulfonic acid recovered from the mother liquor of dextrorotatory camphorsulfonic acid clopidogrel and dextrorotatory camphorsulfonic acid recovered from the aqueous phase extracted from dextrorotatory camphorsulfonic acid clopidogrel

[0039] As can be seen from Table 5, the sulfate content, appearance, purity, loss on drying, specific rotation, melting point, iron ion content and moisture content of the dextrorotatory camphorsulfonic acid recovered from the dextrorotatory camphorsulfonic acid clopidogrel mother liquor of this embodiment all reached the standards of fresh dextrorotatory camphorsulfonic acid; and the dextrorotatory camphorsulfonic acid recovered from the dextrorotatory camphorsulfonic acid clopidogrel extraction aqueous phase, except for the higher sulfate content compared with fresh dextrorotatory camphorsulfonic acid, the appearance, purity, loss on drying, specific rotation, melting point, iron ion content and moisture content all reached the standards of fresh dextrorotatory camphorsulfonic acid.

[0040] The method for preparing clopidogrel (D-camphorsulfonate) by using the D-camphorsulfonic acid recovered above comprises the following steps: S1: Dissolve 30 g of crude clopidogrel hydrogen sulfate in 180 g of dichloromethane, cool the resulting solution to 10 °C, and stir for 1 h; S2 adjusts the pH of the resulting solution to 6.5 by sodium bicarbonate aqueous solution (in the sodium bicarbonate aqueous solution, the mass of sodium bicarbonate is 13.8 g and the mass of water is 100 g), stirs at 15°C for 2 h, and retests to ensure that the pH is 6.5; S3: Transfer the solution obtained in step S2 to a separatory funnel, let it stand for 30 minutes to separate the layers, and retain the lower organic phase; add 60g of dichloromethane to the upper aqueous phase, stir for 10 minutes, let it stand for 30 minutes, and retain the lower organic phase after separation; then add 60g of dichloromethane to the upper aqueous phase, stir for 10 minutes, let it stand for 30 minutes, and retain the lower organic phase after separation; S4: Combine the organic phases in step S3 in a separatory funnel, wash with 100 g of water, stir for 10 min, let stand for 30 min, and retain the lower organic phase after separation; wash the lower organic phase with 100 g of water, stir for 10 min, let stand for 2 h, and retain the lower organic phase after separation; S5: The organic phase in step S4 is transferred to a volumetric flask and concentrated under reduced pressure, the temperature is controlled to be less than 35°C, the pressure is ≤-0.08MPa, and the liquid is concentrated under reduced pressure until it flows out in a linear manner; 15g of acetone is added, and the phase is concentrated under reduced pressure again, the temperature is controlled to be less than 35°C, the pressure is ≤-0.08MPa, and the liquid is concentrated under reduced pressure until it flows out in a linear manner; S6 added 26g of acetone and stirred, and the free base in the resulting solution was 22g; S7 added 59.4g acetone, then added 3.3g activated carbon and 2.2g anhydrous sodium sulfate, controlled the temperature at 30°C, stirred for 2h and filtered; S8 Take the filtrate, add 12.76 g of dextrorotatory camphorsulfonic acid recovered in step (7) or step 4) at 25°C, stir for 1 hour, cool to 8°C, crystallize for 7 hours and then centrifuge; S9 vacuum degree>0.08MPa, cold blow for 2h, heat to 40℃, dry for 8h to obtain dextrorotatory clopidogrel camphorsulfonate.

[0041] The dextrorotatory clopidogrel camphorsulfonate prepared in this example was tested, and the test results are shown in Table 6: Table 6 Detection results of clopidogrel camphorsulfonate

[0042] As can be seen from Table 6, the isomer content and impurity content of clopidogrel camphorsulfonate prepared by using the dextrorotatory camphorsulfonic acid recovered in this example both reach the standard of clopidogrel camphorsulfonate prepared by fresh dextrorotatory camphorsulfonic acid.

Claims

1. A recovery process for right-rotation camphorsulfonic acid, characterized in that: It includes a process for recovering dextrorotatory camphorsulfonic acid in clopidogrel dextrorotatory camphorsulfonic acid mother liquor and a process for recovering dextrorotatory camphorsulfonic acid in a dextrorotatory camphorsulfonic acid clopidogrel extraction water phase; The process for recovering dextrorotatory camphorsulfonic acid from the dextrorotatory clopidogrel camphorsulfonic acid mother liquor comprises the following steps: (1) concentrating and evaporating the clopidogrel camphorsulfonate mother liquor to dryness to obtain a solid material; (2) Dissolve the solid material in dichloromethane, keep stirring at 5-10°C for 0.5-1h, and then adjust the pH of the resulting solution to 6.5-7.5; (3) The temperature is lowered to room temperature, and after the solution is separated into layers, dichloromethane is added to the aqueous phase after separation for extraction; (4) Concentrating and evaporating the extracted aqueous phase; (5) Add ethyl acetate and sulfuric acid, wash with ethyl acetate, then heat to 60-70°C and stir for 0.5-1h; (6) filtration, crystallization at room temperature, centrifugation, washing with ethyl acetate, secondary crystallization and secondary centrifugation; (7) drying the solid obtained by the secondary centrifugation at 15-20° C. and vacuum degree >-0.08 MPa for 1-2 h, and then drying at 30-40° C. and vacuum degree >0.08 MPa for 6-8 h to obtain recovered dextrorotatory camphorsulfonic acid; The process for recovering dextrorotatory camphorsulfonic acid in the aqueous phase of clopidogrel dextrorotatory camphorsulfonic acid extraction comprises the following steps: 1) Concentrating and evaporating the aqueous phase extracted from clopidogrel camphorsulfonate; 2) Add ethyl acetate and sulfuric acid, wash with ethyl acetate, then heat to 60-70°C, keep warm and stir for 0.5-1h; 3) Filter by pressure, wash with ethyl acetate, crystallize at room temperature, centrifuge, crystallize a second time, and centrifuge a second time; 4) The solid obtained by the secondary centrifugation is dried at 15-20° C. and vacuum degree >0.08 MPa for 1-2 h, and then dried at 30-40° C. and vacuum degree >0.08 MPa for 6-8 h to obtain recovered dextrorotatory camphorsulfonic acid.

2. The recovery process of right-rotation camphorsulfonic acid as claimed in claim 1, characterized in that: In step (1), during concentration and evaporation, the vacuum degree is greater than 0.08 MPa and the temperature is 30-40°C.

3. The recovery process of right-rotation camphorsulfonic acid as claimed in claim 1, characterized in that: In step (2), the mass ratio of dichloromethane to dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is (5.5-6):1; the pH of the obtained solution is adjusted by sodium bicarbonate aqueous solution, wherein the mass ratio of sodium bicarbonate to dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is (0.42-0.48):1, and the mass ratio of water to dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is (3.6-4):

1.

4. The recovery process of right-rotation camphorsulfonic acid as claimed in claim 1, characterized in that: In step (3), the mass ratio of dichloromethane to dextrorotatory camphorsulfonic acid in the dextrorotatory clopidogrel camphorsulfonic acid mother liquor is (2.2-2.6):1; in step (4), during concentration and evaporation, the vacuum degree is greater than 0.08 MPa, and the temperature rises to 60-70°C.

5. The recovery process of right-rotation camphorsulfonic acid as claimed in claim 1, characterized in that: In step (5), the mass ratio of ethyl acetate added for the first time to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is (4-6):1, the mass ratio of sulfuric acid to ethyl acetate added for the first time is 0.1:(0.8-1), and the mass ratio of ethyl acetate used for washing to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is (0.25-0.3):1; in step (6), the mass ratio of ethyl acetate used for washing to the dextrorotatory camphorsulfonic acid in the dextrorotatory camphorsulfonic acid mother liquor is (0.25-0.3):

1.

6. The recovery process of right-rotation camphorsulfonic acid as claimed in claim 1, characterized in that: In step 1), when concentrating and evaporating to dryness, the vacuum degree is greater than 0.08 MPa and the temperature rises to 45-55°C.

7. The recovery process of right-rotational camphorsulfonic acid as claimed in claim 1, characterized in that: In step 2), the mass ratio of ethyl acetate added for the first time to the dextrorotatory camphorsulfonic acid in the aqueous phase extracted with clopidogrel camphorsulfonic acid is (3.6-4):1, the mass ratio of sulfuric acid to ethyl acetate added for the first time is (0.1-0.12):1, and the mass ratio of ethyl acetate used for washing to the dextrorotatory camphorsulfonic acid in the aqueous phase extracted with clopidogrel camphorsulfonic acid is (0.25-0.3):1; in step 3), the mass ratio of ethyl acetate used for washing to the dextrorotatory camphorsulfonic acid in the aqueous phase extracted with clopidogrel camphorsulfonic acid is (0.25-0.3):

1.

8. Use of dextrorotatory camphorsulfonic acid recovered by the recovery process of dextrorotatory camphorsulfonic acid according to any one of claims 1 to 7 in the preparation of clopidogrel dextrorotatory camphorsulfonic acid, characterized in that: The following steps are involved: S1: dissolve the crude clopidogrel hydrogen sulfate in dichloromethane, cool the resulting solution to 5-10°C, and stir for 0.5-1h; S2 adjusts the pH of the resulting solution to 6.2-6.5, stirs at 10-15°C for 1-2h, and retests to ensure that the pH is 6.2-6.5; S3: transferring the solution obtained in step S2 to a separatory funnel, allowing it to stand for stratification, and retaining the lower organic phase; adding dichloromethane to the upper aqueous phase, stirring and allowing it to stand for 20-30 minutes, and retaining the lower organic phase after stratification; adding dichloromethane to the upper aqueous phase, stirring and allowing it to stand for 20-30 minutes, and retaining the lower organic phase after stratification; S4 Combine the organic phases in step S3 in a separatory funnel, wash with water, stir and let stand for 20-30 minutes, and retain the lower organic phase after separation; wash the lower organic phase with water, stir and let stand for 1-2 hours, and retain the lower organic phase after separation; S5: transferring the organic phase in step S4 to a volumetric flask and concentrating under reduced pressure, controlling the temperature to be less than 35°C and the pressure to be less than -0.08MPa, and concentrating under reduced pressure until the liquid adheres to the wall and flows out; adding acetone, and concentrating under reduced pressure again, controlling the temperature to be less than 35°C and the pressure to be less than -0.08MPa, and concentrating under reduced pressure until the liquid adheres to the wall and flows out; S6 Add acetone and stir; Add acetone, activated carbon and anhydrous sodium sulfate to S7, control the temperature to 20-30°C, stir for 1-2h and then filter; S8: Take the filtrate, add the dextrorotatory camphorsulfonic acid recovered by the dextrorotatory camphorsulfonic acid recovery process according to any one of claims 1 to 7 at 20-25° C., stir for 0.5-1 h, cool to 6-8° C., crystallize for 5-7 h, and then centrifuge; S9 vacuum degree>0.08MPa, cold blow for 1-2h, heat to 35-40℃, dry for 6-8h to obtain dextrorotatory clopidogrel camphorsulfonate.

9. Use of dextrorotatory camphorsulfonic acid recovered by the recovery process of dextrorotatory camphorsulfonic acid as claimed in claim 8 in the preparation of clopidogrel dextrorotatory camphorsulfonic acid, characterized in that: In step S1, the mass ratio of dichloromethane to the crude clopidogrel hydrogen sulfate is (5.5-6):1; in step S3, the mass ratios of dichloromethane added twice to the crude clopidogrel hydrogen sulfate are respectively (2-2.5):1; in step S4, the mass ratios of water used for two washings to the crude clopidogrel hydrogen sulfate are respectively (3-4):1; in step S5, the mass ratio of acetone to the crude clopidogrel hydrogen sulfate is (0.4-0.6):1; in step S6, the mass ratio of acetone to the crude clopidogrel hydrogen sulfate is (0.8-1):

1.

10. Use of the dextrorotatory camphorsulfonic acid recovered by the recovery process of dextrorotatory camphorsulfonic acid as claimed in claim 8 in the preparation of clopidogrel dextrorotatory camphorsulfonic acid, characterized in that: In step S7, the mass ratio of acetone to the free alkali in the solution obtained in step S6 is (2.5-2.8):1; the mass ratio of activated carbon to the free alkali in the solution obtained in step S6 is (0.01-0.015):1; the mass ratio of anhydrous sodium sulfate to the free alkali in the solution obtained in step S6 is (0.08-0.1):1; in step S8, the mass ratio of dextrorotatory camphorsulfonic acid to the free alkali in the solution obtained in step S6 is (0.56-0.58):1.

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