Method for splitting clopidogrel and camphorsulfonic acid

Abstract

The invention belongs to the field of drug synthesis, and relates to a method for simultaneously separating clopidogrel and camphorsulfonic acid, which comprises the following steps: reacting (+ / -)-clopidogrel with (+ / -)-10-camphorsulfonic acid in an organic solvent to generate a crystal precipitate of (R)-10-camphorsulfonate of (S)-clopidogrel, filtering, and separating out the crystal precipitate of (R)-10-camphorsulfonate of (R)-clopidogrel. Or separating out the crystal precipitate of the (S)-10-camphorsulfonate of the (R)-clopidogrel, filtering, and then separating out the crystal precipitate of the (R)-10-camphorsulfonate of the (S)-clopidogrel. And four chiral substances, namely (S)-clopidogrel, (R)-clopidogrel, (R)-10-camphorsulfonic acid and (S)-10-camphorsulfonic acid, can be co-produced at the same time.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, relates to a preparation method of (S)-clopidogrel, and also relates to a separation method of chiral 10-camphorsulfonic acid. Background Art

[0002] Clopidogrel, molecular formula: C 16 H 16 ClNO 2 S is an inducible platelet aggregation inhibitor that prevents blood clots from forming in blood vessels by inhibiting platelet aggregation. There is a chiral carbon atom in the molecular structure of clopidogrel, and its S isomer is used clinically because the R isomer has almost no activity in inhibiting platelet aggregation.

[0003] One method of obtaining (S)-clopidogrel is to perform chiral resolution from racemic clopidogrel. For example, Chinese patent application CN101463038 uses (R)-10-camphorsulfonic acid to resolve racemic clopidogrel. The obtained (R)-10-camphorsulfonic acid salt of (S)-clopidogrel can be neutralized with an inorganic weak base, and the (R)-10-camphorsulfonic acid enters the aqueous phase. (S)-clopidogrel is extracted into the organic phase and finally salified with sulfuric acid to generate a conventional pharmaceutical raw material. The remaining (R)-clopidogrel after resolution can be racemized with a strong base to obtain the racemate again.

[0004] The price of chiral 10-camphorsulfonic acid is relatively high. If a lower-priced resolution reagent can be found, it will help reduce the production cost of clopidogrel. Summary of the invention

[0005] The present invention uses a sulfonic acid with a lower price, racemic 10-camphorsulfonic acid, to split racemic clopidogrel, and simultaneously co-produces chiral 10-camphorsulfonic acid, thereby achieving higher economic benefits. From another perspective, the method uses racemic clopidogrel as a splitting reagent to split racemic 10-camphorsulfonic acid into chiral isomers.

[0006] The present invention is achieved through the following technical solutions:

[0007] Step 1: Add (±)-clopidogrel and (±)-10-camphorsulfonic acid to an organic solvent A, and the resulting solution crystallizes spontaneously, or under the induction of a seed crystal of (R)-10-camphorsulfonic acid salt of (S)-clopidogrel, crystals of (R)-10-camphorsulfonic acid salt of (S)-clopidogrel are precipitated.

[0008] Step 2: After filtering out the crystals, the mother liquor is heated to dissolve and then cooled to crystallize spontaneously or under the induction of seed crystals of (S)-10-camphorsulfonate of (R)-clopidogrel, crystals of (S)-10-camphorsulfonate of (R)-clopidogrel are precipitated. Filter.

[0009] Step 3, the two crystals are treated with an aqueous solution of an inorganic weak base, respectively, and extracted with an organic solvent B that is immiscible in water. The crystals of (R)-10-camphorsulfonate of (S)-clopidogrel are treated to obtain a (S)-clopidogrel solution and an (R)-10-camphorsulfonate aqueous solution; the crystals of (S)-10-camphorsulfonate of (R)-clopidogrel are treated to obtain a (R)-clopidogrel solution and an (S)-10-camphorsulfonate aqueous solution.

[0010] The above crystallization order can be reversed, that is, step 1, add (±)-clopidogrel and (±)-10-camphorsulfonic acid to organic solvent A, and the obtained solution crystallizes spontaneously, or under the induction of the crystal seeds of (S)-10-camphorsulfonic acid salt of (R)-clopidogrel, the crystals of (S)-10-camphorsulfonic acid salt of (R)-clopidogrel are precipitated. Step 2, after filtering out the crystals, the mother liquor is heated to dissolve and then cooled, and crystallizes spontaneously, or under the induction of the crystal seeds of (R)-10-camphorsulfonic acid salt of (S)-clopidogrel, the crystals of (R)-10-camphorsulfonic acid salt of (S)-clopidogrel are precipitated. Filter. Step 3 is the same.

[0011] In the above technical scheme, (±)-clopidogrel refers to a mixture of (R)-clopidogrel and (S)-clopidogrel in a molar ratio of 1:1 or close to 1:1, and may sometimes be written as rac-clopidogrel. (±)-10-camphorsulfonic acid refers to a mixture of (R)-10-camphorsulfonic acid and (S)-10-camphorsulfonic acid in a molar ratio of 1:1 or close to 1:1, and may sometimes be written as rac-10-camphorsulfonic acid or DL-camphor-10-sulfonic acid.

[0012] The molar ratio of (±)-clopidogrel to (±)-10-camphorsulfonic acid is (0.9-2):1, preferably (0.95-1.1):1. Experiments have shown that when this ratio is lower than 0.9:1, the yield of crystallization is significantly reduced.

[0013] The organic solvent A of step 1 is selected from toluene, acetone, butanone, ethyl acetate, isopropyl acetate, ethanol, and isopropanol. Toluene, acetone, or ethyl acetate is preferred. The solution can spontaneously crystallize, but the first crystal precipitated may be (S)-10-camphorsulfonate of (R)-clopidogrel, or (R)-10-camphorsulfonate of (S)-clopidogrel. Therefore, it is preferred to use seed crystals to control the type of crystals precipitated each time. In the seed crystals and the precipitated crystals, the molar ratio of clopidogrel to camphorsulfonic acid is 1:1.

[0014] The crystallization temperature of step 1 or step 2 is 0°C to 50°C, preferably 20°C to 30°C. The amount of crystals precipitated in each step must be controlled to be less than 25% yield (relative to the amount of rac-10-camphorsulfonic acid fed), preferably 10% to 20%. Experiments have shown that if the yield is higher than 25%, the optical purity of the product is likely to decrease significantly, and a recrystallization purification step needs to be added.

[0015] The control of the crystallization yield can be achieved by detecting the solute content of the mother liquor in the crystallization system, for example, sampling to detect the density of the mother liquor, titrating to detect the content of camphorsulfonic acid, titrating to detect the content of amino groups, and detecting the content of clopidogrel by high performance liquid chromatography.

[0016] Step 2: After filtering the second batch of crystals, the mother liquor obtained can be supplemented with appropriate amounts of (±)-clopidogrel and (±)-10-camphorsulfonic acid for the next round of separation.

[0017] In step 3, the inorganic weak base can be selected from ammonia, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate. The camphorsulfonic acid in the crystalline product forms ammonium salt, sodium salt or potassium salt respectively and enters the aqueous phase. The released clopidogrel is a water-insoluble oily tertiary amine. The organic solvent B can be selected from dichloromethane, ethyl acetate, isopropyl acetate, n-hexane, cyclohexane, petroleum ether, n-heptane, toluene, isopropyl ether, tert-butyl methyl ether, etc. After the organic solution is concentrated to dryness, clopidogrel is obtained. After the aqueous solution is concentrated to dryness, the corresponding camphorsulfonic acid inorganic salt solid is obtained, or it is converted into camphorsulfonic acid by a known ion exchange method.

[0018] The method starts from non-chiral materials and can simultaneously produce four chiral substances: (S)-clopidogrel, (R)-clopidogrel, (R)-10-camphorsulfonic acid and (S)-10-camphorsulfonic acid.

[0019] BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The organic phase of the present invention is detected by chiral column HPLC method. DETAILED DESCRIPTION

[0021] The present invention is further explained below by way of examples, but the present invention is not limited thereto.

[0022] Example 1

[0023] 180 ml of ethyl acetate was added to 32.2 g (±)-clopidogrel (0.1 mol), and the mixture was heated in a warm water bath to dissolve. 23.2 g (±)-10-camphorsulfonic acid (0.1 mol) was added under stirring, and the mixture was cooled to about 28°C after dissolving. About 0.5 g of crystals of (R)-10-camphorsulfonic acid salt of (S)-clopidogrel were added, and the mixture was stirred for crystallization. The solution was sampled during the reaction, and the concentration change of camphorsulfonic acid therein was detected according to the HPLC method in CN103185750. When the concentration was about 0.8 times that before crystallization, the mixture was filtered, and the crystals were washed with an appropriate amount of ethyl acetate and dried in vacuo to obtain 11.1 g (yield 19% after deducting the seed crystals), which was (R)-10-camphorsulfonic acid salt of (S)-clopidogrel.

[0024] Crystals were treated with an equimolar amount of NaHCO 3 The aqueous solution was treated and extracted with cyclohexane. The specific rotation of the obtained aqueous solution of sodium camphorsulfonate was -20° (c=5). The organic phase was detected by the chiral column HPLC method in CN103308636. Figure 1 As shown, (S)-clopidogrel / (R)-clopidogrel=99.7 / 0.08.

[0025] The mother liquor after crystallization is heated to about 60°C, and after dissolving, the temperature is lowered to about 28°C. About 0.5 g of crystals of (S)-10-camphorsulfonate of (R)-clopidogrel are added, and the mixture is stirred for crystallization. The solution is sampled midway, and when the concentration of camphorsulfonic acid therein decreases to about 0.2 times that before crystallization, it is filtered, and the crystals are washed with an appropriate amount of ethyl acetate and vacuum dried to obtain 11.6 g (yield 21% after deducting the seed crystals).

[0026] Crystals were treated with an equimolar amount of NaHCO 3 The aqueous solution was treated and extracted with cyclohexane, and the specific rotation of the obtained sodium camphorsulfonate aqueous solution was +19° (c=5). The organic phase was detected by chiral column HPLC method, (R)-clopidogrel / (S)-clopidogrel=98.0 / 2.0.

[0027] Example 2

[0028] Referring to Example 1, the solvent ethyl acetate was changed to 200 ml of acetone, the amount of (±)-10-camphorsulfonic acid was changed to 22 g (0.095 mol), and the crystallization temperature was about 22°C. About 0.5 g of (S)-10-camphorsulfonic acid salt of (R)-clopidogrel was first added, and the mixture was stirred for crystallization. The solution was sampled midway, and filtered when the concentration of camphorsulfonic acid therein was about 0.8 times that before crystallization. The crystals were washed with an appropriate amount of cold acetone and vacuum dried to obtain 9.9 g (yield 17% after deducting the seed crystals).

[0029] Crystals were treated with an equimolar amount of NaHCO 3The aqueous solution was treated and extracted with cyclohexane, and the specific rotation of the obtained sodium camphorsulfonate aqueous solution was +20° (c=5). The organic phase was detected by chiral column HPLC method, (R)-clopidogrel / (S)-clopidogrel=99.86 / 0.14.

[0030] The mother liquor after crystallization is heated to about 60°C, cooled to about 25°C after dissolving. About 0.5 g of crystals of (R)-10-camphorsulfonate of (S)-clopidogrel are added, stirred and crystallized. The solution is sampled midway, and filtered when the concentration of camphorsulfonic acid therein decreases to about 0.23 times that before crystallization. The crystals are washed with an appropriate amount of cold acetone and vacuum dried to obtain 13.7 g (yield 24% after deducting the seed crystals).

[0031] Crystals were treated with an equimolar amount of NaHCO 3 The aqueous solution was treated and extracted with cyclohexane, and the specific rotation of the obtained sodium camphorsulfonate aqueous solution was -20° (c=5). The organic phase was detected by chiral column HPLC method, (S)-clopidogrel / (R)-clopidogrel=99.85 / 0.15.

[0032] Comparative Example 1

[0033] Referring to Example 1, after dissolving (±)-clopidogrel and (±)-10-camphorsulfonic acid, the temperature was lowered to 20°C, and about 0.5 g of crystals of (R)-10-camphorsulfonic acid salt of (S)-clopidogrel was added, and the mixture was stirred for crystallization. The solution was sampled midway, and when the concentration of camphorsulfonic acid therein was about 0.6 times that before crystallization, it was filtered, and the crystals were washed with an appropriate amount of ethyl acetate and vacuum dried to obtain 22.1 g (yield after deducting the seed crystals was 39%). The crystals were treated with an equimolar amount of NaHCO 3 The mixture was treated with aqueous solution and extracted with cyclohexane. The organic phase was detected by chiral column HPLC method. (S)-clopidogrel / (R)-clopidogrel=59 / 41.

[0034] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A method for splitting clopidogrel, characterized in that: Step 1, (±)-clopidogrel reacts with (±)-10-camphorsulfonic acid in an organic solvent A, and spontaneous crystallization occurs, or crystals of (R)-10-camphorsulfonic acid salt of (S)-clopidogrel are precipitated under the induction of seed crystals of (R)-10-camphorsulfonic acid salt of (S)-clopidogrel; Step 2: After filtering out the crystals, the mother liquor is spontaneously crystallized, or under the induction of seed crystals of (S)-10-camphorsulfonate of (R)-clopidogrel, crystals of (S)-10-camphorsulfonate of (R)-clopidogrel are precipitated and filtered; Step 3, treating the above two crystals with an aqueous solution of an inorganic weak base respectively, extracting with an organic solvent B that is immiscible with water, and treating the crystals of (R)-10-camphorsulfonate of (S)-clopidogrel to obtain a (S)-clopidogrel solution and an (R)-10-camphorsulfonate aqueous solution; treating the crystals of (S)-10-camphorsulfonate of (R)-clopidogrel to obtain a (R)-clopidogrel solution and an (S)-10-camphorsulfonate aqueous solution; Alternatively, the method for splitting clopidogrel is characterized by: Step 1, (±)-clopidogrel reacts with (±)-10-camphorsulfonic acid in an organic solvent A, and spontaneous crystallization occurs, or crystals of (S)-10-camphorsulfonic acid salt of (R)-clopidogrel are precipitated under the induction of seed crystals of (S)-10-camphorsulfonic acid salt of (R)-clopidogrel; Step 2: After filtering out the crystals, the mother liquor is spontaneously crystallized, or under the induction of seed crystals of (R)-10-camphorsulfonate of (S)-clopidogrel, crystals of (R)-10-camphorsulfonate of (S)-clopidogrel are precipitated and filtered; Step three, the above two crystals are treated with an aqueous solution of an inorganic weak base, respectively, and extracted with an organic solvent B that is immiscible in water. The crystals of (R)-10-camphorsulfonate of (S)-clopidogrel are treated to obtain a (S)-clopidogrel solution and a (R)-10-camphorsulfonate aqueous solution; the crystals of (S)-10-camphorsulfonate of (R)-clopidogrel are treated to obtain a (R)-clopidogrel solution and a (S)-10-camphorsulfonate aqueous solution.

2. The method for splitting clopidogrel according to claim 1, characterized in that: The organic solvent A is selected from toluene, acetone, butanone, ethyl acetate, isopropyl acetate, ethanol, and isopropanol; the organic solvent B is selected from dichloromethane, ethyl acetate, isopropyl acetate, n-hexane, cyclohexane, petroleum ether, n-heptane, toluene, isopropyl ether, tert-butyl methyl ether, etc.; the inorganic weak base is selected from ammonia, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

3. The method for splitting clopidogrel according to claim 1, characterized in that: The molar ratio of (±)-clopidogrel to (±)-10-camphorsulfonic acid is (0.9~2):

1.

4. The method for splitting clopidogrel according to claim 1, characterized in that: The amount of precipitated crystals in step 1 and step 2 must be controlled to be less than 25% yield (relative to the amount of rac-10-camphorsulfonic acid fed).

5. The method for splitting clopidogrel according to claim 1, characterized in that: The organic solvent A is selected from toluene, acetone, and ethyl acetate, and the molar ratio of (±)-clopidogrel to (±)-10-camphorsulfonic acid is (0.95-1.1):1; seed crystals are added in both step 1 and step 2 to induce crystallization; and the amount of precipitated crystals must be controlled within a yield of 10%-20% (relative to the amount of rac-10-camphorsulfonic acid fed).

6. A method for splitting camphorsulfonic acid, characterized in that: Step 1, (±)-clopidogrel reacts with (±)-10-camphorsulfonic acid in an organic solvent A, and spontaneous crystallization occurs, or crystals of (R)-10-camphorsulfonic acid salt of (S)-clopidogrel are precipitated under the induction of seed crystals of (R)-10-camphorsulfonic acid salt of (S)-clopidogrel; Step 2: After filtering out the crystals, the mother liquor is spontaneously crystallized, or under the induction of the seed crystals of (S)-10-camphorsulfonate of (R)-clopidogrel, the crystals of (S)-10-camphorsulfonate of (R)-clopidogrel are precipitated and filtered. Step 3, treating the above two crystals with an aqueous solution of an inorganic weak base respectively, extracting with an organic solvent B that is immiscible with water, and treating the crystals of (R)-10-camphorsulfonate of (S)-clopidogrel to obtain a (S)-clopidogrel solution and an (R)-10-camphorsulfonate aqueous solution; treating the crystals of (S)-10-camphorsulfonate of (R)-clopidogrel to obtain a (R)-clopidogrel solution and an (S)-10-camphorsulfonate aqueous solution; Alternatively, the method for resolving camphorsulfonic acid is characterized by: Step 1, (±)-clopidogrel and (±)-10-camphorsulfonic acid react in an organic solvent A, and spontaneous crystallization occurs, or crystals of (S)-10-camphorsulfonic acid salt of (R)-clopidogrel are precipitated under the induction of seed crystals of (S)-10-camphorsulfonic acid salt of (R)-clopidogrel, Step 2: After filtering out the crystals, the mother liquor spontaneously crystallizes, or under the induction of the seed crystals of (R)-10-camphorsulfonate of (S)-clopidogrel, crystals of (R)-10-camphorsulfonate of (S)-clopidogrel are precipitated. Filter. Step three, the above two crystals are treated with an aqueous solution of an inorganic weak base, respectively, and extracted with an organic solvent B that is immiscible in water. The crystals of (R)-10-camphorsulfonate of (S)-clopidogrel are treated to obtain a (S)-clopidogrel solution and a (R)-10-camphorsulfonate aqueous solution; the crystals of (S)-10-camphorsulfonate of (R)-clopidogrel are treated to obtain a (R)-clopidogrel solution and a (S)-10-camphorsulfonate aqueous solution.

7. The method for splitting camphorsulfonic acid according to claim 6, characterized in that: The organic solvent A is selected from toluene, acetone, butanone, ethyl acetate, isopropyl acetate, ethanol, and isopropanol; the organic solvent B is selected from dichloromethane, ethyl acetate, isopropyl acetate, n-hexane, cyclohexane, petroleum ether, n-heptane, toluene, isopropyl ether, tert-butyl methyl ether, etc.; the inorganic weak base is selected from ammonia, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

8. The method for splitting camphorsulfonic acid according to claim 6, characterized in that: The molar ratio of (±)-clopidogrel to (±)-10-camphorsulfonic acid is (0.9~2):

1.

9. The method for splitting camphorsulfonic acid according to claim 6, characterized in that: The amount of precipitated crystals in step 1 and step 2 must be controlled to be less than 25% yield (relative to the amount of rac-10-camphorsulfonic acid fed).

10. The method for splitting camphorsulfonic acid according to claim 6, characterized in that: The organic solvent A is selected from toluene, acetone, and ethyl acetate. The molar ratio of (±)-clopidogrel to (±)-10-camphorsulfonic acid is (0.95-1.1):1, and seed crystals are added in both step 1 and step 2 to induce crystallization; the amount of precipitated crystals must be controlled within a yield of 10%-20% (relative to the amount of rac-10-camphorsulfonic acid).

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