Preparation method of clopidogrel intermediate (S)-2-(2-chlorphenyl)-2-(2-thiophene ethylamino) methyl acetate hydrochloride

Abstract

The invention discloses a preparation method of a clopidogrel intermediate (S)-2-(2-chlorphenyl)-2-(2-thiophene ethylamino) methyl acetate hydrochloride, and belongs to the technical field of medicine synthesis. (S)-2-chlorophenylglycine methyl ester is used as an initial raw material and firstly reacts with benzaldehyde to generate Schiff base, then the Schiff base reacts with 2-(2-bromoethyl) thiophene to generate imine bromide, and finally the imine bromide is hydrolyzed into salt to obtain the product. The one-pot preparation method adopted by the invention has the advantages of simple process, convenience in operation, no need of resolution, no racemization of the product and the like, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a method for preparing a clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride. Background Art

[0002] Clopidogrel (Clopidogrel, chemical name: (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridinyl-5(4H)-acetic acid methyl ester) is a second-generation adenosine diphosphate receptor antagonist that can irreversibly inhibit platelet aggregation by selectively binding to the ADP receptor coupled to adenylate cyclase on the platelet surface. It is often used to prevent atherosclerosis in patients with a history of myocardial infarction, stroke or peripheral arterial disease. Clopidogrel is usually administered in the form of its hydrogen sulfate salt. Clopidogrel can be prepared by a one-step pictet-Spengler reaction using (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester and formaldehyde, and this method is widely used.

[0003] (S)-2-(2-chlorophenyl)-2-(2-thiopheneethylamino)acetic acid methyl ester is an important intermediate for the synthesis of clopidogrel, a drug for inhibiting platelet aggregation. CN103509035, WO2011012961, CN102320986, and CN107523594 report that the intermediate can be obtained by N-alkylation reaction of chiral o-chlorophenylglycine methyl ester and thiophene ethanol sulfonate (route 1). Although this method can use chiral o-chlorophenylglycine as a starting material, the alkylation step requires the use of a base as an acid-binding agent, which will lead to racemization of the chiral amino acid position and affect the quality of the final product.

[0004]

[0005] Route 1

[0006] CN103450005 reports that the intermediate can also be obtained by first subjecting 2-bromo-(2-chloro)phenylacetic acid methyl ester and thiopheneethylamine to an alkylation reaction and then undergoing chiral separation (route 2). This method requires subsequent separation, which will cause at least half of the materials to be wasted, resulting in excessively high costs.

[0007]

[0008] route

[0009] CN104370935 reports that the intermediate can also be obtained by reductive amination reaction of chiral o-chlorophenylglycine methyl ester and thiophene acetaldehyde (route three). The raw material thiophene acetaldehyde required for this method is too expensive and easily deteriorates, and reducing agents such as sodium borohydride have safety hazards during use and storage.

[0010]

[0011] Route 3 Summary of the invention

[0012] The technical problem solved by the present invention is to provide a method for preparing clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thiopheneethylamino)acetic acid methyl ester hydrochloride to solve the deficiencies of the above-mentioned prior art.

[0013] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0014] A method for preparing a clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride, the method comprising the following steps:

[0015] 1) mixing (S)-o-chlorophenylglycine methyl ester and benzaldehyde to react until completion;

[0016] 2) adding a reaction solvent to the system of step 1), then adding 2-(2-bromoethyl)thiophene, and raising the temperature;

[0017] 3) Cooling the system of step 2) to room temperature, adding water and stirring the reaction until the hydrolysis is complete, adjusting the pH value of the system to 8-9, extracting the product and dissolving it in an alcohol solvent;

[0018] 4) adding an aqueous solution of hydrogen chloride or an organic solution of hydrogen chloride to the alcohol solution obtained in step 3) to obtain (S)-methyl 2-(2-chlorophenyl)-2-(2-thiopheneethylamino)acetate hydrochloride, and refining it with a solvent.

[0019] The reaction formula is as follows:

[0020]

[0021] The step 1) is carried out in the absence of solvent, and the reaction temperature is 25-35°C.

[0022] The molar ratio of (S)-o-chlorophenylglycine methyl ester to benzaldehyde in step 1) is 1:1.

[0023] The step 2) is carried out in an organic solvent, and the organic solvent used is one or more of N-methylpyrrolidone, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, toluene, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0024] The volume of the organic solvent used in step 2) is 3 to 5 times the mass of (S)-o-chlorophenylglycine methyl ester, and the molar amount of 2-(2-bromoethyl)thiophene added is 1.0 to 1.1 times the molar amount of (S)-o-chlorophenylglycine methyl ester.

[0025] The heating temperature of step 2) is 120-130° C., and the reaction time is 10-12 hours.

[0026] The reagent used in step 3) to adjust the pH of the system is one of ammonia water, sodium bicarbonate solution, sodium carbonate solution, and potassium carbonate solution.

[0027] The alcohol solvent in step 3) is one of methanol, ethanol and isopropanol.

[0028] The organic hydrogen chloride solution in step 4) is one of hydrogen chloride methanol solution, hydrogen chloride ethanol solution, hydrogen chloride isopropanol solution, hydrogen chloride ethyl acetate solution, and hydrogen chloride 1,4-dioxane solution.

[0029] The solvent used for refining in step 4) is one or more of methanol, ethanol, isopropanol, acetone and water.

[0030] Compared with the prior art, the present invention has the following advantages:

[0031] The invention provides a method for preparing a clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride by a "one-pot method", which has the advantages of simple process, convenient operation, shortened cycle, safety and environmental protection, no need for splitting, non-racemization of the product, etc., and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0032] The present invention is further illustrated below in conjunction with specific examples. The examples are implemented based on the technical solutions of the present invention. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0033] Example 1

[0034] 1.0 kg (S)-o-chlorophenylglycine methyl ester and 0.53 kg benzaldehyde were added to the reaction bottle and stirred at 25°C for 2 hours. After the reaction was complete, 3.0 L N-methylpyrrolidone was added to the system and stirred for 15 minutes. Then 1.05 kg 2-(2-bromoethyl)thiophene was added and the reaction system was slowly heated to 120°C and kept for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 10 L water was added and stirred for 3 hours. After the hydrolysis was complete, ammonia water was slowly added to adjust the pH value of the system to 8-9, 10 L ethyl acetate was added and stirred for 30 minutes and then allowed to stand for stratification. The organic layer was washed with 10 L water, 10 L The mixture was washed with 10% sodium bisulfite solution, dried over anhydrous sodium sulfate for 2 hours, filtered with suction, the filtrate was concentrated, and 5 L of methanol was added for redissolution; the redissolution was cooled to 0°C, 1.8 L of 4 M hydrogen chloride methanol solution was slowly added, stirred for 30 minutes, and methanol was removed by rotary evaporation to obtain a crude product of (S)-2-(2-chlorophenyl)-2-(2-thiopheneethylamino)acetic acid methyl ester hydrochloride, 4.0 L of methanol was added to the crude product, heated to reflux for 1 hour, cooled to 0°C to precipitate a large amount of white solid, filtered with suction, the filter cake was washed with cold methanol, and dried to obtain 1.31 kg of white powder with a yield of 75.6%, HPLC purity of 99.2%, and optical purity of 99.5%.

[0035] Example 2

[0036] 1.0 kg (S)-o-chlorophenylglycine methyl ester and 0.53 kg benzaldehyde were added to the reaction bottle and stirred at 30°C for 2 hours. After the reaction was complete, 3.0 L N-methylpyrrolidone was added to the system and stirred for 15 minutes. Then 1.15 kg 2-(2-bromoethyl)thiophene was added and the reaction system was slowly heated to 130°C and kept for 11 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 10 L water was added and stirred for 3 hours. After the hydrolysis was complete, ammonia water was slowly added to adjust the pH value of the system to 8-9, 10 L ethyl acetate was added and stirred for 30 minutes and then allowed to stand for stratification. The organic layer was washed with 10 L water, 10 L The product was washed with 10% sodium bisulfite solution, dried over anhydrous sodium sulfate for 2 hours, filtered with suction, the filtrate was concentrated, and 5 L of methanol was added for redissolution; the redissolution was cooled to 0-5°C, 1.8 L of 4 M hydrogen chloride methanol solution was slowly added, stirred for 30 minutes, and methanol was removed by rotary evaporation to obtain a crude product of (S)-2-(2-chlorophenyl)-2-(2-thiopheneethylamino)acetic acid methyl ester hydrochloride, 4.0 L of methanol was added to the crude product, heated to reflux for 1 hour, cooled to 0°C to precipitate a large amount of white solid, filtered with suction, the filter cake was washed with cold methanol, and dried to obtain 1.25 kg of white powder with a yield of 72.1%, HPLC purity of 98.9%, and optical purity of 99.4%.

[0037] Example 3

[0038] 1.0 kg (S)-o-chlorophenylglycine methyl ester and 0.53 kg benzaldehyde were added to the reaction bottle and stirred at 25°C for 2 hours. After the reaction was complete, 3.0 L N, N-dimethylformamide was added to the system and stirred for 15 minutes. Then 1.05 kg 2-(2-bromoethyl)thiophene was added and the reaction system was slowly heated to 130°C and kept for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 10 L water was added and stirred for 3 hours. After the hydrolysis was complete, ammonia water was slowly added to adjust the pH value of the system to 8-9, 10 L ethyl acetate was added and stirred for 30 minutes and then allowed to stand for stratification. The organic layer was washed with 10 L water, 10 L The product was washed with 10% sodium bisulfite solution, dried over anhydrous sodium sulfate for 2 hours, filtered with suction, the filtrate was concentrated, and 5 L of methanol was added for redissolution; the redissolution was cooled to 0°C, 1.8 L of 4 M hydrogen chloride methanol solution was slowly added, stirred for 30 minutes, and methanol was removed by rotary evaporation to obtain a crude product of (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride, 4.0 L of methanol was added to the crude product, heated under reflux for 1 hour, cooled to 0°C to precipitate a large amount of white solid, filtered with suction, the filter cake was washed with cold methanol, and dried to obtain 1.18 kg of white powder with a yield of 68.1%, HPLC purity of 97.6%, and optical purity of 99.1%.

[0039] Example 4

[0040] 100g (S)-o-chlorophenylglycine methyl ester and 53g benzaldehyde were added to the reaction bottle and stirred at 35°C for 2 hours. After the reaction was complete, 500mL N-methylpyrrolidone was added to the system and stirred for 15 minutes. Then 105g 2-(2-bromoethyl)thiophene was added and the reaction system was slowly heated to 125°C and kept for 10 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 1L water was added and stirred for 3 hours. After the hydrolysis was complete, ammonia water was slowly added to adjust the pH value of the system to 8-9, 1L ethyl acetate was added and stirred for 30 minutes and then allowed to stand for stratification. The organic layer was washed with 1L water, 1L The product was washed with 10% sodium bisulfite solution, dried over anhydrous sodium sulfate for 2 hours, filtered with suction, the filtrate was concentrated, and 500 mL of methanol was added for redissolution; the redissolution was cooled to 0°C, 180 mL of 4 M hydrogen chloride methanol solution was slowly added, stirred for 30 minutes, and methanol was removed by rotary evaporation to obtain a crude product of (S)-2-(2-chlorophenyl)-2-(2-thiopheneethylamino)acetic acid methyl ester hydrochloride, 400 mL of methanol was added to the crude product, heated under reflux for 1 hour, cooled to 0°C to precipitate a large amount of white solid, filtered with suction, the filter cake was washed with cold methanol, and dried to obtain 127 g of white powder with a yield of 73.2%, HPLC purity of 99.3%, and optical purity of 99.4%.

[0041] Example 5

[0042] 100g (S)-o-chlorophenylglycine methyl ester and 53g benzaldehyde were added to the reaction bottle and stirred at 35°C for 2 hours. After the reaction was complete, 300mL N-methylpyrrolidone was added to the system and stirred for 15 minutes. Then 105g 2-(2-bromoethyl)thiophene was added and the reaction system was slowly heated to 120°C and kept for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 1L water was added and stirred for 3 hours. After the hydrolysis was complete, a saturated sodium carbonate solution was slowly added to adjust the pH value of the system to 8-9. 1L ethyl acetate was added and stirred for 30 minutes and then allowed to stand for stratification. The organic layer was washed with 1L water, 1L The product was washed with 10% sodium bisulfite solution, dried over anhydrous sodium sulfate for 2 hours, filtered with suction, the filtrate was concentrated, and 500 mL of methanol was added for redissolution; the redissolution was cooled to 0°C, 180 mL of 4 M hydrogen chloride methanol solution was slowly added, stirred for 30 minutes, and methanol was removed by rotary evaporation to obtain a crude product of (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride, 400 mL of methanol was added to the crude product, heated under reflux for 1 hour, cooled to 0°C to precipitate a large amount of white solid, filtered with suction, the filter cake was washed with cold methanol, and dried to obtain 132 g of white powder with a yield of 76.2%, HPLC purity of 99.3%, and optical purity of 99.3%.

[0043] Example 6

[0044] 100g (S)-o-chlorophenylglycine methyl ester and 53g benzaldehyde were added to a reaction bottle and stirred at 25°C for 2 hours. After the reaction was complete, 300mL N-methylpyrrolidone was added to the system and stirred for 15 minutes. Then 105g 2-(2-bromoethyl)thiophene was added and the reaction system was slowly heated to 120°C and kept for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 1L water was added and stirred for 3 hours. After the hydrolysis was complete, ammonia water was slowly added to adjust the pH value of the system to 8-9, 1L ethyl acetate was added and stirred for 30 minutes and then allowed to stand for stratification. The organic layer was washed with 1L water, 1L The product was washed with 10% sodium bisulfite solution, dried over anhydrous sodium sulfate for 2 hours, filtered with suction, the filtrate was concentrated, and 500 mL of methanol was added for redissolution; the redissolution was cooled to 0°C, 180 mL of 4 M hydrogen chloride ethyl acetate solution was slowly added, stirred for 30 minutes, and the solvent was removed by rotary evaporation to obtain a crude product of (S)-2-(2-chlorophenyl)-2-(2-thiopheneethylamino)acetic acid methyl ester hydrochloride, 400 mL of methanol was added to the crude product, heated under reflux for 1 hour, cooled to 0°C to precipitate a large amount of white solid, filtered with suction, the filter cake was washed with cold methanol, and dried to obtain 130 g of white powder with a yield of 75.0%, HPLC purity of 99.3%, and optical purity of 99.2%.

[0045] Example 7

[0046] 100g (S)-o-chlorophenylglycine methyl ester and 53g benzaldehyde were added to the reaction bottle and stirred at 25°C for 2 hours. After the reaction was complete, 300mL N-methylpyrrolidone was added to the system and stirred for 15 minutes. Then 105g 2-(2-bromoethyl)thiophene was added and the reaction system was slowly heated to 120°C and kept for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 1L water was added and stirred for 3 hours. After the hydrolysis was complete, ammonia water was slowly added to adjust the pH value of the system to 8-9, 1L ethyl acetate was added and stirred for 30 minutes and then allowed to stand for stratification. The organic layer was washed with 1L water, 1L The product was washed with 10% sodium bisulfite solution, dried over anhydrous sodium sulfate for 2 hours, filtered with suction, the filtrate was concentrated, and 500 mL of methanol was added for redissolution; the redissolution was cooled to 0°C, 180 mL of 4 M hydrogen chloride methanol solution was slowly added, stirred for 30 minutes, and methanol was removed by rotary evaporation to obtain a crude product of (S)-2-(2-chlorophenyl)-2-(2-thiopheneethylamino)acetic acid methyl ester hydrochloride, 400 mL of a methanol / water (volume ratio of 3 / 1) mixed solution was added to the crude product, heated to reflux for 1 hour, cooled to 0°C to precipitate a large amount of white solid, filtered with suction, the filter cake was washed with cold methanol, and dried to obtain 139 g of white powder with a yield of 80.1%, HPLC purity of 98.4%, and optical purity of 99.4%.

[0047] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride, characterized in that: The following steps are involved: 1) mixing (S)-o-chlorophenylglycine methyl ester and benzaldehyde to react until completion; 2) adding a reaction solvent to the system of step 1), then adding 2-(2-bromoethyl)thiophene, and raising the temperature; 3) Cooling the system of step 2) to room temperature, adding water and stirring the reaction until the hydrolysis is complete, adjusting the pH value of the system to 8-9, extracting the product and dissolving it in an alcohol solvent; 4) adding an aqueous solution of hydrogen chloride or an organic solution of hydrogen chloride to the alcohol solution obtained in step 3) to obtain (S)-2-(2-chlorophenyl)-2-(2-thiopheneethylamino)acetic acid methyl ester hydrochloride, and refining it with a solvent; The reaction formula is as follows:

2. The method for preparing the clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride according to claim 1, characterized in that: The step 1) is carried out in the absence of solvent, and the reaction temperature is 25-35°C.

3. The method for preparing the clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride according to claim 1, characterized in that: The molar ratio of (S)-o-chlorophenylglycine methyl ester to benzaldehyde in step 1) is 1:

1.

4. The method for preparing the clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride according to claim 1, characterized in that: The step 2) is carried out in an organic solvent, and the organic solvent used is one or more of N-methylpyrrolidone, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, toluene, N,N-dimethylacetamide, and dimethyl sulfoxide.

5. The method for preparing the clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride according to claim 1, characterized in that: The volume of the organic solvent used in step 2) is 3 to 5 times the mass of (S)-o-chlorophenylglycine methyl ester, and the molar amount of 2-(2-bromoethyl)thiophene added is 1.0 to 1.1 times the molar amount of (S)-o-chlorophenylglycine methyl ester.

6. The method for preparing the clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride according to claim 1, characterized in that: The heating temperature of step 2) is 120-130° C., and the reaction time is 10-12 hours.

7. The method for preparing the clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride according to claim 1, characterized in that: The reagent used in step 3) to adjust the pH of the system is one of ammonia water, sodium bicarbonate solution, sodium carbonate solution, and potassium carbonate solution.

8. The method for preparing the clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride according to claim 1, characterized in that: The alcohol solvent in step 3) is one of methanol, ethanol and isopropanol.

9. The method for preparing the clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride according to claim 1, characterized in that: The organic hydrogen chloride solution in step 4) is one of hydrogen chloride methanol solution, hydrogen chloride ethanol solution, hydrogen chloride isopropanol solution, hydrogen chloride ethyl acetate solution, and hydrogen chloride 1,4-dioxane solution.

10. The method for preparing the clopidogrel intermediate (S)-2-(2-chlorophenyl)-2-(2-thienylethylamino)acetic acid methyl ester hydrochloride according to claim 1, characterized in that: The solvent used for refining in step 4) is one or more of methanol, ethanol, isopropanol, acetone and water.

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