CN111606923B - Synthesis method of racemic clopidogrel - Google Patents
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Abstract
The invention relates to a synthesis method of racemic clopidogrel, which comprises the following steps: 1) uniformly mixing methyl benzoylformate, N-chlorosuccinimide, palladium acetate, a ligand and trifluoroacetic acid, and performing ortho-position chlorination to obtain o-chlorobenzoyl methyl formate; 2) uniformly mixing methyl o-chlorobenzoyl formate and 2-thiophene ethylamine, adding sodium cyanoborohydride and a small amount of acetic acid, and carrying out reductive amination reaction to obtain 2- (2-thiophene ethylamine) (2-chlorphenyl) methyl acetate; 3) uniformly mixing 2- (2-thiophene ethylamino) (2-chlorphenyl) methyl acetate, paraformaldehyde and an acid solution, and carrying out cyclization reaction to obtain racemic clopidogrel. The synthesis method has the advantages of low cost, mild and easily-controlled reaction conditions, and about 50% of overall yield, and has good industrial production prospect.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of racemic clopidogrel.
Background
Clopidogrel is a primary drug of Sanofi, france, and is commonly used as an antithrombotic drug. Mechanistically, clopidogrel is an adenosine diphosphate inhibitor and can react with P2Y on platelets12Receptor binding inhibits the release of the first messenger ADP, which can reduce platelet aggregation and prevent thrombosis. It has wide clinical application and important medical value and economic value.
Clopidogrel is a chiral drug molecule, and can be obtained as a pure product by preparing racemic clopidogrel and splitting, or can be synthesized step by carrying out chiral splitting on raw materials. For example, in patents US4529596, US5036156 and US5204469 of Sanofi corporation, alpha-halogenated o-chlorophenyl methyl acetate and alpha-amino o-chlorophenyl methyl acetate are reacted with corresponding thiophene raw materials respectively to obtain racemic clopidogrel, and then a clopidogrel product with a medium yield can be obtained by chiral resolution. CN100338068 discloses a synthesis method of racemic clopidogrel, which takes benzaldehyde containing substituent groups as a raw material to react with tetrahydrothieno [3,2-c ] pyridine to prepare corresponding clopidogrel and derivatives. These processes still suffer from the disadvantage of using low melting tetrahydrothieno [3,2-c ] pyridine. To avoid the direct use of this compound, CN101845050 uses tetrahydrothieno [3,2-c ] pyridine hydrochloride to introduce thienopyridine group, and R, S-o-chloromandelic acid as a starting material, undergoes four-step reaction and is resolved at a later stage to obtain optically pure clopidogrel. However, in the synthetic route, benzenesulfonyl chloride is required to be used for introducing benzenesulfonyl group, and the benzenesulfonyl chloride is unstable in property, and releases hydrogen chloride irritant gas after absorbing moisture, thereby causing certain harm. Subsequently, CN102336766 discloses a one-pot method for preparing racemic clopidogrel, which takes alpha-bromo-o-chlorophenyl acetic acid as a starting material, and tetrahydrothieno [3,2-c ] pyridine hydrochloride and inorganic base are added in the intermediate process to realize the one-pot method for completing the synthesis of racemic clopidogrel. The method is simpler, but the tetrahydrothieno [3,2-c ] pyridine hydrochloride has higher market price, which causes the increase of the overall cost.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel clopidogrel synthesis method aiming at the defects in the prior art, wherein methyl benzoylformate is taken as a raw material, a catalyst and a ligand play a guiding role together, and an ortho-position C-H bond of the methyl benzoylformate is directly chlorinated, so that the preparation of an important intermediate methyl o-chlorobenzoylformate is realized, and the introduction of a thienopyridine group is realized in an acidic aqueous solution by taking cheap 2-thiopheneethylamine as the raw material and providing a formaldehyde source by paraformaldehyde. Therefore, the synthesis method of racemic clopidogrel has the advantages of cheap and easily obtained raw materials and mild and easily controlled reaction conditions, the whole-process yield is close to 50 percent, and the synthesis method is suitable for industrial mass production.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
provides a synthesis method of racemic clopidogrel, which comprises the following steps:
the specific synthesis method comprises the following steps:
1) dissolving methyl benzoylformate, N-chlorosuccinimide (NCS), palladium acetate, a ligand and trifluoroacetic acid in a solvent, uniformly mixing, reacting at 30-120 ℃ for 8-48 hours, and performing aftertreatment to obtain o-chlorobenzoyl methyl formate;
2) adding the o-chlorobenzoyl methyl formate obtained in the step 1) and 2-thiophene ethylamine into a solvent, stirring and mixing uniformly, and then adding sodium cyanoborohydride (NaBH)3CN) and a small amount of acetic acid, and 2- (2-thiophene ethylamino) (2-chlorphenyl) methyl acetate is obtained through reductive amination reaction;
3) adding the methyl 2- (2-thiophene ethylamino) (2-chlorphenyl) acetate obtained in the step 2), paraformaldehyde and an acid solution into a solvent, stirring and mixing uniformly, and carrying out cyclization reaction to obtain the racemic clopidogrel.
According to the scheme, the molar ratio of the N-chlorosuccinimide in the step 1) to the methyl benzoylformate is 1-3: 1, the dosage of palladium acetate is 10-20% of the molar weight of methyl benzoylformate, the dosage of ligand is 20-50% of the molar weight of methyl benzoylformate, and the dosage of trifluoroacetic acid is 5-30 times of the molar weight of methyl benzoylformate.
According to the above scheme, the ligand in step 1) is polysubstituted trifluoromethylaniline selected from the group consisting of 2, 5-bis (trifluoromethyl) aniline (CAS: 328-93-8), 2, 4-bis (trifluoromethyl) aniline (CAS: 367-71-5), 3, 5-bis (trifluoromethyl) aniline (CAS: 328-74-5), 2-methyl-3-trifluoromethylaniline, 3-trifluoromethyl-4-methylaniline (CAS: 54396-44-0). Preferably 3, 5-bis (trifluoromethyl) aniline.
According to the scheme, the solvent in the step 1) is selected from 1, 2-dichloroethane, toluene and chlorobenzene, and the molar volume ratio of the methyl benzoylformate to the solvent is 0.2-1 mol/L.
According to the scheme, the molar ratio of the 2-thiophene ethylamine to the o-chlorobenzoyl methyl formate in the step 2) is 1-1.1: 1, the using amount of the sodium cyanoborohydride is 1-3 times of the molar amount of the o-chlorobenzoyl methyl formate.
According to the scheme, the solvent in the step 2) is selected from dichloromethane, dichloroethane and tetrahydrofuran, and the molar volume ratio of the o-chlorobenzoyl methyl formate to the solvent is 0.5-1 mol/L.
According to the scheme, the reductive amination reaction conditions in the step 2) are as follows: reacting at room temperature (15-35 ℃) for 2-8 hours.
According to the scheme, the molar ratio of the paraformaldehyde to the 2- (2-thiophene ethylamino) (2-chlorphenyl) methyl acetate in the step 3) is 3: 1. the common industrial paraformaldehyde can meet the use requirement.
According to the scheme, the solvent in the step 3) is selected from water, methanol or ethanol.
According to the scheme, the acid solution in the step 3) is an aqueous solution of inorganic acid, the concentration of the acid solution is 0.8-1.2 mol/L, and the volume ratio of the acid solution to the solvent is 0.2-0.3: 100, the inorganic acid is one of sulfuric acid, hydrochloric acid and phosphoric acid. Hydrochloric acid is preferred. The acid solution can promote the hydrolysis of paraformaldehyde to formaldehyde and can also promote the formation of imine intermediates.
According to the scheme, the cyclization reaction conditions in the step 3) are as follows: the molar volume ratio of the 2- (2-thiophene ethylamino) (2-chlorphenyl) methyl acetate to the solvent is 0.1-0.2 mol/L, and the reaction lasts for 2-8 hours at the temperature of 70-90 ℃. The preferable reaction time is 4 to 6 hours.
The method comprises the steps of taking methyl benzoylformate as a raw material, exerting a guiding effect together with a ligand through a catalyst, adding trifluoroacetic acid to promote the methyl benzoylformate and the ligand to form an imine intermediate, directly chlorinating an ortho-position C-H bond of the methyl benzoylformate to realize the direct chlorination of the ortho-position of the methyl benzoylformate to obtain an important intermediate, namely methyl o-chlorobenzoylformate, generating imine through 2-thienylethylamine, carrying out reductive amination, building an acidic environment with a small amount of acetic acid to promote the reaction to occur, providing a formaldehyde source through paraformaldehyde, and introducing a thienopyridine group through a cyclization reaction in an acidic aqueous solution.
The invention has the beneficial effects that: the invention takes methyl benzoylformate as a starting material, has stable property, is cheap and easy to obtain, obtains methyl o-chlorobenzoylformate through direct ortho-position chlorination reaction, further obtains 2- (2-thiophene ethylamine) (2-chlorphenyl) methyl acetate through reductive amination reaction with 2-thiophene ethylamine, and then obtains racemic clopidogrel through cyclization reaction with paraformaldehyde, rather than using tetrahydrothieno [3,2-c ] pyridine or introducing thienopyridine group in the form of hydrochloride thereof, thereby reducing the cost, having mild and easy-controlled reaction conditions in the whole synthesis process, realizing better separation of products in each step, being beneficial to accurately controlling the reaction process, and having the yield of 65 percent in step 1), 82 percent in step 2), 93 percent in step 3) and about 50 percent in the whole process under the conditions of the invention, has good industrial production prospect.
Drawings
FIG. 1 shows the preparation of methyl o-chlorobenzoate according to the invention in example 11H NMR spectrum;
FIG. 2 is a diagram of o-chlorobenzoyl methyl ester prepared in example 113C NMR spectrum;
FIG. 3 is a drawing showing the preparation of methyl 2- (2-thienylethylamino) (2-chlorophenyl) acetate prepared in example 11H NMR spectrum;
FIG. 4 is a drawing showing the preparation of methyl 2- (2-thienylethylamino) (2-chlorophenyl) acetate prepared in example 113C NMR spectrum;
FIG. 5 is a representation of racemic clopidogrel prepared in example 11H NMR spectrum;
FIG. 6 is a representation of racemic clopidogrel prepared in example 113C NMR spectrum.
Detailed Description
In order to make the technical solutions of the present invention better understood, the present invention is further described in detail below with reference to the accompanying drawings.
Example 1
A method for synthesizing racemic clopidogrel comprises the following specific steps:
the first step is as follows: adding 1.5mmol of N-chlorosuccinimide, 0.1mmol of palladium acetate and 2mL of 1, 2-dichloroethane into a pressure-resistant reaction tube, mixing to obtain a solution, adding 1mmol of methyl benzoylformate into the solution, adding 0.2mmol of ligand 3, 5-bis (trifluoromethyl) aniline into the solution, adding 10mmol of trifluoroacetic acid, reacting at 80 ℃ for 24 hours, diluting the obtained reaction solution to 50mL by using dichloromethane, quenching by using 50mL of saturated sodium bicarbonate solution, extracting for three times by using dichloromethane, combining organic phases, adding anhydrous sodium sulfate, drying, carrying out reduced pressure rotary evaporation at 40 ℃ to remove the solvent, and carrying out column chromatography separation in 200-300-mesh silica gel (the eluent is petroleum ether: ethyl acetate ═ 40:1, v/v) to obtain methyl o-chlorobenzoylformate. The yield of this step was 65%.
The second step is that: adding 1.1mmol of 2-thienylethylamine into 2mL of dichloromethane, adding 1.1mmol of methyl o-chlorobenzoate obtained in the first step, 3mmol of sodium cyanoborohydride and a few drops of acetic acid, stirring the obtained mixture at room temperature for 6 hours, quenching the obtained mixture by using 10mL of saturated sodium bicarbonate solution after the reaction is finished, extracting the obtained product for three times by using dichloromethane, combining organic phases, adding anhydrous sodium sulfate for drying, carrying out reduced pressure rotary evaporation at 40 ℃ to remove the solvent, and carrying out column chromatography separation in 200-300-mesh silica gel (the eluent is petroleum ether, and ethyl acetate is 5:1, v/v) to obtain 2- (2-thienylethylamino) (2-chlorophenyl) methyl acetate. The reaction yield for this step was 82%.
The third step: adding 0.3mmol of methyl 2- (2-thienylethylamino) (2-chlorophenyl) acetate obtained in the second step and 0.9mmol of paraformaldehyde into 2mL of water, adding 5. mu.L of HCl solution (1M), stirring the resulting mixture at 80 ℃ for 2 hours, cooling, extracting with ethyl acetate (3X 15mL), combining the organic layers, washing the organic layers with brine (50mL), and adding Na2SO4Drying, concentrating, rotary evaporating at 40 deg.C under reduced pressure to remove solvent, and separating by column chromatography in 200-300 mesh silica gel (eluent dichloromethane: methanol: 30:1, v/v) to obtain the target productRacemic clopidogrel as a colored oil. The yield of this step was 93%. By integrating the three steps, the total yield of the product is 49.7 percent.
As shown in FIG. 1 and FIG. 2, respectively, the o-chlorobenzoyl methyl formate obtained in this example1H NMR spectrum and13the C NMR spectrum of the mixture is shown,1H NMR(500MHz,CDCl3)δ7.76(dd,J＝7.7,1.6Hz,1H),7.55–7.51(m,1H),7.45(dd,J＝8.0,0.9Hz,1H),7.41(td,J＝7.6,1.1Hz,1H),3.96(s,3H).13C NMR(126MHz,CDCl3) δ 186.30,163.53,134.45,134.03,133.37,131.70,130.67,127.36,53.37 from fig. 1 and 2, the chemical structural formula of the obtained product can be judged as follows:
as shown in FIGS. 3 and 4, the production of methyl 2- (2-thienylethylamino) (2-chlorophenyl) acetate obtained in this example1H NMR spectrum and13the C NMR spectrum of the mixture is shown,1H NMR(500MHz,CDCl3)δ7.39–7.36(m,1H),7.35–7.32(m,1H),7.27–7.21(m,2H),7.12(dd,J＝5.1,1.0Hz,1H),6.91(dd,J＝5.1,3.4Hz,1H),6.82(d,J＝3.3Hz,1H),4.93(s,1H),3.69(s,3H),3.02(t,J＝6.9Hz,2H),2.95–2.88(m,1H),2.78(dt,J＝11.4,7.1Hz,1H).13C NMR(126MHz,CDCl3) δ 172.72,142.15,136.10,134.18,129.91,129.27,128.66,127.33,126.86,125.10,123.66,61.61,52.48,49.00,30.54 from fig. 3 and fig. 4, the chemical structural formula of the obtained product can be judged as follows:
as shown in FIG. 5 and FIG. 6, the racemic clopidogrel obtained in the present example is1H NMR spectrum and13the C NMR spectrum of the mixture is shown,1H NMR(500MHz,CDCl3)δ7.71(dd,J＝7.5,2.0Hz,1H),7.41(dd,J＝7.7,1.6Hz,1H),7.32–7.24(m,2H),7.06(d,J＝5.1Hz,1H),6.67(d,J＝5.1Hz,1H),4.93(s,1H),3.77(d,J＝14.1Hz,1H),3.73(s,3H),3.64(d,J＝14.2Hz,1H),2.89(s,4H).13C NMR(126MHz,CDCl3) δ 171.33,134.71,133.87,133.33,133.27,129.98,129.81,129.44,127.17,125.24,122.76,67.90,52.17,50.71,48.32,25.55 from fig. 5 and 6, it can be judged that the chemical structural formula of the obtained product is:
example 2
A method for synthesizing racemic clopidogrel comprises the following specific steps:
the first step is as follows: adding 1.5mmol of N-chlorosuccinimide into a pressure-resistant reaction tube, adding 0.1mmol of palladium acetate, adding 2mL of 1, 2-dichloroethane as a solvent, adding 1mmol of methyl 3-methylbenzoate into the solution, adding 0.3mmol of 3, 5-bis (trifluoromethyl) aniline as a ligand, adding 10mmol of trifluoroacetic acid, reacting at 80 ℃ for 24 hours, diluting the obtained reaction solution to 50mL by dichloromethane, quenching by 50mL of saturated sodium bicarbonate solution, extracting three times by dichloromethane, combining organic phases, adding anhydrous sodium sulfate for drying, removing the solvent by rotary evaporation at 40 ℃ under reduced pressure, and carrying out column chromatography separation in 200-300-mesh silica gel (the eluent is petroleum ether: ethyl acetate: 40:1, v/v) to obtain the methyl o-chlorobenzoate. The yield of this step was 71%.
The second step is that: adding 1.1mmol of 2-thiophene ethylamine into 2mL of dichloromethane, adding 1mmol of o-chlorobenzoyl methyl formate obtained in the first step, 3mmol of sodium cyanoborohydride and a few drops of acetic acid, stirring the obtained mixture at room temperature for 6 hours, quenching the obtained mixture by using 10mL of saturated sodium bicarbonate solution after the reaction is finished, extracting the obtained product for three times by using dichloromethane, combining organic phases, adding anhydrous sodium sulfate for drying, carrying out reduced pressure rotary evaporation at 40 ℃ to remove the solvent, and carrying out column chromatography separation in 200-mesh 300-mesh silica gel (the eluent is petroleum ether, and ethyl acetate is 5:1, v/v) to obtain 2- (2-thiophene ethylamino) (2-chlorphenyl) methyl acetate, wherein the reaction yield of the step is 82%.
The third step: adding 0.3mmol of methyl 2- (2-thienylethylamino) (2-chloro-3-methylphenyl) acetate obtained in the second step and 0.9mmol of paraformaldehyde into 2mL of water, adding 5. mu.L of HCl solution (1M), reacting the resulting mixture at 80 ℃ with stirring for 2 hours, cooling, and reacting with waterEthyl acetate (3X 15mL) was extracted, the organic layers were combined, washed with brine (50mL), Na2SO4Drying, concentrating, rotary evaporating at 40 deg.C under reduced pressure to remove solvent, and performing column chromatography on 200-300 mesh silica gel (eluent is dichloromethane: methanol-30: 1, v/v) to obtain the objective product, namely, racemic clopidogrel as colorless oil. The yield of this step was 93%. The total yield of the product obtained by integrating the three steps is 54.1 percent. The nuclear magnetic data of the product of each step are the same as in example 1.
Claims (10)
1. The synthesis method of racemic clopidogrel is characterized by comprising the following steps:
the specific synthesis method comprises the following steps:
1) dissolving methyl benzoylformate, N-chlorosuccinimide, palladium acetate, a ligand and trifluoroacetic acid in a solvent, uniformly mixing, reacting at 30-120 ℃ for 8-48 hours, and performing post-treatment to obtain o-chlorobenzoyl methyl formate;
2) adding the o-chlorobenzoyl methyl formate obtained in the step 1) and 2-thiophene ethylamine into a solvent, uniformly stirring and mixing, adding sodium cyanoborohydride and a small amount of acetic acid, and carrying out reductive amination reaction to obtain 2- (2-thiophene ethylamino) (2-chlorphenyl) methyl acetate;
3) adding the methyl 2- (2-thiophene ethylamino) (2-chlorphenyl) acetate obtained in the step 2), paraformaldehyde and an acid solution into a solvent, stirring and mixing uniformly, and carrying out cyclization reaction to obtain the racemic clopidogrel.
2. The method for synthesizing racemic clopidogrel according to claim 1, wherein the molar ratio of the N-chlorosuccinimide to the methyl benzoylformate in the step 1) is 1-3: 1, the dosage of palladium acetate is 10-20% of the molar weight of methyl benzoylformate, the dosage of ligand is 20-50% of the molar weight of methyl benzoylformate, and the dosage of trifluoroacetic acid is 5-30 times of the molar weight of methyl benzoylformate.
3. The method for synthesizing racemic clopidogrel according to claim 1, wherein the ligand in step 1) is polysubstituted trifluoromethylaniline selected from the group consisting of 2, 5-bis (trifluoromethyl) aniline, 2, 4-bis (trifluoromethyl) aniline, 3, 5-bis (trifluoromethyl) aniline, 2-methyl-3-trifluoromethylaniline, and 3-trifluoromethyl-4-methylaniline.
4. The method for synthesizing racemic clopidogrel according to claim 1, characterized in that the solvent in step 1) is selected from 1, 2-dichloroethane, toluene and chlorobenzene, and the molar volume ratio of the methyl benzoylformate to the solvent is 0.2-1 mol/L.
5. The method for synthesizing racemic clopidogrel according to claim 1, wherein the molar ratio of 2-thienylethylamine to methyl o-chlorobenzoylformate in the step 2) is 1-1.1: 1, the using amount of the sodium cyanoborohydride is 1-3 times of the molar amount of the o-chlorobenzoyl methyl formate.
6. The method for synthesizing racemic clopidogrel according to claim 1, wherein the solvent in the step 2) is selected from dichloromethane, dichloroethane and tetrahydrofuran, and the molar volume ratio of the o-chlorobenzoyl methyl formate to the solvent is 0.5-1 mol/L.
7. The method for synthesizing racemic clopidogrel according to claim 1, characterized in that the reductive amination reaction conditions of the step 2) are as follows: reacting for 2-8 hours at room temperature.
8. The method for synthesizing racemic clopidogrel according to claim 1, wherein the molar ratio of paraformaldehyde to methyl 2- (2-thienylethylamino) (2-chlorophenyl) acetate in the step 3) is 3: 1; the solvent is selected from water, methanol or ethanol.
9. The method for synthesizing racemic clopidogrel according to claim 1, wherein the acid solution in the step 3) is an aqueous solution of an inorganic acid, the concentration of the acid solution is 0.8-1.2 mol/L, and the volume ratio of the acid solution to the solvent is 0.2-0.3: 100, the inorganic acid is one of sulfuric acid, hydrochloric acid and phosphoric acid.
10. The process for the synthesis of racemic clopidogrel according to claim 1, characterized in that the cyclization reaction conditions of step 3) are: the molar volume ratio of the 2- (2-thiophene ethylamino) (2-chlorphenyl) methyl acetate to the solvent is 0.1-0.2 mol/L, and the reaction lasts for 2-8 hours at the temperature of 70-90 ℃.
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