Preparation method of intermediate N-methyl-2-hydroxyethyl pyrrolidine for clomastine

Abstract

The invention discloses a preparation method of an intermediate N-methyl-2-hydroxyethyl pyrrolidine for clomastine, and relates to the technical field of synthesis of medical intermediates, and the preparation method comprises the following steps: adding triphenylphosphine into an organic solvent, adding ethyl bromoacetate, stirring for reaction, filtering, washing the obtained precipitate with the organic solvent, and carrying out vacuum drying to obtain an intermediate I; adding N-methyl pyrrolidone into a benzene solvent, adding the intermediate I under stirring, carrying out stirring reaction, filtering to remove solids, and carrying out reduced pressure distillation on filtrate to obtain an intermediate II; adding the intermediate II into an alcohol solvent, carrying out palladium-carbon hydrogenation, adding sodium borohydride in three batches, carrying out a stirring reaction, adjusting the pH value, extracting with dichloromethane, extracting an obtained water phase with dichloromethane, combining organic phases, drying, and carrying out reduced pressure distillation to obtain N-methyl-2-hydroxyethyl pyrrolidine; the preparation method disclosed by the invention is high in yield, convenient to separate and purify, low in cost, simple and convenient to operate and low in risk.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, in particular to a method for preparing N-methyl-2-hydroxyethyl pyrrolidine, an intermediate for clemastine. Background Art

[0002] Clemastine is a potent allergy drug, belonging to the histamine H1 receptor antagonist, and is recognized worldwide as one of the best anti-allergy drugs. N-methyl-2-hydroxyethyl pyrrolidine is a key intermediate of Clemastine. The existing synthesis routes mainly include three: Route 1 uses pyrrolidone as a raw material, reacts with vinyl acetate, and obtains N-methyl-2-hydroxyethyl pyrrolidine through reduction, hydrolysis, and methylation. The reaction with vinyl acetate is a free radical addition reaction, and there are relatively obvious side reactions, which makes it difficult to obtain pure products during the product distillation process. In addition, reduction and hydrolysis require the use of sodium borohydride and phosphorus oxychloride reduction systems, which are costly and dangerous. Route 2 uses N-methyl pyrrolidone as a raw material, avoiding the side reactions in the free radical addition reaction, but the reduction and hydrolysis steps are still relatively dangerous. Route 3 avoids free radical addition reactions and sugar reduction and ester hydrolysis reactions, but the synthesis route is extended, the total yield is reduced, and the dimethyl sulfate used in the process is a highly toxic substance, and skin contact alone can cause life-threatening danger to operators. In addition, nickel-catalyzed hydrogenation is also a very dangerous reaction. The production process needs to be strictly controlled in both laboratory operations and industrial production, and high requirements are placed on operators.

[0003]

[0004]

[0005] Therefore, it is urgent to develop a method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine, which has high yield, convenient separation and purification, low cost, simple and convenient operation and low risk. Summary of the invention

[0006] To solve the above problems, the present invention aims to provide a method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine.

[0007] In order to achieve the above object, the present invention is implemented through the following technical solutions:

[0008] A method for preparing N-methyl-2-hydroxyethyl pyrrolidine, an intermediate for clemastine, comprises the following steps:

[0009] ① Add triphenylphosphine to an organic solvent, add ethyl bromoacetate under stirring, react at 20-30°C for 8-12 hours, filter, wash the resulting precipitate with the above organic solvent, and vacuum dry at 20-30°C to obtain intermediate 1;

[0010] The mass volume ratio of triphenylphosphine, organic solvent and ethyl bromoacetate is 240g:1600-1800ml:160-180g;

[0011] ② Add N-methylpyrrolidone to a benzene solvent, add the intermediate 1 obtained in step ① under stirring conditions, react at 20-30° C. for 10-16 hours with stirring, filter to remove the solid, and distill the filtrate under reduced pressure to obtain the intermediate 2;

[0012] The mass volume ratio of N-methylpyrrolidone, benzene solvent and intermediate 1 obtained in step ① is 51-60g:1500-1600ml:180g;

[0013] ③ The intermediate 2 obtained in step ② is added to an alcohol solvent, nitrogen is introduced into the reactor at a nitrogen flow rate of 0.5 to 2 L / min and a ventilation time of 3 to 5 minutes, palladium carbon is added to the reactor, hydrogen is introduced to replace nitrogen at a hydrogen flow rate of 0.5 to 2 L / min and a ventilation time of 3 to 5 minutes, and then hydrogen is introduced to make the pressure in the reactor reach 4 to 5 MPa, stirred for 2 to 4 hours, filtered, and sodium borohydride is added to the filtrate in three batches, and each batch is stirred for reaction for 10 to 15 minutes after addition. After the addition is completed, the reaction is stirred at 20 to 30° C. for 4 to 6 hours, the temperature is raised to 40 to 50° C. and the reaction is stirred for 3 to 5 hours, the temperature is lowered to 0±2° C., the pH is adjusted to 6 to 7 with aqueous hydrochloric acid to obtain a mixed solution, extracted with dichloromethane, and the obtained aqueous phase is extracted with dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain N-methyl-2-hydroxyethyl pyrrolidine;

[0014] The mass volume ratio of the intermediate 2 obtained in step ②, the alcohol solvent, palladium carbon, and sodium borohydride is 80g: 800-900ml: 2-4g: 18-36g;

[0015] The reaction route is as follows:

[0016]

[0017] Preferably, the organic solvent is ethyl acetate or benzene.

[0018] Preferably, the benzene solvent is benzene, toluene or xylene.

[0019] Preferably, the alcohol solvent is methanol or ethanol.

[0020] Preferably, the vacuum degree of the reduced pressure distillation in step ② is 0.25-0.35 kPa, and the fraction at 190-198° C. is collected.

[0021] Preferably, the mass concentration of the aqueous hydrochloric acid solution in step ③ is 1-2 mol / L.

[0022] Preferably, the vacuum degree of the reduced pressure distillation in step ③ is 1.5-1.7 kPa, and the fraction at 111-114° C. is collected.

[0023] Compared with the prior art, the present invention has the following advantages:

[0024] The preparation method of the intermediate N-methyl-2-hydroxyethyl pyrrolidine for clemastine of the present invention has high yield, convenient separation and purification, low cost, simple and convenient operation and low danger. Firstly, the intermediate one is efficiently prepared by reacting triphenylphosphine with ethyl bromoacetate, the reaction conditions are mild and the efficiency is high, and the intermediate one can be obtained by simple filtration and washing after the reaction is completed, and is directly used for the next step reaction, and the yield is close to 100%; the reaction of the intermediate one of the present invention with N-methyl pyrrolidone is a classic Wittig reaction, the reaction conditions are mild and the efficiency is high, and it also only needs to stir the reaction at room temperature for a certain time, and the intermediate two can be obtained by reduced pressure distillation after filtration; the intermediate two of the present invention only needs to be subjected to palladium carbon hydrogenation and sodium borohydride reduction to obtain N-methyl-2-hydroxyethyl pyrrolidine, avoiding the use of phosphorus oxychloride with high danger and complicated post-treatment process, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0025] The object of the present invention is to provide a method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine. The present invention is further described below in conjunction with specific examples.

[0026] The following examples all adopt the following reaction route:

[0027]

[0028] Embodiment 1 A method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine, comprises the following steps:

[0029] ① Add 240g of triphenylphosphine to 1600ml of ethyl acetate, add 160g of ethyl bromoacetate under stirring, react at 20°C for 12 hours, filter, wash the resulting precipitate with the above organic solvent, and vacuum dry at 20°C to obtain 306.0g of the intermediate (unpurified product yield 96%);

[0030] ② Add 51g of N-methylpyrrolidone to 1500ml of benzene, add 180g of the intermediate 1 obtained in step ① under stirring, react at 20°C for 16 hours, filter to remove the solid, and distill the filtrate under reduced pressure to obtain 80.2g of the intermediate 2 (the yield of the unpurified product is 91.8%); the vacuum degree of the reduced pressure distillation is 0.25kPa, and the fraction at 190-198°C is collected;

[0031] ③ 80g of the intermediate 2 obtained in step ② was added to 800ml of methanol, nitrogen was introduced into the reactor at a nitrogen flow rate of 0.5L / min and a ventilation time of 3 minutes, 2g of palladium carbon was added to the reactor, hydrogen was introduced to replace nitrogen at a hydrogen flow rate of 0.5L / min and a ventilation time of 3 minutes, and then hydrogen was introduced to make the pressure in the reactor reach 4MPa, stirred for 2 hours, filtered, and 18g of sodium borohydride was added to the filtrate in three batches, and each batch was stirred for 10 minutes after addition. After the addition was completed, the reaction was stirred at 20°C for 6 hours, the temperature was raised to 40°C and the reaction was stirred for 5 hours, and the temperature was lowered to -2°C, and the pH was adjusted to 6 with a mass concentration of 1mol / L hydrochloric acid aqueous solution to obtain a mixed solution, which was extracted with dichloromethane, and the obtained aqueous phase was extracted with dichloromethane again, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 26.3g of N-methyl-2-hydroxyethylpyrrolidine (yield 43%);

[0032] The vacuum degree of the reduced pressure distillation was 1.5 kPa, and the fractions at 111-114°C were collected.

[0033] Embodiment 2 A method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine, comprises the following steps:

[0034] ① Add 240g of triphenylphosphine to 1800ml of benzene, add 180g of ethyl bromoacetate under stirring, react at 30°C for 8 hours, filter, wash the resulting precipitate with the above organic solvent, and vacuum dry at 30°C to obtain 315.6g of intermediate (unpurified product yield 99%);

[0035] ② Add 60g of N-methylpyrrolidone to 1600ml of xylene, add 180g of the intermediate 1 obtained in step ① under stirring, react at 30°C for 10 hours, filter to remove the solid, and distill the filtrate under reduced pressure to obtain 83.0g of the intermediate 2 (unpurified product yield 95%); the vacuum degree of the reduced pressure distillation is 0.35kPa, and the fraction at 190-198°C is collected;

[0036] ③ 80g of the intermediate 2 obtained in step ② was added to 900ml of ethanol, nitrogen was introduced into the reactor at a nitrogen flow rate of 2L / min and a ventilation time of 5 minutes, 4g of palladium carbon was added to the reactor, hydrogen was introduced to replace nitrogen at a hydrogen flow rate of 2L / min and a ventilation time of 5 minutes, and then hydrogen was introduced to make the pressure in the reactor reach 5MPa, stirred for 2 hours, filtered, 36g of sodium borohydride was added to the filtrate in three batches, and each batch was stirred for 15 minutes after addition. After the addition was completed, the reaction was stirred at 30°C for 4 hours, the temperature was raised to 50°C and the reaction was stirred for 3 hours, the temperature was lowered to 2°C, and the pH was adjusted to 7 with a mass concentration of 2mol / L hydrochloric acid aqueous solution to obtain a mixed solution, which was extracted with dichloromethane, and the obtained aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 44.0g of N-methyl-2-hydroxyethylpyrrolidine (yield 72%);

[0037] The vacuum degree of the reduced pressure distillation was 1.7 kPa, and the fractions at 111 to 114°C were collected.

[0038] Embodiment 3 A method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine, comprises the following steps:

[0039] ① Add 240g of triphenylphosphine to 1640ml of ethyl acetate, add 164g of ethyl bromoacetate under stirring, react at 22°C for 9 hours, filter, wash the resulting precipitate with the above organic solvent, and vacuum dry at 22°C to obtain 312.4g of intermediate (unpurified product yield 98%);

[0040] ② Add 52g of N-methylpyrrolidone to 1550ml of xylene, add 180g of the intermediate 1 obtained in step ① under stirring, react at 22°C for 11 hours, filter to remove solids, and distill the filtrate under reduced pressure to obtain 80.4g of intermediate 2 (unpurified product yield 92%); the vacuum degree of the reduced pressure distillation is 0.3kPa, and the fraction at 190-198°C is collected;

[0041] ③ 80g of the intermediate 2 obtained in step ② was added to 820ml of methanol, nitrogen was introduced into the reactor at a nitrogen flow rate of 1L / min and a ventilation time of 4 minutes, 3g of palladium carbon was added to the reactor, hydrogen was introduced to replace nitrogen at a hydrogen flow rate of 1L / min and a ventilation time of 4 minutes, and then hydrogen was introduced to make the pressure in the reactor reach 4MPa, stirred for 3 hours, filtered, 20g of sodium borohydride was added to the filtrate in three batches, and stirred for 12 minutes after each batch was added. After the addition was completed, the reaction was stirred at 24°C for 4.5 hours, the temperature was raised to 42°C and the reaction was stirred for 3.5 hours, the temperature was lowered to 0°C, and the pH was adjusted to 6.5 with a hydrochloric acid aqueous solution with a mass concentration of 1mol / L to obtain a mixed solution, which was extracted with dichloromethane, and the obtained aqueous phase was extracted with dichloromethane again. The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 32.4g of N-methyl-2-hydroxyethylpyrrolidine (yield 53%);

[0042] The vacuum degree of the reduced pressure distillation was 1.6 kPa, and the fractions at 111 to 114°C were collected.

[0043] Embodiment 4 A method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine, comprises the following steps:

[0044] ① Add 240g of triphenylphosphine to 1760ml of benzene, add 168g of ethyl bromoacetate under stirring, react at 28°C for 10 hours, filter, wash the resulting precipitate with the above organic solvent, and vacuum dry at 28°C to obtain 318.6g of the intermediate (unpurified product yield 100%);

[0045] ② Add 58g of N-methylpyrrolidone to 58g of toluene, add 180g of the intermediate 1 obtained in step ① under stirring, react at 28°C for 15 hours, filter to remove the solid, and distill the filtrate under reduced pressure to obtain 81.3g of the intermediate 2 (the yield of the unpurified product is 93%); the vacuum degree of the reduced pressure distillation is 0.28kPa, and the fraction at 190-198°C is collected;

[0046] ③ 80g of the intermediate 2 obtained in step ② was added to 860ml of methanol, nitrogen was introduced into the reactor at a nitrogen flow rate of 1L / min and a ventilation time of 4 minutes, 3g of palladium carbon was added to the reactor, hydrogen was introduced to replace nitrogen at a hydrogen flow rate of 1L / min and a ventilation time of 4 minutes, and then hydrogen was introduced to make the pressure in the reactor reach 4.5MPa, stirred for 3 hours, filtered, and 24g of sodium borohydride was added to the filtrate in three batches, and stirred for 14 minutes after each batch was added. After the addition was completed, the reaction was stirred at 28°C for 5.5 hours, the temperature was raised to 48°C and the reaction was stirred for 4.5 hours, the temperature was lowered to 1°C, and the pH was adjusted to 6.5 with a mass concentration of 1.5mol / L hydrochloric acid aqueous solution to obtain a mixed solution, which was extracted with dichloromethane, and the obtained aqueous phase was extracted with dichloromethane again, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 35.4g of N-methyl-2-hydroxyethylpyrrolidine (yield 58%);

[0047] The vacuum degree of the reduced pressure distillation was 1.65 kPa, and the fractions at 111 to 114°C were collected.

[0048] Embodiment 5 A method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine, comprises the following steps:

[0049] ① Add 240g of triphenylphosphine to 1720ml of ethyl acetate, add 168g of ethyl bromoacetate under stirring, react at 26°C for 11 hours, filter, wash the resulting precipitate with the above organic solvent, and vacuum dry at 24°C to obtain 317.8g of intermediate (unpurified product yield 99.7%);

[0050] ② Add 55g of N-methylpyrrolidone to 1580ml of toluene, add 180g of the intermediate 1 obtained in step ① under stirring, react at 26°C for 15 hours, filter to remove the solid, and distill the filtrate under reduced pressure to obtain 80.5g of the intermediate 2 (the yield of the unpurified product is 92.1%); wherein the vacuum degree of the reduced pressure distillation is 0.30kPa, and the fraction at 190-198°C is collected;

[0051] ③ 80g of the intermediate 2 obtained in step ② was added to 840ml of ethanol, nitrogen was introduced into the reactor at a nitrogen flow rate of 1.5L / min and a ventilation time of 5 minutes, 4g of palladium carbon was added to the reactor, hydrogen was introduced to replace nitrogen at a hydrogen flow rate of 1.5L / min and a ventilation time of 5 minutes, and then hydrogen was introduced to make the pressure in the reactor reach 5MPa, stirred for 4 hours, filtered, 30g of sodium borohydride was added to the filtrate in three batches, and each batch was stirred for 12 minutes after addition. After the addition was completed, the reaction was stirred at 24°C for 4.5 hours, the temperature was raised to 46°C and the reaction was stirred for 4 hours, the temperature was lowered to 0°C, and the pH was adjusted to 6.4 with a mass concentration of 1.8mol / L hydrochloric acid aqueous solution to obtain a mixed solution, which was extracted with dichloromethane, and the obtained aqueous phase was extracted with dichloromethane again. The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 39.7g of N-methyl-2-hydroxyethylpyrrolidine (yield 65%);

[0052] The vacuum degree of the reduced pressure distillation was 1.55 kPa, and the fractions at 111 to 114°C were collected.

[0053] Example 6 A method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine, comprises the following steps:

[0054] ① Add 240g of triphenylphosphine to 1700ml of ethyl acetate, add 170g of ethyl bromoacetate under stirring, react at 25°C for 10 hours, filter, wash the resulting precipitate with the above organic solvent, and vacuum dry at 25°C to obtain 318.7g of intermediate (unpurified product yield 100%);

[0055] ② Add 55g of N-methylpyrrolidone to 1550ml of toluene, add 180g of the intermediate 1 obtained in step ① under stirring conditions, react at 20-30°C for 10-16 hours, filter to remove solids, and distill the filtrate under reduced pressure to obtain 80.9g of the intermediate 2 (unpurified product yield 92.6%); the vacuum degree of the reduced pressure distillation is 0.30kPa, and the fractions at 190-198°C are collected;

[0056] ③ 80g of the intermediate 2 obtained in step ② was added to 850ml of ethanol, nitrogen was introduced into the reactor at a nitrogen flow rate of 1L / min and a ventilation time of 4 minutes, 3g of palladium carbon was added to the reactor, hydrogen was introduced to replace nitrogen at a hydrogen flow rate of 1L / min and a ventilation time of 4 minutes, and then hydrogen was introduced to make the pressure in the reactor reach 4MPa, stirred for 4 hours, filtered, 32g of sodium borohydride was added to the filtrate in three batches, and stirred for 12 minutes after each batch was added. After the addition was completed, the reaction was stirred at 25°C for 5 hours, the temperature was raised to 45°C and the reaction was stirred for 4 hours, the temperature was lowered to 0°C, and the pH was adjusted to 6.5 with a mass concentration of 1mol / L hydrochloric acid aqueous solution to obtain a mixed solution, which was extracted with dichloromethane, and the obtained aqueous phase was extracted with dichloromethane again. The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 43.3g of N-methyl-2-hydroxyethylpyrrolidine (yield 71%);

[0057] The vacuum degree of the reduced pressure distillation was 1.6 kPa, and the fractions at 111 to 114°C were collected.

[0058] H NMR spectrum of intermediate 2: 1 H NMR (400MHz, CDCl3): δ4.07(m,3H,OCH2CH3,C=CH),3.38(t,J=7.2Hz,2H,CH2),3.04(s, 3H, NCH3), 2.98 (t, J = 7.2Hz, 2H, CH2), 2.08 (m, 2H, CH2), 1.33 (t, J = 8.0Hz, 3H, OCH2CH3).

[0059] High resolution mass spectrum of intermediate 2, ESI-TOF HRMS (m / z): C9H 16 NO2 + , [M+H] + , theoretical value 170.1176; measured value 170.1185.

Claims

1. A method for preparing N-methyl-2-hydroxyethyl pyrrolidine, an intermediate for clemastine, characterized in that: The following steps are involved: ① Add triphenylphosphine to an organic solvent, add ethyl bromoacetate under stirring, react at 20-30°C for 8-12 hours, filter, wash the resulting precipitate with the above organic solvent, and vacuum dry at 20-30°C to obtain intermediate 1; The mass volume ratio of triphenylphosphine, organic solvent and ethyl bromoacetate is 240g:1600-1800ml:160-180g; ② Add N-methylpyrrolidone to a benzene solvent, add the intermediate 1 obtained in step ① under stirring conditions, react at 20-30° C. for 10-16 hours with stirring, filter to remove the solid, and distill the filtrate under reduced pressure to obtain the intermediate 2; The mass volume ratio of N-methylpyrrolidone, benzene solvent and intermediate 1 obtained in step ① is 51-60g:1500-1600ml:180g; ③ The intermediate 2 obtained in step ② is added to an alcohol solvent, nitrogen is introduced into the reactor at a nitrogen flow rate of 0.5 to 2 L / min and a ventilation time of 3 to 5 minutes, palladium carbon is added to the reactor, hydrogen is introduced to replace nitrogen at a hydrogen flow rate of 0.5 to 2 L / min and a ventilation time of 3 to 5 minutes, and then hydrogen is introduced to make the pressure in the reactor reach 4 to 5 MPa, stirred for 2 to 4 hours, filtered, and sodium borohydride is added to the filtrate in three batches, and stirred for 10 to 15 minutes after each batch is added. After the addition is completed, the reaction is stirred at 20 to 30° C. for 4 to 6 hours, the temperature is raised to 40 to 50° C. and the reaction is stirred for 3 to 5 hours, the temperature is lowered to 0±2° C., and the pH is adjusted to 6 to 7 with aqueous hydrochloric acid to obtain a mixed solution, extracted with dichloromethane, and the obtained aqueous phase is extracted with dichloromethane again, the organic phases are combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain N-methyl-2-hydroxyethyl pyrrolidine; The mass volume ratio of the intermediate 2 obtained in step ②, the alcohol solvent, palladium carbon, and sodium borohydride is 80g: 800-900ml: 2-4g: 18-36g; The reaction route is as follows:

2. A method for preparing a clemastine intermediate N-methyl-2-hydroxyethyl pyrrolidine according to claim 1, characterized in that: The organic solvent is ethyl acetate or benzene.

3. A method for preparing a clemastine intermediate N-methyl-2-hydroxyethyl pyrrolidine according to claim 1, characterized in that: The benzene solvent is benzene, toluene or xylene.

4. The method for preparing N-methyl-2-hydroxyethyl pyrrolidine, an intermediate for clemastine according to claim 1, characterized in that: The alcohol solvent is methanol or ethanol.

5. The method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine according to claim 1, characterized in that: The vacuum degree of the reduced pressure distillation in step ② is 0.25-0.35 kPa, and the fraction at 190-198° C. is collected.

6. The method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine according to claim 1, characterized in that: The mass concentration of the hydrochloric acid aqueous solution in step ③ is 1-2 mol / L.

7. The method for preparing a clemastine intermediate N-methyl-2-hydroxyethyl pyrrolidine according to claim 1, characterized in that: The vacuum degree of the reduced pressure distillation in step ③ is 1.5-1.7 kPa, and the fraction at 111-114° C. is collected.

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