A process for the preparation of an intermediate for clemastine, N-methyl-2-hydroxyethylpyrrolidine

Abstract

The application discloses a preparation method of an intermediate N-methyl-2-hydroxyethyl pyrrolidine of clemastine, relates to the technical field of medicine intermediate synthesis, and comprises the following steps: triphenylphosphine is added into an organic solvent, ethyl bromoacetate is added, stirring reaction is carried out, filtration is carried out, the obtained precipitate is washed with the above-mentioned organic solvent, vacuum drying is carried out, and an intermediate one is obtained; N-methyl pyrrolidone is added into a benzene solvent, the intermediate one is added under stirring, stirring reaction is carried out, solid is removed through filtration, the filtrate is distilled under reduced pressure, and an intermediate two is obtained; the intermediate two is added into an alcohol solvent, hydrogenation is carried out through palladium-carbon, sodium borohydride is added in three batches, stirring reaction is carried out, pH is adjusted, extraction is carried out with dichloromethane, the obtained aqueous phase is extracted with dichloromethane again, organic phases are combined, drying is carried out, and N-methyl-2-hydroxyethyl pyrrolidine is obtained through reduced pressure distillation; the preparation method is high in yield, convenient in separation and purification, low in cost, simple and convenient to operate, and small in danger.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically a method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for chlormastine. Background Technology

[0002] Clomastine is a potent allergy medication, belonging to the histamine H1 receptor antagonist class, and is recognized worldwide as one of the best anti-allergy drugs. N-Methyl-2-hydroxyethylpyrrolidone is a key intermediate in clomastine. Existing synthetic routes mainly include three routes: Route 1 uses pyrrolidone as a starting material, reacting it with vinyl acetate, followed by reduction, hydrolysis, and methylation to obtain N-methyl-2-hydroxyethylpyrrolidone. The reaction with vinyl acetate is a free radical addition reaction, resulting in significant side reactions, making it difficult to obtain pure product during distillation. Furthermore, the reduction and hydrolysis require a sodium borohydride and phosphorus oxychloride reduction system, which is costly and dangerous. Route 2 uses N-methylpyrrolidone as a starting material, avoiding the side reactions present in the free radical addition reaction; however, the reduction and hydrolysis steps still pose significant risks. Route 3 avoids free radical addition reactions and glycosyl reduction and ester hydrolysis reactions, but the synthetic route is longer, the overall yield is lower, and the dimethyl sulfate used in the process is a highly toxic substance; even skin contact can pose a life-threatening risk to operators. In addition, nickel-catalyzed hydrogenation is a very dangerous reaction, and the production process needs to be strictly controlled in both laboratory operations and industrial production, requiring highly skilled operators.

[0003]

[0004]

[0005] Therefore, there is an urgent need to develop a method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for chlormastine, which has a high yield, is easy to separate and purify, has low cost, is simple and convenient to operate, and has low risk. Summary of the Invention

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

[0007] To achieve the above objectives, the present invention employs the following technical solution:

[0008] A method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for chlormastine, includes the following steps:

[0009] ① Triphenylphosphine was added to an organic solvent, and ethyl bromoacetate was added while stirring. The mixture was stirred at 20–30°C for 8–12 hours. After filtration, the precipitate was washed with the organic solvent and dried under vacuum at 20–30°C to obtain intermediate one.

[0010] The mass-to-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 intermediate one obtained in step ① under stirring, stir and react at 20-30℃ for 10-16 hours, filter to remove solid, and distill the filtrate under reduced pressure to obtain intermediate two;

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

[0013] ③ Add intermediate 2 obtained in step ② to an alcohol solvent, purge nitrogen into the reactor at a flow rate of 0.5–2 L / min for 3–5 minutes, add palladium on carbon into the reactor, purge hydrogen to replace the nitrogen at a flow rate of 0.5–2 L / min for 3–5 minutes, then purge hydrogen to bring the pressure inside the reactor to 4–5 MPa, stir for 2–4 hours, filter, add sodium borohydride to the filtrate in three batches, stirring for 10–15 minutes after each batch, stir and react at 20–30°C for 4–6 hours after the addition is complete, raise the temperature to 40–50°C and stir and react for 3–5 hours, cool to 0±2°C, adjust the pH to 6–7 with hydrochloric acid aqueous solution to obtain a mixture, extract with dichloromethane, extract the aqueous phase again with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, and distill under reduced pressure to obtain N-methyl-2-hydroxyethylpyrrolidine;

[0014] The mass-volume ratio of intermediate II obtained in step ②, alcohol solvent, palladium on 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, in step ②, the vacuum degree of the reduced pressure distillation is 0.25 to 0.35 kPa, and the fraction collected at 190 to 198°C is collected.

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

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

[0023] The present invention has the following advantages over the prior art:

[0024] The method for preparing the intermediate N-methyl-2-hydroxyethylpyrrolidine for chlormastine of the present invention has high yield, convenient separation and purification, low cost, simple and convenient operation, and low risk. First, intermediate one is efficiently prepared by reacting triphenylphosphine with ethyl bromoacetate. This reaction condition is mild and efficient. After the reaction, only simple filtration and washing are required to obtain intermediate one, which can be directly used for the next reaction with a yield close to 100%. The reaction of intermediate one with N-methylpyrrolidone is a classic Wittig reaction. The reaction condition is mild and efficient. Similarly, only stirring at room temperature for a certain period of time is required. After filtration, vacuum distillation yields intermediate two. Intermediate two of the present invention only requires hydrogenation of palladium on carbon and reduction with sodium borohydride to obtain N-methyl-2-hydroxyethylpyrrolidine, avoiding the use of phosphorus oxychloride, which is highly dangerous and has a complicated post-processing. This method is suitable for large-scale industrial production. Detailed Implementation

[0025] The purpose of this invention is to provide a method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for chlormastine. The invention will be further described below with reference to specific embodiments.

[0026] The following embodiments all employ the following reaction routes:

[0027]

[0028] Example 1: A method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for chlormastine, comprising the following steps:

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

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

[0031] ③ Add 80g of intermediate 2 obtained in step ② to 800ml of methanol. Purge nitrogen gas into the reactor at a flow rate of 0.5L / min for 3 minutes. Add 2g of palladium on carbon to the reactor. Purge hydrogen gas to replace the nitrogen gas at a flow rate of 0.5L / min for 3 minutes. Then purge hydrogen gas to make the pressure in the reactor reach 4MPa. Stir for 2 hours, filter, and add 18g of sodium borohydride to the filtrate in three batches. Stir for 10 minutes after each batch. After the addition is complete, stir and react at 20℃ for 6 hours. Increase the temperature to 40℃ and stir and react for 5 hours. Cool down to -2℃ and adjust the pH to 6 with a 1mol / L hydrochloric acid aqueous solution to obtain a mixture. Extract with dichloromethane. Extract the aqueous phase with dichloromethane again. Combine the organic phases, dry with anhydrous sodium sulfate, and distill under reduced pressure to obtain 26.3g of N-methyl-2-hydroxyethylpyrrolidine (yield 43%).

[0032] The vacuum degree of the reduced pressure distillation is 1.5 kPa, and the fraction collected at 111–114 °C is collected.

[0033] Example 2: A method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for chlormastine, comprising the following steps:

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

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

[0036] ③ Add 80g of intermediate II obtained in step ② to 900ml of ethanol. Purge nitrogen gas into the reactor at a flow rate of 2L / min for 5 minutes. Add 4g of palladium on carbon to the reactor. Purge hydrogen gas to replace the nitrogen gas at a flow rate of 2L / min for 5 minutes. Then purge hydrogen gas to make the pressure in the reactor reach 5MPa. Stir for 2 hours, filter, and add 36g of sodium borohydride to the filtrate in three batches. Stir for 15 minutes after each batch. After the addition is complete, stir and react at 30℃ for 4 hours. Increase the temperature to 50℃ and stir and react for 3 hours. Cool down to 2℃ and adjust the pH to 7 with a 2mol / L hydrochloric acid aqueous solution to obtain a mixture. Extract with dichloromethane. Extract the aqueous phase again with dichloromethane. Combine the organic phases, dry with anhydrous sodium sulfate, and distill under reduced pressure to obtain 44.0g of N-methyl-2-hydroxyethylpyrrolidine (yield 72%).

[0037] The vacuum degree of the reduced pressure distillation is 1.7 kPa, and the fraction collected at 111–114 °C is collected.

[0038] Example 3: A method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for chlormastine, comprising the following steps:

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

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

[0041] ③ Add 80g of intermediate 2 obtained in step ② to 820ml of methanol. Purge nitrogen gas into the reactor at a flow rate of 1L / min for 4 minutes. Add 3g of palladium on carbon to the reactor. Purge hydrogen gas to replace the nitrogen gas at a flow rate of 1L / min for 4 minutes. Then purge hydrogen gas to make the pressure in the reactor reach 4MPa. Stir for 3 hours, filter, and add 20g of sodium borohydride to the filtrate in three batches. Stir for 12 minutes after each batch. After the addition is complete, stir and react at 24℃ for 4.5 hours. Increase the temperature to 42℃ and stir and react for 3.5 hours. Cool down to 0℃ and adjust the pH to 6.5 with a 1mol / L hydrochloric acid aqueous solution to obtain a mixture. Extract with dichloromethane. Extract the aqueous phase again with dichloromethane. Combine the organic phases, dry with anhydrous sodium sulfate, and distill under reduced pressure to obtain 32.4g of N-methyl-2-hydroxyethylpyrrolidine (yield 53%).

[0042] The vacuum degree of the reduced pressure distillation is 1.6 kPa, and the fraction collected at 111–114 °C is collected.

[0043] Example 4: A method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for chlormastine, comprising the following steps:

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

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

[0046] ③ Add 80g of intermediate 2 obtained in step ② to 860ml of methanol. Purge nitrogen gas into the reactor at a flow rate of 1L / min for 4 minutes. Add 3g of palladium on carbon to the reactor. Purge hydrogen gas to replace the nitrogen gas at a flow rate of 1L / min for 4 minutes. Then purge hydrogen gas to make the pressure in the reactor reach 4.5MPa. Stir for 3 hours, filter, and add 24g of sodium borohydride to the filtrate in three batches. Stir for 14 minutes after each batch. After the addition is complete, stir and react at 28℃ for 5.5 hours. Increase the temperature to 48℃ and stir and react for 4.5 hours. Cool down to 1℃ and adjust the pH to 6.5 with a 1.5mol / L hydrochloric acid aqueous solution to obtain a mixture. Extract with dichloromethane. Extract the aqueous phase again with dichloromethane. Combine the organic phases, dry with anhydrous sodium sulfate, and distill under reduced pressure to obtain 35.4g of N-methyl-2-hydroxyethylpyrrolidine (yield 58%).

[0047] The vacuum degree of the reduced pressure distillation is 1.65 kPa, and the fraction collected at 111–114 °C is collected.

[0048] Example 5: A method for preparing N-methyl-2-hydroxyethylpyrrolidine, an intermediate for chlormastine, comprising the following steps:

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

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

[0051] ③ Add 80g of intermediate II obtained in step ② to 840ml of ethanol. Purge nitrogen gas into the reactor at a flow rate of 1.5L / min for 5 minutes. Add 4g of palladium on carbon to the reactor. Purge hydrogen gas to replace the nitrogen gas at a flow rate of 1.5L / min for 5 minutes. Then purge hydrogen gas to make the pressure in the reactor reach 5MPa. Stir for 4 hours, filter, and add 30g of sodium borohydride to the filtrate in three batches. Stir for 12 minutes after each batch. After the addition is complete, stir and react at 24℃ for 4.5 hours. Increase the temperature to 46℃ and stir and react for 4 hours. Cool down to 0℃ and adjust the pH to 6.4 with a 1.8mol / L hydrochloric acid aqueous solution to obtain a mixture. Extract with dichloromethane. Extract the aqueous phase again with dichloromethane. Combine the organic phases, dry with anhydrous sodium sulfate, and distill under reduced pressure to obtain 39.7g of N-methyl-2-hydroxyethylpyrrolidine (yield 65%).

[0052] The vacuum degree of the reduced pressure distillation is 1.55 kPa, and the fraction collected at 111–114 °C is collected.

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

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

[0055] ② Add 55g of N-methylpyrrolidone to 1550ml of toluene, and add 180g of intermediate one obtained in step ① under stirring. Stir and react at 20-30℃ for 10-16 hours. Filter to remove solids, and distill the filtrate under reduced pressure to obtain 80.9g of intermediate two (yield of unpurified product 92.6%). The vacuum degree of the reduced pressure distillation is 0.30kPa, and the fraction at 190-198℃ is collected.

[0056] ③ Add 80g of intermediate II obtained in step ② to 850ml of ethanol. Purge nitrogen gas into the reactor at a flow rate of 1L / min for 4 minutes. Add 3g of palladium on carbon to the reactor. Purge hydrogen gas to replace the nitrogen gas at a flow rate of 1L / min for 4 minutes. Then purge hydrogen gas to make the pressure in the reactor reach 4MPa. Stir for 4 hours, filter, and add 32g of sodium borohydride to the filtrate in three batches. Stir for 12 minutes after each batch. After the addition is complete, stir and react at 25℃ for 5 hours. Then raise the temperature to 45℃ and stir and react for 4 hours. Cool down to 0℃ and adjust the pH to 6.5 with a 1mol / L hydrochloric acid aqueous solution to obtain a mixture. Extract with dichloromethane. Extract the aqueous phase again with dichloromethane. Combine the organic phases, dry with anhydrous sodium sulfate, and distill under reduced pressure to obtain 43.3g of N-methyl-2-hydroxyethylpyrrolidine (yield 71%).

[0057] The vacuum degree of the reduced pressure distillation is 1.6 kPa, and the fraction collected at 111–114 °C is collected.

[0058] The proton 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 spectrometry of intermediate 2, ESI-TOF HRMS (m / z): C9H 16 NO2 + [M+H] + Theoretical value: 170.1176; Measured value: 170.1185.

Claims

1. A process for the preparation of an intermediate for clemastine, N-methyl-2-hydroxyethylpyrrolidine, characterized by: The method comprises the following steps: ①adding triphenylphosphine into an organic solvent, adding ethyl bromoacetate under stirring, stirring and reacting at 20-30 ℃ for 8-12 hours, filtering, washing the obtained precipitate with the above-mentioned organic solvent, and drying under vacuum at 20-30 ℃ to obtain intermediate one; wherein the mass-volume ratio of triphenylphosphine, the organic solvent and ethyl bromoacetate is 240 g: 1600-1800 ml: 160-180 g; ②adding N-methylpyrrolidone into a benzene solvent, adding intermediate one obtained in step ① under stirring, stirring and reacting at 20-30 ℃ for 10-16 hours, removing the solid by filtering, and distilling the filtrate under reduced pressure to obtain intermediate two; wherein the mass-volume ratio of N-methylpyrrolidone, the benzene solvent and intermediate one obtained in step ① is 51-60 g: 1500-1600 ml: 180 g; ③adding intermediate two obtained in step ② into an alcohol solvent, introducing nitrogen into the reaction kettle, the nitrogen flow rate being 0.5-2 L / min, the aeration time being 3-5 minutes, adding palladium-carbon into the reaction kettle, introducing hydrogen to replace the nitrogen, the hydrogen flow rate being 0.5-2 L / min, the aeration time being 3-5 minutes, then introducing hydrogen to make the pressure in the reaction kettle reach 4-5 MPa, stirring for 2-4 hours, filtering, adding sodium borohydride into the filtrate in three batches, stirring for 10-15 minutes after each batch, stirring and reacting at 20-30 ℃ for 4-6 hours after the addition is completed, stirring and reacting at 40-50 ℃ for 3-5 hours after the temperature is raised, adjusting the pH to 6-7 by using hydrochloric acid aqueous solution after the temperature is lowered to 0±2 ℃, obtaining a mixed solution, extracting with dichloromethane, extracting the obtained aqueous phase with dichloromethane again, drying the combined organic phase with anhydrous sodium sulfate, and distilling under reduced pressure to obtain N-methyl-2-hydroxyethylpyrrolidine; wherein the mass-volume ratio of intermediate two obtained in step ②, the alcohol solvent, palladium-carbon and sodium borohydride is 80 g: 800-900 ml: 2-4 g: 18-36 g; The reaction route is as follows:

2. The process for the preparation of N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine, according to claim 1, characterized by the fact that: The organic solvent is ethyl acetate or benzene.

3. A process for the preparation of N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine, according to claim 1, characterized by: The benzene solvent is benzene, toluene or xylene.

4. The process for the preparation of N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine, according to claim 1, characterized by the fact that: The alcohol solvent is methanol or ethanol.

5. The process for the preparation of N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine, according to claim 1, characterized by the fact that: The vacuum degree of the distillation under reduced pressure in step ② is 0.25-0.35 kPa, and the fraction collected is at 190-198 ℃.

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

7. A process for the preparation of N-methyl-2-hydroxyethylpyrrolidine, an intermediate for clemastine, according to claim 1, characterized by: The vacuum degree of the distillation under reduced pressure in step ③ is 1.5-1.7 kPa, and the fraction collected is at 111-114 ℃.

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