A process for the preparation of N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide

Abstract

The application belongs to the field of medicine, and specifically provides a method for preparing an important intermediate compound N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide of dextromethorphan. The application uses 2-(1-cyclohexenyl)ethylamine and p-methoxyphenylacetic acid as raw materials, selects N,N-carbonyldiimidazole as a condensation reagent, optimizes the reaction conditions, reduces the reaction temperature, shortens the reaction time, and has the advantages of simple post-treatment, high product yield and purity, low cost, and being more beneficial to industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of medicine, and specifically provides a method for preparing N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide. BACKGROUND

[0002] Dextromethorphan is a powerful central antitussive drug, which is a right isomer of morphine, and mainly inhibits the cough center of the diencephalon to play a role. N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide is an important intermediate compound for preparing dextromethorphan, and the conventional process route is as shown below:

[0003]

[0004] At present, the compound is mainly prepared by using cyclohexene ethylamine and p-methoxyphenylacetic acid as raw materials, refluxing in xylene at high temperature for 10-15 hours, or adding a diimine condensing agent (DIC, DCC, EDCI, etc.) and an activating agent (DMAP) to react for 8-10 hours at a lower temperature, or preparing methoxyphenylacetyl chloride from p-methoxyphenylacetic acid by using thionyl chloride under heating, and condensing with cyclohexene ethylamine in the presence of an acid binding agent. The above methods need to be carried out under heating or at a lower temperature, the reaction time is relatively long, the energy consumption is relatively high, a diimine condensing agent is used, which is expensive, and by-products such as the by-product DCU of DCC are difficult to remove. The thionyl chloride used in the acyl chloride method produces acid gas in the process, which causes relatively large corrosion to the equipment, and is not conducive to environmental protection.

[0005] Therefore, it is of great significance to develop a new method for preparing the dextromethorphan intermediate N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, which is high in efficiency, suitable for industrial production, and good in comprehensive effect. SUMMARY

[0006] The application aims to provide a method for preparing N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, which can overcome the defects in the prior art, make the reaction proceed under relatively mild conditions, is simple in post-treatment, high in yield and purity of the product, low in cost, and short in reaction time, and is more conducive to industrial scale production.

[0007] A method for preparing N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, comprising the following steps:

[0008] (1) dissolving p-methoxyphenylacetic acid in an organic solvent, adding N,N-carbonyldiimidazole, and controlling the temperature below 40 DEG C to carry out the reaction;

[0009] (2) Next, add a mixture of 2-(1-cyclohexenyl)ethylamine and organic solvent, and control the temperature to be below 50°C for reaction;

[0010] (3) The product is obtained after post-processing following the completion of the reaction;

[0011] The molar ratio of p-methoxyphenylacetic acid, 2-(1-cyclohexenyl)ethylamine, and N,N-carbonyldiimidazole is (1.2-2):1:(1.2-2).

[0012] In a further preferred embodiment of the present invention, the organic solvent in step (1) or (2) is one or more of nitrile, haloalkanes, esters, aromatic hydrocarbons, monoalkyl or polyalkyl-substituted aromatic hydrocarbons, and monohalogenated or polyhalogenated aromatic hydrocarbons, preferably C. 2-4 Fatty nitrile, halogenated C 1-6 Alkanes, esters, benzene, monocarbons 1-6 Alkyl or polycarbonate 1-6 One or more of alkyl-substituted benzene, monohalogenated or polyhalogenated benzene, more preferably one or more of acetonitrile, dichloromethane, ethyl acetate, and toluene. Further, the organic solvent used in steps (1) and (2) is dichloromethane, ethyl acetate, or toluene.

[0013] In a further preferred embodiment of the present invention, N,N-carbonyldiimidazole may be added in batches in step (1), and a mixture of 2-(1-cyclohexenyl)ethylamine and organic solvent may be added in batches in step (2).

[0014] In a further preferred embodiment of the present invention, in step (1), the reaction is carried out under stirring conditions for 0.5-2 hours, preferably 0.8-1.5 hours, and more preferably 1 hour; in step (2), the reaction is carried out under stirring conditions for 0.5-2 hours, preferably 0.8-1.5 hours, and more preferably 1 hour.

[0015] In a further preferred embodiment of the present invention, the temperature in step (1) is controlled at 5-40°C, preferably 5-35°C, more preferably 10-30°C, even more preferably 10-25°C, even more preferably 10-20°C, and particularly preferably 15°C.

[0016] In a further preferred embodiment of the present invention, the temperature in step (2) is controlled at 10-50°C, preferably 10-40°C, more preferably 10-30°C, and particularly preferably 20-30°C.

[0017] In a further preferred embodiment of the present invention, the molar ratio of p-methoxyphenylacetic acid to N,N-carbonyldiimidazole in step (1) is (0.9-1.1):1, preferably 1:1.

[0018] In a further preferred embodiment of the present invention, the molar ratio of p-methoxyphenylacetic acid to 2-(1-cyclohexenyl)ethylamine in step (1) is 1.2-1.5:1, preferably 1.2-1.4:1, and more preferably 1.3:1.

[0019] In a further preferred embodiment of the present invention, the post-treatment in step (3) includes sequentially washing the organic phase of the reaction solution with acid and then with alkali.

[0020] In a further preferred embodiment of the present invention, the post-processing in step (3) includes pulping using a solvent.

[0021] In a further preferred embodiment of the present invention, the organic solvent used in steps (1) and (2) is dichloromethane, ethyl acetate or toluene. In step (3), the organic phase of the reaction solution is successively acid-washed and alkali-washed to remove the organic solvent. Then, a solvent is added and the mixture is slurried. The solvent is then separated to obtain the product.

[0022] In a further preferred embodiment of the present invention, the pulping solvent in step (3) is one or more of n-heptane, n-hexane, cyclohexane, and water.

[0023] In a further preferred embodiment of the present invention, the pickling in step (3) uses a 5-15% wt hydrochloric acid aqueous solution, preferably a 10% wt hydrochloric acid aqueous solution.

[0024] In a further preferred embodiment of the present invention, the alkaline washing in step (3) uses a 5-10% wt sodium carbonate aqueous solution, a 5-10% wt sodium bicarbonate aqueous solution, or a 5-10% wt sodium hydroxide aqueous solution, preferably a 5-10% wt sodium carbonate aqueous solution, more preferably a 10% wt sodium carbonate aqueous solution.

[0025] In a further preferred embodiment of the present invention, the yield of N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide is 92% or more, and the maximum content of a single impurity is less than 1%, preferably 95% or more, and the maximum content of a single impurity is less than 0.5%.

[0026] In this invention, "%wt" represents weight percentage.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] This invention uses 2-(1-cyclohexenyl)ethylamine and p-methoxyphenylacetic acid as raw materials, and selects N,N-carbonyldiimidazole as the condensation reagent. Following existing methods, it was found that the 2-(1-cyclohexenyl)ethylamine raw material suffers from incomplete reaction, a problem that cannot be solved even with extended reaction time, and unnecessary impurities are generated due to excessively long reaction times. The inventors disassembled and analyzed the reaction, determining the reaction mechanism of this invention as follows:

[0029]

[0030] This invention scientifically screened the ratio of raw materials and reduced the intermediate reaction temperature and the reaction temperature with 2-(cyclohexenyl)ethylamine during the preparation process, carrying out the reaction at a temperature close to room temperature. While reducing the reaction temperature, the reaction time was significantly shortened, energy consumption was reduced, and unexpectedly, the product yield was significantly improved, with the product yield increasing to over 95%.

[0031] The preparation method of the present invention has relatively simple subsequent processing. High-purity products can be obtained by conventional acid washing and alkali washing.

[0032] In this invention, through optimization and screening of reaction solvents, it was found that toluene, dichloromethane, ethyl acetate, etc., can yield products with high yield and purity when used as reaction solvents.

[0033] The method of the present invention maintains a high level of product yield and purity during process scale-up, making it suitable for large-scale industrial production. Detailed Implementation

[0034] The present invention will be explained in more detail below with reference to the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and the nature and scope of the present invention are not limited thereto.

[0035] Comparative example:

[0036] Take 2.16 g of p-methoxyphenylacetic acid, 17 ml of acetonitrile, and 2.27 g of N,N-carbonyldiimidazole, heat to 60-65 °C, stir for 1 h, add 1.63 g of 2-(cyclohexenyl)ethylamine, maintain the temperature at 60-65 °C, stir for 3 h, after the reaction is complete, cool to room temperature, add purified water, stir, filter, extract the filtrate with dichloromethane, combine the organic layers, dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, add cyclohexane to the residue, stir at 0-5 °C for 30 min, filter, wash the solid with an appropriate amount of cyclohexane, dry, and give 2.72 g of solid, which is N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, yield 76.4%, HPLC 99.02%.

[0037] Example 1:

[0038] Add p-methoxyphenylacetic acid (8.62 g) and acetonitrile (50 ml) to the reaction flask and stir until dissolved. Cool to 10 ± 5 °C in an ice-water bath, then add N,N-carbonyldiimidazole (8.41 g) in portions, controlling the temperature ≤ 20 °C. After the addition is complete, stir for 1 hour. Add a mixture of 2-(1-cyclohexenyl)ethylamine (5 g) and acetonitrile (10 ml) in portions, controlling the temperature ≤ 30 °C. After the addition is complete, react at 10-30 °C for 1 hour. Monitor the reaction of the starting material 2-(1-cyclohexenyl)ethylamine by TLC until complete.

[0039] After the reaction was complete, the acetonitrile was concentrated under reduced pressure, and 100 ml of dichloromethane was added. The organic phase was washed successively with 10% wt hydrochloric acid aqueous solution and 10% wt sodium carbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to constant weight to give 10.47 g of solid, which was N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, with a yield of 95.8%, HPLC 95.31%, and a maximum single impurity of 3.76%.

[0040] Example 2:

[0041] Add 15.93 g of p-methoxyphenylacetic acid and 100 ml of dichloromethane to the reaction flask, cool to 10-20 °C in an ice-water bath, then add N,N-carbonyldiimidazole (15.54 g) in portions, maintaining the temperature ≤25 °C. After the addition is complete, stir for 1 hour. Add a mixture of 10 g of 2-(1-cyclohexenyl)ethylamine and 20 ml of dichloromethane in portions, maintaining the temperature ≤30 °C. After the addition is complete, react at 10-30 °C for 1 hour. Monitor the reaction of the starting material 2-(1-cyclohexenyl)ethylamine by TLC until complete.

[0042] After the reaction was completed, the organic phase was washed successively with 5% wt hydrochloric acid aqueous solution and 10% wt NaOH aqueous solution, dried over anhydrous sodium sulfate, and rotary evaporated to obtain 20.79 g of solid, which was N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, with a yield of 95.2%, HPLC 99.40%, and a maximum single impurity of 0.14%.

[0043] Example 3:

[0044] Add 17.25 g of p-methoxyphenylacetic acid and 100 ml of dichloromethane to the reaction flask, cool to 10-20 °C in an ice-water bath, then add N,N-carbonyldiimidazole (16.83 g) in portions, maintaining the temperature ≤25 °C. After the addition is complete, stir for 1 hour. Add a mixture of 10 g of 2-(1-cyclohexenyl)ethylamine and 20 ml of dichloromethane in portions, maintaining the temperature ≤30 °C. After the addition is complete, react at 10-30 °C for 1 hour. Monitor the reaction of the starting material 2-(1-cyclohexenyl)ethylamine by TLC until complete.

[0045] After the reaction was completed, the organic phase was washed successively with 5% wt hydrochloric acid aqueous solution and 10% wt NaOH aqueous solution, dried over anhydrous sodium sulfate, and rotary evaporated to obtain 20.29 g of solid, which was N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, with a yield of 92.9%, HPLC 99.33%, and a maximum single impurity of 0.15%.

[0046] Example 4:

[0047] Add 18.58 g of p-methoxyphenylacetic acid and 100 ml of dichloromethane to the reaction flask, cool to 10-20 °C in an ice-water bath, then add N,N-carbonyldiimidazole (18.13 g) in portions, maintaining the temperature ≤25 °C. After the addition is complete, stir for 1 hour. Add a mixture of 10 g of 2-(1-cyclohexenyl)ethylamine and 20 ml of dichloromethane in portions, maintaining the temperature ≤30 °C. After the addition is complete, react at 10-30 °C for 1 hour. Monitor the reaction of the starting material 2-(1-cyclohexenyl)ethylamine by TLC until complete.

[0048] After the reaction was completed, the organic phase was washed successively with 5% wt hydrochloric acid aqueous solution and 10% wt NaOH aqueous solution, dried over anhydrous sodium sulfate, and rotary evaporated to obtain 20.79 g of solid, which was N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, with a yield of 95.2%, HPLC 99.29%, and a maximum single impurity of 0.16%.

[0049] Example 5:

[0050] Add 8.62 g of p-methoxyphenylacetic acid and 50 ml of toluene to a reaction flask, stir, and heat to 30 °C until clear. Then add N,N-carbonyldiimidazole (8.41 g) in portions, controlling the temperature ≤35 °C. After the addition is complete, stir for 1 hour. Subsequently, add a mixture of 5 g of 2-(1-cyclohexenyl)ethylamine and 10 ml of toluene in portions, controlling the temperature ≤40 °C. After the addition is complete, react at 30-40 °C for 1 hour. TLC monitoring shows that the reaction of the starting material 2-(1-cyclohexenyl)ethylamine is complete.

[0051] After the reaction was complete, the organic phase was washed successively with 10% wt hydrochloric acid aqueous solution and 10% wt sodium carbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to constant weight to give 10.58 g of solid, which was N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, with a yield of 96.9%, HPLC 98.86%, and a maximum single impurity of 0.18%.

[0052] Example 6:

[0053] Add 8.62 g of p-methoxyphenylacetic acid and 50 ml of ethyl acetate to the reaction flask and stir until dissolved. Cool the mixture to 10 ± 5 °C in an ice-water bath, then add N,N-carbonyldiimidazole (8.41 g) in portions, maintaining the temperature ≤ 20 °C. After the addition is complete, stir for 1 hour. Add a mixture of 5 g of 2-(1-cyclohexenyl)ethylamine and 10 ml of ethyl acetate in portions, maintaining the temperature ≤ 30 °C. After the addition is complete, react at 10-30 °C for 1 hour. Monitor the reaction of the starting material 2-(1-cyclohexenyl)ethylamine by TLC until complete.

[0054] After the reaction was complete, the organic phase was washed successively with 10% wt hydrochloric acid aqueous solution and 10% wt sodium carbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to constant weight to give 10.37 g of solid, which was N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, with a yield of 94.9%, HPLC 98.88%, and a maximum single impurity of 0.13%.

[0055] Example 7:

[0056] Add dichloromethane (15 L) and p-methoxyphenylacetic acid (2.59 kg) to the reaction flask and stir;

[0057] Turn on the refrigeration to lower the temperature to 10±5℃; add N,N-carbonyldiimidazole (2.52kg) in batches, controlling the temperature ≤15℃. After the addition is complete, stir the reaction at 5-15℃ for 1 hour. Add a mixture of 2-(1-cyclohexenyl)ethylamine (1.5kg) and dichloromethane (2.25L) dropwise, controlling the temperature ≤30℃. After the addition is complete, rinse the dropping funnel with 0.75L of dichloromethane; after the addition is complete, control the temperature at 10-30℃ and react for 1 hour.

[0058] After the reaction was completed, the system was cooled to 5-10℃, and the organic phase was washed successively with 10% wt dilute hydrochloric acid and 10% wt sodium carbonate aqueous solution. The solvent was then concentrated to dryness under normal pressure.

[0059] Add 18 L of n-heptane, heat to 65-70 °C and stir for 1.5 hours; turn on the refrigeration and cool to below 25 °C, stirring for 1 hour; filter, wash the filter cake with 2 L of n-heptane; dry the obtained solid at 60 °C with a forced-air circulation to obtain 3.215 kg of solid, which is N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, with a yield of 98.2%, HPLC 99.41%, and a maximum single impurity of 0.13%.

[0060] Example 8:

[0061] Add 5.17 kg of p-methoxyphenylacetic acid and 36 L of toluene to the reactor, stir, and heat to 30-40 °C until dissolved. Then add N,N-carbonyldiimidazole (5.05 kg) in batches, controlling the temperature ≤40 °C. After the addition is complete, stir for 1 hour. Subsequently, add a mixture of 3 kg of 2-(1-cyclohexenyl)ethylamine and 3 L of toluene in batches, controlling the temperature ≤50 °C. After the addition is complete, react at 20-50 °C for 1 hour. Monitor the reaction of the 2-(1-cyclohexenyl)ethylamine starter by TLC until complete.

[0062] After the reaction was complete, the organic phase was washed successively with 10% wt hydrochloric acid aqueous solution and 10% wt sodium carbonate aqueous solution, dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the resulting solid was dried under blast air circulation at 60°C to obtain 6.45 kg of solid, which was N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, with a yield of 98.5%, HPLC 99.42%, and a maximum single impurity of 0.13%.

[0063] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications or variations made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing N-(2-(cyclohexyl-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, comprising the following steps: (1) Dissolve p-methoxyphenylacetic acid in an organic solvent, add N,N-carbonyldiimidazole, and carry out the reaction at a temperature below 40°C; (2) Next, add a mixture of 2-(1-cyclohexenyl)ethylamine and organic solvent, and control the temperature to be below 50°C for reaction; (3) After the reaction is complete, the product is obtained through post-processing; The molar ratio of p-methoxyphenylacetic acid, 2-(1-cyclohexenyl)ethylamine, and N,N-carbonyldiimidazole is (1.2-2):1:(1.2-2); the organic solvent in step (1) or (2) is one or more of dichloromethane, ethyl acetate, and toluene; the temperature in step (1) is controlled at 5-40℃, and the temperature in step (2) is controlled at 10-50℃; the reaction in step (1) is carried out for 0.5-2 hours under stirring, and the reaction in step (2) is carried out for 0.5-2 hours under stirring.

2. The method according to claim 1, wherein in step (1) the reaction is carried out under stirring conditions for 0.8-1.5 hours; and in step (2) the reaction is carried out under stirring conditions for 0.8-1.5 hours.

3. The method according to claim 1, wherein the molar ratio of p-methoxyphenylacetic acid to N,N-carbonyldiimidazole is (0.9-1.1):

1.

4. The method according to claim 1, wherein the molar ratio of p-methoxyphenylacetic acid to 2-(1-cyclohexenyl)ethylamine is (1.2-1.5):

1.

5. The method according to any one of claims 1-4, wherein the post-treatment in step (3) includes sequentially washing the organic phase of the reaction solution with acid and alkali.

6. The method according to claim 1, wherein the post-processing in step (3) includes pulping with a solvent.

7. According to the method of claim 1, in step (3), the organic phase of the reaction solution is successively acid-washed and alkali-washed to remove the organic solvent, then a solvent is added and the mixture is slurried, and then the solvent is separated to obtain the product.

8. The method according to claim 6 or 7, wherein the pulping solvent in step (3) is one or more of n-heptane, n-hexane, cyclohexane, and water.

9. The method according to claim 7, wherein acid washing uses a 5-15% wt hydrochloric acid aqueous solution, and alkaline washing uses a 5-10% wt sodium carbonate aqueous solution, a 5-10% wt sodium bicarbonate aqueous solution, or a 5-10% wt sodium hydroxide aqueous solution.

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