Method for preparing N-(2-(cyclohex-1-ene-1-yl) ethyl)-2-p-methoxyphenylacetamide

Abstract

The invention belongs to the field of medicines, and particularly provides a method for preparing an important intermediate compound N-(2-(cyclohex-1-ene-1-yl) ethyl)-2-p-methoxyphenylacetamide of dextromethorphan. According to the method, 2-(1-cyclohexenyl) ethylamine and p-methoxyphenylacetic acid are used as raw materials, N, N-carbonyldiimidazole is selected as a condensation reagent, reaction conditions are optimized, the reaction temperature is reduced, the reaction time is shortened, aftertreatment is simple, the product yield and purity are high, cost is low, and industrial production is facilitated.

Description

Technical Field

[0001] The invention belongs to the field of medicine and specifically provides a method for preparing N-(2-(cyclohex-1-ene-1-yl)ethyl)-2-p-methoxyphenylacetamide. Background Art

[0002] Dextromethorphan is the dextrorotatory isomer of morphine-like levorphan methyl ether and is a strong central antitussive drug that mainly inhibits the cough center in the medulla oblongata to exert its effects. N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide is an important intermediate compound for the preparation of dextromethorphan. The conventional process route is as follows:

[0003]

[0004] At present, the preparation of this compound in the prior art mainly uses cyclohexeneethylamine and p-methoxyphenylacetic acid as raw materials, refluxes at high temperature in xylene for 10-15 hours, or adds diimine condensation agents (DIC, DCC, EDCI, etc.) and activators (DMAP) at a relatively low temperature to react for 8-10 hours, or p-methoxyphenylacetic acid is prepared into methoxyphenylacetyl chloride by thionyl chloride under heating conditions, and condenses with cyclohexeneethylamine in the presence of an acid binding agent. The above methods either need to be carried out under heating or at a relatively low temperature, with a long reaction time and high energy consumption; or use diimine condensation agents, which are expensive and difficult to remove by-products, such as DCU, a by-product of DCC. The thionyl chloride used in the acyl chloride method produces acid gas during the process, which is highly corrosive to the equipment and is not conducive to environmental protection.

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

[0006] The purpose of the present invention is to provide a method for preparing N-(2-(cyclohex-1-ene-1-yl)ethyl)-2-p-methoxyphenylacetamide. The method can overcome the defects existing in the prior art, so that the reaction can be carried out under milder conditions, the post-treatment is simple, the product yield and purity are both high, the cost is low, the reaction time is short, and it is more conducive to industrial scale-up production.

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

[0008] (1) dissolving p-methoxyphenylacetic acid in an organic solvent, adding N,N-carbonyldiimidazole, and controlling the temperature to be below 40° C. to react;

[0009] (2) then adding a mixture of 2-(1-cyclohexenyl)ethylamine and an organic solvent, and controlling the temperature to be below 50° C. to react;

[0010] (3) after the reaction is completed, the product is obtained by post-treatment;

[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, halogenated alkane, ester, aromatic hydrocarbon, monoalkyl or polyalkyl substituted aromatic hydrocarbon, monohalogenated or polyhalogenated aromatic hydrocarbon, preferably C 2-4 Aliphatic nitrile, halogenated C 1-6 Alkanes, esters, benzene, single C 1-6 Alkyl or poly C 1-6 One or more of alkyl-substituted benzene, monohalogenated or polyhalogenated benzene, more preferably one or more of acetonitrile, dichloromethane, ethyl acetate, 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 can be added in batches in step (1), and a mixture of 2-(1-cyclohexenyl)ethylamine and an organic solvent can be added in batches in step (2).

[0014] In a further preferred embodiment of the present invention, the reaction in step (1) is carried out under stirring conditions for 0.5-2 hours, preferably for 0.8-1.5 hours, and more preferably for 1 hour; and the reaction in step (2) is carried out under stirring conditions for 0.5-2 hours, preferably for 0.8-1.5 hours, and more preferably for 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, further preferably 10-25°C, further preferably 10-20°C, 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 described in step (3) comprises 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-treatment in step (3) comprises 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, and in step (3), the organic phase of the reaction solution is sequentially acid washed and alkaline washed to remove the organic solvent, and then a solvent is added for slurrying, and then the solvent is 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 alkali washing in step (3) uses a 5-10%wt aqueous solution of sodium carbonate, a 5-10%wt aqueous solution of sodium bicarbonate or a 5-10%wt aqueous solution of sodium hydroxide, preferably a 5-10%wt aqueous solution of sodium carbonate, more preferably a 10%wt aqueous solution of sodium carbonate.

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

[0026] "%wt" in the present invention means weight percentage.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The present invention uses 2-(1-cyclohexenyl)ethylamine and p-methoxyphenylacetic acid as raw materials, selects N,N-carbonyldiimidazole as a condensation reagent, and operates according to the method of the prior art. It is found that the raw material 2-(1-cyclohexenyl)ethylamine has the problem of incomplete reaction. Even if the reaction time is extended, the problem cannot be solved, and unnecessary impurities will be generated due to the long reaction time. The inventor disassembled and analyzed the reaction and determined that the reaction mechanism of the present invention is as follows:

[0029]

[0030] The invention scientifically screens the ratio of raw materials, reduces the intermediate reaction temperature and the reaction temperature with 2-(cyclohexenyl)ethylamine during the preparation process, performs the reaction at a temperature close to room temperature, significantly shortens the reaction time while reducing the reaction temperature, reduces energy consumption, and unexpectedly finds that the product yield is significantly improved, and the product yield can be increased to more than 95%.

[0031] The subsequent treatment in the preparation method of the present invention is relatively simple, and a product with high purity can be obtained through conventional acid washing and alkali washing.

[0032] In the present invention, by optimizing and screening the reaction solvent, it is found that toluene, dichloromethane, ethyl acetate and the like can be used as the reaction solvent to obtain a product with a higher yield and purity.

[0033] During the process of process amplification, the product yield and purity of the method of the present invention are still maintained at a relatively high level, and the method is suitable for large-scale industrial production. DETAILED DESCRIPTION

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

[0035] Comparative Example:

[0036] Take 2.16g of p-methoxyphenylacetic acid, 17ml of acetonitrile, and 2.27g of N,N-carbonyldiimidazole, heat to 60-65°C, stir and react for 1h, then add 1.63g of 2-(cyclohexenyl)ethylamine, maintain the temperature at 60-65°C, stir and react for 3h, and after the reaction is completed, 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 30min, filter, wash the solid with an appropriate amount of cyclohexane, and dry to obtain 2.72g of solid, which is N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, with a yield of 76.4% and HPLC 99.02%.

[0037] Embodiment 1:

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

[0039] After the reaction, the acetonitrile was concentrated under reduced pressure, 100 ml of dichloromethane was added, and the organic phase was washed with 10% wt aqueous hydrochloric acid solution and 10% wt aqueous sodium carbonate solution in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to constant weight to obtain 10.47 g of solid, which was N-(2-(cyclohex-1-en-1-yl)ethyl)-2-p-methoxyphenylacetamide, with a yield of 95.8%, HPLC95.31%, and a maximum single impurity of 3.76%.

[0040] Embodiment 2:

[0041] Add p-methoxyphenylacetic acid (15.93 g) and dichloromethane (100 ml) to the reaction bottle, cool to 10-20°C in an ice-water bath, then add N,N-carbonyldiimidazole (15.54 g) in batches, control the temperature to ≤25°C, stir for 1 hour after addition. Add a mixture of 2-(1-cyclohexenyl)ethylamine (10 g) and dichloromethane (20 ml) in batches, control the temperature to ≤30°C, add, and react at 10-30°C for 1 hour. TLC monitors the reaction of the raw material 2-(1-cyclohexenyl)ethylamine.

[0042] After the reaction, the organic phase was washed with 5% wt aqueous hydrochloric acid solution and 10% wt aqueous NaOH 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] Embodiment 3:

[0044] Add p-methoxyphenylacetic acid (17.25 g) and dichloromethane (100 ml) to the reaction bottle, cool to 10-20°C in an ice-water bath, then add N,N-carbonyldiimidazole (16.83 g) in batches, control the temperature to ≤25°C, stir for 1 hour after addition. Add a mixture of 2-(1-cyclohexenyl)ethylamine (10 g) and dichloromethane (20 ml) in batches, control the temperature to ≤30°C, add, and react at 10-30°C for 1 hour. TLC monitors the reaction of the raw material 2-(1-cyclohexenyl)ethylamine.

[0045] After the reaction, the organic phase was washed with 5% wt aqueous hydrochloric acid solution and 10% wt aqueous NaOH 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] Embodiment 4:

[0047] Add p-methoxyphenylacetic acid (18.58 g) and dichloromethane (100 ml) to the reaction bottle, cool to 10-20°C in an ice-water bath, then add N,N-carbonyldiimidazole (18.13 g) in batches, control the temperature ≤25°C, stir for 1 hour after addition. Add a mixture of 2-(1-cyclohexenyl)ethylamine (10 g) and dichloromethane (20 ml) in batches, control the temperature ≤30°C, add, and react at 10-30°C for 1 hour. TLC monitors the reaction of the raw material 2-(1-cyclohexenyl)ethylamine.

[0048] After the reaction, the organic phase was washed with 5% wt aqueous hydrochloric acid solution and 10% wt aqueous NaOH 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] Embodiment 5:

[0050] Add p-methoxyphenylacetic acid (8.62 g) and toluene (50 ml) to the reaction bottle, stir, heat to 30 ° C to clarify, then add N, N-carbonyldiimidazole (8.41 g) in batches, control the temperature ≤ 35 ° C, stir for 1 hour after addition. Then add a mixture of 2-(1-cyclohexenyl)ethylamine (5 g) and toluene (10 ml) in batches, control the temperature ≤ 40 ° C, add, and react at 30-40 ° C for 1 hour. TLC monitoring shows that the raw material 2-(1-cyclohexenyl)ethylamine reacts completely.

[0051] After the reaction, the organic phase was washed with 10% wt aqueous hydrochloric acid solution and 10% wt aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to constant weight to obtain 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] Embodiment 6:

[0053] Add p-methoxyphenylacetic acid (8.62g) and ethyl acetate (50ml) to the reaction bottle and stir until dissolved. Cool to 10±5℃ in an ice-water bath, then add N,N-carbonyldiimidazole (8.41g) in batches, control the temperature ≤20℃, stir for 1 hour after addition. Add a mixture of 2-(1-cyclohexenyl)ethylamine (5g) and ethyl acetate (10ml) in batches, control the temperature ≤30℃, add, and react at 10-30℃ for 1 hour. TLC monitors the reaction of the raw material 2-(1-cyclohexenyl)ethylamine.

[0054] After the reaction, the organic phase was washed with 10% wt aqueous hydrochloric acid solution and 10% wt aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to constant weight to obtain 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] Embodiment 7:

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

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

[0058] After the reaction, the system was cooled to 5-10° C., and the organic phase was washed with 10% wt dilute hydrochloric acid and 10% wt sodium carbonate aqueous solution in sequence, and the solvent was concentrated to dryness under normal pressure.

[0059] Add n-heptane (18 L), raise the temperature to 65-70° C. and stir for 1.5 hours; turn on the refrigeration, cool to below 25° C., and stir for 1 hour; filter with suction, and wash the filter cake with 2 L of n-heptane; dry the obtained solid at 60° C. with 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] Embodiment 8:

[0061] Add p-methoxyphenylacetic acid (5.17 kg) and toluene (36 L) to the reactor, stir, heat to 30-40 ° C to dissolve, then add N, N-carbonyldiimidazole (5.05 kg) in batches, control the temperature ≤ 40 ° C, stir for 1 hour after addition. Then add a mixed solution of 2-(1-cyclohexenyl)ethylamine (3 kg) and toluene (3 L) in batches, control the temperature ≤ 50 ° C, add, and react at 20-50 ° C for 1 hour. TLC monitoring shows that the raw material 2-(1-cyclohexenyl)ethylamine reacts completely.

[0062] After the reaction, the organic phase was washed with 10% wt aqueous hydrochloric acid solution and 10% wt aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained solid was dried at 60° C. with forced air circulation to obtain 6.45 kg of solid, which was N-(2-(cyclohex-1-ene-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 only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications or changes made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing N-(2-(cyclohex-1-ene-1-yl)ethyl)-2-p-methoxyphenylacetamide, comprising the steps of: (1) dissolving p-methoxyphenylacetic acid in an organic solvent, adding N,N-carbonyldiimidazole, and controlling the temperature to be below 40° C. to react; (2) then adding a mixture of 2-(1-cyclohexenyl)ethylamine and an organic solvent, and controlling the temperature to be below 50° C. to react; (3) after the reaction is completed, the product is obtained by post-treatment; The molar ratio of p-methoxyphenylacetic acid, 2-(1-cyclohexenyl)ethylamine and N,N-carbonyldiimidazole is (1.2-2):1:(1.2-2).

2. The method according to claim 1, wherein the organic solvent in step (1) or (2) is one or more of nitrile, halogenated alkane, ester, aromatic hydrocarbon, monoalkyl or polyalkyl substituted aromatic hydrocarbon, monohalogenated or polyhalogenated aromatic hydrocarbon, preferably one or more of acetonitrile, dichloromethane, ethyl acetate and toluene.

3. The method according to claim 1 or 2, wherein the temperature in step (1) is controlled at 5-40°C, and the temperature in step (2) is controlled at 10-50°C; the reaction in step (1) is carried out under stirring for 0.5-2 hours, preferably for 0.8-1.5 hours, and more preferably for 1 hour; the reaction in step (2) is carried out under stirring for 0.5-2 hours, preferably for 0.8-1.5 hours, and more preferably for 1 hour.

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

1.

5. The method according to any one of claims 1 to 4, wherein the molar ratio of p-methoxyphenylacetic acid to 2-(1-cyclohexenyl)ethylamine is 1.2-1.5:1, preferably 1.3:

1.

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

7. The method according to any one of claims 1 to 6, wherein the post-treatment in step (3) comprises pulping using a solvent.

8. The method according to any one of claims 1 to 7, wherein the organic solvent used in steps (1) and (2) is dichloromethane, ethyl acetate or toluene, and in step (3), the organic phase of the reaction solution is sequentially acid-washed and alkaline-washed to remove the organic solvent, followed by adding a solvent for slurrying, and then separating the solvent to obtain the product.

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

10. The method according to claim 6 or 8, wherein the acid wash uses a 5-15%wt hydrochloric acid aqueous solution, and the alkali wash 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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