Synthesis method of trans-N-ethyl-N-(2 '-methylphenyl)-2-butenamide

Abstract

The invention relates to the technical field of pharmaceutical chemical synthesis. The synthetic method comprises the following steps: step 1, adding a solvent, dichloromethane and crotonic acid into a reaction kettle, stirring to form turbid liquid, adding 0.5% of DMF (Dimethyl Formamide), cooling to 10-15 DEG C, controlling the temperature to 5-15 DEG C, dropwise adding thionyl chloride, reacting at 5-15 DEG C, and then taking out the mixed liquid for later use; 2, a solvent, N-ethyl-2-methylaniline, DMF and organic alkali are added into a reaction kettle, the temperature is reduced to 0-5 DEG C, the temperature is controlled to 0-10 DEG C, the mixed solution obtained in the step 1 is slowly dropwise added, and heat preservation reaction is conducted after dropwise adding is completed; the method is easy to operate and high in product yield, a high-purity trans-structure product can be obtained, and the yield of the method is gt; the purity gt of trans-N-ethyl-N-(2 '-methylphenyl)-2-butenamide is 90%, the purity gt of trans-N-ethyl-N-(2'-methylphenyl)-2-butenamide is 97%, and the method is low in cost and has important industrial value.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a method for synthesizing trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide. Background Art

[0002] N-ethyl-N-(2'-methylphenyl)-2-buteneamide (R=-CH ) is traded under the name of crotamiton, which is currently a widely used drug in medicine. It is a raw material for anti-skin parasites and anti-seborrhea drugs, and is also used as a cosmetic additive. The structural formula is as follows:

[0003] The preparation of ethyl-N-(2'-methylphenyl)-2-buteneamide usually uses o-alkylaniline as the starting material and is synthesized by the following two methods:

[0004]

[0005] Method 1: British patent GB615137A reported direct heating reaction without solvent, but the reaction of this method is not easy to operate and requires high production equipment. Japanese patent JP2006249039A reported using toluene as solvent and using phase transfer catalyst triethylbenzylammonium chloride to separate and purify the product. The method is complicated to operate and the purification process is complicated. Chinese patent CN106431892A reported that the second step uses an alkane solvent and an aqueous solution of an inorganic base to participate in the reaction. After repeating the operation of this technology, we found that the reaction could not obtain a product with satisfactory purity and yield, and the reproducibility was poor.

[0006] Method 2: The Journal of China Pharmaceutical University reported on page 56 of issue 1 in 1991 that the route of method 2 was adopted. In the first step of this method, a large amount of triethyl orthoformate was used. The N-formyl component formed needs to be replaced and removed in the second step reaction. The reaction is not atomic and the cost is high.

[0007] In the above two methods, due to the cis-trans conversion caused by the reaction process, the cis-trans ratio of the product in the obtained result is generally 5-20:95-80, it is difficult to obtain a high-purity trans structure and the production cost is high. Summary of the invention

[0008] The purpose of the present invention is to solve the problems existing in the prior art and to propose a method for synthesizing trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide.

[0009] In order to achieve the above object, the present invention adopts the following technical solutions: The synthetic method of trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide comprises the following steps: Step 1, add solvent, dichloromethane and crotonic acid into a reaction kettle and stir to form a suspension, add 5‰ DMF, cool to 10-15°C, control the temperature at 5-15°C, add thionyl chloride dropwise, react at 5-15°C, and then take out the mixed solution for standby use; Step 2, adding solvent, N-ethyl-2-methylaniline, DMF and organic base into the reaction kettle, cooling to 0-5°C, controlling the temperature at 0-10°C, slowly dropping the mixed solution obtained in step 1, and keeping the temperature for reaction after the dropping is completed; Step 3, after the reaction is completed, water is added to quench the reaction, and after separation, the pH is adjusted to acidic with hydrochloric acid, and the liquids are separated; the pH of the organic phase is adjusted to alkaline with sodium bicarbonate solution, the organic phase is distilled to remove the solvent at room temperature, and then the product is separated by reduced pressure distillation.

[0010] Preferably, the solvent in step 2 is one or more of dichloromethane, chloroform and dichloroethane.

[0011] Preferably, in step 1, the amount of solvent in the mixed solution is 1V-4V.

[0012] Preferably, the molar ratio of crotonic acid, thionyl chloride and DMF in step 1 is 1:(1-1.2):(0.005-0.05).

[0013] Preferably, the reaction temperature in step 1 is 10-15° C., and the reaction time is 2-6 hours.

[0014] Preferably, the purity of the crotonic acid used in step 1 is >98%, so as to ensure product quality and reduce the introduction of impurities into the raw materials.

[0015] Preferably, the molar ratio of N-ethyl-2-methylaniline in step 2 to crotonic acid in step 1 is 1:(1-1.5), and the amount of solvent is 1V-4V.

[0016] Preferably, the organic base in step 2 comprises one or more of pyridine, triethylamine, and diisopropylethylamine, and the molar ratio of the organic base to trans-2-butenoyl chloride is (1.5-5):1.

[0017] Preferably, the insulation reaction time in step 2 is 20 min-5 h.

[0018] It should be noted here that V is the weight-to-volume ratio, for example, 1 kg of raw material, 1V is 1L of solvent.

[0019] Compared with the prior art, the present invention has the following beneficial effects: The method of the invention is simple, easy to operate, has a high product yield, and can obtain a high-purity trans-structure product. The yield of the method is greater than 90%, wherein the purity of trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide is greater than 97%. The method has low cost and important industrial value. DETAILED DESCRIPTION

[0020] The technical solutions in the embodiments of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Example

[0021] Add 200kg of crotonic acid and 530kg of dichloromethane to a 1000L kettle. Stir until the solid gradually dissolves and cool to 10-15°C. Add 1kg of DMF to the system and continue stirring. Slowly add 279kg of thionyl chloride to the system at a temperature of 5-15°C. Add the solution after about 5 hours. Keep the temperature at 5-15°C for 3-5 hours. Store the reaction solution for later use. Add 810kg of dichloromethane, 2kg of pyridine, and 270kg of N-ethyl-2-methylaniline to a 3000L reactor at room temperature of 20-30°C. Stir and cool to 0-5°C under nitrogen protection. Control the temperature at 0-10°C and slowly add the previously stored dichloromethane solution of crotonyl chloride. Add the solution after about 14 hours. The system becomes turbid. Continue to react for 20 minutes. Add 1080kg of water to the reaction solution to quench the reaction. Stir for 20 minutes, let stand and separate. Add about 1000kg of water to the lower organic phase. 810kg1N hydrochloric acid was used to wash and remove residual pyridine, and the pH of the aqueous phase was adjusted to 2-3. The lower organic phase was washed once with about 810kg of semi-saturated sodium bicarbonate aqueous solution and allowed to stand for separation. The organic phase was desolvated to a weak fraction at 60-65°C under normal pressure, and then desolvated under reduced pressure until no liquid flowed down. The desolvation was continued under reduced pressure for 2h. The material was transferred to a 1000L distillation kettle for reduced pressure distillation, and finally 373kg of product was obtained, with a yield of 91.88%, purity: 99.53%, cis isomerism: 2.57%, chloride ion ≤0.01%, Example

[0022] At room temperature of 20-30°C, add 2.0kg of crotonic acid and 4.0L of dichloromethane to a 50L double-layer jacketed reactor. Stir and the solid gradually dissolves and cools to 10-15°C. Add 10g of DMF and slowly add 3kg of thionyl chloride at a temperature of 5-12°C. The addition is completed in 3 hours. After reacting at 5-12°C for 3 hours, the crotonic acid is <1.0%. The reaction solution is temporarily stored for later use. At room temperature of 20-30°C, add 5.4L of dichloromethane, 2.84kg of pyridine, and 2.70kg of N-ethyl-2-methylaniline to a 50L double-layer jacketed reactor in sequence. Stir and cool to 0-5°C under nitrogen protection. Control the temperature at 0-10°C and slowly add the previously stored dichloromethane solution of crotonyl chloride. Exotherm is obvious and the drop rate is controlled. The addition is completed in about 2 hours. Continue to react for 20 minutes. Add 10.8L of water to the reaction solution to quench the reaction. Stir for 20 minutes. After 30 min, the mixture was allowed to stand for separation. 8.1L 1N hydrochloric acid was added to the organic phase to remove residual pyridine. The pH of the aqueous phase was adjusted to about 3, and the mixture was allowed to stand for separation. The lower organic phase was washed once with 8.1L semi-saturated sodium bicarbonate aqueous solution, and the pH of the aqueous phase was 7-8. The mixture was allowed to stand for separation. The organic phase was desolvated under reduced pressure at 40-45°C. The fractions were collected for distillation under reduced pressure to obtain 3.76kg of colorless and transparent oily product with a yield of 92.61%. The product was qualified in all tests with a purity of 99.38% and cis-isomerization of 1.59%. Example

[0023] At room temperature of 20-30°C, add 2.0 kg of crotonic acid and 2.0 L of dichloroethane to a 50 L double-layer jacketed reactor. Stir and gradually dissolve the solid. Cool to 10-15°C. Add 16 g of DMF and slowly add 3.0 kg of thionyl chloride dropwise at a temperature of 5-12°C. The addition is completed within 3 hours. After reacting at 5-12°C for about 4 hours, the crotonic acid is <1.0%. The reaction solution is temporarily stored for later use. At room temperature of 20-30°C, 5.4L of dichloroethane, 3.16kg of pyridine, and 2.70kg of N-ethyl-2-methylaniline were added to a 50L double-layer jacketed reactor in sequence, and the temperature was lowered to 0-5°C under nitrogen protection with stirring; the temperature was controlled at 0-10°C, and the dichloroethane solution of crotonyl chloride stored previously was slowly added dropwise, and the heat release was obvious, and the dropping rate was controlled; the addition was completed in about 2 hours, and the reaction was continued for 30 minutes, and 10.8L of water was added to the reaction solution to quench the reaction, and the reaction was allowed to stand for separation after stirring for 20 minutes. 8.1L of 1N hydrochloric acid was added to the organic phase to wash to remove residual pyridine, and the pH of the aqueous phase was adjusted to about 3; the organic phase was washed with 8 .1L water for one time, and stand for separation; the lower organic phase was washed once with 8.1L semi-saturated sodium bicarbonate aqueous solution, the pH of the aqueous phase was 7-8, and the aqueous phase was allowed to stand for separation; the lower organic phase was washed once with 8.1L water until the pH of the aqueous phase was 6-7; the organic phase was desolvated under reduced pressure at 40-45°C; vacuum distillation was performed on a 20cm vertical thorn distillation column, and low boiling was removed at an oil temperature of 60-80°C, the oil temperature was 160°C, the vacuum degree was 300-400pa, the top temperature was 125-127°C, and the fractions were collected to obtain 3.67kg of colorless transparent oily product, with a yield of 90.5%, and all tests were qualified, with a purity of 99.44%, and cis isomerism: 1.89% Example

[0024] At room temperature of 20-30°C, add 2.0kg of crotonic acid and 4.0L of chloroform to a 50L double-layer jacketed reactor. Stir and gradually dissolve the solid. Cool to 10-15°C. Add 34g of DMF and slowly add 2.79kg of thionyl chloride dropwise at a temperature of 5-12°C. The addition takes about 3 hours. After reacting at 5-12°C for about 2-4 hours, the crotonic acid is <1.0%. The reaction solution is temporarily stored for later use. At room temperature of 20-30°C, 10.8L chloroform, 2.84kg pyridine, and 2.70kg N-ethyl-2-methylaniline were added to a 50L double-layer jacketed reactor in sequence, and the temperature was lowered to 0-5°C under nitrogen protection with stirring; the temperature was controlled at 0-10°C, and the previously stored dichloromethane solution of crotonyl chloride was slowly added dropwise, and the heat release was obvious, and the dropping rate was controlled; the addition was completed in about 2 hours, and the reaction was continued for 20 minutes without temperature control. 10.8L water was added to the reaction solution to quench the reaction, and the reaction was allowed to stand for separation after stirring for 20 minutes. 8.1L 1N hydrochloric acid was added to the organic phase to wash to remove residual pyridine, and the pH of the aqueous phase was adjusted to about 3; the organic phase was washed with 8 .1L water once, let stand and separate the liquid; the lower organic phase was washed once with 8.1L semi-saturated sodium bicarbonate aqueous solution, the pH of the aqueous phase was 7-8, let stand and separate the liquid; the lower organic phase was washed once with 8.1L water, and the pH of the aqueous phase was 6-7; the organic phase was desolvated under reduced pressure at 40-45℃; vacuum distillation, 20cm vertical thorn distillation column, low boiling oil was removed at 60-80℃, oil temperature was 160℃, vacuum degree was 300-400pa, top temperature was 125-127℃, and the fractions were collected to obtain 3.76kg of colorless transparent oily product, with a yield of 92.61%, qualified in all inspections, purity: 99.38%, cis isomerization: 2.29%.

[0025] Comparative Example 1 (using traditional inorganic alkali) At room temperature of 20-30°C, add 2.0kg of crotonic acid and 4.0L of dichloromethane to a 50L double-layer jacketed reactor. Stir and gradually dissolve the solid. Cool to 10-15°C. Add 34g of DMF and slowly add 2.79kg of thionyl chloride dropwise at a temperature of 5-12°C. The addition takes about 3 hours. After reacting at 5-12°C for about 2-4 hours, the crotonic acid content is <1.0%. The reaction solution is temporarily stored for later use. At room temperature of 20-30°C, 10.8L of dichloromethane, 2.84kg of pyridine, and 2.70kg of N-ethyl-2-methylaniline were added to a 50L double-layer jacketed reactor in sequence, and the temperature was lowered to 10-15°C with stirring under nitrogen protection; the temperature was controlled at 10-20°C, and the dichloromethane solution of crotonyl chloride previously temporarily stored was slowly added dropwise, and the heat release was obvious, and the dropping rate was controlled; the addition was completed in about 2h, and the reaction was continued for 20min without temperature control, and 10.8L of water was added to the reaction solution to quench the reaction, and the reaction was allowed to stand for separation after stirring for 20min. 8.1L of 1N hydrochloric acid was added to the organic phase to wash and remove the residual pyridine, and the pH of the aqueous phase was adjusted to about 3; The organic phase was washed once with 8.1 L of water and allowed to stand for separation; the lower organic phase was washed once with 8.1 L of semi-saturated sodium bicarbonate aqueous solution, the pH of the aqueous phase was 7-8, and allowed to stand for separation; the lower organic phase was washed once with 8.1 L of water until the pH of the aqueous phase was 6-7; the organic phase was desolvated under reduced pressure at 40-45°C; vacuum distillation was performed on a 20 cm vertical stab distillation column, low boiling points were removed at an oil temperature of 60-80°C, the oil temperature was 160°C, the vacuum degree was 300-400 Pa, the top temperature was 125-127°C, and the fractions were collected to obtain 3.46 kg of a colorless transparent oily product with a yield of 85.13%, a purity of 98.28%, and a cis isomerization of 2.49%.

[0026] It can be proved by the above examples and comparative examples that: The method of the invention is simple, easy to operate, and has a high product yield. On the one hand, since the selected base is pyridine, the alkalinity is weaker than that of the inorganic base in the traditional process, cis-trans conversion is avoided, and a high-purity trans-structure product can be obtained. In addition, the temperature conditions specified in the invention can obtain the product with the highest purity. Generally speaking, the yield of the method of the invention is greater than 90%, wherein the purity of trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide is greater than 97%, the cost is low, and the method has important industrial value.

[0027] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for synthesizing trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide, characterized in that: The following steps are involved: Step 1, add solvent, dichloromethane and crotonic acid into a reaction kettle and stir to form a suspension, add 5‰ DMF, cool to 10-15°C, control the temperature at 5-15°C, add thionyl chloride dropwise, react at 5-15°C, and then take out the mixed solution for standby use; Step 2, adding solvent, N-ethyl-2-methylaniline, DMF and organic base into the reaction kettle, cooling to 0-5°C, controlling the temperature at 0-10°C, slowly dropping the mixed solution obtained in step 1, and keeping the temperature for reaction after the dropping is completed; Step 3, after the reaction is completed, water is added to quench the reaction, and after separation, the pH is adjusted to acidic with hydrochloric acid, and the liquids are separated; the pH of the organic phase is adjusted to alkaline with sodium bicarbonate solution, the organic phase is distilled to remove the solvent at room temperature, and then the product is separated by reduced pressure distillation.

2. The method for synthesizing trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide according to claim 1, characterized in that: The solvent in step 2 is one or more of dichloromethane, chloroform and dichloroethane.

3. The method for synthesizing trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide according to claim 1, characterized in that: In the step 1, the solvent volume of the mixed solution is 1V-4V.

4. The method for synthesizing trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide according to claim 2, characterized in that: The molar ratio of crotonic acid, thionyl chloride and DMF in step 1 is 1:(1-1.2):(0.005-0.05).

5. The method for synthesizing trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide according to claim 1, characterized in that: The reaction temperature in step 1 is 10-15° C., and the reaction time is 2-6 hours.

6. The method for synthesizing trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide according to claim 1, characterized in that: The purity of the crotonic acid used in step 1 is >98%.

7. The method for synthesizing trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide according to claim 1, characterized in that: The molar ratio of N-ethyl-2-methylaniline in step 2 to the crotonic acid in step 1 is 1:(1-1.5), and the amount of solvent is 1V-4V.

8. The method for synthesizing trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide according to claim 1, characterized in that: The organic base described in step 2 includes one or more of pyridine, triethylamine, and diisopropylethylamine, and the molar ratio of the organic base to trans-2-butenoyl chloride is (1.5-5):

1.

9. The method for synthesizing trans-N-ethyl-N-(2'-methylphenyl)-2-buteneamide according to claim 1, characterized in that: The insulation reaction time in step 2 is 20 min-5 h.

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