Preparation method of crotamiton

Abstract

The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of crotamiton, which comprises the following steps: adding N-ethyl o-toluidine, crotonic acid and an acylating chlorination reagent into a reaction container, reacting at room temperature, distilling after the reaction is finished, and collecting crotamiton fractions to obtain crotamiton, and no solvent is used in the reaction. According to the present invention, the one-pot crotamiton preparation process has advantages of simple operation, low cost, environmental protection, no pollution, and suitableness for industrial production, and the obtained crotamiton has characteristics of high yield and high purity.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and relates to a preparation method of crotamiton, specifically to a one-pot preparation process of crotamiton. Background Art

[0002] Crotamiton (C 13 H 17 NO), with the chemical name N-crotonoyl-N-ethyl-o-toluidine, is a colorless or light yellow oily liquid. It has a slight special odor and can be partially or completely solidified at low temperatures. Its 10% cream is used to treat anal, vulvar, scrotal pruritus, senile pruritus, infantile eczema, dermatitis, chilblains, tinea pedis, and can also be used to treat scabies. The drug effect is rapid and persistent, and the safety is high; crotamiton is also used as a solvent in loxoprofen sodium cataplasm and has a certain antipruritic effect.

[0003] In 2023, the market demand for crotamiton in China was 58,000 tons, with a year-on-year growth of 9%. With the continuous development of the pharmaceutical industry, it is expected that by 2025, the market demand will reach 70,000 tons, and the annual compound growth rate will be about 8.5%.

[0004] Patent CN 106431892 A discloses a preparation method of trans-N-ethyl-N-(2-methylphenyl)-2-butenamide. In this method, crotonic acid is first converted into sodium crotonate, and then reacted with N-ethyl-o-toluidine and phosphorus trichloride to obtain crotamiton. This reaction first synthesizes sodium crotonate, and the steps are cumbersome; moreover, solvents such as toluene, ethylbenzene, xylene, chlorobenzene, and dichlorobenzene are used in the reaction process, which are highly toxic and have high boiling points, and it is difficult to remove the residual solvents in the later stage; in the post-treatment process, washing with water, washing with alkali, washing with acid, washing with water and distilling the solvent are relatively complex operations. The specific reaction process is as follows:

[0005]

[0006] In the existing technology, there are defects such as low yield, low efficiency, cumbersome operation, and high toxicity of materials in the preparation process of crotamiton.

[0007] Therefore, it is necessary to provide an improved preparation method of crotamiton. Summary of the Invention

[0008] In view of the above technical status quo, the present invention provides a preparation method of crotamiton, which includes: adding N-ethyl-o-toluidine, crotonic acid and an acyl chlorination reagent into a reaction vessel, reacting at room temperature, and after completion, distilling to collect the fraction of crotamiton, wherein no solvent is used in the reaction.

[0009] In the present invention, as one of the embodiments, N-ethyl-o-toluidine, crotonic acid and an acyl chlorination reagent are sequentially added to a reaction vessel, stirred at room temperature. After the reaction is completed, under a reduced pressure of 1000 - 3000 Pa, distillation is carried out under reduced pressure, and the fraction at 140 - 145 °C is collected under a reduced pressure of 1000 - 3000 Pa to obtain crotamiton.

[0010] In the present invention, as one of the embodiments, the acyl chlorination reagent is thionyl chloride, oxalyl chloride, or phosphorus oxychloride, or a combination of two or three of them, preferably thionyl chloride.

[0011] In the present invention, as one of the embodiments, the molar ratio of crotonic acid to the acyl chlorination reagent is 1:0.5 - 3. As an illustrative example, the molar ratio of crotonic acid to the acyl chlorination reagent is 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, or any real number between them; as one of the embodiments, the preferred molar ratio is 1:1.

[0012] In the present invention, as one of the embodiments, the molar ratio of N-ethyl-o-toluidine to crotonic acid is 1:0.8 - 1.2. As an illustrative example, the molar ratio of N-ethyl-o-toluidine to crotonic acid is 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, or any real number between them; as one of the embodiments, the preferred molar ratio of N-ethyl-o-toluidine to crotonic acid is 1:1.

[0013] In the present invention, as one of the embodiments, the reaction time in the method is 3 - 5 hours; as an illustrative example, it can be 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0 hours, or any real number between them.

[0014] In the present invention, as one of the embodiments, the method includes distillation under reduced pressure, and the crotamiton fraction at 140 - 145 °C is collected under a reduced pressure of 1000 - 3000 Pa.

[0015] In the present invention, as one of the embodiments, the method further comprises: adding N-ethyl-o-toluidine, crotonic acid and thionyl chloride into a reaction flask in a molar ratio of 1:1:1 in sequence. After the addition, stir at room temperature for 3-5 h. After the reaction is completed, perform vacuum distillation under 1000-3000 Pa, and collect the fraction at 140-145 °C to obtain crotamiton.

[0016] The method of the present invention uses crotonic acid and N-ethyl-o-toluidine as starting materials and prepares crotamiton by a one-pot method under the condition of thionyl chloride.

[0017] Compared with the prior art, the method of the present invention only needs one post-treatment to obtain the crotamiton product, simplifies the process operation, and improves the production capacity; and the method of the present invention does not require solvents (such as benzene, bromoethane, etc.), avoids harm to the environment and personnel, and also saves costs; after the reaction is completed, direct distillation is used for purification, the operation is simple, the efficiency is improved, higher yield and purity are achieved, the product quality is guaranteed, and the cost is low. Description of the Drawings

[0018] Figure 1 : 1H NMR spectrum of crotamiton obtained in Example 1. Detailed Description of the Invention

[0019] The following examples are used to further illustrate the present invention, but do not limit the effective scope of the present invention in any way.

[0020] The synthesis route of crotamiton of the present invention is as follows:

[0021]

[0022] Example 1: Preparation of crotamiton by one-pot method

[0023] Add 135.2 g of N-ethyl-o-toluidine, 86 g of crotonic acid and 119 g of thionyl chloride into a reaction flask in sequence. After the addition, stir at room temperature for 4 hours. After the reaction is completed, perform vacuum distillation under 1000-3000 Pa, and collect the fraction at 140-145 °C to obtain 198 g of crotamiton, with a yield of 97.40% and a purity of 99.8%. 1H NMR (CDCl3) δ 1.48 (m, 3H), 1.68 (m, 3H), 2.19 (s, 3H), 3.38 (m, 1H), 4.09 (m, 1H), 5.51 (q, 1H), 6.91 (q, 1H), 7.10-7.31 (m, 4H), as shown in the appendix Figure 1 as shown.

[0024] Example 2: Preparation of crotamiton by one-pot method using oxalyl chloride

[0025] 135.2 g of N-ethyl-o-toluidine, 86 g of crotonic acid and 127 g of oxalyl chloride were successively added to a reaction flask. After the addition, the mixture was stirred at room temperature for 4 hours. After the reaction was completed, under a reduced pressure of 1000 - 3000 Pa, vacuum distillation was carried out, and the fraction at 140 - 145 °C was collected to obtain 190 g of cromolyn, with a yield of 93.47% and a purity of 99.6%.

[0026] Example 3: Preparation of cromolyn by a one-pot method using 0.5 eq of thionyl chloride

[0027] 135.2 g of N-ethyl-o-toluidine, 86 g of crotonic acid and 59.5 g of 0.5 eq of thionyl chloride were successively added to a reaction flask. After the addition, the mixture was stirred at room temperature for 4 h. After the reaction was completed, under a reduced pressure of 1000 - 3000 Pa, vacuum distillation was carried out, and the fraction at 140 - 145 °C was collected to obtain 159 g of cromolyn, with a yield of 78.22% and a purity of 98.6%.

[0028] Example 4: Preparation of cromolyn by a one-pot method using 3 eq of thionyl chloride

[0029] 135.2 g of N-ethyl-o-toluidine, 86 g of crotonic acid and 357 g of 3 eq of thionyl chloride were successively added to a reaction flask. After the addition, the mixture was stirred at room temperature for 4 h. After the reaction was completed, under a reduced pressure of 1000 - 3000 Pa, vacuum distillation was carried out, and the fraction at 140 - 145 °C was collected to obtain 168 g of cromolyn, with a yield of 82.64% and a purity of 98.4%.

[0030] Example 5: Preparation of cromolyn by a one-pot method using 0.8 eq of crotonic acid

[0031] 135.2 g of N-ethyl-o-toluidine, 68.8 g of crotonic acid and 119 g of thionyl chloride were successively added to a reaction flask. After the addition, the mixture was stirred at room temperature for 4 h. After the reaction was completed, under a reduced pressure of 1000 - 3000 Pa, vacuum distillation was carried out, and the fraction at 140 - 145 °C was collected to obtain 153 g of cromolyn, with a yield of 75.27% and a purity of 99.1%.

[0032] Example 6: Preparation of cromolyn by a one-pot method using 1.2 eq of crotonic acid

[0033] 135.2 g of N-ethyl-o-toluidine, 103.2 g of crotonic acid and 119 g of thionyl chloride were successively added to a reaction flask. After the addition, the mixture was stirred at room temperature for 4 h. After the reaction was completed, under a reduced pressure of 1000 - 3000 Pa, vacuum distillation was carried out, and the fraction at 140 - 145 °C was collected to obtain 190 g of cromolyn, with a yield of 93.47% and a purity of 99.3%.

[0034] Example 7: Preparation of cromolyn by a one-pot method using phosphorus oxychloride

[0035] 135.2 g of N-ethyl-o-toluidine, 86 g of crotonic acid and 153.3 g of phosphorus oxychloride were successively added to the reaction flask. After the addition, the mixture was stirred at room temperature for 3 h. After the reaction was completed, under a reduced pressure of 1000 - 3000 Pa, vacuum distillation was carried out to collect the fraction at 140 - 145 °C, obtaining 195 g of cromolyn, with a yield of 95.93% and a purity of 99.7%.

[0036] Example 8: Scale-up experiment for the preparation of cromolyn by one-pot method

[0037] 1352 g of N-ethyl-o-toluidine, 860 g of crotonic acid and 1190 g of thionyl chloride were successively added to the reaction flask. After the addition, the mixture was stirred at room temperature for 5 h. After the reaction was completed, under a reduced pressure of 1000 - 3000 Pa, vacuum distillation was carried out to collect the fraction at 140 - 145 °C, obtaining 2000 g of cromolyn, with a yield of 98.39% and a purity of 99.8%.

[0038] Example 9: Preparation of cromolyn using dichloromethane as a solvent

[0039] 270 g of dichloromethane, 135.2 g of N-ethyl-o-toluidine, 86 g of crotonic acid and 119 g of thionyl chloride were successively added to the reaction flask. After the addition, the mixture was stirred at room temperature for 4 h. After the reaction was completed, under a reduced pressure of 1000 - 3000 Pa, vacuum distillation was carried out to collect the fraction at 140 - 145 °C, obtaining 188 g of cromolyn, with a yield of 92.48% and a purity of 99.7%.

[0040] Example 10: Repeating the method of CN 106431892A

[0041] 30 g of ethylbenzene and 10 g of crotonic acid were added to the reaction flask. While stirring, 21.9 g of 30% sodium methoxide - methanol solution was added dropwise. The reaction was exothermic and the temperature was controlled below 50 °C using a water bath. After the addition was complete, methanol was distilled off by heating, and the temperature was cooled to room temperature. 16.5 g of N-ethyl-o-toluidine was added, and the mixture was stirred and heated to 60 °C. At 60 - 70 °C, 5.58 g of phosphorus trichloride was added dropwise. After the addition was complete, the mixture was kept at 60 - 70 °C for 0.5 h, then slowly heated to 100 °C and kept at 100 - 110 °C for 2 h. After the holding was completed, the temperature was cooled to room temperature. Tap water was added to the reaction solution, and after thorough stirring and mixing, it was allowed to stand and separate layers. The aqueous layer was separated. Liquid alkali was added to the organic layer, and after thorough stirring and mixing, it was allowed to stand and separate layers. The alkaline aqueous layer was separated. An acetic acid aqueous solution was added, and after thorough stirring and mixing, it was allowed to stand and separate layers. The acidic aqueous layer was separated. Finally, it was washed three times with purified water to obtain a crude product solution. The crude product solution was put into a distillation flask, ethylbenzene was distilled off, and then the fraction at 150 °C was collected to obtain 17.67 g of the finished product trans-N-ethyl-N-(2-methylphenyl)-2-butenamide, with a yield of 71.23% and a purity of 98.0%;

[0042] For comparison, dichloromethane was added as a solvent based on Example 1, but the yield of crotamiton was relatively low, and the quality was almost the same. Considering cost, it was chosen not to add a solvent to save costs; considering environmental protection, it was also chosen not to add a solvent as it is green and has little pollution. Therefore, the method of CN 106431892 A is cumbersome to operate, even more cumbersome in post-treatment, has a low yield, and solvents such as toluene are added during the reaction process, which is highly toxic.

Claims

1. A method for preparing crotamiton, characterized in that, The method includes: adding N-ethyl-o-toluidine, crotonic acid and an acyl chlorination reagent into a reaction vessel, reacting at room temperature, and after completion, distilling to collect the fraction of cromolyn to obtain the product, wherein no solvent is used in the reaction.

2. The method according to claim 1, wherein The method includes: sequentially adding N-ethyl-o-toluidine, crotonic acid and an acyl chlorination reagent into a reaction vessel, stirring and reacting at room temperature, and after completion, performing vacuum distillation to collect the fraction of cromolyn to obtain the product.

3. The method according to claim 1 or 2, characterized in that, The acyl chlorination reagent is thionyl chloride, oxalyl chloride, or phosphorus oxychloride, or a combination of two or three of them, preferably thionyl chloride.

4. The method according to claim 1 or 2, characterized in that, The molar ratio of crotonic acid to the acyl chlorination reagent is 1:0.5 - 3, preferably 1:

1.

5. The method according to claim 1 or 2, characterized in that, The molar ratio of N-ethyl-o-toluidine to crotonic acid is 1:0.8 - 1.2, preferably 1:

1.

6. The method according to claim 1 or 2, characterized in that, The method includes: performing vacuum distillation, collecting the fraction of cromolyn at 140 - 145 °C under 1000 - 3000 Pa.

7. The method according to claim 1 or 2, characterized in that, The reaction time in the method is 3 - 5 h.

8. The method according to any one of claims 1 to 7, characterized in that, The method further includes: Sequentially adding N-ethyl-o-toluidine, crotonic acid and thionyl chloride into a reaction flask at a molar ratio of 1:1:1, stirring and reacting at room temperature for 3 - 5 h. After completion of the reaction, perform vacuum distillation under 1000 - 3000 Pa to collect the fraction at 140 - 145 °C to obtain cromolyn.

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