阅读说明：本技术 一种甲磺司特的制备方法 (Preparation method of suplatast tosilate ) 是由 尚光华 肖玉梅 陈渝 曾燕 卢冲 邓祥林 于 2020-12-17 设计创作，主要内容包括：本发明公开了一种甲磺司特的制备方法,所述制备方法化合物(5)为起始原料,在缩合剂存在下,通过与化合物(6)缩合反应制得化合物1,原料易得,后处理简单,减少反应步骤,收率高,质量好,成本低。(The invention discloses a preparation method of suplatast tosilate, which is characterized in that a compound (5) is used as a starting raw material, and is subjected to condensation reaction with a compound (6) in the presence of a condensing agent to prepare a compound 1, wherein the raw material is easy to obtain, the post-treatment is simple, the reaction steps are reduced, the yield is high, the quality is good, and the cost is low.)

1. The preparation method of the suplatast tosilate comprises the following steps of taking a compound (5) as a starting material, and carrying out one-step amidation reaction with a compound (6) under the action of a condensing agent to obtain the suplatast tosilate:

。

2. the process according to claim 1, wherein the amidation reaction is carried out in an organic solvent, and the organic solvent is one of N, N-dimethylformamide, N-dimethylacetamide, toluene, acetonitrile, dichloromethane, tetrahydrofuran, and acetone, preferably acetone or acetonitrile.

3. The process according to claim 1, wherein the molar ratio of the compound (5) to the compound (6) is 1 (0.8-2), preferably 1: 1.05.

4. The method according to claim 1, wherein the condensing agent is one selected from the group consisting of Carbonyldiimidazole (CDI), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI)/1-Hydroxybenzotriazole (HOBT), Dicyclohexylcarbodiimide (DCC)/4-N, N-Dimethylpyridine (DMAP), and Diisopropylcarbodiimide (DIC), preferably CDI.

5. The process according to claim 1, wherein the reaction temperature of the amidation reaction is from 0 ℃ to 80 ℃, preferably from 0 ℃ to 30 ℃, more preferably from 20 ℃ to 30 ℃.

6. The process according to claim 1, wherein the molar ratio of the compound (5) to the condensing agent is 1 (1.0 to 2.0), preferably 1:1.1.

7. The production method according to any one of claims 1 to 6, wherein the compound (6) is produced by methylating the compound (7) with methyl p-toluenesulfonate:

。

8. the process according to claim 7, wherein the reaction solvent for the methylation reaction is acetone, acetonitrile, toluene, or dichloromethane, or no solvent, preferably no solvent.

9. The process according to claim 7 or 8, wherein the methylation reaction is carried out at a reaction temperature of 0 ℃ to 100 ℃, preferably 0 ℃ to 40 ℃, more preferably 30 ℃ to 40 ℃.

10. The process according to claim 7 or 8, wherein the molar ratio of the compound (7) to methyl p-toluenesulfonate is 1 (1-2), preferably 1: 1.2.

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of suplatast tosilate.

Background

Asthma is one of the most common chronic diseases in the world today, and most allergic asthma patients have the characteristic feature of overproducing a specific Immunoglobulin (IGE) protein in response to stimulation by a variety of external allergens. Sulfast (Suplatast tosilate) is a selective Th2 cytokine inhibitor developed by pharmaceutical company of Japan Roc (Taiho), marketed in Japan in 1995. The composition can significantly inhibit eosinophil production in bronchial wall, and can be used for treating allergic diseases such as bronchial asthma, atopic dermatitis, and allergic rhinitis.

The chemical name of suplatast tosilate is: (±) - [2- [4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl ] ethyl ] dimethylsulfonium p-toluenesulfonate having a structural formula:

the patent US4556737 reports a preparation method thereof, and the synthetic route is as follows;

the inventor finds that: in the above preparation method, the final product has methylation impurities of hydroxyl, and the structure is as follows:

disclosure of Invention

The invention provides a preparation method of the suplatast tosilate, which has the advantages of simple reaction conditions, stable quality and higher yield. The preparation method adopts the compound (5) as a starting material, and the compound (6) is subjected to condensation reaction, so that the raw material is easy to obtain, the post-treatment is simple, the reaction steps are reduced, the yield is high, the quality is good, and the cost is low.

The invention provides a preparation method of suplatast tosilate, which comprises the following steps of taking a compound (5) as a starting material, and carrying out one-step amidation reaction with a compound (6) under the action of a condensing agent to obtain the suplatast tosilate:

in the above production method, the amidation reaction is carried out in an organic solvent which is one of N, N-dimethylformamide, N-dimethylacetamide, toluene, acetonitrile, dichloromethane, tetrahydrofuran, and acetone, preferably acetone or acetonitrile.

In the above preparation method, the molar ratio of the compound (5) to the compound (6) is 1 (0.8-2), preferably 1: 1.05.

In the above preparation method, the condensing agent may be one of Carbonyldiimidazole (CDI), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI)/1-Hydroxybenzotriazole (HOBT), Dicyclohexylcarbodiimide (DCC)/4-N, N-lutidine (DMAP), and Diisopropylcarbodiimide (DIC), and preferably, is CDI.

In the above production method, the molar ratio of the compound (5) to the condensing agent is 1 (1.0 to 2.0), preferably 1:1.1.

In the above preparation method, the reaction temperature of the amidation reaction is 0 to 80 ℃, preferably 0 to 30 ℃, and more preferably 20 to 30 ℃.

In the above production method, the compound (6) is produced by methylating the compound (7) with methyl p-toluenesulfonate:

in the above production method, the methylation reaction is carried out in a solvent such as acetone, acetonitrile, toluene, or dichloromethane; alternatively, the methylation reaction does not use a solvent; preferably, the methylation reaction does not use a solvent.

In the above preparation method, the reaction temperature of the methylation reaction is 0 to 100 ℃, preferably 0 to 40 ℃, and more preferably 30 to 40 ℃.

In the above production method, the molar ratio of the compound (7) to methyl p-toluenesulfonate is 1 (1 to 2), preferably 1: 1.2.

Compared with the prior art, the technology has the following advantages: the preparation method of the suplatast tosilate has the advantages of easily available raw materials, simple process, high purity and easy industrial generation.

Drawings

FIG. 1 shows a high performance liquid chromatography of suplatast tosilate prepared by reference patent US4556737

FIG. 2 shows a high performance liquid chromatography of suplatast tosilate prepared by the invention

Detailed Description

The present invention will be further described with reference to the following examples, but the present invention is not limited to these examples.

Comparative examples

Refer to patent US4556737 for suplatast tosilate, take compound (5)10.55g and triethylamine 10.0g to add 20mL of N' N-dimethylformamide solution, add 3-methylthiopropionyl chloride 6.25g under ice bath, stir at room temperature for 12h, remove solvent by distillation under reduced pressure, extract residue with chloroform, wash with water, concentrate dry chloroform, residue with ethanol: dichloromethane (1:5) was purified by column chromatography to obtain 14.2g of compound (3).

Dissolving 12.0g of the compound (3) by using 80mL of dichloromethane, adding 22.0g of methyl p-toluenesulfonate, reacting at room temperature for 24 hours, adding diethyl ether, filtering, recrystallizing a filter cake by using dichloromethane and diethyl ether to obtain 12.5g of the product of the mesolast, wherein the retention time is 12.442 minutes shown in figure 1, and the obtained product is methylated impurities.

HPLC detection conditions of suplatast tosilate:

octadecylsilane chemically bonded silica gel as filler (Shimadzu C18, 250X 4.6mm, 5 μm), and 7.7g ammonium acetate was added into 1000mL water to obtain mobile phase A; acetonitrile is used as a mobile phase B, and linear gradient elution is carried out according to the following table; the flow rate is 1.0 mL/min; the detection wavelength is 250 nm; the column temperature was 35 ℃. Elution procedure:

example 1

Synthesis of Compound (6)

Adding 10.00g of compound (7) and 18.6g of methyl p-toluenesulfonate into a three-necked flask, stirring, reacting at 30-40 ℃ for 5 hours, adding 50mL of ethyl acetate, cooling to 0-10 ℃, stirring for 3 hours, filtering, washing a filter cake with 10mL of ethyl acetate, and drying the filter cake at 30-40 ℃ under reduced pressure to obtain 23.7g of compound (6) with the yield of 93%.

Example 2

Synthesis of Compound (1)

Adding 15.22g (0.049mol) of the compound (6) (obtained in example 1) and 100mL of acetone into a 250mL three-necked flask, stirring and dissolving, then adding 8.44g of the compound CDI, stirring for 2 hours at a controlled temperature of 20-30 ℃, then adding 10.0g of the compound (5), reacting for 4 hours at a temperature of 20-30 ℃, cooling to 0-5 ℃, stirring overnight, filtering, washing a filter cake with 10mL of acetone, heating the filter cake to 45-50 ℃ with 100mL of acetone, dissolving, slowly cooling to 0-10 ℃, carrying out heat preservation and crystallization overnight, filtering, and drying the filter cake under reduced pressure at a temperature of 40-50 ℃ to obtain 19.6g of the product of the methylsilast with a yield of 83% (shown in FIG. 2) and no methylated impurities.

¹H NMR(600MHz,DMSOd⁶)δ:1.09～1.12(t,3H,CH₃)、2.28(s，3H，Ar-CH₃)、2.91～2.97(m,8H,CH2-S-(CH3)₂)、3.39～3.47(m,4H,CH₂-O-CH₂)、3.51～3.53(t,2H,S-CH₂)、3.82～3.86(m,1H,Ar-O-CH₂)、3.87～3.92(m,2H,Ar-O-CH₂,CH)、5.06～5.07(d,1H,J＝6.0Hz,-OH)、6.89～6.90(d,2H,J＝6.0Hz,Ar-H)、7.11～7.12(d,2H,J＝6.0Hz,Ar-H)、7.47～7.50(m,4H,Ar-H)、10.11(s，1H，-NH)。

Finally, it is noted that the above-mentioned embodiments illustrate rather than limit the invention, and that, while the invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.