阅读说明：本技术 3-（（4-氟苯基）磺酰基）-4-羟基-2-甲基噻唑烷-2-羧酸甲酯的制备方法 (Preparation method of methyl 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylate ) 是由 高宇宁 刘振江 陈惠渝 杜葩 贺朝 高永红 严美玉 于 2021-07-15 设计创作，主要内容包括：本发明涉及3-((4-氟苯基)磺酰基)-4-羟基-2-甲基噻唑烷-2-羧酸甲酯的制备方法,以2-((4-氟苯基)磺酰胺基)丙烯酸甲酯原料,在室温下,1,4-二硫-2,5-二醇与之进行环化反应,反应时间为12h,可以方便地制得3-((4-氟苯基)磺酰基)-4-羟基-2-甲基噻唑烷-2-羧酸甲酯化合物。本发明所用的原料价格便宜,容易获得,反应条件温和,操作简便,后处理简单,是一种制备3-((4-氟苯基)磺酰基)-4-羟基-2-甲基噻唑烷-2-羧酸甲酯化合物的新方法,具有很好的应用前景。(The invention relates to a preparation method of 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylic acid methyl ester, which is characterized in that 1, 4-dithio-2, 5-diol and 2- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylic acid methyl ester raw materials are subjected to cyclization reaction at room temperature for 12 hours, and a 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylic acid methyl ester compound can be conveniently prepared. The raw materials used in the invention are cheap and easy to obtain, the reaction conditions are mild, the operation is simple and convenient, the post-treatment is simple, and the method is a novel method for preparing the 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylic acid methyl ester compound and has good application prospect.)

1. A preparation method of 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylic acid methyl ester is characterized in that 1, 4-dithio-2, 5-diol and 2- ((4-fluorophenyl) sulfonamide) methyl acrylate are used as raw materials to perform catalytic reaction under the condition of an organic solvent, and a target product is obtained.

2. The method for preparing methyl 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylate according to claim 1, wherein the catalyst used in the catalytic reaction is triethylenediamine.

3. The process according to claim 2, wherein the amount of catalyst used is 8% to 12% based on the molar amount of 1, 4-dithio-2, 5-diol.

4. The process according to claim 1, wherein the reaction is carried out at room temperature for 8-16h at a temperature of about room temperature.

5. The process according to claim 4, wherein the reaction time is about 12 hours.

6. The process according to claim 1, wherein the molar ratio of 1, 4-dithio-2, 5-diol to methyl 2- ((4-fluorophenyl) sulfonamide) acrylate is 1: (0.8 to 1.2).

7. The process according to claim 6, wherein the molar ratio of methyl 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylate to 1, 4-dithio-2, 5-diol to methyl 2- ((4-fluorophenyl) sulfonamide) acrylate is 1: 1.

8. the process according to claim 1, wherein the organic solvent is CH, and the organic solvent is methyl 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylate₂Cl₂、CHCl₃Any one or more of diethyl ether, toluene or THF.

9. The process of claim 8, wherein the organic solvent is CHCl, methyl 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylate₃。

10. The method for preparing methyl 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylate according to claim 1, wherein after the reaction, the reaction product is separated and purified by column chromatography.

Technical Field

The invention belongs to the technical field of organic synthesis, and relates to a preparation method of 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylic acid methyl ester.

Background

The thiazolidine skeleton is widely present in the living bodyAmong the bioactive molecules, thiazolidine compounds are important intermediates in organic synthesis and play an important role in the fields of research and development of spices, food additives, dyes, medicaments and the like. ([1]Roy,R.U.；Desai,K.R.J.Chem.Sci.2005,3,529-536.[2]Londhe, a., Gupta, b., Khatri, p.j.hetrocycyclic chem.2005,15,137-In the field of medicine, the antidiabetic agent rosiglitazoneAre all thiazolidine compounds. ([1]National pesticide variety manual [ M ] of pesticide information head office of chemical industry]Beijing, Chinese chemical Press 1996,122[ 2]]Gushuixi, Seedu, George, progress of synthesis research of rosiglitazone maleate, proceedings of Wuhan university of engineering, 2013,035, 1-6.). There are many applications of thiazolidine-containing drugs, and studies on their synthesis have been reported.

Currently, thiazolidine compounds can be synthesized by reacting thiourea, ammonium thiocyanate or isothiocyanate with alpha-haloacid and derivatives thereof. The reaction time is long, the yield is low, and a water separator is often used or a catalyst, a condensing agent, a dehydrating agent and the like are added to improve the yield. [1] Ottana, R.; Maccari, R.; Barreca, M.L, Bmno Q.; Rossi, A.Bioorg.Med.Chem.2005,13, 4243-. With the continuous development of organic synthesis technology, methods such as ionic liquid, microwave promotion, solid acid catalysis and polymers are gradually applied to the synthesis of thiazolidine compounds, and the methods have the advantages of short reaction time, high yield and the like, but are limited due to harsh experimental conditions, and the methods are not widely applied. ([1] Fraga-dubreuil, J.; Bazureau J. P. tetrahedron 2003,59,6121-

In conclusion, the existing methods for preparing thiazolidine compounds are complex and harsh in reaction conditions, and are difficult to produce and prepare on a large scale.

Disclosure of Invention

The invention aims to provide a preparation method of methyl 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylate, which has the advantages of cheap and easily obtained raw materials, mild reaction conditions, simple post-treatment and the like.

The purpose of the invention can be realized by the following technical scheme:

a preparation method of 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylic acid methyl ester comprises the steps of taking 1, 4-disulfide-2, 5-diol and 2- ((4-fluorophenyl) sulfonamide) methyl acrylate as raw materials, and carrying out catalytic reaction under the condition of an organic solvent to obtain a target product.

Furthermore, the catalyst used in the catalytic reaction is triethylene diamine.

Furthermore, the catalyst is used in an amount of 8 to 12 mole% based on the 1, 4-dithio-2, 5-diol.

Furthermore, the temperature of the catalytic reaction is room temperature, and the time is 8-16 h. Optionally, the time for catalytic reaction is 12 h. If the temperature is increased, a part of the product is decomposed, and the yield is lowered.

Further, the molar ratio of 1, 4-dithio-2, 5-diol to methyl 2- ((4-fluorophenyl) sulfonamide) acrylate was 1: (0.8 to 1.2). Optionally, the molar ratio of 1, 4-dithio-2, 5-diol to methyl 2- ((4-fluorophenyl) sulfonamide) acrylate is 1: 1. under the condition of the molar ratio, the yield of the reaction is better, and excessive certain reactants are not wasted.

Further, the organic solvent is CH₂Cl₂、CHCl₃Any one or more of diethyl ether, toluene or THF. Optionally, the organic solvent is CHCl₃. If DMF, ethanol or the like is used as the solvent, the reaction yield is lowered.

Further, after the reaction, the reaction product is separated and purified by column chromatography.

In the present invention, 1, 4-dithio-2, 5-bisThe alcohol has the formula:methyl ((4-fluorophenyl) sulfonamide) acrylate has the formula:

the reaction formula is as follows:

according to the invention, a commercial 1, 4-dithio-2, 5-diol reagent and methyl 2- ((4-fluorophenyl) sulfonamide) acrylate prepared by a literature are subjected to cyclization reaction, so that a 3- ((4-fluorophenyl) sulfonyl) -4-hydroxy-2-methylthiazolidine-2-carboxylic acid methyl ester compound which is not easy to obtain is prepared simply, efficiently and at high yield. Compared with the prior art, the invention has remarkable technical progress. The method has the advantages of cheap and easily-obtained raw materials, simple operation of the synthetic method, short reaction time, high yield of the product and good application prospect.

Detailed Description

The present invention will be described in detail with reference to specific examples. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.

In the following examples, 1, 4-dithio-2, 5-diol was obtained from commercial sources, and methyl 2- ((4-fluorophenyl) sulfonamide) acrylate was obtained from laboratory preparations, and the specific procedures thereof were described in the relevant literature (Zhang, Y. -S.; Gui, H. -Z.; Wei, Y.; Shi, M.Eur.J.Org.Chem.2019,42, 7179-.

The rest of the raw material reagents or processing techniques are conventional commercial products or conventional processing techniques in the field unless otherwise specified.

Example 1:

at room temperature, 2- ((4-fluorophenyl) sulfonamide) propylene was added to the reaction tubeMethyl ester of acid (51.4mg,0.2mmol), triethylene diamine (2.2mg,0.02mmol), CHCl₃(2mL) was stirred for 10 min, then 1, 4-dithio-2, 5-diol (30.5mg,0.2mmol) was added and reacted for 12 h. Transferring the mixture into an eggplant-shaped bottle after the reaction is finished, performing rotary evaporation and column chromatography to obtain a product60.7mg, 91% yield.

¹H NMR(501MHz,CHCl₃)δ7.935–7.846(m,2H),7.046(t,J＝8.5Hz,2H),5.838(dd,J＝8.7,4.0Hz,1H),3.661(s,3H),3.387(dd,J＝11.9,4.0Hz,1H),3.096(d,J＝8.9Hz,1H),2.758(d,J＝11.8Hz,1H),1.738(s,3H).¹³C NMR(126MHz,CHCl₃)δ171.86,130.78,130.70,116.55,116.37,87.56,77.48,77.10,71.46,53.57,38.75,25.29.HRMS(ESI)Calcd.For C₁₂H₁₄FNO₅S₂(M⁺Na)⁺requires 358.0189.Found:358.0186.

Comparative example 1:

compared with example 1, the most part of the process was the same except that the amount of 1, 4-dithio-2, 5-diol added was changed to 0.4 mmol. After the reaction was complete, the same product was obtained 59.4mg, 89% yield. The yield is not improved and the excess raw material is not fully utilized.

Comparative example 2:

compared with example 1, the addition amount of triethylene diamine was changed to 0.01 mmol. The yield dropped to 82%.

Comparative example 3:

compared with example 1, most of them were the same except that the reaction temperature was adjusted to 0 ℃. The reaction time was extended to 32 hours and the yield dropped to 81%.

Comparative example 4:

compared with example 1, most of them were the same except that the reaction temperature was adjusted to 50 ℃. The reaction time was shortened to 8 hours, but the yield dropped to 72%.

Example 2:

compared with example 1, the catalyst was largely the same, except that the amount of catalyst used was 8% of the molar amount of 1, 4-dithio-2, 5-diol, i.e. 0.016 mmol.

Example 3:

compared with example 1, the catalyst was largely identical, except that the amount of catalyst used was 12% of the molar amount of 1, 4-dithio-2, 5-diol, i.e. 0.024 mmol.

Example 4:

compared with example 1, the same was observed for the most part, except that the molar amount of methyl 2- ((4-fluorophenyl) sulfonamide) acrylate was adjusted to 0.16 mmol.

Example 5:

compared with example 1, the same was observed for the most part, except that the molar amount of methyl 2- ((4-fluorophenyl) sulfonamide) acrylate was adjusted to 0.24 mmol.

In the above examples, CHCl was used as the organic solvent₃Can be replaced by equal volume of CH₂Cl₂Ether, toluene or THF.

The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.