CN113461677B - Preparation method of 4-hydroxy-2-methyl-3- (thiophene-2-sulfonyl) thiazolidine-2-carboxylic acid methyl ester - Google Patents
Preparation method of 4-hydroxy-2-methyl-3- (thiophene-2-sulfonyl) thiazolidine-2-carboxylic acid methyl ester Download PDFInfo
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- CN113461677B CN113461677B CN202110796669.6A CN202110796669A CN113461677B CN 113461677 B CN113461677 B CN 113461677B CN 202110796669 A CN202110796669 A CN 202110796669A CN 113461677 B CN113461677 B CN 113461677B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a preparation method of 4-hydroxy-2-methyl-3- (thiophene-2-sulfonyl) thiazolidine-2-carboxylic acid methyl ester, which is characterized in that 1, 4-dithio-2, 5-diol and 2- (thiophene-2-sulfonamide) methyl acrylate raw materials are subjected to cyclization reaction at room temperature for 12 hours to conveniently prepare a 4-hydroxy-2-methyl-3- (thiophene-2-sulfonyl) thiazolidine-2-carboxylic acid methyl ester compound. 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 4-hydroxy-2-methyl-3- (benzenesulfonyl) thiazolidine-2-carboxylic acid methyl ester compound and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a preparation method of 4-hydroxy-2-methyl-3- (thiophene-2-sulfonyl) thiazolidine-2-carboxylic acid methyl ester.
Background
Thiazolidine is a very important five-membered heterocyclic compound, present in a variety of natural and biologically active molecules, containing sulfur and nitrogen atoms. The thiazolidine compound is a very important synthetic intermediate and has wide application. The compounds show some important biological pharmacological activities in the field of medicine, such as anticancer, anticonvulsive, antibacterial, anti-inflammatory, neuroprotection, antioxidation, etc. ([ 1]]Zhang,Q.；Zhou,H.；Yan,B.Curr.Pharm.Des.2010,16,1826-1842.[2]Agarwal,S.；Agarwal,D,K.；Gautam,N.；Agarwal,K.J.Korean.Chem.Soc.2014,58,33-38.[3]Ma, l.; xie, c.; ma, y; liu, j.j.med.chem.2011,54, 2060-2068.) therefore thiazolidine compounds are key components of many effective drugs, such as rosiglitazone, a drug for treating diabetes
And the like. ([1]The method for synthesizing thiazolidine compounds at present mainly comprises acid catalysis or alkali catalysis, nanoparticle catalysis, solvent-free synthesis performed by a microwave technology and the like. ([1]Bhattacharyya,A.；Kavitha,C,V.；Ghorai,M,K.J.Org.Chem.2016,81,6433-6443.[2]Bayat,M.；Hosseini,F,S.；Nasri,S.J.Sulfur.Chem.2018,39,99-111.[3]Sadeghzadeh,S,M.；Malekzadeh,M.J.Mol.Liq.2015,202,46-51.[4]Perumal,S.；Vivek Kumar,S.；Muthusubramanian,S.RSC Adv.2015,5,90451-90456.)
Thiophene is an important five-membered heterocyclic compound containing sulfur atoms, which widely exists in natural products and has wide and important application in the fields of drug development, functional materials and the like ([ 1]]Teruyuki,K.；Take-aki,M.Chem.Rev.2000,100,3205-3220.[2]Matthew, d.; joseph, m.chem.rev.2004,104, 2239-2258). For example, the drug Xarelto (rivaroxaban) containing a thiophene skeleton
Is an anticoagulant drug jointly developed by Bayer and Qiangsheng companies; plavix (boli vitamin)
As a non-peptide fibrinogen receptor antagonist, it is effective in treating stroke, myocardial infarction, etc. ([1]Acharya, a.; param, g.j.org.chem.2015,80, 414-427.) the strategy of introducing thiophene skeletons into compound molecules has attracted strong interest to chemists based on the broad application prospects of thiopheneic compounds.
There are few reports in this field, and expensive catalysts, ligands or complex routes to corresponding compounds are generally required, such as thiazolidine compounds obtained by cyclization reaction of aryl isothiocyanate with 1, 4-dithio-2, 5-diol by microwave irradiation or thiazolidine compounds obtained by heating 1, 4-dithio-2, 5-diol with acyl azide. ([ 1] Perumal, S.; vivek Kumar, S.; muthuramanian, S.RSC adv.2015,5,90451-90456.[2] Zhu, Y.; wang, Q.; luo, H.Synthesis 2019,51, 2397-2401.) existing methods for preparing thiazolidine compounds are complicated, harsh in reaction conditions, and difficult to mass-produce and prepare.
Disclosure of Invention
The invention aims to provide a preparation method of a 4-hydroxy-2-methyl-3- (benzenesulfonyl) thiazolidine-2-carboxylic acid methyl ester compound, which has simple and efficient reaction, high yield and the like.
The purpose of the invention can be realized by the following technical scheme:
a preparation method of 4-hydroxy-2-methyl-3- (thiophene-2-sulfonyl) thiazolidine-2-carboxylic acid methyl ester comprises the steps of taking 1, 4-disulfide-2, 5-diol and 2- (thiophene-2-sulfonamide) methyl acrylate as raw materials, and carrying out catalytic reaction under the condition of an organic solvent to obtain a target product.
Further, the molar ratio of the 1, 4-dithio-2, 5-diol to the methyl 2- (thiophene-2-sulfonamide) acrylate is 0.9 to 1.2. Further, the molar ratio of 1, 4-dithio-2, 5-diol to methyl 2- (thiophene-2-sulfonamide) acrylate was 1. Under the condition of the molar ratio, the yield of the reaction is better, and excessive certain reactants are not wasted.
Furthermore, the catalyst used in the catalytic reaction is triethylene diamine. Furthermore, the catalyst is used in an amount of 7 to 11% by mole based on the 1, 4-dithio-2, 5-diol. More preferably, the catalyst is used in an amount of 10% by mole of the 1, 4-dithio-2, 5-diol.
Furthermore, the temperature of the catalytic reaction is room temperature, and the reaction time is 10-14 h. If the temperature is increased, a part of the product is decomposed, and the yield is lowered.
Further, the organic solvent is CH 2 Cl 2 、CHCl 3 Any one or more of diethyl ether, toluene or THF. Further, the organic solvent is CH 2 Cl 2 Or CHCl 3 . 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, the chemical formula of 1, 4-dithio-2, 5-diol is:
the chemical formula of the methyl 2- (thiophene-2-sulfonamide) acrylate is as follows:
the reaction formula of the invention is as follows:
the invention prepares the 4-hydroxy-2-methyl-3- (thiophene-2-sulfonyl) thiazolidine-2-carboxylic acid methyl ester compound which is not easy to obtain in a concise, high-efficiency and high-yield manner by carrying out cyclization reaction on commercial 1, 4-dithio-2, 5-diol reagent and benzene 2- (thiophene-2-sulfonamide) methyl acrylate prepared by the literature. 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 each of the following examples, 1, 4-dithio-2, 5-diol was obtained commercially and methyl 2- (thiophene-2-sulfonamide) acrylate was prepared in the laboratory by the following method: to a 25mL round bottom flask equipped with a water trap were added thiophene-2-sulfonamide (163 mg), methyl pyruvate (0.92 g), p-toluenesulfonic acid (2 mg), 4-methoxyphenol (1.2 mg), and toluene (10 mL). The stirred mixture was reacted at 110 ℃ for 24h, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography (SiO) 2 ) Purifying to obtain the 2- (thiophene-2-sulfonamide) methyl acrylate.
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- (thiophene-2-sulfonamide) is added into the reaction tubeMethyl acrylate (50.1mg, 0.2mmol), triethylene diamine (2.2mg, 0.02mmol), CHCl 3 (2 mL) was stirred for 10 minutes, and then 1, 4-dithio-2, 5-diol (30.5mg, 0.2mmol) was added and reacted for 12 hours. Transferring the mixture into an eggplant-shaped bottle after the reaction is finished, performing rotary evaporation and column chromatography to obtain a product
60.0mg, 91% yield.
1 H NMR(501MHz,Chloroform-d)δ7.760(dd,J＝3.8,1.4Hz,1H),7.639(dd,J＝5.0,1.4Hz,1H),7.094(dd,J＝5.0,3.8Hz,1H),6.005(dd,J＝8.1,3.9Hz,1H),3.798(s,3H),3.506(dd,J＝11.8,4.0Hz,1H),3.186(d,J＝8.2Hz,1H),2.922(d,J＝11.9Hz,1H),2.010(s,3H). 13 C NMR(126MHz,CHCl 3 )δ171.46,133.55,132.85,127.24,87.42,71.50,53.34,38.32,25.24.HR-MS(ESI)Calcd.For C 10 H 13 O 5 NS 2 (M + Na) + requires345.9848.Found.345.9844.
Comparative example 1:
compared with example 1, the amount was largely the same, except that the amount of 1, 4-dithio-2, 5-diol added was changed to 0.4mmol. After the reaction was complete, the same product was obtained in 90% 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 0.01mmol. The yield dropped to 81%.
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 24 hours and the yield dropped to 89%.
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 6 hours, but the yield dropped to 75%.
Example 2:
compared with example 1, the catalyst was mostly the same except that the amount of the catalyst used was 7% of the molar amount of 1, 4-dithio-2, 5-diol, i.e., 0.014mmol.
Example 3:
compared with example 1, the catalyst was largely the same except that the amount of the catalyst used was 11% of the molar amount of 1, 4-dithio-2, 5-diol, i.e., 0.022mmol.
Example 4:
compared with example 1, the molar amount of 1, 4-dithio-2, 5-diol was adjusted to 0.18mmol.
Example 5:
compared with example 1, the molar amount of 1, 4-dithio-2, 5-diol was adjusted to 0.24mmol.
In the above examples, CHCl was used as the organic solvent 3 Can be replaced by equal volume of CH 2 Cl 2 Diethyl ether, toluene or THF.
The embodiments described above are intended to facilitate a person of ordinary skill in the art in understanding and using the invention. 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 modifications and alterations without departing from the scope of the present invention.
Claims (6)
1. A preparation method of 4-hydroxy-2-methyl-3- (thiophene-2-sulfonyl) thiazolidine-2-carboxylic acid methyl ester is characterized in that under the condition of an organic solvent, 1, 4-disulfide-2, 5-diol and 2- (thiophene-2-sulfonamide) methyl acrylate are used as raw materials to carry out catalytic reaction to obtain a target product;
the molar ratio of the 1, 4-dithio-2, 5-diol to the methyl 2- (thiophene-2-sulfonamide) acrylate is 0.9 to 1.2;
the catalyst used in the catalytic reaction is triethylene diamine;
the temperature of the catalytic reaction is room temperature, and the reaction time is 10-14 h;
the organic solvent isCH 2 Cl 2 、CHCl 3 Any one or more of diethyl ether, toluene or THF.
2. The process according to claim 1, wherein the molar ratio of 1, 4-dithio-2, 5-diol to methyl 2- (thiophene-2-sulfonamide) acrylate is 1.
3. The process according to claim 1, wherein the amount of the catalyst is 7 to 11 mole% based on the 1, 4-dithio-2, 5-diol.
4. The process according to claim 3, wherein the catalyst is used in an amount of 10% by mole based on the 1, 4-dithio-2, 5-diol.
5. The process according to claim 1, wherein the organic solvent is CH, and the organic solvent is CH, for example, in the form of methyl 4-hydroxy-2-methyl-3- (thiophene-2-sulfonyl) thiazolidine-2-carboxylate 2 Cl 2 Or CHCl 3 。
6. The method for preparing 4-hydroxy-2-methyl-3- (thiophene-2-sulfonyl) thiazolidine-2-carboxylic acid methyl ester according to claim 1, wherein after the reaction, the reaction product is separated and purified by column chromatography.
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