CN115974735A - Synthesis method of carboxylic ester compound containing trifluoromethylthio group - Google Patents

Abstract

The invention belongs to the technical field of organic compound synthesis, and relates to a synthesis method of carboxylic ester compounds containing trifluoromethylthio. According to the method, an epoxy compound is used as a reaction substrate, trifluoromethyl thioester is used as a bifunctional reagent, and under the activation of fluorine anions, trifluoromethylthio anions and acyl fluorides are generated, the generated trifluoromethylthio anions quickly attack the epoxy compound to open the epoxy ring, and then the generated oxygen anions are regulated and controlled to quickly react with the acyl fluorides to realize an acylation reaction, so that the quick preparation of the carboxylic ester compound containing trifluoromethylthio is realized in one step, and the carboxylic ester compound containing trifluoromethylthio is obtained after separation and purification. According to the synthesis method of the carboxylic ester compound containing the trifluoromethylthio, raw materials and reaction reagents are easy to obtain, the reaction has good step economy, and the one-step rapid preparation of various carboxylic ester compounds containing the trifluoromethylthio can be realized.

Description

Synthesis method of carboxylic ester compound containing trifluoromethylthio group

Technical Field

The invention belongs to the technical field of organic compound synthesis, and relates to a synthesis method of carboxylic ester compounds containing trifluoromethylthio.

Background

Fluorine atoms play an important role in modern drug design and synthesis (Liu X, xu C, wang M, et al. Trifluoromethyl. Nitrile: nucleoophilic fluorination and beyond [ J]Chem Rev,2015,115 (2): 683-730), statistically, 15-20% of modern drugs contain fluorine-containing groups(Hui R,Zhang S,Tan Z,et al.Research Progress of Trifluoromethylation with Sodium Trifluoromethanesulfinate[J]Chin J Org Chem (organic chemistry), 2017,37 (12): 3060-3075). The presence of fluorine-containing groups helps to increase the lipophilicity, metabolic stability of the drug molecule (Yang B, xu XH, qi FL. Cope-mediated chemical 1,2-bis (fluorination) of the drugs with sodium trifluoromethanesulfonate [ J]orgLett,2015,17 (8): 1906-1909.) also reduces the development of drug resistance, while trifluoromethylthio (-SCF) ₃ ) Is one of the most lipophilic fluorine-containing functional groups (Hansch parameter pi) _R = 1.44), the introduction of the group into the medicine can obviously change the liposolubility of the medicine, and improve the bioavailability and the biomembrane permeability of the medicine. (Glenadil Q, tlili A, billard T.Metal-Free Direct DeHydroxyytri-fluoromethlylation of alcoholic vista the reaction of fluoromethlyamines [ J].Eur J Org Chem,2016(11):1955-1957.)

Meanwhile, the team developed an important generation low-cost synthesis method of fluorine-containing sulfur-containing compound trifluoromethylthioester (ZL 202011200750.5) in 2020, and then developed a plurality of conversion methods of trifluoromethylthioester (ZL 202110211672.7; ZL202110209605.1; ZL202110214011. X). The trifluoromethyl thioester contains an acyl group and a trifluoromethylthio group, and if both are available, introduction of another molecule will allow rapid construction of a complex compound containing an acyl group and a trifluoromethylthio group, and will have good step economy and atom utilization.

Carboxylate compounds are frequently found in drug molecules and are important pharmacophore structures. Accordingly, the present invention has developed a synthetic method for producing a carboxylic ester compound containing a trifluoromethylthio group by using a trifluoromethylthio ester as an acyl donor and reacting the trifluoromethylthio donor with an epoxy compound.

Disclosure of Invention

The invention aims to provide a novel high-efficiency synthesis method for a novel carboxylic ester compound containing trifluoromethylthio. The synthesis method has the advantages of easily obtained synthesis raw materials and a trifluoro-methylthio reagent, low cost, no need of transition metal catalysis in the reaction, simple synthesis process, high step economy and the like.

The traditional method for synthesizing the carboxylic ester compound containing the trifluoromethylthio group mostly needs to introduce the trifluoromethylthio group and the ester group step by step, the steps are often more than two steps, the atom economy is often low, and reagents participating in the reaction cannot be generally introduced into a final molecule completely. Meanwhile, the traditional trifluoromethanesulfonyl reagent, such as trifluoromethanesulfonyl silver, is expensive, which increases the synthesis cost of the trifluoromethanesulfonyl compound. Therefore, the development of a synthetic method of the carboxylic ester compound containing the trifluoromethylthio group, which has economic steps, low cost and high atom economy, has important significance.

In order to achieve the purpose, the invention adopts the technical scheme that:

a synthetic method of carboxylic ester compounds containing trifluoromethylthio is characterized in that: synthesizing carboxylic ester compounds containing trifluoromethylthio by taking an epoxy compound as a reaction substrate and trifluoromethylthioester as a reaction reagent in the presence of a fluorine anion activating reagent;

the reaction equation is:

in the formula (2), R ¹ Is an aryl group;

in the formula (3), R ² Is an aryl group;

the synthesis process of the compound shown in the formula (1) comprises the following steps: dissolving a compound shown as a formula (2) in a solvent in the presence of a fluorine anion activating reagent, and then mixing the compound with a compound shown as a formula (3) for reaction to generate a compound shown as a formula (1);

the fluorine anion activating reagent is any one of fluoride metal salt and fluoride organic salt containing univalent fluoride ions or a mixture thereof;

the solvent is any one of 1,2-dichloroethane, dichloromethane, acetonitrile, 1,4-dioxane, benzene, toluene, xylene, benzotrifluoride, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and diethyl ether;

in the reaction system, the molar ratio of the epoxy compound shown in the formula (3), the trifluromethyl thioester shown in the formula (2) and the fluorine anion activating reagent is 1 (1-10) to 1-10;

the reaction temperature is 10-90 ℃, and the reaction time is 0.5-72 h.

Further preferably, the reaction system contains an additive, and the reaction equation is as follows:

the additive is crown ether;

the molar ratio of the compound shown in the formula (2) to the additive is 1: 0.25-10.

Compared with the existing synthesis method, the synthesis method of the carboxylic ester compound containing trifluoromethylthio has the following beneficial effects:

(1) The reaction reagent adopted by the invention is easy to prepare, and the trifluoromethyl thioester is taken as a trifluoromethyl sulfide donor, has low price compared with the prior noble metal salt type trifluoromethyl sulfide donor, and is beneficial to industrial production;

(2) The synthetic method has high atom utilization rate and economic step, and two functional groups are introduced in one step;

(3) The method is simple, convenient and safe to operate, mild in condition, free of transition metal catalysis in reaction, and green and environment-friendly.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.

Example 1: in this example, an epoxy compound 3a was reacted with 4-benzenebenzoic acid trifluoromethylthioester (S- (trifluoromethyl) [1,1' -biphenyl ] -4-carbothioate) to synthesize a carboxylic ester compound 1a containing trifluoromethylthio group:

the reaction equation is:

the synthesis steps are as follows: 4-chlorobenzoic acid trifluoromethylthioester 3a (2mmol, 564mg), potassium fluoride (1.8mmol, 104.4mg), 18-crown-6 (1.8mmol, 475.2mg), and 3.0mL acetonitrile were added to a 10mL reaction tube equipped with a magnetic stirrer, and after stirring for 5min or more until the solution became black, 2a (1mmol, 120mg) was added; fixing the reaction tube on a magnetic stirrer, reacting for 12 hours at 70 ℃, separating and purifying to obtain a target product 1a with yield of 70%, and identifying the structure of 1a by using a gas chromatography-mass spectrometer and a nuclear magnetic resonance spectrometer.

The nuclear magnetic data for compound 1a is:

¹ H NMR(600MHz,Chloroform-d):δ8.16-8.14(m,2H),7.68(d,J＝10.2Hz,2H),7.62(d,J＝10.2Hz,2H),7.48-4.39(m,8H),6.22-6.19(m,1H),3.54-3.37(m,2H)。

example 2: in this example, an epoxy compound 3a was reacted with 4-benzenebenzoic acid trifluoromethylthioester (S- (trifluoromethyl) [1,1' -biphenyl ] -4-carbothioate) to synthesize a trifluoromethylthio group-containing carboxylate compound 1a in gram-order:

the reaction equation is:

the synthesis steps are as follows: 4-chlorobenzoic acid trifluoromethylthioester 3a (20mmol, 5640mg), potassium fluoride (18mmol, 1044mg), 18-crown-6 (18mmol, 4752mg), and 30mL acetonitrile were added to a 100mL round-bottomed flask equipped with a magnetic stirrer, and after stirring for 10min or more until the solution became black, 2a (10mmol, 1200mg) was added; fixing the reaction tube on a magnetic stirrer, reacting for 15 hours at 70 ℃, and separating and purifying to obtain the target product 1a with the yield of 65%.

Claims (2)

1. A synthetic method of carboxylic ester compounds containing trifluoromethylthio is characterized in that: synthesizing carboxylic ester compounds containing trifluoromethylthio by taking an epoxy compound as a reaction substrate and trifluoromethylthioester as a reaction reagent in the presence of a fluorine anion activating reagent;

the reaction equation is:

in the formula (2), R ¹ Is aryl;

in the formula (3), R ² Is aryl;

the synthesis process of the compound shown in the formula (1) comprises the following steps: dissolving a compound shown as a formula (2) in a solvent in the presence of a fluorine anion activating reagent, and then mixing the compound with a compound shown as a formula (3) for reaction to generate a compound shown as a formula (1);

the fluorine anion activating reagent is any one of fluoride metal salt and fluoride organic salt containing negative univalent fluorine ions or a mixture thereof;

the solvent is any one of 1,2-dichloroethane, dichloromethane, acetonitrile, 1,4-dioxane, benzene, toluene, xylene, benzotrifluoride, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and diethyl ether;

in the reaction system, the molar ratio of the epoxy compound shown in the formula (3), the trifluromethyl thioester shown in the formula (2) and the fluorine anion activating reagent is 1 (1-10) to 1-10;

the reaction temperature is 10-90 ℃, and the reaction time is 0.5-72 h.

2. The method for synthesizing carboxylic ester compounds containing trifluoromethylthio groups according to claim 1, wherein the reaction system contains an additive, and the reaction equation is as follows:

the additive is crown ether;

the molar ratio of the compound shown in the formula (2) to the additive is 1: 0.25-10.