CN116283688A - Synthesis method of trifluoro methyl thioester - Google Patents

Abstract

The invention belongs to the technical field of synthesis of organic compounds, and relates to a method for synthesizing trifluoro methyl thioester. A method for synthesizing trifluoromethylthio ester, which is to use acyl chloride as a reaction substrate, trifluoromethanesulfonic anhydride as a reaction reagent and halogen anion providing reagent as an additive to synthesize the trifluoromethylthio ester. According to the invention, trifluoromethanesulfonic anhydride is used as a reaction reagent, trifluoromethanesulfonic anions are generated under the combined action of the reduction effect of a trivalent phosphine reducer and halogen anions, and by reacting with acyl donors in a system, the quick preparation of trifluoromethanethioester is realized, and the trifluoromethanethioester is obtained after separation and purification. Compared with the technology of using carboxylic acid as a substrate in the first generation developed by the team of the invention, the synthesis method of the trifluoro methyl thioester has the advantages of easily available raw materials, stable and safe reaction reagent, low cost, faster reaction rate, higher yield, lower cost, less waste, less required reaction reagent amount, obviously reduced triphenylphosphine sulfide impurity, more cost saving and utilization of industrial production.

Description

Synthesis method of trifluoro methyl thioester

Technical Field

The invention belongs to the technical field of synthesis of organic compounds, and relates to a method for synthesizing trifluoro methyl thioester.

Background

Fluorine atoms are important in modern drug design and synthesis (Liu X, xu C, wang M, et al, trifluoromethyl trilinely: nucleophilic trifluoromethylation and beyond [ J)]Chem Rev,2015,115 (2): 683-730.) it has been found that 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). ContainingThe presence of fluorine groups helps to increase the lipophilicity, metabolic stability of the drug molecule (Yang B, xu XH, qing FL. Encoder-mediated radiol 1,2-bis (trifluoromethylation) of alkenes with sodium trifluoromethanesulfinate [ J)]OrgLett,2015,17 (8): 1906-1909.) also reduces the development of drug resistance, while trifluoromethylthio (-SCF 3) is currently one of the most lipophilic fluorine-containing functional groups (Hansch parameter pi) _R =1.44), the introduction of this group into the drug can significantly alter the drug's lipid solubility, improve the drug's bioavailability and biofilm penetration properties (Glenadel Q, tlili a, bilard t.metal-Free Direct Dehydroxytri-fluoromethylthiolation of Alcohols via the Umpolung Reactivity of Trifluoromethanesulfenamides [ J)].Eur J Org Chem,2016(11):1955-1957.)。

The trifluoro methylthio compound is a trifluoro methylthio compound with novel structure, but several traditional synthesizing methods can be used for synthesizing the trifluoro methylthio compound, which generally need to react with acyl donor by using expensive trifluoro methylthio reagent (E.H.Man, D.D.CoffmanandE.L.Muetterties.SynthesisandPropertiesofBis- (trifluoromethyl thio) -mercuriy [ J ]. J.am.chem.Soc.1959;81:3575-3577;M.M.Kremlev,W.Tyrra,D.Naumann,et al.S-Trifluoromethyl esters of thiocarboxylic acids, RC (O) SCF3[ J ]. Tetrahedron letters [ 2004;45 (32): 6101-6104;M.Zhang,J.Chen,Z.Chen,et al.Copper-8235 [ J ]. Tetrahedron.2016;72 (24): 3525-3530;S.Mukherjee,T.Patra and F.Glorius.Cooperative Catalysis:A Strategy To Synthesize Trifluoromethyl-thioesters from Aldehydes [ J ]. Catalysis.2018;8 (7): 5842-5846.; et al fluoroalkylthiolation of aldehydes with PhSO SRf (Rf=CF 3, C2F5, CF2H 2F 26 ]. J35): 35 ]. 35:9555:35 (37): 35:35:35:35:35:35:35:35:35:6:35:35:35:35:35 (35:35:35:35:35:35). However, the utility of these synthetic methods is limited by the cost of these reagents being too expensive or requiring prior synthesis and the problems of toxicity, difficulty in storage, etc.

In order to solve the problem, the invention develops a method for synthesizing the trifluoromethylthio by using easily available carboxylic acid as a raw material and trifluoromethanesulfonic anhydride as a source of trifluoromethanethio in 2020 (CN 112358427A), so that the synthesis cost of the trifluoromethanethio is greatly reduced, and various trifluoromethanethio can be rapidly prepared in a laboratory and a pilot plant at low cost. Meanwhile, the invention team utilizes low-cost synthesized trifluoromethylthio to develop a series of conversion reactions subsequently, which are used for synthesizing an important nucleophilic trifluoromethylthio silver reagent and an electrophilic trifluoromethylthio reagent (CN 112778173A, CN112778190B, CN 112876404B), and important scientific progress and industrial conversion are achieved. Therefore, the method for synthesizing the triflate gradually enlarges the production scale along with the establishment of a subsequent conversion reaction system and the deepening of the industrialization degree.

However, during the production practice, with the gradual enlargement of the scale of the reaction, we have gradually found that this process has a certain problem and needs further improvement:

1. the total mass of raw materials used in the reaction is more, more wastes are generated, and the influence is small in small test and pilot test, but the total feeding amount is further reduced by optimizing the raw materials in consideration of environmental protection during further amplification.

2. The solubility of carboxylic acid is poor, the raw materials are more, the reaction is in a suspension state rather than a heterogeneous state for most of time, the solvent is more, the suspension system is unfavorable for subsequent amplification, the solubility of the whole system is increased by optimizing, and the subsequent amplification is facilitated.

3. If the reaction temperature is not well controlled, a certain amount of triphenylphosphine sulfide impurities are easy to generate to influence separation, which has an influence on further amplified production.

4. Considering that trifluoromethylthio is often used as an intermediate reagent in production, industry should choose some specific trifluoromethylthio for scale-up, and preparation of these trifluoromethylthio can be comprehensively considered on the basis of availability of raw materials, and a special targeted post-treatment method can be adopted.

In order to solve the problems, further industrialization is realized, the reaction cost is effectively enlarged, and the steps are optimized. Through research in recent years, a second generation synthesis technology of trifluoromethyl thioester using acyl chloride as a basic raw material is developed, and the technology is used for replacing the existing first generation synthesis technology when the acyl chloride is produced above a kilogram level, so that a basic synthesis method is provided for large-scale industrial production and subsequent conversion of the trifluoromethyl thioester compound.

Disclosure of Invention

In summary, due to the defects and shortcomings of the existing synthesis methods, the invention aims to develop a novel method for synthesizing the trifluoromethyl thioester compound, solve the shortcomings of the existing synthesis methods, replace the first generation technology and further promote the mass production of the trifluoromethyl thioester.

The outline of the problems to be solved is as follows: firstly, materials are required to be further reduced, the utilization rate of raw materials is improved, the yield is improved, and the cost is reduced; secondly, the solubility needs to be improved, and the uniformity of the system is improved; third, the amount of impurities needs to be reduced.

Therefore, in the development process, the team of the invention has the following considerations:

1. firstly, regarding the improvement of yield and reduction of raw materials, we consider that the raw materials may be suspended in a system, have high viscosity, and after amplification, have poor mass and heat transfer, may cause problems of overlarge local concentration, overhigh temperature and the like, and cause poor matching of each step of reaction, so that a large amount of raw materials are required. Therefore, homogenization may be able to be a development direction.

2. With respect to increasing the solubility of the system, reducing the solvent, one of the core strategies is to reduce poorly soluble materials. In previous practice, carboxylic acids were poorly soluble, and therefore, substitution of carboxylic acids with readily soluble acyl donors, such as acid chlorides, may increase the solubility of the system.

3. Although most acid chlorides are prepared from acids, in theory acid chlorides are more costly than acids, and acid chlorides are volatile and toxic. However, there are many inexpensive acid chlorides which have been commercially produced in large quantities at present, and which can be used as raw materials, such as benzoyl chloride, 4-chlorobenzoyl chloride and the like. Meanwhile, when industrial production is carried out, the volatilization of acyl chloride can be effectively avoided by using specialized equipment, such as pumping, which is essentially different from the daily synthesis in a laboratory in demand. Thus, acid chloride is considered as an acyl donor instead of carboxylic acid, and there is no significant problem in terms of cost and use.

4. At present, triphenylphosphine sulfide is easy to generate as an impurity in the reaction, and the problems of overhigh local concentration and overhigh local temperature caused by the fact that the system is easy to suspend and the mass and heat transfer are poor after the system is amplified are considered, so that the uniformity of the reaction system needs to be better controlled if the impurity is reduced.

In summary, the team of the invention considers the use of acyl chloride instead of carboxylic acid to make preliminary attempts, and although the dissolution state of the system is remarkably improved, the invention discovers that the use of acyl chloride directly reacts with triphenylphosphine and trifluoromethanesulfonic anhydride, only a small amount of trifluoromethanethioester is generated, and the yield cannot be effectively improved after the temperature and time are studied. Thus, this approach may require critical regulatory reagents.

The team analysis of the present invention considers that the reaction rates of the hypothesized groups may not match, particularly after the use of acid chlorides, it appears that the acid chloride activity is greater than that of the carboxylic acid, but the carboxylic acid may be able to be activated with triphenylphosphine to produce highly active acyl species which may then be nucleophilic substituted to produce triphenylphosphine oxide, with obvious thermodynamic advantages. Thus, the reaction of transiently generated trifluoromethylthio anions with acid chloride may not be very advantageous. Therefore, the present team contemplates that certain similarly catalyzed methods may be selected to produce transient, highly active acyl donors that participate in the reaction. Through researches, the specific strategy is to add bromide or iodide, utilize the energy in the system, especially the local energy generated by heat release, generate a high-activity acyl bromide-acyl iodide compound in a transient state, and then react with the trifluoromethyl sulfide anions generated by the system quickly to generate the trifluoromethyl sulfide. Thus, the bromide and iodide can theoretically act like a catalyst, so that some improvement in kinetics of each step in the elementary reaction is possible, thereby improving the yield.

Through experiments, after bromine salt and iodine salt are added, the yield is improved to a certain extent, so that the yield is greatly improved after the organic solvent soluble salt is used.

After the breakthrough progress is obtained, the team of the invention synthesizes comprehensive factors such as production requirements, cost requirements, environmental protection requirements and the like, and discovers that tetrabutylammonium bromide is the best choice, and the bromine salt can be scientifically used as a phase transfer catalyst, has excellent solubility and can provide bromine anions while promoting dissolution; in the aspect of the process, the cost of the compound is extremely low, and the compound is only 30-40 yuan per kilogram, so that the compound is a very ideal choice in the aspect of the process. The reagent is used as an additive, so that the yield can be obviously improved, the yield can be more than 90 percent and can be up to 94 percent, meanwhile, the consumption of triphenylphosphine and trifluoromethanesulfonic anhydride is reduced, the yield is improved, the raw materials are saved, and the cost is further reduced to be only half of that of the original generation method; meanwhile, as substances in the system are reduced, the system is homogeneous under most conditions, which plays an important role in effective stirring and mixing during amplification, and provides a basis for subsequent development of continuous flow production process and further amplification; furthermore, the reaction reduces the formation of triphenylphosphine sulfide impurities, which may be associated with a homogeneous system and good temperature control.

In summary, the technical scheme adopted by the invention is as follows: a method for synthesizing a trifluoromethylthio ester compound adopts acyl chloride as a reaction substrate and trifluoromethanesulfonic anhydride as a source of trifluoromethanesulfur to synthesize the trifluoromethanethio ester compound.

In the formula (1) and (2), R is aryl or alkyl;

the synthesis process of the compound shown in the formula (1) comprises the following steps: dissolving a compound shown in a formula (2), triphenylphosphine and a halogen anion providing reagent in a solvent, and slowly adding trifluoromethanesulfonic anhydride to react to generate a compound shown in a formula (1);

the solvent is an organic solvent which does not contain hydroxyl, sulfhydryl and amino, and does not comprise tetrahydrofuran;

in the reaction system, the molar ratio range of the compound shown in the formula (2) to the trifluoro methanesulfonic anhydride to the triphenylphosphine is 1 (2-5) (2-8);

the halogen anion providing reagent is any one or a mixture of brominated organic salt, brominated inorganic salt, iodinated organic salt and iodinated inorganic salt;

in the reaction system, the mol ratio range of the compound shown in the formula (2) and the halogen anion providing reagent is 1 (1-5);

the reaction temperature is 0-50 ℃ and the reaction time is 0.5-30 h.

Further preferably, the solvent is any one of 1, 2-dichloroethane, dichloromethane, acetonitrile, 1, 4-dioxane, benzene, toluene, and xylene.

Further preferably, the halide anion providing reagent is any one or a mixture of tetrabutylammonium bromide, tetrabutylammonium iodide, tetramethylammonium bromide, and tetramethylammonium iodide.

Compared with the existing synthesis method, the synthesis method of the trifluoro methyl thioester compound has the following beneficial effects:

(1) The yield is higher, the raw materials are less, and the cost is lower: the invention mainly uses acyl chloride and bromine salt which are produced in large quantities, such as 4-chlorobenzoyl chloride, the price is only 20 yuan per kilogram, tetrabutylammonium bromide is 40 yuan per kilogram; meanwhile, the amount of the reaction reagent is only about 80% of the optimal condition of the first-generation method, and the waste is reduced; the yield is obviously improved, the optimal yield can reach 94 percent, and the cost is only half of the lowest cost of the first-generation technology by combining the characteristics, which is about one tenth of the cost of other traditional methods.

(2) The reaction system is more uniform, belongs to good fluid, has good mass and heat transfer effects, and has fewer impurities.

(3) The synthesis method disclosed by the invention is mild in condition, can be carried out under the air atmosphere and normal pressure, is insensitive to water and humidity, does not need to replace inert gas, use anhydrous solvent and the like in large-scale production, and has low requirements on equipment and good robustness.

(4) The operation is simple and safe, the reaction does not need to participate in transition metal, and the method is green and environment-friendly.

Detailed Description

The following description of the embodiments of the present invention will be made clearly and completely, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Example 1 illustrates the industrial applicability of the process of the present invention under optimal reaction conditions, and examples 2 to 6 illustrate that the process of the present invention can obtain corresponding trifluoromethylthio esters under conditions of substrate exchange, halide anion-providing reagent, solvent, reaction temperature, etc.

Example 1: in this example, 4-chlorobenzoic acid trifluoromethylthioester (S- (trifluoromethyl) 4-chlorobenzoate) was synthesized by reacting 4-chlorobenzoyl chloride with trifluoromethanesulfonic anhydride:

the reaction equation is:

the synthesis steps and processes are as follows: 4-chlorobenzoyl chloride (5 mol,875 g), triphenylphosphine (20 mol,5240 g), tetrabutylammonium bromide (12.5 mol,4025 g) and about 17.5L of methylene chloride were added to a 50L glass reactor equipped with a stirring paddle; after stirring uniformly and introducing cooling water into the equipment, the temperature of the reaction system is kept at room temperature, trifluoromethanesulfonic anhydride (15 mol,4230 g) is slowly added, and the total time of adding anhydride dropwise and completing the reaction is 24 hours. After the reaction was completed, the solvent was removed by a rotary evaporator, and the crude product was filtered through silica gel, and the target product (1 a) was obtained by separation and purification using petroleum ether as an eluting reagent in a separation yield of 94%. The reaction was repeated several times in daily production, the daily dosing scale was in the range of 4-6mol calculated as 4-chlorobenzoyl chloride, and the average yield was greater than 90%.

The nuclear magnetic data of the compound (1 a) are:

¹ H NMR(300MHz,CDCl ₃ ):δ7.83–7.75(m,2H),7.52–7.44(m,2H)ppm；

¹³ C NMR(75MHz,CDCl ₃ ):δ182.2,141.8,133.4(q,J＝2.7Hz),129.6,127.8(q,J＝307.9Hz),128.9ppm.

¹⁹ F NMR(282MHz,CDCl ₃ ):δ-39.57ppm。

example 2: in this example, 4-phenylbenzoic acid trifluoromethylthio (S- (trifluoromethyl) 1,1' -biphenyl ] -4-carbo-thioate) was synthesized by reacting 4-phenylbenzoyl chloride with trifluoromethanesulfonic anhydride:

the reaction equation is:

the synthesis steps and processes are as follows: to a 10mL reaction tube equipped with a magnetic stirrer were added 4-phenylbenzoyl chloride (0.4 mmol,86 mg), triphenylphosphine (1.6 mmol,420 mg), tetrabutylammonium bromide (1.2 mmol, 383 mg), and 4.0mL of 1.2-dichloroethane; the reaction tube was fixed on a magnetic stirrer, and trifluoromethanesulfonic anhydride (1.2 mmol,336 mg) was slowly added under ice-water bath, and reacted at 25℃for 1 hour after completion. After the reaction, the solvent is removed by a rotary evaporator, the crude product is filtered by silica gel, petroleum ether is used as an eluting reagent, and the target product (1 b) is obtained by separation and purification, wherein the separation yield is 72 percent

The nuclear magnetic data of the compound (1 a) are:

¹ H NMR(600MHz,CDCl ₃ ):δ7.94–7.92(m,2H),7.73–7.71(m,2H),7.64–7.62(m,2H),7.51–7.49(m,2H),7.46–7.44(m,1H)ppm.

¹³ C NMR(151MHz,CDCl ₃ ):δ182.76,147.91,139.13,133.75(q,J＝2.3Hz),129.15,128.84,128.28,128.12(q,J＝309.5Hz),127.76,127.33ppm.

¹⁹ F NMR(565MHz,CDCl ₃ ):δ-39.48ppm。

example 3: in this example, 4-chlorobenzoic acid trifluoromethylthioester (S- (trifluoromethyl) 4-chlorobenzoate) was synthesized by reacting 4-chlorobenzoyl chloride with trifluoromethanesulfonic anhydride:

the reaction equation is:

the synthesis steps and processes are as follows: to a 50mL round bottom flask equipped with a magnetic stirrer was added 4-chlorobenzoyl chloride (4 mmol,700 mg), triphenylphosphine (18 mmol,4716 mg), tetrabutylammonium iodide (12 mmol,4428 mg), followed by about 20mL1, 2-dichloroethane; the round bottom flask was fixed on a magnetic stirrer and trifluoromethanesulfonic anhydride (13.2 mmol,3722 mg) was slowly added under ice-water bath and reacted at 25℃for 2 hours after the addition was completed. After the reaction, part of the solvent was removed by a rotary evaporator, and the crude product was filtered through silica gel, and the target product (1 a) was obtained by separation and purification using petroleum ether as an eluting reagent, with a separation yield of 42%.

Example 4: in this example, benzotriflate (S- (trifluoromethyl) benzoate) was synthesized using the reaction of benzoyl chloride with trifluoromethanesulfonic anhydride:

the reaction equation is:

the synthesis steps and processes are as follows: to a 30L glass reactor equipped with a distillation apparatus and containing stirring paddles was added benzoyl chloride (5 mol,875 g), triphenylphosphine (20 mol,5240 g), tetrabutylammonium bromide (15 mol,4830 g), and about 20L acetonitrile; after stirring uniformly and introducing cooling water into the equipment, the temperature of the reaction system is kept at room temperature, trifluoromethanesulfonic anhydride (15 mol,4230 g) is slowly added, and the total time of adding anhydride dropwise and completing the reaction is 24 hours. After the reaction is finished, the product and the solvent acetonitrile can be simultaneously extracted by using a distillation device of the device, but separation of the product and the acetonitrile cannot be realized, and a large number of molecular weight peaks (m/z=206) of the product can be found through GC-MS analysis, and the solution can be used for a reaction using acetonitrile as a solvent and using triflate in excess, such as a reaction with silver fluoride to prepare silver triflate. Meanwhile, the formation of trifluoromethylthio was confirmed by silver trifluoromethylthio.

Example 5: in this example, lauroyl chloride was used to synthesize trifluoromethylthio laurate (S- (trifluoromethyl) dodecanethioate) by reaction with trifluoromethanesulfonic anhydride:

the reaction equation is:

the synthesis steps and processes are as follows: to a 50mL round bottom flask equipped with a magnetic stirrer was added benzoyl chloride (5 mmol,1090 mg), triphenylphosphine (20 mmol,5240 mg), tetrabutylammonium bromide (15 mmol,4830 mg), and about 20mL1, 2-dichloroethane; after stirring, trifluoromethanesulfonic anhydride (15 mmol,4230 mg) was slowly added under ice-water bath, and the mixture was reacted at 25℃for 2 hours after the completion of the dropwise addition. After the reaction, the solvent was dried by spinning, the residue was extracted several times with petroleum ether, and the crude product was analyzed by GC-MS to find a large number of product molecular weight peaks (m/z=284).

Example 6: in this example, the reaction equation was as follows using 4-phenylbenzoic acid to synthesize the product, 4-phenylbenzoic acid trifluoromethylthio ester (S- (trifluormethyl) [1,1' -biphenyl ] -4-carbothioate), using the reaction of 4-phenylbenzoic acid with trifluoromethanesulfonic anhydride:

the synthesis steps and processes are as follows: to a 10mL reaction tube equipped with a magnetic stirrer were added 4-phenylbenzoyl chloride (0.4 mmol,86 mg), triphenylphosphine (2.0 mmol,420 mg), tetramethylammonium iodide (1.2 mmol,241 mg), and 4.0mL of 1.2-dichloroethane; after stirring uniformly, the reaction tube was fixed on a magnetic stirrer, and trifluoromethanesulfonic anhydride (2.0 mmol,564 mg) was slowly added under ice bath, followed by reaction at room temperature for 2 hours, followed by separation and purification, with a yield of 37%.

Claims (3)

1. A method for synthesizing trifluoromethylthio is characterized in that acyl chloride is used as a reaction substrate, trifluoromethanesulfonic anhydride is used as a source of trifluoromethanesulfur, and the reaction equation is as follows:

in the formula (1) and (2), R is aryl or alkyl;

the synthesis process of the compound shown in the formula (1) comprises the following steps: dissolving a compound shown in a formula (2), triphenylphosphine and a halogen anion providing reagent in a solvent, and slowly adding trifluoromethanesulfonic anhydride to react to generate a compound shown in a formula (1);

the solvent is an organic solvent which does not contain hydroxyl, sulfhydryl and amino, and does not comprise tetrahydrofuran;

in the reaction system, the molar ratio range of the compound shown in the formula (2) to the trifluoro methanesulfonic anhydride to the triphenylphosphine is 1 (2-5) (2-8);

the halogen anion providing reagent is any one or a mixture of brominated organic salt, brominated inorganic salt, iodinated organic salt and iodinated inorganic salt;

in the reaction system, the mol ratio range of the compound shown in the formula (2) and the halogen anion providing reagent is 1 (1-5);

the reaction temperature is 0-50 ℃ and the reaction time is 0.5-30 h.

2. The method for synthesizing trifluoromethylthio according to claim 1, wherein the solvent is any one of 1, 2-dichloroethane, dichloromethane, acetonitrile, 1, 4-dioxane, benzene, toluene, and xylene.

3. The method for synthesizing trifluoromethylthio ester according to any one of claims 1 to 2, wherein the halide anion-providing reagent is any one or a mixture of tetrabutylammonium bromide, tetrabutylammonium iodide, tetramethylammonium bromide, tetramethylammonium iodide.