Synthesis method of difluoroalkyl sulfone compound and / or difluoroalkyl sulfoxide compound

Abstract

The invention relates to a synthesis method of a difluoroalkyl sulfone compound and / or a difluoroalkyl sulfoxide compound. The synthesis method comprises the following steps: taking a compound 1 and a compound 2 as raw materials, adding alkali, reacting in a solvent, oxidizing and decarboxylating; the structure of the compound 1 is shown as a formula (I-1) or a formula (I-2); the structures of the difluoroalkyl sulfone compound and the difluoroalkyl sulfoxide compound are respectively shown as a formula (II) and a formula (III); ; wherein M is selected from Na, K, NH4 or a hydrogen atom; r1 is selected from C1-C8 straight chain or straight chain alkyl; r2 is selected from a C1-C8 straight chain or branched chain alkylene group; r is selected from C1-C8 linear chain or branched chain alkyl; the structural general formula of the compound 2 is ClRf; and Rf is selected from a linear chain or branched chain alkyl group containing a difluoromethyl group of C1-C15. The one-pot method is adopted, the alkyl sulfone and the alkyl sulfoxide are prepared by using the same synthetic route, the synthetic reaction is simple, the substrate limitation is less, the cost is low, the reaction is fast, the yield is high, and the industrial production can be realized.

Description

Technical Field

[0001] This invention relates to the field of technology, and in particular to a method for synthesizing difluoroalkyl sulfone compounds and / or difluoroalkyl sulfoxide compounds. Background Technology

[0002] Introducing fluorine atoms into organic molecules can improve the lipophilicity, metabolic stability, and bioavailability of drug molecules, making organofluorine chemistry a research hotspot in recent years. The core of organofluorine chemistry is organofluorine reactions and organofluorine reagents, with the latter based on these reagents. Difluoromethyl sulfones are excellent difluoromethylating reagents, capable of achieving difluoroalkylation, gem-difluoroalkenylation, and difluorophenyl sulfone alkylation reactions of various aromatic hydrocarbons, heteroaromatic hydrocarbons, and aliphatic compounds.

[0003] Besides their widespread use in synthetic reactions, difluoroalkyl sulfones and difluoroalkyl sulfoxides are also found in some important bioactive molecules, such as HIF-2a. Difluoroalkyl sulfone structures possess unique physiological activities and can be used in the design of many drug molecules. However, the preparation of geminal difluoroalkyl compounds currently faces several challenges. Either they require reagents that are difficult to handle, or they are costly, and a suitable method for the industrial-scale preparation of these reagents is still lacking.

[0004] The main methods for preparing difluoroalkyl sulfones include: reacting thiols with difluorocarbene reagents to obtain difluoroalkylthio compounds, followed by oxidation to difluoroalkyl sulfones. While this method is widely used, it requires the use of thiols with a strong, pungent odor, is complex to operate, and incurs high safety costs. Another method involves reacting sodium difluoroalkyl sulfinate with diazonium salts to prepare difluoroalkyl sulfones, but this suffers from expensive raw materials, and diazonium salts require sophisticated reaction equipment. CN112574076A discloses the reaction of sulfinic acid and / or its salts with dichlorodifluoroane in an alkaline environment and a phase-transfer catalyst to prepare difluoroalkyl sulfones, but sodium sulfinate is expensive, lacking industrialization potential, and the reaction efficiency is low, requiring a phase-transfer catalyst. WO2015051141A discloses the reaction of thiolates and dichlorodifluoroane under alkaline conditions, followed by reaction with hydrogen peroxide in the presence of tantalum pentachloride catalyst to prepare difluoroalkyl sulfones. However, this method requires the use of strongly odorous sodium thiolate and the precious metal tantalum, and the harsh conditions necessitate a high-pressure reactor, making industrialization difficult. CN 110981768 A describes the use of aryl fluoromethyl sulfoxide as a raw material to react with haloalkanes (bromine, iodoalkanes) under low temperature conditions by adding alkali and reaction solvent to obtain aryl difluoroalkyl sulfoxide compounds, but the raw materials are not easy to obtain.

[0005] The preparation of sulfoxides is mainly achieved through nucleophilic substitution of sulfinyl derivatives with organometallic reagents, or through transition metal-catalyzed sulfide oxidation in the presence of equivalent amounts of high-valent iodine or peroxides. However, this method requires the use of heavy metals and has poor reaction selectivity.

[0006] Therefore, there is an urgent need for a method that can efficiently and cost-effectively synthesize difluoroalkyl sulfones and / or difluoroalkyl sulfones. Summary of the Invention

[0007] Therefore, it is necessary to provide a method for synthesizing difluoroalkyl sulfones and / or difluoroalkyl sulfoxides. This method is a one-pot process using mercaptophosphates or mercapto acids (esters) and difluoromethyl-containing alkyl compounds as raw materials. Under alkaline conditions, difluoroalkyl substitution is achieved to obtain a difluoro intermediate compound, which is then oxidized and decarboxylated to obtain the difluoroalkyl sulfones and / or difluoroalkyl sulfoxides. This method has advantages such as low raw material cost and high reaction yield, and it can achieve a one-pot synthesis of the product from raw materials, possessing high industrialization potential.

[0008] A first aspect of this application provides a method for synthesizing difluoroalkyl sulfone compounds and / or difluoroalkyl sulfoxide compounds, comprising: Using compounds 1 and 2 as raw materials, a first basic substance is added, and the mixture is reacted in a solvent to obtain a difluoro intermediate; an oxidizing agent is added to the difluoro intermediate, and after oxidation, decarboxylation is performed; the structure of compound 1 is shown in formula (I-1) or formula (I-2); the structure of the difluoroalkyl sulfone compound is shown in formula (II), and the structure of the difluoroalkyl sulfoxide compound is shown in formula (III). Wherein, M is selected from one of Na, K, NH4, and H atoms; R1 is selected from a C1-C8 straight-chain or straight-chain alkyl group; R2 is selected from a C1-C8 straight-chain or branched alkylene group; R is selected from a C1-C8 straight-chain or branched alkyl group; and Rf is selected from C1-C 15 The compound 2 is a straight-chain or branched alkyl group containing a difluoromethyl group; the general structural formula of compound 2 is: ClRf; wherein, Rf is selected from C1-C1. 15 Alkyl groups containing difluoromethyl groups, either straight-chain or branched.

[0009] Preferably, M is a Na or H atom; R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl; R2 is selected from methylene, ethylene, n-propylene, isopropylene, and n-butylene; R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl; and Rf is selected from C1-C8 straight-chain or branched alkyl groups containing difluoromethyl groups.

[0010] Preferably, the molar ratio of compound 1 to compound 2 is 1:(1-5).

[0011] Preferably, the solvent includes at least one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, ethylene glycol dimethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dioxane, and water; the mass ratio of compound 1 to the solvent is 1:(2-10); the first alkaline substance includes any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, and sodium tert-butoxide; the molar ratio of compound 1 to the first alkaline substance is 1:(1-3); the reaction temperature for obtaining the difluorinated intermediate is 15℃-80℃, and the time is 10h-16h.

[0012] Preferably, when synthesizing difluoroalkyl sulfoxide compounds, the molar ratio of compound 1 to the oxidant is 1:(0.9-1.1); when synthesizing difluoroalkyl sulfoxide compounds, the molar ratio of compound 1 to the oxidant is 1:(1.8-3.6).

[0013] Preferably, the oxidant includes at least one of potassium persulfate, sodium persulfate, potassium persulfate, sodium persulfate, ammonium persulfate, sodium percarbonate, sodium perborate, m-chloroperoxybenzoic acid, and hydrogen peroxide.

[0014] Preferably, the oxidation reaction is carried out at a temperature of 0℃-85℃ for a time of 1h-24h; the decarboxylation reaction is carried out at a temperature of 40℃-100℃ for a time of 1h-16h.

[0015] Preferably, when the structure of compound 1 is formula (Ⅰ-2), after adding an oxidant to the difluorine intermediate for oxidation reaction, a second basic substance is added to form a salt, and then decarboxylation is carried out.

[0016] Preferably, the second alkaline substance is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen hydrate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

[0017] Preferably, the molar ratio of compound 1 to the second basic substance is 1:(0.9-2.7).

[0018] Compared with traditional technologies, the present invention has the following advantages: This application provides a method for synthesizing difluoromethane sulfones and / or difluoromethane sulfoxides, which achieves the preparation from raw materials to products in a one-pot process. The preparation method is simple, has few steps, few substrate restrictions, is environmentally friendly, has low cost, fast reaction, and high yield, which is conducive to industrial production.

[0019] Furthermore, this application improves purity and yield by selecting different raw materials and controlling reaction conditions. Detailed Implementation

[0020] To facilitate understanding of the present invention, a more complete description will be given below with reference to embodiments and other details. It will be understood that the present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0022] In this application, unless otherwise defined, all technical terms and jargon not explicitly stated have the same meaning as commonly understood by those skilled in the art and are common knowledge to them. Methods not explicitly stated are all conventional methods known to those skilled in the art. The term "multiple" in this application means at least two, such as two, three, etc., unless otherwise explicitly specified. In this application, technical features described in an open-ended manner include both closed-ended technical solutions composed of the listed features and open-ended technical solutions that include the listed features.

[0023] In this application, numerical ranges are referred to as continuous and, unless otherwise specified, include the minimum and maximum values ​​of the range, and every value between such minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0024] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions.

[0025] Unless otherwise specified, all technical features and optional technical features of this application may be combined to form new technical solutions.

[0026] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included.

[0027] Unless otherwise specified, the term "or" is inclusive in this application. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, the condition "A or B" is satisfied by any of the following conditions: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0028] Unless otherwise stated or in case of contradiction, the terms or phrases used herein shall have the following meanings: "Alkyl" refers to a saturated hydrocarbon containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing this term, such as "C1-C9 alkyl," refer to alkyl groups containing 1 to 9 carbon atoms, and each time it appears, it can independently be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, or C9 alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(C H3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), 1-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH( CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 and octyl (-(CH2)7CH3).

[0029] In this application, alkylene refers to a divalent group formed by further losing a hydrogen atom from an alkyl group. For example, "C1-C5 alkylene" refers to a divalent group formed by losing a hydrogen atom from a C1-C5 alkyl group, including C1-C5 straight-chain alkylene and C3-C5 branched alkylene.

[0030] The first aspect of this invention protects a method for synthesizing difluoroalkyl sulfone compounds and / or difluoroalkyl sulfoxide compounds, comprising: using compound 1 and compound 2 as raw materials, reacting them in a solvent with an alkali to obtain a difluoro intermediate; adding an oxidant to the difluoro intermediate, and performing an oxidation reaction followed by decarboxylation; wherein the structure of compound 1 is shown as formula (I-1) or formula (I-2); the structure of the difluoroalkyl sulfone compound is shown as formula (II); and the structure of the difluoroalkyl sulfoxide compound is shown as formula (III). ; Wherein, M is selected from one of Na, K, NH4, and H atoms; R1 is selected from a C1-C8 straight-chain or straight-chain alkyl group; R2 is selected from a C1-C8 straight-chain or branched alkylene group; R is selected from a C1-C8 straight-chain or branched alkyl group; and Rf is selected from C1-C 15 The compound 2 is a straight-chain or branched alkyl group containing a difluoromethyl group; the general structural formula of compound 2 is: ClRf; wherein, Rf is selected from C1-C1. 15 Alkyl groups containing difluoromethyl groups, either straight-chain or branched.

[0031] In some embodiments, M is a Na or H atom; R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl; R2 is selected from methylene, ethylene, n-propylene, isopropylene, and n-butylene; R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl; Rf is selected from C1-C8 straight-chain or branched alkyl groups containing difluoromethyl groups.

[0032] In some embodiments, compound 1 is selected from compounds with the following structures:

[0033] In some embodiments, compound 2 is selected from compounds with the following structures:

[0034] In some embodiments, the molar ratio of compound 1 to compound 2 is 1:(1-5), including but not limited to 1:1, 1:2, 1:3, 1:4, and 1:5.

[0035] In some embodiments, the solvent includes at least one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, ethylene glycol dimethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dioxane, and water.

[0036] In some embodiments, the mass ratio of compound 1 to solvent is 1:(2-10), including but not limited to 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10; the first alkaline substance includes any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen hydrate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

[0037] In some embodiments, the molar ratio of compound 1 to the first basic substance is 1:(1-3), including but not limited to 1:1, 1:2, and 1:3.

[0038] In some embodiments, the reaction temperature for obtaining the difluorine intermediate is 15°C-80°C, including but not limited to 15°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, and 80°C, and the reaction time is 10h-16h, including but not limited to 10h, 11h, 12h, 13h, 14h, 15h, and 16h.

[0039] In some embodiments of the present invention, the structure of the difluorine intermediate is as shown in formula (Ⅳ-1) or formula (Ⅳ-2): The limitations of M, R2, and R1 are the same as above.

[0040] In some embodiments, when synthesizing difluoroalkyl sulfoxide compounds, the molar ratio of compound 1 to oxidant is 1:(0.9-1.1), including but not limited to 1:0.9, 1:1.0, and 1:1.1; when synthesizing difluoroalkyl sulfoxide compounds, the molar ratio of compound 1 to oxidant is 1:(1.8-3.6), including but not limited to 1:1.8, 1:2.0, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3.0, 1:3.2, 1:3.4, and 1:3.6.

[0041] It is understood that in this invention, the amount of oxidant used will affect the degree of oxidation of the product and the type of product obtained. The synthesis conditions within the scope defined in this application improve the purity of the synthesis.

[0042] In some embodiments, the oxidant includes at least one of potassium persulfate, potassium persulfate, sodium persulfate, ammonium persulfate, sodium percarbonate, sodium perborate, m-chloroperoxybenzoic acid, and hydrogen peroxide. Sodium persulfate or m-chloroperoxybenzoic acid is preferred.

[0043] In some embodiments, the oxidation temperature is 0℃-85℃, including but not limited to 0℃, 5℃, 10℃, 15℃, 20℃, 30℃, 50℃, 60℃, 70℃, 80℃, and 85℃, preferably 0-30℃, more preferably 30℃; the time is 1h-24h, including but not limited to 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 14h, 16h, 18h, 20h, 22h, and 24h, preferably 3-8h, more preferably 3h.

[0044] In some embodiments, the temperature of the decarboxylation reaction is 40℃-100℃, including but not limited to 40℃, 50℃, 60℃, 70℃, 80℃, 90℃, and 100℃, preferably 60-90℃, more preferably 90℃, and the time is 1-16h, including but not limited to 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 10h, 9h, 11h, 12h, 13h, 14h, 15h, and 16h, preferably 10-14h, more preferably 12h.

[0045] In some embodiments, when compound 1 has the structure of formula (Ⅰ-2), the oxidation reaction further includes a process of adding a second basic substance to form a salt. That is, after adding an oxidant to the difluorine intermediate for oxidation, a second basic substance is added to form a salt, and finally decarboxylation is performed. In some embodiments, the second basic substance is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen hydrate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, and sodium tert-butoxide. In some embodiments, the molar ratio of compound 1 to the second basic substance is 1:(0.9-2.7), including but not limited to 1:0.9, 1:1.0, 1:1.5, 1:2.0, 1:2.5, and 1:2.7.

[0046] In some embodiments, the synthesis method of difluoroalkyl sulfones or difluoroalkyl sulfoxides is as follows: Compound 1 and Compound 2, as shown in Formula (I-1), are reacted with a first basic compound to obtain a difluoro intermediate; then an oxidizing agent is added, followed by high-temperature decarboxylation to obtain the product. The synthetic route is as follows:

[0047] The limitations of M, R2, R, and Rf are the same as above.

[0048] In some embodiments, the synthesis method of difluoroalkyl sulfones or difluoroalkyl sulfoxides is as follows: Compound 1 and Compound 2, as shown in Formula (I-2), are reacted under the action of a first basic compound to obtain a difluoro intermediate; then an oxidizing agent is added to react, followed by the addition of a second basic compound to form a salt, and then decarboxylation is performed at high temperature to obtain the product. The synthetic route is as follows:

[0049] The constraints for R1, R2, R, and Rf are the same as above.

[0050] It is understood that the method of this invention uses mercapto acid salts or mercapto acids (esters) and difluoromethyl-containing alkyl compounds, such as dichlorodifluoroane, as raw materials to achieve difluoroalkyl substitution under alkaline conditions; then, the difluoro intermediate compound is oxidized and decarboxylated to obtain difluoroalkyl sulfone compounds. This method has many advantages, such as fewer substrate restrictions, low raw material costs, and high reaction yields. It also allows for a "one-pot" synthesis, synthesizing the product from the raw materials alone, achieving low cost and high efficiency. The synthesis of difluoromethane sulfone compounds and / or difluoromethane sulfoxide compounds is achieved through essentially the same synthetic route, demonstrating high industrialization potential.

[0051] A difluoromethane sulfone compound and / or difluoromethane sulfoxide compound synthesized by the above-described synthetic method.

[0052] It should be noted that, unless otherwise specified, all raw materials used in this invention are commercially available. The invention will be further illustrated below through examples and other means.

[0053] Example 1 A method for preparing difluoromethyl ethyl sulfone using sodium mercaptopropionate and dichlorodifluoromethane as raw materials, sodium hydroxide as a base, to obtain a difluoro intermediate, followed by oxidation of the sulfide with potassium persulfate as an oxidant and subsequent decarboxylation, is described below:

[0054] The preparation steps are as follows: Accurately weigh 128g of sodium mercaptopropionate, 44g of sodium hydroxide, and 1024g of water into a 2000mL four-necked flask. Slowly introduce 173g of dichlorofluoromethane, then slowly heat to 40℃ and react for 16 hours, then lower the temperature to 25℃. Slowly add 567g of potassium persulfate, keeping the temperature below 30℃. After the addition is complete, maintain the reaction temperature for 3 hours, then heat to 90℃ and react for 12 hours. Distillation yields 118.3g of the product with a GC purity of 99.3% and a yield of 82.1%.

[0055] Example 2 A method for preparing difluoromethyl isopropyl sulfone using sodium 2-methylmercaptopropionate and dichlorodifluoromethane as raw materials, sodium hydride as base, and sodium persulfate as oxidant to oxidize the sulfide followed by decarboxylation is described below:

[0056] The preparation steps are as follows: 142g of sodium 2-methylmercaptopropionate, 44g of sodium hydride, and 1024g of DMAC were accurately weighed into a 2000mL four-necked flask. 260g of dichlorofluoromethane was slowly introduced, and the mixture was kept at 25℃ for 12 hours. The temperature was then lowered to 0℃, and 500g of sodium persulfate was slowly added, with the temperature not exceeding 10℃. After the addition was completed, the mixture was kept at 50℃ for 6 hours, and then heated to 50℃ for 13 hours. The product was obtained by distillation, with a GC purity of 99.0% and a yield of 84.1%.

[0057] Example 3 A method for preparing difluoromethyl tert-butyl sulfone using sodium 2,2-dimethylmercaptopropionate and dichlorodifluoromethane as raw materials, potassium hydroxide as base, and after reacting to obtain a difluoro intermediate, 30% hydrogen peroxide as oxidant to oxidize the sulfide followed by decarboxylation, is described below:

[0058] The preparation steps are as follows: 156g of sodium 2,2-dimethylmercaptopropionate, 62g of potassium hydroxide, and 1024g of MeCN were accurately weighed into a 2000mL four-necked flask. 346g of dichlorofluoromethane was slowly introduced, and the mixture was kept at 75℃ for 16 hours. Then, 300g of 30% hydrogen peroxide was slowly added, with the temperature not exceeding 85℃. After the addition was complete, the mixture was kept at 80℃ for 6 hours, and then heated to 80℃ for 10 hours. The product was obtained by distillation, with a GC purity of 99.2% and a yield of 80.9%.

[0059] Example 4 A method for preparing difluorobutylethyl sulfone using sodium mercaptopropionate and 4-chloro-1,1-difluorobutane as raw materials, sodium hydroxide as a base, to obtain a difluoro intermediate, followed by oxidation of the sulfide with potassium persulfate as an oxidant and subsequent decarboxylation, is described below:

[0060] The preparation steps are as follows: accurately weigh 128g of sodium mercaptopropionate, 44g of sodium hydroxide, and 1024g of water into a 2000mL four-necked flask. Slowly add 193g of 4-chloro-1,1-difluorobutane, and slowly heat to 40℃ and react for 16 hours. Lower the temperature to 25℃, and slowly add 567g of potassium persulfate, keeping the temperature below 30℃. After the addition is complete, maintain the temperature for 3 hours, then heat to 90℃ and react for 12 hours. Distill to obtain 152.1g of product with a GC purity of 99.1% and a yield of 81.8%.

[0061] Example 5 A method for preparing difluoroethyl methyl sulfone using sodium mercaptoacetate and 2-chloro-1,1-difluoroethane as raw materials, sodium hydroxide as a base, and potassium persulfate as an oxidant to oxidize the sulfide followed by decarboxylation is described below:

[0062] The preparation steps are as follows: Accurately weigh 114g of sodium mercaptoacetate, 44g of sodium hydroxide, and 1024g of water into a 2000mL four-necked flask. Slowly add 150g of 2-chloro-1,1-difluoroethane, and slowly heat to 40℃ and react for 16 hours. Then lower the temperature to 25℃. Slowly add 567g of potassium persulfate, keeping the temperature below 30℃. After the addition is complete, maintain the temperature for 3 hours, then heat to 90℃ and react for 12 hours. Distill to obtain 117.9g of product with a GC purity of 99.2% and a yield of 81.9%.

[0063] Example 6 A method for preparing difluoromethylpropyl sulfoxide using sodium 3-methylmercaptopropionate and dichlorodifluoromethane as raw materials, potassium carbonate as base, to obtain a difluoro intermediate, followed by oxidation of a sulfide with m-chloroperoxybenzoic acid as oxidant and subsequent decarboxylation, is described below:

[0064] The preparation steps are as follows: 142g of sodium 3-methylmercaptopropionate, 152g of potassium carbonate, and 1024g of ethanol were accurately weighed into a 2000mL four-necked flask. 432g of dichlorofluoromethane was slowly introduced, and the mixture was slowly heated to 80℃ and reacted for 10 hours. The temperature was then lowered to 35℃, and 189g of m-chloroperoxybenzoic acid was slowly added, with the temperature not exceeding 40℃. After the addition was complete, the mixture was kept at this temperature for 3 hours, then heated to 60℃ and reacted for 9 hours. The product was obtained by distillation, with a GC purity of 99.5% and a yield of 85.8%.

[0065] Example 7 A method for preparing difluoroethyl ethyl sulfoxide using sodium mercaptopropionate and 2-chloro-1,1-difluoroethane as raw materials, sodium hydroxide as base, and potassium persulfate as oxidant to oxidize the sulfide followed by decarboxylation is described below:

[0066] The preparation steps are as follows: Accurately weigh 128g sodium mercaptopropionate, 44g sodium hydroxide, and 1024g water into a 2000mL four-necked flask. Slowly add 150g of 2-chloro-1,1-difluoroethane, and slowly heat to 40℃ and react for 16 hours. Lower the temperature to 25℃, and slowly add 284g of potassium persulfate, keeping the temperature below 30℃. After the addition is complete, maintain the temperature for 3 hours, then heat to 90℃ and react for 12 hours. Distill to obtain 120.0g of product with GC purity of 99.0% and a yield of 84.5%.

[0067] Example 8 A method for preparing difluoromethyl ethyl sulfoxide using sodium mercaptopropionate and dichlorodifluoromethane as raw materials, sodium hydroxide as base, to obtain a difluoro intermediate, followed by oxidation of the sulfide with potassium persulfate as oxidant and subsequent decarboxylation, is described below:

[0068] The preparation steps are as follows: Accurately weigh 128g sodium mercaptopropionate, 44g sodium hydroxide, and 1024g water into a 2000mL four-necked flask. Slowly introduce 173g of dichlorofluoromethane, then slowly heat to 40℃ and react for 16 hours. Lower the temperature to 25℃, and slowly add 284g of potassium persulfate, keeping the temperature below 30℃. After the addition is complete, maintain the temperature for 3 hours, then heat to 90℃ and react for 12 hours. Distill to obtain 96.1g of product with GC purity of 98.5% and a yield of 75.1%.

[0069] Example 9 A method is provided for preparing difluoroethyl methyl sulfone by reacting ethyl mercaptoacetate and 2-chloro-1,1-difluoroethane as raw materials, using sodium ethoxide as a base, reacting to obtain a difluoro intermediate, oxidizing the sulfide with potassium persulfate as an oxidant, then forming a salt with sodium hydroxide, and finally decarboxylating. The synthetic route is as follows:

[0070] The preparation steps are as follows: Accurately weigh 120g of ethyl mercaptoside, 68g of sodium ethoxide, and 1024g of ethanol into a 2000mL four-necked flask. Slowly add 150g of 2-chloro-1,1-difluoroethane, and slowly heat to 40℃ and react for 16 hours. Lower the temperature to 25℃, and slowly add 567g of potassium persulfate, keeping the temperature below 30℃. After the addition is complete, maintain the temperature for 3 hours. Add 40g of sodium hydroxide, heat to 80℃, and react for 12 hours. Distill to obtain 110.0g of product with a GC purity of 98.8% and a yield of 76.4%.

[0071] Example 10 A method for preparing difluoromethyl ethyl sulfone using mercaptopropionic acid and dichlorodifluoromethane as raw materials, sodium hydroxide as a base, to obtain a difluoro intermediate, followed by oxidation of a sulfide with potassium persulfate as an oxidant and subsequent decarboxylation, is described below:

[0072] The preparation steps include: Accurately weigh 106 g of mercaptopropionic acid, 84 g of sodium hydroxide, and 1024 g of water into a 2000 mL four-necked flask. Slowly introduce 173 g of dichlorofluoromethane, then slowly heat to 40 °C and react for 16 hours. Lower the temperature to 25 °C. Slowly add 567 g of potassium persulfate, maintaining the temperature below 30 °C. After the addition is complete, maintain the temperature for 3 hours, then heat to 90 °C and react for 12 hours. Distillation yields 117.1 g of the product with a GC purity of 99.2% and a yield of 81.3%.

[0073] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0074] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for synthesizing a difluoroalkyl sulfone compound and / or a difluoroalkyl sulfoxide compound, characterized by, The application relates to a synthesis method of a difluoroalkyl sulfone compound and a difluoroalkyl sulfoxide compound. The compound 1 and the compound 2 are used as raw materials, a first alkaline substance is added, and a difluoro intermediate is obtained by reaction in a solvent; An oxidizing agent is added to the difluoro intermediate, and decarboxylation is carried out after oxidation reaction; The structure of the compound 1 is shown in formula (I-1) or formula (I-2); the structure of the difluoroalkyl sulfone compound is shown in formula (II), and the structure of the difluoroalkyl sulfoxide compound is shown in formula (III); M is selected from Na, K, NH4 and H atoms; R1 is selected from C1-C8 linear or linear alkyl; R2 is selected from C1-C8 linear or branched alkylene; R is selected from C1-C8 linear or branched alkyl; The structure of the compound 2 is shown in formula ClRf; wherein said Rf is selected from C1-C 15 linear or branched alkyl containing difluoromethyl group.

2. The method of synthesis of claim 1, wherein, M is Na or an H atom; R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t-butyl; R2 is selected from methylene, ethylene, n-propylene, isopropylene and n-butylene; R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t-butyl; Rf is selected from C1-C8 linear or branched alkyl containing difluoromethyl.

3. The method of synthesis of claim 1, wherein, The molar ratio of the compound 1 to the compound 2 is 1: (1-5).

4. The method of synthesis of claim 1, wherein, The solvent comprises at least one of N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, ethylene glycol dimethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dioxane and water; the mass ratio of the compound 1 to the solvent is 1: (2-10); The first alkaline substance comprises any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide and sodium tert-butoxide; the molar ratio of the compound 1 to the first alkaline substance is 1: (1-3); The reaction temperature for obtaining the difluoro intermediate is 15-80 DEG C, and the reaction time is 10-16 hours.

5. The synthesis method according to claim 1, characterized in that, When the difluoroalkyl sulfoxide compound is synthesized, the molar ratio of the compound 1 to the oxidizing agent is 1: (0.9-1.1); When the difluoroalkyl sulfone compound is synthesized, the molar ratio of the compound 1 to the oxidizing agent is 1: (1.8-3.6).

6. The method of synthesis of claim 1, wherein, The oxidizing agent comprises at least one of potassium hydrogen persulfate, sodium hydrogen persulfate, potassium persulfate, sodium persulfate, ammonium persulfate, sodium percarbonate, sodium perborate, m-chloroperbenzoic acid and hydrogen peroxide.

7. The method of synthesis of claim 1, wherein, The oxidation reaction temperature is 0-85 DEG C, and the oxidation reaction time is 1-24 hours; the decarboxylation temperature is 40-100 DEG C, and the decarboxylation time is 1-16 hours.

8. The method of synthesis of claim 1, wherein, When the structure of the compound 1 is formula (I-2), a second alkaline substance is added after oxidation reaction of the difluoro intermediate by adding the oxidizing agent, and then salt formation and decarboxylation are carried out.

9. The method of synthesis of claim 8, wherein, The second alkaline compound is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide and sodium tert-butoxide.

10. The method of synthesis of claim 8, wherein, The molar ratio of the compound 1 to the second alkaline substance is 1: (0.9-2.7).

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