CN115594617B - Synthesis method of difluoromethyl sulfonyl chloride - Google Patents
Synthesis method of difluoromethyl sulfonyl chloride Download PDFInfo
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- CN115594617B CN115594617B CN202210907839.8A CN202210907839A CN115594617B CN 115594617 B CN115594617 B CN 115594617B CN 202210907839 A CN202210907839 A CN 202210907839A CN 115594617 B CN115594617 B CN 115594617B
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- JYQLKKNUGGVARY-UHFFFAOYSA-N difluoromethanesulfonyl chloride Chemical compound FC(F)S(Cl)(=O)=O JYQLKKNUGGVARY-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000001308 synthesis method Methods 0.000 title claims abstract description 20
- 239000000243 solution Substances 0.000 claims abstract description 110
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims abstract description 33
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims abstract description 33
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims abstract description 8
- 238000004821 distillation Methods 0.000 claims abstract description 6
- 239000012074 organic phase Substances 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 230000035484 reaction time Effects 0.000 claims description 10
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000012071 phase Substances 0.000 abstract description 5
- 239000002341 toxic gas Substances 0.000 abstract description 4
- 238000007086 side reaction Methods 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 37
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/18—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by reaction of sulfides with compounds having functional groups with formation of sulfo or halosulfonyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of difluoromethyl sulfonyl chloride, which comprises the following steps: adding benzyl mercaptan into a freon-22 solution to obtain a solution A; adding tetrabutylammonium bromide into a sodium hydroxide aqueous solution to obtain a solution B; introducing the solution A and the solution B into a continuous flow micro-reactor, removing a lower water phase from the mixture obtained by the reaction, and carrying out reduced pressure distillation on an upper organic phase to obtain an intermediate; and dissolving the intermediate in a solvent to obtain an intermediate solution, introducing the intermediate solution and chlorosulfonic acid solution into a continuous flow microreactor, and distilling a mixture obtained by the reaction to obtain a target product difluoromethyl sulfonyl chloride. The synthesis method provided by the invention has the advantages of simple operation, high yield, less side reaction, low production difficulty and high production safety, and avoids the high-pressure reaction and the use of toxic gases in the prior art.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a synthesis method of difluoromethyl sulfonyl chloride.
Background
Difluoromethylsulfonyl chloride is a pharmaceutical chemical intermediate that may be in great demand in the future. The existing synthetic routes for difluoromethylsulfonyl chloride are four:
(1)
(2)
(3)
(4)
the four synthesis paths are divided into two steps, in the first step, the difluoride used in the methods (1), (2) and (3) is not easy to obtain, the price is high, the cost is not easy to control, and the freon-22 used in the method (4) is easy to obtain, but as gas, high-pressure reaction equipment is required according to the traditional synthesis path, the requirement on equipment sites is high, and the cost is not easy to control; the second process is essentially identical, in that chlorine is used as the chlorinating starting material, which converts the intermediate obtained in the first step into the final product, and as a highly toxic gas, is not suitable for use in large scale synthesis.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a synthesis method of difluoromethyl sulfonyl chloride, which has the advantages of simple operation, high yield, less side reaction, low production difficulty and high production safety, and avoids the high-pressure reaction and the use of toxic gas in the prior art.
The invention provides the following technical scheme:
the synthesis method of the difluoromethyl sulfonyl chloride comprises the following steps:
adding benzyl mercaptan into a freon-22 solution to obtain a solution A;
adding tetrabutylammonium bromide into a sodium hydroxide aqueous solution to obtain a solution B;
introducing the solution A and the solution B into a continuous flow micro-reactor, removing a lower water phase from the mixture obtained by the reaction, and carrying out reduced pressure distillation on an upper organic phase to obtain an intermediate;
dissolving the intermediate in a solvent to obtain an intermediate solution, introducing the intermediate solution and chlorosulfonic acid solution into a continuous flow microreactor, and distilling a mixture obtained by the reaction to obtain a target product difluoromethyl sulfonyl chloride;
the chemical reaction formula is:
further, the freon-22 solution is obtained by cooling dimethyl tetrahydrofuran to the temperature of minus 78 ℃ and then introducing freon-22, and the mass fraction of freon-22 in the freon-22 solution is 1-10%.
Further, the benzyl mercaptan is added into the freon-22 solution at the temperature of minus 10 ℃, and the molar ratio of the benzyl mercaptan to the freon-22 is 1:1-1:100.
Further, the mass fraction of sodium hydroxide in the sodium hydroxide aqueous solution is 0.1-20%, and the added mass of tetrabutylammonium bromide is 0.1-20% of the mass of the sodium hydroxide aqueous solution.
Further, the solution A and the solution B are introduced into a continuous flow micro-reactor according to the volume ratio of 1:1, and the reaction time is controlled to be 1-30 min, preferably 3-15 min, and more preferably 5-8 min; the reaction temperature is 0 to 200 ℃, preferably 70 to 130 ℃, and more preferably 90 to 110 ℃.
Further, the sum of the flow rates of the solution A and the solution B is 3.3-100 ml/min, preferably 12.5-20 ml/min; the flow rate ratio of the solution A to the solution B is 1:10-10:1, preferably 1:1.
Further, the solvent used for preparing the intermediate solution is a mixed solution of acetonitrile, acetic acid and water, and the mass fraction of the intermediate in the intermediate solution is 1-20%, preferably 5%.
Further, the chlorosulfonic acid solution is obtained by dissolving chlorosulfonic acid in acetonitrile, and the mass fraction of chlorosulfonic acid in the chlorosulfonic acid solution is 1-25%, preferably 10%.
Furthermore, the intermediate solution and chlorosulfonic acid solution are introduced into a continuous flow micro-reactor according to the volume ratio of 1:1, and the reaction time is controlled to be 1-30 min, preferably 3-15 min, and more preferably 5-8 min; the reaction temperature is 0 to 200 ℃, preferably 60 to 120 ℃, and more preferably 80 to 100 ℃.
Further, the sum of the flow rates of the intermediate solution and the chlorosulfonic acid solution is 3.3-100 ml/min, and the flow rate ratio of the intermediate solution to the chlorosulfonic acid solution is 1:10-10:1, preferably 1:1.
Compared with the prior art, the invention has the beneficial effects that:
(1) According to the invention, the Freon-22 solution is used as a raw material, and the continuous flow microreactor is used as a reaction place, so that the first-step synthesis reaction is realized to obtain an intermediate, the problem that an additional pressure device is required to be equipped to realize high-pressure reaction in the prior art is avoided, the production difficulty is reduced, and the production safety is improved;
(2) According to the invention, chlorosulfonic acid solution is used as a raw material, and a continuous flow microreactor is used as a reaction place, so that a target product difluoromethylsulfonyl chloride is obtained through a second step of synthesis reaction, the use of toxic gas chlorine in the prior art is avoided, and the production safety is improved;
(3) The raw materials of Freon-22, benzyl mercaptan, chlorosulfonic acid and the like adopted by the invention are all readily available primary chemical raw materials, and the raw material cost is low;
(4) The synthesis method provided by the invention has the advantages of high yield, less side reaction, simple post-treatment and purification process, easy operation and less pollution;
(5) The synthesis method provided by the invention can realize automatic continuous production, can easily realize kilogram-level production, and has the advantages that the whole reaction system occupies several square meters, and the requirements on the field are low.
Detailed Description
The following examples are only for more clearly illustrating the technical aspects of the present invention, and are not intended to limit the scope of the present invention.
Synthesis of (one) intermediates
Example 1
(1) Cooling 1L of dimethyl tetrahydrofuran to-78 ℃, introducing freon-22 to obtain a freon-22 solution with the mass fraction of 5%, and then adding 50g of benzyl mercaptan at the temperature of-10 ℃ to obtain a solution A;
(2) 1000g of sodium hydroxide aqueous solution with the mass fraction of 10% is prepared, and 8g of tetrabutylammonium bromide is added to obtain solution B;
(3) And (3) introducing the solution A and the solution B into a continuous flow microreactor with the volume of 30ml, controlling the flow rate of the solution A and the flow rate of the solution B to be 5ml/min, controlling the reaction time to be 3min, controlling the reaction temperature to be 90 ℃, removing a lower water phase from the obtained mixture, taking an upper organic phase, and carrying out reduced pressure distillation to obtain an intermediate, wherein the nuclear magnetic yield is 22%.
Example 2
This example uses the synthesis method of example 1, and differs from example 1 in that the reaction temperature is controlled to 100℃and the nuclear magnetic yield of the intermediate is 62%.
Example 3
This example uses the synthesis method of example 1, and differs from example 1 in that the reaction temperature is controlled to 110℃and the nuclear magnetic yield of the intermediate is 94%.
Example 4
This example uses the synthesis method of example 1, and differs from example 1 in that the flow rates of solution A and solution B are controlled to be 2.5ml/min, and the nuclear magnetic yield of the intermediate is 65%.
Example 5
The synthesis method of example 1 was used in this example, except that the flow rates of the solution A and the solution B were each controlled to 2.5ml/min, the reaction temperature was controlled to 100℃and the nuclear magnetic yield of the intermediate was 100%.
Example 6
The synthesis method of example 1 was used in this example, except that the flow rates of the solution A and the solution B were each controlled to 2.5ml/min, the reaction temperature was controlled to 110℃and the nuclear magnetic yield of the intermediate was 100%.
Example 7
(1) Cooling 1L of dimethyl tetrahydrofuran to-78 ℃, introducing freon-22 to obtain a freon-22 solution with the mass fraction of 10%, and then adding 50g of benzyl mercaptan at the temperature of-10 ℃ to obtain a solution A;
(2) 1000g of sodium hydroxide aqueous solution with the mass fraction of 10% is prepared, and 8g of tetrabutylammonium bromide is added to obtain solution B;
(3) And (3) introducing the solution A and the solution B into a continuous flow microreactor with the volume of 30ml, controlling the flow rate of the solution A and the flow rate of the solution B to be 2.5ml/min, controlling the reaction time to be 6min, controlling the reaction temperature to be 90 ℃, removing a lower water phase from the mixture obtained by the reaction, and taking an upper organic phase for reduced pressure distillation to obtain an intermediate, wherein the nuclear magnetic yield is 100%.
Example 8
(1) Cooling 1L of dimethyl tetrahydrofuran to-78 ℃, introducing freon-22 to obtain a freon-22 solution with the mass fraction of 1%, and then adding 10g of benzyl mercaptan at the temperature of-10 ℃ to obtain a solution A;
(2) 1000g of sodium hydroxide aqueous solution with the mass fraction of 10% is prepared, and 8g of tetrabutylammonium bromide is added to obtain solution B;
(3) And (3) introducing the solution A and the solution B into a continuous flow microreactor with the volume of 30ml, controlling the flow rate of the solution A and the flow rate of the solution B to be 2.5ml/min, controlling the reaction time to be 6min, controlling the reaction temperature to be 120 ℃, removing a lower water phase from the obtained mixture, and taking an upper organic phase for reduced pressure distillation to obtain an intermediate, wherein the nuclear magnetic yield is 53%.
Synthesis of (di) difluoromethylsulfonyl chloride
Example 9
100g of the intermediate was dissolved in a mixed solution of acetonitrile/acetic acid/water (2L/200 ml/10 ml) to obtain an intermediate solution; 100g of chlorosulfonic acid is dissolved in 1L of acetonitrile to obtain chlorosulfonic acid solution; and then introducing the intermediate solution and the chlorosulfonic acid solution into a continuous flow microreactor with the volume of 30ml, controlling the flow rates of the intermediate solution and the chlorosulfonic acid solution to be 4ml/min, controlling the reaction time to be 3.75min, controlling the reaction temperature to be 60 ℃, and distilling the mixture obtained by the reaction to obtain the target product difluoromethylsulfonyl chloride, wherein the nuclear magnetic yield is 28%.
Example 10
This example uses the synthesis method of example 9, except that the reaction temperature was controlled to 80℃and the nuclear magnetic yield of difluoromethyl sulfonyl chloride was 55%.
Example 11
This example uses the synthesis method of example 9, except that the reaction temperature was controlled to 90℃and the nuclear magnetic yield of difluoromethyl sulfonyl chloride was 78%.
Example 12
This example uses the synthesis method of example 9, and differs from example 9 in that the flow rates of the intermediate solution and chlorosulfonic acid solution are both controlled to be 2ml/min, and the nuclear magnetic yield of difluoromethylsulfonyl chloride is 51%.
Example 13
This example uses the synthesis method of example 9, and differs from example 9 in that the flow rates of the intermediate solution and chlorosulfonic acid solution are both controlled to be 2ml/min, the reaction temperature is controlled to be 80 ℃, and the nuclear magnetic yield of difluoromethylsulfonyl chloride is controlled to be 69%.
Example 14
This example uses the synthesis method of example 9, and differs from example 9 in that the flow rates of the intermediate solution and chlorosulfonic acid solution are both controlled to be 2ml/min, the reaction temperature is controlled to be 90 ℃, and the nuclear magnetic yield of difluoromethylsulfonyl chloride is controlled to be 98%.
Example 15
200g of the intermediate was dissolved in a mixed solution of acetonitrile/acetic acid/water (2L/200 ml/10 ml) to obtain an intermediate solution; 200g of chlorosulfonic acid is dissolved in 1L of acetonitrile to obtain chlorosulfonic acid solution; and then introducing the intermediate solution and the chlorosulfonic acid solution into a continuous flow microreactor with the volume of 30ml, controlling the flow rates of the intermediate solution and the chlorosulfonic acid solution to be 6ml/min, controlling the reaction time to be 2.5min, controlling the reaction temperature to be 80 ℃, and distilling the mixture obtained by the reaction to obtain the target product difluoromethylsulfonyl chloride, wherein the nuclear magnetic yield is 82%.
Example 16
50g of the intermediate was dissolved in a mixed solution (2L/200 ml/10 ml) of acetonitrile/acetic acid/water to obtain an intermediate solution; 50g of chlorosulfonic acid was dissolved in 1L of acetonitrile to obtain a chlorosulfonic acid solution; and then introducing the intermediate solution and the chlorosulfonic acid solution into a continuous flow microreactor with the volume of 30ml, controlling the flow rates of the intermediate solution and the chlorosulfonic acid solution to be 3ml/min, controlling the reaction time to be 5min, controlling the reaction temperature to be 100 ℃, and distilling the mixture obtained by the reaction to obtain the target product difluoromethylsulfonyl chloride, wherein the nuclear magnetic yield is 51%.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and variations could be made by those skilled in the art without departing from the technical principles of the present invention, and such modifications and variations should also be regarded as being within the scope of the invention.
Claims (3)
1. The synthesis method of the difluoromethyl sulfonyl chloride is characterized by comprising the following steps of:
adding benzyl mercaptan into a freon-22 solution at the temperature of minus 10 ℃ to obtain a solution A, wherein the molar ratio of the benzyl mercaptan to the freon-22 is 1:1-1:100, the freon-22 solution is obtained by cooling dimethyl tetrahydrofuran to the temperature of minus 78 ℃ and then introducing the freon-22, and the mass fraction of the freon-22 in the freon-22 solution is 1-10%;
adding tetrabutylammonium bromide into a sodium hydroxide aqueous solution to obtain a solution B, wherein the mass fraction of sodium hydroxide in the sodium hydroxide aqueous solution is 0.1-20%, and the added mass of the tetrabutylammonium bromide is 0.1-20% of the mass of the sodium hydroxide aqueous solution;
introducing the solution A and the solution B into a continuous flow microreactor according to the volume ratio of 1:1, controlling the reaction time to be 1-30 min, controlling the reaction temperature to be 0-200 ℃, taking an upper organic phase from the mixture obtained by the reaction, and carrying out reduced pressure distillation to obtain an intermediate, wherein the sum of the flow rates of the solution A and the solution B is 3.3-100 ml/min, and the flow rate ratio of the solution A to the solution B is 1:10-10:1;
dissolving the intermediate in a solvent to obtain an intermediate solution, introducing the intermediate solution and chlorosulfonic acid solution into a continuous flow microreactor according to the volume ratio of 1:1, wherein the mass fraction of the intermediate in the intermediate solution is 1-20%, the mass fraction of chlorosulfonic acid in the chlorosulfonic acid solution is 1-25%, the reaction time is controlled to be 1-30 min, the reaction temperature is controlled to be 0-200 ℃, and the mixture obtained by the reaction is distilled to obtain the target product difluoromethylsulfonyl chloride, wherein the sum of the flow rates of the intermediate solution and the chlorosulfonic acid solution is 3.3-100 ml/min, and the flow rate ratio of the intermediate solution and the chlorosulfonic acid solution is 1:10-10:1.
2. The method for synthesizing difluoromethyl sulfonyl chloride according to claim 1, wherein the solvent used for preparing the intermediate solution is a mixture of acetonitrile, acetic acid and water.
3. The method for synthesizing difluoromethyl sulfonyl chloride according to claim 1, wherein the chlorosulfonic acid solution is obtained by dissolving chlorosulfonic acid in acetonitrile.
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2022
- 2022-07-29 CN CN202210907839.8A patent/CN115594617B/en active Active
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