CN116730911A - Preparation method of difluoromethyl (2-pyridyl) sulfone compound - Google Patents
Preparation method of difluoromethyl (2-pyridyl) sulfone compound Download PDFInfo
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- CN116730911A CN116730911A CN202210194584.5A CN202210194584A CN116730911A CN 116730911 A CN116730911 A CN 116730911A CN 202210194584 A CN202210194584 A CN 202210194584A CN 116730911 A CN116730911 A CN 116730911A
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- difluoromethyl
- bromate
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- pyridyl
- mercapto
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- -1 difluoromethyl (2-pyridyl) sulfone compound Chemical class 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- UGNCMUSLJBGOQW-UHFFFAOYSA-N 2-(difluoromethylsulfanyl)pyridine Chemical compound FC(F)SC1=CC=CC=N1 UGNCMUSLJBGOQW-UHFFFAOYSA-N 0.000 claims abstract description 19
- YRQNSTAWTLXCEZ-UHFFFAOYSA-N 2-(difluoromethylsulfonyl)pyridine Chemical compound FC(F)S(=O)(=O)C1=CC=CC=N1 YRQNSTAWTLXCEZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 19
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical group [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 12
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 230000001590 oxidative effect Effects 0.000 claims description 7
- XWNSFEAWWGGSKJ-UHFFFAOYSA-N 4-acetyl-4-methylheptanedinitrile Chemical compound N#CCCC(C)(C(=O)C)CCC#N XWNSFEAWWGGSKJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004153 Potassium bromate Substances 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 4
- 229940094037 potassium bromate Drugs 0.000 claims description 4
- 235000019396 potassium bromate Nutrition 0.000 claims description 4
- 229910052707 ruthenium Inorganic materials 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000003444 phase transfer catalyst Substances 0.000 claims description 3
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 239000007800 oxidant agent Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- 239000013078 crystal Substances 0.000 description 9
- 238000003760 magnetic stirring Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000010265 sodium sulphite Nutrition 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 7
- 239000002699 waste material Substances 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- NALMPLUMOWIVJC-UHFFFAOYSA-N n,n,4-trimethylbenzeneamine oxide Chemical compound CC1=CC=C([N+](C)(C)[O-])C=C1 NALMPLUMOWIVJC-UHFFFAOYSA-N 0.000 description 3
- 235000015281 sodium iodate Nutrition 0.000 description 3
- 239000011697 sodium iodate Substances 0.000 description 3
- 229940032753 sodium iodate Drugs 0.000 description 3
- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003304 ruthenium compounds Chemical class 0.000 description 1
- BIXNGBXQRRXPLM-UHFFFAOYSA-K ruthenium(3+);trichloride;hydrate Chemical compound O.Cl[Ru](Cl)Cl BIXNGBXQRRXPLM-UHFFFAOYSA-K 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of difluoromethyl (2-pyridyl) sulfone. Difluoromethyl (2-pyridyl) sulfone is prepared from the compound 2- (difluoromethyl mercapto) pyridine of formula I by oxidation reaction in which the oxidizing agent is bromate compound or its mixture with water.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of a difluoromethyl (2-pyridyl) sulfone compound.
Background
Difluoromethylation can be used to synthesize organofluorine compounds, which are used in the synthesis of many fluorine-containing pharmaceutically active molecules. Over the years, a variety of commercial difluoromethyl reagents have been synthesized, but fewer are available for use in industrialization. Difluoromethyl (2-pyridyl) sulfones are a few recently developed difluoromethylating agents for industrialization.
In journal literature (org. Lett.2010,12,1444), difluoromethyl (2-pyridyl) sulfones are used in the deoxo geminal difluoroalkenylation of aldehydes and ketones. At present, difluoromethyl (2-pyridyl) sulfone has become an important reagent for converting carbonyl compounds into gem-difluoro olefins, and the preparation method comprises the steps of taking 2-mercaptopyridine as a raw material, and carrying out S-difluoromethylation reaction and oxidation reaction, wherein the reaction formula is as follows:
two oxidation systems used in the oxidation reaction, one being sodium iodate oxidation and the other being hydrogen peroxide oxidation, are further reported in the journal literature (angel. Chem. Int. Ed.2011,50, 2559-2563).
2- (difluoromethyl mercapto) pyridine is oxidized by sodium iodate to prepare difluoromethyl (2-pyridyl) sulfone, the reaction formula is:
2- (difluoromethyl mercapto) pyridine is oxidized by hydrogen peroxide to prepare difluoromethyl (2-pyridyl) sulfone, and the reaction formula is:
the technology for preparing difluoromethyl (2-pyridyl) sulfone by a sodium iodate oxidation system has the defects of more waste and complicated operation after the reaction is finished; the technology for preparing difluoromethyl (2-pyridyl) sulfone by using a hydrogen peroxide oxidation system has the defects of complex post-treatment and uneconomical and environment-friendly effects.
In view of the above-mentioned drawbacks of the process for preparing difluoromethyl (2-pyridyl) sulfone, the requirement of industrial production cannot be met, and therefore, it is necessary to develop a process for preparing difluoromethyl (2-pyridyl) sulfone which is low in cost, safe and reliable, has few three wastes and is simple to operate.
Disclosure of Invention
The technical purpose of the invention is to provide a preparation method of difluoromethyl (2-pyridyl) sulfone, which has the advantages of low cost, safety, reliability, less three wastes and simple operation. In order to achieve the technical purpose, the technical scheme provided by the invention is as follows:
difluoromethyl (2-pyridyl) sulfone is prepared from the compound 2- (difluoromethyl mercapto) pyridine of formula I by oxidation reaction in which the oxidizing agent is bromate compound or its mixture with water.
Further, in the oxidation reaction, a trivalent ruthenium catalyst (RuX 3 ) The method comprises the steps of carrying out a first treatment on the surface of the Such as ruthenium trichloride or ruthenium trichloride hydrate, and the like. Wherein X is halogen, more preferably Cl, br or I, etc.
Further, the bromate is sodium bromate, potassium bromate and the like.
Further, the molar ratio of the bromate to the 2- (difluoromethyl mercapto) pyridine compound is (0.7-1.05): 1.
In the above-mentioned oxidation reaction, the temperature of the oxidation reaction is more preferably: 25-45 ℃.
In the oxidation reaction, the molar ratio of the trivalent ruthenium catalyst to the 2- (difluoromethyl mercapto) pyridine compound is (0.001-0.005): 1.
Preferably, an organic solvent is added in the oxidation reaction, and the organic solvent may be: acetonitrile, dichloromethane, toluene, or the like.
In a more preferred embodiment of the present invention, difluoromethyl (2-pyridyl) sulfone is prepared by reacting a compound of formula I, i.e., 2- (difluoromethyl mercapto) pyridine, with sodium bromate in the presence of a trivalent ruthenium chloride catalyst. The reaction formula is as follows:
the bromate in the reaction of the invention can be added in batches or with water. In the reaction, the mixing mode of the 2- (difluoromethyl mercapto) pyridine, the bromate and the catalyst can be sequentially exchanged, namely, the 2- (difluoromethyl mercapto) pyridine is added firstly, and then the bromate and the catalyst are added; or adding catalyst and bromate, and then adding 2- (difluoromethyl mercapto) pyridine; the above-mentioned order of addition is arbitrary.
In the above reaction of the present invention, a phase transfer catalyst may be optionally added, and the phase transfer catalyst may be an aqueous tetrabutylammonium sulfate solution or the like.
The post-treatment in the reaction of the invention adopts an extraction mode commonly. In addition, the invention can directly delaminate to obtain the target product without extraction after the reaction is complete. This results in a saving of operating steps for the working-up, and no additional extraction solvent is required.
The invention provides the method for synthesizing the difluoromethyl (2-pyridyl) sulfone by oxidation, which solves the problems of high cost, complex operation, high safety risk and more three wastes in the prior art.
The invention uses RuCl 3 The advantages of oxidizing thioether with bromate are as follows: 1. the consumption of the oxidant is small; 2. sodium bromate or potassium bromate is low in price; 3. the byproduct after oxidation is sodium bromide, which can be removed by simple water washing, and has less three wastes, simple post treatment of 4, safety and amplification.
The invention uses bromate as an oxidizing agent and a trivalent ruthenium compound as a catalyst, when the set of oxidizing system is applied to oxidizing thioether into sulfone, the reaction environment of the whole reaction system is different from that of oxidizing alcohol into aldehyde, and the system of oxidizing alcohol into aldehyde needs to be an acidic environment. Compared with the prior art, the invention has the following beneficial effects:
compared with the prior art which needs high cost, more three wastes, complex operation and poor safety, the invention has the advantages of low cost, less three wastes, simple operation, high safety and the like; the method is not only suitable for small-scale synthesis in a laboratory, but also suitable for industrial large-scale production, and has good application prospect.
Detailed Description
In order to further understand the present invention, a method for producing a difluoromethyl (2-pyridyl) sulfone compound provided by the present invention will be described in detail with reference to examples. It should be understood that these examples are presented merely to further illustrate the features of the present invention and are not intended to limit the scope of the invention or the scope of the claims.
Example 1
To a 1L three-necked flask, 250mL of water was added, and the flask was cooled in an ice-water bath, 270g of potassium hydroxide, 500mL of ethylene glycol dimethyl ether and 50g of 2-mercaptopyridine were added. Excess freon gas was vented to the flask and monitored by TLC until the starting material was complete. Filtering to remove insoluble substances, standing and layering filtrate. The upper organic phase was separated, washed with 150mL of saturated brine and dried over anhydrous magnesium sulfate. Suction filtration, vacuum concentration and drying of filtrate, vacuum distillation and purification to obtain 57.5g of 2- (difluoromethyl mercapto) pyridine yellow liquid with the yield of 79.4%.
Example 2
To a 100mL three-necked flask was added 30mL acetonitrile, 30mL water, 4.83g 2- (difluoromethyl mercapto) pyridine (30 mmol,1.0 equiv.) and 15.7mg RuCl with magnetic stirring turned on 3 ·3H 2 O (0.06 mmol, 0.002equiv.) 3.17g sodium bromate (21 mmol,0.7 equiv.) are added in portions. After the addition was completed, the reaction was continued with stirring at 25 ℃. TLC was monitored until the starting material was complete. Saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate, and the organic layer was separated, washed with 10% aqueous sodium sulfite solution, and dried over anhydrous magnesium sulfate. Suction filtration and vacuum concentration are carried out to obtain white crystals with the yield of 5.68g and the purity of 99.8 percent.
Example 3
To a 100mL three-necked flask was added 30mL of acetonitrile, 4.83g of 2- (difluoromethyl mercapto) pyridine (30 mmol,1.0 equiv.) and 15.7mg of RuCl 3 ·3H 2 O (0.06 mmol, 0.002equiv.). Magnetic stirring was turned on and a solution of 3.17g sodium bromate (21 mmol,0.7 equiv.) and 30mL water was added dropwise. After the addition was completed, the reaction was continued with stirring at 25 ℃. TLC was monitored until the starting material was complete. Saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate, and the organic layer was separated, washed with 10% aqueous sodium sulfite solution, and dried over anhydrous magnesium sulfate. Suction filtration and vacuum concentration are carried out to obtain 5.51g of white crystal with the yield of 95 percent and the purity of 99.9 percent.
Example 4
Into a 100mL three-necked flask, 30mL of water, 15.7mg of RuCl was added 3 ·3H 2 O (0.06 mmol, 0.002equiv.), 3.17g sodium bromate (21 mmol,0.7 equiv.). To the reaction flask, a solution of 4.83g of 2- (difluoromethyl mercapto) pyridine (30 mmol,1.0 equiv.) in 30mL of acetonitrile was added dropwise with magnetic stirring. After the addition was completed, the reaction was continued with stirring at 25 ℃. TLC was monitored until the starting material was complete. Saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate, and the organic layer was separated, washed with 10% aqueous sodium sulfite solution, and dried over anhydrous magnesium sulfate. Suction filtration and vacuum concentration are carried out to obtain 5.56g of white crystal with the yield of 96 percent and the purity of 99.8 percent.
Example 5
To a 100mL three-necked flask was added 30mL acetonitrile, 30mL water, 4.83g 2- (difluoromethyl mercapto) pyridine (30 mmol,1.0 equiv.) and 15.7mg RuCl with magnetic stirring turned on 3 ·3H 2 O (0.06 mmol, 0.002equiv.) 3.51g potassium bromate (21 mmol,0.7 equiv.) are added in portions. After the addition was completed, the reaction was continued with stirring at 25 ℃. TLC was monitored until the starting material was complete. Saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate, and the organic layer was separated, washed with 10% aqueous sodium sulfite solution, and dried over anhydrous magnesium sulfate. Suction filtration and vacuum concentration are carried out to obtain white crystals with the yield of 5.46g and the purity of 99.7 percent.
Example 6
To a 100mL three-necked flask was added 30mL acetonitrile, 30mL water, 4.83g 2- (difluoromethyl mercapto) pyridine (30 mmol,1.0 equiv.) and 15.7mg RuCl with magnetic stirring turned on 3 ·3H 2 O (0.06 mmol, 0.002equiv.) 3.17g sodium bromate (21 mmol,0.7 equiv.) are added in portions. After the addition was completed, the reaction was continued with stirring at 25 ℃. TLC was monitored until the starting material was complete. Saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate, and the organic layer was separated, washed with 10% aqueous sodium sulfite solution, and dried over anhydrous magnesium sulfate. Suction filtration and vacuum concentration are carried out to obtain 5.70g of white crystal with the yield of 98 percent and the purity of 98.8 percent.
Example 7
To a 100mL three-necked flask was added 20mL acetonitrile, 40mL water, 4.83g 2- (difluoromethyl mercapto) pyridine (30 mmol,1.0 equiv.) and 15.7m was added with magnetic stirring ong RuCl 3 ·3H 2 O (0.06 mmol, 0.002equiv.) 3.17g sodium bromate (21 mmol,0.7 equiv.) are added in portions. After the addition was completed, the reaction was continued with stirring at 25 ℃. TLC was monitored until the starting material was complete. Saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate, and the organic layer was separated, washed with 10% aqueous sodium sulfite solution, and dried over anhydrous magnesium sulfate. Suction filtration and vacuum concentration are carried out to obtain white crystals with the yield of 5.33g and the purity of 99.8 percent.
Example 8
To a 100mL three-necked flask, 30mL of methylene chloride, 4.83g of 2- (difluoromethyl mercapto) pyridine (30 mmol,1.0 equiv.), a 50% mass fraction aqueous solution of tetrabutylammonium sulfate (3 mmol,1.0 equiv.), 15.7mg of RuCl were added 3 ·3H 2 O (0.06 mmol, 0.002equiv.). Magnetic stirring was turned on and a solution of 3.17g sodium bromate (21 mmol,0.7 equiv.) and 30mL water was added dropwise. After the addition was completed, the reaction was continued with stirring at 35 ℃. TLC was monitored until the starting material was complete. Saturated aqueous sodium hydrogencarbonate was added to separate an organic layer, which was washed with 10% aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate. Suction filtration and vacuum concentration are carried out to obtain 5.40g of white crystal with the yield of 93 percent and the purity of 99.9 percent.
Example 9
To a 100mL three-necked flask, 30mL of toluene, 4.83g of 2- (difluoromethyl mercapto) pyridine (30 mmol,1.0 equiv.), 50% strength by mass aqueous tetrabutylammonium sulfate solution, 15.7mg of RuCl were added 3 ·3H 2 O (0.06 mmol, 0.002equiv.). Magnetic stirring was turned on and a solution of 3.17g sodium bromate (21 mmol,0.7 equiv.) and 30mL water was added dropwise. After the addition was completed, the reaction was continued with stirring at 35 ℃. TLC was monitored until the starting material was complete. Saturated aqueous sodium hydrogencarbonate was added to separate an organic layer, which was washed with 10% aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate. Suction filtration and vacuum concentration are carried out to obtain 5.49g of white crystal with the yield of 95 percent and the purity of 99.9 percent.
Example 10
Into a 100mL three-necked flask, 30mL of water, 12.4mg of RuCl was added 3 (0.06 mmol, 0.002equiv.) 3.17g sodium bromate (21 mmol,0.7 equiv.). To the reaction flask, a solution of 4.83g of 2- (difluoromethyl mercapto) pyridine (30 mmol,1.0 equiv.) in 30mL of acetonitrile was added dropwise with magnetic stirring. After the addition, 40 DEG CThe reaction was continued with stirring. TLC was monitored until the starting material was complete. Saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate, and the organic layer was separated, washed with 10% aqueous sodium sulfite solution, and dried over anhydrous magnesium sulfate. Suction filtration and vacuum concentration are carried out to obtain 5.57g of white crystal with the yield of 96 percent and the purity of 99.8 percent.
Claims (10)
1. A preparation method of difluoromethyl (2-pyridyl) sulfone is characterized in that difluoromethyl (2-pyridyl) sulfone is prepared from 2- (difluoromethyl mercapto) pyridine compound through oxidation reaction, wherein in the oxidation reaction, oxidizing reagent is bromate compound or mixture of bromate compound and water,
2. the process of claim 1, wherein the reaction is carried out in the presence of a catalyst which is a trivalent ruthenium catalyst.
3. The method of claim 1, wherein the bromate is sodium bromate or potassium bromate.
4. A preparation method of difluoromethyl (2-pyridyl) sulfone is characterized in that a 2- (difluoromethyl mercapto) pyridine compound and sodium bromate are reacted with trivalent ruthenium chloride catalyst to prepare difluoromethyl (2-pyridyl) sulfone; the reaction formula is as follows:
5. the process according to claim 1 or 4, wherein the molar ratio of bromate to 2- (difluoromethyl mercapto) pyridine compound is 0.7 to 1.05:1.
6. The process according to claim 1 or 4, wherein the molar ratio of the trivalent ruthenium catalyst to the 2- (difluoromethyl mercapto) pyridine compound is 0.001 to 0.005:1.
7. The process according to claim 1 or 4, wherein the reaction temperature of the oxidation reaction is 25℃to 45 ℃.
8. The method according to claim 1 or 4, wherein the reaction solvent is acetonitrile, dichloromethane or toluene.
9. The process according to claim 1 or 4, wherein a phase transfer catalyst is selectively added to the reaction.
10. The process according to claim 1 or 4, wherein the 2- (difluoromethyl mercapto) pyridine is added with bromate and catalyst in any order.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117003692A (en) * | 2023-10-07 | 2023-11-07 | 山东东岳高分子材料有限公司 | Process for producing difluoromethyl (2-pyridyl) sulfone |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117003692A (en) * | 2023-10-07 | 2023-11-07 | 山东东岳高分子材料有限公司 | Process for producing difluoromethyl (2-pyridyl) sulfone |
| CN117003692B (en) * | 2023-10-07 | 2023-12-29 | 山东东岳高分子材料有限公司 | Process for producing difluoromethyl (2-pyridyl) sulfone |
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