CN110724091B - Synthetic method of 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride - Google Patents
Synthetic method of 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride Download PDFInfo
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- 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
Abstract
The invention provides a synthetic method of 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride, belonging to the field of organic chemical synthesis. The method takes 2-methoxy-3-bromo-6-methylpyridine as an initial raw material, and a final product, namely 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride is obtained through reactions such as oxidation, hydrolysis, demethylation, coupling and the like. The synthesis method disclosed by the invention is simple, the post-treatment has good operability and is easy to control, and a synthesis route is provided for the synthesis of the product.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a synthetic method of 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride.
Background
The fluorine-containing pyridine compound is an important drug intermediate, is quite wide in organic synthesis and drug intermediate synthesis application, and particularly has very important functions of synthesizing antibiotics, drugs for treating cardiovascular diseases, agricultural pesticides, bactericides and herbicides.
A hydroxyl group with a strong electron-donating group is introduced to the pyridine ring to increase the activity of the substance; the introduction of sulfonyl chloride group can react with other many drug template molecules to synthesize various drug molecules with different requirements, such as various sulfonamides. Therefore, by utilizing the known pyridine compounds and introducing some specific groups through organic reaction, the novel fluorine-containing pyridine compounds can be developed more efficiently.
In view of the importance of the potential performance of the fluorine-containing pyridine compound and the specific functional group thereof, the development of a novel synthesis process of the fluorine-containing pyridine compound has important significance.
Disclosure of Invention
The invention aims to provide a synthetic method of 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride. The method is simple to operate and easy to control, and provides a process route for synthesizing 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a synthetic method of 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride comprises the following steps:
the method comprises the following steps:
(1) dissolving the compound A in dichloromethane, and oxidizing with m-chloroperoxybenzoic acid to obtain a compound B;
(2) reacting the compound B with acetic anhydride to obtain a compound C;
(3) dissolving the compound C in methanol, and hydrolyzing under the action of an alkaline aqueous solution to obtain a compound D;
(4) dissolving the compound D in dichloromethane, and oxidizing with manganese dioxide to obtain a compound E;
(5) dissolving the compound E in dichloromethane, and reacting with diethylaminosulfur trifluoride under the protection of nitrogen to obtain a compound F;
(6) dissolving the compound F in acetonitrile, and reacting with sodium iodide and trimethylchlorosilane under the protection of nitrogen to obtain a compound G;
(7) dissolving the compound G in toluene, adding benzylmercaptan, 4, 5-bis (diphenylphosphine) -9, 9-dimethyl xanthene, alkali and a catalyst, and reacting under the protection of nitrogen to obtain a compound H;
(8) dissolving the compound H in acetic acid, and reacting with N-chlorosuccinimide to obtain a compound I.
Preferably, in the step (1), the reaction temperature is 25 ℃, the reaction time is 5-25 hours, and the molar ratio of the compound A to the m-chloroperoxybenzoic acid is 1: 2.
preferably, the reaction temperature in the step (2) is 120 ℃, and the reaction time is 0.25-3 hours.
Preferably, in the step (3), the alkaline aqueous solution is sodium hydroxide, potassium hydroxide or lithium hydroxide aqueous solution, the reaction temperature is 25 ℃, the reaction time is 30 minutes, and the molar ratio of the compound C to the alkali is 1: 2.
preferably, in the step (4), the reaction temperature is 10-40 ℃, the reaction time is 2-20 hours, and the molar ratio of the compound D to the manganese dioxide is 1: 10.
preferably, in the step (5), the temperature is reduced to-78 ℃, then the diethylamino sulfur trifluoride is added, the reaction temperature is 5-40 ℃, the reaction time is 3-30 hours, and the molar ratio of the compound E to the diethylamino sulfur trifluoride is 1: 4.
preferably, in the step (6), the reaction temperature is 50-80 ℃, the reaction time is 0.5-8 hours, and the molar ratio of the compound F to the sodium iodide to the trimethylchlorosilane is 1: 3: 3.
preferably, in the step (7), the reaction temperature is 80-110 ℃, the reaction time is 5-30 hours, the base is N, N-diisopropylethylamine or triethylamine, the catalyst is tris (dibenzylideneacetone) dipalladium, and the molar ratio of the compound G, benzylmercaptan, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene to the base to the catalyst is 1: 1.1: 0.1: 2: 0.02 to 0.1.
Preferably, in the step (8), the reaction temperature is 0-40 ℃, the reaction time is 1-10 hours, and the molar ratio of the compound H to the N-chlorosuccinimide is 1: 4.
the Chinese explanation of the invention: m-CPBA: m-chloroperoxybenzoic acid; ac of2O: acetic anhydride; MeOH: methanol; MnO2: manganese dioxide; DAST: diethylaminosulfur trifluoride; TMSCl: trimethylchlorosilane; xanthphos 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene; AcOH: acetic acid; NCS: n-chlorosuccinimide.
The invention has the beneficial effects that:
the invention provides a synthetic method of 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride for the first time, and provides a synthetic route for preparing 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride; and the reaction condition is mild, the post-treatment has good operability and is easy to control.
Detailed Description
The invention is further illustrated by the following examples, without restricting its scope to these examples. Numerous other changes and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention. In particular, certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve the same or similar results, and reactions may be carried out under conditions outside the preferred ranges, albeit less than optimally. Accordingly, such obvious substitutions and modifications are intended to be included within the scope of the appended claims.
Example 1
(1) Synthesis of Compound B
2-methoxy-3-bromo-6-methylpyridine (20.6g, 100mmol, 1eq.) was dissolved in 300ml of dichloromethane, m-chloroperoxybenzoic acid (35.2g, 200mmol, 2eq.) was added in portions, and the reaction was carried out at 25 ℃ for 16 hours.
After the reaction, the reaction solution was made alkaline with a saturated sodium carbonate solution. The mixture solution of dichloromethane/methanol (volume ratio is 10: 1) is used for extraction, and the organic phase is subjected to column chromatography to obtain 19.4g of beige solid 2-methoxy-3-bromo-6-methylpyridine nitrogen oxide with yield of 89%.
(2) Synthesis of Compound C
2-methoxy-3-bromo-6-methylpyridine nitroxide (19.4g, 89mmol, 1eq.) was dissolved in 160ml acetic anhydride, heated to 120 ℃ and reacted for 40 min.
After the reaction was completed, the reaction mixture was concentrated. 100ml of water and 100ml of ethyl acetate were added, and the mixture was made alkaline with a saturated sodium carbonate solution. The organic phase is concentrated and the residue is chromatographed to give 20.8g of methyl (5-bromo-6-methoxypyridin-2-yl) acetate as an oil in 90% yield.
(3) Synthesis of Compound D
Methyl (5-bromo-6-methoxypyridin-2-yl) acetate (20.8g, 80.1mmol, 1eq.) was dissolved in 200ml methanol. Sodium hydroxide (6.5g, 160.2mmol, 2eq.) was dissolved in 10ml of water, cooled, added dropwise to the above reaction system, and reacted at 25 ℃ for 30 minutes.
After the reaction was completed, the reaction mixture was concentrated. Extraction with dichloromethane and concentration of the organic phase gave 16.2g of white solid (5-bromo-6-methoxypyridin-2-yl) methanol in 93% yield. Directly applied to the next step.
(4) Synthesis of Compound E
(5-bromo-6-methoxypyridin-2-yl) methanol (16.2g, 74.5mmol, 1eq.) was dissolved in 330ml dichloromethane, manganese dioxide (64.8g, 745mmol, 10eq.) was added and the reaction was carried out at 40 ℃ for 8 hours.
After the reaction is finished, cooling. And (3) carrying out suction filtration, washing a filter cake by using dichloromethane, concentrating a filtrate, and carrying out column chromatography to obtain 15g of white solid 5-bromo-6-methoxypyridine-2-formaldehyde with the yield of 93%.
(5) Synthesis of Compound F
5-bromo-6-methoxypyridine-2-carbaldehyde (15g, 69.3mmol, 1eq.) was dissolved in 300ml of dichloromethane and the temperature was reduced to-78 ℃. Diethylaminosulfur trifluoride (44.7g, 277.2mmol, 4eq.) was added dropwise under nitrogen protection. After completion of the dropwise addition, the reaction was carried out at 18 ℃ for 18 hours.
After the reaction was completed, the reaction solution was dropped into ice water and made alkaline with a saturated sodium bicarbonate solution. Extraction is carried out with dichloromethane, the organic phase is concentrated and column chromatography is carried out to obtain 15g of white solid 3-bromo-6- (difluoromethyl) -2-methoxypyridine with the yield of 91%.
(6) Synthesis of Compound G
3-bromo-6- (difluoromethyl) -2-methoxypyridine (15g, 63mmol, 1eq.) was dissolved in 300ml acetonitrile, and sodium iodide (28.4g, 189mmol, 3eq.) and chlorotrimethylsilane (20.5g, 189mmol, 3eq.) were added under nitrogen protection, and the mixture was heated to 80 ℃ for 4 hours.
After the reaction was completed, the reaction mixture was concentrated. Ethyl acetate was added to the concentrated residue, and a saturated sodium bicarbonate solution was made alkaline, and the layers were separated, and the organic phase was concentrated to obtain 13.4g of 3-bromo-6- (difluoromethyl) -2-hydroxypyridine as a dark brown solid with a yield of 95%.
(7) Synthesis of Compound H
3-bromo-6- (difluoromethyl) -2-hydroxypyridine (13.4g, 59.9mmol, 1eq.) was dissolved in 270ml of toluene, and benzylthiol (8.3g, 65.9mmol, 1.1eq.) 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (3.5g, 6mmol, 0.1eq.) N, N-diisopropylethylamine (20ml, 119.8mmol, 2eq.) and tris (dibenzylideneacetone) dipalladium (2.8g, 3mmol, 0.05eq.) were added in this order under nitrogen protection, and the mixture was heated to 110 ℃ for 16 hours.
After the reaction is finished, cooling. 100ml of water was added, extraction was carried out with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography to give 14.4g of 6- (difluoromethyl) -2-hydroxypyridine-3-thiol as a white solid in a yield of 90%.
(8) Synthesis of Compound I
6- (difluoromethyl) -2-hydroxypyridine-3-thiol (14.4g, 53.9mmol, 1eq.) was dissolved in 150ml of acetic acid, and 50ml of water was added, resulting in turbidity. N-chlorosuccinimide (28.8g, 215.6mmol, 4eq.) was added portionwise at 15 ℃ and the reaction was stirred for 4 hours.
After completion of the reaction, 400ml of water was added to the reaction mixture. The organic phase was washed with water and then with saturated sodium bicarbonate solution to alkalinity. After concentration, the mixture was slurried with a mixture of n-hexane/ethyl acetate (volume ratio: 3: 1), filtered, and the filter cake was dried to obtain 11.3g of a white solid, 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride, with a yield of 86%.
1H NMR(d6-DMSO):13.58(s,br,1H),7.90(d,J＝9Hz,1H),7.64(t,J＝54.3Hz,1H),6.67(d, J＝9Hz,1H)。
Example 2
(1) Synthesis of Compound B
2-methoxy-3-bromo-6-methylpyridine (30.9g, 150mmol, 1eq.) was dissolved in 450ml of dichloromethane, m-chloroperoxybenzoic acid (52.8g, 300mmol, 2eq.) was added in portions, and the reaction was carried out at 25 ℃ for 6 hours.
After the reaction, the reaction solution was made alkaline with a saturated sodium carbonate solution. The mixture solution of dichloromethane/methanol (volume ratio is 10: 1) is used for extraction, and 24.2g of beige solid 2-methoxy-3-bromo-6-methylpyridine nitrogen oxide is obtained by column chromatography of an organic phase, with the yield of 74%.
(2) Synthesis of Compound C
2-methoxy-3-bromo-6-methylpyridine nitroxide (24.2g, 111mmol, 1eq.) was dissolved in 200ml acetic anhydride, and the reaction was carried out at 120 ℃ for 2.5 hours.
After the reaction was completed, the reaction mixture was concentrated. 120ml of water and 120ml of ethyl acetate were added, and the mixture was made alkaline with a saturated sodium carbonate solution. The organic phase is concentrated and subjected to column chromatography to give 26.6g of methyl (5-bromo-6-methoxypyridin-2-yl) acetate as an oil in 92% yield.
(3) Synthesis of Compound D
Methyl (5-bromo-6-methoxypyridin-2-yl) acetate (26.6g, 102.1mmol, 1eq.) was dissolved in 280ml methanol. Potassium hydroxide (11.7g, 204.2mmol, 2eq.) was dissolved in 20ml of water, cooled, added dropwise to the reaction system, and reacted at 25 ℃ for 30 minutes.
After the reaction was completed, the reaction mixture was concentrated. Extraction with dichloromethane and concentration of the organic phase gave 20.9g of white solid (5-bromo-6-methoxypyridin-2-yl) methanol in 94% yield. Directly applied to the next step.
(4) Synthesis of Compound E
(5-bromo-6-methoxypyridin-2-yl) methanol (20.9g, 96mmol, 1eq.) was dissolved in 420ml dichloromethane, manganese dioxide (83.5g, 960mmol, 10eq.) was added and the reaction was carried out at 20 ℃ for 18 hours.
After the reaction is finished, cooling. Suction filtration is carried out, a filter cake is washed by dichloromethane, and 18.9g of white solid 5-bromo-6-methoxypyridine-2-formaldehyde is obtained by column chromatography after the filtrate is concentrated, with the yield of 91%.
(5) Synthesis of Compound F
5-bromo-6-methoxypyridine-2-carbaldehyde (18.9g, 87.4mmol, 1eq.) was dissolved in 400ml of dichloromethane and the temperature was reduced to-78 ℃. Diethylaminosulfur trifluoride (56.3g, 349.6mmol, 4eq.) was added dropwise under nitrogen protection. After completion of the dropwise addition, the reaction was carried out at 6 ℃ for 28 hours.
After the reaction was completed, the reaction solution was dropped into ice water and made alkaline with a saturated sodium bicarbonate solution. Extraction with dichloromethane, concentration of the organic phase and column chromatography gave 17.7g of 3-bromo-6- (difluoromethyl) -2-methoxypyridine as a white solid in 85% yield.
(6) Synthesis of Compound G
3-bromo-6- (difluoromethyl) -2-methoxypyridine (17.7g, 74.3mmol, 1eq.) was dissolved in 350ml acetonitrile, and sodium iodide (33.4g, 222.9mmol, 3eq.) and trimethylchlorosilane (24.2g, 222.9mmol, 3eq.) were added under nitrogen protection, and the mixture was heated to 55 ℃ for 7.5 hours.
After the reaction was completed, the reaction mixture was concentrated. Ethyl acetate was added to the concentrated residue, and a saturated sodium bicarbonate solution was made alkaline, and the layers were separated, and the organic phase was concentrated to obtain 12.1g of 3-bromo-6- (difluoromethyl) -2-hydroxypyridine as a dark brown solid in a yield of 73%.
(7) Synthesis of Compound H
3-bromo-6- (difluoromethyl) -2-hydroxypyridine (12.1g, 54.2mmol, 1eq.) was dissolved in 250ml of toluene, and benzylthiol (7.5g, 59.6mmol, 1.1eq.) 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (3.2g, 5.4mmol, 0.1eq.) N, N-diisopropylethylamine (18.1ml, 108.4mmol, 2eq.) and tris (dibenzylideneacetone) dipalladium (1g, 1.1mmol, 0.02eq.) were added in this order under nitrogen protection, and the mixture was heated to 97 ℃ for 6 hours.
After the reaction is finished, cooling. 90ml of water was added, extraction was carried out with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography to give 10.3g of 6- (difluoromethyl) -2-hydroxypyridine-3-thiol as a white solid in a yield of 71%.
(8) Synthesis of Compound I
6- (difluoromethyl) -2-hydroxypyridine-3-thiol (10.3g, 38.5mmol, 1eq.) was dissolved in 120ml of acetic acid, and 40ml of water was added, resulting in turbidity. N-chlorosuccinimide (20.6g, 154mmol, 4eq.) was added portionwise at 38 ℃ and the reaction stirred for 1.5 h.
After completion of the reaction, 300ml of water was added to the reaction mixture. The organic phase was washed with water and then with saturated sodium bicarbonate solution to alkalinity. After concentration, the mixture is pulped by a mixed solution of n-hexane and ethyl acetate (volume ratio is 3: 1), and then is filtered, and a filter cake is dried to obtain 6.8g of white solid 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride with the yield of 72 percent.
1H NMR(d6-DMSO):13.58(s,br,1H),7.90(d,J＝9Hz,1H),7.64(t,J＝54.3Hz,1H),6.67(d, J＝9Hz,1H)。
Example 3
(1) Synthesis of Compound B
2-methoxy-3-bromo-6-methylpyridine (25.7g, 125mmol, 1eq.) was dissolved in 380ml of dichloromethane, and m-chloroperoxybenzoic acid (44g, 250mmol, 2eq.) was added in portions and reacted at 25 ℃ for 25 hours.
After the reaction, the reaction solution was made alkaline with a saturated sodium carbonate solution. The mixture solution of dichloromethane/methanol (volume ratio is 10: 1) is used for extraction, and the organic phase is subjected to column chromatography to obtain 23.7g of beige solid 2-methoxy-3-bromo-6-methylpyridine nitrogen oxide, wherein the yield is 87%.
(2) Synthesis of Compound C
2-methoxy-3-bromo-6-methylpyridine nitroxide (23.7g, 108.8mmol, 1eq.) was dissolved in 200ml acetic anhydride, and the reaction was carried out for 20 minutes at 120 ℃.
After the reaction was completed, the reaction mixture was concentrated. 120ml of water and 120ml of ethyl acetate were added, and the mixture was made alkaline with a saturated sodium carbonate solution. The organic phase is concentrated and column chromatographed to give 23.5g of methyl (5-bromo-6-methoxypyridin-2-yl) acetate as an oil in 83% yield.
(3) Synthesis of Compound D
Methyl (5-bromo-6-methoxypyridin-2-yl) acetate (23.5g, 90.3mmol, 1eq.) was dissolved in 250ml methanol. Lithium hydroxide (4.4g, 180.6mmol, 2eq.) was dissolved in 50ml of water, cooled and added dropwise to the above reaction system, followed by reaction at 25 ℃ for 30 minutes.
After the reaction was completed, the reaction mixture was concentrated. Extraction with dichloromethane and concentration of the organic phase gave 18.1g of white solid (5-bromo-6-methoxypyridin-2-yl) methanol in 92% yield. Directly applied to the next step.
(4) Synthesis of Compound E
(5-bromo-6-methoxypyridin-2-yl) methanol (18.1g, 83mmol, 1eq.) was dissolved in 360ml dichloromethane, manganese dioxide (72.2g, 830mmol, 10eq.) was added and the reaction was carried out at 12 ℃ for 4 hours.
After the reaction is finished, cooling. Suction filtration is carried out, a filter cake is washed by dichloromethane, and 12.9g of white solid 5-bromo-6-methoxypyridine-2-formaldehyde is obtained by column chromatography after the filtrate is concentrated, wherein the yield is 72%.
(5) Synthesis of Compound F
5-bromo-6-methoxypyridine-2-carbaldehyde (12.9g, 59.8mmol, 1eq.) was dissolved in 250ml of dichloromethane and the temperature was reduced to-78 ℃. Diethylaminosulfur trifluoride (38.6g, 239.2mmol, 4eq.) was added dropwise under nitrogen. After completion of the dropwise addition, the reaction was carried out at 38 ℃ for 4 hours.
After the reaction was completed, the reaction solution was dropped into ice water and made alkaline with a saturated sodium bicarbonate solution. Extraction with dichloromethane, concentration of the organic phase and column chromatography gave 11.2g of 3-bromo-6- (difluoromethyl) -2-methoxypyridine as a white solid in 79% yield.
(6) Synthesis of Compound G
3-bromo-6- (difluoromethyl) -2-methoxypyridine (11.2g, 47.2mmol, 1eq.) was dissolved in 230ml acetonitrile, and sodium iodide (21.2g, 141.6mmol, 3eq.) and trimethylchlorosilane (15.4g, 141.6mmol, 3eq.) were added under nitrogen protection, and the mixture was heated to 68 ℃ for 40 minutes.
After the reaction was completed, the reaction mixture was concentrated. Ethyl acetate was added to the concentrated residue, and a saturated sodium bicarbonate solution was made alkaline, and the layers were separated, and the organic phase was concentrated to obtain 8.6g of 3-bromo-6- (difluoromethyl) -2-hydroxypyridine as a dark brown solid in a yield of 81%.
(7) Synthesis of Compound H
3-bromo-6- (difluoromethyl) -2-hydroxypyridine (8.6g, 38.3mmol, 1eq.) was dissolved in 180ml of toluene, and benzylmercaptan (5.3g, 42.1mmol, 1.1eq.) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (2.2g, 3.8mmol, 0.1eq.) and triethylamine (10.7ml, 76.6mmol, 2eq.) and tris (dibenzylideneacetone) dipalladium (3.2g, 3.4mmol, 0.09eq.) were added in this order under nitrogen protection, and the mixture was heated to 85 ℃ for 28 hours.
After the reaction is finished, cooling. 60ml of water was added, extraction was carried out with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography to give 8.4g of 6- (difluoromethyl) -2-hydroxypyridine-3-thiol as a white solid in a yield of 82%.
(8) Synthesis of Compound I
6- (difluoromethyl) -2-hydroxypyridine-3-thiol (8.4g, 31.4mmol, 1eq.) was dissolved in 90ml of acetic acid, and 30ml of water was added, resulting in turbidity. N-chlorosuccinimide (16.8g, 125.6mmol, 4eq.) was added portionwise at 5 ℃ and the reaction was stirred for 10 hours.
After completion of the reaction, 250ml of water was added to the reaction mixture. The organic phase was washed with water and then with saturated sodium bicarbonate solution to alkalinity. After concentration, the mixture is pulped by a mixed solution of normal hexane and ethyl acetate (the volume ratio is 3: 1), the mixture is filtered, and a filter cake is dried to obtain 6g of white solid 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride with the yield of 78 percent.
1H NMR(d6-DMSO):13.58(s,br,1H),7.90(d,J＝9Hz,1H),7.64(t,J＝54.3Hz,1H),6.67(d, J＝9Hz,1H)。
Claims (9)
1. A synthetic method of 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride is characterized by comprising the following steps:
the method comprises the following steps:
(1) dissolving the compound A in dichloromethane, and oxidizing with m-chloroperoxybenzoic acid to obtain a compound B;
(2) reacting the compound B with acetic anhydride to obtain a compound C;
(3) dissolving the compound C in methanol, and hydrolyzing under the action of an alkaline aqueous solution to obtain a compound D;
(4) dissolving the compound D in dichloromethane, and oxidizing with manganese dioxide to obtain a compound E;
(5) dissolving the compound E in dichloromethane, and reacting with diethylaminosulfur trifluoride under the protection of nitrogen to obtain a compound F;
(6) dissolving the compound F in acetonitrile, and reacting with sodium iodide and trimethylchlorosilane under the protection of nitrogen to obtain a compound G;
(7) dissolving the compound G in toluene, adding benzylmercaptan, 4, 5-bis (diphenylphosphine) -9, 9-dimethyl xanthene, alkali and a catalyst, and reacting under the protection of nitrogen to obtain a compound H;
(8) dissolving the compound H in acetic acid, and reacting with N-chlorosuccinimide to obtain a compound I.
2. The method for synthesizing 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride according to claim 1, wherein the reaction temperature in step (1) is 25 ℃, the reaction time is 5-25 hours, and the molar ratio of the compound a to m-chloroperoxybenzoic acid is 1: 2.
3. the method for synthesizing 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride according to claim 1, wherein the reaction temperature in step (2) is 120 ℃ and the reaction time is 0.25-3 hours.
4. The method for synthesizing 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride according to claim 1, wherein the basic aqueous solution in step (3) is an aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide, the reaction temperature is 25 ℃, the reaction time is 30 minutes, and the molar ratio of compound C to the base is 1: 2.
5. the method for synthesizing 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride according to claim 1, wherein the reaction temperature in step (4) is 10 to 40 ℃, the reaction time is 2 to 20 hours, and the molar ratio of the compound D to the manganese dioxide is 1: 10.
6. the method for synthesizing 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride according to claim 1, wherein in the step (5), the temperature is reduced to-78 ℃, then diethylaminosulfur trifluoride is added, the reaction temperature is 5-40 ℃, the reaction time is 3-30 hours, and the molar ratio of the compound E to the diethylaminosulfur trifluoride is 1: 4.
7. the method for synthesizing 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride according to claim 1, wherein the reaction temperature in step (6) is 50 to 80 ℃, the reaction time is 0.5 to 8 hours, and the molar ratio of the compound F to the compound sodium iodide to the trimethylchlorosilane is 1: 3: 3.
8. the method for synthesizing 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride according to claim 1, wherein the reaction temperature in step (7) is 80 to 110 ℃, the reaction time is 5 to 30 hours, the base is N, N-diisopropylethylamine or triethylamine, the catalyst is tris (dibenzylideneacetone) dipalladium, the molar ratio of the compound G, benzylthiol, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, the base, and the catalyst is 1: 1.1: 0.1: 2: 0.02 to 0.1.
9. The method for synthesizing 6- (difluoromethyl) -2-hydroxypyridine-3-sulfonyl chloride according to claim 1, wherein the reaction temperature in step (8) is 0-40 ℃, the reaction time is 1-10 hours, and the molar ratio of compound H to N-chlorosuccinimide is 1: 4.
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