A method for improving the stability of aromatic difluoromethyl compounds during preparation and use

Abstract

The invention discloses a method for improving the stability of aromatic difluoromethyl compounds during preparation and use, specifically: by adding an inorganic fluoride salt to a reaction system during the use of an aromatic difluoromethyl compound having an electron-donating group on a benzene ring, the stability of the aromatic difluoromethyl compound under a reaction state can be effectively improved, thereby increasing the yield of the target product; in addition, by adding an organic fluoride salt to the reaction system during the preparation of an aromatic difluoromethyl compound having an electron-withdrawing group or containing a pyridyl group on a benzene ring, the yield of the target product aromatic difluoromethyl compound can be effectively increased. The above method is simple and easy to operate, and the required fluoride salt is cheap, easy to obtain and easy to separate, which can effectively improve the stability of the aromatic difluoromethyl compound under preparation or reaction state, improve the yield of the target product, and improve the functional group tolerance of the aromatic difluoromethyl compound, which has important scientific significance and use value in organic synthesis.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for improving the stability of an aromatic difluoromethyl compound during preparation and use. Background Art

[0002] The introduction of fluorine atoms will change the lipophilicity, hydrogen bonding, bioavailability and other properties of the compound. Introducing fluorine atoms into drug structures is a common method of drug design. About 20%-25% of drug molecules contain fluorine atoms. Common fluorine-containing functional groups include fluorine atoms F, trifluoromethyl CF3, difluoromethyl CF2, trifluoromethoxy OCF3, etc. Fluorine-containing drug molecules are an important direction for the future development of new drugs.

[0003] Difluoromethyl can be divided into two categories: those directly connected to aromatic groups and those directly connected to aliphatic groups. Among them, difluoromethyl directly connected to aromatic groups is more widely used. This type of aromatic difluoromethyl compound is usually obtained by reacting aromatic aldehydes and fluorination reagents such as diethylaminosulfur trifluoride (DAST) in dichloromethane (DCM). The general reaction formula is:

[0004]

[0005] Due to the different properties of the substituent R on the aromatic compound, the stability of the difluoromethyl group in the product will also be greatly different. When the substituent R is an electron donating group (EDG), the stability of the product is very poor. For example, when 4-difluoromethylaniline is dissolved in dichloromethane containing a trace amount of water, it will hydrolyze into 4-aminobenzaldehyde. The reaction formula is as follows:

[0006]

[0007] For example, the difluoromethyl indole derivative 6-difluoromethylindole will quickly hydrolyze to 6-formyl indole in an aqueous solution with Ph>13 (Tetrahedron Letters, 30, 1989, 6117-6120).

[0008]

[0009] When the substituent R is an electron withdrawing group (EWG), although the stability of the difluoromethyl group in the product molecule to water will be greatly improved, its stability to other nucleophiles will be reduced to a certain extent. For example, when 4-pyridinecarboxaldehyde or 4-nitrobenzaldehyde is difluoromethylated with DAST, diethylamine is easily obtained as a byproduct replacing fluorine. This not only reduces the reaction yield, but also introduces byproducts that are difficult to separate, which greatly limits the difluoromethylation of this type of substrate.

[0010]

[0011] In summary, for aromatic difluoromethyl compounds, whether the substituent is EDG or EWG, there are many uncertainties in the stability of the compound, and the aromatic rings in drug molecules are often connected to various types of substituents, which undoubtedly limits the introduction of difluoromethyl and the subsequent reactions of the compound to a large extent. As an important functional group in drug molecules, the difluoromethyl group must not only maintain the molecular structure of the compound but also improve its stability. This problem has long troubled chemists. Summary of the invention

[0012] The technical problem to be solved by the present invention is to provide a method for improving the stability of aromatic difluoromethyl compounds during preparation and use, by adding fluoride salts during the preparation or use of aromatic difluoromethyl compounds, the yield of the target product with the aromatic difluoromethyl compounds as reactants or products is effectively improved.

[0013] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0014] The present invention provides a method for improving the stability of an aromatic difluoromethyl compound during preparation and use. During the preparation or use of the aromatic difluoromethyl compound, a fluoride salt is added to the reaction system; the aromatic difluoromethyl compound has the following general structural formula:

[0015]

[0016] Among them, Ar is R1 is an electron donating group or an electron withdrawing group, and R2 is H or halogen.

[0017] Furthermore, the electron donating group includes amino, alkoxy, alkenyl, but is not limited to the above groups; amino, alkoxy, alkenyl and other strong electron donating substituents having lone pairs of electrons or π electrons can be conjugated with the large π bond on the benzene ring, increasing the electron cloud density of the benzene ring, thereby producing an electron donating effect on the benzene ring.

[0018] Furthermore, the electron-withdrawing group includes nitro, cyano, and halogen, but is not limited to the above groups; nitro, cyano, and halogen all have induced electron-withdrawing ability, and nitro also has conjugated electron-withdrawing ability. When such substituents are connected to the benzene ring, the electron cloud density on the benzene ring can be reduced.

[0019] Furthermore, the fluoride salt is an inorganic fluoride salt and / or an organic fluoride salt.

[0020] Furthermore, the inorganic fluoride salt includes at least one of potassium fluoride, cesium fluoride, and antimony fluoride, but is not limited to the inorganic fluoride salts listed above, and any inorganic fluoride salt that can play the same or similar role is applicable.

[0021] Furthermore, the organic fluoride salt includes tetrabutylammonium fluoride and hexadecyltrimethylammonium fluoride, but is not limited to the organic fluoride salts listed above, and any organic fluoride salt that can play the same or similar role is applicable.

[0022] Furthermore, in the process of using the aromatic difluoromethyl compound, an inorganic fluoride salt is added to the reaction system; R1 in the aromatic difluoromethyl compound is an electron-donating group.

[0023] When the aromatic group in the aromatic difluoromethyl compound is a phenyl group substituted with an electron-donating group, the aromatic difluoromethyl compound has poor stability and is very prone to hydrolysis in a water-containing environment, and the corresponding difluoromethyl group is hydrolyzed into an aldehyde group. In the present invention, an inorganic fluoride salt is introduced to fill the solution with fluoride ions. The high concentration of fluoride ions can effectively inhibit the nucleophilic attack of water molecules on the difluoromethyl group, thereby improving the stability of the aromatic difluoromethyl compound and further improving the yield of the target product.

[0024] Furthermore, the molar ratio of the aromatic difluoromethyl compound to the inorganic fluoride salt is 1:10 to 20, for example, 1:10, 1:12, 1:14, 1:15, 1:17, 1:18, 1:20, etc., but is not limited to the ratios listed above.

[0025] In some preferred embodiments, when the aromatic difluoromethyl compound is 4-difluoromethylaniline, 4-difluoromethylaniline is reacted with 4-methylbenzenesulfonyl chloride in the presence of an acid binding agent, an inorganic fluoride salt and a solvent to prepare the product N-(4'-difluoromethylphenyl)-4-methylbenzenesulfonamide.

[0026] Furthermore, in the process of preparing the aromatic difluoromethyl compound, an organic fluoride salt is added to the reaction system; wherein Ar in the aromatic difluoromethyl compound is R1 is an electron withdrawing group, and R2 is H or halogen.

[0027] When preparing an aromatic difluoromethyl compound whose aryl group is a phenyl or pyridyl group substituted with an electron-withdrawing group, an organic fluoride salt is added to a solvent (especially an aprotic solvent) to maintain a high concentration of fluoride ions in the reaction system, thereby effectively increasing the yield of the aromatic difluoromethyl compound.

[0028] Furthermore, the molar ratio of the aromatic dimethyl compound to the organic fluoride salt is 1:1 to 5, such as 1:1, 1:2, 1:3, 1:4, 1:5, etc., but is not limited to the ratios listed above.

[0029] Furthermore, the preparation of the aromatic difluoromethyl compound is specifically as follows: Ar-CHO is reacted with diethylaminosulfur trifluoride in the presence of an organic fluoride salt and a solvent to prepare the aromatic difluoromethyl compound; Ar in Ar-CHO is R1 is an electron withdrawing group, and R2 is H or halogen.

[0030] Further, Ar-CHO, an organic fluoride salt and a solvent are added to a reaction device, diethylaminosulfur trifluoride is added dropwise in an ice-water bath, and after the addition is completed, the mixture is stirred at 20 to 30° C. for 2 to 4 hours, and the reaction is quenched with a sodium bicarbonate solution. After multiple extractions, the organic phases are combined and dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation to obtain a crude product; the crude product is purified by column chromatography to obtain a product aromatic difluoromethyl compound.

[0031] In some preferred embodiments, the Ar-CHO is 3-chloro-4-pyridinecarboxaldehyde or 4-nitrobenzaldehyde.

[0032] Furthermore, the solvent is one or more of dichloromethane, N,N-dimethylformamide, acetonitrile and water.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] 1. The present invention effectively improves the stability of the aromatic difluoromethyl compound in the preparation or reaction state by introducing a fluoride salt in the process of preparing or using the aromatic difluoromethyl compound, and the yield of the corresponding target product is significantly improved. For example, in the absence of a fluoride salt, the target product N-(4'-difluoromethylphenyl)-4-methylbenzenesulfonamide is almost not obtained by reacting 4-difluoromethylaniline with 4-methylbenzenesulfonyl chloride, but in the presence of potassium fluoride, the yield of the target product is as high as 67%; the yield of the product 2-chloro-4-difluoromethylpyridine is only 48% when 3-chloro-4-pyridinecarboxaldehyde reacts with diethylaminotrifluoride, but in the presence of tetrabutylammonium fluoride, the yield is increased to 81%; the yield of the direct reaction of 4-nitrobenzaldehyde with diethylaminosulfur trifluoride is 79%, but in the presence of tetrabutylammonium fluoride, the yield is as high as 95%.

[0035] 2. The present invention improves the stability of the aromatic difluoromethyl compound during the preparation and use process through the above method, which not only effectively improves the yield of the target product, but also increases the functional group tolerance of the aromatic difluoromethyl compound when participating in the reaction, which is conducive to promoting new applications of the aromatic difluoromethyl compound in chemical synthesis.

[0036] 3. The fluoride salt used to improve the stability of the aromatic difluoromethyl compound during preparation and use is cheap, easily available and easy to separate, does not affect the purity of the product, and is suitable for industrial production. DETAILED DESCRIPTION

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. The terms used herein in the specification of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items. The term "includes" or "comprising" described in the present invention means that it may include or contain other components in addition to the components described. The term "includes" or "comprising" described in the present invention may also be replaced by the closed form "for" or "consisting of..."

[0038] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0039] Example 1

[0040] This embodiment relates to the preparation of N-(4'-difluoromethylphenyl)-4-methylbenzenesulfonamide, using 4-difluoromethylaniline and 4-methylbenzenesulfonyl chloride as reactants, reacting in the presence of solvent dichloromethane (DCM), KF and triethylamine, and the reaction equation is as follows:

[0041]

[0042] The specific operations are as follows:

[0043] In a 50mL round-bottom flask equipped with a magnetic stirrer, add 4-difluoromethylaniline (143.1mg, 1mmol), 4-methylbenzenesulfonyl chloride (228.8mg, 1.2mmol), KF (580mg, 10mmol) and DCM (10mL), place the round-bottom flask in an ice-water bath, add triethylamine (Et3N, 121.4mg, 1.2mmol), stir at room temperature for 4h, then add water (10mL), separate the liquids, extract the aqueous phase with DCM (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain a crude product. The crude product is purified by column chromatography (n-hexane: ethyl acetate = 10:1) to obtain the product N-(4'-difluoromethylphenyl)-4-methylbenzenesulfonamide (200mg, 0.67mmol, yield: 67%). 1 H NMR (400MHz, CDCl3): δ (ppm) = 10.11 (br, 1H), 7.76 (d, 2H), 7.45 (d, 2H), 7.34 (d, 2H), 7.15 (d, 2H), 6.45 (t, 3H), 2.40 (s, 3H).

[0044] Example 2

[0045] This embodiment relates to the preparation of 2-chloro-4-difluoromethylpyridine, using 3-chloro-4-pyridinecarboxaldehyde and diethylaminosulfur trifluoride (DAST) as reactants, reacting in the presence of solvent dichloromethane (DCM) and tetrabutylammonium fluoride, and the reaction equation is as follows:

[0046]

[0047] The specific operations are as follows:

[0048] In a 250mL round-bottom flask equipped with a magnetic stirrer, add 3-chloro-4-pyridinecarboxaldehyde (14.2g, 100mmol), tetrabutylammonium fluoride (26.1g, 100mol) and DCM (100mL), place the round-bottom flask in an ice-water bath, then add DAST (24.2g, 150mmol) dropwise, stir at room temperature for 2h, quench the reaction with sodium bicarbonate solution, extract with DCM (100mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain a crude product. The crude product is purified by column chromatography (n-hexane: ethyl acetate = 100:1) to obtain the product 2-chloro-4-difluoromethylpyridine (13.2g, 81mmol, yield: 81%). 1 H NMR (400MHz, CDCl3): δ (ppm) = 8.51 (d, 1H), 7.45 (s, 1H), 7.34 (d, 1H), 6.61 (t, 1H).

[0049] Example 3

[0050] This embodiment relates to the preparation of 4-difluoromethylnitrobenzene, using 4-nitrobenzaldehyde and diethylaminosulfur trifluoride (DAST) as reactants, reacting in the presence of solvent dichloromethane (DCM) and tetrabutylammonium fluoride, and the reaction equation is as follows:

[0051]

[0052] The specific operations are as follows:

[0053] In a 250mL round-bottom flask equipped with a magnetic stirrer, add 4-nitrobenzaldehyde (15.1g, 100mmol), tetrabutylammonium fluoride (26.1g, 100mol) and DCM (100mL), place the round-bottom flask in an ice-water bath, then add DAST (24.2g, 150mmol) dropwise, stir at room temperature for 2h, quench the reaction with sodium bicarbonate solution, extract with DCM (100mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain a crude product. The crude product is purified by column chromatography (n-hexane: ethyl acetate = 50:1) to obtain the product 4-difluoromethylnitrobenzene (16.5g, 95mmol, yield: 95%). 1 H NMR (400MHz, CDCl3): δ (ppm) = 8.33 (d, 2H), 7.72 (d, 2H), 6.75 (t, 1H).

[0054] Comparative Example 1

[0055] This comparative example involves the preparation of N-(4'-difluoromethylphenyl)-4-methylbenzenesulfonamide, using 4-difluoromethylaniline and 4-methylbenzenesulfonyl chloride as reactants, reacting in the presence of solvent dichloromethane (DCM) and triethylamine. The only difference from Example 1 is that KF is not added.

[0056] The specific operations are as follows:

[0057] In a 50mL round-bottom flask equipped with a magnetic stirrer, add 4-difluoromethylaniline (143.1mg, 1mmol), 4-methylbenzenesulfonyl chloride (228.8mg, 1.2mmol) and DCM (10mL), place the round-bottom flask in an ice-water bath, then add Et3N (121.4mg, 1.2mmol), stir at room temperature for 4h, add water (10mL), separate the liquids, extract the aqueous phase with DCM (10mL×3), combine the organic phases, TLC shows that there are only a few product spots in the organic phase, and a large amount of hydrolysis impurities (4-difluoromethylbenzaldehyde) are generated. The product has no meaning of purification and the reaction basically fails.

[0058] Comparative Example 2

[0059] This comparative example relates to the preparation of N-(4'-difluoromethylphenyl)-4-methylbenzenesulfonamide, using 4-difluoromethylaniline and 4-methylbenzenesulfonyl chloride as reactants, reacting in the presence of solvent dichloromethane (DCM), tetrabutylammonium fluoride and triethylamine, and the only difference from Example 1 is that tetrabutylammonium fluoride is used instead of KF.

[0060] The specific operations are as follows:

[0061] In a 50mL round-bottom flask equipped with a magnetic stirrer, add 4-difluoromethylaniline (143.1mg, 1mmol), 4-methylbenzenesulfonyl chloride (228.8mg, 1.2mmol), tetrabutylammonium fluoride (2.61g, 10mmol) and DCM (10mL), place the round-bottom flask in an ice-water bath, then add Et3N (121.4mg, 1.2mmol), stir at room temperature for 4h, add water (10mL), separate the liquids, extract the aqueous phase with DCM (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain a crude product. The crude product is purified by column chromatography (n-hexane: ethyl acetate = 10:1) to obtain the product N-(4'-difluoromethylphenyl)-4-methylbenzenesulfonamide (38.6mg, 0.13mmol, yield: 13%).

[0062] Comparative Example 3

[0063] This comparative example relates to the preparation of 2-chloro-4-difluoromethylpyridine, using 3-chloro-4-pyridinecarboxaldehyde and diethylaminosulfur trifluoride (DAST) as reactants, and reacting in the presence of a solvent, dichloromethane (DCM). The only difference from Example 2 is that no tetrabutylammonium fluoride is added.

[0064] The specific operations are as follows:

[0065] In a 250mL round-bottom flask equipped with a magnetic stirrer, add 3-chloro-4-pyridinecarboxaldehyde (14.2g, 100mmol) and DCM (100mL), place the round-bottom flask in an ice-water bath, then add DAST (24.2g, 150mmol) dropwise, stir at room temperature for 2h after the addition is complete, quench the reaction with sodium bicarbonate solution, extract with DCM (100mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain a crude product. The crude product is purified by column chromatography (n-hexane: ethyl acetate = 100:1) to obtain the product 2-chloro-4-difluoromethylpyridine (7.8g, 48mmol, yield: 48%).

[0066] Comparative Example 4

[0067] This comparative example relates to the preparation of 2-chloro-4-difluoromethylpyridine, using 3-chloro-4-pyridinecarboxaldehyde and diethylaminosulfur trifluoride (DAST) as reactants, and reacting in the presence of solvent dichloromethane (DCM) and KF. The only difference from Example 2 is that KF is used instead of tetrabutylammonium fluoride.

[0068] In a 250mL round-bottom flask equipped with a magnetic stirrer, add 3-chloro-4-pyridinecarboxaldehyde (14.2g, 100mmol), KF (5.8g, 100mol) and DCM (100mL), place the round-bottom flask in an ice-water bath, then add DAST (24.2g, 150mmol) dropwise, stir at room temperature for 2h, quench the reaction with sodium bicarbonate solution, extract with DCM (100mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain a crude product. The crude product is purified by column chromatography (n-hexane: ethyl acetate = 100:1) to obtain the product 2-chloro-4-difluoromethylpyridine (9.3g, 57mmol, yield: 57%).

[0069] Comparative Example 5

[0070] This comparative example relates to the preparation of 4-difluoromethylnitrobenzene, using 4-nitrobenzaldehyde and diethylaminosulfur trifluoride (DAST) as reactants, reacting in the presence of a solvent, dichloromethane (DCM). The only difference from Example 3 is that no tetrabutylammonium fluoride is added.

[0071] In a 250mL round-bottom flask equipped with a magnetic stirrer, add 4-nitrobenzaldehyde (15.1g, 100mmol), tetrabutylammonium fluoride (26.1g, 100mol) and DCM (100mL), place the round-bottom flask in an ice-water bath, then add DAST (24.2g, 150mmol) dropwise, stir at room temperature for 2h, quench the reaction with sodium bicarbonate solution, extract with DCM (100mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain a crude product. The crude product is purified by column chromatography (n-hexane: ethyl acetate = 50:1) to obtain the product 4-difluoromethylnitrobenzene (13.7g, 79mmol, yield: 79%).

[0072] The products and yields prepared in the above examples and comparative examples are shown in the following table:

[0073] Table 1

[0074]

[0075] As shown in Table 1, Examples 1 to 3 effectively improve the yield of the corresponding target product by introducing fluoride salts during the preparation (Examples 2 and 3) or use (Example 1) of aromatic difluoromethyl compounds. In the process of preparing N-(4'-difluoromethylphenyl)-4-methylbenzenesulfonamide by reacting 4-difluoromethylaniline with 4-methylbenzenesulfonyl chloride, the effect of introducing KF is better than that of tetrabutylammonium fluoride; and in the process of preparing the corresponding aromatic difluoromethyl compounds by reacting 3-chloro-4-pyridinecarboxaldehyde with diethylaminosulfur trifluoride, the yield of the reaction product is greatly improved after the introduction of fluoride salts, and the improvement effect of tetrabutylammonium fluoride is significantly better than that of KF; at the same time, tetrabutylammonium fluoride also shows a good yield improvement effect in the preparation of 4-difluoromethylnitrobenzene.

[0076] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. A method for improving the stability of an aromatic difluoromethyl compound during use, characterized in that: In the process of using the aromatic difluoromethyl compound, a fluoride salt is added to the reaction system; the fluoride salt is an inorganic fluoride salt, and the inorganic fluoride salt is at least one of potassium fluoride, cesium fluoride, and antimony fluoride; the feeding molar ratio of the aromatic difluoromethyl compound to the inorganic fluoride salt is 1:10-20; the reaction system contains water; the aromatic difluoromethyl compound has the following general structural formula: ， Among them, Ar is , R1 is an electron donating group.

2. The method according to claim 1, characterized in that The electron donating group is an amino group, an alkoxy group or an alkenyl group.

3. The method according to claim 1, characterized in that When the aromatic difluoromethyl compound is 4-difluoromethylaniline, 4-difluoromethylaniline is reacted with 4-methylbenzenesulfonyl chloride in the presence of an acid-binding agent, an inorganic fluoride salt and a solvent to prepare the product N-(4'-difluoromethylphenyl)-4-methylbenzenesulfonamide.

4. A method for improving the stability of an aromatic difluoromethyl compound during preparation, characterized in that: The preparation of the aromatic difluoromethyl compound is specifically as follows: Ar-CHO is reacted with diethylaminosulfur trifluoride in the presence of an organic fluoride salt and a solvent to prepare the aromatic difluoromethyl compound; the Ar-CHO is 3-chloro-4-pyridinecarboxaldehyde or 4-nitrobenzaldehyde; the organic fluoride salt is tetrabutylammonium fluoride; and the solvent is dichloromethane.

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