Process for the preparation of substituted sulfonic acid compounds

Abstract

The application relates to a preparation method of a substituted sulfonic acid compound, in particular to a preparation method of 2-fluoro-5-methanesulfonylbenzoic acid. A compound of formula I is prepared through sulfonation reaction of 2-fluoro-5-halobenzoic acid and derivatives thereof with a sulfonation reagent and further through alkylation reaction. A reaction formula is as follows: the preparation method has the advantages of high yield, low raw material cost, short reaction period, mild reaction condition, easy operation, less three wastes and the like, and can realize industrialized production.

Description

TECHNICAL FIELD

[0001] The present application relates to the preparation method of substituted sulfonic acid compounds, in particular to a preparation method of 2-fluoro-5-methanesulfonylbenzoic acid. BACKGROUND

[0002] 2-fluoro-5-methanesulfonylbenzoic acid is an important pharmaceutical intermediate, which is a key intermediate for synthesizing 【4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl】-【5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl】-methanone, as disclosed in international patent document WO2005014563.

[0003] The synthesis method is generally as follows: 2-fluorobenzoic acid is reacted with chlorosulfonic acid, then sodium sulfite is used to reduce the sulfonic acid into sulfinic acid, and then the sulfinic acid is methylated with methyl iodide, and finally the product is obtained by alkaline hydrolysis and acid adjustment. The specific technical scheme is as follows:

[0004]

[0005] Please refer to Chinese patent CN104628679B. However, the process route has the following disadvantages: the total yield of the three-step reaction is 27%, the chlorosulfonic acid is used as the reaction solvent in the first step, which is dangerous, a large amount of three wastes is generated in the post-processing, DMF is used as the solvent in the third step, and the cost of methyl iodide as the methylating agent is high and the toxicity is great, and the post-processing of removing DMF by evaporation is not suitable for industrial production.

[0006] On this basis, another process is disclosed in Chinese patent CN106397312B. The product is prepared by the following steps: 2-fluorobenzoic acid is reacted with chlorosulfonic acid, then sodium sulfite is used to reduce the sulfonic acid into sulfinic acid, and then the sulfinic acid is reacted with sodium chloroacetate, and finally the product is obtained by decarboxylation with sulfuric acid at high temperature. The specific technical scheme is as follows:

[0007]

[0008] The disadvantages of the route are as follows: the total yield of the two-step reaction is 30.3%, the chlorosulfonic acid is used as the reaction solvent in the first step, which is dangerous, a large amount of three wastes is generated in the post-processing, sulfuric acid is used in the second step, and the reaction time is long, and the amount of three wastes in the post-processing is large, which is not suitable for industrial production.

[0009] In view of the disadvantages of the process routes of 2-fluoro-5-methanesulfonylbenzoic acid reported in the prior art, which are not suitable for industrial production, it is necessary to develop a process route with technical advantages to overcome the disadvantages of low yield and unsuitability for industrial production. SUMMARY

[0010] In order to overcome the technical problems existing in the prior art, the present application provides a preparation method of a substituted sulfonic acid compound 2-fluoro-5-methanesulfonylbenzoic acid and its derivatives. In order to achieve the technical purpose of the present application, the technical scheme of the present application is:

[0011] The structural formula of the above-mentioned substituted sulfonic acid compound is as follows:

[0012]

[0013] The present application further provides a preparation method of the above-mentioned compound of formula I, which comprises two types of reactions, i.e. sulfonation reaction and alkylation reaction.

[0014] Specifically, 2-fluoro-5-halobenzoic acid and its derivatives are used as raw materials, and after sulfonation reaction with a sulfonation reagent, further alkylation reaction is carried out to prepare the compound of formula I. The reaction formula is as follows:

[0015]

[0016] The sulfonation reaction is carried out in the presence of a metal catalyst, which can be a nickel catalyst and the like, and is preferably bis(diphenylphosphinylethane) nickel chloride.

[0017] The sulfonation reaction is carried out in the presence of a phase transfer catalyst, which is tetrabutylammonium bromide, 18-crown-6 and the like.

[0018] The sulfonation reagent is potassium pyrosulfite, sodium pyrosulfite and the like.

[0019] The alkylation reaction involves the reaction of the intermediate product of the sulfonation reaction with an alkylation reagent. The alkylation reagent can be iodomethane, dimethyl sulfate, dimethyl carbonate and the like.

[0020] The two-step reaction of the sulfonation reaction and the alkylation reaction can be carried out by "one-pot method".

[0021] The solvent for the "one-pot method" reaction of the present application can be acetonitrile, dioxane, tetrahydrofuran, DMSO, DMF and the like, and is preferably acetonitrile or dioxane.

[0022] The reaction temperature of the "one-pot method" is 10-80°C, and is preferably 75°C.

[0023] A preferred embodiment of the present application is that 2-fluoro-5-methanesulfonylbenzoic acid is prepared by nickel-catalyzed aryl bromide sulfonation reaction and then methylating the methyl group of the methylating reagent using 2-fluoro-5-bromobenzoic acid as the raw material;

[0024]

[0025] The above-mentioned "one-pot" reaction of the present application can also selectively add additives, such as potassium carboxylate, and the most preferred is potassium formate.

[0026] The present application uses 2-fluoro-5-bromobenzoic acid as raw material, and prepares 2-fluoro-5-methanesulfonylbenzoic acid through sulfonation and methylation "one-pot" method, which has high yield, low raw material cost, short reaction period, mild reaction conditions, easy operation, less waste, and can realize industrialized production. DETAILED DESCRIPTION

[0027] The present application is further illustrated in detail by the following examples, but it should be noted that the scope of the present application is not limited by any of these examples.

[0028] The reagents used in the present application can be purchased from the market.

[0029] In the present application, mol represents mole, h represents hour, g represents gram, L represents liter, and ml represents milliliter.

[0030] Example 1: synthesis of 2-fluoro-5-methanesulfonylbenzoic acid using methyl iodide as a methyl reagent

[0031] A 1L flask was added with 2-fluoro-5-bromobenzoic acid (50.00g 0.23mol), potassium formate (38.70g 0.46mol), 1,2-bis(diphenylphosphino)ethane nickel chloride (12.14g 0.023mol), potassium pyrosulfite (153.40g 0.69mol), tetrabutylammonium bromide (51.90g 0.16mol), and acetonitrile (500ml 10Vol) under stirring, and after nitrogen replacement, the temperature was increased to 75℃ for 20h, and then decreased to 20℃. Iodomethane (81.62g 0.575mol) was added, and the temperature was increased to 75℃ for 2h until the raw material was completely reacted. The temperature was decreased to 15℃, 6mol hydrochloric acid was added to adjust the pH value to 1, and ethyl acetate was added for stirring and extraction for 3 times (200ml 4Vol each time). The ethyl acetate phase was concentrated and dried, and then 40% potassium hydroxide aqueous solution (150ml 3Vol) was added for stirring for 2h, and 6mol hydrochloric acid was added to adjust the pH value to 2 to precipitate the solid which was filtered. The solid was further slurried in acetone (3Vol) for 10h to obtain white 2-fluoro-5-methanesulfonylbenzoic acid 41.35g, with a yield of 83%.

[0032] Example 2: A flask containing 2-fluoro-5-bromobenzoic acid (50.00 g 0.23 mol), potassium formate (38.70 g 0.46 mol), 1,2-bis(diphenylphosphino)ethane nickel chloride (12.14 g 0.023 mol), potassium pyrosulfite (153.40 g 0.69 mol), tetrabutylammonium bromide (51.90 g 0.16 mol) and acetonitrile (500 ml 10 Vol) was stirred and opened, iodomethane (81.62 g 0.575 mol) was added, after nitrogen replacement, the temperature was raised to 75 °C and the reaction was carried out for 24 h until the starting material was completely consumed. The temperature was lowered to 15 °C and the pH was adjusted to 1 with 6 mol hydrochloric acid. Ethyl acetate (200 ml 4 Vol) was added and the mixture was stirred and extracted three times. The ethyl acetate phase was concentrated to dryness and then stirred with 40% aqueous potassium hydroxide solution (150 ml 3 Vol) for 2 h. The pH was adjusted to 2 with 6 mol hydrochloric acid and the solid was filtered. The solid was slurried with acetone (3 Vol) for 10 h to give white 2-fluoro-5-methanesulfonylbenzoic acid 39.85 g in 80% yield.

[0033] Following a similar procedure to Example 2 above, 2-fluoro-5-methanesulfonylbenzoic acid was synthesized using other methylating reagents. The yields are shown in Table 1.

[0034] Table 1. Yields of 2-fluoro-5-methanesulfonylbenzoic acid

[0035]

[0036] Following a similar procedure to Example 2 above, 2-fluoro-5-methanesulfonylbenzoic acid was synthesized using dimethyl sulfate as the methylating reagent and varying other conditions. The yields are shown in Table 2.

[0037] Table 2. Yields of 2-fluoro-5-methanesulfonylbenzoic acid

[0038]

[0039] (0.56% moisture in potassium formate in 5a, 3.26% moisture in potassium formate in 7b)

[0040] Structural information for 2-fluoro-5-methanesulfonylbenzoic acid

[0041]

[0042] 1H NMR (400 MHz, DMSO-d6): δ 13.8 (br s, 1H), 8.37 (m, 1H), 8.18 (m, 1H), 7.64 (m, 1H), 3.29 (s, 3H). MS (EI) m / e: 217.0 (M-H) -

[0043] Example 3: Synthesis of methyl 2-fluoro-5-methanesulfonylbenzoate 1L A flask was charged with methyl 2-fluoro-5-bromobenzoate (50.00 g 0.216 mol), potassium formate (36.35 g 0.46 mol), 1,2-bis(diphenylphosphino)ethane nickel chloride (11.40 g 0.023 mol), potassium pyrosulfite (144.09 g 0.69 mol), tetrabutylammonium bromide (48.75 g 0.16 mol) and acetonitrile (500 ml 10 Vol) under stirring and nitrogen replacement, then heated to 75 °C for 20 h. The reaction mixture was cooled to 20 °C, and iodomethane (76.67 g 0.575 mol) was added. The reaction mixture was heated to 75 °C for 2 h until the starting material was consumed. The reaction mixture was cooled to 15 °C and adjusted to pH 1 with 6 mol / L hydrochloric acid. The reaction mixture was extracted with ethyl acetate (200 ml 4 Vol) three times. The ethyl acetate phase was concentrated to dryness. The residue was stirred with 40% aqueous potassium hydroxide solution (150 ml 3 Vol) for 2 h, and adjusted to pH 2 with 6 mol / L hydrochloric acid. The solid was filtered and slurried with acetone (3 Vol) for 10 h to give white methyl 2-fluoro-5-methanesulfonylbenzoate 43.49 g in 82% yield.

[0044]

[0045] 1 H NMR (400 MHz, DMSO-d6): δ 8.21 (m, 1H), 8.03 (m, 1H), 7.53 (m, 1H), 3.98 (s, 3H), 3.28 (s, 3H). MS (EI) m / e: 233.0 (M+H) +

[0046] While the application has been fully described in connection with the preferred embodiments, various modifications and substitutions can be made by those skilled in the art without departing from the spirit and scope of the application, as described in the appended claims.

Claims

1. A method for preparing a substituted sulfonic acid compound of formula I, characterized in that, It is prepared by sulfonation of 2-fluoro-5-halobenzoic acid with a sulfonating agent, followed by methylation. ， Where X is a halogen, R1 is a hydroxyl group, methyl ester, ethyl ester, benzyl ester, amide, aromatic ester, cycloalkyl ester, and R2 is a methyl group; The sulfonation reaction is carried out in the presence of a metal catalyst, which is nickel chloride of 1,2-bis(diphenylphosphine)ethane. The methylating agent is iodomethane, dimethyl sulfate, or dimethyl carbonate.

2. The preparation method according to claim 1, characterized in that, The two-step reactions of sulfonation and methylation are carried out in a "one-pot" process.

3. The preparation method according to claim 2, characterized in that, The structural formula of the intermediate compound in the "one-pot" reaction is as follows: 。 4. The preparation method according to claim 1, characterized in that, X represents bromine or iodine.

5. The preparation method according to claim 1 or 2, characterized in that, The sulfonating agent is potassium metabisulfite or sodium metabisulfite.

6. The preparation method according to claim 1, 2 or 3, characterized in that, The sulfonation reaction is carried out in the presence of a phase transfer catalyst.

7. The preparation method according to claim 6, characterized in that, The phase transfer catalyst is tetrabutylammonium bromide or 18-crown ether-6.

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