A process for the preparation of 2-chlorosulfonyl-4-methanesulfonamidomethyl benzoic acid methyl ester

Abstract

The present application relates to a kind of 2-chlorosulfonyl-4-methanesulfonamide methylbenzoic acid methyl ester preparation method, which is by diazotization reaction first, then sulfonylation reaction.The present application selects copper chloride as catalyst, compared with cuprous chloride, it is simple and easy to operate, green and environmental protection, less feeding amount, high catalytic efficiency.The present application uses sodium hypochlorite as chloro-oxidizing agent, can promote the reaction to proceed, accelerate the generation of sulfonyl chloride, make sulfonic acid intermediate quickly convert into sulfonyl chloride, greatly shorten reaction time, to improve reaction yield and purity.The preparation method of the present application, the final yield can be increased by more than 20%, the purity of product crude product can reach more than 96%, without complex post-treatment process, save cost and equipment investment, reduce the amount of three wastes, suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and in particular to a method for preparing methyl 2-chlorosulfonyl-4-methanesulfonamide methyl benzoate. Technical Background

[0002] 2-Chlorosulfonyl-4-methanesulfonamide methyl benzoate, molecular formula: C 10 H 12 ClNO6S2.

[0003]

[0004] 2-Chlorosulfonyl-4-methanesulfonamide methyl benzoate is a key intermediate in the preparation of the herbicide mesulfanilamide, and the main synthetic methods are as follows:

[0005] Sodium methanethiol method (patent CN 109879817 A): Methyl 2-nitro-4-cyanobenzoate reacts with sodium methanethiol to produce methyl sulfide. The cyano group is reduced to a methylene amino group, which then reacts with methanesulfonyl chloride, ultimately chlorinated to produce methyl 2-chlorosulfonyl-4-methanesulfonamide methyl benzoate. This route uses sodium methanethiol in the synthesis, and the post-processing generates an excess of very foul-smelling methanethiol gas. Furthermore, the yield of this step is low, and the final chlorination step uses chlorine gas, which is a key hazardous chemical under national regulation and is unsuitable for industrial production.

[0006]

[0007] The cuprous chloride catalytic method (patent CN 1443159 A) uses methyl 2-amino-4-methanesulfonamide methyl benzoate as the starting material, which undergoes diazotization and sulfonation to obtain methyl 2-chlorosulfonyl-4-methanesulfonamide methyl benzoate. However, literature reports that the sulfonation reaction is carried out in the presence of CuCl and SO2, with simultaneous chlorination and sulfonation, and the yield is 63%. This method still has significant shortcomings. Some of the product obtained by this process remains in the organic phase, a large amount of product precipitates from the solvent toluene, and the product decomposes upon contact with water, generating a large amount of impurities. The reaction rate is slow and incomplete, with some unreacted intermediates, resulting in a low overall yield. The product exists simultaneously in both the aqueous and organic phases, and a large amount of impurities are generated during the reaction, making post-treatment complex and resulting in a significant amount of waste. Summary of the Invention

[0008] The purpose of this invention is to solve the problems of high impurities and low yield in the above-mentioned process, and to provide a method for preparing methyl 2-chlorosulfonyl-4-methanesulfonamide methyl benzoate with high yield and high purity.

[0009] To achieve the above objectives, the technical solution provided in this application is as follows:

[0010] A method for preparing methyl 2-chlorosulfonyl-4-methanesulfonamide methyl benzoate includes the following steps:

[0011] (1) Diazotization reaction: The aqueous solution of methyl 2-amino-4-methanesulfonamide methyl benzoate was stirred and heated to 35-42℃. Hydrochloric acid solution was added dropwise and kept at the temperature for 0.5h. The temperature was then lowered to 0-5℃ and sodium nitrite aqueous solution was slowly added dropwise until the reaction was completed, thus obtaining a diazonium salt solution.

[0012]

[0013] (2) Sulfonation reaction: Methyl isobutyl ketone and phase transfer catalyst are mixed to obtain mixture 1; sulfur dioxide is dissolved in mixture 1 to obtain mixture 2; copper chloride with a molar equivalent of 0.05-0.15 relative to methyl 2-amino-4-methanesulfonamide methyl benzoate is added to mixture 2, and the reaction is kept at a constant temperature to obtain mixture 3; the diazonium salt reaction solution prepared in step (1) is slowly added dropwise to mixture 3 to obtain mixture 4; sodium hypochlorite aqueous solution is slowly added dropwise to mixture 4; after the addition is complete, the mixture is stirred evenly and allowed to stand, the aqueous layer is separated, the methyl isobutyl ketone in the organic layer is evaporated, xylene is added, crystallization is performed, centrifugation is performed, and drying is performed to obtain the product;

[0014]

[0015] In the reaction, the molar ratio of methyl 2-amino-4-methanesulfonamide methyl benzoate to sodium hypochlorite is 1:1.5-3.

[0016] The phase transfer catalyst is selected from trioctylmethylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, benzalkonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride; more preferably, it is trioctylmethylammonium chloride, benzalkonium chloride, or a mixture thereof.

[0017] In the reaction, the molar ratio of methyl isobutyl ketone to phase transfer catalyst is 1:0.03.

[0018] This invention incorporates a phase-transfer catalyst, allowing the reaction to occur within the same phase, ensuring thorough contact between reactants and a complete reaction. The use of methyl isobutyl ketone (Methyl isobutyl ketone) as the reaction solvent overcomes the problem of product precipitation and decomposition upon contact with water when using toluene as the solvent. In toluene, the product has low solubility, leading to continuous precipitation into the aqueous phase during the reaction, partial decomposition upon contact with water, and the generation of numerous impurities, resulting in a decreased product yield. In contrast, the product exhibits high solubility in Methyl isobutyl ketone, and the presence of the phase-transfer catalyst ensures sufficient contact during the reaction. The product is completely dissolved in Methyl isobutyl ketone, ultimately existing only in the organic phase, thus avoiding the problem of decomposition upon contact with water. This process reduces post-processing steps such as aqueous phase extraction and product purification compared to traditional methods. The crude product can meet industrial production requirements without purification, and the solvent Methyl isobutyl ketone is easily recovered and reused, with a recovery rate exceeding 85%, significantly reducing waste, equipment investment, and raw material costs.

[0019] This invention uses copper chloride as a catalyst, which is simpler to operate, more environmentally friendly, requires less feed, and has higher catalytic efficiency compared to cuprous chloride. Since cuprous chloride is a solid, it is poorly soluble in water but soluble in concentrated hydrochloric acid, increasing the amount of acid used and thus increasing waste emissions. In this invention, the molar ratio of methyl 2-amino-4-methanesulfonamide methyl benzoate to copper chloride is 1:0.05-0.15, significantly lower than the conventional amount of copper catalyst used in this type of reaction. In patent CN1195732C, the molar ratio of reactant to cuprous chloride is approximately 1:0.3.

[0020] Since sulfonation is a reversible reaction, the reactants first generate sulfonic acid intermediates during the sulfonation process, and then slowly convert to sulfonyl chloride in the hydrochloric acid system. Traditional processes have slow reaction rates and incomplete reactions, and unreacted sulfonic acid intermediates still exist in the reaction system. The yield of sulfonyl chloride is low and there are many impurities.

[0021] This invention uses sodium hypochlorite as a chlorine oxidant, which promotes the forward reaction, accelerates the formation of sulfonyl chloride, and rapidly converts the sulfonic acid intermediate into sulfonyl chloride, greatly shortening the reaction time and thus improving the reaction yield and purity. Compared with chlorine gas, it is safer, more environmentally friendly, easier to operate, and allows for easier control of the reaction rate, effectively controlling side reactions and avoiding the generation of unnecessary impurities.

[0022] The route of this invention can increase the final yield by more than 20%, and the purity of the crude product can reach more than 96%. It eliminates the need for complex post-processing, saves costs and equipment investment, reduces the amount of waste emissions, and is suitable for industrial production. Detailed Implementation

[0023] Example 1

[0024] (1) Diazotization reaction: 41.27 g (34.75 eq) of water and 17.00 g (1.00 eq) of methyl 2-amino-4-methanesulfonamide methyl benzoate were added to a round-bottom flask. The temperature was raised to 35-42℃, and 29.20 g (3.64 eq) of 30% hydrochloric acid was added dropwise with stirring. After the addition was complete, stirring was continued for 0.5 h, and the temperature was lowered to 0-5℃. Then, 12.59 g (1.10 eq) of 40% sodium nitrite solution was slowly added dropwise. After the addition was complete, the temperature was maintained for 0.5 h. The reaction was tested with KI / starch test paper. If the test paper was positive, the reaction was continued for 0.5 h, and then 1.07 g (0.05 eq) of 30% aminosulfonic acid aqueous solution was added until the test paper was negative. The reaction was then complete. The diazonium salt reaction solution was stored at 0-5℃.

[0025] (2) Sulfonation reaction: 53.08 g (8.00 eq) of methyl isobutyl ketone and 1.42 g (0.03 eq) of benzalkonium chloride were added to a round-bottom flask. 8.97 g (2.10 eq) of sulfur dioxide gas was slowly introduced. 3.17 g (0.11 eq) of 31% copper chloride solution was added, and the mixture was stirred for 15 minutes before the temperature was raised to 35°C. The diazonium salt reaction solution from the previous step was slowly added dropwise to the round-bottom flask. After the addition was complete, the temperature was controlled at 35-40°C and the mixture was stirred for 0.5 h. 9.68 g (2.00 eq) of 30% sodium hypochlorite aqueous solution was slowly added dropwise. After the addition was complete, the mixture was allowed to stand and separate into layers. The upper organic layer was taken for analysis. After the test results met the standards, the organic layer was transferred to a round-bottom flask, and the solvent was removed by vacuum distillation. When 46.80g of methyl isobutyl ketone liquid was distilled off, the distillation was stopped. 18.05g of xylene was added, and the mixture was slowly stirred and cooled to crystallize. The solution was crystallized at -5℃ to 0℃ for 2 hours, filtered, dried and cooled to obtain the product.

[0026] Yield (based on aniline): 88.10%, Purity: 96.56%

[0027] Example 2

[0028] Except for replacing the catalyst dosage with 4.29 g (0.15 eq), the rest is the same as in Example 1.

[0029] Product yield: 87.24%, purity: 95.81%

[0030] Example 3

[0031] Except for replacing the catalyst dosage with 1.43g (0.05eq), the rest is the same as in Example 1.

[0032] Product yield: 86.83%, purity: 95.78%

[0033] Example 4

[0034] Except that the amount of chlorine oxidant was replaced with 7.37g (1.5eq), the rest was the same as in Example 1.

[0035] Product yield: 87.62%, purity: 95.24%

[0036] Example 5

[0037] Except that the amount of chlorine oxidant was replaced with 14.74 g (3.0 eq), the rest was the same as in Example 1.

[0038] Product yield: 85.10%, purity: 95.06%

[0039] Example 6

[0040] Except that 1.40g of 50% benzalkonium chloride was replaced with 0.80g of trioctylmethylammonium chloride, the rest was the same as in Example 1.

[0041] Product yield: 87.21%, purity: 96.10%

[0042] Example 7

[0043] Except that 1.40g of 50% benzalkonium chloride was replaced with 0.40g of trioctylmethylammonium chloride and 0.71g of 50% benzalkonium chloride, the rest was the same as in Example 1.

[0044] Product yield: 85.97%, purity: 95.94%

[0045] Comparative Example 1

[0046] Except that the chlorine oxidant was replaced with 9.22g (2.0eq) of chlorine gas, the rest was the same as in Example 1.

[0047] Product yield: 71.18%, purity: 84.10%

[0048] Comparative Example 2

[0049] Except that no chlorine oxidizing agent is added, the rest is the same as in Example 1.

[0050] Product yield: 67.40%, purity: 83.67%

[0051] Comparative Example 3

[0052] Except for replacing the catalyst with 0.72 g (0.11 eq) cuprous chloride, the rest was the same as in Example 1.

[0053] Product yield: 80.85%, purity: 92.20%

[0054] Comparative Example 4

[0055] Except for replacing the solvent with 48.83 g (8.00 eq) of toluene, the rest was the same as in Example 1.

[0056] Product yield: 70.41%, purity: 78.64%

[0057] Comparative Example 5

[0058] Except that the amount of chlorine oxidant was replaced with 6.40g (1.30eq), the rest was the same as in Example 1.

[0059] Product yield: 77.61%, purity: 91.80%

[0060] Comparative Example 6

[0061] Except that the amount of chlorine oxidant was replaced with 15.63g (3.20eq), the rest was the same as in Example 1.

[0062] Product yield: 75.70%, purity: 90.49%

[0063] Comparative Example 7

[0064] Except for replacing the catalyst dosage with 1.14 g (0.04 eq), the rest is the same as in Example 1.

[0065] Product yield: 78.45%, purity: 89.84%

[0066] Comparative Example 8

[0067] Except for the absence of any phase transfer catalyst, the process is the same as in Example 1.

[0068] Product yield: 69.73%, purity: 85.56%

[0069] Comparative Example 9

[0070] Referring to patent CN1195732C, toluene is used as the solvent, cuprous chloride as the catalyst, and the molar ratio of methyl 2-amino-4-methanesulfonamide methyl benzoate to cuprous chloride is 1:0.3.

[0071] Product yield: 58.76%, purity: 63.80%

[0072] Comparative Example 10

[0073] Except for the addition of 1.71g (2.0eq) sodium hypochlorite, the rest were the same as in comparative example 9.

[0074] Product yield: 62.62%, purity: 68.34%

[0075] Comparative Example 11

[0076] Except for replacing the catalyst with 1.51 g (0.3 eq) of 31% copper chloride solution and adding 1.71 g (2.0 eq) of sodium hypochlorite, the rest was the same as in comparative example 9.

[0077] Product yield: 64.15%, purity: 72.11%.

[0078] As can be seen from Examples 1-7 and Comparative Examples 1-11, the yield and purity of the product from this process are closely related to the chlorination oxidant, catalyst, solvent, and phase transfer catalyst.

[0079] In Comparative Example 1, replacing sodium hypochlorite, the chlorine oxidant, with chlorine gas resulted in a decrease in product yield, purity, and a significant increase in impurities, as well as a decrease in solvent recovery rate. In Comparative Example 2, without the addition of sodium hypochlorite, the reaction yield was significantly reduced. In Comparative Examples 5 and 6, both excessively low and excessively high amounts of chlorine oxidant led to a decrease in reaction yield, and excessively high amounts of chlorine oxidant resulted in an increase in impurities.

[0080] Cuprous chloride was used as a catalyst (Comparative Example 3), and the reaction yield was slightly lower than that of Example 1. When the amount of catalyst was too low (Comparative Example 7), the reaction rate slowed down and the yield decreased; when the amount of catalyst was too high, it would lead to an increase in waste and increase production costs.

[0081] The type of solvent also affects the product yield. In Comparative Example 4, when toluene was used as the reaction solvent, the yield and purity decreased, and the number of impurities increased.

[0082] Whether or not a phase transfer catalyst is added also has a significant impact on the product yield. Compared with Comparative Example 8, the addition of a phase transfer catalyst to the reaction system increased the product yield by 15-18 percentage points and significantly improved the purity.

[0083] Comparative Example 9 used toluene as a solvent and cuprous chloride as a catalyst, resulting in low purity and a yield of less than 60%. Compared with Comparative Example 9, Examples 1-5 showed a yield increase of more than 20%.

[0084] The comparison between Examples 1-7 and Comparative Examples 1-11 is summarized in Table 1.

[0085] Table 1 Summary of Examples 1-7 and Comparative Examples 1-11

[0086]

[0087] The preparation method of methyl 2-chlorosulfonyl-4-methanesulfonamide methyl benzoate of the present invention has been described through specific examples. Those skilled in the art can refer to the content of the present invention and appropriately change the raw materials, process conditions and other links to achieve other corresponding objectives. Such changes do not depart from the content of the present invention. All similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of the present invention.

Claims

1. A method for preparing methyl 2-chlorosulfonyl-4-methanesulfonamide methyl benzoate, characterized in that, The preparation method includes the following steps: (1) Diazotization reaction: The aqueous solution of methyl 2-amino-4-methanesulfonamide methyl benzoate was stirred and heated to 35-42℃. Hydrochloric acid solution was added dropwise and kept at the temperature for 0.5h. The temperature was then lowered to 0-5℃ and sodium nitrite aqueous solution was slowly added dropwise until the reaction was completed, thus obtaining a diazonium salt solution. (2) Sulfonation reaction: Methyl isobutyl ketone and phase transfer catalyst are mixed to obtain mixture 1; sulfur dioxide is dissolved in mixture 1 to obtain mixture 2; copper chloride with a molar equivalent of 0.05-0.15 relative to methyl 2-amino-4-methanesulfonamide methyl benzoate is added to mixture 2, and the reaction is kept at a constant temperature to obtain mixture 3; the diazonium salt reaction solution prepared in step (1) is slowly added dropwise to mixture 3 to obtain mixture 4; sodium hypochlorite aqueous solution is slowly added dropwise to mixture 4; after the addition is complete, the mixture is stirred evenly and allowed to stand, the aqueous layer is separated, methyl isobutyl ketone in the organic layer is evaporated, xylene is added, crystallization is performed, centrifugation is performed, and drying is performed to obtain the product. The molar ratio of the phase transfer catalyst trioctylmethyl ammonium chloride to benzalkonium chloride is 1:0.2-5. In the reaction, the molar ratio of methyl 2-amino-4-methanesulfonamide methyl benzoate to sodium hypochlorite is 1:1.5-3.

2. The preparation method according to claim 1, characterized in that, In the reaction, the molar ratio of methyl isobutyl ketone to phase transfer catalyst is 1:0.03.

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