Method for synthesizing 6-chloro-4-hydroxyl-2-methyl-2H-thieno(2.3.e)-1.2thiazide-1.1-dioxide-3-methyl formate
A technology of methyl formate and dioxide, applied in 6-chloro-4-hydroxy-2-methyl-2H-thieno(2.3.e)-1.2thiazine-1.1-dioxide-3-carboxylic acid In the field of methyl ester synthesis, it can solve the problems of high long-term cost, low total yield, and poor quality of the route, and achieve the effects of reducing production risk, good product quality, and low cost
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Embodiment 1
[0024] Add 100g of 5-chloro-3-sulfonamidoacetic acid methyl thiophene-2-methyl carboxylate and 1000ml of toluene to a 2000ml four-necked flask, then add 90g of dimethyl sulfate, and dropwise add 30% sodium methoxide solution (volume percentage) After the 250g dropwise addition, keep the temperature at 40°C for 30h, and HPLL will track the completion of the reaction.
[0025] Cool the liquid temperature in the reactor to 5°C, then add 120g of 30% sodium methoxide dropwise, then raise the temperature to 65°C for 15 hours, HPLL detects that the reaction is complete, after the reaction is completed, cool to 0-10°C, pour into 800ml 2N HCL Extract the aqueous phase with 100ml*2, combine the organic phases, dry with anhydrous sodium sulfate, filter, and condense the resulting solid, add 800ml of methanol, rinse for 1.0h, cool below 5°C, filter with suction, and dry to obtain the product 6-chloro-4- Hydroxy-2-methyl-2H-thieno(2.3.e)-1.2thiazine-1.1-dioxide-3-methyl carboxylate 74.0 g,...
Embodiment 2
[0027] Put 1000ml of xylene and 100g of methyl 5-chloro-3-sulfonamidoacetate thiophene-2-carboxylate into a four-necked flask, then add 90.0g of dimethyl sulfate, and dropwise add 20% magnesium methanolate solution (volume percentage) 340g, the dropwise addition was completed and kept at 50°C for 25h, and the HPLL tracked the completion of the reaction.
[0028] Cool the liquid temperature in the reactor to 6°C, then add 170g of 20% magnesium methoxide solution dropwise, then raise the temperature to 65°C and react for 15h, HPLL detects that the reaction is complete, and the post-treatment is the same as in Example 1 to obtain the product 6-chloro-4-hydroxyl-2 -Methyl-2H-thieno(2.3.e)-1.2thiazine-1.1-dioxide-3-carboxylic acid methyl ester 76.0 g, yield 80.6.%. HPLC≥99.5%
Embodiment 3
[0030] Add 100g of methyl 5-chloro-3-sulfonamidoacetate thiophene-2-carboxylate and 1000ml of toluene to a 2000ml four-necked flask, then add 90g of dimethyl sulfate, and add dropwise 30% sodium ethylate solution (volume percentage) After the 280g dropwise addition, keep the temperature at 40°C for 30h, and HPLL will track the completion of the reaction.
[0031] Cool the liquid temperature in the reactor to 5°C, then add 150g of 30% sodium ethylate dropwise, then raise the temperature to 65°C for 15 hours, HPLL detects that the reaction is complete, after the reaction is completed, cool to 0-10°C, pour into 800ml 2N HCL for layering, and use toluene Extract the aqueous phase with 100ml*2, combine the organic phases, dry with anhydrous sodium sulfate, filter, and condense the resulting solid, add 800ml of methanol, rinse for 1.0h, cool below 5°C, filter with suction, and dry to obtain the product 6-chloro-4- Hydroxy-2-methyl-2H-thieno(2.3.e)-1.2thiazine-1.1-dioxide-3-methyl ca...
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