Preparation method of hydrochlorothiazide intermediate

Abstract

The invention discloses a preparation method of a hydrochlorothiazide intermediate, which comprises the following steps: reacting 4-amino-6-chloro-1, 3-benzene disulfonyl chloride with ammonia water in tetrahydrofuran to obtain a crude product of 4-amino-6-chloro-1, 3-benzene disulfonamide, heating the crude product in a potassium hydroxide solution, decolorizing and purifying, cooling to 5-10 DEG C, crystallizing, filtering, and drying to obtain the hydrochlorothiazide intermediate. The purity of the hydrochlorothiazide intermediate 4-amino-6-chloro-1, 3-benzene disulfonamide refined product reaches 99.5% or above, the content of a single impurity is controlled to be 0.1% or below, and the process is simple and controllable, easy to reproduce and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a method for preparing a hydrochlorothiazide intermediate. Background Art

[0002] Hydrochlorothiazide is a common diuretic on the market. It can be combined with various types of antihypertensive drugs to treat hypertension and is widely used. Its structure is shown below .

[0003] Impurities in hydrochlorothiazide have always been a major concern for researchers, and many impurities have not been thoroughly studied. Generally speaking, the content of known impurities in the drug is preferably no more than 0.15%. According to current research, one of the reasons why it is difficult to obtain high-purity hydrochlorothiazide is because of the presence of impurities that are difficult to remove.

[0004] 4-Amino-6-chloro-1,3-benzenedisulfonamide is an important intermediate in the preparation process of hydrochlorothiazide. Its general synthesis method is to use 4-amino-6-chloro-1,3-benzenedisulfonyl chloride as a raw material for amination reaction. Some impurities will be generated in the synthesis reaction of 4-amino-6-chloro-1,3-benzenedisulfonamide. The properties of these impurities are similar to those of hydrochlorothiazide, and they are difficult to separate and remove in the subsequent stages. Therefore, controlling the impurity content in 4-amino-6-chloro-1,3-benzenedisulfonamide can reduce the difficulty of subsequent refining and effectively improve the purity of the product. A feasible method is to recrystallize and purify 4-amino-6-chloro-1,3-benzenedisulfonamide, remove the impurities in advance, and then proceed to the next step of the reaction. According to the existing public technical information, the crude product 4-amino-6-chloro-1,3-benzenedisulfonamide has poor solubility in conventional solvents (methanol, ethanol, ethyl acetate, acetone, dichloromethane, acetonitrile, etc.), and it is not easy to find a suitable solvent for refining; the existing technology has a method of dissolving and crystallizing in an alkaline aqueous solution, but there are some defects in the selection of the base; for example, the amount of ammonia water required is too large, otherwise it is difficult to dissolve, and the reduced pressure concentration to remove the ammonia gas crystallization will cause serious air pollution. The selection of alkali metal salt weak bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc. has the problem of poor solubility. If organic amines such as triethylamine are used, the solubility is better, but the reagents are expensive and the cost is too high. Summary of the invention

[0005] In order to solve the problems existing in the preparation process of the above-mentioned hydrochlorothiazide intermediate 4-amino-6-chloro-1,3-benzenedisulfonamide, the present invention proposes a preparation process of high-purity 4-amino-6-chloro-1,3-benzenedisulfonamide, which has the advantages of high yield and high product purity, with a content of more than 99.5%, a single impurity content controlled below 0.1%, and a total impurity controlled below 0.5%. This process includes purifying 4-amino-6-chloro-1,3-benzenedisulfonamide after synthesis, heating and decolorizing the crude product in a potassium hydroxide solution, adjusting the pH and crystallizing to obtain the hydrochlorothiazide intermediate 4-amino-6-chloro-1,3-benzenedisulfonamide fine product, thereby removing impurities that are difficult to separate from the pure hydrochlorothiazide product in the early steps, specifically the following steps:

[0006]

[0007] The specific steps are as follows: (1) dissolving 4-amino-6-chloro-1,3-benzenedisulfonyl chloride in tetrahydrofuran, rapidly adding ammonia water at 10°C, keeping the temperature at 35°C for reaction, and concentrating under reduced pressure after the reaction to obtain a concentrated residue; (2) adding water to the concentrated residue, cooling to 10°C for crystallization, and obtaining a crude product of 4-amino-6-chloro-1,3-benzenedisulfonamide; (3) dissolving the crude product of 4-amino-6-chloro-1,3-benzenedisulfonamide in potassium hydroxide solution, adding activated carbon for heating for decolorization, filtering, adjusting the pH to 7, cooling to 5-10°C for crystallization, and drying to obtain a fine product of 4-amino-6-chloro-1,3-benzenedisulfonamide.

[0008] Furthermore, the mass ratio of the 4-amino-6-chloro-1,3-benzenedisulfonyl chloride to tetrahydrofuran is 1:5-1:10.

[0009] Furthermore, the concentration of the potassium hydroxide solution is 30%.

[0010] Beneficial effects: The prior art process is difficult to obtain high-purity hydrochlorothiazide due to the presence of impurities in hydrochlorothiazide that are difficult to remove. The post-treatment usually involves a large amount of alkali or expensive reagents, which results in excessively high costs. Compared with the prior art, this solution has the advantages of high yield and high product purity, and the process is environmentally friendly, with little pollution to the environment, and can simply and efficiently obtain high-purity 4-amino-6-chloro-1,3-benzenedisulfonamide. Implementation Example 1

[0011] Dissolve 20g of 4-amino-6-chloro-1,3-benzenedisulfonyl chloride in 100g of tetrahydrofuran; control the temperature at 10℃, quickly add 40g of ammonia water, and heat to 35℃ for reaction. After the reaction is completed, concentrate under reduced pressure until no linear liquid flows out of the condenser, add 50g of drinking water, cool to 10℃ for crystallization, and obtain crude 4-amino-6-chloro-1,3-benzenedisulfonamide. Dissolve the crude 4-amino-6-chloro-1,3-benzenedisulfonamide in 50ml of 30% potassium hydroxide solution, add medicinal charcoal for decolorization, control the temperature at 75℃ for heating for 30 minutes, filter, adjust the pH to 7, cool to 10℃, crystallize, filter and dry to obtain 16.0g of 4-amino-6-chloro-1,3-benzenedisulfonamide (yield 91%, purity 99.6%). Example 2

[0012] Dissolve 20g of 4-amino-6-chloro-1,3-benzenedisulfonyl chloride in 160g of tetrahydrofuran; control the temperature at 10℃, quickly add 40g of ammonia water, heat to 35℃ for reaction, and after the reaction is completed, reduce the pressure and concentrate until no linear liquid flows out of the condenser, add 50g of drinking water, cool to 10℃ for crystallization, and obtain crude 4-amino-6-chloro-1,3-benzenedisulfonamide. Dissolve the crude 4-amino-6-chloro-1,3-benzenedisulfonamide in 50ml of 30% potassium hydroxide solution, add medicinal charcoal for decolorization, control the temperature at 75℃ for heating for 30 minutes, filter, adjust the pH to 7, cool to 5℃, crystallize, filter and dry to obtain 16.7g of 4-amino-6-chloro-1,3-benzenedisulfonamide (yield 95%, purity 99.0%).

[0013] Comparative Example 1

[0014] Dissolve 20g of 4-amino-6-chloro-1,3-benzenedisulfonyl chloride in 160g of tetrahydrofuran; control the temperature at 10℃, quickly add 40g of ammonia water, heat to 35℃ for reaction, and after the reaction is completed, reduce the pressure and concentrate until no linear liquid flows out of the condenser, add 50g of drinking water, cool to 10℃ for crystallization, and obtain crude 4-amino-6-chloro-1,3-benzenedisulfonamide. Dissolve the crude 4-amino-6-chloro-1,3-benzenedisulfonamide in 200ml of ammonia water, stir at room temperature for 30 minutes, adjust pH=7, cool to 5℃, crystallize, filter and dry to obtain 14.1g of 4-amino-6-chloro-1,3-benzenedisulfonamide (yield 80%, purity 96.9%).

[0015] Comparative Example 2

[0016] Dissolve 20g of 4-amino-6-chloro-1,3-benzenedisulfonyl chloride in 160g of tetrahydrofuran; control the temperature at 10℃, quickly add 40g of ammonia water, heat to 65℃ for reaction, and after the reaction is completed, reduce the pressure and concentrate until no linear liquid flows out of the condenser, add 50g of drinking water, cool to 10℃ for crystallization, and obtain crude 4-amino-6-chloro-1,3-benzenedisulfonamide. Dissolve the crude 4-amino-6-chloro-1,3-benzenedisulfonamide in 200ml of ammonia water, stir at room temperature for 30 minutes, adjust pH=7, cool to 5℃, crystallize, filter and dry to obtain 13.4g of 4-amino-6-chloro-1,3-benzenedisulfonamide (yield 76%, purity 92.2%).

Claims

1. A method for preparing 4-amino-6-chloro-1,3-benzenedisulfonamide, comprising the following steps: (1) Dissolve 4-amino-6-chloro-1,3-benzenedisulfonyl chloride in tetrahydrofuran, quickly add aqueous ammonia at 10°C, raise the temperature to 35°C, keep the temperature to react, and after the reaction is completed, concentrate under reduced pressure to obtain a concentrated residue; (2) adding water to the concentrated residue, cooling to 10°C for crystallization to obtain a crude product of 4-amino-6-chloro-1,3-benzenedisulfonamide; (3) Dissolve the crude product of 4-amino-6-chloro-1,3-benzenedisulfonamide in potassium hydroxide solution, add activated carbon to heat for decolorization, filter, adjust the pH to 7, cool to 5-10°C for crystallization, and dry to obtain the refined product of 4-amino-6-chloro-1,3-benzenedisulfonamide.

2. The method according to claim 1, wherein the mass ratio of 4-amino-6-chloro-1,3-benzenedisulfonyl chloride to tetrahydrofuran is 1:5-1:

10.

3. method as claimed in claim 1, in step 1, the concentration of potassium hydroxide solution is 30%.

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