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A kind of synthetic method of hydrochlorothiazide

A synthesis method and hydrochlorothiazide technology are applied in the synthesis field of hydrochlorothiazide, can solve problems such as difficult removal, high-salt waste water, and pollute the environment, and achieve the effects of mild process conditions, low purification difficulty, and improved yield and purity

Active Publication Date: 2022-03-08
CHANGZHOU PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] After cyclization with formaldehyde, there will be dihydrodimer impurities and formaldehyde residues in the product, which are difficult to remove and difficult to meet the ICH quality requirements of existing drugs; moreover, more wastewater is required for refining, forming high-salt wastewater and polluting the environment

Method used

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  • A kind of synthetic method of hydrochlorothiazide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Preparation of 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide

[0063] Add sodium borohydride (2.5g, 67.6mmol, 2eq) into tetrahydrofuran (50mL), cool down to 0-5°C, add formic acid (6.2g, 135.2mmol, 4eq) dropwise at this temperature, stir for 1h after addition, cool down to -10°C, add the compound-chlorothiazide (10g, 33.8mmol, 1eq) at this temperature, keep it at -10~0°C for 3h, filter with suction, rinse the filter cake with a small amount of tetrahydrofuran (10mL), and obtain about 9.3g of white Solid (92.9% yield).

[0064] Product Characterization:

[0065] 1 HNMR (deuterated acetone, 400MHz): δ8.18(s,1H); 7.21(s,-NH,1H); 7.07(s,1H); 6.81(s,SO 2 NH,1H); 6.68(s,SO 2 NH 2 ,2H); 4.95-4.94(d,2H);

[0066] ESI-MS(m / z):297[M-H] - .

Embodiment 2

[0068] Preparation of 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide

[0069] Add potassium borohydride (3.65g, 67.6mmol, 2eq) into methanol (50mL), cool down to 0-5°C, add acetic acid (8.11g, 135.2mmol, 4eq) dropwise at this temperature, and stir for 1-2h after addition. Cool down to -10°C, add the compound-chlorothiazide (10g, 33.8mmol, 1eq) at this temperature, keep it at -10~5°C for 4h, filter with suction, rinse the filter cake with a small amount of methanol (10mL), and obtain about 9.4 g white solid (93.9% yield).

[0070] Product Characterization:

[0071] 1 HNMR (deuterated acetone, 400MHz): δ8.18(s,1H); 7.21(s,-NH,1H); 7.07(s,1H); 6.81(s,SO 2 NH,1H); 6.68(s,SO 2 NH 2 ,2H); 4.95-4.94(d,2H);

[0072] ESI-MS(m / z):297[M-H] - .

Embodiment 3

[0074] The difference with embodiment 1 is that the consumption of sodium borohydride is different, specifically as follows:

[0075] Add sodium borohydride (1.3g, 33.9mmol, 1eq) into tetrahydrofuran (50mL), cool down to 0-5°C, add formic acid (3.1g, 67.6mmol, 2eq) dropwise at this temperature, stir for 1h after addition, cool down to -10°C, add the compound-chlorothiazide (10g, 33.8mmol, 1eq) at this temperature, keep it at -10~0°C for 3h, filter with suction, rinse the filter cake with a small amount of tetrahydrofuran (10mL), and obtain about 7.8g of white Solid (78.0% yield).

[0076] Product Characterization:

[0077] 1 HNMR (deuterated acetone, 400MHz): δ8.18(s,1H); 7.21(s,-NH,1H); 7.07(s,1H); 6.81(s,SO 2 NH,1H); 6.68(s,SO 2 NH 2 ,2H); 4.95-4.94(d,2H);

[0078] ESI-MS(m / z):297[M-H] - .

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Abstract

The invention relates to a method for synthesizing hydrochlorothiazide. A method for synthesizing hydrochlorothiazide comprises the following steps: using chlorothiazide as a reactant, under the action of an organic acid and a hydroboration reagent, a reduction reaction occurs to generate crude hydrochlorothiazide. Using borohydride as a reducing agent, the carbon-nitrogen double bond in chlorothiazide is reduced to generate hydrochlorothiazide, without the participation of formaldehyde or similar substances in the whole process, so it is safer and more environmentally friendly than the existing synthetic methods, and the present invention has advantages in yield and Purity has been improved.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a method for synthesizing hydrochlorothiazide. Background technique [0002] Hydrochlorothiazide (Hydrochlorothiazide), chemical name 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide, is a diuretic, anti Hypertensive drugs, mainly applicable to cardiogenic edema, hepatic edema and nephrogenic edema. Hydrochlorothiazide can be used in combination with other antihypertensive drugs (such as sartan and puril), mainly for the treatment of essential hypertension, and has broad market prospects and clinical value. [0003] Its structural formula is as follows: [0004] [0005] Many preparation methods of hydrochlorothiazide have been reported so far, such as those described below. [0006] In the patent IN 2008MU01149, Shriprakash et al. used 4-amino-6-chloro-1,3-benzenedisulfonamide as the raw material, reacted and condensed with paraformaldehyde under l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D285/28
CPCC07D285/28
Inventor 朱怡君巫美金孙忠华吴路新
Owner CHANGZHOU PHARMA FACTORY
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