Synthesis method of intermediate of bumetanib

A synthetic method and intermediate technology, applied in the field of medicine, to achieve the effects of facilitating production organization, avoiding nitration reactions, and improving safety

Pending Publication Date: 2021-12-03
南京卓康医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Moreover, during the reaction process, concentrated sulfuric acid and concentrated nitric acid need...

Method used

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  • Synthesis method of intermediate of bumetanib
  • Synthesis method of intermediate of bumetanib
  • Synthesis method of intermediate of bumetanib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Embodiment 1: preparation compound 2a

[0065]

[0066] 3-amino-4-chlorobenzoic acid (100g, 0.583mol) was added to the reaction flask, dichloromethane (600ml) was added to dissolve, triethylamine (162ml, 1.166mol) was added, benzyl chloride (81.18g, 0.641mol) was added dropwise, the drop rate was controlled, the temperature was not higher than 40°C, the dropwise addition was completed, and the reaction was monitored by TLC until the reaction was completed, and 0.5mol / L sodium hydroxide solution (500ml) was added for extraction, the aqueous phase was separated, and the solution was washed with dilute hydrochloric acid Adjust the pH value to 4-5, crystallize at 0-10°C to obtain an off-white solid, and blow dry at 40-50°C to obtain compound 2a (141.9g), with a yield of 93%.

[0067] ESI-MS(+):262.2[M+H] + . 1 H-NMR (400MHz, DMSO-d6+D 2 O): 7.49(d, 1H, J=7.0Hz), 7.47(d, 1H, J=7.0Hz), 7.31-7.27(m, 6H), 4.31(s, 2H).

Embodiment 2

[0068] Embodiment 2: preparation compound 2a

[0069]

[0070] 3-amino-4-chlorobenzoic acid (100g, 0.583mol) was added to the reaction flask, dichloromethane (600ml) was added to dissolve, triethylamine (162ml, 1.166mol) was added, benzyl bromide (109.64g, 0.641mol) was added dropwise, the drop rate was controlled, the temperature was not higher than 40°C, the dropwise addition was completed, and the reaction was monitored by TLC until the reaction was completed, and 0.5mol / L sodium hydroxide solution (500ml) was added for extraction, the aqueous phase was separated, and the solution was washed with dilute hydrochloric acid Adjust the pH value to 4-5, and crystallize at 0-10°C to obtain an off-white solid, which is air-dried at 40-50°C to obtain compound 2a (138.8g), with a yield of 91%.

Embodiment 3

[0071] Embodiment 3: preparation compound 2a

[0072] 3-amino-4-chlorobenzoic acid (100g, 0.583mol) was added to the reaction flask, dichloromethane (600ml) was added to dissolve, triethylamine (162ml, 1.166mol) was added, benzyl bromide (149.66g, 0.875mol) was added dropwise, the drop rate was controlled, and the temperature was not higher than 40°C. After the dropwise addition was completed, the reaction was monitored by TLC until the reaction was completed, and 0.5mol / L sodium hydroxide solution (500ml) was added for extraction, and the aqueous phase was separated and washed with dilute hydrochloric acid Adjust the pH value to 4-5, crystallize at 0-10°C to obtain an off-white solid, and blow dry at 40-50°C to obtain compound 2a (140.3g), with a yield of 92%.

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Abstract

The invention discloses a synthesis method of an intermediate of bumetanib. The comprises the following steps: protecting amino in 3-amino-4-chlorobenzoic acid as shown in a formula 1 by using a compound containing a benzyl protecting group to obtain a compound as shown in a formula 2; reacting the compound as shown in the formula 2 with thionyl chloride, and treating with ammonia water to obtain a compound as shown in a formula 3; reacting the compound as shown in the formula 3 with phenol to obtain a compound as shown in a formula 4; and reacting the compound as shown in the formula 4 with an oxidizing agent to obtain a bumetanib intermediate as shown in a formula 5, namely 3-amino-4-phenoxy-5-sulfamoyl benzoic acid. Compared with the prior art, the method provided by the invention has the advantages that the use of highly toxic chlorosulfonic acid is avoided, the nitration reaction is avoided, the production organization is facilitated, and the production safety is improved.

Description

technical field [0001] The invention belongs to the field of medicine, and furthermore, belongs to the raw material drug synthesis industry, in particular to a method for synthesizing an intermediate of bumetanide. Background technique [0002] Bumetanide is a potent diuretic, clinically mainly used to treat heart failure, liver disease, kidney disease edema including various intractable edema and acute pulmonary edema, the structural formula is as follows: [0003] [0004] In the route of synthesizing bumetanide, compound 5 (3-amino-4-phenoxy-5-sulfamoylbenzoic acid) is a key intermediate, after it reacts with n-butanol for alkylation, after ester Hydrolysis gives bumetanide (compound 7). [0005] [0006] Regarding the synthetic method of Compound 5, Journal of Labeled Compound and Radiopharmaceuticals.21(2):173-80, 1984 reported the following synthetic route. [0007] [0008] In this synthetic route, chlorosulfonic acid needs to be used, which is a highly tox...

Claims

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Application Information

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IPC IPC(8): C07C303/40C07C311/39
CPCC07C303/40C07C303/38C07C227/18C07C311/39C07C229/60Y02P20/55
Inventor 李强刘华权姚尧沈正文胡志恒
Owner 南京卓康医药科技有限公司
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