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Method for preparing isoquinoline hydrochloride intermediate and rho kinase inhibitor by using btc/ph3po chlorination system

A technology of kinase inhibitor and sulfonyl chloride hydrochloride, which is applied in the field of medicine, can solve the problems of potential safety hazards in storage and transportation, environmental pollution of by-product sulfides, low reaction efficiency of chlorinated reagents, etc. The effect of high product yield and high product quality

Active Publication Date: 2022-03-01
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In summary, the key intermediates of fasudil and lisudil, isoquinoline-5-sulfonyl chloride and 4-fluoroisoquinoline-5-sulfonyl chloride, all use thionyl chloride as the chlorination reagent , there are many disadvantages in the production process: 1) the use of excessive thionyl chloride, the acidic substances produced will seriously corrode the workshop equipment, and the production environment is poor. The last step needs to evaporate thionyl chloride, and the energy consumption is also large. And the discharge of the generated by-product sulfide is easy to pollute the environment, and the treatment cost of "three wastes" is relatively large; 2) thionyl chloride is liquid at normal temperature, and there are potential safety hazards in storage and transportation; 3) during the chlorination process, due to chlorine A large excess of sulfoxide will produce by-products that are chlorinated at other positions on the isoquinoline ring, and the introduced impurities will have a certain impact on subsequent reactions, resulting in the production of isoquinoline sulfonates such as fasudil and lisudil. The total impurities of amide compounds are increased, and related impurities need to be separated in the purification and separation steps
There is no patent report to utilize bis-(trichloromethyl)carbonate as chlorination reagent to prepare fasudil and its analogues
And, utilize DMF and BTC as the reaction efficiency of chlorination reagent is not high and the system is more complicated

Method used

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  • Method for preparing isoquinoline hydrochloride intermediate and rho kinase inhibitor by using btc/ph3po chlorination system
  • Method for preparing isoquinoline hydrochloride intermediate and rho kinase inhibitor by using btc/ph3po chlorination system
  • Method for preparing isoquinoline hydrochloride intermediate and rho kinase inhibitor by using btc/ph3po chlorination system

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Embodiment 1: the synthesis of isoquinoline-5-sulfonyl chloride hydrochloride

[0047] With isoquinoline-5-sulfonic acid (31.38g, 150mmol), BTC (14.84g, 50mmol), Ph 3 PO (2.09g, 7.5mmol) and ethyl acetate (300mL) were added to a 500mL reaction flask, heated to 25°C for 1 hour, cooled down to room temperature, added dichloromethane (150mL) and stirred, and suction filtered to obtain a white solid. Vacuum-dried at 40°C-50°C to obtain 33.68g of solid, with a yield of 85% and an HPLC content of 99.92%. After the filtrate part is concentrated, Ph is precipitated at low temperature 3 PO (precipitation temperature at low temperature is 30°C, the same below), after washing with a small amount of petroleum ether, suction filtration, and drying to obtain Ph 3 PO (1.91g) is reusable.

Embodiment 2

[0048] Embodiment 2: the synthesis of isoquinoline-5-sulfonyl chloride hydrochloride

[0049] With isoquinoline-5-sulfonic acid (31.38g, 150mmol), BTC (14.84g, 50mmol), Ph 3 PO (2.09g, 7.5mmol) and ethyl acetate (300mL) were added to a 500mL reaction flask, heated to 25°C for 5 hours, cooled to room temperature, added dichloromethane (150mL) and stirred, and suction filtered to obtain a white solid. Vacuum-dried at 40°C-50°C to obtain 34.86g of solid, with a yield of 88% and an HPLC content of 99.95%. After the filtrate part is concentrated, Ph is precipitated at low temperature 3 PO, washed with a small amount of petroleum ether, suction filtered, and dried to obtain Ph 3 PO (2.01g) is reusable.

Embodiment 3

[0050] Embodiment 3: the synthesis of isoquinoline-5-sulfonyl chloride hydrochloride

[0051] With isoquinoline-5-sulfonic acid (31.38g, 150mmol), BTC (14.84g, 50mmol), Ph 3 PO (2.09g, 7.5mmol) and ethyl acetate (300mL) were added to a 500mL reaction flask, heated to 25°C for 14 hours, cooled to room temperature, added dichloromethane (150mL) and stirred, suction filtered to obtain a white solid, Vacuum-dried at 40°C-50°C to obtain 34.47g of solid, with a yield of 87% and an HPLC content of 99.94%. After the filtrate part is concentrated, Ph is precipitated at low temperature 3 PO, washed with a small amount of n-hexane, suction filtered and dried to obtain Ph 3 PO (1.89g) is reusable.

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Abstract

The invention discloses the use of BTC / Ph 3 A method for preparing isoquinoline hydrochloride intermediates and Rho kinase inhibitors by PO chlorination system, wherein the method for preparing isoquinoline hydrochloride intermediates is as follows: isoquinoline-5-sulfonic acid compounds, BTC and a catalytic amount of Ph 3 PO are placed together in a reaction bottle, and organic solvent A is added to mix, heated for reaction, after the reaction is completed, suction filtered and dried to obtain a white solid isoquinoline hydrochloride intermediate, and the isoquinoline hydrochloride intermediate The body is isoquinoline-5-sulfonyl chloride hydrochloride compound; after the filtrate mother liquor is partially concentrated, the Ph 3 PO, Ph 3 PO was washed with a small polar solvent and continued to be applied repeatedly. The present invention has the advantages of few side reactions, high product quality, less "three wastes" pollution, and high atom economy. The present invention also provides a method for further preparing Rho kinase inhibitors by using the obtained isoquinoline hydrochloride intermediates. The impurity in the Rho kinase inhibitor prepared by the invention is obviously lower than that in the medicine obtained by the traditional method.

Description

technical field [0001] The present invention relates to the field of medical technology, in particular to the use of BTC / Ph 3 A method for preparing isoquinoline hydrochloride intermediates and Rho kinase inhibitors through a PO chlorination system. Background technique [0002] Fasudil Hydrochloride is a new type of isoquinoline sulfonamide derivatives jointly developed by Asahi Kasei Co., Ltd. and Nagoya University. It is the first Rho kinase inhibitor in the world. It was launched in Japan in 1995 and can effectively relieve Cerebral vasospasm, improve subarachnoid hemorrhage, prevent chronic ischemic cerebral vasospasm, etc. The chemical structure is as formula (I): [0003] [0004] Ripasudil Hydrochloride (Ripasudil Hydrochloride) is an isoquinoline sulfonamide derivative developed by Japan Kowa Co., Ltd. It was launched in 2014 and can be used as a Rho kinase inhibitor to treat glaucoma and ocular hypertension. The chemical structure is as formula (II): [0005...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/02C07D217/22C07D401/12
CPCC07D217/02C07D217/22C07D401/12
Inventor 翁意意李南慧孙晨
Owner ZHEJIANG UNIV OF TECH
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