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Purification method of (s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride

A technology of fluoroisoquinoline and refining method, which is applied in the direction of organic chemistry, etc., can solve the problems of unsuitability for large-scale production, troublesome operation, cumbersome process, etc., and achieve the improvement of liquid phase purity and active ingredient content, convenient operation, low cost effect

Active Publication Date: 2019-09-03
SHANDONG CHENGCHUANG BLUE OCEAN PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The target obtained by this method is a base with high purity. If you want to get the desired hydrochloride, you need to acidify the base into a salt on this basis. This method is cumbersome and troublesome to operate.
[0010] Method 2: Patent application WO9920620A refines the crude hydrochloride obtained by column chromatography with chloroform:methanol=10:1 (volume ratio). The purity of the refined product obtained by this method is 98.2%, and the yield is only 58.6%. Suitable for mass production

Method used

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  • Purification method of (s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride
  • Purification method of (s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride
  • Purification method of (s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0042] Under argon protection, 49.5g (s)-tert-butyl 4-[(4-fluoroisoquinone) dissolved in 89.0g ethyl acetate was added dropwise to 517g 4N hydrogen chloride / ethyl acetate under ice water cooling Lin-5-yl)sulfonyl]-3-methyl-1,4-diazepane-1-carboxylate, stirred under ice-water cooling for 2 hours, filtered, and dried under reduced pressure at 35°C to constant 42.0 g of (s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride was obtained again;

[0043]Add 42.0g (s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride crude product into 210mL ethanol and 42mL of acetonitrile, heated to reflux and stirred to dissolve, stirred and cooled to room temperature, stirred and crystallized for 2 hours, filtered, and dried under reduced pressure at 35°C to constant weight to obtain (s)-4-[(4-fluoroisoquinoline-5 -yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride refined product 40.3g, yield: 96%, purity: 99.93%, single and heterogeneous are l...

Embodiment 2

[0045] Under argon protection, 64.4g (s)-tert-butyl 4-[(4-fluoroisoquinone) dissolved in 115.7g ethyl acetate was added dropwise to 672g 4N hydrogen chloride / ethyl acetate under ice water cooling Lin-5-yl)sulfonyl]-3-methyl-1,4-diazepane-1-carboxylate, stirred under ice-water cooling for 2 hours, filtered, and dried under reduced pressure at 40°C to constant 54.6 g of (s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride was obtained again;

[0046] Add 54.6g (s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride crude product into 284mL ethanol and In 60mL of acetonitrile, heated to reflux and stirred to dissolve, stirred and cooled to room temperature, stirred and crystallized for 3 hours, filtered, and dried under reduced pressure at 40°C to constant weight to obtain (s)-4-[(4-fluoroisoquinoline-5 -yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride refined product 51.87g, yield: 95%, purity: 99.86%, single heterogeneity les...

Embodiment 3

[0048] Under the protection of argon, 0.65kg(s)-tert-butyl 4-[(4-fluoroiso Quinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane-1-carboxylate, stirred for 2 hours under ice-water cooling, filtered, and dried under reduced pressure at 38°C to Constant weight obtained (s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride 0.56kg;

[0049] Add 0.56kg(s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride crude product into 2.8L ethanol and 0.62L of acetonitrile, heated to reflux and stirred to dissolve, stirred and cooled to room temperature, stirred and crystallized for 3 hours, filtered, and dried under reduced pressure at 38°C to constant weight to obtain (s)-4-[(4-fluoroisoquinoline -5-yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride refined product 0.54kg, yield: 95.8%, purity: 99.90%, single heterogeneity is less than 0.1%, >99.9% ee (HPLC).

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Abstract

The invention discloses a refinement method of (s)-4-[(4-fluoroisoquinolyl-5-yl)sulfonyl]-3-methyl-1,4-diazacycloheptane hydrochloride. The method comprises the following steps: adding a (s)-4-[(4-fluoroisoquinolyl-5-yl)sulfonyl]-3-methyl-1,4-diazacycloheptane hydrochloride crude product into a mixed solvent composed of ethanol and acetonitrile, carrying out heating under reflux until the (s)-4-[(4-fluoroisoquinolyl-5-yl)sulfonyl]-3-methyl-1,4-diazacycloheptane hydrochloride crude product is completely dissolved, carrying out stirring and cooling to crystallize, and carrying out filtering and drying to obtain the refined product. The method obviously enhances the liquid-phase purity and effective component content of the product, so that the purity of the refined product reaches 99.85% or above, and the content of any individual impurity is less than 0.1%. The method is also convenient for large-scale production of the product, and is convenient to operate and lower in cost.

Description

technical field [0001] The present invention relates to a refining method, in particular to a (s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane Refining method of alkane hydrochloride. It belongs to the field of medical technology. Background technique [0002] Glanatec eye drops listed in Japan, its active ingredient is (s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane Alkane hydrochloride hydrate is used to treat ocular hypertension and glaucoma (use this product when other glaucoma treatment drugs are not effective or cannot be used). [0003] (s)-4-[(4-fluoroisoquinolin-5-yl)sulfonyl]-3-methyl-1,4-diazepane hydrochloride without water of crystallization can be used as Preventive and therapeutic agents for cerebrovascular disorders such as infarction, cerebral hemorrhage, subarachnoid hemorrhage, cerebral edema, etc., especially useful as inhibitors of cerebral vasospasm diseases such as stroke, the structural formula of the compound is ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
Inventor 于瑞同毛成龙姚松芝
Owner SHANDONG CHENGCHUANG BLUE OCEAN PHARM TECH CO LTD