Refining method of fasudil hydrochloride

Abstract

The invention relates to the field of pharmaceutical chemicals, and specifically relates to a refining method of fasudil hydrochloride. The method comprises the steps of: adding a fasudil hydrochloride crude product into an organic solvent A, carrying out heating reflux, filtering while hot and drying the filter cake; adding the filter cake into water, heating for solvent cleaning and filtration, adjusting pH value of the filtrate to 4.5-6.5 by alkali, cooling for crystallization, filtering and drying the filter cake; and adding the filter cake into water for solvent cleaning and filtration, adding a poor solvent of fasudil in the filtrate, cooling for crystallization, filtering and drying the filter cake to obtain fasudil hydrochloride.

Description

technical field

[0001] The invention relates to the field of medicine and chemical industry, in particular to a process for refining the drug fasudil hydrochloride. Background technique

[0002] Fasudil Hydrochloride, chemical name hexahydro-1-(5-sulfonylisoquinoline)-1(H)-1,4-diazepine hydrochloride, is a protein kinase Inhibitors can potently dilate blood vessels and protect ischemic brain tissue. It is clinically used for the prevention and treatment of cerebral vasospasm and cerebral ischemia after subarachnoid hemorrhage surgery.

[0003] The structural formula of Fasudil Hydrochloride is shown in formula (I):

[0004]

[0005] The preparation technology of Fasudil Hydrochloride mainly passes through the following steps:

[0006]

[0007] The finished product of fasudil hydrochloride produced by this synthesis process all contains two types of impurities: excessive raw material homopiperazine and by-product dimer, the compound shown in the structure as formula (...

Examples

Embodiment 1

[0028] a. Add 2.1kg of Fasudil hydrochloride crude product to 1 times volume of acetone and heat to reflux, filter with suction, and dry the filter cake;

[0029] b. Add the filter cake to 0.1 times the volume of water, heat to dissolve, then filter with suction, adjust the pH value of the filtrate to 4.5~5 with 0.1mol / L sodium carbonate aqueous solution, and fully crystallize at -5~0°C , filter, and filter cake drying;

[0030] c. Add the filter cake to 1 times the volume of water, heat to dissolve, filter with suction, add isopropanol 10 times the volume of water to the filtrate, cool and stir at -5 ~ 0°C for 4 ~ 5 hours, and filter with suction After the filter cake was dried, 1.91kg of Fasudil hydrochloride fine product was obtained, with a total yield of 90.9% and a purity of 99.86% (detected by HPLC).

Embodiment 2

[0032] a. Add 2.1kg of Fasudil hydrochloride crude product to 10 times the amount of volume of dioxane and heat to reflux, filter with suction, and dry the filter cake;

[0033] b. Add the filter cake to 5 times the volume of water, heat to dissolve, then filter with suction, adjust the pH value of the filtrate to 6-6.5 with 1mol / L sodium bicarbonate aqueous solution, fully crystallize at 5-10°C, and filter , filter cake drying;

[0034] c. Add the filter cake to 5 times the volume of water, heat to dissolve, filter with suction, add acetonitrile 3 times the volume of water to the filtrate, cool and stir at -5 ~ 0°C for 4 ~ 5 hours, and filter with suction. After the cake was dried, 1.81 kg of Fasudil hydrochloride fine product was obtained, with a total yield of 86.2% and a purity of 99.97% (detected by HPLC).

Embodiment 3

[0036] a. Add 2.1kg of Fasudil hydrochloride crude product to the mixed solvent of methanol and ethyl acetate (volume ratio: methanol: ethyl acetate=1: 10) of 5 times the amount of volume and heat to reflux, filter with suction, and dry the filter cake Dry;

[0037] b. Add the filter cake to 3 times the volume of water, heat to dissolve, then filter with suction, adjust the pH value of the filtrate to 5-5.5 with 0.5mol / L potassium hydroxide aqueous solution, and fully crystallize at 0-5°C , filter, and filter cake drying;

[0038] c. Add the filter cake to 3 times the volume of water, heat to dissolve, filter with suction, add tetrahydrofuran 4 times the volume of water to the filtrate, cool and stir at -5 ~ 0°C for 3 ~ 4 hours, and filter with suction. After the cake was dried, 1.87 kg of Fasudil hydrochloride fine product was obtained, with a total yield of 89.0% and a purity of 99.93% (detected by HPLC).

technical field

[0001] The invention relates to the field of medicine and chemical industry, in particular to a process for refining the drug fasudil hydrochloride. Background technique

[0002] Fasudil Hydrochloride, chemical name hexahydro-1-(5-sulfonylisoquinoline)-1(H)-1,4-diazepine hydrochloride, is a protein kinase Inhibitors can potently dilate blood vessels and protect ischemic brain tissue. It is clinically used for the prevention and treatment of cerebral vasospasm and cerebral ischemia after subarachnoid hemorrhage surgery.

[0003] The structural formula of Fasudil Hydrochloride is shown in formula (I):

[0004]

[0005] The preparation technology of Fasudil Hydrochloride mainly passes through the following steps:

[0006]

[0007] The finished product of fasudil hydrochloride produced by this synthesis process all contains two types of impurities: excessive raw material homopiperazine and by-product dimer, the compound shown in the structure as formula (...

Examples

Embodiment 1

[0028] a. Add 2.1kg of Fasudil hydrochloride crude product to 1 times volume of acetone and heat to reflux, filter with suction, and dry the filter cake;

[0029] b. Add the filter cake to 0.1 times the volume of water, heat to dissolve, then filter with suction, adjust the pH value of the filtrate to 4.5~5 with 0.1mol / L sodium carbonate aqueous solution, and fully crystallize at -5~0°C , filter, and filter cake drying;

[0030] c. Add the filter cake to 1 times the volume of water, heat to dissolve, filter with suction, add isopropanol 10 times the volume of water to the filtrate, cool and stir at -5 ~ 0°C for 4 ~ 5 hours, and filter with suction After the filter cake was dried, 1.91kg of Fasudil hydrochloride fine product was obtained, with a total yield of 90.9% and a purity of 99.86% (detected by HPLC).

Embodiment 2

[0032] a. Add 2.1kg of Fasudil hydrochloride crude product to 10 times the amount of volume of dioxane and heat to reflux, filter with suction, and dry the filter cake;

[0033] b. Add the filter cake to 5 times the volume of water, heat to dissolve, then filter with suction, adjust the pH value of the filtrate to 6-6.5 with 1mol / L sodium bicarbonate aqueous solution, fully crystallize at 5-10°C, and filter , filter cake drying;

[0034] c. Add the filter cake to 5 times the volume of water, heat to dissolve, filter with suction, add acetonitrile 3 times the volume of water to the filtrate, cool and stir at -5 ~ 0°C for 4 ~ 5 hours, and filter with suction. After the cake was dried, 1.81 kg of Fasudil hydrochloride fine product was obtained, with a total yield of 86.2% and a purity of 99.97% (detected by HPLC).

Embodiment 3

[0036] a. Add 2.1kg of Fasudil hydrochloride crude product to the mixed solvent of methanol and ethyl acetate (volume ratio: methanol: ethyl acetate=1: 10) of 5 times the amount of volume and heat to reflux, filter with suction, and dry the filter cake Dry;

[0037] b. Add the filter cake to 3 times the volume of water, heat to dissolve, then filter with suction, adjust the pH value of the filtrate to 5-5.5 with 0.5mol / L potassium hydroxide aqueous solution, and fully crystallize at 0-5°C , filter, and filter cake drying;

[0038] c. Add the filter cake to 3 times the volume of water, heat to dissolve, filter with suction, add tetrahydrofuran 4 times the volume of water to the filtrate, cool and stir at -5 ~ 0°C for 3 ~ 4 hours, and filter with suction. After the cake was dried, 1.87 kg of Fasudil hydrochloride fine product was obtained, with a total yield of 89.0% and a purity of 99.93% (detected by HPLC).

Images