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Preparation method for isosorbide 5-mononitrate

A technology of isosorbide dinitrate and nitro, applied in the field of medicine, can solve the problems of high industrialization cost, poor catalyst reduction selectivity, high catalyst cost, etc., and achieve the effect of reducing production cost

Active Publication Date: 2015-09-09
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Though, the literature report of selective reduction method is more, but, the reduction selectivity of catalyzer is poor, still have a large amount of 2-isosorbide mononitrate, isosorbide dinitrate to mix in the product in the method of report, bring purification band here comes the difficulty
At the same time, the cost of selective reducing agent and catalyst is relatively high, resulting in high industrialization cost

Method used

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  • Preparation method for isosorbide 5-mononitrate
  • Preparation method for isosorbide 5-mononitrate
  • Preparation method for isosorbide 5-mononitrate

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Dissolve 12.14g (0.12mol) of triethylamine in a mixture of 1350mL of ethanol and 150mL of purified water, add it to the high-pressure hydrogenation autoclave, stir for 10min, then add 100.00g (0.42mol) of isosorbide dinitrate and 1.50g of 10% Add Pd / C into the high-pressure hydrogenation kettle, lower the temperature and stir, wait until the temperature drops to about 0°C, maintain the hydrogen pressure at 0.3 MPa, and continue the reaction for 12 hours. Quantitative detection and analysis of the product (except a very small amount of unreacted isosorbide dinitrate) obtained: 1.5% of isosorbide 2-mononitrate, 82.4% of isosorbide 5-mononitrate, 16.1% of isosorbide.

[0039] Finally, the concentrated solution was extracted with ethyl acetate, the extract was washed 2-3 times with 0.2mol / L hydrochloric acid, then washed with water until neutral, dried with anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure to obtain 5- 66.00 g of is...

Embodiment 2

[0041] 4.25g (0.04mol) triethylamine was dissolved in the mixed solution of 900mL ethanol and 100mL purified water, it was added in the high pressure hydrogenation kettle, stirred for 10min, then 100.00g (0.42mol) isosorbide dinitrate and 1.50g10% Add Pd / C into the high-pressure hydrogenation kettle, lower the temperature and stir, wait until the temperature drops to about 0°C, maintain the hydrogen pressure at 0.3 MPa, and continue the reaction for 12 hours. Extract with ethyl ester, wash the extract with 0.2mol / L hydrochloric acid for 2-3 times, then wash with water until neutral, dry with anhydrous magnesium sulfate, evaporate ethyl acetate under reduced pressure to obtain isosorbide 5-mononitrate crystals 44.00g, the purity of 5-isosorbide mononitrate detected by liquid phase is 97.40%, and the yield is 54.37%.

Embodiment 3

[0043] Dissolve 12.14g (0.12mol) of triethylamine in a mixture of 1350mL of ethanol and 150mL of purified water, add it into a high-pressure hydrogenation autoclave, stir for 10min, then add 100.00g (0.42mol) of isosorbide dinitrate and 2.00g of 10% Add Pd / C into the high-pressure hydrogenation kettle, lower the temperature and stir, wait until the temperature drops to about 5°C, maintain the hydrogen pressure at 1.0 MPa, and continue the reaction for 9 hours. Extract with ethyl ester, wash the extract with 0.2mol / L hydrochloric acid for 2-3 times, then wash with water until neutral, dry with anhydrous magnesium sulfate, evaporate ethyl acetate under reduced pressure to obtain isosorbide 5-mononitrate crystals 56.70g, the purity of 5-isosorbide mononitrate detected by liquid phase is 98.40%, and the yield is 70.06%.

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Abstract

The invention provides a preparation method for isosorbide 5-mononitrate. The preparation method comprises the following steps: with isosorbide dinitrate as a raw materials and Pd / C as a catalyst in a special mixed solvent, carrying out selective hydrogenation reduction on 2-nitro, filtering after reaction, steaming to remove ethyl alcohol in filtrate, extracting residual concentrated liquid through ethyl acetate, washing extracting liquid through dilute acid, washing to be neutral through water, drying through anhydrous magnesium sulfate, filtering to remove a drying agent and steaming to remove ethyl acetate so as to obtain high-purity isosorbide 5-mononitrate. Compared with the prior art, the synthetic method provided by the invention is simple and easy to operate, impurities are easy to remove, the yield and purity are higher, the cost is reduced since the Pd / C and the solvent can be recycled and reused, isosorbide generated through over reduction can be recycled and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of isosorbide 5-mononitrate. Background technique [0002] 5-isosorbide mononitrate (isosorbide 5-mononitrate, 5-ISMN) is a nitrate antianginal drug developed and marketed by Bochringer Cnbh in Germany in 1981. 5-ISMN is the in vivo metabolite of isosorbide dinitrate. It has no hepatic first-pass effect after taking it, has high bioavailability, has the advantages of fast onset of action, few side effects, high efficacy and long duration of action. Isosorbide 5-mononitrate is suitable for the long-term treatment of coronary heart disease, the prevention of angina pectoris, and the treatment of persistent angina pectoris after myocardial infarction. The chemical name of 5-ISMN is 1,4:3,6-dianhydro-D-sorbitol-5-mononitroester, the English name is 1,4; 3,6-Dianllydro-D-Glueitol-5-Mononitrate . The molecular weight is 191, and the molecular formul...

Claims

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Application Information

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IPC IPC(8): C07D493/04
CPCC07D493/04
Inventor 张贵民陈成富祝士国
Owner SHANDONG NEWTIME PHARMA
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