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Prepn process of isosorbide mononitrate

A technology of nitrate ester and isosorbide, applied in the field of preparation of the compound isosorbide mononitrate, can solve the problems of long process route and increased cost

Active Publication Date: 2005-04-27
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] When adopting this type of method, the yield and purity are all improved, but the process route is long, and during selective acylation, there are higher requirements for the selection of reagents and the control of reaction conditions, wherein a small amount of 5 -Acyl isosorbide by-products require several recrystallizations to remove, increasing costs

Method used

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  • Prepn process of isosorbide mononitrate
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  • Prepn process of isosorbide mononitrate

Examples

Experimental program
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Embodiment 1

[0025] Embodiment 1: Synthesis of intermediate 1,4:3,6-dianhydro-D-sorbitol (3)

[0026] Add 9.5mL of p-toluenesulfonic acid slowly to 310g of 70% sorbitol with stirring and keep warm at 40°C, then slowly raise the temperature under a vacuum of 0.08Mpa to evaporate the water. When the temperature rises to about 117°C, the water is basically evaporated. The vacuum is 0.096Mpa, and the sorbitan is collected below 220°C, with a yield of 91%.

Embodiment 2

[0027] Embodiment 2: 2, the preparation of 5-isosorbide dinitrate (4)

[0028] Dissolve 100g of sorbitan in a mixed solution of 300mL ether, 100mL of acetic acid and 100mL of acetic anhydride. When the internal temperature is controlled at 20-30°C, add a mixed solution of 110g of fuming nitric acid and 30g of concentrated sulfuric acid. After the addition is completed, Continue to react at room temperature for 2.5 h, slowly pour the reaction solution into 1L of ice water, adjust the pH value to 7 with a 30% NaOH solution, let stand to separate the layers, separate the organic phase, and evaporate to dryness under reduced pressure to obtain yellow Concentrate 110g.

Embodiment 3

[0029] Example 3: 1,4; Preparation of 3,6-dianhydro-D-sorbitol-5-nitrate (1)

[0030] Add 100g 2,5-isosorbide dinitrate, 1.7g RuBr to 1000mL isopropanol 2 -(R)-BINAP and 2mL 2,6-lutidine were stirred in 10 atmospheres of hydrogen at room temperature for 2.5h, the resulting solution was filtered, the solvent was evaporated under reduced pressure, and the obtained pale yellow concentrate was dissolved in chloroform and water, Filter out the insoluble matter, separate the chloroform layer, wash with water, anhydrous MgSO 4 Dry, evaporate the solvent by heating to precipitate crystals, and obtain 57 g of 1,4:3,6-dianhydro-D-sorbitol-5-nitrate crystals, yield 70.1%, melting point 91.0-92.0 °C, [α] D 20 +175.6° (ethanol). The infrared spectrum is the same as that of the standard product.

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Abstract

The preparation process of isosorbide mononitrate as angina pectoris resisting medicine includes the following steps: directly nitrating sorbitol with fuming nitric acid and concentrated sulfuric acid in 0-0.5 time to obtain 2, 5-dinitro isosorbate; and the subsequent catalytic hydrogenation with ruthenium complex as catalyst and selective reduction of 2-nitro group. The present invention has simple process and high yield.

Description

technical field [0001] The invention relates to a preparation method of the compound isosorbide mononitrate (1,4:3,6-dianhydro-D-sorbitol-5-nitrate), which belongs to the field of chemical industry and chemical medicine. Background technique [0002] Isosorbide Mononitrate (Isosorbide Mononitrate) is the general name of 1,4:3,6-dianhydro-D-sorbitol-5-nitrate, also known as 5-isosorbide mononitrate, its structural formula is: [0003] [0004] It is a long-acting nitrate antianginal drug, which was discovered in the metabolites of isosorbide dinitrate in the body in the 1960s. In the 1980s, it was first introduced to the market by Bochringer Cnbh in Germany, and then it has been listed in more than ten countries in Europe and America, and has been widely used in clinical practice. my country imported the drug in 1988, and it was widely welcomed by patients. However, the currently used synthetic route has high cost and low yield, which limits the industrial production of ...

Claims

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Application Information

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IPC IPC(8): A61P9/10C07D493/04
Inventor 赵志全
Owner SHANDONG NEWTIME PHARMA
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