Method for synthesizing 5-isosorbide mononitrate by aid of micro-channel reactors

A technology of microchannel reactor and isosorbide dinitrate, which is applied in the direction of organic chemistry, can solve the problems of poor reaction selectivity, potential safety hazards in the process, and low yield, and achieve less side reactions, easy control of reaction conditions, and high specific surface area. big effect

Active Publication Date: 2018-10-02
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Aiming at the low yield existing in the direct nitration method in the above-mentioned prior art, the reaction selectivity is poor, and the def

Method used

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  • Method for synthesizing 5-isosorbide mononitrate by aid of micro-channel reactors
  • Method for synthesizing 5-isosorbide mononitrate by aid of micro-channel reactors
  • Method for synthesizing 5-isosorbide mononitrate by aid of micro-channel reactors

Examples

Experimental program
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Effect test

Embodiment 1

[0047] (1) Preparation of nitrating reagent: Add acetic anhydride (260g, 2.5mol) into a 500mL dry three-neck flask, control the temperature at 0-10°C, slowly add fuming nitric acid (108g, 1.7mol) dropwise, after the addition is complete , heat preservation spare.

[0048] (2) Preparation of isosorbide solution: in a 2L dry there-necked flask, add isosorbide (250g, 1.7mol), add 750mL of acetic acid / ethyl acetate (v / v=2:1) ​​mixed solvent, stir Ready to use after dissolving.

[0049] (3) Feed nitrating reagent and isosorbide liquid into microchannel reactor by respective metering pumps and carry out mixed reaction, set nitrating reagent flow rate as 15mL / min, the flow rate of isosorbide liquid is 45mL / min, control reaction The temperature is 0°C, 5 templates are connected in series, the liquid holding capacity is 50mL, and the reaction time of the reaction solution in the microchannel reactor is 50s.

[0050] (4) The reaction effluent is sampled and detected by GC, and the rem...

Embodiment 2

[0054] Example 2 (1) Preparation of nitrating reagent: In a 1L dry there-necked flask, add acetic anhydride (347g, 3.4mol), control the temperature at 0-10°C, slowly add fuming nitric acid (108g, 1.7mol) dropwise, After adding, keep warm for later use. (2) Preparation of isosorbide solution: in a 2L dry there-necked flask, add isosorbide (250g, 1.7mol), add 750mL acetic acid / dichloromethane (v / v=1:2) mixed solvent, stir Ready to use after dissolving. (3) Feed nitrating reagent and isosorbide liquid into the microchannel reactor by respective metering pumps and carry out mixed reaction, setting nitrating reagent flow rate is 5mL / min, and the flow rate of isosorbide liquid is 15mL / min, control reaction The temperature is 20°C, 10 templates are connected in series, the liquid holding capacity is 100mL, and the reaction time of the reaction solution in the microchannel reactor is 300s. (4) The reaction effluent is sampled and detected by GC, and the remaining amount of isosorbid...

Embodiment 3

[0058] Example 3 (1) Preparation of nitrating reagent: In a 1L dry there-necked flask, add acetic anhydride (347g, 3.4mol), control the temperature at 0-10°C, slowly add fuming nitric acid (108g, 1.7mol) dropwise, dropwise After adding, keep warm for later use. (2) Preparation of isosorbide solution: in a 2L dry there-necked flask, add isosorbide (250g, 1.7mol), add 950mL acetic acid / dichloromethane / tetrahydrofuran (v / v / v=3:1:1 ) mixed solvent, stirred and dissolved for later use. (3) Feed nitrating reagent and isosorbide liquid into microchannel reactor by respective metering pumps and carry out mixed reaction, set nitrating reagent flow rate as 20mL / min, the flow rate of isosorbide liquid is 50mL / min, control reaction The temperature is 10°C, 5 templates are connected in series, the liquid holding capacity is 50mL, and the reaction time of the reaction solution in the microchannel reactor is 43s. (4) Reaction effluent sampling and GC detection: calculate the remaining amou...

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Abstract

The invention belongs to the field of medicine synthesis, and particularly discloses a method for synthesizing 5-isosorbide mononitrate by the aid of micro-channel reactors. The method includes pumping nitrification reagents and isosorbide liquid into the micro-channel reactors and carrying out hybrid reaction; allowing products to flow out from outlets of the micro-channel reactors after the reaction is completely carried out; carrying out after-treatment on the products and separating and purifying the products to obtain the 5-isosorbide mononitrate which is a target product. The method hasthe advantages that the method is short in reaction time and is safe as compared with the traditional processes, and the yield of the 5-isosorbide mononitrate can be greatly increased.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, in particular to a method for synthesizing isosorbide 5-mononitrate, in particular to a method for synthesizing isosorbide 5-mononitrate by using a microchannel reactor. Background technique [0002] 5-isosorbide mononitrate (1,4:3,6-dianhydro-D-sorbitol-5-nitrate, structural formula as compound 1 in formula I) is isosorbide dinitrate (1,4:3,6 -dianhydro-D-sorbitol-2,5-dinitrate, structural formula such as compound 2 in formula I) main metabolite in vivo, compared to isosorbide dinitrate and 2-isosorbide mononitrate (1, 4: 3,6-dianhydro-D-sorbitol-2-nitrate, the structural formula is as compound 3 in formula I), it has no liver first-pass effect after oral administration, high bioavailability, small side effects and long duration of action It was developed and marketed by Boehringer Mannheim GmbH in Germany in 1981. At present, isosorbide 5-mononitrate has been widely used in clinical...

Claims

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Application Information

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IPC IPC(8): C07D493/04
CPCC07D493/04
Inventor 祝士国张福利
Owner LUNAN PHARMA GROUP CORPORATION
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