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Method for synthesizing 5-isosorbide mononitrate through micro-channel reactor

A technology of isosorbide dinitrate and microchannel reactor, which is applied in organic chemistry and other fields, can solve problems such as poor reaction selectivity, low yield, and potential safety hazards in the process, and achieve less side reactions, large specific surface area, and easy reaction conditions The effect of control

Active Publication Date: 2018-09-28
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 defect that the technology has potential safety hazards, the inventor provides a kind of safe and efficient synthesis of 5- Isosorbide mononitrate method

Method used

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  • Method for synthesizing 5-isosorbide mononitrate through micro-channel reactor
  • Method for synthesizing 5-isosorbide mononitrate through micro-channel reactor
  • Method for synthesizing 5-isosorbide mononitrate through micro-channel reactor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] (1) Preparation of nitrating reagent: Add acetic anhydride (260.0g, 2.5mol) into a 500mL dry three-neck flask, control the temperature at 0-10°C, slowly add fuming nitric acid (108.0g, 1.7mol) dropwise, add dropwise When finished, keep warm for later use.

[0047] (2) Preparation of isosorbide solution: in a 2L dry there-necked flask, add isosorbide (250.0g, 1.7mol), isosorbide dinitrate (12.5g, 0.053mol), add 750mL acetic acid / ethyl acetate ( v / v=2:1) ​​mixed solvent, stirred and dissolved for later use.

[0048] (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.

[0049] (4) After the reaction efflu...

Embodiment 2

[0054] (1) Preparation of nitrating reagent: In a 1L dry three-necked flask, add acetic anhydride (347.0g, 3.4mol), control the temperature at 0-10°C, slowly add fuming nitric acid (108.0g, 1.7mol) dropwise, add dropwise When finished, keep warm for later use.

[0055] (2) Preparation of isosorbide solution: in a 2L dry there-necked flask, add isosorbide (250.0g, 1.7mol), isosorbide dinitrate (37.5g, 0.159mol), add 750mL acetic acid / dichloromethane ( v / v=1:2) mixed solvent, stirred and dissolved for later use.

[0056] (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.

[0057] (4) After the r...

Embodiment 3

[0062] (1) Preparation of nitrating reagent: In a 1L dry three-necked flask, add acetic anhydride (347.0g, 3.4mol), control the temperature at 0-10°C, slowly add fuming nitric acid (108.0g, 1.7mol) dropwise, add dropwise When finished, keep warm for later use.

[0063] (2) Preparation of isosorbide solution: In a 2L dry three-necked flask, add isosorbide (250.0g, 1.7mol), isosorbide dinitrate (75.0g, 0.318mol), add 950mL acetic acid / dichloromethane / A mixed solvent of tetrahydrofuran (v / v / v=3:1:1), stirred and dissolved for later use.

[0064] (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.

[0065] (4) ...

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Abstract

The invention belongs to the field of medicine synthesis, and particularly discloses a method for synthesizing 5-isosorbide mononitrate through a micro-channel reactor. According to the method, a nitrating reagent and isosorbide liquid are pumped into the micro-channel reactor respectively for mixing reaction, after the reaction is completed, a product flows out from an outlet of the micro-channelreactor, and through post-treatment, separation and purification, the objective product 5-isosorbide mononitrate is obtained. According to the method, reaction time is short, and compared with a traditional technology, the method is safe, and the yield of the 5-isosorbide mononitrate is greatly improved.

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 in 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 pract...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04
CPCC07D493/04
Inventor 张贵民陈成富朱健波
Owner LUNAN PHARMA GROUP CORPORATION
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