Method for synthesizing candesartan cilexetil intermediate

A technology of nitrobenzoate and microchannel reactor, which is applied in chemical instruments and methods, preparation of organic compounds, chemical/physical/physicochemical processes, etc., and can solve high reaction heat, long production time, and raw material consumption and other problems, to achieve the effect of simple preparation process, stable product quality and short residence time

Pending Publication Date: 2022-01-14
LINHAI HUANAN CHEM CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the poor thermal stability of the acyl azide, it is easy to decompose and explode. Usually, the heat transfer efficiency of the reactor is poor. Hidden dangers; the rearrangement reaction has a high heat of reaction, requires extremely slow feeding speed to control heat transfer, the process operation is cumbersome, the production time is long, and the production efficiency is low; moreover, the acyl azide is unstable and easily decomposes itself, resulting in products , consumes raw materials and affects product quality at the same time

Method used

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  • Method for synthesizing candesartan cilexetil intermediate
  • Method for synthesizing candesartan cilexetil intermediate
  • Method for synthesizing candesartan cilexetil intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0053] Synthesis of ethyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate

[0054]Dissolve ethyl 2-(chlorocarbonyl)-3-nitrobenzoate in a non-polar organic solvent to make a 1mol / L solution, dissolve sodium azide in a polar solvent to make a 0.5mol / L solution; In the continuous flow reactor, the ethyl 2-(chlorocarbonyl)-3-nitrobenzoate solution is passed through the first pre-cooling module with a metering pump (flow rate 1mL / s), and the temperature of the pre-cooling medium is controlled at 0°C; The sodium azide solution passes through the second pre-cooling module with a metering pump (flow rate 2mL / s), and the pre-cooling medium is controlled at 0°C; after the two solutions are mixed, they pass through the first reaction module at 0°C within 30 seconds; for drinking water The metering pump (flow rate 1mL / s) passes through the third pre-cooling module, and the pre-cooling medium is controlled at 2°C. After the feed liquid is output from the first reaction module, it is mixed w...

Embodiment 2

[0058] Synthesis of ethyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate

[0059] Dissolve ethyl 2-(chlorocarbonyl)-3-nitrobenzoate in toluene to make a toluene solution, dissolve sodium azide in water to make an aqueous solution; in a continuous flow reactor, 2-(chlorocarbonyl)- The toluene solution of ethyl 3-nitrobenzoate passes through the first pre-cooling module at a flow rate of 1mL / s with a metering pump, and the temperature of the pre-cooling medium is controlled at 0°C; The flow rate passes through the second pre-cooling module, and the pre-cooling medium is controlled at 0°C; after the two solutions are mixed, they pass through the first reaction module at 0°C within 30 seconds; the drinking water passes through the first reaction module at a flow rate of 0.5mL / s Three pre-cooling modules, the pre-cooling medium is controlled at 2°C, the feed liquid is output from the first reaction module, mixed with the drinking water from the pre-cooling module, and enters the co...

Embodiment 3

[0063] Synthesis of Methyl 2-((tert-Butoxycarbonyl)amino)-3-nitrobenzoate

[0064] Dissolve methyl 2-(chlorocarbonyl)-3-nitrobenzoate in toluene to make a 0.5mol / L solution, dissolve sodium azide in water to make a 0.5mol / L solution; in a continuous flow reactor , the ethyl 2-(chlorocarbonyl)-3-nitrobenzoate solution is passed through the first pre-cooling module with a metering pump (flow rate 1mL / s), and the temperature of the pre-cooling medium is controlled at 0°C; the sodium azide solution is metered The pump (flow rate 1mL / s) passes through the second pre-cooling module, and the pre-cooling medium is controlled at 0°C; after the two solutions are mixed, they pass through the first reaction module at 0°C within 30 seconds; the metering pump for drinking water (flow rate 0.5mL / s) After the third pre-cooling module, the pre-cooling medium is controlled at 2°C. After the feed liquid is output from the first reaction module, it is mixed with the drinking water from the pre-c...

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Abstract

The invention relates to a continuous-flow production process for synthesizing a candesartan cilexetil intermediate, belonging to the technical field of fine chemical engineering. The invention particularly relates to a process for continuously preparing 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate by using a microchannel reactor. The process comprises the following steps: carrying out staying reaction on 2-(chlorocarbonyl)-3-nitrobenzoate and sodium azide in a first reaction module; then allowing reaction liquid and water to simultaneously enter a continuous separator for separation; and subjecting an organic layer obtained through separation to reacting with tert-butyl alcohol in a second reaction module to obtain a target product. The method provided by the invention is safe, simple to operate, efficient and easy for large-scale production.

Description

technical field [0001] The invention relates to a continuous flow production process for synthesizing candesartan cilexetil intermediate, which belongs to the application technical field of fine chemical process in the production of raw materials. Background technique [0002] Candesartan cilexetil is an effective highly selective angiotensin II type receptor antagonist antihypertensive drug, which was developed by Takeda Corporation of Japan and first listed in Sweden in November 1997. Its chemical name is ( ±)-2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzimidazole -7-Formic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester, the chemical structural formula is as shown in formula I: [0003] [0004] 2-((tert-butoxycarbonyl) amino)-3-nitrobenzoate is a key intermediate for the synthesis of candesartan cilexetil, and its structural formula is as shown in formula II: [0005] [0006] Wherein R is methyl or ethyl. [0007] The synthesis route o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/00C07C269/08C07C271/28B01J19/00
CPCC07C269/00C07C269/08B01J19/0093B01J19/0046B01J2219/00873B01J2219/00889C07C271/28
Inventor 黄健升涂国良靳和平王甦刘恒
Owner LINHAI HUANAN CHEM CO LTD
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