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Method for preparing Roflumilast raw material and intermediates

A technology of roflumilast and intermediates, which is applied in the field of preparation of roflumilast raw materials and intermediates, can solve problems such as low yield, difficult storage and use, and greenhouse effect, and achieve high product yield and low production cost. Low, well-conceived effects

Inactive Publication Date: 2012-07-04
SICHUAN BAILI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In this preparation method, difluorochloromethane is used in the first step reaction, the product is a gas, and the reaction requires the use of high-pressure equipment, which is not easy to store and use in production
Simultaneously this gas is extremely easy to destroy the ozone layer, causes greenhouse effect; Used aminosulfuric acid and glacial acetic acid in the second step reaction, and after reaction processing is complicated and product purity is not high, needs to be refined with acetonitrile and sherwood oil, causes yield very low, is not good conducive to industrial production

Method used

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  • Method for preparing Roflumilast raw material and intermediates
  • Method for preparing Roflumilast raw material and intermediates
  • Method for preparing Roflumilast raw material and intermediates

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Experimental program
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Embodiment 1

[0025] Embodiment 1: a kind of preparation method of roflumilast raw material and intermediate, comprises the following steps:

[0026] 1. Preparation of 4-difluoromethoxy-3-cyclopropylmethoxybenzaldehyde (intermediate Ⅰ)

[0027]

[0028] Add 1000ml of N,N-dimethylformamide into the three-necked flask, add 350g of 4-difluoromethoxy-3-hydroxybenzaldehyde, 200ml of bromomethylcyclopropane, 350g of anhydrous potassium carbonate, Potassium iodide 140g, stirred and reacted for 6 hours, added 2000ml of water and 1000ml of ethyl acetate, stirred and separated, the aqueous phase was extracted once with 200ml of ethyl acetate, the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was depressurized to recover ethyl acetate Ester to dryness, the obtained 423g oily substance is intermediate I, the yield of this process is 94%, and the HPLC purity is 99.7%.

[0029] 2. Preparation of 4-difluoromethoxy-3-cyclopropylmethoxybenzoic acid (intermed...

Embodiment 2

[0037] Embodiment 2: a kind of preparation method of roflumilast raw material and intermediate, comprises the following steps:

[0038] 1. Preparation of 4-difluoromethoxy-3-cyclopropylmethoxybenzaldehyde (intermediate Ⅰ)

[0039]

[0040] Add 1000ml of N,N-dimethylformamide into the three-necked flask, add 300g of 4-difluoromethoxy-3-hydroxybenzaldehyde, 150ml of bromomethylcyclopropane, 220g of anhydrous potassium carbonate, Potassium iodide 120g, stirred and reacted for 3 hours, added 2000ml of water and 1000ml of ethyl acetate, stirred and separated, the water phase was extracted once with 200ml of ethyl acetate, the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was depressurized to recover ethyl acetate Ester to dryness, the obtained 347g oily substance is Intermediate I, the yield of this process is 90%, and the HPLC purity is 98.6%.

[0041] 2. Preparation of 4-difluoromethoxy-3-cyclopropylmethoxybenzoic acid (intermedia...

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Abstract

The invention discloses a method for preparing a Roflumilast raw material and intermediates. The method includes steps as follows:, 4-difluoromethoxy-3-hydroxy benzaldehyde reacts with cyclopropylmethylbromide under the conditions of solvent and catalytic agents, and then 4-difluoromethoxy-3-cyclopropyl methoxybenzaldehyde is obtained after extraction and recovery; 4-difluoromethoxy-3-cyclopropyl methoxybenzaldehyde reacts with potassium permanganate in a solvent environment, and 4-difluoromethoxy-3-cyclopropyl methoxybenzoic acid is obtained through post-processing; and 4-difluoromethoxy-3-cyclopropyl methoxybenzoic acid reacts with 4-amino-3,5-dichloropyridine under the conditions of solvent and thionyl chloride, and crude Roflumilast products are obtained through post-processing. The method has the advantages of skillful concept, simple process, low manufacturing cost, high product yield coefficient and no generation of harmful gas.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and relates to a preparation method of roflumilast raw materials and intermediates. Background technique [0002] Roflumilast (Roflumilast, Chinese chemical name ： N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide) is a second-generation phosphodiesterase IV inhibitor of benzamides Agent for the treatment of tracheobronchial asthma, chronic obstructive pneumonia. Compared with other second-generation phosphodiesterase IV inhibitors, roflumilast has the advantages of repairing damaged airway tissue and less side effects. Roflumilast can specifically act on a certain enzyme involved in smooth muscle contraction, thereby blocking the signal transmission of pro-inflammatory response, has anti-inflammatory activity, and has achieved good curative effect in the clinical treatment of asthma and COPD. Smooth muscle contraction is one of the characteristics of bronc...

Claims

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Application Information

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IPC IPC(8): C07D213/75
CPCY02P20/584
Inventor 王一茜戚太林刘威加
Owner SICHUAN BAILI PHARM CO LTD
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