Roflumilast intermediates, preparation methods of intermediates and preparation method of roflumilast
A technology for roflumilast and intermediates, which is applied in the preparation of organic compounds, the preparation of carboxylic acids by oxidation, and the preparation of carbon-based compounds, can solve the problems of many reaction steps, complex synthesis conditions, and difficult to master.
Active Publication Date: 2015-03-25
广西铭磊维生制药有限公司
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Problems solved by technology
[0004] The object of the present invention is to provide two kinds of improved roflumilast intermediates for the above-mentioned deficiencies in the prior art, and provide an improved preparation method of roflumilast with the improved intermediates as raw materials to solve the existing problems There are many reaction steps in the process, complex synthesis conditions, difficult to master and other shortcomings
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[0057] 1. Preparation of roflumilast grade I intermediate:
[0058] Add 160ml DMF to the reactor containing 80gRM1, stir evenly, add 117.5g potassium carbonate and 62.8g RM2 under the water bath condition of 40°C, then raise the temperature to 60°C for 2h, add TLC (developing agent, petroleum ether) after 2h / ethyl acetate), no raw material RM1 can be detected, indicating that RM1 disappears, and the reaction is over; then cool down to 10°C in an ice-water bath, add 400ml of pure water dropwise, stir for 30min, let stand and separate the organic phase, and pour into Add 200ml isopropyl ether to the water layer for extraction, the extracted organic phase and the separated organic phase are combined and washed three times with pure water, 50ml each time; then add 50ml saturated saline to wash once, and then dry with magnesium sulfate to isopropyl ether. The ether solution was not turbid and had no water droplets on the surface. Finally, it was concentrated under reduced pressure...
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The invention discloses roflumilast intermediates, preparation methods of the intermediates and a preparation method of roflumilast. The preparation methods of the roflumilast intermediates and the preparation method of roflumilast comprise the steps of firstly, carrying out condensation reaction on 3-difluoromethoxy-4-hydroxybenzaldehyde (RM1) serving as a raw material and bromomethyl cyclopropane (RM2) to obtain an I-grade roflumilast intermediate; then, carrying out addition reaction on the I-grade roflumilast intermediate serving as a raw material as well as sulfamic acid and sodium chlorite to obtain an II-grade roflumilast intermediate; and next, carrying out chloroformylation reaction on the II-grade roflumilast intermediate serving as a raw material and thionyl chloride, then, carrying out acylation reaction on the II-grade roflumilast intermediate and 3-amino-2, 4-dichloropyridine (RM3) to obtain crude roflumilast, and purifying the crude roflumilast to obtain fine roflumilast. The I-grade roflumilast intermediate and the II-grade roflumilast intermediate which are used as important intermediates are respectively prepared, so that not only is the technological process simplified, but also the difficulty for working staff to master the method is further lowered, and the work efficiency is increased.
Description
technical field [0001] The invention belongs to the technical field of biomedicine and relates to a preparation method of roflumilast, in particular to several key intermediates of roflumilast, a preparation method of the intermediates and a preparation method using these intermediates of roflumilast. Background technique [0002] Roflumi last, chemical name: 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzyl Amide, whose CAS number is: 162401-32-3, is an oral anti-inflammatory drug developed by Nycomed GmbH in Switzerland for the treatment of tracheobronchial asthma and chronic obstructive pneumonia. Roflumilast is a selective benzamide-based second-generation phosphodiesterase IV inhibitor, which blocks the pulmonary inflammatory process that leads to COPD by inhibiting the activity of PDE4, thereby reducing the symptoms of patients and preventing disease progression . [0003] The original roflumilast preparation method has the following defec...
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IPC IPC(8): C07C45/61C07C47/575C07C51/16C07C65/26C07D213/75
CPCC07C45/68C07C47/575C07C51/16C07C2601/02C07D213/75C07C65/26
Inventor 晏柳清田兴华翁生林
Owner 广西铭磊维生制药有限公司