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Method for preparing Roflumilast

A technology of roflumilast and difluoromethoxybenzaldehyde, which is applied in the field of preparing N--3-cyclopropylmethoxy-4-difluoromethoxybenzamide, can solve the problem of low yield and difficult Purification, many by-products and other problems, to achieve the effect of high reaction selectivity, easy to obtain raw materials and simple post-treatment

Inactive Publication Date: 2013-04-17
SHANDONG RUIHE PHARMA R&D CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In addition, formula (5) is the key intermediate for the synthesis of roflumilast. The world patent WO2005026095 reports that 3,4-dihydroxybenzoic acid methyl ester is used as the starting material through selective cyclopropylmethylation and chlorofluorocarbon difluoromethane The key intermediate formula 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (5) of roflumilast is synthesized by 3-step reaction of hydrolysis and hydrolysis of sodium hydroxide. The advantage of this scheme is that the steps are short, but There are also obvious disadvantages: many by-products and difficult to purify
The first step of this method is poor in selectivity, that is, there are many by-products, it is not easy to purify and the yield is low, which is the shortcoming of this route; in addition, the bromine step, the temperature is about -55 °C, which is relatively harsh and not suitable for industrial production ; Bromine is converted into carboxyl in one step, palladium catalyst and carbon monoxide poisonous gas are used, and the cost and safety aspects are not suitable for industrial production

Method used

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  • Method for preparing Roflumilast
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  • Method for preparing Roflumilast

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Synthesis of 3-cyclopropylmethoxy-4-methoxybenzaldehyde formula (2):

[0031] 1.3kg isovanillin (8.55mol), 1.768kg (13.09mol) bromomethylcyclopropane, 1.768kg (12.8mol) anhydrous potassium carbonate, 6.175L anhydrous dimethylformamide, 6.5 g benzyltriethylammonium chloride (0.028mol), stirred at 30°C. The system is yellow and turbid, and gradually turns white as the reaction progresses. After reacting for 9 hours, TLC detected that the reaction was complete.

[0032] After the reaction was completed, filter, the filtrate was concentrated under reduced pressure, dissolved in 5L ethyl acetate, washed five times with 1L saturated sodium carbonate solution, washed with water until neutral, dried over sodium sulfate, concentrated under reduced pressure to obtain 1.655kg (8.03mol) of off-white solid, yield 93.8% (HPLC purity 99%)

Embodiment 2

[0034] Synthesis of 3-cyclopropylmethoxy-4-methoxybenzaldehyde formula (2):

[0035] 1.3kg isovanillin (8.55mol), 1.185kg (13.09mol) chloromethylcyclopropane, 1.768kg (12.8mol) anhydrous potassium carbonate, 6.175L anhydrous dimethylformamide, 6.5 g benzyltriethylammonium chloride (0.028mol), stirred at 80°C. The system is yellow and turbid, and gradually turns white as the reaction progresses. After reacting for 9 hours, TLC detected that there was still a small amount of unreacted raw material in the reaction.

[0036] Filtrate, concentrate the filtrate under reduced pressure, dissolve in 5L ethyl acetate, wash with 1L saturated sodium carbonate solution five times, wash with water until neutral, dry over sodium sulfate, concentrate under reduced pressure to obtain off-white solid 1.12kg (8.03mol), yield 93.5% ( HPLC purity 96%)

Embodiment 3

[0038] Synthesis of important intermediate formula (3) of roflumilast:

[0039] Add 2.68kg dodecanethiol (13.24mol), 716.8g (13.27mol) sodium methylate, 6kg dimethylformamide, 12g benzyltriethylammonium chloride (0.052mol) successively in the 20L reaction flask, 1.6kg ( 7.77mol) of 3-cyclopropylmethoxy-4-methoxybenzaldehyde, under nitrogen protection, then heated in an oil bath to an internal temperature of 100°C, and kept warm at 100°C, the system was gray and turbid, and as time went on, the system became It is dark gray and cloudy. The temperature was maintained at 100° C. for 8 hours, and TLC detected that the reaction was complete.

[0040] Cool down to room temperature and add a solution of 742g sodium hydroxide and 21.7kg deionized water, stir for 15 minutes, filter, and extract 2.7L×3 times with ethyl acetate. While stirring the water phase, add concentrated hydrochloric acid dropwise to adjust pH = 4, extract 4.5 L x 3 times with ethyl acetate, combine the organic p...

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Abstract

The invention discloses a method for preparing Roflumilast. The method comprises the following steps of: performing cyclopropyl methylation on isovanillin to obtain 3-cyclopropylmethoxy-4-methoxybenzaldehyde; performing demethylation to synthesize an important intermediate of the Roflumilast, namely 3-cyclopropylmethoxy-4hydroxyl-benzaldehyde; and further synthesizing a key intermediate in a formula (5) according to American patent US5712298 and finally synthesizing the Roflumilast in a formula (7). A crude product of the Roflumilast is treated by isopropanol and water, and is recrystallized by ethyl acetate and petroleum ether. The preparation method has a few steps, raw materials are readily available and cheap, the reaction selectivity is high, the yield is high and the post treatment is simple.

Description

technical field [0001] The present invention relates to a new method for preparing N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (Roflumilast) The method belongs to the technical field of medicine. Background technique [0002] Roflumilast is a drug used to treat chronic obstructive pulmonary disease. Chinese name: Roflumilast; English name: Roflumilast Cas: 162401-32-3; Chemical name: 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)- 4-(difluoromethoxy)benzamide, the structural formula is as follows. [0003] [0004] US Patent No. 5,712,298 reports a synthetic method for preparing roflumilast, and formula (3) is the starting material of its synthetic method, but this raw material is hardly commercially available. [0005] [0006] In addition, formula (5) is the key intermediate for the synthesis of roflumilast. The world patent WO2005026095 reports that 3,4-dihydroxybenzoic acid methyl ester is used as the starting material throu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/75
Inventor 丁克朱克明肖广常
Owner SHANDONG RUIHE PHARMA R&D CO LTD
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