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Synthetic method for roflumilast

A synthetic method, the technology of roflumilast, applied in the field of preparation of small molecule chemical drugs, can solve the problems of difficult scale-up production, high price and high production cost, and achieve the effects of high total yield, low cost and short process route

Active Publication Date: 2015-04-15
ARROMAX PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In the above method, expensive palladium acetate, Pd / C catalyst and dehydrating agent HATU are used, and the production cost is relatively high; in addition, the synthesis requires special equipment, and it is not easy to scale up production

Method used

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  • Synthetic method for roflumilast
  • Synthetic method for roflumilast
  • Synthetic method for roflumilast

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Synthetic compound (II)

[0033]

[0034] Example 1-1: Add anhydrous THF (50ml) and a small amount of iodine to a 250ml three-necked bottle of magnesium metal strips (0.12mol, 2.88g), and heat to 40°C. Then compound (I) (0.1 mol, 29.3 g) in THF (100 ml) was added dropwise. After the dropwise addition, continue heating to reflux for 2 hours, and then pass CO at 50°C 2 gas. After the reaction was completed, dilute hydrochloric acid was added to the reaction solution to adjust to acidity, extracted with EtOAc (60ml×3), anhydrous Na 2 SO 4 Dry, filter, and concentrate to obtain carboxylic acid compound (II) (white solid, 23.5 g, yield 91%).

[0035] 1 H-NMR (CDCl 3 ,400MHz,δppm):0.32-0.36(m,2H),0.60-0.68(m,2H),1.20-1.24(m,1H),3.90(d,J=6.6Hz,2H),6.70(t,J =76Hz,1H,CHF 2 ), 7.16 (d, J=7.2Hz, 1H), 7.60-7.66 (m, 2H).

example 1-2

[0036] Example 1-2: Add anhydrous 2-methyltetrahydrofuran (50ml) and a small amount of iodine to a 250ml three-necked flask of metal magnesium strips (0.12mol, 2.88g), and heat to 40°C. Then compound (I) (0.1 mol, 29.3 g) in THF (100 ml) was added dropwise. After the dropwise addition was completed, continue heating to reflux for 2 hours, and then put crushed dry ice (10 g) at 40°C. After the reaction was finished, dilute hydrochloric acid was added to the reaction solution to adjust to acidity, extracted with EtOAc (70ml×3), anhydrous Na 2 SO 4 Dry, then filter and concentrate to obtain carboxylic acid compound (II) (23.8 g, yield 92.2%).

[0037] Example 1-3: At room temperature, compound (I) (0.1mol, 29.3g) was dissolved in 1,4-dioxane (100ml) in a 250ml three-necked flask, and then methylmagnesium chloride (MeMgCl, 0.11mol ) THF solution. After the dropwise addition was completed, heat to reflux for 1 hour, and then put crushed dry ice at 30°C. After the reaction was ...

example 1-8

[0042] Example 1-8: at room temperature, compound (I) (0.1mol, 29.3g) was dissolved in n-butyl ether (100ml) in a 250ml three-necked flask, and then added dropwise with isopropylmagnesium chloride (MeMgCl, 0.11mol) THF solution. After the dropwise addition was completed, it was heated to reflux for 1 hour. It was then cooled to 0°C and put into crushed dry ice. After the reaction was completed, dilute hydrochloric acid was added to adjust to acidity, extracted with EtOAc (80ml×3), anhydrous Na 2 SO 4 Dry, then filter and concentrate to obtain carboxylic acid compound (II) (23.5 g, yield 90.9%).

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Abstract

The invention provides a synthetic method for roflumilast. The method comprises the following steps: (a), in an organic solvent, producing an exchange reaction of a compound (I) and magnesium or a Grignard reagent under the backflow condition to generate an intermediate, and producing a carbonyl insertion reaction of the intermediate and carbon dioxide at 0-50 DEG C to obtain a compound (II); or in the organic solvent, reacting the compound (I) with n-butyl lithium at 90 DEG C below zero to 70 DEG C below zero to generate an intermediate, and producing a carbonyl insertion reaction of the intermediate and carbon dioxide at 90 DEG C below zero to 70 DEG C below zero to obtain a compound (II); (b) in the organic solvent, reacting the compound (II) obtained in the step (a) with pivaloyl chloride or sulfonyl chloride at 0-50 DEG C in the presence of alkali to generate a mixed anhydride intermediate, and reacting the mixed anhydride intermediate with 3,5-dichloro-4-aminopyridine at 0-70 DEG C to obtain a compound (III) which is roflumilast. The method is short in process route, low in raw material and reagent costs, high in total yield, mild in reaction condition and suitable for industrialized production. The synthetic route of the method is as shown in the descriptions.

Description

technical field [0001] The invention relates to the field of preparation of small molecule chemical drugs, and more particularly relates to a synthesis method of roflumilast. Background technique [0002] Roflumilast (roflumilast), the chemical name is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide, which is produced by Germany Anda (Altana) company research and development, the phosphodiesterase 4 (PDE4) inhibitor of Swiss Nycomed Pharma GmbH completed the phase III clinical trial, and was approved in Europe in July 2010, and then in Germany, the United Kingdom and China Listed in Spain, its trade name is Daxas. In March 2011, it was approved by the US FDA and launched in the US. Roflumilast is a selective phosphodiesterase type 4 (PDE-4) long-acting inhibitor with anti-inflammatory effects. Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor and a new type of COPD treatment drug. It is used to treat symptoms of bronchitis-associated cou...

Claims

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Application Information

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IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 洪健刘国斌
Owner ARROMAX PHARMATECH
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