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A kind of preparation method of 5-substituted cyclopropyl carboxamido indole derivatives

A kind of technology of cyclopropylcarboxamido indole derivatives and substituents, which is applied in the preparation of Tezacaftor and the field of preparation of 5-substituted cyclopropylcarboxamido indole derivatives, can solve the problem of long synthetic route steps and unfavorable industrialization Production, poor atom economy and other problems, to achieve the effect of low cost, suitable reactivity and good stability

Active Publication Date: 2021-09-07
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The above synthetic route has long steps, cumbersome operation, poor atom economy and high cost, which is not conducive to the realization of industrial production

Method used

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  • A kind of preparation method of 5-substituted cyclopropyl carboxamido indole derivatives
  • A kind of preparation method of 5-substituted cyclopropyl carboxamido indole derivatives
  • A kind of preparation method of 5-substituted cyclopropyl carboxamido indole derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080]Embodiment 1: Preparation of 2-nitro-4-fluoro-5-aminophenylacetonitrile (Ⅲ)

[0081] In a 1000 ml stainless steel pressure vessel connected with a stirring and thermometer, add 300 g of tetrahydrofuran, 198.2 g (1.0 mole) of 2-nitro-4,5-difluorophenylacetonitrile (II 1 ), 250.0 grams (2.5 moles) of 17% ammonia water, close the autoclave, stir and react at 80 to 85°C for 5 hours, cool to 25-30°C, transfer the resulting reaction liquid to a four-necked flask, distill and recover the solvent, and transfer to the residue Add 400 grams of water to the mixture, filter, wash with water twice, each time with 100 grams of water, and dry to obtain 186.0 grams of 2-nitro-4-fluoro-5-aminobenzylnitrile (Ⅲ), the yield is 95.3%, and the liquid phase 99.6% purity.

Embodiment 2

[0082] Example 2: Preparation of 2-nitro-4-fluoro-5-aminophenylacetonitrile (Ⅲ)

[0083] Add 198.2 grams (1.0 moles) of 2-nitro-4,5-difluorophenylacetonitrile (II 1 ), 530 grams of 8% ammonia isopropanol solution, close the autoclave, stir and react at 90 to 95°C for 3 hours, cool to 25-30°C, transfer the resulting reaction liquid to a four-necked flask, distill and reclaim the solvent, and transfer to the residue Add 400 grams of water to the mixture, filter, wash with water twice, each time with 100 grams of water, and dry to obtain 187.1 grams of 2-nitro-4-fluoro-5-aminobenzylnitrile (Ⅲ), the yield is 95.9%, and the liquid phase 99.7% purity.

Embodiment 3

[0084] Example 3: Preparation of 2-nitro-4-fluoro-5-aminophenylacetonitrile (Ⅲ)

[0085] To a 1000 ml four-necked flask connected with stirring, a thermometer and a reflux condenser, add 214.5 g (1.0 mole) of 2-nitro-4-fluoro-5-chlorophenylacetonitrile (II 2 ), 550 grams of 8% ammonia-n-butanol solution, stirred and reacted for 3 hours at 100 to 105 ° C, cooled to 75-80 ° C, and reclaimed the solvent by distillation under reduced pressure, added 400 grams of water to the residue, filtered, and washed twice with water, 100 g of water each time and dried to obtain 186.6 g of 2-nitro-4-fluoro-5-aminophenylacetonitrile (Ⅲ), with a yield of 95.6% and a liquid phase purity of 99.5%.

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Abstract

The invention provides a method for preparing a 5-substituted cyclopropylcarboxamide indole derivative, specifically a method for preparing Tezacaftor. Using 2-nitro-4-fluoro-5-halogenated phenylacetonitrile as the starting material, through ammonia substitution reaction, amidation reaction, dehydration condensation reaction, reductive ring closure reaction-elimination reaction, ring-opening substitution reaction and catalytic hydrogenolysis The reaction gives Tezacaftor. The raw materials of the method of the present invention are cheap and easy to obtain, the reaction steps are short, the preparation method is simple and safe, easy to implement, and low in cost; the design of the route of the present invention fully combines the inherent characteristics of the functional group reaction to ensure that the unit reaction activity of each step is suitable and the selectivity is high. The method provides an essential guarantee for the high yield and high purity of the product; the route of the present invention has high atomic economy, high product yield and purity, less waste acid waste water generation, green environmental protection, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a 5-substituted cyclopropylcarboxamide indole derivative, specifically a preparation method of Tezacaftor, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] The 5-substituted cyclopropylcarboxamidoindole derivative Tezacaftor is the main component of the CFTR activity modulator combination drug Tezacaftor / Ivacaftor developed by Vertex Pharms, which was approved by the US FDA on February 13, 2018. It is used for Treatment of cystic fibrosis patients over 12 years of age. The chemical name of Tezacaftor is (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-di Hydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropylcarboxamide, CAS number is [1152311-62- 0], the molecular formula is C 26 h 27 f 3 N 2 o 6 , its structural formula is as follows: [0003] [0004] At present, there are few reports on the preparation method...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 王全龙屈虎戚聿新
Owner XINFA PHARMA