A kind of alectinib intermediate and the preparation method of alectinib

A technology for intermediates and compounds, applied in the field of preparation of alectinib intermediates and alectinib, can solve the problems of high price and unfavorable green industrial production, and achieve high product yield and purity, mild conditions, The effect of a short process flow

Active Publication Date: 2020-07-17
XINFA PHARMA
View PDF9 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Routes 4 and 5 use the indole-phenylhydrazine scheme to construct the Alectinib structure, and the raw material 6-cyano-1H-indole or 6-cyano-1H-indole-3-ethyl carboxylate is expensive and the process Multiple steps use a large amount of acidic materials, such as trichloroacetic acid and trifluoroacetic acid, and post-treatment produces a large amount of acidic wastewater, which is not conducive to green industrial production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A kind of alectinib intermediate and the preparation method of alectinib
  • A kind of alectinib intermediate and the preparation method of alectinib
  • A kind of alectinib intermediate and the preparation method of alectinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1: 3-dimethylamino-4-methyl-4-(4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl-2-(2 -Preparation of nitro-4-cyano)phenyl n-pent-2-enoic acid (IV1)

[0076]

[0077] To a 500 ml four-neck flask connected with stirring, a thermometer, a reflux condenser and a dropping funnel, add 180 grams of tetrahydrofuran, 14.6 grams (0.13 moles) of potassium tert-butoxide, between 40 and 45 ° C, dropwise add 22.0 grams of ( 0.1 mol) 2-nitro-4-cyanophenylacetic acid methyl ester (Ⅱ1), 40.0 grams (0.106 mol) 2-methyl-2-(4-ethyl-3-[4-(morpholine-4- Base) piperidin-1-yl] the mixture of phenylpropionyl chloride (Ⅲ1) and 100 grams of tetrahydrofuran, about 3 hours to drop, 45 to 50 ° C stirring reaction for 4 hours. Cool to 30 to 35 ° C, add 16.3 grams of ( 0.2 mole) dimethylamine hydrochloride, stirred and reacted at 30 to 35° C. for 4 hours. Cooled to 20 to 25° C., added 25.0 grams of 20% aqueous sodium hydroxide solution, and stirred and reacted at 20 to 25° C. for 3 hours...

Embodiment 2

[0078] Example 2: 3-dimethylamino-4-methyl-4-(4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl-2-(2 -Preparation of nitro-4-cyano)phenyl n-pent-2-enoic acid (IV1)

[0079]To a 500 ml four-neck flask connected with a stirring, thermometer, reflux condenser and dropping funnel, add 150 g of N,N-dimethylformamide, 15.0 g (0.13 moles) of potassium tert-butoxide, 40 to 45°C Between, drop 22.0 grams (0.1 mol) methyl 2-nitro-4-cyanophenylacetate (Ⅱ1), 37.5 grams (0.1 mol) 2-methyl-2-(4-ethyl-3-[ A mixture of 4-(morpholin-4-yl)piperidin-1-yl]phenylpropionic acid methyl ester (Ⅲ2) and 100 grams of N,N-dimethylformamide, about 3 hours, dropwise, 50 Stir and react at 55°C for 3 hours. Cool to 30 to 35°C, add 16.3 grams (0.2 moles) of dimethylamine hydrochloride, stir and react at 30 to 35°C for 4 hours. Cool to 20 to 25°C, add 50.0 grams of 30% Potassium carbonate aqueous solution, stirred and reacted at 30 to 35°C for 3 hours. Distilled under reduced pressure to recover N,N-dimethyl...

Embodiment 3

[0080] Example 3: 3-dimethylamino-4-methyl-4-(4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl-2-(2 -Preparation of nitro-4-cyano)phenyl n-pent-2-enoic acid (IV1)

[0081] Add 150 g of N,N-dimethylformamide and 8.8 g (0.13 moles) of sodium ethylate to a 500 ml four-necked flask connected with a stirring, thermometer, reflux condenser and dropping funnel, between 60 and 65°C , add dropwise 23.5 grams (0.1 moles) of ethyl 2-nitro-4-cyanophenylacetate (Ⅱ2), 39.0 grams (0.1 moles) of 2-methyl-2-(4-ethyl-3-[4- (Morpholine-4-yl) piperidin-1-yl] the mixture of ethyl phenyl propionate (Ⅲ3) and 100 grams of N,N-dimethylformamide, about 3 hours, dropwise, 60 to 65 ℃ stirring reaction for 3 hours. Cooling to 30 to 35 ℃, adding 50.0 grams of 30% potassium carbonate aqueous solution, 30 to 35 ℃ stirring reaction for 3 hours. Cooling to 30 to 35 ℃, adding 16.3 grams (0.2 moles) of dimethylamine hydrochloric acid Salt, stirred and reacted at 40 to 45°C for 3 hours. Distilled under reduce...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
chromatographic purityaaaaaaaaaa
chromatographic purityaaaaaaaaaa
Login to view more

Abstract

The invention relates to an Alectinib intermediate and a preparation method of Alectinib. The method comprises the following steps of: carrying out condensation on 2-nitro-4-cyanophenyl acetate with 2-methyl-2-(4-ethyl-3-substituted)phenyl propionate / propionyl chloride, hydrolyzing ester groups, carrying out amination by dimethylamine hydrochloride, then carrying out a reduction-cyclization reaction to obtain an intermediate 2,3,6-trisubstituted indole derivative, and carrying out a cyclization reaction with a cyclization reagent to prepare Alectinib. The method has the advantages of cheap andeasily-obtained raw materials, short process flow and safe and simple operation; the related unit reactions have high unit reaction selectivity and small waste water amount; and green and simple production of the Alectinib is facilitated.

Description

technical field [0001] The invention relates to an alectinib intermediate and a preparation method of alectinib, belonging to the technical field of medicinal chemistry. Background technique [0002] Alectinib (Ⅰ), the English name is Alectinib, the chemical name is 9-ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-6 ,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile is a new type of anaplastic lymphoma kinase (ALK) inhibitor developed by Chugai Pharmaceutical Co., Ltd., a subsidiary of Roche Pharmaceuticals, in 2014 In July, it was approved for marketing in Japan. In December 2015, it was approved by the U.S. FDA as a breakthrough drug. It was approved as an oral anti-lung cancer new drug for the treatment of advanced (metastatic) non-small cell lung cancer (NSCLC) with ALK gene mutation, and Treatment of patients resistant to crizotinib. The structural formula of alectinib is shown below. [0003] [0004] At present, the synthetic route of alectinib is differe...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04C07D209/42
CPCC07D209/42C07D401/04
Inventor 戚聿新王保林鞠立柱刘月盛钱余锋
Owner XINFA PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap