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Preparing method of Afatinib

A technology of afatinib and nitro, which is applied in the field of preparation of afatinib, can solve the problems of unfavorable scale-up production and industrial operation, unfavorable industrial production promotion, and affecting the quality of intermediate products, so as to meet the requirements of industrial scale-up production requirements, environmental friendliness, and high product yield

Inactive Publication Date: 2016-10-26
SUZHOU FUSHILAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Etherification of 4-chloro-6-amino-7-hydroxyquinazoline with (S)-3-hydroxytetrahydrofuran, and 6-amino-7-[(S)-(tetrahydrofuran-3-yl)oxy] The amidation reaction of -3,4-dihydroquinazolin-4-one may produce corresponding competitive side reactions, introduce impurities, affect the quality of intermediate products and the subsequent steps of the reaction, which need to pass through the column layer Analysis to separate and purify, cumbersome operation, not conducive to scale-up production and industrial operation
Since the docking etherification reaction between hydroxyl and hydroxyl requires an expensive condensing agent, the cost is high, which is not conducive to the promotion of industrial production

Method used

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  • Preparing method of Afatinib
  • Preparing method of Afatinib
  • Preparing method of Afatinib

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Experimental program
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Effect test

Embodiment 1

[0039] A) Etherification reaction, dissolve 10.0g (0.113mol) of (S)-3-hydroxytetrahydrofuran in 100mL of tetrahydrofuran, add 2.85g (0.124mol) of sodium metal under nitrogen protection, and stir at 25°C for 2h to obtain (S) )-3-hydroxytetrahydrofuran sodium salt solution in tetrahydrofuran, 21.6g (0.10mol) of 6-nitro-7-fluoro-3,4-dihydroquinazolin-4-one was dissolved in 60mL of tetrahydrofuran, at 30 ℃ Add dropwise to the tetrahydrofuran solution of (S)-3-hydroxytetrahydrofuran sodium salt in a stirring state, reflux at 70°C for 10 hours until the reaction is complete, cool to room temperature, condense to dryness by rotary evaporation under reduced pressure, add 1L ethyl acetate Extract with 1L of water, separate the organic phase, dry over anhydrous sodium sulfate, concentrate to dryness by rotary evaporation under reduced pressure, recrystallize from ethanol, and dry in vacuum at 60°C for 12h to obtain off-white to light yellow powdery solid, that is, to obtain 6-nitro -7-[...

Embodiment 2

[0051] A) Etherification reaction, dissolve 8.8g (0.10mol) of (S)-3-hydroxytetrahydrofuran in 100mL of methyl tert-butyl ether, add 4.0g (0.10mol) of 60% sodium hydride under nitrogen protection, at 25°C Under stirring for 2h, (S)-3-hydroxytetrahydrofuran sodium salt in methyl tert-butyl ether solution, 21.6g (0.10mol) 6-nitro-7-fluoro-3,4-dihydroquinazoline- Dissolve 4-ketone in 60 mL of methyl tert-butyl ether, add dropwise at 30°C to the stirred methyl tert-butyl ether solution of (S)-3-hydroxytetrahydrofuran sodium salt, and react at 40°C for 4h to Complete reaction, cooled to room temperature, concentrated to dryness by rotary evaporation under reduced pressure, added 1L ethyl acetate and 1L water for extraction, separated the organic phase, dried over anhydrous sodium sulfate, concentrated to dryness by rotary evaporation under reduced pressure, recrystallized from ethanol, 60°C Dry in vacuo for 12 hours to obtain off-white to light yellow powdery solid, that is, to obta...

Embodiment 3

[0057] A) Etherification reaction, dissolve 11.5g (0.13mol) of (S)-3-hydroxytetrahydrofuran in 100mL of N,N-dimethylformamide, add 8.6g (0.16mol) sodium methylate under nitrogen protection, 25 Stirring at ℃ for 2h to obtain (S)-3-hydroxytetrahydrofuran sodium salt in N,N-dimethylformamide solution, 21.6g (0.10mol) 6-nitro-7-fluoro-3,4-dihydro Quinazolin-4-one was dissolved in 60 mL of N,N-dimethylformamide, and was added dropwise to the N,N-dimethylformamide of (S)-3-hydroxytetrahydrofuran sodium salt in a stirring state at 30°C. Formamide solution, react at 60°C for 24 hours until the reaction is complete, cool to room temperature, concentrate to dryness by rotary evaporation under reduced pressure, add 1L ethyl acetate and 1L water for extraction, separate the organic phases, dry over anhydrous sodium sulfate, and spin under reduced pressure Evaporate and concentrate to dryness, recrystallize from ethanol, and dry in vacuo at 60°C for 12 hours to obtain off-white to light ye...

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Abstract

The invention relates to a preparing method of Afatinib. The preparing method includes the steps that 6-nitro-7-fluoro-3,4-dihydro quinazoline-4-ketone is used as a raw material and is subjected to etherification reaction with S-3-hydroxy-tetrahydrofuran; obtained 6-nitro-7-[S-(tetrahydrofuran-3-yl)oxyl]-3,4-dihydro quinazoline-4-ketone is subjected to chlorination reaction; obtained 4-chloro-6-nitro-7-[S-(tetrahydrofuran-3-yl)oxyl] quinazoline is subjected to condensation reaction; obtained 4-[(3-chloro-4-fluoro-phenyl)amino]-6-nitro-7-[S-(tetrahydrofuran-3-yl)oxyl] quinazoline is subjected to reduction reaction; E-4-dimethyl amido crotonic acid is subjected to chloroformylation reaction, and E-4-dimethyl amido crotonyl chloride and 4-[(3-chloro-4-fluoro-phenyl)amino]-6-amino-7-[S-(tetrahydrofuran-3-yl)oxyl] quinazoline are subjected to amidation reaction to obtain the finished product.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of afatinib. Background technique [0002] The chemical name of Afatinib (Afatinib, I) is 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo Substitute-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxyl]quinazoline, whose chemical structural formula is: [0003] [0004] It is an oral anti-tumor targeted drug developed by Boehringer Ingelheim (Germany). It is used for the treatment of EGFR (ErB1) mutation-positive non-small cell lung cancer. It is suitable for advanced non-small cell lung cancer (NSCLC) and HER2 Positive advanced breast cancer patients. Afatinib is a second-generation highly effective dual irreversible tyrosine kinase inhibitor, which has irreversible dual inhibitory effects on epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinase , when NSC...

Claims

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Application Information

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IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 莫国宁
Owner SUZHOU FUSHILAI PHARMA CO LTD
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