Method for synthesizing erlotinib hydrochloride

A technology of erlotinib hydrochloride and a synthetic method, which is applied in the field of drug synthesis, can solve the problems of unsuitability for industrial production, high production cost, and high cost, and achieve the effects of cheap raw materials, low production cost, and easy operation

Active Publication Date: 2014-12-10
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But they all need to use expensive palladium catalyst and protection reagent, make the production cost of this method on the high side, are not suitable for industrialized production

Method used

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  • Method for synthesizing erlotinib hydrochloride
  • Method for synthesizing erlotinib hydrochloride
  • Method for synthesizing erlotinib hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The synthesis of embodiment 1 m-nitroacetophenone

[0025]

[0026] Add 400ml of concentrated sulfuric acid to a 1000ml reaction bottle, add 180.0g (1.5mol) of acetophenone dropwise, mix 200ml of concentrated sulfuric acid with 150ml of concentrated nitric acid and add it dropwise into the system. During the whole process, the temperature of the system should not exceed -5°C. Afterwards, the reaction was continued for 20 min, and the reaction was detected by TLC. Slowly pour the system into a large amount of ice water while stirring, filter with suction, and wash the filter cake with saturated sodium carbonate to remove residual acid to obtain a crude product. The crude product was recrystallized from ethanol to obtain 220.1 g of light yellow needle-like crystals, with a yield of 88.9% and a content of ≥99%.

[0027] NMR data: 1 H NMR (400MHz, CDCl 3 )δ8.78(s,1H),8.47–8.40(m,1H),8.30(d,J=7.8Hz,1H),7.69(t,J=8.0Hz,1H),2.70(s,3H)

Embodiment 2

[0028] The synthesis of embodiment 2 m-nitroacetophenone

[0029] Add 400ml of concentrated sulfuric acid to a 1000ml reaction bottle, add 180.0g (1.5mol) of acetophenone dropwise, mix 120ml of concentrated sulfuric acid with 80ml of fuming nitric acid and add it dropwise into the system. After completion, the reaction was continued for 10 min, and the reaction was detected by TLC. Slowly pour the system into a large amount of ice water while stirring, filter with suction, and wash the filter cake with saturated sodium carbonate to remove residual acid to obtain a crude product. The crude product was recrystallized from ethanol to obtain 223.5 g of light yellow needle-like crystals, with a yield of 90.3% and a content of ≥99%.

Embodiment 3

[0030] Example 3 Synthesis of 1-chloro-1-(3-nitrophenyl)ethene

[0031]

[0032] Add 132.0g (0.8mol) of m-nitroacetophenone, 450ml of toluene, and 31.6g (0.4mol) of pyridine into a 1000ml reaction flask, stir to dissolve the raw materials, and slowly add 146.9g (0.96mol) of phosphorus oxychloride dropwise at room temperature , after the dropwise addition was completed, the temperature was raised to 115°C for reaction, and the reaction progress was detected by TLC. After the reaction was finished, it was cooled, and 100ml of water was added to the system. The organic layer was washed with saturated sodium carbonate and saturated brine, dried and concentrated to obtain a crude product, which was distilled under reduced pressure to obtain 133.2 g of a light yellow product with a yield of 91.0% and a content of ≥97%.

[0033] NMR data: 1 H NMR (400MHz, CDCl 3 )δ8.48(s, 1H), 8.21(d, J=8.4Hz, 1H), 7.95(d, J=7.8Hz, 1H), 7.56(t, J=8.0Hz, 1H), 5.93(d, J=2.1Hz, 1H), 5.70(d, J=2.0...

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Abstract

The invention relates to the technical field of medicines, and particularly relates to a novel method for synthesizing erlotinib hydrochloride. The method comprises the following steps: (1) carrying out a nitration reaction in mixed acid on acetophenone serving as an initial raw material to obtain 3-nitroacetophenone; (2) carrying out a chlorination reaction on 3-nitroacetophenone and a chloride agent in an organic solvent to obtain 1-chloro-1-(3-nitrophenyl) ethylene; (3) removing hydrogen chloride from 1-chloro-1-(3-nitrophenyl) ethylene in existence of the organic solvent and strong alkali to obtain m-nitrophenylacetylene; (4) carrying out selective reduction on m-nitrophenylacetylene by means of nitryl to obtain 3-aminophenylacetylene, wherein the reduction method performs reduction by a reducing agent or catalytic hydrogenation; (5) reacting 3-aminophenylacetylene and 4-chloro-6,7-bis-(2-methoxyethoxy) quinazoline in the organic solvent to obtain erlotinib hydrochloride. The method has the advantages of low production cost, mild reaction conditions and the like, is simple and convenient to operate, and is suitable for industrial production; and the raw materials are low in cost and easily available.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing erlotinib hydrochloride. Background technique [0002] Erlotinib Hydrochloride (Erlotinib Hydrochloride), trade name Tarceva, is a kind of epidermal growth factor tyrosine kinase inhibitor jointly developed by Roche, Océ Biopharmaceutical Company and Genentech Pharmaceutical Company. Treatment of locally advanced and metastatic non-small cell lung cancer. Its chemical structure is shown in the following formula: [0003] [0004] The synthesis of erlotinib hydrochloride is mainly obtained through the reaction of 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline and m-aminophenylacetylene. Patents US5747498, WO20070606091, CN101463013A, etc. all relate to the synthesis method of 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline, but as another key intermediate of erlotinib hydrochloride , there are relatively few reports on the synthesis method of m-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
CPCC07D239/94
Inventor 孟庆伟房金海曾辉刘广志王亚坤杨帆
Owner DALIAN UNIV OF TECH
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