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Gefitinib preparation method

A technology of gefitinib and compounds, which is applied in the field of preparation of gefitinib, can solve the problems of many steps of side reactions, many by-products, unprotected hydroxyl groups, etc.

Active Publication Date: 2019-05-07
BIOCOMPOUNDS PHARMACEUTICAL INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This route uses 3,4-dimethoxybenzoic acid as raw material, undergoes nitration, demethylation, reduction, cyclization, chlorination, aromatic amine substitution, and introduces morpholine N-alkyl side chains to obtain gefitinib , there are many side reactions in the steps of reduction, cyclization and chlorination in this method, and the yield is low
In the fourth step of the cyclization reaction, 2-amino-4-methoxy-5-hydroxybenzoic acid is directly cyclized with formamide to construct the 4-carbonylquinazoline parent ring. The reaction temperature is preferably 170-180°C. High temperature, many by-products, low yield
Moreover, due to the existence of the hydroxyl group of the active group, in the next step of the aromatic amine substitution reaction, the hydroxyl group is not protected, and side reactions are prone to occur.
[0014] In addition, Chinese Patent Publication Nos. CN103130729A and CN105693630A reported the preparation method of intermediate 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-alcohol acetate as raw material in the chlorination reaction step , does not involve the preparation method of this intermediate

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] The preparation of formula II compound:

[0094] Add 200g (1.2mol) of 3,4-dimethoxybenzaldehyde into a 2L three-necked flask, add 1L of dichloroethane, stir until completely dissolved at 25°C, add 200mL (2.93mol) of 65% nitric acid dropwise into the reaction flask, Control the dropping temperature between 25-40°C, and the dropping is completed in about 1 hour. Stirring was continued at 35°C for 6 hours, and the reaction was monitored by HPLC to complete. Add water (1.5 L) for extraction, collect the organic phase, wash once with saturated sodium bicarbonate solution, and once with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter the organic phase and concentrate under reduced pressure to obtain the crude compound of formula II, use After beating with n-hexane, 226.2 g of the yellow compound of formula II was obtained by filtration, with a molar yield of 89% and a purity of 98%. 1 H-NMR (CDCl 3 , 400MHz) δ4.04(3H, s), 4.05(3H, s), 7.42(1H, ...

Embodiment 2

[0096] The preparation of formula III compound:

[0097] Add 370 g (1.75 mol) of the compound of formula II into a 5 L three-necked flask, add 1.75 L of acetonitrile, 0.7 L of water, and 64.4 g (0.47 mol) of potassium dihydrogen phosphate, and stir to obtain a cloudy solution. 2.38 kg (2.63 mol) of 10% sodium chlorite solution was added dropwise, the temperature of the addition was controlled at 25-35° C., the stirring was continued for 1 hour after the addition was completed, and the reaction was monitored by HPLC. 36% hydrochloric acid was added dropwise until the pH was about 2, a large amount of solids were precipitated, the solids were collected by filtration, and dried at 50° C. to obtain 350.5 g of a yellow compound of formula III with a molar yield of 88% and a purity of 97%. 1 H-NMR (DMSO-d 6 , 400MHz) δ3.83(6H, s), 7.72(1H, s), 7.90(1H, s), 11.00(1H, s); MS(ESI, m / z): 228[M+H] + .

Embodiment 3

[0099] The preparation of formula IV compound:

[0100] Add 227g (1mol) of the compound of formula III to a 2L three-neck flask, add 224g (4mol) of 85% potassium hydroxide and 900mL of water, heat to 98-100°C, keep stirring for 3-4 hours, and monitor the completion of the reaction by HPLC. Cool to 10°C, add 36% hydrochloric acid dropwise to about pH=2, a large amount of solids precipitate out, collect the solids by filtration, and air-dry at 50°C to obtain 181 g of a yellow compound of formula IV with a molar yield of 85% and a purity of 96%. 1 H-NMR (CDCl 3 , 400MHz) δ3.80(3H, s), 6.89(1H, s), 7.34(1H, s); MS(ESI, m / z): 214[M+H] + .

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Abstract

The invention relates to the technical field of organic chemistry and medicine, particularly to a gefitinib preparation method, and provides a gefitinib preparation method, wherein gefitinib is obtained from a compound represented by a formula I, and the preparation method of the compound represented by the formula I comprises: a nitration reaction, an oxidation reaction, a selective demethylationreaction, a reduction reaction, a cyclization reaction and a phenolic hydroxyl acetylation reaction. According to the present invention, the preparation method can simultaneously reduce the cost, easily achieve refining purification and easily prepare and control various related impurities, substantially optimizes the overall preparation process route, and is suitable for industrial scale production.

Description

technical field [0001] The invention relates to the technical fields of organic chemistry and medicine, in particular to a preparation method of gefitinib. Background technique [0002] Gefitinib (Gefitinib, Yiruike, Iressa) is an oral epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor (a small molecule compound) developed by AstraZeneca, released in 2002 Listed in Japan, it is used to treat advanced non-small cell lung cancer. It was launched in China in 2005 under the trade name Iressa, and is used to treat locally advanced or metastatic non-small cell carcinoma that has previously received chemotherapy. Inhibition of EGFR-TK can hinder tumor growth, metastasis and angiogenesis, and increase tumor cell apoptosis. Gefitinib (CAS number: 184475-35-2, molecular formula: C 22 h 24 ClFN 4 o 3 , molecular weight: 446.90) has the structure shown below, and its chemical name is: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholine-4-propoxy) Quinazolin-4-a...

Claims

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Application Information

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IPC IPC(8): C07D239/94
Inventor 杨世琼康立涛李倩项杰蔡峰峰
Owner BIOCOMPOUNDS PHARMACEUTICAL INC
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