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Method for preparing gefitinib and intermediate thereof

A gefitinib, Chinese-style technology, applied in the field of preparation of gefitinib and its intermediates, can solve the problems of low total yield and the like

Active Publication Date: 2011-08-10
SHAANXI NORMAL UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The route first obtains quinazolinone through cyclization reaction, and then obtains the target product through chlorination and other reactions. In the process, it is still unavoidable to use highly polluting chlorination reagents, and the total yield is low

Method used

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  • Method for preparing gefitinib and intermediate thereof
  • Method for preparing gefitinib and intermediate thereof
  • Method for preparing gefitinib and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1: the preparation of 4-methoxy-3-(3-chloropropoxy) benzonitrile

[0069] Take 20.10g (134mmol) of 3-hydroxy-4-methoxybenzonitrile, 16.0mL (161mmol) of 1,3-bromochloropropane, anhydrous K 2 CO 3 18.52g (134mmol), 5.00g of polyethylene glycol-400 and 150mL of absolute ethanol were placed in a 250mL three-necked bottle, and heated to reflux for 5h. Filter off K while hot 2 CO 3 , The filtrate was concentrated to dryness under reduced pressure, and the obtained solid was dissolved in 250 mL of methyl tert-butyl ether, and washed 3 times with water in a separatory funnel, each time with 50 mL of water. Anhydrous Na for organic layer 2 SO 4 Dry and concentrate to dryness to obtain 27.31 g (121 mmol) of 4-methoxy-3-(3-chloropropoxy)benzonitrile as a white solid, with a yield of 90%.

[0070] mp: 73.1~74.1℃; IR v max (KBr)cm -1 : 3008, 2968, 2219, 1598, 1581, 1517, 1422, 1270, 1246, 1139, 1017, 860, 810, 653, 617; 1 H-NMR (300MHz, CDCl 3 )δ: 2.30(m, 2H), ...

Embodiment 2

[0071] Embodiment 2: Preparation of 2-nitro-4-methoxy-5-(3-chloropropoxy)benzonitrile

[0072] Take 10.00 g (44.4 mmol) of 4-methoxy-3-(3-chloropropoxy) benzonitrile and dissolve it in 25 mL of acetic acid, mix and cool 25 mL of sulfuric acid (70%) and 5 mL of nitric acid (70%) Finally, it was added dropwise to the system under an ice-water bath, and after the dropwise addition was completed, the reaction was continued at 25°C for 50h. Then 200 mL of water was added to the system, and a milky yellow solid was precipitated, which was suction filtered, and the filter cake was washed with water until neutral, and dried to obtain a light yellow solid 2-nitro-4-methoxy-5-(3-chloropropoxy ) Benzonitrile 11.48g (42.5mmol), yield 96%.

[0073] mp: 111.8~112.2℃; IR v max (KBr)cm -1 : 3064, 2945, 2225, 1570, 1527, 1337, 1293, 1234, 1059, 1004, 938, 887, 801; 1 H-NMR (300MHz, CDCl 3 )δ: 2.35(m, 2H), 3.78(t, J=5.93Hz, 2H), 4.01(s, 3H), 4.30(t, J=5.61Hz, 2H), 7.24(s, 1H), 7.80( s, 1H...

Embodiment 3

[0074]Embodiment 3: Preparation of 2-amino-4-methoxy-5-(3-chloropropoxy)benzonitrile

[0075] Take 13.53 g (50.1 mmol) of 2-nitro-4-methoxy-5-(3-chloropropoxy) benzonitrile, a mixture of methanol and water (methanol: water = 3: 1) 150 mL, Na 2 S 2 o 4 26.12g (150.0mmol) was placed in a 250mL two-neck flask, heated to 50°C for 2.5h. Then the temperature of the reactant was raised to 70°C, and 50 mL of 25% dilute hydrochloric acid was added in portions, and the addition was completed within 0.5 h, and cooled to room temperature. Adjust the pH of the mixture to about 10 with 50% NaOH aqueous solution, filter with suction, wash the filter cake with water, and dry to obtain a light yellow solid 2-amino-4-methoxy-5-(3-chloropropoxy)benzene Formaldehyde 11.29g (47.0mmol), yield 94%.

[0076] mp: 74.6~75.0℃; IR v max (KBr)cm -1 : 3464, 3359, 3234, 3072, 2930, 2201, 1640, 1619, 1576, 1524, 1507, 1270, 1236, 1130, 1008, 948, 867, 827; 1 H-NMR (300MHz, DMSO-d 6 )δ: 2.08(m, 2H), ...

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Abstract

The invention relates to a preparation method of an anilinoquinazoIine compound, in particular to a method for preparing gefitinib and an intermediate thereof. The preparation method of the invention not only avoids the use of highly-pollutant halogenating agents to greatly reduce environmental pollution, but is also characterized by the connection with a 3-halogenated propyl side chain at first prior to the synthesis of a quinazoline parent ring and then introduction of a morpholine ring at the last step of the synthesis, thus repeated adjustment for pH value in the purification of a reaction product of every step is avoided, a purification method is simplified and the yield is raised.

Description

technical field [0001] The invention relates to a preparation method of anilinoquinazoline compounds, in particular to a preparation method of gefitinib and its intermediates. Background technique [0002] Gefitinib (Gefitinib) is a new type of anti-tumor drug developed by AstraZeneca. It is an inhibitor of epidermal growth factor receptor (EGFR) protein tyrosine kinase and can be used for human or animal proliferation. Treatment of diseases such as tumors. It was first launched in Japan in 2002 for the treatment of inoperable or metastatic and recurrent non-small cell lung cancer. Its chemical name is 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline and has the structure of formula I . [0003] [0004] The following preparation method is disclosed in the patent application CN101348471A. The route uses 3-hydroxyl-4-methoxybenzaldehyde (isovanillin) as raw material, introduces side chains through cyanation, alkylation, nitration, reductio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94C07C255/59C07C253/30C07C255/54
Inventor 李宝林李娇毅王留昌王帆杨玲顾红梅
Owner SHAANXI NORMAL UNIV
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