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Gefitinib synthesis intermediate, and its preparing method and use

A use and compound technology, which is applied in the field of synthetic gefitinib intermediate compounds and its preparation, can solve problems such as increasing production costs, affecting product quality, and affecting yield, so as to improve quality, reduce two-step reactions, The effect of increasing selectivity

Active Publication Date: 2008-09-24
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] 2. When compound 4 removes the methyl group at the C-6 position, it will inevitably remove the methyl group at the C-7 position to form a by-product 9. The structural formula is as follows, which not only affects the yield and increases the production cost, but also because the compound 9 is similar in structure to compound 5, it is difficult to separate completely, which will seriously affect the product quality

Method used

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  • Gefitinib synthesis intermediate, and its preparing method and use
  • Gefitinib synthesis intermediate, and its preparing method and use
  • Gefitinib synthesis intermediate, and its preparing method and use

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Example 1: Preparation of 6-benzyloxy-4-(3'-chloro-4'-fluoroaniline)-7-methoxyquinazoline

[0039] 6-Benzyloxy-7-methoxyquinazolinone (1.5g) was dissolved in 15mL SOCl 2 and 0.5mL DMF, heated to reflux for 5 hours, cooled, and evaporated SOCl under reduced pressure 2 , to obtain 6-benzyloxy-7-methoxy-4-chloroquinazolinone as an orange solid. Isopropanol (42ml) was added to the residue, and after dissolution, 3-chloro-4-fluoroaniline (0.9g) was added, heated to 90°C, and reacted for 3 hours. Cooled, filtered, and the precipitate was filtered off, washed once with methanol (2 ml), and dried to give 1.4 g (64%) of a white solid.

[0040] 1 H-NMR (DMSO): δ=3.99(s, 3H), 5.35(s, 2H), 7.37(s, 1H), 7.39-8.08(m, 8H), 8.62(s, 1H), 8.89(s, 1H).

Embodiment 2

[0041] Example 2: Preparation of 6-(2'-4'-dichloro)benzyloxy-7-methoxy-4-(3'-chloro-4'-fluoroaniline)quinazoline

[0042] According to the method of Example 1, take an equimolar amount of 6-(2'-4'-dichloro)benzyloxy-7-methoxyquinazolone instead of 6-benzyloxy-7-methoxyquinazolone For oxazolinone, operate in the same way to obtain 6-(2'-4'-dichloro)benzyloxy-7-methoxy-4-(3'-chloro-4'-fluoroaniline)quinazoline.

[0043] 1 H-NMR (DMSO): δ = 3.94 (s, 3H), 5.29 (s, 2H), 7.26 (s, 1H), 7.44-8.15 (m, 7H), 8.53 (s, 1H).

Embodiment 3

[0044] Example 3: Preparation of 6-(4'-methyl)benzyloxy-7-methoxy-4-(3'-chloro-4'-fluoroaniline)quinazoline

[0045] According to the method of embodiment 1, take the 6-(4'-methyl) benzyloxy-7-methoxyquinazolone of equimolar amount instead of 6-benzyloxy-7-methoxyquinazolone , and operated in the same way to obtain 6-(4'-methyl)benzyloxy-7-methoxy-4-(3'-chloro-4'-fluoroaniline)quinazoline.

[0046] 1H-NMR (DMSO): δ = 2.37 (s, 3H), 3.99 (s, 3H), 5.18 (s, 2H), 7.13-7.51 (m, 9H), 7.90 (s, 1H).

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Abstract

This invention relates to gefetinib synthesis intermediate and its preparation method and application. Compound of formula (II) is halogenated to make formula (III) compound, then condensed with 3-chlorine-4-fluoroaniline to make formula (I) compound. The formula (I) compound is new intermediate compound that used to synthesize the gefetinib, another important intermediate compound 6-hydroxy group- 7-methoxyl group-4-(3'-chlorine-4'-fluoroaniline) quinazoline (2) that used to synthesize gefetinib can be easily made by (I) compound.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular, the invention relates to an intermediate compound for synthesizing Gefitinib medicine, a preparation method and application thereof. Background of the invention [0002] Gefitinib (Gefitinib) is a new type of antineoplastic drug developed by AstraZeneca. It is an orally available small molecule inhibitor against EGFR tyrosine kinase and was launched in September 2003. Its structural formula is shown in Figure 1: [0003] [0004] Disclosed in WO9633980A is a method for economically synthesizing Gefitinib: [0005] [0006] The intermediate 6-hydroxyl-7-methoxy-4-(3'-chloro-4'-fluoroaniline) quinazoline (2) is an important intermediate for the synthesis of gefitinib compounds, disclosed in WO9633980 and WO9742187 The synthetic method of this intermediate is shown: take 6,7-dimethoxyquinazolinone as raw material, obtain through 5 steps of reaction: ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94
Inventor 金春华肖玲常江
Owner ZHEJIANG HISUN PHARMA CO LTD
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