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Preparation method of antineoplastic drug maleic acid neratinib

A technology of neratinib and maleic acid, which is applied in the field of chemical preparation of the antineoplastic drug neratinib maleate, can solve the problem of unfavorable personnel and environment for the chlorination agent phosphorus oxychloride, difficult source of raw materials, and total synthesis. Low yield and other problems, to achieve the effect of convenient post-reaction treatment, high product yield, and wide source of raw materials

Active Publication Date: 2016-02-17
SHANGHAI XUNHE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The main deficiencies of this synthetic process route are: synthetic steps are longer, synthetic total yield is on the low side, and the cyclization reaction of constructing quinoline ring needs to be carried out under high temperature conditions, and the use of chlorinating agent phosphorus oxychloride is harmful to personnel. and the environment will have adverse effects
[0013] In this synthetic route, the reaction steps are short, but the source of raw materials is difficult, the yields of condensation reaction and cyclization reaction are all low, only about 60%, the total yield is not good, and there is no cost competitive advantage

Method used

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  • Preparation method of antineoplastic drug maleic acid neratinib
  • Preparation method of antineoplastic drug maleic acid neratinib
  • Preparation method of antineoplastic drug maleic acid neratinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Preparation of 4-(4-((pyridin-2-yl)methoxy)-3-chloroaniline)-7-ethoxy-6-nitro-3-cyanoquinoline (VI):

[0034]

[0035] Under nitrogen protection, compound III 4-amino-7-ethoxy-3-cyano-6-nitroquinoline (2.58g, 10mmol) was suspended in absolute ethanol, and compound II (4-bromo-2-chloro Phenoxy)methyl-2-pyridine (2.99g, 10mmol) and methanesulfonic acid (48mg, 0.5mmol) were reacted at 70°C for 2 hours, and the reaction liquid gradually became clear and solid precipitated out. After heating stopped, cool to room temperature, filter, wash with 50% ethanol, and dry to obtain 4.38 g of the title compound with a yield of 92%. ESI-MS: [M+H] + =476.79, 1 HNMR-δ(CDCl 3 ) / 300MHz): 1.6(t, 3H, J=6.8, 13.7), 4.3(q, 2H, J=7.2, 13.8), 5.3(s, 2H), 6.1(d, 1H, J=15.0), 6.3 (d, 1H, J=15.0), 7.3(s, 1H), 7.4(s, 1H), 7.6(d, IH, J=8.2), 7.8(d, 1H, J=7.6), 8.0(s, 1H), 8.5 (s, 1H), 8.6 (d, 1H, J=4.7), 9.2 (s, 1H).

Embodiment 2

[0036] Example 2: Preparation of 4-(4-((pyridin-2-yl)methoxy)-3-chloroaniline)-7-ethoxy-6-nitro-3-cyanoquinoline (VI):

[0037] Under nitrogen protection, compound III 4-amino-7-ethoxy-3-cyano-6-nitroquinoline (2.58g, 10mmol) was suspended in anhydrous methanol, and compound II (2,4-dichlorobenzene Oxy)methyl-2-pyridine (2.54g, 10mmol) and trifluoroacetic acid (57mg, 0.5mmol) were reacted at 20°C for 4 hours, and the reaction liquid gradually became clear and solid precipitated out. After heating stopped, cool to room temperature, filter, wash with 50% methanol, and dry to obtain 4.09 g of the title compound with a yield of 86%. ESI-MS: [M+H] + =476.79, 1 HNMR-δ(CDCl 3 ) / 300MHz): 1.6(t, 3H, J=6.8, 13.7), 4.3(q, 2H, J=7.2, 13.8), 5.3(s, 2H), 6.1(d, 1H, J=15.0), 6.3 (d, 1H, J=15.0), 7.3(s, 1H), 7.4(s, 1H), 7.6(d, 1H, J=8.2), 7.8(d, 1H, J=7.6), 8.0(s, 1H), 8.5 (s, 1H), 8.6 (d, 1H, J=4.7), 9.2 (s, 1H).

Embodiment 3

[0038] Example 3: Preparation of 4-(4-((pyridin-2-yl)methoxy)-3-chloroaniline)-7-ethoxy-6-nitro-3-cyanoquinoline (VI):

[0039] Under nitrogen protection, compound III 4-amino-7-ethoxy-3-cyano-6-nitroquinoline (2-58g, 10mmol) was suspended in anhydrous DMF, and compound II (4-trifluoromethanesulfonate Acyloxy-2-chlorophenoxy)methyl-2-pyridine (3.68g, 10mmol) and sulfuric acid (50mg, 0.5mmol) were reacted at 150°C for 1 hour, and the reaction liquid gradually became clear and solid precipitated out. After heating stopped, cool to room temperature, filter, wash with 50% ethanol, and dry to obtain 4.28 g of the title compound with a yield of 90%. ESI-MS: [M+H] + =476.79, 1 HNMR-δ(CDCl 3 ) / 300MHz): 1.6(t, 3H, J=6.8, 13.7), 4.3(q, 2H, J=7.2, 13.8), 5.3(s, 2H), 6.1(d, 1H, J=15.0), 6.3 (d, 1H, J=15.0), 7.3(s, 1H), 7.4(s, 1H), 7.6(d, 1H, J=8.2), 7.8(d, 1H, J=7.6), 8.0(s, 1H), 8.5 (s, 1H), 8.6 (d, 1H, J=4.7), 9.2 (s, 1H).

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Abstract

The invention provides a preparation method of antineoplastic drug maleic acid neratinib. The defects in the prior art are overcome. The preparation method comprises the steps that the formula II and the formula III are coupled to form the formula IV under the effect of a catalyst; a nitro-compound IV is reduced under the effect of a reduction system to form a formula V; an amino compound V and a formula VI are condensed to obtain neratinib VII, and then the neratinib VII and maleic acid form a salt to obtain the maleic acid neratinib I. By the adoption of the technical route, the preparation method has the advantages that the synthetic route is short, reaction conditions are mild, the yield is high, raw materials are wide in source, and environmental protection is achieved.

Description

Technical field: [0001] The invention relates to a chemical preparation method of neratinib maleate, an antineoplastic drug, which has the advantages of short synthesis route, mild reaction conditions, high yield, wide source of raw materials, and environmental friendliness. Background technique: [0002] Neratinib Maleate is an oral epidermal growth factor receptor (EGFR) inhibitor developed by Wyeth in the United States. It is a small molecule tyrosine targeting HER2 and HER1 after lapatinib Acid kinase inhibitor, an irreversible pan-ErbB receptor tyrosine kinase inhibitor. The mechanism of action of this product is to inhibit the ATP sites of EGFR (ErbB-1) and HER2 (ErbB-2) in cells to prevent phosphorylation and activation of tumor cells, through the activation of EGFR (ErbB-1) and HER2 (ErbB-1) Homo- and heterodimers block down-regulated signaling, thereby achieving tumor control. [0003] The structural formula of neratinib maleate (formula I) is as follows: [0004...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07C57/145C07C51/41
CPCC07D401/12
Inventor 周峰金华郑永勇黄美花孟欣
Owner SHANGHAI XUNHE PHARMA TECH CO LTD
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