The preparation method of neratinib intermediate

A neratinib and intermediate technology, applied in the field of organic synthesis, can solve the problems of low yield and high reaction temperature, and achieve the effects of reducing reaction temperature, avoiding high-temperature reaction and improving yield

Active Publication Date: 2018-07-03
CHONGQING WEIPENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are many reports on this preparation method, but the yield of this method is low, only 35-45%, and the reaction temperature is high, requiring 200-250°C

Method used

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  • The preparation method of neratinib intermediate
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  • The preparation method of neratinib intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0018] Example 1 Preparation of 4-chloro-3-cyano-7-ethoxy-6-acetylquinoline

[0019] Add compound A (7.17g, 20mmol), catalyst triethylamine (286mg, 2mmol), acetonitrile (100mL) into a 500mL two-neck flask, and a magnetic stirring bar. Then install the reflux condenser, the constant pressure dropping funnel, and then add POCl to the constant pressure dropping funnel 3 (7.4mL, 80mmol). A mixed solution of acetonitrile (44mL) was added dropwise in 15 minutes. Under stirring, slowly drop the mixed solution into the reactant system, and the reaction solution gradually becomes a transparent solution. The reaction solution was heated to 65° C., and reacted under this condition for 5 hours. The reaction solution was detected with a TLC plate, and it was found that the raw material disappeared completely, and a compound with a lower polarity than the raw material was generated, and the compound appeared blue under a 254 nm ultraviolet lamp. At this time, the heating reaction was sto...

Embodiment 2

[0020] Example 2 Preparation of 4-chloro-3-cyano-7-ethoxy-6-acetylquinoline

[0021] Add compound A (7.17g, 20mmol), catalyst N,N-lutidine (122mg, 1.0mmol), propionitrile (100mL) and a magnetic stirrer into a 500mL two-necked flask. Then install the upper reflux condenser and constant pressure dropping funnel. Add POCl to the constant pressure dropping funnel 3 (9.2mL, 100mmol). A mixed solution of propionitrile (44mL) was added dropwise in 15 minutes. Under stirring, slowly drop the mixed solution into the reactant system, and the reaction solution gradually becomes a transparent solution. The reaction solution was heated to 70° C., and reacted under this condition for 3 hours. The reaction solution was detected with a TLC plate, and it was found that the raw material disappeared completely, and a compound with a lower polarity than the raw material was generated, and the compound appeared blue under a 254 nm ultraviolet lamp. At this time, the heating reaction was stoppe...

Embodiment 3

[0022] Example 3 Preparation of 4-chloro-3-cyano-7-ethoxyl-6-acetylquinoline

[0023] Add compound A (7.17g, 20mmol), catalyst triethylenediamine (200mg, 1.8mmol), ethyl acetate (100mL) and a magnetic stirring bar into a 500mL two-necked flask. Then install the reflux condenser and the constant pressure dropping funnel, and drop it in 15 minutes. Add POCl to the constant pressure dropping funnel 3 (8.3mL, 90mmol) and ethyl acetate (44mL) mixed solution. Under stirring, slowly drop the mixed solution into the reactant system, and the reaction solution gradually becomes a transparent solution. The reaction solution was heated to 75° C., and reacted under this condition for 2 hours. The reaction solution was detected with a TLC plate, and it was found that the raw material disappeared completely, and a compound with a lower polarity than the raw material was generated, and the compound appeared blue under a 254 nm ultraviolet lamp. At this time, the heating reaction was stopp...

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Abstract

The invention discloses a preparation method of a Neratinib intermediate. The preparation method comprises the following steps: by taking a compound A and POCl3 as raw materials, and a nitrogenous compound as a catalyst, allowing the compound A and POCl3 to react with the nitrogenous compound to obtain the Neratinib intermediate, wherein the compound A is (E)-N-(4-((2-cyano-3-morpholino-3-oxopropionic-1-alky-1-base)amino)-2-ethoxy phenyl) acetamide. According to the method, the nitrogenous compound is used as the catalyst, high temperature is not needed in the reaction, the reaction can be performed at the temperature of 65 to 75 DEG C, compared with the traditional method requiring the high temperature of 200 to 250 DEG C, the reaction temperature is greatly reduced, the high-temperature reaction is avoided, operation safety is ensured, the reaction yield is also increased to 45 to 57 percent, and the yield is obviously increased.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of a neratinib intermediate. Background technique [0002] Neratinib is an anticancer drug, and 4-chloro-3-cyano-7-ethoxyl-6-acetylquinoline is a key intermediate in the synthesis of Neratinib. The traditional preparation of this intermediate The method is mainly to use ethyl 3-(4-acetamido-3-ethoxy-anilino)-2-cyanoacrylate in biphenyl-biphenyl ether (Dowtherm A) as a solvent at a high temperature of 250°C Under heating, cyclization generates 3-cyano-7-ethoxy-4-hydroxyl-6-acetylquinoline, and then the compound is separated and purified; then the obtained intermediate is combined with POCl 3 Reaction, after chlorination, generates 4-chloro-3-cyano-7-ethoxy-6-acetylquinoline. There are many reports on this preparation method, but the yield of this method is low, only 35-45%, and the reaction temperature is high, requiring 200-250°C. The general reaction form...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/54
CPCC07D215/54
Inventor 李春林石开云韩公超周兴国向林玲陈露龚雪
Owner CHONGQING WEIPENG PHARMA
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