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Synthetic method of bosutinib intermediate

A technology of bosutinib and a synthesis method, applied in the field of chemistry, can solve the problems of increased environmental protection pressure, difficult recycling and application, and high boiling point difference, and achieves the effects of convenient post-processing and purification, good reaction selectivity, and easy removal.

Active Publication Date: 2020-05-08
JIANGSU YUANDA XIANLE PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In the existing synthesis process, the first step is to use a mixture of acetic acid and acetic anhydride for acetylation reaction. The boiling point of acetic acid is 117.9°C, and the boiling point of acetic anhydride is 139.8°C. Relatively high; the fourth step uses concentrated hydrochloric acid to deacetylate, and the product needs to be neutralized with sodium hydroxide before it can be released, resulting in a large amount of acidic high-salt wastewater, which increases the pressure on environmental protection

Method used

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  • Synthetic method of bosutinib intermediate
  • Synthetic method of bosutinib intermediate
  • Synthetic method of bosutinib intermediate

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Effect test

Embodiment 1

[0038] The synthesis method of the bosutinib intermediate, the bosutinib intermediate is 2,4-dichloro-5-methoxyaniline, add 545g of formic acid to a 3000mL three-necked flask, start stirring, and add m-aminophenol in batches 109g (1.0mol), 1.82g (10mmol) of vanadium pentoxide, heated to 100°C, TLC monitored the completion of the reaction (PE:EA=1:1), cooled to room temperature, and reacted with chlorine gas in about 3h, the color Turned into light yellow, spot plate to monitor the completion of the reaction (PE: EA = 1: 1). After the reaction is finished, filter, and the filtrate recovers formic acid for recycling. The intermediate was directly carried out to the next reaction without purification. Add 1500mL of dimethylformamide and 207.3g (1.5mol) of potassium carbonate to the reaction flask filled with 2,4-dichloro-5-carboxamidophenol that recovered the complete formic acid, stir at 40°C for 30min, then add dropwise for about 1h 189.2 g (1.5 mol) of dimethyl sulfate was h...

Embodiment 2

[0042] Add 1417g of formic acid to a 3000mL three-necked flask, start stirring, add 109g (1.0mol) of m-aminophenol and 16.2g (70mmol) of tungsten trioxide in batches, heat to 50°C, and monitor the completion of the reaction by TLC (PE:EA=1: 1), then cooled to 20°C, cooled to room temperature, and added dropwise 337.4g (2.5mol) of sulfuryl chloride. After the dropwise addition, the color gradually changed to light yellow, and the reaction was completed by spotting the plate to monitor (PE:EA=1:1). After the reaction is finished, filter, and the filtrate recovers formic acid for recycling. Add an appropriate amount of dichloroethane to the reaction flask where the formic acid has been recovered, dissolve it, wash it with water until neutral, and concentrate to obtain the crude product of 2,4-dichloro-5-carboxamidophenol, which is directly carried out to the next step reaction without purification. Transfer all the obtained crude 2,4-dichloro-5-carboxamidophenol into a 3000mL aut...

Embodiment 3

[0045]Into a 3000mL three-neck flask, add 1090g of formic acid, start stirring, add 109g (1.0mol) of m-aminophenol, 9.1g (50mmol) of vanadium pentoxide in batches, heat to 70°C, and monitor the completion of the reaction by TLC (PE:EA=1 : 1), then cooled to 40°C, added 175.3g (3.0mol) of sodium chloride in batches, added dropwise 510.2g (4.5mol) of 30% hydrogen peroxide in 30 minutes, and monitored the reaction by TLC (PE:EA=1:1) , After the reaction is finished, filter, and the filtrate recovers formic acid for recycling. The intermediate was directly carried out to the next reaction without purification. Add 1500mL of propanol, 165.9g (1.2mol) of potassium carbonate to the 3000mL reaction flask filled with 2,4-dichloro-5-carboxamidophenol that recovered complete formic acid, stir at 40°C for 30min, add disulfuric acid dropwise for about 1h 151.4 g (1.2 mol) of methyl ester was heated up to 50° C., and stirring was continued for 1 h to obtain a white suspension. The reactio...

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Abstract

The invention relates to a synthetic method of a bosutinib intermediate. The method comprises the following steps: reacting m-aminophenol with formic acid to generate 3-formamido phenol; carrying outa benzene ring chlorination reaction on 2, 4-dichloro-5-carboxamido phenol to generate 2, 4-dichloro-5-carboxamido phenol, carrying out a phenolic hydroxyl methylation reaction on the 2, 4-dichloro-5-carboxamido phenol to generate 2, 4-dichloro-5-carboxamido anisole, and removing formyl by using illumination to generate 2, 4-dichloro-5-methoxyaniline. The method has the advantages of mild reactionconditions, good selectivity, high yield, no need of purification of the intermediate, easily available raw materials, environmental protection, simplicity, high efficiency, energy saving, reductionof the production cost, improvement of the operation environment, simple operation, high automation degree, and especially easy realization of industrialization.

Description

technical field [0001] The invention relates to the technical field of chemistry, and specifically provides a method for synthesizing a bosutinib intermediate. Background technique [0002] The chemical name of Bosutinib is 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1 -piperazine)propoxyl]-3-quinolinecarbonitrile is a potent protein kinase Scr / Ab1 dual inhibitor, its inhibitory effect is stronger than imatinib, both can inhibit the The autophosphorylation of Src protein also has high anti-proliferative activity, which can inhibit the proliferation and survival of CML cells. It is mainly used for patients with Ph chromosome-positive CML in chronic phase, accelerated phase or blast phase who are intolerant or resistant to other treatments including imatinib. Bosutinib is a good alternative drug. Adverse reactions were within acceptable range. It has been confirmed by clinical trials that bosutinib is effective against a variety of tumors, including bre...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C231/12C07C233/25C07C213/02C07C217/84B01J23/22B01J23/28B01J23/30
CPCC07C231/02C07C231/12C07C213/02B01J23/22B01J23/28B01J23/30C07C233/25C07C217/84
Inventor 刘年金胡丽娟张邦国赵百合杜艳
Owner JIANGSU YUANDA XIANLE PHARMA
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