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A kind of preparation method of nintedanib intermediate

A technology for nintedanib and intermediates, which is applied in the field of preparation of nintedanib intermediates, can solve the problems of human harm, low purity, and reduced yield, so as to reduce harm and ensure drug quality and yield. improved effect

Active Publication Date: 2021-06-18
SHANGHAI HANSOH BIOMEDICAL +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This process uses toluene as a solvent, which reduces the consumption of acetic anhydride correspondingly, but the yield is significantly reduced. Therefore, it is necessary to find a process route that can reduce the consumption of acetic anhydride and have a good yield while ensuring that the impurity content is reduced.
[0013] 4. In the Chinese patent CN111465594A published by Fermi in 2018, a preparation method for improving the yield of the above-mentioned process route was proposed, including adding methyl 2-oxoindole-6-carboxylate to xylene, and then adding 9 Heat the equivalent amount of acetic anhydride to 130°C, add xylene after 5 hours, and add trimethyl orthobenzoate to react at 120°C to finally obtain 1-acetyl-3-(methoxy(phenyl)methylene base)-2-oxoindoline-6-carboxylic acid methyl ester, the molar yield reaches 79.29%, but the purity is not high, only 93.20%
[0014] Acetic anhydride has a strong smell of acetic acid, which is very harmful to the human body. Therefore, it is necessary to find a process route that can reduce the amount of acetic anhydride, increase the product yield, and reduce the impurity content. very important

Method used

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  • A kind of preparation method of nintedanib intermediate
  • A kind of preparation method of nintedanib intermediate
  • A kind of preparation method of nintedanib intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Example 1 Preparation of 1-acetyl-3-(ethoxy(phenyl)methylene)-2-oxoindoline-6-carboxylic acid methyl ester

[0039] Add methyl 2-oxoindole-6-carboxylate (15g, 78.5mmol), triethyl orthobenzoate (49.5g, 220.7mmol) and acetic anhydride (150ml, 1.59mol) into the reaction flask in turn, and heat to 110°C, heat preservation reaction for 4 hours, cooling down, solids precipitated, filtered, and vacuum dried at 50°C for 16 hours to obtain 22g, with a mass yield of 146.7% and a molar yield of 76.8%. HPLC purity 93.35%*, impurity 1 0.82%, impurity 2 4.9%.

[0040] NMR data: 1 H-NMR: δ1.35(t, 3H), 2.44 (s, 3H), 3.87(s, 3H), 3.98-4.03 (q, 2H), 7.52-7.57 (m, 5H), 7.87-7.89(d , 1H), 8.07-8.09(d, 1H), 8.73(s, 1H).

[0041] Wherein, the HPLC detection spectrum of the formula III compound that embodiment 1 prepares is as follows figure 1 shown.

Embodiment 2

[0042] Example 2 Preparation of 1-acetyl-3-(ethoxy(phenyl)methylene)-2-oxoindoline-6-carboxylic acid methyl ester

[0043] Methyl 2-oxoindole-6-carboxylate (20g, 104.6mmol), triethyl orthobenzoate (46.9g, 209.2mmol), acetic anhydride (32.0g, 313.8mmol) and 200mL xylene were added to the reaction in sequence In the bottle, heated to 110°C, kept the reaction for 4 hours, cooled to room temperature, filtered, and vacuum dried at 50°C for 16 hours to obtain 30.9g, mass yield 154.5%, molar yield 80.9%, HPLC purity 99.43%*, impurity 1 0.03 %, impurity 2 0.03%.

[0044] Analysis through structural confirmation shows that the resulting product is identical to 1-acetyl-3-(ethoxyl (phenyl) methylene)-2-oxoindoline-6-formic acid methyl ester in Example 1 substance.

Embodiment 3

[0045] Example 3 Preparation of 1-acetyl-3-(ethoxy(phenyl)methylene)-2-oxoindoline-6-carboxylic acid methyl ester

[0046]Methyl 2-oxoindole-6-carboxylate (20g, 104.6mmol), triethyl orthobenzoate (46.9g, 209.2mmol), acetic anhydride (32.0g, 313.8mmol) and xylene 200mL were added to the reaction in sequence In the bottle, heated to 120°C, kept for reaction for 4 hours, cooled to room temperature, filtered, and vacuum-dried at 50°C for 16 hours to obtain 31.5g, mass yield 157.5%, molar yield 82.4%, HPLC purity 99.75%*, impurity 1 not Detected, impurity 2 <0.01%.

[0047] Analysis through structural confirmation shows that the product obtained is identical to 1-acetyl-3-(ethoxyl (phenyl) methylene)-2-oxoindoline-6-formic acid methyl ester in Example 1 substance.

[0048] Wherein, the HPLC detection spectrum of the formula III compound that embodiment 3 prepares is as follows Figure 4 shown.

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Abstract

The invention relates to a preparation method of nintedanib intermediate. By using an appropriate equivalent of acetic anhydride and / or solvent and the amount thereof, the nintedanib intermediate is prepared from methyl 2-oxindole-6-carboxylate. This method not only improves the product yield, but also effectively controls the content of impurities , to ensure the quality of medicines;

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a preparation method of nintedanib intermediate. Background technique [0002] The chemical name of nintedanib ethanesulfonate is 1H-indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl) Acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-, methyl ester, (3Z)-, ethanesulfonate (1:1). Product name: Vegat ® / Ofev ® , its structural formula is as follows: [0003] [0004] Nintedanib ethanesulfonate is a triple angiokinase inhibitor for the treatment of idiopathic pulmonary fibrosis (IPF) by inhibiting growth factor receptors associated with the pathogenesis of idiopathic pulmonary fibrosis effect. [0005] There are multiple methods for preparing nintedanib ethanesulfonate disclosed internationally at present, wherein the compound of formula II or formula III is an important intermediate for the synthesis of nintedanib ethanesulfonate, an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/34
CPCC07D209/34
Inventor 邹国勇曹金游军辉王磊刘建平
Owner SHANGHAI HANSOH BIOMEDICAL
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