Preparation method of nintedanib intermediate

Abstract

The invention relates to a preparation method of a nintedanib intermediate. According to the method, acetic anhydride and / or solvent with proper equivalent weight and dosage thereof are / is used for preparing the nintedanib intermediate from methyl 2-oxoindole-6-formate, so not only is the product yield improved, but also the content of impurities can be effectively controlled, and the medicine quality is guaranteed; and the molecular formula is shown in the description.

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...

Examples

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 xylene 200mL were added to the reaction in sequence In the bottle, heat to 110°C, keep the reaction for 4 hours, cool to room temperature, filter, and vacuum dry 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 product obtained 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.

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...

Examples

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 xylene 200mL were added to the reaction in sequence In the bottle, heat to 110°C, keep the reaction for 4 hours, cool to room temperature, filter, and vacuum dry 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 product obtained 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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