Preparation method of crystalline nintedanib esylate

A technology of nintedanib ethanesulfonate and crystalline form, applied in the field of chemical drug synthesis, can solve the problems of low total yield, long synthesis steps, unsuitable for industrial production and the like

Inactive Publication Date: 2016-03-23
NANJING CORE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The preparation method disclosed in this patent is similar to the preparation method disclosed in WO2012068441A. This method uses Pd / C metal catalyst in the preparation process, and the synthesis steps are long, the total yield is low, the production cost is high, and it is not suitable for industrial production

Method used

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  • Preparation method of crystalline nintedanib esylate
  • Preparation method of crystalline nintedanib esylate
  • Preparation method of crystalline nintedanib esylate

Examples

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Embodiment 1

[0038] Embodiment 1 Preparation of crystalline nintedanib ethanesulfonate

[0039] (1) Synthesis of 1-(chloroacetyl chloride)-2-oxoindoline-6-formic acid methyl ester (formula (C))

[0040] In a 3000mL four-neck round bottom flask, install mechanical stirring, reflux condenser, thermometer, and add 1500mL toluene, 240g 6-methoxycarbonyl-2-oxoindoline, 272g chlorine dioxide to the round bottom flask under nitrogen protection. Acetic anhydride, start stirring, heat up to 80-90°C, keep warm and stir for 6 hours, turn off heating and naturally drop to 80°C, add 600ml cyclohexane, continue stirring to cool down, drop to room temperature, solids precipitate, suction filter, filter cake Wash with ice ethanol and dry in vacuo to obtain 233.6g. Yield: 78%.

[0041] (2) Synthesis of (1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-formic acid methyl ester (formula (D))

[0042] In a 5000mL three-necked flask, 195g of methyl 1-(chloroacetyl chloride)-2-oxoindoline-6-carb...

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Abstract

The invention discloses a preparation method of crystalline nintedanib esylate (3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-dihydroindolone monoethyl sulfonate). The method comprises steps as follows: (1) a compound represented in the formula (B) and acylating chlorination reagent chloroacetic anhydride react, and acyl chloride (C) is obtained; (2) the compound represented in the formula (C) and trimethyl orthobenzoate have a condensation reaction, and a compound represented in the formula (D) is obtained; (3) the compound represented in the formula (D) is deprotected, and a compound represented in the formula (E) is obtained; (4) the compound represented in the formula (E) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide have a condensation reaction, and a compound represented in the formula (F) is obtained; (5) the compound represented in the formula (F) and ethanesulfonic acid have a salification reaction, and a nintedanib esylate compound represented in the formula (A) is obtained. The stable crystalline nintedanib esylate can be obtained with the method, technological conditions are mild, aftertreatment is simple, the purity is high, the reaction cost is low, and industrial production is easy to realize.

Description

technical field [0001] The invention belongs to the technical field of chemical drug synthesis, and relates to crystalline 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl- Amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-dihydroindolinone monoethanesulfonate (nintedanib ethylsulfonate) preparation method. Background technique [0002] Nintedanibesylate, chemical name 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl Base-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone monoethanesulfonate compound, the structural formula is as follows: [0003] [0004] Nintedanib ethanesulfonate, developed by Boehringer Ingelheim, is a derivative of 2-indolinones, a triple angiokinase inhibitor, used for the treatment of idiopathic pulmonary fibrosis, and a potential Liver failure and cancer treatment drugs, including metastatic non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, colon cancer and renal ce...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34C07C309/04C07C303/32
CPCC07D209/34
Inventor 王雪根何凌云李晓静李贻文余洋郭莉芹
Owner NANJING CORE TECH CO LTD
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