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Asymmetric bisamidation of malonic ester derivatives

A malonic acid diamide, asymmetric technology, applied in the preparation of carboxylic acid amides, the preparation of organic compounds, organic chemistry, etc., can solve problems such as undisclosed asymmetric dianiline, and achieve the effect of excellent yield

Inactive Publication Date: 2018-01-30
SANDOZ LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, no method for the formation of unsymmetrical dianilines by direct conversion of the ester functionality into amides without saponification and subsequent acid activation has been disclosed so far

Method used

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  • Asymmetric bisamidation of malonic ester derivatives
  • Asymmetric bisamidation of malonic ester derivatives
  • Asymmetric bisamidation of malonic ester derivatives

Examples

Experimental program
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Effect test

Embodiment 1

[0807] Embodiment 1: Preparation of 1-((4-fluorophenyl) carbamoyl) methyl cyclopropanecarboxylate

[0808] 4-Fluoroaniline (1.11 g, 10 mmol) was dissolved in toluene (12 mL), and sodium methoxide (0.54 g, 10 mmol) was added. The mixture was then stirred under an inert atmosphere for 30 minutes, with the bath temperature raised to 80 to 100° C., and about 2 mL of the azeotropic methanol / toluene mixture was evaporated. Then, a solution of dimethyl cyclopropane-1,1-dicarboxylate (1.58 g, 10 mmol) in toluene (5 mL) was added and the azeotropic distillation was continued for a further 30 minutes under stirring and inert gas flow. Upon cooling to room temperature, water (10 mL) and 1N hydrochloric acid (10 mL 1M) were added, and the mixture was stirred for 10 minutes, extracted with dichloromethane (10 mL). The organic layer was dried over magnesium sulfate and the solvent was evaporated. The residue (2.07 g) was extracted with isopentane (12 x 10 mL). Evaporation of the solvent ...

Embodiment 2

[0809] Example 2: N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluoro-phenyl)cyclo-propane-1,1 - Preparation of dimethylformamide (cabotinib)

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Abstract

The present invention relates to processes, process steps and intermediates useful in the asymmetric bisamidation of malonic ester derivatives wherein the new processes, process steps and intermediates are, for example, useful in the preparation of asymmetric malonic acid bisanilides such as cabozantinib.

Description

technical field [0001] The present invention relates to processes, process steps and intermediates for the asymmetric bisamidation of malonate derivatives. The novel process, process steps and intermediates can for example be used for the preparation of unsymmetrical malonates such as cabozantinib. Background technique [0002] Disubstituted malonate asymmetric dianilines are structural motifs present in novel tyrosine kinase inhibitors such as altiratinib, cabozantinib, foretinib, golvatinib and sitravatinib (MG-516) in clinical investigation. N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(4-fluorophenyl)-1,1-cyclo Propanedicarboxamide (International Nonproprietary Name (INN): Cabozantinib) is represented by the following chemical structure: [0003] [0004] It is a RET, MET, KIT and VEGFR2 receptor tyrosine kinase inhibitor. It is currently used under the brand name Cometriq to treat thyroid cancer. Cabozantinib is a BCS class II compound with low water solubility...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C233/59C07D215/233C07D401/12C07D495/04C07D213/75
CPCC07D215/233C07C235/82C07C231/02C07C233/59
Inventor E·施赖纳S·纳丁格G·劳斯
Owner SANDOZ LTD
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