Lercanidipine hydrochloride polymorphs and an improved process for preparation of 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate

A technology of ethyl aminoacetoacetate and lercanidipine hydrochloride, which is applied in the preparation of amorphous lercanidipine hydrochloride, new crystalline lercanidipine hydrochloride and its preparation field, can solve problems such as difficulty in implementation, and achieve low risk Effect

Inactive Publication Date: 2010-10-20
ACTAVIS GRP PTC EHF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Methods involving column chromatographic purification are generally unpopular with large-scale operations, thereby making the method commercially difficult

Method used

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  • Lercanidipine hydrochloride polymorphs and an improved process for preparation of 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate
  • Lercanidipine hydrochloride polymorphs and an improved process for preparation of 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate
  • Lercanidipine hydrochloride polymorphs and an improved process for preparation of 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate

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preparation example Construction

[0069] According to another aspect of the present invention, a method for preparing lercanidipine hydrochloride crystal form Y is provided, the method comprising:

[0070] a) providing a solution of lercanidipine hydrochloride in an amide solvent;

[0071] b) adding an aliphatic ester solvent to the solution; and

[0072] c) recovering substantially pure lercanidipine hydrochloride Form Y from the solution.

[0073] Exemplary amide solvents include, but are not limited to, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dimethylacetoacetamide, N,N-diethylacetoacetamide , formanilide, N-methylformanilide, N, N-di-n-propylacetamide, N, N-diisopropylacetamide, di-n-butylacetamide, N, N-dimethyl- 2,2-Diphenylacetamide and mixtures thereof. A more specific amide solvent is N,N-dimethylacetamide.

[0074] The step (a) of providing a solution of lercanidipine hydrochloride comprises dissolving any form of lercanidipine hydrochloride in an appropriate amide solvent, or obtaining ...

Embodiment 1

[0108] Preparation of 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoacetoacetate ethyl ester:

[0109] 2,N-Dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol (5 g) and methyl acetoacetate (7.5 g) were dissolved at 25-30 °C In xylene (50ml), zinc dust (1.75g) was then added. The reaction mixture was heated at 140-145°C for 7 hours. Next, xylene was distilled off while adding xylene to maintain the volume of xylene in the reaction mixture. The reaction mixture was cooled at 25-30°C, then the catalyst was removed by filtration. Distillation was performed under reduced pressure to remove xylene. The resulting residue was degassed for 1 hour to yield the title compound as a viscous brown oil.

Embodiment 2

[0111] Preparation of 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl α-acetyl-3-nitrocinnamate hydrochloride:

[0112] A mixture of ethyl 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoacetoacetate (5 g) and 3-nitrobenzaldehyde (2 g) was dissolved in toluene (50ml). The solution was cooled to 0 °C, and dry hydrogen chloride gas was bubbled through the solution until the solution was saturated. The reaction mixture was stirred at 0°C for 9 hours. The organic layer was separated from the reaction mixture and washed with toluene (25ml). The resulting oily residue was dissolved in dichloromethane (100ml). The resulting solution was dried over calcium chloride, followed by distillation of dichloromethane at 30-35°C under reduced pressure to yield 5.5 g of 1,1,N-trimethyl-N-(3,3-diphenylpropyl)- 2-Aminoethyl alpha-acetyl-3-nitrocinnamate hydrochloride.

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Abstract

Disclosed herein is an improved, commercially viable and industrially advantageous process for the preparation of substantially pure Lercanidipine intermediate, 1,1,N- trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate. The intermediate is useful for preparing Lercanidipine, or a pharmaceutically acceptable salt thereof, in high yield and purity. The present invention further provides a novel crystalline form of Lercanidipine hydrochloride and a process for its preparation. The present invention also provides a process for the preparation of amorphous form of Lercanidipine hydrochloride.

Description

[0001] Cross reference to related applications [0002] This application claims the benefit of Indian Provisional Application No. 434 / CHE / 2007, filed 5th March, 2007, Indian Provisional Application No. 498 / CHE / 2007, filed 12th March, 2007, and 5th April, 2007 Priority of Indian Provisional Application No. 720 / CHE / 2007, which are hereby incorporated by reference. field of invention [0003] Disclosed herein is an improved, commercially viable preparation of a substantially pure lercanidipine intermediate, ethyl 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoacetoacetate An industrially advantageous preparation method. The intermediate is used to prepare lercanidipine or a pharmaceutically acceptable salt thereof with high yield and high purity. The invention also provides new crystal form of lercanidipine hydrochloride and its preparation method. The invention also provides a preparation method of the amorphous lercanidipine hydrochloride. Background of the invention [0...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/06C07C219/06C07D211/86A61K31/4422
CPCC07C219/06C07C213/06C07D213/803A61P9/12
Inventor 吉利士·迪克西特奎师那达特·巴尔德夫普拉萨德·夏尔马尼廷·萨拉德钱德拉·普拉德汉乔恩·瓦尔盖尔森
Owner ACTAVIS GRP PTC EHF
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