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Method for preparing optically pure 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)3,5-dipicolinic acid 2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethyl methyl ester

A technique of dipicolinic acid, dimethyl, applied to optically pure 1,4-dihydro-2,6-dimethyl-4-(3-nitrobenzene) 3,5-pyridinedicarboxylic acid The field of preparation of 2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethylmethyl ester can solve the problem of low optical purity

Active Publication Date: 2011-10-19
ANHUI YONSENT PHARMA
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  • Abstract
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Problems solved by technology

Chemical resolution is a very important method. CN101357901 discloses a preparation method for splitting 1,4-dihydropyridine main ring carboxylic acid, and the obtained chiral isomers can be transformed into lercanidipine by transformation isomers, but its disadvantage is that racemization may occur during the conversion process, resulting in low optical purity

Method used

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  • Method for preparing optically pure 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)3,5-dipicolinic acid 2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethyl methyl ester
  • Method for preparing optically pure 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)3,5-dipicolinic acid 2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethyl methyl ester
  • Method for preparing optically pure 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)3,5-dipicolinic acid 2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethyl methyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of S-(+)-lercanidipine free base (formula Ⅱ) and R-(-)-lercanidipine free base (formula Ⅲ)

[0026] Add 12.3g (20mmol) racemic compound of formula Ⅰ, 7.2g D-(+)-benzoyl tartaric acid (DDBTA) (22mmol) into 70ml acetone, heat to about 50°C to dissolve, filter while hot, and cool down the filtrate slowly At about 5°C, stand for 24 hours, the DDBTA salt of formula II precipitates out, filter, and wash with a small amount of cold acetone. At the same time, the separation mother liquor was collected. Dry the solid to obtain 8.0 g of crude product of DDBTA salt of formula II, [α] D 20 =+58.9 。 (C=1.1 MeOH), recrystallized twice from acetone to obtain 6.5 g of DDBTA salt of formula II. [α] D 20 =+61.5 。 (C=1.0 MeOH)

[0027] 6.5g of DDBTA salt of formula II was dissolved in 25ml of methanol, 10%Na 2 CO 3 The pH of the solution was adjusted to about 9, 150ml of water was added, and the compound of formula II was extracted with dichloromethane. The dichloro...

Embodiment 2

[0032] Preparation of S-(+)-lercanidipine free base (formula Ⅱ) and R-(-)-lercanidipine free base (formula Ⅲ)

[0033] Add 12.3g (20mmol) racemic compound of formula Ⅰ, 7.2g L-(-)-benzoyl tartaric acid (LDBTA) (22mmol) into 70ml acetone, heat to about 50°C to dissolve, filter while hot, and cool down the filtrate slowly To about 5 ℃, stand for 24h, the LDBTA salt of formula III precipitates out, filter, and wash with a small amount of cold acetone. At the same time, the separation mother liquor was collected. Dry the solid to obtain 8.0 g of crude product of LDBTA salt of formula III, [α] D 20 =-58.9 。 (C=1.1 MeOH), recrystallized twice from acetone to obtain 6.5 g of LDBTA salt of formula III. [α] D 20 =-61.0 。 (C=1.0 MeOH)

[0034] 6.5g of the LDBTA salt of formula III was dissolved in 25ml of methanol, 10%Na 2 CO 3 The pH of the solution was adjusted to about 9, 150ml of water was added, and the compound of formula III was extracted with dichloromethane. The dich...

Embodiment 3

[0039] Preparation of S-(+)-lercanidipine free base (formula Ⅱ) and R-(-)-lercanidipine free base (formula Ⅲ)

[0040] Add 12.3g (20mmol) racemic compound of formula Ⅰ, 7.2g D-(+)-di-p-toluoyl tartaric acid (DDTTA) (22mmol) into 70ml acetone, heat to about 50°C to dissolve, filter while hot, and the filtrate Slowly lower the temperature to about 5°C and let it stand for 24 hours, the DDTTA salt of formula II precipitates, filter and wash with a small amount of cold acetone. At the same time, the separation mother liquor was collected. Dry the solid to obtain 8.0 g of crude product of DDTTA salt of formula II, [α] D 20 =+58.9 。 (C=1.1 MeOH), recrystallized twice from acetone to obtain 6.5 g of DDTTA salt of formula II. [α] D 20 =+65.5 。 (C=1.0 MeOH)

[0041] 6.5g of DDTTA salt of formula II was dissolved in 25ml of methanol, 10%Na 2 CO 3 The pH of the solution was adjusted to about 9, 150ml of water was added, and the compound of formula II was extracted with dichlor...

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Abstract

The invention discloses a method for preparing optically pure 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)3,5-dipicolinic acid 2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethyl methyl ester. According to the invention, a racemized compound 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)3,5-dipicolinic acid 2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethyl methyl ester in formula I and tartaric acid derivatives are dissolved in an organic solvent to perform the chemical resolution on the racemized compound in formula I so as to obtain a compound in formula II or III. The invention provides a low-cost method for preparing optically pure lercanidipine free alkali, and the method is suitable for industrialization.

Description

technical field [0001] The present invention relates to an optically pure 1,4-dihydro-2,6-dimethyl-4-(3-nitrobenzene) 3,5-pyridinedicarboxylic acid 2-[(3,3-diphenyl The preparation method of propyl)methylamino]-1,1-dimethylmethyl ester. technical background [0002] 1,4-Dihydropyridine calcium antagonists are a class of new drugs researched and developed in the late 1960s. They have special selectivity for L subtype calcium ion channels, and are currently the most specific and most effective clinically. The most widely used class of calcium antagonists. According to statistics, there are more than 30 kinds of 1,4-dihydropyridine calcium antagonists listed in the world. 1,4-Dihydro-2,6-dimethyl-4-(3-nitrobenzene) 3,5-pyridinedicarboxylic acid 2-[(3,3-diphenylpropyl)methylamino] -1,1-Dimethylmethyl ester hydrochloride (lercanidipine hydrochloride) was developed by the Italian company Recordati and first launched in the Netherlands in 1997. It has the advantages of long-lasti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
CPCY02P20/582
Inventor 夏运喜刘胜乐代俊伟
Owner ANHUI YONSENT PHARMA
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