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Method for preparing levamlodipine from racemic amlodipine maleate

A technology of amlodipine maleate and levamlodipine, which is applied in the directions of organic chemistry, drug combination, cardiovascular system diseases, etc., to achieve the effect of simplified process and low toxicity

Active Publication Date: 2009-09-16
JIANGSU SIMCERE PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The shortcoming of these methods is that the amlodipine L-body obtained is in the form of salt, and the preparation of L-amlodipine besylate also needs to dissociate the free base, and then react with benzenesulfonic acid

Method used

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  • Method for preparing levamlodipine from racemic amlodipine maleate
  • Method for preparing levamlodipine from racemic amlodipine maleate
  • Method for preparing levamlodipine from racemic amlodipine maleate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Preparation of amlodipine free base from amlodipine maleate

[0025] Add 2.0g (3.80mmol) of amlodipine maleate and 20ml of N,N-dimethylformamide into a 100ml single-necked bottle, add 20ml of an aqueous solution containing 0.70g of sodium bicarbonate (8.36mmol), and stir at room temperature for 30min. 50ml of water was added to produce a large amount of solid, which was filtered and dried in vacuo for 4 hours to obtain 1.5g of light yellow solid with a yield of 96%. Preparation of Levo-amlodipine from amlodipine free base

[0026] Add 2g (4.91mmol) amlodipine free base to a 25ml single-necked bottle, add 18ml N,N-dimethylformamide, stir for 10 minutes to dissolve the solid completely, and 276mg (1.84mmol) D-(-) - Dissolve the tartaric acid solid in 2ml of ethanol, add dropwise to the above solution, stir for 4h, the solution becomes turbid, continue to stir for 10h, filter, add 100ml of water to the filtrate, the solution becomes turbid, let stand for 10h, precipitate ...

Embodiment 2

[0030] Preparation of amlodipine free base from amlodipine maleate

[0031] Add 2.0g (3.80mmol) of amlodipine maleate and 20ml of ethanol into a 100ml single-necked bottle, add 20ml of an aqueous solution containing 0.70g of sodium bicarbonate (8.36mmol), stir at room temperature for 30min, add 50ml of water, and produce a large amount of solids. Filter and dry in vacuo for 4 hours to obtain 1.4 g of a light yellow solid with a yield of 90%.

[0032] Preparation of Levo-amlodipine from amlodipine free base

[0033] 2g (4.91mmol) amlodipine free base is added in the 25ml single-neck bottle, adopts the method identical with embodiment 1, adds the D-(-)-tartaric acid of different amounts respectively, gained result is shown in Table 1:

[0034] Table I:

[0035]

[0036]

[0037] Preparation of levamlodipine besylate by levamlodipine

[0038]Using the same method as in Example 1, the levamlodipine obtained in the previous step was prepared into levamlodipine besylate, an...

Embodiment 3

[0040] Preparation of amlodipine free base from amlodipine maleate

[0041] Add 2.0g (3.80mmol) of amlodipine maleate and 20ml of N,N-dimethylformamide into a 100ml single-necked bottle, add 20ml of an aqueous solution containing 0.63g of sodium carbonate (7.60mmol), stir at room temperature for 30min, and add 50ml of water produced a lot of solids, which were filtered and dried in vacuo for 4 hours to obtain 1.5g of pale yellow solids with a yield of 96%.

[0042] Preparation of Levo-amlodipine from amlodipine free base

[0043] Add 2g (4.91mmol) amlodipine free base to a 25ml single-necked bottle, add N,N-dimethylformamide or the mixed solution of N,N-dimethylformamide and ethanol as shown in Table 2 , Add 276mg (1.84mmol) D-(-)-tartaric acid solid, adopt the same method as Example 1, the obtained results are shown in Table II.

[0044] Table II:

[0045]

[0046] Preparation of levamlodipine besylate by levamlodipine

[0047] Using the same method as in Example 1, th...

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Abstract

The invention relates to a method for removing maleate of amlodipine maleate, which prepares free base of amlodipine from weak inorganic base, DMF and water as solvent by a settling method. The invention relates to a method for preparing levamlodipine from the amlodipine, which removes dextroisomer through salifying precipitation by using mixed solvent of N, N-dimethylformamide and ethanol and D(-)tartaric acid taken as a chiral reagent, and prepares the levamlodipine through precipitation by adding excessive water. The levamlodipine can be used for preparing levamlodipine besylate.

Description

technical field [0001] The invention relates to a method for removing maleate radicals with amlodipine maleate. Background technique [0002] Amlodipine, the chemical name is 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedi Carboxylic acid-3-ethyl-5-methyl ester is a third-generation dihydropyridine calcium antagonist developed by Pfizer of the United States. It is mainly used for the treatment of hypertension and angina pectoris. It was first listed in the UK in 1990. There is a chiral center at position 4 in the amlodipine molecule, and the structure of the left-handed body is shown in formula one. [0003] [0004] Compared with the racemate, S-(-)-amlodipine showed better calcium channel inhibitory activity. S-(-)-amlodipine has twice the calcium antagonistic activity of racemic amlodipine in the mouse model (Arrowsmith. J. Med. Chem., (1986) 29, 1696-1702). The use of S-(-)-amlodipine can reduce side effects such as acral edema, hea...

Claims

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Application Information

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IPC IPC(8): C07D211/90A61P9/12A61P9/10
Inventor 刘永辉张连第丁磊何勤飞
Owner JIANGSU SIMCERE PHARMA
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