Synthesis process for high-purity lercanidipine hydrochloride

A technology of lercanidipine hydrochloride and synthesis process, applied in the field of pharmacy, can solve the problems of long cycle, complicated operation, difficult preparation and the like, and achieve the effects of mild conditions, simple operation and easy purification

Active Publication Date: 2014-04-02
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] During the course of the experiment, the applicant found that the purification of intermediates or products such as the above-mentioned methods 1, 3, 4, and 5 was difficult, the operation was complicated, and the content of impurities was high; methods 2 and 6 did not involve the synthesis method of mother nucleic acid, and method 6 The derivatives of the side chain are not easy to prepare, the operation is difficult, the cost is high, and it is not suitable for large-scale industrial production
In summary, the existing methods have disadvantages such as high cost, long cycle, cumbersome operation, and difficulty in purification during the commercialization process.

Method used

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  • Synthesis process for high-purity lercanidipine hydrochloride
  • Synthesis process for high-purity lercanidipine hydrochloride
  • Synthesis process for high-purity lercanidipine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1, the preparation of propionitrile acetoacetate

[0050]Add 14.2g of 3-hydroxypropionitrile and 0.2g of ethylenediamine into the dry reaction flask, add 18g of diketene dropwise at room temperature under full stirring, and control the temperature not higher than 75°C. After stirring and reacting for 2 hours, put the reaction solution in Evaporate under reduced pressure at 70°C until there is no distilled matter to obtain a light yellow oil, add 60ml of dichloromethane, wash twice with 50ml of water, once with 50ml of saturated brine, dry over anhydrous sodium sulfate, filter with suction, and evaporate to dryness under reduced pressure at 45°C. 30 g of light yellow oil was obtained, which was directly used for the next reaction.

Embodiment 2

[0051] Embodiment 2, the synthesis of lercanidipine mother nucleic acid

[0052] Add 15.6g of propionitrile acetoacetate, 17.5g of 3-nitrobenzaldehyde, 50ml of isopropanol, a mixed solution of 0.5g of piperidine and 0.3g of acetic acid into the dry reaction flask, and add 12.593- Aminobutyrylic acid methyl ester, stir and react at room temperature to 50°C for 12 hours, cool down to room temperature (<25°C), add 20ml of newly prepared 5.8gKOH in isopropanol solution in a water bath, stir for 2 hours, and depressurize at 45°C Evaporate the solvent, add 50ml of water and stir at 50°C for 1 hour, collect the water phase, repeat 3 times, combine the water phase and adjust the pH to 3-4 with 4M hydrochloric acid while stirring in a water bath, a large amount of solids are precipitated, suction filtered, and the filter cake is washed with water After three times until the pH was stable, 23.6 g of a white to light yellow solid was obtained by crystallization with methanol, with a yiel...

Embodiment 3

[0053] The synthesis of embodiment 3 lercanidipine hydrochloride

[0054] In dry reaction bottle, add 16.7g (0.05mol) mother nucleus, 90mlDCM, 3mlDMF, in N 2 Under protection, 5.5ml (0.075mol) of thionyl chloride was added dropwise at 0°C-10°C, stirred at this temperature for 2-3 hours, 17.1g (0.06mol) of the side chain was added dropwise, stirred for 5 hours, TLC showed After the reaction is complete, add 100ml of water, separate the liquids, wash the organic phase twice with 100ml of water, once with saturated brine, dry over anhydrous sodium sulfate, filter with suction, evaporate to dryness under reduced pressure to obtain an oily product, add 50ml of DME and stir overnight to obtain a light yellow solid. After filtration and vacuum drying at 60°C, 19.6 g of a light yellow solid was obtained by crystallization from ethanol, with a yield of 63.8% and a purity of 99.82%.

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Abstract

A synthesis process for high-purity lercanidipine hydrochloride is disclosed. The synthesis process comprises the following three steps of: (1) esterifying diketene and 3-hydroxypropionitrile in the presence of an alkali to generate propionitrile acetoacetate; (2) performing condensation and cyclization as well as one-pot hydrolytic acidification on the propionitrile acetoacetate, 3-nitrobenzaldehyde and 3-amido-methyl crotonate to obtain a lercanidipine parent nucleus; and (3) esterifying under the catalysis of thionyl chloride and DMF (dimethyl formamide), and crystallizing to obtain the high-purity lercanidipine hydrochloride. The process disclosed by the invention has the advantages of being simple in steps, moderate and controllable in reaction conditions, high in yield etc.

Description

Technical field: [0001] The invention relates to the field of pharmacy, and relates to a synthesis process of medicine, in particular to a synthesis process of high-purity lercanidipine hydrochloride. Background technique: [0002] Lercanidipine Hydrochloride, a third-generation dihydropyridine calcium antagonist developed for the Italian Recordati company, was first listed in the Netherlands in December 1997, with the trade name Zanidip, and was launched in the UK, Italy, and Greece in 1998. It was subsequently launched in other European countries. [0003] [0004] Lercanidipine hydrochloride is a third-generation dihydropyridine calcium antagonist, which can reversibly block the Ca2+ inflow of L-type calcium channels in vascular smooth muscle cell membranes, dilate peripheral blood vessels and lower blood pressure. Highly lipophilic dihydropyridine calcium antagonist. Its antihypertensive mechanism is to block the calcium channel of arterial vascular smooth muscle an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90
Inventor 刘意林祁伟杨琰
Owner CHINA RESOURCES SAIKE PHARMA
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