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Preparation method of nitrendipine

A technology of nitrendipine and ethyl nitrobenzylidene acetoacetate is applied in the field of medical technology, can solve the problems of not paying attention to transesterification impurities and the like, and achieve the effects of easy industrial application, lowering reaction temperature and reducing consumption

Active Publication Date: 2019-05-10
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, current reports show that these synthetic methods will produce a large amount of transesterification by-products, and the prior art does not pay attention to these transesterification impurities

Method used

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  • Preparation method of nitrendipine
  • Preparation method of nitrendipine
  • Preparation method of nitrendipine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Step (1): Pump 375.8g of weighed absolute ethanol into a 1000ml reactor, then add 140g of ethyl 3-nitrobenzylidene acetoacetate and 61.2g of methyl 3-aminobutenoate, and turn on Stir.

[0044] Step (2): After the feeding is completed, the temperature is raised to 70~75℃, and the reaction is kept at this temperature for 1h; then, the temperature is controlled at 70~75℃, and 6.4g of concentrated hydrochloric acid is slowly added. After the addition is completed, it is carried out by TLC immediately Control (developing agent: PE:EA=3:1);

[0045] Step (3): Immediately (within 10 minutes) after TLC shows that the reaction is complete, the temperature is lowered to 15-20°C, and the temperature is controlled at 15-20°C for 1 hour. Then it was filtered, and the filter cake was rinsed once with 13.82g of absolute ethanol to obtain the crude nitrendipine. The HPLC spectrum is shown in figure 1 . The result of HPLC area normalization method is that the chromatographic content of Ni...

Embodiment 2

[0048] Compared with Example 1, the only difference is that ethyl 3-nitrobenzylidene acetoacetate is prepared by reacting 3-nitrobenzaldehyde with ethyl acetoacetate and then recrystallizing from absolute ethanol. In this embodiment, refined 3-nitrobenzylidene ethyl acetate is used, and its purity is ≥99.9%.

[0049] A method for synthesizing high-purity Nitrendipine, using the following steps:

[0050] (1) Put 3-nitrobenzylidene acetoacetate and 3-aminobutenoic acid methyl ester in the organic solvent, the amount of 3-aminobutenoic acid methyl ester added is 3-nitrobenzylidene acetoacetate 100% of the molar amount of ethyl ester intermediate,

[0051] (2) Raise the temperature of the above-mentioned reactant to 70~75℃, then add a small amount of concentrated hydrochloric acid catalyst dropwise at this temperature. After the dropwise addition is completed, it will be controlled by TLC immediately. After the reaction has disappeared, the temperature will be lowered to crystallize , ...

Embodiment 3

[0054] Compared with Example 1, the only difference is that in step (2), after the temperature is raised to 70-75°C, there is no heat preservation reaction for 1 hour, and concentrated hydrochloric acid is directly added dropwise. The yield of the crude product was 46%, and the product purity and impurity control were similar to those of Example 1, but the yield was lower than that of Example 1.

[0055] Because there is no pre-heating and reaction for 1 hour, the yield is low, which affects the product yield.

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Abstract

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of nitrendipine. The preparation method is characterized by including following steps: (1), allowing 3-nitrobenzylidene ethyl acetoacetate intermediate and 3-aminomethyl crotonate according to a molar ratio of 1:1-1.1 to react at 70-75 DEG C in advance; (2), adding concentrated hydrochloric acidinto a reaction system of the step (1), and allowing reaction at 70-75 DEG C after adding is completed, wherein adding amount of the concentrated hydrochloric acid is 10-15% of molar weight of the 3-nitrobenzylidene ethyl acetoacetate intermediate; (3), cooling to 15-20 DEG C after reaction in the step (2) is completed, continuing reaction, and performing solid-liquid separation and recrystallization to obtain nitrendipine. Through process control, content of ester exchange impurities can be lowered effectively, and product yield can be increased.

Description

Technical field [0001] The invention relates to the technical field of medical technology, in particular to a method for synthesizing high-purity nitrendipine. Background technique [0002] Nitrendipine, molecular formula C18H20N2O6; molecular weight: 360.36 [0003] Structural formula: [0004] Nitrendipine (Nitrendipine) is a dihydropyridine calcium channel blocker. It can inhibit the transmembrane calcium influx of vascular smooth muscle and myocardium, but it is mainly vascular, so vascular selectivity is strong. Nitrendipine can cause systemic vasodilation (including coronary arteries and renal arterioles), and produce the main effect of reducing diastolic pressure. Nitrendipine can also reduce myocardial oxygen consumption and has a protective effect on ischemic myocardium. Unlike diltiazem, verapamil, and nifedipine, nitrendipine has no effect on the transmission of sinus or atrioventricular nodes. In recent years, a lot of research has been done on the synthesis of Nitr...

Claims

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Application Information

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IPC IPC(8): C07D211/90
Inventor 张海军秦敏刘虎袁金桥
Owner HARVEST PHARMA HUNAN CO LTD
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