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Preparation method of methyl 2-nitrobenzal acetoacetate

A technology of methyl nitrobenzylidene acetoacetate and methyl acetoacetate, which is applied in the field of preparation of methyl 2-nitrobenzylidene acetoacetate, can solve problems such as residue and incomplete reaction, and achieve short reaction time , high purity and high yield

Active Publication Date: 2013-03-20
QINGDAO HUANGHAI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the synthesis process of nifedipine is mostly obtained by refluxing o-nitrobenzaldehyde, methyl acetoacetate and ammonia water in methanol. During the reaction, a large amount of nifedipine will be precipitated from the reaction solution in a short time, forming a heterogeneous reaction. , so as to cover a part of the reaction material, and cannot react completely, and these unreacted materials still remain in nifedipine during the purification process

Method used

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  • Preparation method of methyl 2-nitrobenzal acetoacetate
  • Preparation method of methyl 2-nitrobenzal acetoacetate

Examples

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Effect test

Embodiment 1

[0027] The chemical reagents and chemicals in the examples of the present invention are all analytically pure.

[0028] The preparation method of 2-nitrobenzylidene acetoacetate methyl ester of the present invention comprises the following steps:

[0029] (1) In a 250ml three-necked flask, add 15.1g of o-nitrobenzaldehyde, 13.92g of methyl acetoacetate, 25ml of organic solvent methanol, and 0.44g of catalyst piperidine acetate, and react at 70°C for 2 hours to generate 2-nitrobenzyl Methyl acetoacetate was concentrated in vacuo to remove methanol to obtain a crude reddish-brown oily product of methyl 2-nitrobenzylidene acetoacetate.

[0030] Concrete reaction route is as follows:

[0031]

[0032] (2) Add 50ml of ethyl acetate / petroleum ether (volume ratio 1:5) mixture to the crude product of reddish-brown 2-nitrobenzylidene acetoacetate oil, stir at 0°C for 2h and filter to obtain About 25.8 g of solid crude methyl 2-nitrobenzylidene acetoacetate.

[0033] (3) The solid...

Embodiment 2

[0035] (1) In a 250ml three-necked flask, add 15.1g of o-nitrobenzaldehyde, 13.92g of methyl acetoacetate, 25ml of ethanol, and 0.41g of pyridinium acetate. After reacting at 80°C for 2 hours, concentrate in vacuo to remove the ethanol to obtain reddish-brown 2 - Methyl nitrobenzylidene acetoacetate oil.

[0036] (2) Add 50ml of ethyl acetate / cyclohexane (volume ratio: 1:5) mixture to 2-nitrobenzylidene acetoacetate, stir at 0°C for 2h and filter to obtain about 25.1g of wet product ,

[0037] (3) The solid crude product of methyl 2-nitrobenzylidene acetoacetate was recrystallized with 75ml of methanol to obtain a white solid, about 21.4g after drying, with a yield of about 85.9% and a purity of more than 99.5%.

Embodiment 3

[0039] (1) In a 250ml three-neck flask, add 15.1g of o-nitrobenzaldehyde, 13.92g of methyl acetoacetate, 25ml of isopropanol, and 0.38g of pyridinium formate. After reacting at 80°C for 2 hours, concentrate in vacuo to remove ethanol to obtain red Brown 2-nitrobenzylidene acetoacetate methyl ester oil.

[0040] (2) Add 50ml of ethyl acetate / cyclohexane (volume ratio: 1:5) mixture to 2-nitrobenzylidene acetoacetate, stir at 0°C for 2h and filter to obtain about 25.1g of wet product ,

[0041] (3) The solid crude product of methyl 2-nitrobenzylidene acetoacetate was recrystallized with 75ml of methanol to obtain a white solid, about 21.4g after drying, with a yield of about 85.9% and a purity of more than 99.5%.

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Abstract

The invention provides a preparation method of methyl 2-nitrobenzal acetoacetate, which comprises the following steps: (1) reacting initial raw materials o-nitrobenzaldehyde and methyl acetoacetate with methanol under the action of a catalyst to generate a compound methyl 2-nitrobenzal acetoacetate; (2) after carrying out vacuum concentration to remove the back, adding a crystallizing solvent, and stirring at low temperature to generate the methyl 2-nitrobenzal acetoacetate solid crude product; and (3) recrystallizing the solid crude product to obtain the methyl 2-nitrobenzal acetoacetate pure product of which the purity is higher than 99.5%. The preparation method provided by the invention has the advantages of mild reaction conditions, short reaction time, high yield and environmental protection; the obtained nifedipine has high purity of the impurity methyl 2-nitrobenzal acetoacetate; and the impurity can be accurately positioned by comparison in the nifedipine related substance inspection, thereby having important instruction meanings for researching nifedipine.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of methyl 2-nitrobenzylidene acetoacetate. Background technique [0002] Nifedipine (Nifedipin), the chemical name is 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid dimethyl ester. Nifedipine was successfully developed by Bayer Company of Germany in 1969. It was the first dihydropyridine calcium antagonist. It was used to treat angina pectoris of coronary heart disease in 1975 and achieved satisfactory curative effect. It is still the first choice for the treatment of angina pectoris. One of the main drugs. Since it began to be used to treat hypertension in 1980, it has also achieved remarkable curative effect, laying the foundation for calcium antagonists as basic antihypertensive drugs. The structural formula is as follows: [0003] [0004] Nifedipine has the strongest effect on dilating coronary arteries and per...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C205/56C07C201/12
Inventor 李延顺刘晓华胡杰黄清华仇中选赵国栋于华芝吕蓓蓓
Owner QINGDAO HUANGHAI PHARM CO LTD
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