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Synthesis method of methoxy ethyl 2-(3-nitrobenzylidene)acetacetate

A technology of methoxyethyl acetate and acetoacetate methoxyethyl, applied in the field of synthesis of cilnidipine condensation intermediate 2-acetoacetate methoxyethyl, can solve the problem of low yield, poor purity, etc. problems, to achieve the effect of reducing side reactions, shortening the reaction time, and changing the feeding method

Inactive Publication Date: 2012-05-09
BENGBU BBCA MEDICINE SCI DEV
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  • Summary
  • Abstract
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Problems solved by technology

[0005] In order to overcome the defects of low yield and poor purity in the synthetic method of existing cilnidipine intermediate 2-(3-nitrobenzylidene) methoxyethyl acetoacetate, the object of the invention is to provide a kind of A new synthetic method for the compound

Method used

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  • Synthesis method of methoxy ethyl 2-(3-nitrobenzylidene)acetacetate

Examples

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Effect test

Embodiment 1

[0024] (1) Weigh 200g of methoxyethyl acetoacetate, add it to a 500ml three-neck flask, stir, cool down to about 5°C, add 25ml of concentrated sulfuric acid dropwise, keep the temperature below 10°C, and complete the dropwise addition in 40 minutes. Ethyl acetate 100ml, then add m-nitrobenzaldehyde 151g in three equal parts;

[0025] (2) React at room temperature for 2.5 hours, stop stirring, and place overnight;

[0026] (3) Add 450ml of ethyl acetate the next day to dissolve all the solids, add 200ml of purified water to extract twice, and collect the organic layer;

[0027] (4) Ethyl acetate is evaporated under reduced pressure, cooled with ice water, and crystallized;

[0028] (5) The obtained crystals were filtered and washed with a small amount of ethanol to obtain a light yellow solid, which was dried at 70° C. to obtain 208 g of a solid, with a yield of 71% and a content of 99.2% (analyzed by HPLC).

Embodiment 2

[0030] (1) Weigh 164g of methoxyethyl acetoacetate, add it to a 500ml three-neck flask, stir, cool down to about 5°C, add 23ml of concentrated sulfuric acid dropwise, keep the temperature below 10°C, and complete the dropwise addition in 30 minutes. Ethyl acetate 105ml, and then add m-nitrobenzaldehyde 130g in five equal parts;

[0031] (2) React at room temperature for 2.5 hours, stop stirring, and place overnight;

[0032] (3) The next day, add 350ml of ethyl acetate to dissolve all the solids, add 160ml of purified water to extract twice, and collect the organic layer;

[0033] (4) Ethyl acetate is evaporated under reduced pressure, cooled with ice water, and crystallized;

[0034] (5) The obtained crystals were filtered and washed with a small amount of ethanol to obtain a light yellow solid, which was dried at 70° C. to obtain 184 g of a solid, with a yield of 73% and a content of 99.0% (analyzed by high performance liquid chromatography).

Embodiment 3

[0036] (1) Weigh 279g of methoxyethyl acetoacetate, add it to a 1000ml three-neck flask, stir, cool down to about 5°C, add 35ml of concentrated sulfuric acid dropwise, keep the temperature below 10°C, and complete the dropwise addition in 50 minutes. Ethyl acetate 200ml, and then add m-nitrobenzaldehyde 220g in five equal parts;

[0037] (2) React at room temperature for 3.0 hours, stop stirring, and place overnight;

[0038] (3) The next day, add 600ml of ethyl acetate to dissolve all the solids, add 280ml of purified water to extract three times, and collect the organic layer;

[0039] (4) Ethyl acetate is evaporated under reduced pressure, cooled with ice water, and crystallized;

[0040] (5) The obtained crystals were filtered and washed with a small amount of ethanol to obtain a light yellow solid, which was dried at 70° C. to obtain 321 g of a solid with a yield of 75% and a content of 99.1% (analyzed by HPLC).

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Abstract

The invention relates to a synthesis method of a cinildipine intermediate, namely methoxy ethyl 2-(3-nitrobenzylidene)acetacetate. The synthesis method comprises the steps of: (1) dropwise adding concentrated sulfuric acid to methoxy ethyl acetacetate under stirring, and then adding ethyl acetate; (2) adding m-nitrobenzaldehyde, reacting at room temperature, and after the reaction is stopped, standing overnight to separate out solids; (3) adding ethyl acetate until solids are completely dissolved, then washing with water and collecting an organic phase; and (4) evaporating to remove a solvent so as to separate out crystals, filtering and drying. As compared with the traditional preparation method of cinildipine condensation intermediate, the technical scheme provided by the invention has the advantages that: the obtained target product has high purity (more than 99%) and high yield ( more than 70%); and the synthesis method is mild in reaction conditions and simple and convenient to operate.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for synthesizing cilnidipine condensation intermediate 2-(3-nitrobenzylidene)methoxyethyl acetoacetate. Background technique [0002] Cilnidipine was developed by Japan Fuji Co., Ltd., and was first listed in Japan in December 1995. The chemical name of cilnidipine is: racemic 2,6-dimethyl-4(3-nitrobenzene)-1,4-dihydropyridine-3,5-dicarboxylic acid-2-methoxyethyl (E )-3-phenyl-2-propenyl diester. Cinidipine is a lipophilic dihydropyridine calcium antagonist that can bind to the dihydropyridine site of the L-type calcium channel on the membrane of vascular smooth muscle cells and inhibit Ca 2+ Through the transmembrane influx of L-type calcium channels, it relaxes and expands vascular smooth muscle, thereby reducing blood pressure. As a new type of calcium ion antagonist, cilnidipine can not only effectively lower blood pressure, but also effectively prevent reflex sym...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C205/56C07C201/12
Inventor 陈昀汪洪湖张亚孙建华江立新韦亚锋张瑾王栋
Owner BENGBU BBCA MEDICINE SCI DEV
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