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Synthesis method of 2-[2-(4-fluorophenyl)-2-oxa-1-phenylethyl]-4-methyl-3-oxa-N-phenylpentanamide

A technology of phenylpentanamide and phenylethyl, applied in 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo In the field of synthesis of substituted-N-phenylpentanamide, it can solve the problems of low yield and achieve the effects of less pollution, lower production cost and easy control

Inactive Publication Date: 2012-03-21
LIANYUNGANG HONGYE CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

(College of Chemistry and Pharmacy, East China University of Science and Technology, Shanghai 200237) Although the relative method 2 reduces the cost and simplifies the steps, the yield is still not high

Method used

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  • Synthesis method of 2-[2-(4-fluorophenyl)-2-oxa-1-phenylethyl]-4-methyl-3-oxa-N-phenylpentanamide

Examples

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Comparison scheme
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Embodiment 1

[0034] Example 1, a synthesis of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide method, the steps are as follows:

[0035] (1) Preparation of methyl isobutyryl acetate:

[0036]Under the protection of nitrogen, pump toluene into the reaction bottle, add sodium hydride, the sodium hydride is dispersed in mineral oil, and its mass solubility is 40%; under stirring, pump dimethyl carbonate, and heat up to 50°C It is 40% that methyl isopropyl ketone is dissolved in toluene to its mass concentrated substance, and the toluene mixed solution that starts to drop methyl isopropyl ketone slowly, after the dropwise addition is completed, is incubated 1 hour; Sampling TLC tracks, and after reaction finishes, cools down to 15°C, slowly add water dropwise, after the dropwise addition, pour the reaction solution into a hydrochloric acid solution with a mass concentration of 50%, a large amount of carbon dioxide gas is generated; the toluene, sodium hydride, di...

Embodiment 2

[0050] Example 2, a synthesis of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide method, the steps are as follows:

[0051] (1) Preparation of methyl isobutyryl acetate:

[0052] Under the protection of nitrogen, pump toluene into the reaction bottle, add sodium hydride, the sodium hydride is dispersed in mineral oil, and its mass solubility is 60%; under stirring, pump dimethyl carbonate, and heat up to 60°C It is 60% that methyl isopropyl ketone is dissolved in toluene to its mass concentration, and the toluene mixed solution that starts to drop methyl isopropyl ketone slowly, after the dropwise addition is completed, keep warm for 3 hours; Sampling TLC tracking, after the reaction finishes, cool down to 20°C, slowly add water dropwise, after the dropwise addition, pour the reaction solution into a hydrochloric acid solution with a mass concentration of 70%, a large amount of carbon dioxide gas is generated; the toluene, sodium hydride, dimethy...

Embodiment 3

[0066] Example 3, Synthesis experiment of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide.

[0067] 1, the preparation of methyl isobutyryl acetate:

[0068] Under the protection of nitrogen, pump 1000g of toluene into the reaction bottle, add 112g of sodium hydride (dispersed in mineral oil, content 50%), under stirring, pump in 305g of dimethyl carbonate, heat up to 50-60°C, 130g Dissolve methyl isopropyl ketone in 260g toluene, start to slowly add the mixed solution of methyl isopropanone and toluene dropwise, control the dropping time for about 5 hours, and keep the temperature for 1 hour after the dropping is completed. Sampling for TLC tracking. After the reaction, cool down to 15-20°C and slowly add 200g of water dropwise. After the dropwise addition, pour the reaction solution into a mixed solution of 300g of concentrated hydrochloric acid and 500g of water. A large amount of carbon dioxide gas is generated. The layers were separated, the...

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Abstract

The invention discloses a synthesis method of 2-[2-(4-fluorophenyl)-2-oxa-1-phenylethyl]-4-methyl-3-oxa-N-phenylpentanamide. The method is characterized by comprising the following steps: firstly preparing methyl isobutyryl acetate from toluene, sodium hydride, dimethyl cabonate, methyl isopropyl ketone and the like as raw materials; then preparing isobutyryl acetanilide from toluene, methyl isobutyl acetate, HCl, sodium bicarbonate and the like as raw materials; preparing 4-fluorophenylacetophenone from aluminium choride, phenylacetyl chloride and the like as raw materials; preparing 2-chloro-1-(4-fluorophenyl)-acetophenone from 4-fluorophenylacetophenone, dichloromethane, chlorine and the like as raw materials; and finally preparing the finished product from isobutyryl acetanilide, potassium carbonate and 2-chloro-1-(4-fluorophenyl)-acetophenone. The raw materials of the synthesis method are inexpensive and easily available, the reaction has five steps and the yield of each step is high, thus the production cost can be greatly reduced; and the reaction conditions are mild, the method can be controlled easily, the process is simple, the pollution is low and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide synthetic method. Background technique [0002] 2-[2-(4-Fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide is a key to the synthesis of alfastatin The intermediate, alfastatin, is a reductase inhibitor, and is a new generation of highly effective blood lipid-lowering drug. The drug can not only lower cholesterol, but also lower triglyceride, its effect is far superior to other statin drugs, and has broad market prospects. [0003] Publicly reported that there are many synthetic routes of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, Wherein industrialization or have industrialization application prospect mainly contain three routes: 1, take isobutyryl acetanilide as raw material to carry out Knoevenagel condensation with benzaldehyde under the catalysis of β-alanine, ...

Claims

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Application Information

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IPC IPC(8): C07C235/80C07C231/12
Inventor 蔡跃冬王明潘林见
Owner LIANYUNGANG HONGYE CHEM
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