New synthetic method for (earth)4-fluor-alpha-(2-methyl-1-oxypropyl )-gamma-oxo-N, beta-diphenyl benzene butanamide

A technology of diphenylbenzamide and oxypropyl is applied in the preparation of carboxylic acid amides, chemical instruments and methods, preparation of organic compounds, etc., and can solve the problems of high industrialization cost, low yield of isobutyrylacetanilide, and raw materials. It is more expensive and other problems to achieve the effects of low production cost, improved total yield and short process route.

Inactive Publication Date: 2008-11-19
ZHEJIANG JINGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The whole route is long, the yield of isobutyrylacetanilide is very low, and th

Method used

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  • New synthetic method for (earth)4-fluor-alpha-(2-methyl-1-oxypropyl )-gamma-oxo-N, beta-diphenyl benzene butanamide
  • New synthetic method for (earth)4-fluor-alpha-(2-methyl-1-oxypropyl )-gamma-oxo-N, beta-diphenyl benzene butanamide
  • New synthetic method for (earth)4-fluor-alpha-(2-methyl-1-oxypropyl )-gamma-oxo-N, beta-diphenyl benzene butanamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Embodiment 1: Preparation of 4-fluorophenyl benzyl ketone (2)

[0018] 15.5g (0.10mol) of phenylacetyl chloride was dissolved in 30mL of fluorobenzene for later use.

[0019] 16g (0.12mol) AlCl 3 and 70mL of fluorobenzene were added to the reaction flask, and the fluorobenzene solution of phenylacetyl chloride was added dropwise under cooling in an ice bath, and the dropwise addition was completed in about 30 minutes. The reaction solution was stirred at -10 to 0°C for 3 hours, raised to room temperature, poured into 100 g of crushed ice and 30 mL of concentrated hydrochloric acid, separated to remove the water layer, washed the organic layer with 50 mL×3 water, dried over anhydrous sodium sulfate, and distilled off the fluorobenzene. The resulting solid was recrystallized from absolute ethanol to obtain 19.3 g of the product, with a yield of 90%. The melting point is 76-78°C.

Embodiment 2

[0020] Embodiment 2: Preparation of α-chloro-4-fluorophenyl benzyl ketone (3)

[0021] Compound (2) 21.4g (0.1mol) was dissolved in 100mL of dichloromethane, and chlorine gas was introduced at room temperature. After the detection was complete, the chlorine gas was stopped, washed with 50mL×3 water, the organic layer was dried over anhydrous sodium sulfate, and the dichloromethane was evaporated. The obtained crude product can be directly used in the next reaction.

Embodiment 3

[0022] Embodiment 3: the preparation of isobutyrylacetanilide (4)

[0023] In a 500mL three-necked flask, add 30g (0.33mol) dimethyl carbonate and 80mL toluene, add 11.2g (0.47mol) sodium hydrogen under stirring, heat to 70°C, add dropwise 10.4g (0.12mol) methyl isopropyl ketone, The dropwise addition was completed in about 1 hour, and then reacted for 4 hours after the dropwise addition. Under cooling, 50 mL of acetic acid was added dropwise, washed with 100 mL×3 water, dried over anhydrous sodium sulfate, evaporated toluene, and distilled under reduced pressure to obtain 18.1 g of methyl isobutyrylacetate with a yield of 95%.

[0024] In a 100mL three-necked flask, add 50mL toluene and 18.1g methyl isobutyryloacetate, add 10.7g (0.11mol) aniline dropwise under reflux, continue to react for 2 hours after the dropwise addition, cool to room temperature, wash with 3×100mL 10% hydrochloric acid , the organic layer was dried over anhydrous sodium sulfate, the toluene was distill...

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Abstract

The invention discloses a method for preparing an intermediate product of an Atorvastatin medicine. The isobutyrylacetanilide utilized in the prior method has low yield coefficient, expensive raw materials and high industrial cost. The method comprises the following steps that: 4- fluorophenyl benzyl ketone is obtained by performing the Friedel-Crafts reaction on phenylacetyl chloride and fluorobenzene which are catalyzed by aluminium chloride; methyl isopropyl ketone reacts with dimethyl carbonate or diethyl carbonate in an inert solvent with sodium hydrosulfate as catalyst to produce methyl 4-methyl-3-Oxopentanoate or ethyl isobutyrylacetate; next, the methyl 4-methyl-3-Oxopentanoate or the ethyl isobutyrylacetate reacts with aniline to produce isobutyrylacetanilide; carbon-based alpha position of the 4-fluorophenyl benzyl ketone is chloridized in the solvent to produce alpha-chlorine-4-fluorophenyl benzyl ketone; afterwards, the alpha-chlorine-4-fluorophenyl benzyl ketone reacts with the isobutyrylacetanilide in the action of alkali. The process for synthesizing isobutyrylacetanilide has short flow, the yield coefficient is high, and the cost is low, thereby improving the total yield of reaction directly.

Description

technical field [0001] The present invention relates to the preparation method of drug atorvastatin intermediate, specifically a kind of (earth) 4-fluoro-α-(2-methyl-1-oxypropyl)-γ-oxo-N,β- Synthetic method of diphenylbenzenebutyramide. Background technique [0002] Atorvastatin is a hepatic tissue-selective HMG-CoA reductase inhibitor, which is clinically used to treat hypercholesterolemia and hyperlipidemia. (Soil) 4-fluoro-α-(2-methyl-1-oxypropyl)-γ-oxo-N, β-diphenylbenzenebutyramide is a key intermediate for the synthesis of atorvastatin, according to literature reports There are two different strategies for the synthesis of this compound: one is the linear synthesis route, and the other is the convergent synthesis route. [0003] US 5155251, WO 0172706 and other patent documents adopt a linear synthesis route. Compound (1) uses isobutyrylacetanilide as a raw material, and then undergoes Knoevengale condensation with benzaldehyde under the catalysis of β-alanine, and t...

Claims

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Application Information

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IPC IPC(8): C07C235/80C07C231/14
Inventor 李瑞军谢作念栾国金
Owner ZHEJIANG JINGXIN PHARMA
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