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Synthetic method of 4-(4-halobutyryl)-alpha, alpha-dimethyl phenylacetate

A technology of dimethyl phenylacetate and halobutyryl, applied in the field of organic compound synthesis, can solve the problems of high cost, low yield, complicated operation and the like, and achieve the effects of low cost, simple operation and high purity

Inactive Publication Date: 2013-10-02
ZHEJIANG QIMING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The product obtained by the above-mentioned existing method is 4-(4-halobutyryl)-α, ethyl α-dimethylphenylacetate and 3-(4-halobutyryl)-α, ethyl α-dimethylphenylacetate The mixture of esters needs to be purified to obtain the p-product 4-(4-halobutyryl)-α,α-ethyl dimethylphenylacetate, which has the disadvantages of cumbersome operation, low yield, and high cost.

Method used

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  • Synthetic method of 4-(4-halobutyryl)-alpha, alpha-dimethyl phenylacetate
  • Synthetic method of 4-(4-halobutyryl)-alpha, alpha-dimethyl phenylacetate
  • Synthetic method of 4-(4-halobutyryl)-alpha, alpha-dimethyl phenylacetate

Examples

Experimental program
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Effect test

Embodiment 1

[0061] 1) Synthesis of 4-chloro-1-butyne:

[0062]

[0063] In a 100ml round bottom flask, add 3-butyn-1-ol (5.4g, 77.04mmol) and 4 drops of pyridine in an ice-water bath, stir for a few minutes, then add SOCl with a constant pressure dropping funnel 2 (9.2g, 77.04mmol, added dropwise for about 15 minutes), remove the ice-water bath after the addition, and stir for 30 minutes. Then, the temperature was raised to 70°C for 3.5 hours, and the reaction was stopped. The reaction solution was poured into 150ml of ice water, extracted 3 times with dichloromethane, 50ml of dichloromethane / each time (recorded as 3×50ml), and the organic layer was NaHCO 3 Wash with saturated solution (2×100ml), and wash with water (2×100ml). Then use anhydrous Na 2 SO 4 The organic layer was dried, dichloromethane was distilled off and fractions between 70°C and 84°C were collected to obtain 2.9 g of colorless liquid, namely 4-chloro-1-butyne. Repeat the operation once or increase the amount of ...

Embodiment 2

[0073] 1) Preparation of methyl 4-(4-hydroxy-1-ynyl)-α,α-dimethylphenylacetate

[0074]

[0075] Under nitrogen protection, first add 4-bromo-α, α-dimethylphenylacetic acid methyl ester (12.8g, 49.7mmol) and triethylamine (10.06g, 99.4mmol) to a 100ml three-necked flask, then add triphenyl Phosphorus (0.156g, 0.6mmol) and cuprous iodide (0.038g, 0.3mmol) were heated up to 80°C and palladium dichloride (0.009g, 0.05mmol) was added, and kept at this temperature for 30 minutes. Then the temperature was lowered to 70°C to 73°C, and 3-butyn-1-ol (3.48g, 49.7mmol) was slowly added with a syringe pump. After about 3 hours of dropwise addition, the reaction was basically completed. 100ml of ethyl acetate was added, filtered, and the filtrate was distilled to remove the solvent to obtain 11.2g of a brownish-yellow liquid, that is, methyl 4-(4-hydroxy-1-ynyl)-α,α-dimethylphenylacetate.

[0076] 2) Preparation of methyl 4-(4-chloro-1-ynyl)-α,α-dimethylphenylacetate

[0077]

[00...

Embodiment 3

[0085] 1) Preparation of methyl 4-(4-hydroxy-1-ynyl)-α,α-dimethylphenylacetate

[0086]

[0087] Under nitrogen protection, add 4-bromo-α, α-dimethylphenylacetic acid methyl ester (12.8g, 49.7mmol) and triethylamine (10.06g, 99.4mmol) into a 100ml three-necked flask, and add triphenylphosphine (0.156g, 0.6mmol) and cuprous iodide (0.038g, 0.3mmol), warming up to 80°C, adding palladium dichloride (0.009g, 0.05mmol), keeping at this temperature for 30 minutes. Then the temperature was lowered to 70°C to 73°C, and 3-butyn-1-ol (3.48g, 49.7mmol) was slowly added with a syringe. After about 3 hours of dropwise addition, the reaction was basically completed. 100ml of ethyl acetate was added, filtered, and the filtrate was distilled to remove the solvent to obtain 11.2g of a brownish-yellow liquid, that is, methyl 4-(4-hydroxy-1-ynyl)-α,α-dimethylphenylacetate.

[0088] 2) Preparation of methyl 4-(4-hydroxybutyryl)-α,α-dimethylphenylacetate

[0089]

[0090] 4-(4-Hydroxy-1-yn...

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Abstract

The invention discloses a synthetic method of 4-(4-halobutyryl)-alpha, alpha-dimethyl phenylacetate, and the method comprises three synthetic routes, wherein in the three routes, 3-butyne-1-ol and 4-halo-alpha, alpha-dimethyl phenylacetate are used as raw materials and high-purity 4-(4-halobutyryl)-alpha, alpha-dimethyl phenylacetate is obtained through coupling reaction, halogenation reaction, and hydration reaction. The method has the advantages of cheap and easily available raw materials, low cost, and high operability; the method is suitable for industrial production; and the prepared products have high purity.

Description

technical field [0001] The invention relates to the field of synthesis of organic compounds, in particular to a synthesis method of 4-(4-halobutyryl)-α,α-dimethylphenylacetate. Background technique [0002] 4-(4-Halobutyryl)-α,α-dimethylphenylacetate is a key intermediate in the preparation of the antihistamine drug Fexofenadine, which is a novel specific histamine H 1 Receptor antagonists have the characteristics of no central nervous sedation and low cardiotoxicity, and can significantly improve the quality of life of patients. [0003] The chemical name of fexofenadine is 4-{1-hydroxy-4-[4-(hydroxybenzhydryl)-1-piperidinyl]butyl}-α,α-dimethylphenylacetic acid, which has The structure shown in structural formula 2, US Pat. After alkylation of phenylacetate (shown in structural formula 1, R is an alkyl group and X is a halogen), the ketone carbonyl is reduced and the ester group is hydrolyzed to obtain fexofenadine. Wherein 4-(4-halobutyryl)-α,α-dimethylphenylacetate is...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/738C07C67/313C07C67/307
Inventor 杨光丁小博卢小逸蔡明德张启明姜申德
Owner ZHEJIANG QIMING PHARMA
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