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A kind of purification method of ethyl 7-chloro-2-oxoheptanoate

A technology of ethyl oxoheptanoate and purification method, applied in chemical instruments and methods, preparation of carboxylate, organic chemistry, etc., can solve problems such as multiple impurities in ethyl 7-chloro-2-oxoheptanoate

Active Publication Date: 2019-05-17
SHENZHEN HAIBIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But test finds that the 7-chloro-2-oxoheptanoic acid ethyl ester that this method obtains still contains more impurity

Method used

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  • A kind of purification method of ethyl 7-chloro-2-oxoheptanoate
  • A kind of purification method of ethyl 7-chloro-2-oxoheptanoate
  • A kind of purification method of ethyl 7-chloro-2-oxoheptanoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1 Purification of ethyl 7-chloro-2-oxoheptanoate

[0084] 1) At room temperature, 50.0 g of crude ethyl 7-chloro-2-oxoheptanoate (oil, GC normalized content 60.6%, external standard content 58.3%, equivalent to containing 7-chloro-2-oxoheptanoate Ethyl ester (29.2 g, 0.14 mol) was slowly dropped into a saturated solution prepared by dissolving 21.9 g of sodium bisulfite (0.21 mol) in 37 ml of water, and the rate of addition was controlled to maintain the temperature of the reaction solution at room temperature. After the dropwise addition, stir at room temperature, and a white solid precipitates out after about 0.5 h.

[0085] 2) The reaction mixture obtained in step 1) was continuously stirred at 0-5°C for 2 hours, then filtered, and the filter cake was washed with an appropriate amount of absolute ethanol, drained, and dried to obtain ethylene oxide of ethyl 7-chloro-2-oxoheptanoate Sodium hydrogen sulfate (white solid) 40.1g.

[0086] 3) At room temperat...

Embodiment 2

[0090] Example 2 Purification of ethyl 7-chloro-2-oxoheptanoate

[0091] 1) At room temperature, dissolve 18.7g of sodium bisulfite (0.18mol) in 32ml of water, then add 11ml of absolute ethanol and stir well; 50.0g of crude ethyl 7-chloro-2-oxoheptanoate (oil , GC normalized content of 64.3%, external standard content of 62.4%, which is equivalent to containing 31.2 g of 7-chloro-2-oxoheptanoic acid ethyl ester, 0.15 mol) slowly dropwise to keep the temperature of the reaction solution at room temperature. After the dropwise addition, stir at room temperature, and a white solid precipitates out after about 0.5 h.

[0092] 2) The reaction mixture obtained in step 1) was continuously stirred at 0-5°C for 3 hours, then filtered, and the filter cake was washed with an appropriate amount of ethyl acetate, sucked dry, and dried to obtain ethylene oxide of ethyl 7-chloro-2-oxoheptanoate Sodium bisulfate salt (white solid) 43.9g.

[0093] 3) At room temperature, 43.9 g of the whi...

Embodiment 3

[0095] Example 3 Purification of ethyl 7-chloro-2-oxoheptanoate

[0096] 1) At room temperature, 50.0 g of crude ethyl 7-chloro-2-oxoheptanoate (oil, GC normalized content 50.8%, external standard content 49.6%, equivalent to containing 7-chloro-2-oxoheptanoate Ethyl acetate (24.8g, 0.12mol) was dissolved in 50ml of absolute ethanol, then slowly dripped into a saturated solution made of 16.2g sodium bisulfite (0.16mol) dissolved in 28ml of water, and the rate of addition was controlled so that the temperature of the reaction solution Maintain room temperature. After the dropwise addition, stir at room temperature, and a white solid precipitates out after about 0.5 h.

[0097] 2) The reaction mixture obtained in step 1) was continuously stirred at 0-5°C for 2 hours, then filtered, and the filter cake was washed with an appropriate amount of toluene, drained, and dried to obtain hydrogen sulfite of ethyl 7-chloro-2-oxoheptanoate Sodium (white solid) 34.7g.

[0098] 3) At r...

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Abstract

The invention provides a purification method of ethyl 7-chloro-2-oxoheptanoate, wherein the purification method comprises the steps: firstly, carrying out a reaction of ethyl 7-chloro-2-oxoheptanoate oil crude product and a hydrosulphite solution, and separating to obtain a sulfite solid of ethyl 7-chloro-2-oxoheptanoate; then, dissolving the sulfite solid of ethyl 7-chloro-2-oxoheptanoate in water, adding an acid or alkali at a certain temperature, and decomposing the sulfite of ethyl 7-chloro-2-oxoheptanoate into ethyl 7-chloro-2-oxoheptanoate; and finally, extracting with an organic solvent immiscible with water, to obtain ethyl 7-chloro-2-oxoheptanoate having the purity improved. The method is simple in operation and suitable for industrialized production, and ensures the purity of a subsequent product and final product cilastatin sodium.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a method for purifying ethyl 7-chloro-2-oxoheptanoate, a key intermediate of cilastatin sodium. Background technique [0002] Cilastatin sodium, structural formula as shown in (I), is a kind of renal dehydrodipeptidase inhibitor developed by Merck of the United States when developing β-carbapenem antibiotic imipenem (imipenem) , used in combination with imipenem, can effectively inhibit the degradation of imipenem by renal dehydrodipeptidase, and can reduce the nephrotoxicity of imipenem. Imipenem / cilastatin sodium has been widely used as a compound broad-spectrum antibacterial preparation, and its trade name in the United States is "Primaxin". [0003] [0004] The preparation method of multiple cilastatin sodium (I) has occurred in the prior art, wherein the method reported by the patent US5147868 is the most commonly used and has realized large-scale industrial...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/60C07C69/716
CPCC07C67/60C07C69/716
Inventor 卢兆强吴健
Owner SHENZHEN HAIBIN PHARMA
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