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Method for synthesizing 7-chloro-2-oxoheptanoate

A technology of ethyl oxoheptanoate and synthetic method, applied in the synthesis of cilastatin intermediate, the synthetic field of cilastatin intermediate ---7-chloro-2-oxoheptanoate ethyl, can Solve the problems of high cost, harsh reaction conditions, and environmental pollution, and achieve the effects of simple steps, low cost, and high product yield

Inactive Publication Date: 2014-06-18
左国幼
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The technical problem to be solved by the present invention is to overcome defects such as harsh reaction conditions, high cost, and environmental pollution existing in the synthetic method of existing 7-chloro-2-oxoheptanoate, and to provide a new 7- A synthetic method for ethyl chloro-2-oxoheptanoate, which has the advantages of simple steps, wide reaction conditions, low cost, and environmental friendliness

Method used

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  • Method for synthesizing 7-chloro-2-oxoheptanoate
  • Method for synthesizing 7-chloro-2-oxoheptanoate
  • Method for synthesizing 7-chloro-2-oxoheptanoate

Examples

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Embodiment 1

[0019] Dissolve ethyl pyruvate in tetrahydrofuran, and the mass ratio of ethyl pyruvate to tetrahydrofuran is 1:2 to obtain mixed solvent 1; control the temperature at 60°C, add lithium diisopropylamide dropwise to mixed solvent 1 (in the form of tetrahydrofuran is the solvent), and the time for adding lithium diisopropylamide is controlled to be 0.5 hours to obtain mixed solvent 2; keep the temperature at 60°C, then add 1-bromo-4-chlorobutane to mixed solvent 2, add 1-bromo The time control of -4-chlorobutane is 0.5 hour; Wherein, in molar ratio, the consumption of added ethyl pyruvate, 1-bromo-4-chlorobutane and lithium diisopropylamide is: ethyl pyruvate : 1-bromo-4-chlorobutane: Lithium diisopropylamide=0.5:0.5:2. After adding 1-bromo-4-chlorobutane, keep the temperature of the mixed solvent at 60°C and react for 6 hours; the reaction is completed , filter the reaction product, distill the filtrate under reduced pressure (remove the solvent), and purify by rectification to...

Embodiment 2

[0023] Dissolve ethyl pyruvate in a mixed organic solvent composed of tetrahydrofuran and n-hexane in any proportion. The mass ratio of ethyl pyruvate to the mixed organic solvent is 1:15 to obtain mixed solvent 1; control the temperature at -78°C, Add butyllithium (tetrahydrofuran / n-hexane as solvent) dropwise to mixed solvent 1, and control the time of adding butyllithium to 3 hours to obtain mixed solvent 2; keep the temperature at -78°C, add 1-bromo-4-chlorobutane, the time of adding 1-bromo-4-chlorobutane is controlled as 3 hours; wherein, in molar ratio, the added ethyl pyruvate, 1-bromo-4-chlorobutane The amount of butyllithium and butyllithium is controlled as follows: ethyl pyruvate: 1-bromo-4-chlorobutane: butyllithium=0.5:1:2. After adding 1-bromo-4-chlorobutane, keep the volume of the mixed solvent The temperature was -78°C, and the reaction was carried out for 15 hours; after the reaction was completed, the reaction product was filtered, and the filtrate was disti...

Embodiment 3

[0027] Dissolve ethyl pyruvate in dimethyl sulfoxide, and the mass ratio of ethyl pyruvate to dimethyl sulfoxide is 1:5 to obtain mixed solvent 1; control the temperature at -4°C, and add sodium hydride to the mixed solvent , the time of adding sodium hydride was controlled for 2 hours to obtain mixed solvent 2; keep the temperature at -4°C, add 1-bromo-4-chlorobutane to mixed solvent 2, add 1-bromo-4-chlorobutane The time control is 2 hours; Wherein, by molar ratio, the consumption control of added ethyl pyruvate, 1-bromo-4-chlorobutane and sodium hydride is: ethyl pyruvate: 1-bromo-4-chloro Butane: sodium hydride = 1:1:2. After adding 1-bromo-4-chlorobutane, keep the temperature of the mixed solvent at -4°C and react for 12 hours; after the reaction is complete, filter the reaction product and distill the filtrate under reduced pressure (removal of solvent), distillation and purification, that is, 7-chloro-2-oxoheptanoic acid ethyl ester. The yield is 98%.

[0028] Ethyl 7...

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Abstract

The invention discloses a method for synthesizing 7-chloro-2-oxoheptanoate, which comprises: dissolving ethyl pyruvate in an organic solvent, adding alkali and 1-bromo-4-chlorobutane in turn, and performing a condensation reaction; filtering the product of the reaction, removing solvent from filtrate by reduced-pressure distillation; purifying by distillation; and thus, obtaining 7-chloro-2-oxoheptanoate. In the invention, nontoxic and cheap ethyl pyruvate is used as a main raw material and subjected to one-step condensation reaction with 1-bromo-4-chlorobutane under the action of alkali to form the 7-chloro-2-oxoheptanoate, and the yield of the product reaches 88 to 98 percent. The synthesis method disclosed by the invention has the advantages of high product yield, simple steps, wide reaction conditions, low cost, environment friendliness and the like and is suitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to a synthetic method of a cilastatin intermediate, in particular to a synthetic method of a cilastatin intermediate--7-chloro-2-oxoheptanoic acid ethyl ester, belonging to 7-chloro-2-oxo The field of synthesis of ethyl heptanoate. Background technique [0002] Cilastatin (alias: cilastatin sodium) is a dehydropeptidase I inhibitor, which is artificially synthesized. Dehydropeptidase Ⅰ exists in the brush border of renal tubules. When imipenem enters the renal tubules, it is metabolized by this enzyme and loses its antimicrobial activity. Cilastatin can not only inhibit the metabolism of this enzyme, but also prevent the formation of possible nephrotoxic products. Cilastatin can protect imipenem from being destroyed by dehydropeptidase Ⅰ in the renal tubule, so that the rescued imipenem can be recovered from the renal tubule by 70%, and the antibacterial effect of imipenem can be enhanced. Imipenem forms a compound prep...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/716C07C67/343
Inventor 蔡为明陈涛程君健杨福耕何素雅
Owner 左国幼
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