Preparation method of piperazine diketone type compound

A compound and preparation process technology, applied in the field of drug synthesis, can solve problems such as long reaction time, uneconomical environmental protection, environmental pollution, etc., and achieve high yield, cost reduction, and strong operability

Active Publication Date: 2018-07-06
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The synthetic route of the compound of formula I disclosed in patent document EP0330381 and Fine Chemical Intermediates, 2010,4,38-40, Chinese Journal of Medicinal Chemistry, 2003,13(2):106-107 involves (S)-1,2-di The step of preparing (S)-1,2-diaminopropane hydrochloride from the D or L-tartrate of aminopropane under the conditions of hydrochloric acid and methanol; a large amount of hydrochloric acid and methanol solutions are used in the preparation process, and the reaction time Long, complicated operation, uneconomical and environmentally friendly, causing serious pollution to the environment

Method used

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  • Preparation method of piperazine diketone type compound
  • Preparation method of piperazine diketone type compound
  • Preparation method of piperazine diketone type compound

Examples

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Embodiment 1

[0043] Embodiment 1: the preparation of (S)-1,2-diaminopropane-tetraacetic acid methyl ester

[0044] Chloroacetic acid (192.5 g), (S)-1,2-diaminopropane bis-D-tartrate (50 g) and water (400 mL) were added to a round bottom flask, NaOH (125 g) / water (210 mL) was added dropwise, Stir at 45°C for 96h. The reaction solution was concentrated to dryness to obtain a viscous substance, which was impregnated with methanol (1000 mL), filtered, and the filter cake was washed with methanol. The combined filtrates were concentrated under reduced pressure. The residue was dissolved in methanol (1000 mL), concentrated sulfuric acid (50 mL) was added dropwise, and refluxed for 36 h. Cool down to room temperature, add sodium carbonate (70g), adjust pH = 9, distill under reduced pressure to remove methanol, extract the residual solution 3 times with ethyl acetate, combine the extracts, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a colorless li...

Embodiment 2

[0046] Embodiment 2: the preparation of (S)-1,2-diaminopropane-tetraacetic acid methyl ester

[0047] Chloroacetic acid (115.5 g), (S)-1,2-diaminopropane bis-L-tartrate (30 g) and water (250 mL) were added to a round bottom flask, NaOH (75 g) / water (125 mL) was added dropwise, Stir at 45°C for 96h. The reaction solution was concentrated to dryness to obtain a viscous substance, which was impregnated with methanol (600 mL), filtered, and the filter cake was washed with methanol. The combined filtrates were concentrated under reduced pressure. The residue was dissolved in methanol (600 mL), concentrated sulfuric acid (30 mL) was added dropwise, and refluxed for 36 h. Cool down to room temperature, add sodium carbonate (42g), adjust pH = 9, distill off methanol under reduced pressure, extract the residual solution 3 times with ethyl acetate, combine the extracts, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a colorless liquid 34...

Embodiment 3

[0048] Embodiment 3: the preparation of (S)-1,2-diaminopropane-tetraacetic acid methyl ester

[0049]Add bromoacetic acid (170g), (S)-1,2-diaminopropane bis-D-tartrate (30g) and water (250mL) to a round bottom flask, add NaOH (75g) / water (125mL) dropwise, 45 Stir at ℃ for 96h. The reaction solution was concentrated to dryness to obtain a viscous substance, which was impregnated with methanol (600 mL), filtered, and the filter cake was washed with methanol. The combined filtrates were concentrated under reduced pressure. The residue was dissolved in methanol (600 mL), concentrated sulfuric acid (30 mL) was added dropwise, and refluxed for 36 h. Cool down to room temperature, add sodium carbonate (42g), adjust pH = 9, distill off methanol under reduced pressure, extract the residual solution 3 times with ethyl acetate, combine the extracts, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a colorless liquid 35.7g, product yield 73....

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Abstract

The invention discloses a method for preparing a piperazine diketone type compound and specifically relates to a method for preparing a compound shown as a formula (I) by cyclization after substitution. The method takes (S)-1,2-diaminopropane tartrate, haloacetic acid and low-carbon alcohol as raw materials to prepare the compound shown as the formula (I). Compared with the prior art, a pluralityof disadvantages are improved and overcome by the preparation method; the preparation method has the advantages of simple steps, low cost, convenience for post-treatment, cleanness, high yield and purity, low toxicity and less pollution, and industrial production is facilitated.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a preparation method of diketopiperazine compounds, more specifically, the diketopiperazine compounds are shown in formula I. Background technique [0002] (S)-(+)-4,4'-(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione, the chemical structure is shown in formula I. [0003] [0004] The compound of formula I is a lipophilic derivative of chelating agent ethylenediaminetetraacetic acid, which is clinically used as a chemoprotectant, mainly for preventing cardiotoxicity induced by anthracyclines. The mechanism of cardiotoxicity caused by anthracyclines is mainly due to the generation of reactive oxygen species during the formation of stable complexes between anthracyclines and iron, which cause lipid peroxidation to the myocardium and damage the myocardium. As a cardioprotective agent for chemotherapy drugs, the compound of formula I reduces the generation of oxygen free radicals tha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/16C07C227/08C07C227/14C07D241/08
CPCC07B2200/07C07C227/08C07C227/14C07D241/08C07C229/16
Inventor 宗垒付锐
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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