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Novel preparation method of ertapenem side chain

A kind of ertapenem side chain, new technology, applied in the field of preparation of carbapenem antibiotic side chain, can solve the problems such as not easy to be used in mass production, low yield of raw material I′ preparation process, not easy to obtain, etc., to achieve easy industrialization The effect of production

Inactive Publication Date: 2016-03-30
HANDAN KANGRUI BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The shortcoming of this method is, the used reagent of preparation raw material I ' is more expensive, and raw material I ' preparation process yield is low (the existing preparation method of raw material I ' sees Tetrahedron Lett., 37 (17), 2912-2922, 1996 and JournalofOrganicChemistry, 67 ( 14), reported in 4771-4776), so the raw material I' is more expensive and difficult to obtain, so that the cost of compound 1 is higher; and the route is deprotected by HCl gas at the end, the operation is more dangerous, and it is not easy to be used in large-scale industrial production.

Method used

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  • Novel preparation method of ertapenem side chain

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Embodiment 1: the preparation of compound 2

[0028] In the 500mL hydrogenation kettle, add methanol 200g, raw material I15.4g (0.05mol), 4M HCl methanol solution 30ml (0.12mol), 10%Pt / SiO 2 7.6g. Nitrogen was replaced several times, hydrogen was replaced several times, and finally hydrogen was passed to the pressure of 1.5 MPa in the kettle, the temperature was controlled at 40°C, and the reaction was stirred for 1 h. Stirring was stopped, hydrogen was vented and replaced with nitrogen. Filtrate, recover and reuse the filter cake; slowly add 400ml of methylcyclohexane dropwise to the filtrate at 40°C, and after solid precipitation, slowly cool down to 10°C for crystallization for 2h, filter, and vacuum-dry to obtain 27.50g of off-white solid compound , 90% molar yield.

[0029] 1 H-NMR (400MHz, D 2 O): δ2.12(m, 1H), 2.94(m, 1H), 3.30(m, 1H), 3.64(m, 1H), 3.72(m, 1H), 4.57(t, J=8.4Hz, 1H ), 4.65 (brs, 1H)

Embodiment 2

[0030] Embodiment 2: the preparation of compound 2

[0031] Add 300 g of ethanol, 18.5 g (0.06 mol) of raw material I, 37.5 mL (0.15 mol) of 4M / HCl ethanol solution, 10% Pt / γ-Al in the 500 mL hydrogenation kettle 2 o 3 5.0 g. Nitrogen was replaced several times, hydrogen was replaced several times, and finally hydrogen was passed to the pressure of 1.2MPa in the kettle, the temperature was controlled at 50°C, and the reaction was stirred for 1.5h. Stirring was stopped, hydrogen was vented and replaced with nitrogen. Filter and recover the filter cake for reuse; slowly add 600 mL of n-hexane dropwise to the filtrate at 30 °C, stir for 30 min, and after solid precipitation, slowly cool down to 0 °C for crystallization for 1.5 h, filter, and vacuum dry to obtain off-white solid compound 29.32 g, molar yield 92%

Embodiment 3

[0032] Embodiment 3: the preparation of compound 2

[0033] Add THF150g and purified water 100g, raw material I12.32g (0.04mol), concentrated hydrochloric acid 10mL (0.12mol), 10%Pt / γ-Al in 500mL hydrogenation kettle 2 o 3 6g. Nitrogen was replaced several times, hydrogen was replaced several times, and finally hydrogen was passed to the pressure in the kettle to 2 MPa, the temperature was controlled at 30°C, and the reaction was stirred for 2 hours. Stirring was stopped, hydrogen was vented and replaced with nitrogen. Filtration, filter cake recycling; filtrate with 5% NaHCO 3 Adjust the pH of the liquid to 8-9, let stand to separate the liquids, wash the upper layer with purified water, dry over anhydrous sodium sulfide, filter, adjust the filtrate to 3-4 with 4M HCl methanol solution, concentrate, add 50 mL of ethyl acetate and normal Heptane 100mL was stirred and crystallized at 20°C for 2h to obtain 25.72g of off-white solid compound with a molar yield of 85%.

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Abstract

The invention relates to an innovation-type preparation method of an ertapenem side chain (represented by the formula 1). The method comprises the steps: (1) with amino protected thiolactone (represented by the formula I) as a raw material, under an acidic condition, with SiO2 and gamma-Al2O3 as carriers, and with a catalyst prepared with palladium as an active ingredient, carrying out a hydrogenation deprotection reaction, to obtain deprotected thiolactone (represented by the formula 2); and (2) carrying out a reaction of the compound 2 and m-aminobenzoic acid, to obtain the target compound (represented by the formula 1). With easily-available, relatively-inexpensive and amino protected thiolactone having a mature preparation process as the raw material, the improved palladium catalyst is innovatively used for hydrogenation deprotection, the compound 2 is obtained, and then the compound 2 is subjected to a reaction with m-aminobenzoic acid to prepare the target compound; the preparation method has the advantages of cheap and easily available raw materials, high product yield, low production cost, economy, safety and environmental protection, and is more suitable for industrialized production.

Description

technical field [0001] The present invention relates to a preparation method of carbapenem antibiotic side chain, in particular to an innovative preparation method of ertapenem side chain. Background technique [0002] Ertapenem (Ertapenem, MK-0826, L-749, trade name Invanztm) is a new broad-spectrum long-acting 1β-methyl carbapenem antibiotic developed by Merck in the United States. It was released in November 2001 and 2002 respectively. Available in the US and Europe in April. This product has good antibacterial activity and pharmacokinetic properties, and has significant effects on Gram-positive and negative aerobic bacteria and anaerobic bacteria. [0003] The chemical name of compound 1 is 3-[(2S,4S)-4-mercaptopyrrolidine-2-carbonylamido]benzoic acid inorganic acid salt, which is the deprotected side chain of ertapenem. [0004] [0005] (where X represents Cl, Br, I, preferably Cl) [0006] The disclosed preparation method of existing compound 1, as U.S. Pat. re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCY02P20/55C07D207/16
Inventor 张艳玲米国瑞秦玉君
Owner HANDAN KANGRUI BIOTECH CO LTD
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