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Preparation method of carbapenems

A technology of carbapenem and carbapenem, applied in the field of preparation of carbapenem antibiotics, can solve the problems of unavailable raw materials, unfavorable industrial production, and long cycle time

Active Publication Date: 2012-07-11
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw materials involved in this method are not easy to obtain, and the self-made synthesis steps are many and the cycle is long, which is not conducive to industrial production

Method used

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  • Preparation method of carbapenems
  • Preparation method of carbapenems
  • Preparation method of carbapenems

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Example 1: Pivaloyloxymethyl (1R, 5S, 6S)-1-methyl-6-[(R)-1-hydroxyethyl]-2-[1-(1,3-thiazoline- Preparation of 2-base) azetidin-3-yl] thio-1-carbapenem-2-ene-3-carboxylate (tybipenem ester, compound of formula I-1)

[0112] Method A:

[0113] (1) Preparation of tibipenem ester hydrochloride (compound of formula II-1)

[0114] Add tibipenem (compound of formula III-1) 100.0 g (0.26 mol), NaHCO 3 32.9g (0.39mol), chloromethyl pivalate (compound of formula IV-1) 56.3mL (0.39mol), DMF 500mL, stirred at 60°C for 4h. DMF was distilled off under reduced pressure, and 200 mL of acetone was added and stirred for 0.5 h. Filter, wash the filter cake with 50 mL of acetone × 2, and vacuum-dry to obtain 140.8 g of off-white solids of tibipenem ester hydrochloride (compound of formula II-1), with a molar yield of 86.3% and a chromatographic purity of 99.6%.

[0115] 1 H NMR (DMSO, 500MHz) δ: 10.80(s, 1H), 5.89(d, J=6.0Hz, 1H), 5.76(d, J=6.0Hz, 1H), 5.14(s, 1H), 4.76~4.79 (m, 2H...

Embodiment 2

[0129] Example 2: 1-methylcyclohexyloxymethyl (1R, 5S, 6S)-1-methyl-6-[(R)-1-hydroxyethyl]-2-[1-(1,3 -thiazoline-2-yl) azetidin-3-yl] the preparation of thio-1-carbapenem-2-ene-3-carboxylate (formula I-2 compound)

[0130] Method A:

[0131] (1) Preparation of formula I-2 compound hydrochloride (II-2)

[0132] Add tibipenem (compound of formula III-1) 120.0g (0.31mol), triethylamine 86.2g (0.62mol), 1-methylcyclohexyloxymethyl chloride (formula III-1 compound) successively into a 1L four-neck flask Compound IV-2) 118.2g (0.62mol), DMF 600mL, stirred at 50°C for 4h. DMF was distilled off under reduced pressure, and 200 mL of acetone was added and stirred for 0.5 h. After filtration, the filter cake was washed with 50 mL of acetone x 2, and dried in vacuo to obtain 158.6 g of the title compound as an off-white solid, with a molar yield of 88.3% and a chromatographic purity of 98.6%.

[0133] (2) preparation of formula I-2 compound

[0134] Add 180.0 g of the compound of for...

Embodiment 3

[0145] Example 3: Pivaloyloxymethyl (1R, 5S, 6S)-1-methyl-6-[(R)-1-hydroxyethyl]-2-[1-(4-fluorobenzyl)nitrogen The preparation of heterocyclobutan-3-yl]thio-1-carbapenicill-2-ene-3-carboxylate (compound of formula I-5)

[0146] Method A:

[0147] (1) Preparation of formula I-5 compound hydrochloride (formula II-5 compound)

[0148] Add (1R, 5S, 6S)-1-methyl-6-[(R)-1-hydroxyethyl]-2-[1-(4-fluorobenzyl)azepine sequentially into a 1L four-necked flask Cyclobutane-3-yl]thio-1-carbapenem-2-ene-3-carboxylic acid (compound of formula III-2) 80.0g (0.20mol), DIPA 56.2mL (0.40mol), pivalic acid Chloromethyl ester (compound of formula IV-1) 57.7mL (0.40mol), DMF 650mL, stirred at 50°C for 8h. DMF was distilled off under reduced pressure, and 200 mL of acetone was added and stirred for 1 h. After filtering, the filter cake was washed with 100 mL of acetone × 2, and dried under vacuum to obtain 83.3 g of the title compound as an off-white solid, with a molar yield of 64.4% and a chrom...

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Abstract

The invention relates to a preparation method of tebipenem pivoxil and analogue thereof. In the method, carbapenem compound salt with a formula II is used as a raw material to obtain carbapenem compound ester with a formula I under the action of alkali, wherein the carbapenem compound salt with the formula II is prepared by direct reaction of a carbapenem compound with a formula III and ester with a formula IV. According to the invention, high-yield and high-purity salt of tebipenem pivoxil and analogue thereof can be prepared, so that high-yield and high-purity tebipenem pivoxil or analogue thereof can be obtained without column chromatography. Thus, the method provided by the invention is more suitable for industrial production in a large scale.

Description

technical field [0001] The invention relates to a method for preparing carbapenem antibiotics, in particular to a method for preparing tibipenem and analogues thereof. Background technique [0002] Carbapenem antibiotics are a class of broad-spectrum antibiotics developed in the 1970s. They have strong antibacterial activity and have good antibacterial effects on aerobic and anaerobic bacteria. They are stable to β-lactamase and are especially suitable for many A variety of bacteria, especially the mixed infection of aerobic bacteria and anaerobic bacteria, and it also has a killing effect on static bacteria. In addition, because this kind of drug has less adverse reactions, the application time is shorter, and the drug resistance has not been significantly strengthened, it is sometimes used as the last line of defense against bacteria and plays an important role in the treatment of severe hospital infections. At present, there are 7 kinds of carbapenem antibiotics on the m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/06C07D477/08
CPCC07D477/06C07D477/08C07D477/20
Inventor 史颖张雅然马玉秀李园园周付刚张志宝贾铭底辉锋刘洋
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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