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Preparation method of panipenem

A solvent and p-nitrobenzyl ester technology, which is applied in the field of preparation of panipenem, can solve the problems of many imidization side reactions, harsh reaction conditions for the synthesis of panipenem, and unsuitability for industrial production.

Inactive Publication Date: 2009-11-04
ZHEJIANG NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The purpose of the present invention is to solve the above-mentioned synthetic panipenem reaction conditions are harsh, imidization side reactions more, not suitable for industrial production and other problems, to provide a high yield, environmentally friendly, easy to industrialize panipenem Preparation

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  • Preparation method of panipenem
  • Preparation method of panipenem
  • Preparation method of panipenem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] (1) Add 5.8g (50mmol) methyl acetoacetate, 7.65g (50mmol) p-nitrobenzyl alcohol and 0.31g (5mmol) to a 250mL round bottom flask, B(OH) 3 Then add 100mL of anhydrous toluene and heat to reflux at 110°C for 5h. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain 9.95 g of light yellow solid: p-nitrobenzyl acetoacetate (I), with a yield of 84%, m.p.: 42-44°C.

[0061] The nuclear magnetic spectrum of p-nitrobenzyl acetoacetate is: 1 H NMR (400MHz, CDCl 3 ): δ2.30(s, 3H), 3.60(s, 2H), 5.29(s, 2H), 7.55(d, J=8.0Hz, 2H), 8.22(d, J=8.0Hz, 2H); 13 CNMR (100MHz, CDCl 3 ): δ30.3, 49.8, 65.4, 123.7, 128.4, 142.6, 147.8, 166.6, 200.1.

[0062] Elemental analysis is: C 11 h 11 NO 5 Theoretical values ​​for: C, 55.70; H, 4.67; N, 5.90. Found: C, 55.72; H, 4.65; N, 5.93.

[0063] (2) 2.37g (10mmol) p-nitrobenzyl acetoacetate (I) and 40mL acetonitrile were added to a 1...

Embodiment 2

[0101] Adopt DMAP to make catalyst in the step (1), the mol ratio of p-nitrobenzyl alcohol and methyl acetoacetate is 1: 5, 60 ℃ of reaction temperature, the reaction time is 30h, all the other are identical with embodiment 1, productive rate: 80%

[0102] In the step (2), the diazotization reagent is p-toluenesulfonyl azide, the mol ratio of p-nitrobenzyl acetoacetate to p-toluenesulfonyl azide is 1:8, the solvent is tetrahydrofuran, and the reaction temperature is -15°C. The time is 30h, the rest are the same as in Example 1, and the yield is 88%.

[0103] In the step (3), the silicon etherification reagent is trimethylchlorosilane, the base is diethylamine, and the mol ratio of diazotized acetoacetate to p-nitrobenzyl, trimethylchlorosilane and diethylamine is 1: 5:3, the reaction temperature is -20°C, the reaction time is 15h, the rest is the same as in Example 1, and the yield is 94%.

[0104] Lewis acid catalyst is ZnBr in step (4) 2 , 4-acetoxy-3-[1-(tert-butyldimethy...

Embodiment 3

[0116] In the step (1), NBS is used as a catalyst, tetrahydrofuran is a solvent, the mol ratio of p-nitrobenzyl alcohol to methyl acetoacetate is 1: 10, the reaction temperature is 85°C, and the reaction time is 17h. The rest are the same as in Example 1, and the product Rate: 75%.

[0117] In step (2), the molar ratio of p-nitrobenzyl acetoacetate to p-toluenesulfonyl azide is 1:4, the reaction temperature is 20° C., and the reaction time is 15 h. The rest are the same as in Example 1, and the yield is 90%.

[0118] In step (3), the mol ratio of p-nitrobenzyl diazotized acetoacetate, tert-butyldimethylsilyl trifluorosulfonate and triethylamine is 1:3:1, the solvent is tetrahydrofuran, and the reaction temperature 25°C, the reaction time is 9h, the rest is the same as Example 1, and the yield: 92%.

[0119] Lewis acid catalyst is ZnI in step (4) 2 , 4-acetoxy-3-[1-(tert-butyldimethylsilyloxy)ethyl]azetidinone, 2-diazo-3-tert-butyldimethylsilyloxy-3 - p-nitrobenzyl crotonate...

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Abstract

The invention relates to a preparation method of panipenem. Firstly, methyl acetoacetate and p-nitrobenzyl alcohol are taken as raw materials to prepare panipenem parent nucleus by six steps of reactions: ester exchange reaction, diazo reaction, enolization reaction, substitution reaction, hydrolysis reaction and ring closing reaction; then, (3R)-3-hydroxy-pyrrolidine hydrochloride, nitrobenzyl chroformate ester are taken as raw materials to prepare panipenem side chain by amidation reaction, sulfonylation reaction, nucleophilic substitution reaction and saponification reaction; finally, the prepared panipenem parent nucleus and panipenem side chain are in butt joint by condensation and are subjected to catalytic hydrolysis and imidization to obtain panipenem. The preparation method of panipenem features simple operation, mild reaction condition, friendly environment, high yield, good product purity, low cost and better industrialized production prospect.

Description

technical field [0001] The invention relates to the field of synthesis of carbapenem antibiotic drugs, in particular to a preparation method of panipenem. Background technique [0002] Panipenem, chemical name: (5R, 6S)-2-[(S)-1-(iminoacetate pyrrol-3-yl)sulfur]-6-[(R)-1-hydroxyethyl]- 1-Acetamidoylpyrrolidin-3(S)-ylthio]-6-[1(R)-hydroxy-ethyl ]-2-carbapenen-3-carboxylic acid; Molecular formula: C 15 h 21 N 3 o 4 S; molecular weight: 339.41; CAS accession number: 87726-17-8; see the following formula for the structure: [0003] [0004] Panipenem was first developed by Japan’s Sankyo Company in 1983, and it was launched in Japan in 1993. It is used in conjunction with betamipron in equal amounts. Panipenem is a new generation of carbapenem antibiotics with great market development prospects. Due to the market's demand for safe, efficient, and broad-spectrum antibiotics for severe infections and drug-resistant bacterial infections, carbapenem antibiotics have increa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/02C07D477/06
Inventor 王其军李新生徐东成
Owner ZHEJIANG NORMAL UNIVERSITY
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