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Method for preparing 2 beta-methyl penicillanate benzhydryl dioxide

A technology of triazolemethyl penicillanic acid diphenylmethyl ester and dioxide, which is applied in the field of preparation of 2β-triazolemethyl penicillanic acid diphenylmethyl ester dioxide, which can solve the limitation of large-scale production , Explosion in the synthesis process, complex synthesis technology and other problems, to achieve the effect of shortening the reaction cycle, low raw material cost and high synthesis yield

Active Publication Date: 2014-06-04
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Tazobactam is a broad-spectrum and high-efficiency β-lactamase inhibitor developed by Japan Greenhouse Pharmaceutical Company. Promising β-lactamase inhibitors, but due to its long synthesis steps and complex synthesis techniques, it is still a hot spot in drug synthesis research
[0004] 2β-triazolemethyl penicillanic acid diphenylmethyl ester dioxide is one of the most critical intermediates in the synthesis of tazobactam. The following structural formula, because the yield of this step reaction has been very low, so its improvement a lot of space
Its disadvantages: the raw material 1-trimethylsilyl-1,2,3-triazole is difficult to synthesize, the yield is low, and explosion may occur during the synthesis process, and the target product needs to be passed through the column. The above conditions limit it. mass production of

Method used

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  • Method for preparing 2 beta-methyl penicillanate benzhydryl dioxide
  • Method for preparing 2 beta-methyl penicillanate benzhydryl dioxide
  • Method for preparing 2 beta-methyl penicillanate benzhydryl dioxide

Examples

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Effect test

Embodiment 1

[0031] Example 1, compound (II) 3-methyl-[2-oxo-4-(2-benzothiazole dithio)-1-azetidinyl]-3-butene diphenylmethyl ester preparation:

[0032] In a 1000ml four-neck flask, put 57.5g of benzyl penicillanic acid sulfoxide, that is, compound (I), 550ml of toluene, and 26.0g of 2-mercaptobenzothiazole, raise the temperature to 60-112°C, and the reaction time is 2-3 hours , steam the azeotrope of toluene and water under normal pressure, and when the internal temperature reaches 112°C, the toluene is recovered under reduced pressure to dryness, and 75.8 g of the product is obtained, with a yield of 95%. Add 600 ml of dichloromethane and proceed to the next step of reaction.

Embodiment 2

[0033] Example 2, preparation of compound (Ⅲ) 2β-bromomethyl-2α-methyl-6,6-dihydropenicillanic acid benzhydryl ester:

[0034] Add the dichloromethane-containing compound (II) material solution of Example 1 into a 1000ml four-neck flask, then add 33.5g of copper bromide, start stirring and cool down to 5-10°C, react for 8.0h, follow by HPLC. Filter, add 2%NaHCO 3 Wash with 200ml, then wash with 200ml of water, separate the organic phase, and transfer to the next reaction.

Embodiment 3

[0035] Embodiment 3, namely the preparation of compound (Ⅳ) 2α-methyl-2β-(1,2,3,-triazol-1-yl) methyl penicillane-3α-carboxylate benzhydryl ester:

[0036] Add 50g of anion resin, 20g of 1-H-1,2,3-triazole and 60ml of ethanol to the dichloromethane phase containing compound (Ⅲ) in Example 2 in a 1000ml four-necked flask, and stir at 20-25°C 6-8.0h, HPLC tracking, after the reaction is complete, filter, add 150ML water to the anion resin and filtrate, separate layers, wash the organic phase with 100ml water, combine the organic phase to recover dichloromethane under reduced pressure, add 100ml methanol, recrystallize, filter, Dry at 40-50°C under reduced pressure to obtain 46.0 g of material, HPLC ≥ 95%, molar yield 70% (calculated based on compound Ⅱ).

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Abstract

The invention provides a method for preparing a 2 beta-methyl penicillanate benzhydryl dioxide, which is to prepare the 2 beta-methyl penicillanate benzhydryl dioxide by four-step reactions. In the method, hydrobromic acid and sodium nitrite or cupric bromide serving as a brominating agent and other methods are adopted, especially bromide is generated by using adsorption of anionic resin, and water is a side product, so that the method is safe and environmentally friendly; the resin can be used repeatedly; the reaction molar yield can be remarkably improved, reaching over 75 percent; and dichloromethane, water, little glacial acetic acid, particularly as well as a catalytic amount of concentrated sulfuric acid are used to replace massive glacial acetic acid serving as a solvent, so that massive glacial acetic acid is removed. The method has unique process, stable product quality, mild process condition and easy control, the traditional azidation reaction and ethynylation reaction are eliminated, the production cost is reduced, the environmental pollution is greatly reduced, and no special equipment is required. The method is suitable for industrial generation in scale.

Description

Technical field: [0001] The invention relates to a preparation method of 2β-triazolemethyl penicillanic acid benzyl dioxide. Background technique: [0002] 2β-triazolemethyl penicillanic acid diphenylmethyl ester dioxide as described below is one of the main intermediates for the synthesis of a novel β-lactamase inhibitor-tazobactam. [0003] Tazobactam is a broad-spectrum and high-efficiency β-lactamase inhibitor developed by Japan Greenhouse Pharmaceutical Company. Promising β-lactamase inhibitors, but due to their long synthesis steps and complex synthesis techniques, they are still a hot spot in drug synthesis research. [0004] 2β-triazolemethyl penicillanic acid diphenylmethyl ester dioxide is one of the most critical intermediates in the synthesis of tazobactam. The following structural formula, because the yield of this step reaction has been very low, so its improvement There is a lot of space. At present, there are many studies on it at home and abroad. The trad...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D499/87C07D499/04
Inventor 刘雨林张祥明魏海鹏仇诗军柴建华
Owner JIANGXI FUSHINE PHARMA CO LTD
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