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Method for preparing penam sulfoxide acid diphenyl methyl ester which is tazobactam precursor

A technology of diphenylmethyl sulfoxide and aminopenicillanic acid is applied in the field of synthesis of tazobactam pharmaceutical intermediates, and can solve the problems of potential safety hazards, high cost, poor safety and reliability, etc. The effect of reducing the discharge of three wastes and improving process safety

Active Publication Date: 2017-07-21
通辽华旭药业有限公司
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Problems solved by technology

[0019] In the above synthetic route, highly toxic raw material liquid bromine and expensive m-chloroperoxybenzoic acid are used as oxidants in the bromination substitution process in route 1, and high-pressure and explosive hydrogen is used as a reaction reagent during debromination. Production is not only costly, but also has poor safety and reliability, and is not suitable for industrialized production. The cost of using potassium bromide as a brominating agent in the bromination of the route 2 is relatively high, and diphenylmethanol is used as a reaction reagent in the esterification, but the price must be used. Expensive DCC (dicyclohexylcarbodiimide) is as dehydrating agent, and this route is still not suitable for industrial production; In the bromination reaction, the same full use of the higher potassium bromide of the price is the raw material in the route three, and in the oxidation reaction In route 4, the peracetic acid with poor safety is used as the oxidizing agent, which brings potential safety hazards to large-scale industrial production; in the route four, expensive DCC is also used as the dehydrating agent and molybdenum acetylacetonate as the oxidation catalyst, which is not suitable for industrialization Production; the deamination reaction of 6-aminopenicillanic acid in the route five actually needs to be realized at a higher temperature, and this temperature is impossible to bear for penicillin medicines, so this synthetic route is not practical

Method used

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  • Method for preparing penam sulfoxide acid diphenyl methyl ester which is tazobactam precursor
  • Method for preparing penam sulfoxide acid diphenyl methyl ester which is tazobactam precursor
  • Method for preparing penam sulfoxide acid diphenyl methyl ester which is tazobactam precursor

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Embodiment 1

[0039] 1), in the reactor of 1500L, add 500L methylene dichloride, 180kg water, drop into 120kg6-aminopenicillanic acid, stir; Then in reactor, dropwise add 48% hydrogen bromide aqueous solution (188kg) and 25% hypochlorite Sodium nitrate solution (153kg), drop the temperature to -10 ℃ and react for 4 hours after the completion of the dropwise addition, point the plate to monitor until the end of the reaction, wash the organic phase to neutrality, obtain 6-bromopenicillanic acid solution, and obtain the 6- The bromopenicillanic acid solution is transferred to the oxidation reactor;

[0040] 2) Add 55kg of potassium bicarbonate to the oxidation reaction kettle and stir for 1.5 hours, then add 102kg of diphenylmethyl chloride and 1kg of tetrabutylammonium bromide, heat up to 30°C, stir for 3 hours, and detect the end point with thin-layer chromatography After the benzhydryl chloride reaction is complete, add 0.5kg sodium tungstate to the oxidation reaction kettle, and start to a...

Embodiment 2

[0043] 1), add 500L dichloromethane, 180kg water in the reactor of 1500L, drop into 120kg6-aminopenicillanic acid, stir well; Then in reactor, dropwise add 50% hydrogen bromide aqueous solution (89.01kg) and 50% Sodium nitrite solution (37.95.kg), drop the temperature to -5 DEG C and react for 3 hours after the completion of the dropwise addition, point the plate to monitor until the end of the reaction, wash the organic phase with water to neutrality, obtain 6-bromopenicillanic acid solution, and obtain The 6-bromopenicillanic acid solution is transferred in the oxidation reactor;

[0044]2) Add 60kg of potassium bicarbonate to the oxidation reaction kettle and stir for 2 hours, then add 102kg of diphenylmethyl chloride and 1kg of tetrabutylammonium bromide, heat up to 20°C, stir and react for 4 hours, and use thin-layer chromatography to detect the end point After the reaction of benzhydryl chloride is complete, add 0.9kg sodium tungstate to the oxidation reaction kettle, an...

Embodiment 3

[0047] 1), add 500L dichloromethane, 180kg water in the reactor of 1500L, drop into 120kg6-aminopenicillanic acid, stir; Then in reactor, dropwise add 50% hydrogen bromide aqueous solution (267kg) and 60% hypodermic acid Sodium nitrate solution (94.875kg), drop the temperature to 0 DEG C and react for 2 hours after completion of the dropwise addition, point the plate to monitor until the end of the reaction, wash the organic phase to neutrality, obtain 6-bromopenicillanic acid solution, and obtain the 6- The bromopenicillanic acid solution is transferred to the oxidation reactor;

[0048] 2) Add 50kg of potassium bicarbonate to the oxidation reaction kettle and stir for 1 hour, then add 102kg of diphenylmethyl chloride and 1.1kg of tetrabutylammonium bromide, heat up to 30°C, stir for 3 hours, and detect with thin layer chromatography At the end point, after the reaction of benzhydryl chloride is complete, add 0.5kg sodium tungstate to the oxidation reaction kettle, and start ...

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Abstract

The invention provides a method for preparing penam sulfoxide acid diphenyl methyl ester. The method includes steps of carrying out bromination reaction on 6-aminopenicillanic acid to obtain first reaction products; carrying out reaction on the first reaction products and diphenyl-chloromethane under the effects of phase transfer catalysts to obtain second reaction products, adding hydrogen peroxide into the second reaction products, carrying out oxidation reaction on the hydrogen peroxide and the second reaction products to obtain third reaction products and centrifugally washing the third reaction products to obtain 6-bromine penicillin sulfoxide acid diphenyl methyl ester; carrying out further reaction on the 6-bromine penicillin sulfoxide acid diphenyl methyl ester to obtain the penam sulfoxide acid diphenyl methyl ester. The method has the advantages that dichloromethane and water are used as solvents in the bromination reaction, accordingly, side reaction in the bromination reaction can be reduced, and emission of organic matters in wastewater can be reduced; ester with a high yield can be obtained from diphenyl mecloqualone by the aid of the phase transfer catalysts, the cost can be saved as compared with other processes by the aid of diphenyl carbinol used as a raw material and DCC (dicyclohexylcarbodiimide) used as a catalyst and processes by the aid of benzophenone hydrazone and catalysts which comprise explosive peracetic acid and added potassium iodide, and processes for preparing the penam sulfoxide acid diphenyl methyl ester are green and safe.

Description

technical field [0001] The invention relates to the technical field of synthesizing tazobactam pharmaceutical intermediates, in particular to a preparation method of diphenylmethyl penicillane sulfoxide. Background technique [0002] Tazobactam is a new penicillane sulfone β-lactamase inhibitor developed by Japan Dapeng Pharmaceutical Company. Chemical name: [2S-(2α,2β,5α)]-3-methyl-7-oxo-3-(1H-1,2,3,-triazole-1-methyl)-4-thia -1-Azabicyclo(3,2,0)-heptane-2-carboxylic acid-4,4-dioxide. [0003] Structural formula: [0004] [0005] It was first prepared by Hall et al. from 6-amyl penicillanic acid. Its structure is to add a triazole ring on the basis of sulbactam to improve the enzyme inhibitory effect. It has the best clinical effect at present. The β-lactamase inhibitor has the characteristics of high stability, low activity, low toxicity, and strong enzyme inhibitory activity. In 1992, the compound drug of tazobactam, tazobactam / piperacillin (1:8 ), first launched ...

Claims

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Application Information

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IPC IPC(8): C07D499/86C07D499/08
CPCC07D499/08C07D499/86
Inventor 周灏王建卢标
Owner 通辽华旭药业有限公司
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