Method for preparing penicillanic acid sulfoxide diphenyl methyl ester

A technology of diphenylmethyl penicillanic acid sulfoxide and diphenylmethanol, which is applied in the field of preparation of diphenylmethyl penicillanic acid sulfoxide, and can solve problems such as high cost, complicated preparation process, and poor yield quality , to achieve the effect of quality improvement, good chemical selectivity, yield and quality improvement

Active Publication Date: 2011-01-05
江西祥太生命科学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the above technology, in the process of preparing penicillanic acid sulfoxide, bromination needs to use Br2 or KBr, the oxidant needs peracetic acid or m-chlorobenzeneperformic acid, or phenol and hydrogen peroxide, and benzophenone hydrazone or p-nitrogen is needed for esterification. Benzyl bromide or Pd / c is used for reduction, in short, there is a certain step or the poor quality of the yield in a certain step, which leads to complicated preparation process and high cost

Method used

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  • Method for preparing penicillanic acid sulfoxide diphenyl methyl ester
  • Method for preparing penicillanic acid sulfoxide diphenyl methyl ester
  • Method for preparing penicillanic acid sulfoxide diphenyl methyl ester

Examples

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Effect test

Embodiment 1

[0026] Embodiment 1, the preparation of 6-APA brominated penicillanic acid (compound iii):

[0027] Add 100g of 40% ethanol aqueous solution to a 500ml four-necked flask, add 50g, cool 40% hydrobromic acid to -5°C, add 45g of 6-APA, and dropwise add a solution made of 20g of sodium nitrite and 38g of water, and control the temperature at -5°C. ~0°C, about 1.5h, after the dropwise addition, keep warm at 0~5°C for 1.0h, add 180g CH2CL2 and stir for 10min after the heat preservation, stand still for 20min to separate layers, extract the water phase with 180gCH2Cl2 again, combine the organic phase, add 250ml of water, wash and stir After 10 minutes, the solution was separated for 20 minutes to obtain compound (iii) 6-APA bromide penicillanic acid dichloromethane solution. It was detected that 52.5 g of compound (iii) was present, and the molar yield was 91%.

[0028] Adopt KBr, Br in the past Differently as the brominating agent, the present invention adopts hydrobromic acid as th...

Embodiment 2

[0029] The preparation of embodiment 2,6-APA brominated penicillanic acid (compound iv):

[0030] Preparation of catalytic oxidation system:

[0031] Add 45g of 30% hydrogen peroxide and 1.5g of molybdenum acetylacetonate into a four-neck flask equipped with a stirrer, a thermometer, and warm it to 0-5°C. Adjust the pH to 2.0 with a 16% hydrochloric acid solution. , the color of the solution just disappears at this time.

[0032] Add the above prepared dichloromethane phase containing compound (iii) to the flask, and cool to -8°C. Add the above catalytic oxidation system solution, control the temperature at -8-2°C, complete the dropwise addition within 30 minutes, and keep warm at -5-0°C 2.0h, filter, the filter cake was washed with 20ml CH2Cl2, then washed with 10ml water, dried by centrifugation, and vacuum-dried at 20-25°C for 20h to obtain 50.0g of compound iv) with a molar yield of 90% and HPLC≥99%.

[0033] Compound (iii) has an unstable quaternary β-lactam ring struct...

Embodiment 3

[0035] Embodiment 3, the preparation of 6-APA bromide penicillanic acid benzhydryl sulfoxide (compound v):

[0036]Add 500ml of dichloromethane to the flask and cool to 0-5°C, then add 30.0g of compound IV, stir to dissolve and control the temperature at 0-5°C, add 20.0g of diphenylmethanol and 1.0g of DMAP, stir again to dissolve, and control the temperature 0~5℃, then dropwise add DCC.23.0g and 80ml of dichloromethane solution to control the temperature at 0~5℃, about 5.0h after dropping, keep warm for 1.0h, add 50ml of water to the filtered solution, wash, and stir at near temperature 0~5℃ for 10min Stand still for 20 minutes to separate layers, add 80ml of 8% sodium bicarbonate to the organic phase and stir for 10 minutes to stand still for 20 minutes to separate layers, distill the organic phase under normal pressure to recover dichloromethane, then evaporate to dryness under reduced pressure to obtain a white solid, then add 80g of toluene, ℃ for 1.0 h, cooled to -5 ℃ an...

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Abstract

The invention provides a method for preparing penicillanic acid sulfoxide diphenyl methyl ester. Penicillanic acid sulfoxide is prepared by the following four-step reaction. Hydrobromic acid is used as a brominating agent for substituting potassium bromide and bromine, and hydrogen peroxide is used as an oxidant for substituting peracetic acid and chloroperoxybenzoic acid, so the preparation method is safe and environment-friendly; in addition, the hydrogen peroxide is reacted with a compound (iii) under the catalysis action of acetyl molybdenum pyruvate so that the reaction mole yield can be obviously improved and reaches 90 percent; zinc powder which substitutes palladium and carbon is used as a reducing agent, so high-pressure equipment is not needed in the reaction; and the preparation method simplifies the process operation step, is easy for industrialized production, and reduces the production cost.

Description

technical field [0001] The invention relates to a preparation method of benzyl penicillanic acid sulfoxide. Background technique [0002] The penicillanic acid sulfoxide compound shown in the following formula is an important intermediate for the synthesis of a new type of β-lactam acid inhibitor - tazobactam, and is also an important intermediate for obtaining carbapenes and oxycephem-20~ 5°C Spore -20~5°C Element--the key intermediate necessary for the nucleus, which uses 6-aminopenicillanic acid (6-APA) as the starting material. [0003] [0004] Tazobactam is a broad-spectrum and high-efficiency β-lactamase inhibitor developed by Japan Dapeng Pharmaceutical Company. Because of its excellent application performance, small toxic and side effects, strong enzyme inhibitory activity and high stability, Ranked as the most promising β-lactamase inhibitor [0005] The preparation routes of diphenylmethyl penicillanic acid sulfoxide compounds reported in the literature can b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/86C07D499/04
Inventor 包建华刘雨林马俊赵小平彭孙兵
Owner 江西祥太生命科学有限公司
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