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Preparation method of 6-chloropenicillin sulfoxide diphenylmethyl ester and application thereof

A technology of diphenylmethyl sulfoxide and chloropenicillane, which is applied in the preparation and application field of 6-chloropenicillane diphenylmethyl sulfoxide, can solve the problems of low total yield, low safety, The three wastes are large, and the effects of improving the synthesis yield, high safety, and less waste water discharge are achieved.

Active Publication Date: 2018-07-10
潍坊奥通药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Aiming at the defects of large amount of three wastes, low total yield and low safety in the existing production technology, the present invention provides a method for producing antibiotic intermediates with low production of three wastes, higher total molar yield and higher safety. Preparation technology

Method used

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  • Preparation method of 6-chloropenicillin sulfoxide diphenylmethyl ester and application thereof
  • Preparation method of 6-chloropenicillin sulfoxide diphenylmethyl ester and application thereof
  • Preparation method of 6-chloropenicillin sulfoxide diphenylmethyl ester and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Dissolve 40.0g of 6-APA (MW216.26, 0.185mol) in 100g of 30% hydrochloric acid, then add 20g of ethanol, then cool down to -5~5°C, after cooling down, slowly add 50g of 50% sodium nitrite aqueous solution (MW69.00, 0.347mol), after the dropwise addition, keep warm for 1-2 hours. After the heat preservation was completed, the reaction solution was extracted three times with 300 mL of dichloromethane, and the organic phases were combined to obtain a dichloromethane solution of AT-0, which was set aside.

[0060] Transfer the AT-0 dichloromethane solution to a 500mL three-necked flask, add 0.4g sodium tungstate (1%), cool down to 0-5°C, after cooling down, slowly add 40g 40% hydrogen peroxide (MW34.02, 0.471mol ), after dripping, keep warm for 3-4 hours, after keep warm, filter to get AT-1 wet product.

[0061] Add 150mL of dichloromethane and AT-1 wet product to a 500mL three-neck flask in sequence, cool down to 0-10°C, after cooling down, slowly add 10% ATMD dichlorometh...

Embodiment 2

[0065] Add 250mL tetrahydrofuran and the AT-2 (MW417.91) wet product obtained in Example 1 to a 500mL three-necked flask, then add 136g of 36% ammonium acetate aqueous solution, cool down to 0-5°C, and slowly add 15g of Zinc powder, keep warm for 30 minutes, filter, let stand to separate layers, extract the water phase with 100mLTHF once, combine the organic phases, concentrate and crystallize under reduced pressure, filter to obtain the wet product of diphenylmethyl penicillane sulfoxide, at 50-60 After drying at ℃ for 8-12 hours, 58.2g of diphenylmethyl penicillane sulfoxide was discharged, the molar yield was 82.1% (based on 6-APA), the appearance was off-white crystalline powder, the content was 98.0%, the purity 99.0% (identified by HPLC, the retention time is consistent with the retention time of the standard substance, see the spectrogram image 3 ).

Embodiment 3

[0067] Dissolve 40.0g of 6-APA (MW216.26, 0.185mol) in 100g of 25% hydrochloric acid, add 20g of methanol, then cool down to -5~5°C, after cooling down, slowly add 40g of 50% sodium nitrite aqueous solution (MW69.00, 0.290mol), after the dropwise addition, keep warm for 1-2 hours.

[0068] After the heat preservation was completed, the reaction solution was extracted three times with 300 mL of ethyl acetate, and the organic phases were combined to obtain an ethyl acetate solution of AT-0, which was set aside.

[0069] Transfer the AT-0 ethyl acetate solution to a 500mL three-necked flask, add 0.4g sodium molybdate (1%), cool down to 0-5°C, after cooling down, slowly add 40g 30% hydrogen peroxide (MW34.02, 0.471mol ), after dripping, keep warm for 3-4 hours, after keep warm, filter to get AT-1 wet product.

[0070] Add 150mL of ethyl acetate and AT-1 wet product to a 500mL three-neck flask in turn, cool down to 0-10°C, after cooling down, slowly add 15% ATMD ethyl acetate solu...

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Abstract

The invention provides a preparation method of 6-chloropenicillin sulfoxide diphenylmethyl ester and application thereof. The preparation method comprises the following steps that in mixed liquid of hydrochloric acid and alcohol, 6-APA and sodium nitrite are subjected to chlorination to obtain 6-chloropenicillanic acid (AT-0); the AT-0 is extracted with water-insoluble solvent, and then is oxidized with hydrogen peroxide to obtain 6-3-3-dimethyl-7-oxo-4-fluorenyl-1-azabicyclo[3.2.0] n-heptane-2-carboxylic acid (AT-1); AT-1 is reacted with ATMD to obtain chloropenicillin Diphenyl sulfoxide (AT-2) in the water-insoluble solvent. The invention also provides a method for preparing pentamidine sulfoxide diphenylmethyl ester using AT-2 wet products. The molar yield of the method is much higher than the prior art due to the fact that bromide of penicillanic acid and the pentamidine sulfoxide diphenylmethyl ester is less stable compared with chloride of the penicillanic acid and the pentamidine sulfoxide diphenylmethyl ester.

Description

technical field [0001] The invention belongs to the technical field of preparation of intermediates of antibiotic β-lactamase inhibitor drugs, and in particular relates to a preparation method and application of benzhydryl 6-chloropenicillane sulfoxide. Background technique [0002] Since the invention of antibiotics, a large number of lives have been saved clinically, and great benefits have been created for human health. At the same time, with the large-scale application of antibiotics, the immunity (drug resistance) of those pathogenic bacteria to antibiotics is becoming stronger and more powerful, resulting in the clinical elimination of a large number of antibiotic varieties or a substantial increase in dosage. [0003] Later, scientists discovered that the key factor causing drug resistance of pathogenic bacteria is that pathogenic bacteria have evolved an enzyme that can degrade antibiotics (such as: β-lactamase), which can decompose antibiotics before antibiotics kil...

Claims

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Application Information

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IPC IPC(8): C07D499/08C07D499/865C07D499/86
CPCC07D499/08C07D499/86C07D499/865
Inventor 魏海鹏杨栽根晏金华朱国亮
Owner 潍坊奥通药业有限公司
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