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Preparation method of 1-oxacephalosporin-3-epoxymethylene derivatives and use of the 1-oxacephalosporin-3-epoxymethylene derivatives in preparation of 1-oxacephalosporin

A technology of epoxymethylene and oxacephalosporins, applied in the production of bulk chemicals, organic chemistry, etc., to achieve the effects of reducing investment, avoiding equipment corrosion, and reducing the probability of danger

Active Publication Date: 2014-09-03
浙江东邦药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to develop a feasible industrial production method for preparing 1-oxacephalosporin-3-epoxymethylene derivatives (formula I) , to be used in the synthesis of 1-oxacephalosporins, solve the many defects of the existing synthetic routes using 1-oxacephalosporin-3-chloromethyl derivatives, and make 1-oxacephalosporins preparation made easy

Method used

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  • Preparation method of 1-oxacephalosporin-3-epoxymethylene derivatives and use of the 1-oxacephalosporin-3-epoxymethylene derivatives in preparation of 1-oxacephalosporin
  • Preparation method of 1-oxacephalosporin-3-epoxymethylene derivatives and use of the 1-oxacephalosporin-3-epoxymethylene derivatives in preparation of 1-oxacephalosporin
  • Preparation method of 1-oxacephalosporin-3-epoxymethylene derivatives and use of the 1-oxacephalosporin-3-epoxymethylene derivatives in preparation of 1-oxacephalosporin

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Embodiment 1

[0034] Compound II (R1 is phenyl, R2 is hydrogen atom, R3 is benzhydryl) was stirred and dissolved in 10 times the amount of methanol, and compound II weight 0.8% TS-1 molecular sieve was added at room temperature (25°C), and the control was the same 1.8 times the molar amount of compound II in 30% aqueous hydrogen peroxide solution was added dropwise at high temperature. TLC detected that the reaction was complete. The TS-1 molecular sieve catalyst was removed by filtration, and the reaction solution was concentrated to dryness. The yield was about 90% (HPLC external standard method). The residual solid was dissolved in dichloromethane, washed with a small amount of sodium thiosulfate solution, the organic layer was evaporated to dryness, and the residual solid was recrystallized with ethyl acetate:n-heptane (4:1) to obtain off-white compound I (R1 is phenyl, R2 is a hydrogen atom, R3 is a benzhydryl group). Yield 61%. 1 H-NMR (300MHz, CDCl 3 ): δ 8.45 (brs, 1H), 7.72~7.94 ...

Embodiment 2

[0036] Compound II (R1 is a phenyl group, R2 is a hydrogen atom, R3 is a benzhydryl group) was stirred and dissolved in 10 times the amount of methanol, and 0.01 times the molar amount of the compound II was added at room temperature (25°C) [π-C 5 h 5 NC 16 h 33 ] 3 [PO 4 (WO 3 ) 4 ] catalyst, under the control of the temperature, dropwise add 1.2 times the molar amount of compound II in 30% aqueous hydrogen peroxide solution, TLC detects that the reaction is complete, filter and remove the precipitated heteropolytungstate quaternary ammonium salt catalyst, and concentrate the reaction solution to dryness to obtain compound I (R1 is phenyl, R2 is a hydrogen atom, R3 is a benzhydryl group), and the yield is about 95% (HPLC). The reaction product can be directly used in the next reaction without further purification.

Embodiment 3

[0038] Compound II (R1 is a phenyl group, R2 is a hydrogen atom, R3 is a benzhydryl group) was stirred and dissolved in 10 times the amount of dichloromethane, and 0.05 times the molar amount of the compound II was added at room temperature (25°C) [C 18 h 37 N(CH 2 Ph)(CH 3 ) 2 ] 3 [PO 4 (WO 3 ) 4 ] catalyst, under the control of the temperature, dropwise add 1.2 times the molar amount of compound II in 30% aqueous hydrogen peroxide solution, TLC detects that the reaction is complete, filter and remove the precipitated heteropolytungstate quaternary ammonium salt catalyst, and concentrate the reaction solution to dryness to obtain compound I (R1 is phenyl, R2 is a hydrogen atom, R3 is a benzhydryl group), and the yield is about 91% (HPLC).

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Abstract

The present invention relates to the technical field of the synthesis method of 1-oxacephalosporin-3-epoxymethylene derivatives (formula I), which can be used as intermediates for the synthesis of antimicrobial 1-oxacephalosporins. The method of the present invention is to epoxidize 1-oxacephalosporin-3-methylene derivatives (formula II) efficiently and selectively with hydrogen peroxide under the action of a catalyst to obtain 1-oxacephalosporin- 3-epoxymethylene derivatives. The corresponding 1-oxacephalosporin intermediate (formula IV) can be prepared by reacting the epoxide with a mercaptotetrazolium alkali metal salt (formula III) derivative, and then dehydrating under acidic conditions. The method of the present invention avoids the halogen addition reaction, the required catalyst is cheap and easy to obtain, the oxygen source used is clean and environment-friendly, the reaction process does not require low temperature, avoids the equipment corrosion caused by the passage of halogen in industrial production, and reduces the cost of expensive special equipment. The investment also greatly reduces the probability of danger, and makes the preparation of 1-oxacephalosporin simple and easy, so it has greater competitiveness in industrial production.

Description

technical field [0001] The invention relates to the technical field of a synthesis method of an intermediate 1-oxacephalosporin-3-epoxymethylene derivative that can be used as an antimicrobial 1-oxacephalosporin synthesis intermediate. Background technique [0002] 1-Oxacephalosporins such as Latamoxef or Flomoxef are a new class of broad-spectrum antibiotics, which have good antibacterial activity against a variety of Gram-negative bacteria, and are more effective than common cephalosporins. The prime strength is 4~16 times. Because the synthesis of this type of Oxefef is quite difficult, although there are many researchers, there are very few factories that can actually produce it. [0003] The current methods for preparing 1-oxacephalosporins are basically carried out with 1-oxacephalosporin-3-chloromethyl derivatives as intermediates, as shown in the following formula: [0004] [0005] The synthesis of 1-oxacephalosporin-3-chloromethyl derivatives has been reported...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D505/18C07D505/04C07D505/06
CPCY02P20/55
Inventor 王海平池骋夏俊池正明
Owner 浙江东邦药业有限公司
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