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A kind of allyl position hydroxylation prepares the method for the key intermediate of oxycephem antibiotics

A technology of oxycephem and allyl, which is applied in the direction of organic chemistry, can solve the problems of unfavorable post-treatment removal, many side reactions, and poor repeatability of the pilot test, so as to avoid the use of chlorine-resistant equipment and light-proof equipment, Improvement of production competitiveness and reduction of production cost

Active Publication Date: 2016-07-13
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] (1) Intermediate 3 needs to be transformed by 7-ACA in multiple steps, and there are many side reactions, which are not suitable for control
[0008] (2) Chlorine gas needs to be used in the preparation process, which is not friendly to the environment, and has high requirements for production equipment, which is not conducive to industrialized production
[0009] (3) Intermediate 4 can be directly synthesized into Intermediate 2 with the participation of triphenylphosphine, but a large amount of phosphorus-containing waste is produced, which is not conducive to recrystallization, and the repeatability of the pilot test is poor
[0013] (1) Chlorine gas is used in industrial production, which is not conducive to environmental protection
Silver nitrate is expensive and introduces heavy metals, which is not conducive to post-treatment removal
[0014] (2) The use of sodium iodide needs to be protected from light, and there are certain requirements for equipment
[0015] (3) The replacement of the hydrogen atom at the allylic position with a group that is easy to leave requires a multi-step reaction, and the route is relatively long

Method used

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  • A kind of allyl position hydroxylation prepares the method for the key intermediate of oxycephem antibiotics
  • A kind of allyl position hydroxylation prepares the method for the key intermediate of oxycephem antibiotics
  • A kind of allyl position hydroxylation prepares the method for the key intermediate of oxycephem antibiotics

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] 10g of intermediate 1 was dissolved in 80ml of dichloromethane, 3g of selenium dioxide and 0.4g of tetrabutylammonium bromide were added, and reacted at room temperature for 2h. Cool to -5°C, slowly add 7ml of tert-butanol peroxide, and TLC detects that the reaction is complete. At room temperature, the system was poured into 100ml of 20% sodium sulfite aqueous solution, stirred for 1 hour, and allowed to stand to separate layers. The organic phase was washed once with 80 ml of saturated sodium bicarbonate solution, 80 ml of water, and 80 ml of saturated brine, and finally dried by adding 7 g of anhydrous sodium sulfate for 10 h. After suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was recrystallized with 5 ml of ethanol to obtain Intermediate 2. Yield 33%.

[0035] The NMR data of intermediate 1 are as follows: 1 HNMR (400MHz, CDCl 3 )δ7.92(d, J=7.3Hz, 2H), 7.55~7.30(m, 13H), 6.93(s, 1H), 6.34(d, J=3.3Hz, 1H), 5.3...

Embodiment 2

[0038] 100g of intermediate 1 was dissolved in 800ml of dichloromethane, 30g of selenium dioxide and 4g of tetrabutylammonium bromide were added, and reacted at room temperature for 2h. Cool to -5°C, slowly add 70ml of tert-butanol peroxide, and TLC detects that the reaction is complete. At room temperature, the system was poured into 1 L of 20% sodium sulfite aqueous solution, stirred for 1 h, and allowed to stand to separate layers. The organic phase was washed once with 800 ml of saturated sodium bicarbonate solution, 800 ml of water, and 800 ml of saturated brine, and finally dried by adding 70 g of anhydrous sodium sulfate for 10 h. After suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was recrystallized with 60ml of ethanol to obtain Intermediate 2. Yield 32%.

Embodiment 3

[0040] 1kg of intermediate 1 was dissolved in 10L of dichloromethane, 300g of selenium dioxide and 40g of tetrabutylammonium bromide were added, and reacted at room temperature for 2h. Cool to -5°C, slowly add 700ml tert-butanol peroxide, and TLC detects that the reaction is complete. At room temperature, the system was poured into 8L of 20% sodium sulfite aqueous solution, stirred for 1 h, and allowed to stand to separate layers. The organic phase was washed once with 8L of saturated sodium bicarbonate solution, 8L of water, and 8L of saturated brine, and finally dried by adding 700g of anhydrous sodium sulfate for 10 hours. After suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was recrystallized with 600ml of ethanol to obtain Intermediate 2. Yield 30%.

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Abstract

The invention discloses a method for preparing key intermediate of an oxacephem antibiotic through allylic hydroxylation, and belongs to the technical field of pharmaceutical synthesis. The method disclosed by the invention uses [1R-[1 alpha, 5 alpha]]-3-methyl-2-(7-chloro-3-phenyl-4-oxa-2, 6-diazabicyclo [3.2.0] heptyl-2-alkene-6-base)-3-butenoic acid diphenyl methyl ester (compound 1) as a raw material, and [1R-[1 alpha, 5 alpha]]-3-hydroxyl-2-(7-chloro-3-phenyl-4-oxa-2, 6-diazabicyclo [3.2.0] heptyl-2-alkene-6-base)-3-butenoic acid diphenyl methyl ester (compound 2) is synthetized through allylic hydroxylation in one step. Compared with the prior art, the synthetic route of the oxacephem antibiotic is effectively shortened by the method disclosed by the invention, using chlorine and a heavy metal reagent is avoided, light resistant equipment is not needed in industrial production, and the method is convenient in postprocessing, is low in cost and is very suitable for the industrial production.

Description

technical field [0001] The invention relates to a method for preparing a key intermediate of oxycephem antibiotics through hydroxylation of an allyl position, and belongs to the technical field of drug synthesis. Background technique [0002] Oxycephem antibiotics such as Latamoxef or Flomoxef are a class of broad-spectrum antibacterial drugs, which have good antibacterial activity against a variety of Gram-negative bacteria, and the effect is stronger than that of general cephalosporins4 ~16 times. [0003] In industrial production, the synthesis methods of US Patents US4532233, US4138486 and German Patent DE2355209 can be referred to to prepare Oxecefem antibiotics Latamoxef and Flomoxef from Compound 2. [0004] Oxycephem antibiotics key intermediate 2 can be prepared from 3-acetoxymethyl-5-sulfur-7-amino-8-oxo-1-azabicyclooct-2-ene-2 ​​carboxylic acid (7-ACA) Raw material preparation. For references see Tetrahedron Lett., 1982, 23, 3379 and Synth Commun., 1988, 18, 76...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/04
CPCC07D498/04
Inventor 刘宏民付冬君张恩刘英超李峰张彦岭马立英郑甲信王亚娜
Owner ZHENGZHOU UNIV
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