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Preparation method for synthesizing key intermediate 4-BMA of 1beta-methyl carbapenem antibiotic bicyclic nucleus

A technology of methyl carbapenem and 4-BMA, applied in chemical instruments and methods, compounds of group 4/14 elements of the periodic table, organic chemistry, etc., can solve the problem of harsh conditions, many intermediate steps, and synthetic Less steps, etc., to achieve the effect of high product purity, low cost, and short reaction route

Active Publication Date: 2017-05-10
YIYUAN XINQUAN CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] This synthetic route has fewer synthetic steps, but requires anhydrous and oxygen-free conditions, the conditions are harsh, and the amount of zinc powder used is large, the cost is high, and the yield is low
[0023] From the above-mentioned process route for preparing 4-BMA, either there are many intermediate steps, or the purity is not high, or the reaction requires harsh conditions, or the yield is not high

Method used

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  • Preparation method for synthesizing key intermediate 4-BMA of 1beta-methyl carbapenem antibiotic bicyclic nucleus
  • Preparation method for synthesizing key intermediate 4-BMA of 1beta-methyl carbapenem antibiotic bicyclic nucleus
  • Preparation method for synthesizing key intermediate 4-BMA of 1beta-methyl carbapenem antibiotic bicyclic nucleus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 20g 4-AA, 40ml water, 200mlTHF and 4g of indium powder are added in the there-necked flask, and the solution of α-bromopropionamide (XV) with a large inducing group is added dropwise (α-bromopropionamide (XV) ) 32.5g, 1ml triethylamine, 50mlTHF), 40 ~ 45min dropwise, control the temperature of the reaction system 5 ~ 15 ℃, react for 30 ~ 45min, TLC detection raw material reaction is complete, filter, filter residue rinse with 20mlTHF, combine the filtrate and eluent.

[0037] Use 10% sodium bicarbonate aqueous solution to adjust the pH of the combined solution to 8, start to drop 50ml of 30% hydrogen peroxide, and complete the dropwise addition in 0.5h, keep the reaction system at 5-10°C, react for 2h, and TLC detects that the reaction of the raw materials is complete. Use 2N hydrochloric acid to adjust the pH of the reaction solution to 3, add 30ml of toluene and stir for 0.5h, and let it stand to separate into layers. The organic layer was washed twice with saturated...

Embodiment 2

[0039] 20g 4-AA, 40ml water, 120mlTHF and 2.5g of indium powder are added in the there-necked flask, and the solution of α-bromopropionamide (XV) (α-bromopropionamide (α-bromopropionamide ( XV) 32.5g, 1ml triethylamine, 50mlTHF), 40-45min dropwise, control the temperature of the reaction system at 5-15°C, react for 30-45min, TLC detects that the reaction of the raw materials is complete, filter, the filter residue is rinsed with 20mlTHF, and the filtrates are combined and rinse solution.

[0040]Use 10% sodium bicarbonate aqueous solution to adjust the pH of the combined liquid to 8, start to add 40ml of 30% hydrogen peroxide dropwise, and the dropwise addition is completed after 0.5h. Use 2N hydrochloric acid to adjust the pH of the reaction solution to 3, add 30ml of toluene and stir for 0.5h, and let it stand to separate into layers. The organic layer was washed twice with saturated brine, 60ml each time. The organic layer was cooled to 5°C, the pH of the solution was adju...

Embodiment 3

[0042] 20g 4-AA, 40ml water, 160mlTHF and 3.5g of indium powder are added in the there-necked flask, and the solution of α-bromopropionamide (XV) (α-bromopropionamide (α-bromopropionamide ( XV) 32.5g, 1ml triethylamine, 50mlTHF), 40-45min dropwise, control the temperature of the reaction system at 5-15°C, react for 30-45min, TLC detects that the reaction of the raw materials is complete, filter, the filter residue is rinsed with 20mlTHF, and the filtrates are combined and rinse solution.

[0043] Use 10% sodium bicarbonate aqueous solution to adjust the pH of the combined solution to 8, start to add 45ml of 30% hydrogen peroxide dropwise, and the dropwise addition is completed after 0.5h. Use 2N hydrochloric acid to adjust the pH of the reaction solution to 3, add 30ml of toluene and stir for 0.5h, and let it stand to separate into layers. The organic layer was washed twice with saturated brine, 60ml each time. The organic layer was cooled to 5°C, the pH of the solution was a...

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Abstract

The invention relates to a preparation method for synthesizing a key intermediate 4-BMA of 1beta-methyl carbapenem antibiotic bicyclic nucleus and belongs to the technical field of synthesis of carbapenem antibiotics. The method disclosed by the invention comprises the following steps: taking an aqueous solution of tetrahydrofuran as a solvent, taking indium as a catalyst, taking (3R,4R)4-carbethoxy-3-[(R)-((tert-butyldimethylsilyl)oxy)ethyl]-2-2-azetidinone (IV) as a raw material, and carrying out a reaction with alpha-bromo-acrylamide XV with large inductive groups so as to produce a compound XIV; not separating the reaction solution of the compound XIV, and performing oxidation-hydrolysis, thereby obtaining the target product VI. The method disclosed by the invention is stable in process, short in reaction route, simple and convenient in operation, mild in reaction conditions, high in product purity, few in three wastes, low in cost, high in yield and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for preparing a key intermediate 4-BMA for synthesizing a 1β-methyl carbapenem antibiotic bicyclic core, belonging to the technical field of carbapenem antibiotic synthesis. Background technique [0002] 1β-Methyl carbapenem antibiotic bicyclic parent nucleus (MAP for short), the chemical name is (4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-3- Diphenylphosphoryloxy carbapenem-2-carboxylate p-nitrobenzyl ester, the structural formula is as follows: [0003] [0004] 1β-methyl carbapenem antibiotics not only have a broad antibacterial spectrum and strong antibacterial activity, but also have good chemical stability. 1β-methyl carbapenem antibiotics have been commercialized, including meropenem, ertapenem, doripenem, biapenem, etc., which have good antibacterial effects on many drug-resistant bacteria, especially B-type enzymes have a fairly strong inhibitory effect and are a series of unique inhibitors of β-lactama...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
CPCC07F7/1804C07F7/1892
Inventor 张立明周红燕刘成学尹纪松
Owner YIYUAN XINQUAN CHEM
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