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Preparation method of 1Beta-methyl carbapenem antibiotic bicyclic mother nucleus

A technology of methyl carbapenem and antibiotics, which is applied in the field of preparation of 1β-methyl carbapenem antibiotic bicyclic nucleus, can solve the problems of high product destructiveness, severe reaction exotherm, difficult separation of products, etc., and achieves The effect of reducing solvents, high quality, and eliminating potential safety hazards

Active Publication Date: 2010-06-09
ZHEJIANG HUABANG MEDICAL & CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] This route adopts chiral auxiliary agent (19), obtains (6) by stereoselective Reformasky reaction under the catalysis of zinc powder, and bromoacetate alkenyl under the action of low temperature (-60 ℃) and strong base [NaN (TMS)] The propyl ester reaction is converted into allyl ester (20), and then the enol phosphate product (1) of the bicyclic parent nucleus can be obtained through intramolecular Dieckmann condensation and diphenoxyphosphoryl chloride activation step, but the reaction bar of this route is harsh, and the reaction Excessive heat release, great damage to the product, and the product is not easy to separate
[0016] Judging from the above-mentioned process route for the preparation of 1β-methylcarbapenem antibiotic bicyclic nuclei, the intermediate product needs to be purified by silica gel column chromatography to obtain a product with higher purity, or requires harsh reaction conditions such as ultra-low temperature to be realized, and the yield not tall

Method used

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  • Preparation method of 1Beta-methyl carbapenem antibiotic bicyclic mother nucleus
  • Preparation method of 1Beta-methyl carbapenem antibiotic bicyclic mother nucleus
  • Preparation method of 1Beta-methyl carbapenem antibiotic bicyclic mother nucleus

Examples

Experimental program
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Effect test

Embodiment 13

[0053] Example 13-{(2R)-2-[(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one-4 Synthesis of -yl]propionyl}spiro-[2H-1,3-benzoxazin-2,1`-cyclohexane]-4-(3H)-one compound (6)

[0054] Under the protection of nitrogen, add 400ml of dichloromethane and 85.5g of compound (5) into a 1000ml four-necked reaction flask, stir to dissolve, cool the mixture to -10°C, control the temperature at -10~-5°C, and add 62.5g of Titanium tetrachloride, drop in 40 minutes, then add dropwise alkali mixed solution (35g triethylamine and 0.6g 4-dimethylaminopyridine diluted with 20ml dichloromethane) at the same temperature, drop in 40 minutes, heat preservation reaction After 2 hours, add 60g of compound (4), keep the reaction at -5~0°C for 30 minutes, then raise the temperature to 20~25°C and keep it for 5 hours. Sodium aqueous solution and water were washed, and the solvent was concentrated under reduced pressure to obtain a concentrated residue containing compound (6).

Embodiment 2

[0055] Example 2 (3S, 4R)-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-4-[(1R)-1-methyl-1-carboxyethyl] -Synthesis of azetidin-2-one compound (3)

[0056] Add 600ml of acetone to the residue containing compound (6) obtained in step 1), stir to dissolve, then add 60ml of water, cool down to -5~0°C, add 135g of 30% hydrogen peroxide, and add in batches at -5~0°C Add 25.8g of lithium hydroxide monohydrate within 30 minutes, keep warm at 0-5°C for 4 hours, TLC detects that the reaction of the raw materials is complete, add 15% (w / v) sodium sulfite solution dropwise in an ice-salt bath to neutralize excess hydrogen peroxide, Filter, rinse the filter cake with 200ml of water, add 300ml of dichloromethane to the filtrate to extract impurities, add 600ml of ethyl acetate to the water layer, adjust the pH value to 1~2 with 4mol / L hydrochloric acid solution, separate layers, and use the ethyl acetate layer Wash with saturated brine, add anhydrous sodium sulfate and activated carbon for d...

Embodiment 3

[0057] Example 3 (3S, 4R)-4-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-3-[(1R)-1-methyl-3-(p-nitro Synthesis of Benzyloxycarbonyl)-2-oxopropyl]2-azetidin-2-one (7)

[0058] Under the protection of nitrogen, put 600ml of acetonitrile and 60g of compound (3) into a 1000ml four-necked reaction flask, add 42g of N,N'-carbonyldiimidazole in batches at a temperature of 20-25°C, and keep the reaction at 20-25°C for 30 minutes. Add 95g of p-nitromonobenzyl malonate and 30.5g of anhydrous magnesium chloride, add 60g of triethylamine dropwise at a temperature of 20-25°C, drop it within 1 hour, keep the reaction at 20-30°C for 10 hours, and cool to 10 Below ℃, add 600ml of ethyl acetate and 300ml of 3mol / L hydrochloric acid solution successively, stir until the reaction liquid is clear, let stand to separate layers, extract the product with ethyl acetate, use 5% (w / v) brine, 5% (w / v) successively v) Washing with potassium carbonate and 5% (w / v) brine, and ethyl acetate as the reaction s...

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Abstract

The invention relates to a preparation method of 1Beta-methyl carbapenem antibiotic bicyclic mother nucleus, comprising the following steps of: preparing a compound (6) with good stereoselectivity by the condensation between a compound (5) and a compound (4), and further hydrolyzing to obtain a compound (3); carrying out condensation reaction, deprotection reaction and diazotization reaction on the compound (3) by adopting a 'one-pot' method, then carrying out the posttreatment and directly crystallizing to obtain a compound (2), finally cyclizing the compound (2) under the catalyst effect and converting into bicyclic ketonicester, and further carrying out active esterification reaction to obtain a white powder solid compound (1). The invention has stable process, simple and convenient operation, easy reaction control and product separation, less three wastes, low cost and up to 46 percent of overall yield, and is suitable for industrialized mass production.

Description

technical field [0001] The invention relates to a preparation method of a 1β-methyl carbapenem antibiotic bicyclic nucleus. Background technique [0002] 1β-methyl carbapenem antibiotics not only have a broad antibacterial spectrum and strong antibacterial activity, but also have good chemical stability. The 1β-methyl carbapenem antibiotics that have been commercialized include Meropenem, Ertapenem, Doripenem, Biapenem, etc., all of which are named as ( 1) is the mother nucleus. [0003] [0004] At present, there are many synthetic routes for the 1β-methylcarbapenem antibiotic bicyclic nucleus, among which the synthetic route USP4933333 reported by the Japanese Sumitomo Pharmaceuticals Co., Ltd. patent is as follows: [0005] [0006] Although the raw materials of this route are easy to obtain, equivalent optical isomers are produced in the process of synthesizing compound (10), which reduces the utilization rate of raw materials and has high cost. [0007] The syn...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/12
Inventor 谢国云刘毅
Owner ZHEJIANG HUABANG MEDICAL & CHEM
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