Simple and convenient production method of avibactam
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A compound and solvent technology, applied in the field of simple and convenient preparation of avibactam, can solve the problems of unfavorable industrial production, high starting material price, low atom utilization rate and the like, and achieves low cost, high atom utilization rate and simple preparation steps. Effect
Active Publication Date: 2019-07-02
XINFA PHARMA
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[0018] In summary, the intermediate 5R-benzyloxyaminopiperidine-2S-formate oxalate (Ⅷ), the intermediate (2S,5R)-6-benzyloxy-7 involved in the synthesis of avibactam - The synthetic route of oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (VII) is long, the starting material price is high, and a large amount of expensive palladium carbon catalyst is required, " The "three wastes" have large emissions and low atomic utilization, which is not conducive to environmental protection, and the operation is cumbersome, which is not conducive to industrial production
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[0091] Into a 500ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were added 200g of 1,2-dichloroethane, 23.5g (0.15mol) of piperidin-5-one-2S-methyl formate, 20.5 G (0.18 mol) of methoxymethyl hydroxylamine hydrochloride, 25 g of triethylamine, stirred at 40-45°C for 4 hours, cooled to 20-25°C, added 100 g of water, layered, and the water layer used 1, Extract with 2-dichloroethane twice, each with 50 grams of 1,2-dichloroethane, combine the organic layers, and wash twice with saturated brine, each with 25 grams.
[0092] After the solvent was recovered from the organic phase, it was distilled under reduced pressure to obtain 31.3 g of light yellow liquid 5-methoxymethyloxyiminopiperidine-2S-methyl formate, with a GC purity of 99.8% and a yield of 96.5%.
[0117] Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were added 200 g of dichloromethane, 23.5 g (0.15 mole) of piperidin-5-one-2S-methyl formate, 36.5 g (0.2 mole) Tert-butyl dimethylsilyl hydroxylamine hydrochloride, 25 g of triethylamine, stirred at 38-40°C for 5 hours, cooled to 20-25°C, added 100 g of water, layered, and the aqueous layer was extracted with dichloromethane Twice, 50 grams of dichloromethane each time, combine the organic layers, and wash twice with saturated brine, 25 grams each time. After the solvent was recovered from the organic phase, it was distilled under reduced pressure to obtain 41.0 g of light yellow liquid 5-tert-butyldimethylsilyloxyiminopiperidine-2S-methyl formate, with a GC purity of 99.9% and a yield of 95.6%.
[0118] Step (2): 5R-tert-butyldimethyl...
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Abstract
The invention provides a simple and convenient production method of avibactam. The simple and convenient production method of the avibactam comprises the steps of using piperidyl-5-keto-2S-formate IIas a raw material, making the piperidyl-5-keto-2S-formate II and O-protecting group hydroxylamine hydrochloride subjected to condensation reaction, and then obtaining 5R-substituted oxyaminopiperidyl-2S-formic acid V through reduction, chiral resolution and hydrolysis under an alkaline condition; and then making the 5R-substituted oxyamino piperidyl-2S-formic acid V and phosgene or triphosgene ordiphosgene subjected to cyclic urea reaction reaction, acylating chlorination reaction and amidation reaction through a one-pot method, obtaining {[(2S,5R)-2-formamyl-7-oxo-1,6-diazetidine[3.2.1]octane-6-yl]oxy}sulfonyl tetra-n-butylammonium salt VII through protecting group take-off, sulphating and tetrabutyl amination salification, and producing the avibactam I finally through ion exchange. Thesimple and convenient production method of the avibactam is simple and convenient in production route, easy to operate, low in raw material price, low in cost, small in three waste discharge, high inatom utilization rate, economical and environmentally friendly, and the yields of the various steps are high, so that the simple and convenient production method of the avibactam benefits industrial production of the avibactam.
Description
Technical field [0001] The invention relates to a simple and convenient preparation method of Avibactam, belonging to the field of medical biochemical industry. Background technique [0002] Avibactam (Ⅰ) is a non-β-lactam inhibitor of diazabicyclooctanone compounds. Avibactam can inhibit type A (including ESBL and KPC) and type C β-lactamase. When used in combination with various cephalosporins and carbapenem antibiotics, Verbatan has broad-spectrum antibacterial activity, especially for Escherichia coli and Klebsiella pneumoniae containing extended-spectrum β-lactamase, and excessive AmpC enzymes. The activity of Escherichia coli and Escherichia coli containing both AmpC and extended-spectrum β-lactamase is remarkable. The CAS number of Avibactam (I) is 1192491-61-4, and the chemical name is [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[ 3.2.1] octane-6-yl] sodium sulfate, the structural formula is as follows: [0003] [0004] The existing synthesis technology of Aviba...
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