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A kind of preparation method of avibactam intermediate

A technology for intermediates and compounds, applied in the field of preparation of avibactam intermediates, can solve the problems of unfavorable avibactam intermediates, many operation steps, low activity of benzyl esters, etc., and achieves easy operation of reaction conditions and concise process. , the effect of low cost

Active Publication Date: 2020-07-17
XINFA PHARMA
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AI Technical Summary

Problems solved by technology

Benzyl (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate obtained after cyclic ureaification has low activity and cannot be used directly Ammonia methanol solution amidation requires hydrolysis of ester group to carboxyl group, reactivation of carboxyl group to acid anhydride, after which effective amidation can be achieved, and there are many operating steps
[0015] Therefore, the above methods are not conducive to the avibactam intermediate, namely ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane Simple industrial production of -6-yl]oxy}sulfonyl)tetrabutylammonium salt (Ⅱ)

Method used

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  • A kind of preparation method of avibactam intermediate
  • A kind of preparation method of avibactam intermediate
  • A kind of preparation method of avibactam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1: N,N-dibenzyl-5R-benzyloxyaminopiperidine-2S-carboxamide (Ⅴ 1 ) preparation

[0074] Add 250 grams of tetrahydrofuran (THF), 28.0 grams of potassium carbonate, 43.0 grams (0.1 moles) of 5R-benzyloxyaminopiperidine-2S-formic acid benzyl oxalate (Ⅲ) in the 500 milliliter four-neck flask equipped with stirring and thermometer, 30 g (0.15 moles) of dibenzylamine, stirred at 40-45°C for 5 hours. Cool to 20-25°C, filter, and wash the filter cake twice with tetrahydrofuran, 30 grams each time. Combine the organic phases, recover tetrahydrofuran by distillation, add 40 grams of methyl tert-butyl ether to the residue, beat and wash, filter to obtain 41.1 grams of N,N-dibenzyl-5R-benzyloxyaminopiperidine-2S-carboxamide, liquid phase The purity is 99.92%, and the yield is 95.8%.

[0075] The NMR data of the product are as follows: 1 HNMR (400MHz, DMSO-d 6 )

[0076] 1 H-NMR (400MHz, DMSO-d6) δ: 1.12 (1H, q), 1.29 (1H, q), 1.86 (2H, d), 2.29 (1H, t), 2.76 (1H, m), ...

Embodiment 2

[0077] Example 2: N,N-dibenzyl-5R-benzyloxyaminopiperidine-2S-carboxamide (Ⅴ 1 ) preparation

[0078] Add 300 grams of 1,2-dichloroethane, 43.0 grams (0.1 moles) of 5R-benzyloxyaminopiperidine-2S-formic acid benzyl oxalate (Ⅲ) into a 500 ml four-necked flask equipped with a stirring and thermometer , 60 grams (0.30 moles) of dibenzylamine, stirred and reacted at 50-55°C for 4 hours. Cool to 20-25°C, filter, and wash the filter cake twice with 1,2-dichloroethane, 30 grams each time. Combine the organic phases, recover 1,2-dichloroethane by distillation, add 50 grams of methyl tert-butyl ether to the residue, beat and wash, and filter to obtain 40.5 grams of N,N-dibenzyl-5R-benzyloxyaminopiperidine- 2S-Formamide, liquid phase purity 99.86%, yield 94.4%.

Embodiment 3

[0079] Example 3: N, N-two (p-methoxybenzyl)-5R-benzyloxyaminopiperidine-2S-carboxamide (Ⅴ 2 ) preparation

[0080] Add 250 grams of tetrahydrofuran (THF), 28.0 grams of potassium carbonate, 37.0 grams (0.1 moles) of 5R-benzyloxyaminopiperidine-2S-formic acid ethyl oxalate (Ⅲ) in the 500 milliliter four-neck flask equipped with stirring and thermometer, 40 Gram (0.16 moles) of bis(p-methoxy)benzylamine, stirred at 50-55°C for 4 hours. Cool to 20-25°C, filter, and wash the filter cake twice with tetrahydrofuran, 30 grams each time. Combine the organic phases, recover tetrahydrofuran by distillation, add 40 grams of methyl tert-butyl ether to the residue, beat and wash, and filter to obtain 45.7 grams of N,N-di(p-methoxybenzyl)-5R-benzyloxyaminopiperidine-2S -Formamide, the liquid phase purity is 99.93%, and the yield is 93.5%.

[0081] The NMR data of the product are as follows: 1 HNMR (400MHz, DMSO-d 6 )

[0082] 1 H-NMR (400MHz, DMSO-d6) δ: 1.15(1H, q), 1.34(1H, q), 1....

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Abstract

The invention discloses a preparation method of an avibactam intermediate, specifically a ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[ 3.2.1] The preparation method of octane-6-yl]oxy}sulfonyl)tetrabutylammonium salt (II). The present invention uses 5R-benzyloxyaminopiperidine-2S-formate oxalate (Ⅲ) as a raw material, and the aminated compound of formula IV to prepare the compound of formula V through amidation, and the obtained compound V is cyclic ureated with a carbonylating reagent to obtain the compound of formula V Compound VI, the final product (II) is prepared by catalytic hydrogenolysis debenzyl or substituted benzyl, sulfur trioxide complex sulfation, and tetrabutylammonium salination. The reaction conditions of the method of the present invention are easy to operate, strong in operability, simple in process, low in cost, less by-products, high in economy of reaction atoms, and the obtained product (II) has high purity and high yield.

Description

technical field [0001] The present invention relates to a preparation method of an avibactam intermediate, in particular to a ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2 .1] A simple preparation method of octane-6-yl]oxyl}sulfonyl)tetrabutylammonium salt, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Avibactam belongs to the non-β-lactam inhibitors of diazabicyclooctone compounds. Avibactam can inhibit type A (including ESBL and KPC) and type C β-lactamases. Avibactam When used in combination with various cephalosporins and carbapenem antibiotics, it has broad-spectrum antibacterial activity, especially against Escherichia coli and Klebsiella pneumoniae containing extended-spectrum β-lactamases, Escherichia coli containing excessive AmpC enzymes And the activity of Escherichia coli containing both AmpC and extended-spectrum β-lactamases is significant. The CAS number of Avibactam (I) is 1192491-61-4, and its chemical...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/08
CPCC07D471/08C07B57/00C07D211/60
Inventor 戚聿新李新发王保林屈虎徐欣鞠立柱
Owner XINFA PHARMA
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