A kind of convenient preparation method of raylebactam intermediate

An intermediate and solid phosgene technology, which is applied in the field of pharmaceutical biochemical industry, can solve the problems of difficult acquisition, high price of sodium octane-2-formate, and no practical industrial value, etc., and achieves simple operation, easy control of reaction conditions, and wide variety of reagents little effect

Active Publication Date: 2020-04-28
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Reaction Scheme 2 The raw material (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-sodium carboxylate is expensive, not easy to obtain, and has no actual industrialization value

Method used

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  • A kind of convenient preparation method of raylebactam intermediate
  • A kind of convenient preparation method of raylebactam intermediate
  • A kind of convenient preparation method of raylebactam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: (2S,5R)-N-(1-tert-butoxycarbonyl)piperidin-4-yl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2. 1] Octane-2-carboxamide (Ⅱ 1 ) preparation

[0048] Add 200 grams of tetrahydrofuran, 12.5 grams (0.05 mole) (2S, 5R)-5-benzyloxyaminopiperidine-2-carboxylic acid, 50 grams of tri-n-butylamine, 0.1 gram of N,N-dimethylformamide, cooled, at -10-0°C, dropwise added a mixed solution of 23.8g (0.08 moles) of solid phosgene and 80g of tetrahydrofuran, and stirred at 10-20°C for 4 hours. Between 10-20°C, add a mixed solution of 12.0 g (0.06 mole) 1-tert-butoxycarbonyl-4-aminopiperidine and 40 g of tetrahydrofuran, stir and react for 3 hours between 15-20°C, pour the reaction liquid into 300 g of ice-water mixture, separated into layers, and the aqueous layer was extracted twice with dichloromethane, 50 g each time. The combined organic phases were washed twice with saturated sodium chloride solution, each time 20 grams, and after the solvent was recovered from the gained orga...

Embodiment 2

[0051] Example 2: (2S,5R)-N-(1-tert-butoxycarbonyl)piperidin-4-yl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2. 1] Octane-2-carboxamide (Ⅱ 1 ) preparation

[0052] Add 200 grams of dichloromethane, 12.5 grams (0.05 moles) of (2S, 5R)-5-benzyloxyaminopiperidine-2-carboxylic acid, 50 grams of diisopropyl Ethylamine, 0.1 g of N, N-dimethylformamide, cooled, at -5-0 ° C, dropwise add a mixed solution of 23.8 g (0.08 mole) of solid phosgene and 80 g of dichloromethane, dropwise 15-20 The reaction was stirred at °C for 4 hours. Between 15-20°C, add a mixed solution of 14.0 grams (0.07 moles) of 1-tert-butoxycarbonyl-4-aminopiperidine and 40 grams of dichloromethane, stir and react for 3 hours between 15-20°C, and the reaction The liquid was poured into 300 g of ice-water mixture, the layers were separated, and the aqueous layer was extracted twice with 50 g of dichloromethane each time. The combined organic phases were washed twice with saturated sodium chloride solution, 20 grams eac...

Embodiment 3

[0053] Example 3: (2S,5R)-N-(1-tert-butoxycarbonyl)piperidin-4-yl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2. 1] Octane-2-carboxamide (Ⅱ 1 ) preparation

[0054] Add 200 grams of THF, 12.5 grams (0.05 moles) of (2S, 5R)-5-benzyloxyaminopiperidine-2-carboxylic acid, 60 grams of diisopropylethylamine in a 500 milliliter four-necked flask equipped with stirring and a thermometer. , 0.1 g of N,N-dimethylformamide, cooled, and at -10-0°C, dropwise added a mixed solution of 25.0 g (0.13 moles) of diphosgene and 80 g of tetrahydrofuran, and stirred at 10-20°C for 5 Hour. Between 10-20°C, add a mixed solution of 14.0 grams (0.07 moles) of 1-tert-butoxycarbonyl-4-aminopiperidine and 40 grams of tetrahydrofuran, stir and react for 5 hours between 15-20°C, pour the reaction liquid into 300 g of ice-water mixture, separated into layers, and the aqueous layer was extracted twice with dichloromethane, 50 g each time. The combined organic phases were washed twice with saturated sodium chlori...

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Abstract

The invention discloses a simple preparation method of Relebactam intermediate, namely (2S,5R)-N-(1-protective group) piperidine-4-yl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane - 2- formamide, (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl chloride is prepared from (2S, 5R) -5- benzyloxaminopiperidine -2- formic acid and phosgene, solid phosgene or diphosgene in a solventin the presence of an alkali and a catalyst by epoxidation and acylating chlorination reaction by a one-pot method, and the (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl chlorideis not separated and is directly subjected to amidation reaction with (1-protective group)-4-amino piperidine to obtain the (2S,5R)-N-(1-protective group) piperidine-4-yl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane - 2- formamide. The method disclosed by the invention is simple in steps, cheap and easily available in raw materials, green and environment-friendly in process, low in cost, high in reaction atom economy, high in purity, yield and selectivity of the obtained intermediate, and beneficial to industrial production.

Description

technical field [0001] The present invention relates to a simple and convenient preparation method of a relibactam intermediate, in particular to a bicyclic urea intermediate (2S,5R)-N-(1-protecting group)piperidin-4-yl-6-benzyloxy The invention discloses a convenient preparation method of yl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Relebactam (Relebactam) belongs to a new type of non-β-lactam inhibitor of diazabicyclooctone compound, its structure is similar to that of avibactam, Relebactam and imipenem-cilastatin sodium The clinical phase II of the combination drug has shown good performance, and it is of great significance to study its synthesis and action. The CAS number of Relebactam (I) is 1174018-99-5, and its chemical name is [(1R,2S,5R)-2-(N-(4-piperidinyl)aminocarbonyl)-7-oxo -1,6-diazabicyclo[3.2.1]oct-6-yl]sulfuric acid, where (2S,5R)-N-(1-protecting group...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/08
CPCY02P20/55
Inventor 戚聿新李新发王保林徐欣赵银龙腾玉奇
Owner XINFA PHARMA
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