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4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method

An azabicycle and carboxylic acid technology, which is applied in the field of preparation of 4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivatives, It can solve problems such as difficulty in realization, and achieve the effect of simplifying the process steps and being beneficial to industrial large-scale production.

Active Publication Date: 2007-07-11
CHIA TAI TIANQING PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These methods have relatively high requirements on industrial production and are relatively difficult to realize

Method used

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  • 4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method
  • 4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method
  • 4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (4R, 5S, 6S)-3-[(3S, 5S)-5-(dimethylaminoacyl)-3-pyrrolidine]thio-6-[(1R)-1-hydroxyethyl]-4- Preparation of methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate (formula 1a)

[0030] (4R, 5S, 6S)-3-[(3S, 5S)-1-(p-nitrobenzyloxycarbonyl)-5-(dimethylaminoacyl)-3-pyrrolidine]thio-6-[ (1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester (2a) 40g( 0.067mol) by adding 2000ml of ethyl acetate and 400ml of water, after dissolving, place 10g of 5% palladium carbon in a 5L hydrogenation kettle, feed hydrogen, pressurize to 5kg / cm 2 , and stirred at room temperature until the reaction was complete. The reaction solution was filtered and separated into layers, and the aqueous layer was washed with ethyl acetate. Then 1200ml of acetone was added, stirred at room temperature for one hour, filtered, washed with acetone, and dried in vacuo to obtain 15g (0.034mol) of light yellow solid (1a), yield 51.2%.

[0031]...

Embodiment 2

[0037] Preparation of 1a

[0038] (4R, 5S, 6S)-3-[(3S, 5S)-1-(p-nitrobenzyloxycarbonyl)-5-(dimethylaminoacyl)-3-pyrrolidine]thio-6-[ (1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester (formula 2a) 5g (0.0084mol) add 200ml of dichloromethane and 250ml of water, after dissolving, put 1.5g of 5% palladium carbon in a 1L hydrogenation kettle, feed hydrogen, pressurize to 2kg / cm 2 , and stirred at room temperature until the reaction was complete. The reaction solution was filtered and separated into layers, and the aqueous layer was washed with ethyl acetate. Then 200 ml of tetrahydrofuran was added, stirred at room temperature for one hour, filtered, washed with tetrahydrofuran, and vacuum-dried to obtain 1.6 g (0.0036 mol) of light yellow solid (1a), yield 43.2%.

[0039] Elemental analysis: Calculated C: 46.47; H: 7.14; N: 9.60

[0040] Measured value C: 46.52; H: 7.31; N: 9.53

Embodiment 3

[0042] (4R, 5S, 6S)-3-[(3S, 5S)-5-(aminosulfonamido)methyl-3-pyrrolidine]thio-6-[(1R)-1-hydroxyethyl]-4 - Preparation of methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (formula 1c)

[0043] (4R, 5S, 6S)-3-[(3S, 5S)-1-(p-nitrobenzyloxycarbonyl)-5-((aminosulfonamido)methyl-3-pyrrolidine)sulfur-6 -[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester 15g (0.02 mol) by adding 2500ml of ethyl acetate and 450ml of water, after dissolving, put 7.5g of 5% palladium carbon in a 5L hydrogenation kettle, feed hydrogen, pressurize to 10kg / cm 2 , and stirred at room temperature until the reaction was complete. The reaction solution was filtered and separated into layers, and the aqueous layer was washed with ethyl acetate. Then 800 ml of ethanol was added, stirred at room temperature for 1 hour, filtered, washed with ethanol, and dried in vacuo to obtain 5.1 g (0.012 mol) of off-white solid (1c), yield 60.7%.

[0044] Eleme...

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Abstract

The invention discloses a making method of 4-methyl-7-oxy-1-aza bicyclo [3. 2. 0] pimelic-2-olefin-2-carboxyl derivant, which is characterized by the following: adopting two-phase solvent as solvent to catalyze and hydrogenate; simplifying the operating method of separation and purifying; reducing the need of reacting equipment and condition; fitting for large scale of industrial manufacturing.

Description

technical field [0001] The invention relates to a preparation method of 4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivatives, in particular to a reaction process, a solvent and a purification method. Background technique [0002] Many 4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivatives have become β-lactam antibiotics with good antibacterial effect, such as meropenem (as shown in formula 1a), biapenem (as shown in formula 1b), doripenem (as shown in formula 1c), etc. have been marketed in many countries around the world. [0003] The 4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivative in the practical application has the structure shown in the following formula (1): [0004] [0005] where R 1 =-OH,-OSi(CH 3 ) 2 C(CH 3 ) 3 or -OSi(CH 3 ) 3 [0006] [0007] [0008] According to literature reports (J of Antibiotics 1990,43(5):519; Chem Pharm Bull1996,44(12):2326; EP 256,377), 4-methyl-7-oxo-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/06C07D477/20C07D519/06C07F7/18
Inventor 王小妹隋强王哲烽王鹏时惠麟
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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