Carbapenem derivatives
A representative compound technology, applied in the field of medicine, can solve problems such as low clinical utilization, failure to meet clinical needs, and increased bacterial resistance
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Embodiment 1
[0117] Example 1 (2S, 4S)-4-mercapto-2-formyl [(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-tri Azin-3-yl)amine Preparation of base]-1-(tert-butoxycarbonyl)pyrrolidine
[0118] 14.5 g (50 mmol) of (2S,4S)-4-acetylthio-2-carboxy-1-(tert-butoxycarbonyl)pyrrolidine and 200 ml of anhydrous tetrahydrofuran were added to the dry reaction flask. Under nitrogen protection, 13g (80mmol) of 1,1-carbonyldiimidazole was added at room temperature, reacted for 1h, and 11.4g (80mmol) of 3-amino-2-methyl-5,6-dioxo- 1,2-dihydro-1,2,4-triazine in 100ml tetrahydrofuran solution, continue to react for 1h. Then 100ml of 1mol / l hydrochloric acid was added dropwise, extracted with ethyl acetate (100ml×2), the organic phase was washed with water and saturated sodium chloride solution successively, concentrated under reduced pressure, the residue was added with 100ml of 4mol / l hydrochloric acid, stirred for 2h, and The dilute alkali solution was adjusted to be alkaline, and a solid was precipita...
Embodiment 2
[0119] Example 2 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro- 1,2,4-triazin-3-yl) Amino]-1-(tert-butoxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[ 3.2.0] Hept-2- Preparation of ene-2-carboxylic acid p-nitrobenzyl ester
[0120] In a dry reaction flask, add (4R, 5S, 6S)-3-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1- Azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester 23.8g (40mmol) in 200ml of acetonitrile solution, cooled to below 0 ℃, add diisopropylethylamine 10ml and (2S ,4S)-4-mercapto-2-formyl[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl )Amino]-1-(tert-butoxycarbonyl)pyrrolidine 16.7g (45mmol) in 100ml of acetonitrile, stirred at 0°C for 15h. After the reaction was completed, 500 ml of ethyl acetate was added to dilute, washed with water and saturated brine successively, the organic layer was dried and concentrated to obtain 16.7 g of yellow solid, ...
Embodiment 3
[0121] Example 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro- 1,2,4-triazin-3-yl) Amino]-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2- Preparation of ene-2-carboxylic acids prepare
[0122] (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1, 2,4-Triazin-3-yl)amino]-1-(tert-butoxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl 14.3g (20mmol) of p-nitrobenzyl 7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate was dissolved in 100ml of dichloromethane, and 20ml of anisole and nitric acid were added Add 1 mol / L aluminum trichloride nitromethane solution 100ml dropwise at -50°C, stir for 2 hours at -40°C, add 200ml of water, precipitate a solid, filter, and dissolve the filter cake in 400mlTHF and 30ml of water Add 3 g of 10% palladium-carbon to the mixture, stir and react for 2 h at 40° C. under 4 MPa hydrogen pressure, filter off palladium-carbon, add THF 150 ml to...
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