Preparation method of meluopeinan

[0084] [Example 1] (5R, 6S, 8R, 2'S, 4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-1-dimethylaminocarbonyl)pyrrolidine Thio]-6-(1-p-nitrobenzyloxycarbonylethoxy)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (XXIV) Synthesis

[0085] In a bottle equipped with a reflux cooler, add 40 g (0.102 mol) of diazoketone ester (IX) and 200 ml of ethyl acetate, stir and heat the mixture to 60 ° C, add 140 mg of rhodium octanoate, and stir vigorously at the same temperature 30 minutes, until the reaction of the diazoketoester (IX) was completed, a solution of 1-β-methylbicyclic ketoester (X) was obtained. The reaction solution was directly carried on to the next step without separation.

[0086] Take the solution of the above-mentioned 1-β-methylbicyclic ketone ester (X), add 300ml of acetonitrile (dry product), cool in an ice-salt bath to -10~-15°C and protect with nitrogen, then add 14.57g (0.113mol) of Diisopropylethylamine and 27.54 g (0.102 mol) of diphenyl chlorophospha...

[0091] [Example 2] (5R, 6S, 8R, 2'S, 4'S)-3-[4-(2-dimethylaminocarbonyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-nitrogen Synthesis of Heterobicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid (I)

[0092](5R, 6S, 8R, 2'S, 4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)-pyrrolidinylthio] -6-(1-p-nitrobenzyloxycarbonylethoxy)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (XXIV) (ie One-step concentrated oil) 15g (HPLC quantification: 12.5g) was dissolved in 250ml tetrahydrofuran, and 200ml water was added under stirring. The solution was placed in a 1 L autoclave, and then 5.5 g of 2,6-lutidine and 2 g of 10% palladium on carbon were added with stirring. The resulting mixture was hydrogenated for 1 hour under a hydrogen pressure of 1.8 MPa. Remove the catalyst by filtration, dilute the filtrate with 800ml of acetone, then add seed crystals at 5-15°C, after 30 minutes a large amount of crystals will separate out, then add 400ml of acetone dropwise ...

[0097] [Example 3] (5R, 6S, 8R, 2'S, 4'S)-3-[4-(2-dimethylaminocarbonyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-nitrogen Synthesis of Heterobicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid (I)

[0098] (5R, 6S, 8R, 2'S, 4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)-pyrrolidinylthio] -6-(1-p-nitrobenzyloxycarbonylethoxy)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (XXIV) 10g (crystal matter) was dissolved in 250ml tetrahydrofuran, and 200ml water was added under stirring. The solution was placed in a 1 L autoclave, and then 5.5 g of 2,6-lutidine and 2 g of 10% palladium on carbon were added with stirring. The resulting mixture was hydrogenated for 1 hour under a hydrogen pressure of 1.8 MPa. Remove the catalyst by filtration, dilute the filtrate with 800ml of acetone, then add seed crystals at 5-15°C, after 30 minutes a large amount of crystals will separate out, then add 400ml of acetone dropwise at the same temperature, stir for 30 minut...