| 82.5% |
With sodium tris(acetoxy)borohydride; orthoformic acid triethyl ester; In N,N-dimethyl acetamide; at 5 - 50℃; for 12h;Inert atmosphere; Large scale; |
2.46 kg of Compound III and 3.12 kg of Compound II were added to 15 L of N, N-dimethylacetamide, and nitrogenUnder guard,Circulating frozen saline bath to 5 ± 5 ,Added dropwise trimethyl orthoformate 2.2Kg,Sodium borohydride acetate was added in portions3.19Kg,Stirred at 5 ± 5 C for 2 hours,Heated to 50 ± 5 for about 10 hours;Circulating frozen saline bath to 5 ± 5 ,45 C below the drop in water 15L,Add Bi temperature at this temperature for 1 hour,Heated to 50 ± 5 C for 2 hours,Centrifuge,Wet product washed with water 5L three times,Wet product was added to the water 15L beating 1 hour,Centrifuge,50 C for 12 hours under vacuum.Get gray whiteSolid was added isopropyl ether 12L,Heated to 60 ± 5 ,Then add n-heptane 12L, cooled to 15 ± 5 , incubated for 1 hour,Suction filtered and dried under vacuum at 40 C for 12 hours to obtain 3.1Kg of white solid with a yield of 82.5% |
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With sodium tris(acetoxy)borohydride; In N,N-dimethyl acetamide; at 0 - 20℃; for 7.66667h;Large scale; |
Step A: tert-Butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolol[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate A vessel was charged with N,N-dimethylacetamide (520.6 kg), <strong>[1280210-80-1]2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-5-ium benzenesulfonate</strong> (intermediate 2, 30.0 kg, 86.8 mol), and tert-butyl [(2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl]carbamate (intermediate 1, 31.2 kg, 95.3 mol). After dissolving at room temperature, the solution was cooled to 0-10 C. and sodium triacetoxyborohydride (24 kg, 113 mol) was added in four equal portions every 40 min. The reaction was then allowed to warm to room temperature and stirred an additional 5 h. The solution was then cooled to 5-15 C. and water (672 kg) was added over 1-2 h. The resulting slurry was filtered and the cake washed sequentially with N,N-dimethylacetamide, twice with water, and then n-heptane. The solids were dried under vacuum at 40-60 C. to give tert-butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate. |
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With sodium tris(acetoxy)borohydride; In N,N-dimethyl acetamide; at 0 - 20℃; for 7.66667h;Large scale; |
Step A: tert-Butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolol[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate:_A vessel was charged with N,N-dimethylacetamide (520.6 kg), <strong>[1280210-80-1]2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-5-ium benzenesulfonate</strong> (intermediate 2, 30.0 kg, 86.8 mol), and tert-butyl [(2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl]carbamate (intermediate 1, 31.2 kg, 95.3 mol). After dissolving at room temperature, the solution was cooled to 0-10 C. and sodium triacetoxyborohydride (24 kg, 113 mol) was added in four equal portions every 40 min. The reaction was then allowed to warm to room temperature and stirred an additional 5 h. The solution was then cooled to 5-15 C. and water (672 kg) was added over 1-2 h. The resulting slurry was filtered and the cake washed sequentially with N,N-dimethylacetamide, twice with water, and then n-heptane. The solids were dried under vacuum at 40-60 C. to give tert-butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate. |
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