| 92% |
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 19.0h; |
The crude Step 6 compound ( 14 MMOL) was dissolved in anhydrous DMF (50 mL) under argon and treated with K2CO3 (5.90 g, 42 MMOL, 3 equiv) and DI-TERT-BUTYIDICARBONATE (3.14 g, 14 MMOL, 1 equiv) under argon at rt. After 19 h, the DMF was removed by rotary evaporation (pump) and the residue dried further under reduced pressure. The residue was mixed with H2O (100 mL) and Et20 (100 mL), the layers separated, and the alkaline aqueous with ET20 (2X100 ML) to remove the by-product from the HYDROGENOLYSIS step. The aqueous was cooled to 0C, diluted with EtOAc (200 mL), and stirred vigorously while carefully acidifying the aqueous to pH 3 with 1 N aq HCI. The layers separated and the aqueous extracted with EtOAc (100 mL). The combined EtOAc extracts were washed with brine (50 mL), dried (NA2SO4), filtered and the filtrate concentrated by rotary evaporation. The residue was purified by Si02 flash column (5X12 cm) with 5% MEOH/CH2CI2 + 0.5% HOAc. The product was chased with hexanes to afford the product as a white foam (4.07 g, 13 mmol, 92%): MS m/e 310 (m+H) +. |
| 80 g |
|
26.2g, (0.655M) of sodium hydroxide and 665 mL of DM water were charged at room temperature in an oven dried 3 neck flask. The solution was cooled to 0-5C and 80g (0.325M) of compound-IV was added into it at 0-5C and stirred for 15 minutes. 400mL of THF was charged at 0-5 C and then slowly 86.8 g of di-tert butyl di-carbonate was added at 0-5C for 30-45 minutes and maintained for 4 -5 hours at 0 - 5 C up to completion of the reaction. After completion of the reaction, temperature of the reaction mass was raised to room temperature. Aqueous and organic layers were separated and aqueous layer was washed with 150mL of n-hexane. Separated aqueous layer was cooled to 0-5C and 413mL of ethyl acetate was added. The pH was adjusted to 3.0 with 700mL of IN HC1 at 0-5C. The reaction mixture was stirred for 10- 15 minutes and both layers were separated. Aqueous layer was extracted with 600mL of ethyl acetate and total organic layer was combined and washed with saturated sodium chloride solution and dried over sodium sulphate. Organic layer was concentrated under vacuum at 35-40C and co-distilled with 68.9 mL of ethyl acetate and 82.7mL of n-hexane was added at room temperature. Stirred for 1- 2 hrs at room temperature, filtered and washed with 80 mL of n-hexane. The 80g of compound-V was obtained as white solid as resulting precipitate having HPLC purity above 99%. |
| 4.07 g |
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 19.0h;Inert atmosphere; |
The crude Step 6 compound ( 14 mmol) was dissolved in anhydrous DMF (50 mL) under argon and treated with K2CO3 (5.90 g, 42 mmol, 3 equiv) and di-tert-butyldicarbonate (3.14 g, 14 mmol, 1 equiv) under argon at rt. After 19 h, the DMF was removed by rotary evaporation (pump) and the residue dried further under reduced pressure. The residue was mixed with H2O (100 mL) and Et2O (100 mL), the layers separated, and the alkaline aqueous with Et2O (2x100 mL) to remove the by-product from the hydrogenolysis step. The aqueous was cooled to 0C, diluted with EtOAc (200 mL), and stirred vigorously while carefully acidifying the aqueous to pH 3 with 1N aq HCl. The layers separated and the aqueous extracted with EtOAc (100 mL). The combined EtOAc extracts were washed with brine (50 mL), dried (Na2SO4), filtered and the filtrate concentrated by rotary evaporation. The residue was purified by SiO2 flash column (5x12 cm) with 5% MeOH/CH2Cl2 + 0.5% HOAc. The product was chased with hexanes to afford the product as a white foam (4.07 g, 13 mmol, 92%): MS m/e 310 (m+H)+. |
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