(7R,8aS)-1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazin-7-ol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 19D, 1 g, 4.30 mmol) and ethanol (10 mL) was added to 20% palladium hydroxide on carbon, wet (0.100 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude intermediate (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol. The title compound was prepared according to the procedure described in Example 17E substituting (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.58 (m, 2H), 1.97 (m, 2H), 2.10-2.35 (m, 3H), 2.90 (m, 1H), 3.20 (m, 1H), 3.62 (m, 1H), 3.77 (m, 1H), 4.14 (m, 1H), 4.80 (m, 1H), 7.92 (m, 2H), 8.10 (m, 2H); MS (ESI) m/z 351 (M+H)+. The mixture was filtered through a nylon membrane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.81 g (26.8 mmol) of (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 6, Step A), 19.8 g (134 mmol) of 2,5-dichloropyridine, 7.10 g (67.0 mmol) of sodium carbonate and 275 mL of isoamyl alcohol was heated at reflux for 72 h. The mixture was cooled to about 100° C., filtered hot, and the filtrate concentrated in vacuo. Purification of the residue by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.63 g (9%) of the title compound of sufficient purity for use in subsequent reactions. m/z (MH+) 254. was heated at reflux for 72 h filtered hot the filtrate concentrated in vacuo Purification of the residue by flash silica gel chromatography with 9:1 chloroform

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.81 g (26.8 mmol) of (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 6, Step A), 19.8 g (134 mmol) of 2,5-dichloropyridine, 7.10 g (67.0 mmol) of sodium carbonate and 275 mL of isoamyl alcohol was heated at reflux for 72 h. The mixture was cooled to about 100° C., filtered hot, and the filtrate concentrated in vacuo. Purification of the residue by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.63 g (9%) of the title compound of sufficient purity for use in subsequent reactions. m/z (MH+) 254. was heated at reflux for 72 h filtered hot the filtrate concentrated in vacuo Purification of the residue by flash silica gel chromatography with 9:1 chloroform

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 9.75 g (42.0 mmol) of (7R,8aS)-7-hydroxy-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Diafi, L.; et al. J. Het. Chem., 1990, 27, 2181) and 29.4 mL of 5M ammonium formate in 140 mL of methanol was treated with an aqueous slurry of 4.9 g of 10% palladium on carbon and the mixture was stirred at ambient temperature for 18 h. The mixture was filtered through Celite and evaporated to give (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine as a clear oil. The mixture was filtered through Celite evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 9.75 g (42.0 mmol) of (7R,8aS)-7-hydroxy-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Diafi, L.; et al. J. Het. Chem., 1990, 27, 2181) and 29.4 mL of 5M ammonium formate in 140 mL of methanol was treated with an aqueous slurry of 4.9 g of 10% palladium on carbon and the mixture was stirred at ambient temperature for 18 h. The mixture was filtered through Celite and evaporated to give (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine as a clear oil. The mixture was filtered through Celite evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 19D, 1 g, 4.30 mmol) and ethanol (10 mL) was added to 20% palladium hydroxide on carbon, wet (0.100 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude intermediate (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol. The title compound was prepared according to the procedure described in Example 17E substituting (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.58 (m, 2H), 1.97 (m, 2H), 2.10-2.35 (m, 3H), 2.90 (m, 1H), 3.20 (m, 1H), 3.62 (m, 1H), 3.77 (m, 1H), 4.14 (m, 1H), 4.80 (m, 1H), 7.92 (m, 2H), 8.10 (m, 2H); MS (ESI) m/z 351 (M+H)+. The mixture was filtered through a nylon membrane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.81 g (26.8 mmol) of (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 6, Step A), 19.8 g (134 mmol) of 2,5-dichloropyridine, 7.10 g (67.0 mmol) of sodium carbonate and 275 mL of isoamyl alcohol was heated at reflux for 72 hours. The mixture was cooled to about 100° C., filtered hot, and the filtrate concentrated in vacuo. Purification of the residue by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.63 g (9%) of the title compound of sufficient purity for use in subsequent reactions. m/z (MH+) 254. was heated at reflux for 72 hours filtered hot the filtrate concentrated in vacuo Purification of the residue by flash silica gel chromatography with 9:1 chloroform

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the crude (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]-pyrazine, 9.96 g (52.5 mmol) of 2-chloro-5-fluoropyrimidine (Dunaiskis, A. et al., Org. Prep. Proc. Int., 1995, 27, 600-602), 13.4 g (126 mmol) of sodium carbonate and 450 mL of water was heated at 95° C. for 72 hours. The mixture was cooled, extracted with chloroform (2×), and the combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95:5 ethyl acetate:methanol gave 8.54 g (85%) of the title compound. 13C NMR (base, CDCl3): δ 39.1, 43.7, 48.7, 51.0, 60.2, 62.9, 69.4, 144.95, 145.24, 149.9, 153.2,158.9. m/z (MH+) 239. The mixture was cooled extracted with chloroform (2×) the combined organic phase was dried (magnesium sulfate) filtered evaporated Purification by flash silica gel chromatography with 95:5 ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 9.75 g (42.0 mmol) of (7R,8aS)-7-hydroxy-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Diafi, L. et al., J. Het. Chem., 1990, 27, 2181) and 29.4 mL of 5M ammonium formate in 140 mL of methanol was treated with an aqueous slurry of 4.9 g of 10% palladium on carbon and the mixture was stirred at ambient temperature for 18 hours. The mixture was filtered through Celite and evaporated to give (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine as a clear oil. The mixture was filtered through Celite evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 54D, 1 g, 4.30 mmol) and ethanol (10 mL) were added to 20% palladium hydroxide on carbon, wet (0.100 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude intermediate (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol. To a solution of crude (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.422 g, 10 mmol) and triethylamine (1.62 g, 16 mmol) in dichloromethane (50 mL) was slowly added a solution of 3-(trifluoromethyl)benzoyl chloride (2.09 g, 10 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, diluted with ethyl acetate (100 mL), washed with water (20 mL), dried over sodium sulfate, and filtered. The organic solution was concentrated, and the residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.63 (m, 2H), 2.10-2.27 (m, 3H), 2.50 (m, 1H), 2.80-3.00 (m, 2H), 3.20-3.50 (m, 2H), 4.22 (m, 1H), 4.42-4.60 (m, 1H), 4.80 (m, 1H), 7.70 (m, 3H), 7.82 (m, 1H); MS (ESI) m/z 315 (M+H)+. The mixture was concentrated diluted with ethyl acetate (100 mL) washed with water (20 mL) dried over sodium sulfate filtered The organic solution was concentrated the residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 54D, 1 g, 4.30 mmol) and ethanol (10 mL) were added to 20% palladium hydroxide on carbon, wet (0.100 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude intermediate (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol. To a solution of crude (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.422 g, 10 mmol) and triethylamine (1.62 g, 16 mmol) in dichloromethane (50 mL) was slowly added a solution of 3-(trifluoromethyl)benzoyl chloride (2.09 g, 10 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, diluted with ethyl acetate (100 mL), washed with water (20 mL), dried over sodium sulfate, and filtered. The organic solution was concentrated, and the residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.63 (m, 2H), 2.10-2.27 (m, 3H), 2.50 (m, 1H), 2.80-3.00 (m, 2H), 3.20-3.50 (m, 2H), 4.22 (m, 1H), 4.42-4.60 (m, 1H), 4.80 (m, 1H), 7.70 (m, 3H), 7.82 (m, 1H); MS (ESI) m/z 315 (M+H)+. The mixture was filtered through a nylon membrane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.81 g (26.8 mmol) of (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 6, Step A), 19.8 g (134 mmol) of 2,5-dichloropyridine, 7.10 g (67.0 mmol) of sodium carbonate and 275 mL of isoamyl alcohol was heated at reflux for 72 h. The mixture was cooled to about 100° C., filtered hot, and the filtrate concentrated in vacuo. Purification of the residue by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.63 g (9%) of the title compound of sufficient purity for use in subsequent reactions. m/z (MH+) 254. was heated at reflux for 72 h filtered hot the filtrate concentrated in vacuo Purification of the residue by flash silica gel chromatography with 9:1 chloroform