(1,1,1-trichloro-2-methylpropan-2-yl) carbonochloridate

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of compound 7 (10.9 g, 12 mmol) and pyridine (2 ml, 25 mmol) in CH2Cl2 (125 ml) at 0° C. was treated dropwise over 15 min with a solution of 2,2,2-trichloro-1,1-dimethylethyl chloroformate (3.17 g, 13.2 mmol) in CH2Cl2 (25 ml). The reaction mixture was allowed to warm slowly to ambient temperature over 3.5 h. 4-Pyrrolidinopyridine (0.89 g, 6.0 mmol), N,N-diisopropylethylamine (10.5 ml, 60 mmol) and diphenyl chlorophosphate (3.7 ml, 18 mmol) were added sequentially and the resulting mixture was stirred for 5 h at room temperature. The reaction mixture was diluted with CH2Cl2 (500 ml), washed with cold 7.5% aqueous HCl (2×250 ml), water (250 ml), saturated aqueous NaHCO3 (250 ml), dried (Na2SO4), and then concentrated. The residue obtained was purified by flash chromatography on silica gel eluting with 12.5% EtOAc-hexanes to give 15.1 g (95%) of 2-(trimethylsilyl)ethyl 2-deoxy-4-O-diphenylphosphono-3-O-[(R)-3-tetradecanoyloxytetradecanoyl]-6-O-(2,2,2-trichloro-1,1-dimethylethoxycarbonyl)-2-(2,2,2-trichlorethoxycarbonylamino)-β-D-glucopyranoside (compound 8) as a viscous oil: 1H NMR (CDCl3) δ 0.0 (s, 9 H), 0.8-1.0 (m, 8 H), 1.1-1.65 (m, 42 H), 1.83 and 1.90 (2s, 6 H), 2.15-2.45 (m, 4 H), 3.34 (q, 1 H, J=~8 Hz), 3.37 (m, 1 H), 3.81 (m, 1 H), 3.95 (m, 1 H), 4.27 (dd, 1 H, J=12, 5 Hz), 4.34 (d, 1 H, J=12 Hz), 4.58 (d, 1 H, J=12 Hz), 4.66 (q, 1 H, J=~9 Hz), 4.86 (d, 1 H, J=12 Hz), 5.03 (d, 1 H, J=7.9 Hz), 5.21 (m, 1 H), 5.54-5.70 (m, 2 H), 7.2-7.8 (m, 10 H). washed with cold 7.5% aqueous HCl (2×250 ml), water (250 ml), saturated aqueous NaHCO3 (250 ml) dried (Na2SO4) concentrated The residue obtained was purified by flash chromatography on silica gel eluting with 12.5% EtOAc-hexanes

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

Procedure: 2,2,2-Trichloro-1,1-dimethylethyl chloroformate (2.77 g, 11.6 mmol) was added to a sol. of compound C4 (1.40 g, 2.31 mmol) in CH2ClCH2Cl (30 mL), and the mixture was heated to reflux for 2 h. 2,2,2-Trichloro-1,1-dimethylethyl chloroformate (1.40 g, 5.5 mmol) was added again, and the mixture was heated to reflux for 2 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was diluted with EtOAc, and washed with aq. 1M NaOH (2×). The combined aq. layers were extracted back with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4) yielded the title compound (815 mg, 44%). LC-MS: tR=1.25 min; ES+: 796.32. the mixture was heated to reflux for 2 h the mixture was heated to reflux for 2 h the solvents were removed under reduced pressure The residue was diluted with EtOAc washed with aq. 1M NaOH (2×) The combined aq. layers were extracted back with EtOAc (2×) extracts were dried over MgSO4 filtered the solvents were removed under reduced pressure Purification of the residue by FC (EtOAc/heptane 1:4)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of compound B9 (6.16 g, 11.9 mmol) and 2,2,2-trichloro-1,1-dimethylethyl chloroformate (3.15 g, 13.1 mmol) in 1,2-dichloroethane (200 mL) was heated to 60° C. for 20 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 8:2) yielded the title compound (7.58 g, 90%). LC-MS: tR=1.29 min, ES+: 707.36. to cool to rt the solvents were removed under reduced pressure Purification of the residue by FC (EtOAc/heptane 8:2)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of compound B9 (6.16 g, 11.9 mmol) and 2,2,2-trichloro-1,1-dimethylethyl chloroformate (3.15 g, 13.1 mmol) in 1,2-dichloroethane (200 mL) was heated to 60° C. for 20 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 8:2) yielded the title compound (7.58 g, 90%). LC-MS: tR=1.29 min, ES+: 707.36. to cool to rt the solvents were removed under reduced pressure Purification of the residue by FC (EtOAc/heptane 8:2)

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

Procedure: A solution of compound 7 (10.9 g, 12 mmol) and pyridine (2 ml, 25 mmol) in CH2Cl2 (125 ml) at 0° C. was treated dropwise over 15 min with a solution of 2,2,2-trichloro-1,1-dimethylethyl chloroformate (3.17 g, 13.2 mmol) in CH2Cl2 (25 ml). The reaction mixture was allowed to warm slowly to ambient temperature over 3.5 h. 4-Pyrrolidinopyridine (0.89 g, 6.0 mmol), N,N-diisopropylethylamine (10.5 ml 60 mmol) and diphenyl chlorophosphate (3.7 ml, 18 mmol) were added sequentially and the resulting mixture was stirred for 5 h at room temperature. The reaction mixture was diluted with CH2Cl2 (500 ml), washed with cold 7.5% aqueous HCl (2×250 ml), water (250 ml), saturated aqueous NaHCO3 (250 ml), dried (Na2SO4), and then concentrated. The residue obtained was purified by flash chromatography on silica gel eluting with 12.5% EtOAc-hexanes to give 15.1 g (95%) of 2-(trimethylsilyl)ethyl 2-deoxy-4-O-diphenylphosphono-3-O-[(R)-3-tetradecanoyloxytetradecanoyl]-6-O-(2,2,2-trichloro-1,1-dimethylethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-β-D-glucopyranoside (compound 8) as a viscous oil: 1H NMR (CDCl3) δ0.0 (s, 9H), 0.8-1.0 (m, 8H), 1.1-1.65 (m, 42H), 1.83 and 1.90 (2s, 6H), 2.15-2.45 (m, 4H), 3.34 (q, 1H, J=˜8 Hz), 3.37 (m, 1H), 3.81 (m, 1H), 3.95 (m, 1H), 4.27 (dd, 1H, J=12, 5 Hz), 4.34 (d, 1H, J=12 Hz), 4.58 (d, 1H, J=12 Hz), 4.66 (q, 1H, J=9 Hz), 4.86 (d, 1H, J=12 Hz), 5.03 (d, 1H, J=7.9 Hz), 5.21 (m, 1H), 5.54-5.70 (m, 2H), 7.2-7.8 (m, 10H). washed with cold 7.5% aqueous HCl (2×250 ml), water (250 ml), saturated aqueous NaHCO3 (250 ml) dried (Na2SO4) concentrated The residue obtained was purified by flash chromatography on silica gel eluting with 12.5% EtOAc-hexanes

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-4-methyl-5-nitrobenzoic acid (CAS; 101580-96-5, 15 g, 69.6 mmol) and triethylamine (11.1 mL, 80 mmol) in THF (200 mL) was added 1,1,1-trichloro-2-methylpropan-2-yl carbonochloridate (19.2 g, 80 mmol) at 0° C., and then the mixture was stirred at 0° C. for 1 hr. The resulting white solid was filtered off through Celite®. The solid was washed by THF (20 mL). To the filtrate was added NaBH4 (3.2 g, 83 mmol) at 0° C., followed by H2O (50 mL). The mixture was stirred at 0° C. for 0.5 h, and then stirred at room temperature for 1.25 h. The reaction was quenched by half satd. KHSO4. The layers were separated and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, washed with H2O and brine, dried over Na2SO4, and then filtered through a silica pad. The SiO2 cake was washed with EtOAc. The residue was concentrated and then triturated with heptane. The resulting solid was collected by filtration to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 8.11 (s, 1H), 7.47 (s, 1H), 4.68 (s, 2H), 2.53 (s, 3H). The resulting white solid was filtered off through Celite® The solid was washed by THF (20 mL) The mixture was stirred at 0° C. for 0.5 h stirred at room temperature for 1.25 h The reaction was quenched by half satd The layers were separated the aqueous layer was extracted with CH2Cl2 washed with H2O and brine dried over Na2SO4 filtered through a silica pad The SiO2 cake was washed with EtOAc The residue was concentrated triturated with heptane The resulting solid was collected by filtration

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

Procedure: 4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2,2,2-trichloro-1,1-dimethyl-ethyl ester was prepared according to General Procedure E by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 2,2,2-trichloro-1,1-dimethylethyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.87-1.89 (m, 6H), 2.02-2.08 (m, 4H), 3.00-3.10 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.10-4.16 (m, 2H), 5.05-5.09 (m, 1H), 7.62-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.40 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=576.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (28) (8.5 g, 28.4 mmol) in DMF cooled to 0° C. was added 2,4,6-trimethylpyridine and 2,2,2-trichloro-1,1-dimethylethyl chloroformate in DMF. Then, 6-aminoisoquinoline in DMF was added and the solution stirred for 2 h at 0° C. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The organic layers were washed with H2O, dried (Na2SO4), filtered and evaporated to give crude 29. Column chromatography (30% EtOAc-Hexanes) and recrystallization (EtOAc/Hexanes) gave pure (S)-tert-butyl 2-(4-chlorophenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (29, 7.8 g, 64%, >99% S enantiomer). extracted with EtOAc The organic layers were washed with H2O dried (Na2SO4) filtered evaporated to give crude 29 Column chromatography (30% EtOAc-Hexanes) and recrystallization (EtOAc/Hexanes)

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

Procedure: A solution of compound 7 (10.9 g, 12 mmol) and pyridine (2 ml, 25 mmol) in CH2Cl2 (125 ml) at 0° C. was treated dropwise over 15 min with a solution of 2,2,2-trichloro-1,1-dimethylethyl chloroformate (3.17 g, 13.2 mmol) in CH2Cl2 (25 ml). The reaction mixture was allowed to warm slowly to ambient temperature over 3.5 h. 4-Pyrrolidinopyridine (0.89 g, 6.0 mmol), N,N-diisopropylethylamine (10.5 ml, 60 mmol) and diphenyl chlorophosphate (3.7 ml, 18 mmol) were added sequentially and the resulting mixture was stirred for 5 h at room temperature. The reaction mixture was diluted with CH2Cl2 (500 ml), washed with cold 7.5% aqueous HCl (2×250 ml), water (250 ml), saturated aqueous NaHCO3 (250 ml), dried (Na2SO4), and then concentrated. The residue obtained was purified by flash chromatography on silica gel eluting with 12.5% EtOAc-hexanes to give 15.1 g (95%) of 2-(trimethylsilyl)ethyl 2-deoxy-4-O-diphenylphosphono-3-O-[(R)-3-tetradecanoyloxytetradecanoyl]-6-O-(2,2,2-trichloro-1,1-dimethylethoxycarbonyl)-2-(2,2,2-trichlorethoxycarbonylamino)-β-D-glucopyranoside (compound 8) as a viscous oil: 1H NMR (CDCl3) δ 0.0 (s, 9 H), 0.8-1.0 (m, 8 H), 1.1-1.65 (m, 42 H), 1.83 and 1.90 (2s, 6 H), 2.15-2.45 (m, 4 H), 3.34 (q, 1 H, J=~8 Hz), 3.37 (m, 1 H), 3.81 (m, 1 H), 3.95 (m, 1 H), 4.27 (dd, 1 H, J=12, 5 Hz), 4.34 (d, 1 H, J=12 Hz), 4.58 (d, 1 H, J=12 Hz), 4.66 (q, 1 H, J=~9 Hz), 4.86 (d, 1 H, J=12 Hz), 5.03 (d, 1 H, J=7.9 Hz), 5.21 (m, 1 H), 5.54-5.70 (m, 2 H), 7.2-7.8 (m, 10 H). washed with cold 7.5% aqueous HCl (2×250 ml), water (250 ml), saturated aqueous NaHCO3 (250 ml) dried (Na2SO4) concentrated The residue obtained was purified by flash chromatography on silica gel eluting with 12.5% EtOAc-hexanes