2,2,2-trifluoroethyl formate

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

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

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

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

Procedure: A solution (0.1 M) of methyl(7R)-7-[(2-aminoethyl)(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in THF was treated dropwise with 2,2,2-trifluoroethyl formate (1.5 eq.) and stirred overnight at RT. The volatiles were removed in vacuo and the residue dissolved (0.1 M) in THF and treated dropwise with BH3-DMS complex (2M in THF; 5 eq.). The resulting solution was stirred at RT for 3 h. The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) and the resulting solution heated to dryness. The residue was then partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by FC (EtOAc/MeOH 99.5:0.5+1% NEt3) to afford the product (40%). (ES+) m/z 476 (M+H)+. The volatiles were removed in vacuo the residue dissolved (0.1 M) in THF The resulting solution was stirred at RT for 3 h The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) the resulting solution heated to dryness The residue was then partitioned between sat. aq. NaHCO3 and EtOAc The combined organics were washed with brine dried (Na2SO4) filtered concentrated in vacuo The crude was purified by FC (EtOAc/MeOH 99.5:0.5+1% NEt3)

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

Procedure: A solution of methyl(7R)-7-[(3-aminopropyl)(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.16 M) in THF was treated dropwise with 2,2,2-trifluoroethyl formate (1.3 eq.) and stirred overnight at RT. The volatiles were removed in vacuo and the residue dissolved (0.08 M) in THF and treated dropwise with BH3-DMS complex (2 M in THF; 10 eq.). The resulting solution was stirred at RT for 3 h. The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) and the resulting solution refluxed for 2 h. The volatiles were then removed in vacuo and the residue partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (EtOAc/MeOH/Et3N 90:8:2) affording the product as a pale orange solid (80% overall for steps 2, 3, 4, 5). (ES) m/z 490 (M+H)+. The volatiles were removed in vacuo the residue dissolved (0.08 M) in THF The resulting solution was stirred at RT for 3 h The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) the resulting solution refluxed for 2 h The volatiles were then removed in vacuo the residue partitioned between sat. aq. NaHCO3 and EtOAc The combined organics were washed with brine dried (Na2SO4) filtered concentrated in vacuo The crude material was purified by FC (EtOAc/MeOH/Et3N 90:8:2)

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

Procedure: (1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide was prepared by the procedure of Example 7 from N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide (1.6 g, 3.6 mmol) and 2,2,2-trifluoroethyl formate (5 g, 39 mmol) in THF (20 mL) to give a white solid (0.7 g, 41% yield): mp: 81-83° C. 1H NMR (DMSO-d6) δ 1.18 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 2.34-2.38 (m, 2H, CH2), 2.56-2.65 (m, 1H, CH), 3.39-3.51 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.96-4.05 (m, 2H, CH2), 4.16 (d, J=17 Hz, 1H, NCHH), 4.55 (d, J=17 Hz, 1H, NCHH), 5.25-5.29 (m, 1H, NCH), 6.93-6.97 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H, CH), 8.25 (s, 0.5H, CH), 8.28 (d, J=8 Hz, 1H, Ar), 9.63 (s, 0.5H, OH), 10.07 (s, 0.5H, OH), 10.47 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.69, 19.16, 19.21, 28.39, 28.60, 35.94, 43.35, 45.92, 46.26, 46.73, 51.17, 51.92, 55.44, 63.78, 111.97, 112.34, 116.55, 117.54, 117.58, 119.68, 131.54, 132.16, 151.12, 142.28, 147.94, 148.53, 157.36, 161.80, 168.37, 168.53, 174.93; Anal Calcd for C25H31N3O6+0.4 H2O: C, 62.98; H, 6.72; N, 8.81; H2O, 1.51. Found: C, 62.96; H, 6.80; N, 8.84; H2O, 1.48.

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

Procedure: (1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide was prepared by the procedure of Example 7 from N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide (1.6 g, 3.6 mmol) and 2,2,2-trifluoroethyl formate (5 g, 39 mmol) in THF (20 mL) to give a white solid (0.7 g, 41% yield): mp: 81-83° C. 1H NMR (DMSO-d6) δ 1.18 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 2.34-2.38 (m, 2H, CH2), 2.56-2.65 (m, 1H, CH), 3.39-3.51 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.96-4.05 (m, 2H, CH2), 4.16 (d, J=17 Hz, 1H, NCHH), 4.55 (d, J=17 Hz, 1H, NCHH), 5.25-5.29 (m, 1H, NCH), 6.93-6.97 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H, CH), 8.25 (s, 0.5H, CH), 8.28 (d, J=8 Hz, 1H, Ar), 9.63 (s, 0.5H, OH), 10.07 (s, 0.5H, OH), 10.47 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.69, 19.16, 19.21, 28.39, 28.60, 35.94, 43.35, 45.92, 46.26, 46.73, 51.17, 51.92, 55.44, 63.78, 111.97, 112.34, 116.55, 117.54, 117.58, 119.68, 131.54, 132.16, 151.12, 142.28, 147.94, 148.53, 157.36, 161.80, 168.37, 168.53, 174.93; Anal Calcd for C25H31N3O6+0.4 H2O: C, 62.98; H, 6.72; N, 8.81; H2O, 1.51. Found: C, 62.96; H, 6.80; N, 8.84; H2O, 1.48.

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

Procedure: (1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide was prepared by the procedure of Example 7 from N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (0.7 g, 1.7 mmol) and 2,2,2-trifluoroethyl formate (2.2 g, 17 mmol) in THF (10 mL) to give a white solid (480 mg, 64% yield): mp: 79-81° C. 1H NMR (DMSO-d6) δ 1.31 (t, J=7 Hz, 3H, CH3), 1.99 (s, 3H, CH3), 2.32-2.42 (m, 2H, CH2), 3.40-3.52 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.98-4.02 (m, 2H, CH2), 4.14 (d, J=17 Hz, 1H, NCHH), 4.54 (d, J=17 Hz, 1H, NCHH), 5.23-5.28 (m, 1H, NCH), 6.92-6.96 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H, CH), 8.24-8.27 (m, 1.5H, Ar, CH), 9.64 (s, 0.5H, OH), 10.07 (s, 0.5H, OH), 10.30 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.70, 24.50, 28.34, 28.52, 43.39, 45.81, 46.19, 46.74, 51.14, 51.92, 55.45, 63.81, 111.97, 112.39, 116.63, 117.39, 119.66, 131.60, 132.70, 137.02, 142.21, 142.30, 147.96, 148.54, 157.35, 168.21, 168.38, 168.51; Anal Calcd for C23H27N3O6+0.4 H2O: C, 61.57; H, 6.25; N, 9.36; H2O, 1.61. Found: C, 61.77; H, 6.18; N, 8.97; H2O, 0.55.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Lithium hexamethyldisilazide (12.93 ml, 12.93 mmol) was added to diethyl ether (20 mL) at −78° C. (R)-2-tert-butyl 8a-methyl 6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate (WO2005087769) (1.0 g, 3.23 mmol) in ether (5 mL) was added followed by the addition of 2,2,2-trifluoroethyl formate (2.51 ml, 25.9 mmol) after 20 minutes. The reaction was stirred at −78° C. for 2 hours then allowed to slowly warm to room temperature. 1M hydrochloric acid (8 mL) was added, followed by water (10 mL) and ethyl acetate (10 mL). The organic phase was separated, washed with brine, dried (magnesium sulfate) and solvent removed to give (R,Z)-2-tert-butyl 8a-methyl 7-(hydroxymethylene)-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate (1.09 g) as a yellow oil. LCMS (Method F, ES-API): RT 1.99 min, m-H=336. was added to slowly warm to room temperature The organic phase was separated washed with brine dried (magnesium sulfate) and solvent removed

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Lithium hexamethyldisilazide (12.93 ml, 12.93 mmol) was added to diethyl ether (20 mL) at −78° C. (R)-2-tert-butyl 8a-methyl 6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate (WO2005087769) (1.0 g, 3.23 mmol) in ether (5 mL) was added followed by the addition of 2,2,2-trifluoroethyl formate (2.51 ml, 25.9 mmol) after 20 minutes. The reaction was stirred at −78° C. for 2 hours then allowed to slowly warm to room temperature. 1M hydrochloric acid (8 mL) was added, followed by water (10 mL) and ethyl acetate (10 mL). The organic phase was separated, washed with brine, dried (magnesium sulfate) and solvent removed to give (R,Z)-2-tert-butyl 8a-methyl 7-(hydroxymethylene)-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate (1.09 g) as a yellow oil. LCMS (Method F, ES-API): RT 1.99 min, m-H=336. was added to slowly warm to room temperature The organic phase was separated washed with brine dried (magnesium sulfate) and solvent removed

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

Procedure: (1R)—N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide was prepared by the procedure of Example 7 from N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide (1.6 g, 3.6 mmol) and 2,2,2-trifluoroethyl formate (5 g, 39 mmol) in THF (20 mL) to give a white solid (0.7 g, 41% yield): mp: 81-83° C. 1H NMR (DMSO-d6) δ 1.18 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 2.34-2.38 (m, 2H, CH2), 2.56-2.65 (m, 1H, CH), 3.39-3.51 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.96-4.05 (m, 2H, CH2), 4.16 (d, J=17 Hz, 1H, NCHH), 4.55 (d, J=17 Hz, 1H, NCHH), 5.25-5.29 (m, 1H, NCH), 6.93-6.97 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H, CH), 8.25 (s, 0.5H, CH), 8.28 (d, J=8 Hz, 1H, Ar), 9.63 (s, 0.5H, OH), 10.07 (s, 0.5H, OH), 10.47 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.69, 19.16, 19.21, 28.39, 28.60, 35.94, 43.35, 45.92, 46.26, 46.73, 51.17, 51.92, 55.44, 63.78, 111.97, 112.34, 116.55, 117.54, 117.58, 119.68, 131.54, 132.16, 151.12, 142.28, 147.94, 148.53, 157.36, 161.80, 168.37, 168.53, 174.93; Anal Calcd for C25H31N3O6+0.4 H2O: C, 62.98; H, 6.72; N, 8.81; H2O, 1.51. Found: C, 62.96; H, 6.80; N, 8.84; H2O, 1.48.

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

Procedure: (1R)—N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide was prepared by the procedure of Example 7 from N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (0.7 g, 1.7 mmol) and 2,2,2-trifluoroethyl formate (2.2 g, 17 mmol) in THF (10 mL) to give a white solid (480 mg, 64% yield): mp: 79-81° C. 1H NMR (DMSO-d6) δ 1.31 (t, J=7 Hz, 3H, CH3), 1.99 (s, 3H, CH3), 2.32-2.42 (m, 2H, CH2), 3.40-3.52 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.98-4.02 (m, 2H, CH2), 4.14 (d, J=17 Hz, 1H, NCHH), 4.54 (d, J=17 Hz, 1H, NCHH), 5.23-5.28 (m, 1H, NCH), 6.92-6.96 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H, CH), 8.24-8.27 (m, 1.5H, Ar, CH), 9.64 (s, 0.5H, OH), 10.07 (s, 0.5H, OH), 10.30 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.70, 24.50, 28.34, 28.52, 43.39, 45.81, 46.19, 46.74, 51.14, 51.92, 55.45, 63.81, 111.97, 112.39, 116.63, 117.39, 119.66, 131.60, 132.70, 137.02, 142.21, 142.30, 147.96, 148.54, 157.35, 168.21, 168.38, 168.51; Anal Calcd for C23H27N3O6+0.4 H2O: C, 61.57; H, 6.25; N, 9.36; H2O, 1.61. Found: C, 61.77; H, 6.18; N, 8.97; H2O, 0.55.