3-(1,1-dioxo-1,4-thiazinan-4-yl)propan-1-amine

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

Procedure: The title compound was prepared following steps 5 and 6 using methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 4-(3-aminopropyl) thiomorpholine 1,1-dioxide as the reactant amine. The product was isolated as a white solid (50 mg, 55.0%). LCMS: m/e 737.5 (MH+), 2.53 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.85 (d, J=3.8 Hz, 1H), 7.01-7.14 (m, 1H), 6.98 (br. s., 1H), 5.37 (br. s., 1H), 4.78 (br. s., 1H), 4.67 (br. s., 1H), 3.56 (br. s., 4H), 3.43 (br. s., 4H), 3.21 (m, 3H), 3.12 (br. s., 2H), 2.90 (br. s., 1H), 2.53 (br. s., 1H), 2.16 (br. s., 4H), 1.75 (br. s., 10H), 1.53 (br. s., 8H), 1.31 (br. s., 3H), 1.19 (br. s., 5H), 1.10 (br. s., 3H), 1.05 (br. s., 3H), 0.99 (d, J=8.5 Hz, 6H). 19F NMR (376 MHz, MeOD) δ ppm −112.6 (s, 1 F).

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

Procedure: The title compound was prepared following steps 5 and 6 using methyl 3-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 4-(3-aminopropyl) thiomorpholine 1,1-dioxide as the reactant amine. The product was isolated as a white solid (70 mg, 68.0%). LCMS: m/e 737.5 (MH+), 2.59 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.77 (d, J=7.8 Hz, 1H), 7.67 (d, J=9.8 Hz, 1H), 7.19-7.31 (m, 1H), 5.38 (d, J=4.8 Hz, 1H), 4.78 (br. s., 1H), 4.67 (br. s., 1H), 3.41 (br. s., 4H), 3.30-3.38 (m, 4H), 3.27 (d, J=12.5 Hz, 1H), 3.21 (br. s., 2H), 3.00 (t, J=6.4 Hz, 2H), 2.90 (br. s., 1H), 2.53 (br. s., 1H), 2.10 (br. s., 4H), 1.84 (br. s., 3H), 1.75 (br. s., 7H), 1.54 (br. s., 8H), 1.36 (br. s., 3H), 1.20 (br. s., 5H), 1.11 (br. s., 3H), 1.07 (br. s., 3H), 0.98 (br. s., 3H), 0.94 (br. s., 3H). 19F NMR (376 MHz, MeOD) δ ppm −113.31 (s, 1 F).

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

Procedure: The title compound was prepared following steps 5 and 6 using methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 4-(3-aminopropyl) thiomorpholine 1,1-dioxide as the reactant amine. The product was isolated as a white solid (50 mg, 55.0%). LCMS: m/e 737.5 (MH+), 2.53 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.85 (d, J=3.8 Hz, 1H), 7.01-7.14 (m, 1H), 6.98 (br. s., 1H), 5.37 (br. s., 1H), 4.78 (br. s., 1H), 4.67 (br. s., 1H), 3.56 (br. s., 4H), 3.43 (br. s., 4H), 3.21 (m, 3H), 3.12 (br. s., 2H), 2.90 (br. s., 1H), 2.53 (br. s., 1H), 2.16 (br. s., 4H), 1.75 (br. s., 10H), 1.53 (br. s., 8H), 1.31 (br. s., 3H), 1.19 (br. s., 5H), 1.10 (br. s., 3H), 1.05 (br. s., 3H), 0.99 (d, J=8.5 Hz, 6H). 19F NMR (376 MHz, MeOD) δ ppm −112.6 (s, 1 F).

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

Procedure: The title compound was prepared following steps 5 and 6 using methyl 3-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 4-(3-aminopropyl) thiomorpholine 1,1-dioxide as the reactant amine. The product was isolated as a white solid (70 mg, 68.0%). LCMS: m/e 737.5 (MH+), 2.59 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.77 (d, J=7.8 Hz, 1H), 7.67 (d, J=9.8 Hz, 1H), 7.19-7.31 (m, 1H), 5.38 (d, J=4.8 Hz, 1H), 4.78 (br. s., 1H), 4.67 (br. s., 1H), 3.41 (br. s., 4H), 3.30-3.38 (m, 4H), 3.27 (d, J=12.5 Hz, 1H), 3.21 (br. s., 2H), 3.00 (t, J=6.4 Hz, 2H), 2.90 (br. s., 1H), 2.53 (br. s., 1H), 2.10 (br. s., 4H), 1.84 (br. s., 3H), 1.75 (br. s., 7H), 1.54 (br. s., 8H), 1.36 (br. s., 3H), 1.20 (br. s., 5H), 1.11 (br. s., 3H), 1.07 (br. s., 3H), 0.98 (br. s., 3H), 0.94 (br. s., 3H). 19F NMR (376 MHz, MeOD) δ ppm −113.31 (s, 1 F).

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

Procedure: The title compound was prepared following steps 5 and 6 using methyl 3-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 4-(3-aminopropyl) thiomorpholine 1,1-dioxide as the reactant amine. The product was isolated as a white solid (70 mg, 68.0%). LCMS: m/e 737.5 (MH+), 2.59 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.77 (d, J=7.8 Hz, 1H), 7.67 (d, J=9.8 Hz, 1H), 7.19-7.31 (m, 1H), 5.38 (d, J=4.8 Hz, 1H), 4.78 (br. s., 1H), 4.67 (br. s., 1H), 3.41 (br. s., 4H), 3.30-3.38 (m, 4H), 3.27 (d, J=12.5 Hz, 1H), 3.21 (br. s., 2H), 3.00 (t, J=6.4 Hz, 2H), 2.90 (br. s., 1H), 2.53 (br. s., 1H), 2.10 (br. s., 4H), 1.84 (br. s., 3H), 1.75 (br. s., 7H), 1.54 (br. s., 8H), 1.36 (br. s., 3H), 1.20 (br. s., 5H), 1.11 (br. s., 3H), 1.07 (br. s., 3H), 0.98 (br. s., 3H), 0.94 (br. s., 3H). 19F NMR (376 MHz, MeOD) δ ppm −113.31 (s, 1 F).

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

Procedure: To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (100 mg, 0.146 mmol) from Step 3 in DCE (2 mL) was added acetic acid (0.017 mL, 0.291 mmol) and 4-(3-aminopropyl)thiomorpholine 1,1-dioxide (56.0 mg, 0.291 mmol). The mixture was stirred at RT for 2 h, then to the mixture was added sodium triacetoxyborohydride (154 mg, 0.728 mmol) and it was stirred for 24 hours. The mixture was diluted with 7 mL of sat. NaHCO3 and extracted with dichloromethane (3×7 mL). The organic layers were combined and dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified over a silica gel column eluted with mixture of ethyl acetate and hexanes. The fractions containing the expected product were combined to give the title compound as a white solid (90 mg, 71.6% yield). MS: m/e 863.9 (M+H)+, 3.03 min (method 2). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.85 (s, 1H), 5.54-5.43 (m, 1H), 5.14-4.96 (m, 2H), 4.68 (d, J=2.0 Hz, 1H), 4.57 (s, 1H), 3.12-2.90 (m, 9H), 2.83-2.63 (m, 7H), 2.63-2.50 (m, 4H), 2.42 (td, J=11.0, 5.8 Hz, 1H), 2.28-2.17 (m, 1H), 2.13-2.03 (m, 1H), 1.98-1.29 (m, 17H), 1.27-1.18 (m, 16H), 1.13 (s, 3H), 1.09-1.00 (m, 10H), 0.97 (s, 3H), 0.84-0.75 (m, 3H). was stirred for 24 hours extracted with dichloromethane (3×7 mL) dried with Na2SO4 The drying agent was removed by filtration the filtrate was concentrated under reduced pressure The crude product was purified over a silica gel column eluted with mixture of ethyl acetate and hexanes The fractions containing the expected product

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

Procedure: The title compound was prepared following steps 5 and 6 using methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 4-(3-aminopropyl) thiomorpholine 1,1-dioxide as the reactant amine. The product was isolated as a white solid (50 mg, 55.0%). LCMS: m/e 737.5 (MH+), 2.53 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.85 (d, J=3.8 Hz, 1H), 7.01-7.14 (m, 1H), 6.98 (br. s., 1H), 5.37 (br. s., 1H), 4.78 (br. s., 1H), 4.67 (br. s., 1H), 3.56 (br. s., 4H), 3.43 (br. s., 4H), 3.21 (m, 3H), 3.12 (br. s., 2H), 2.90 (br. s., 1H), 2.53 (br. s., 1H), 2.16 (br. s., 4H), 1.75 (br. s., 10H), 1.53 (br. s., 8H), 1.31 (br. s., 3H), 1.19 (br. s., 5H), 1.10 (br. s., 3H), 1.05 (br. s., 3H), 0.99 (d, J=8.5 Hz, 6H). 19F NMR (376 MHz, MeOD) δ ppm −112.6 (s, 1 F).

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

Procedure: The title compound was prepared following steps 5 and 6 using methyl 3-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 4-(3-aminopropyl) thiomorpholine 1,1-dioxide as the reactant amine. The product was isolated as a white solid (70 mg, 68.0%). LCMS: m/e 737.5 (MH+), 2.59 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.77 (d, J=7.8 Hz, 1H), 7.67 (d, J=9.8 Hz, 1H), 7.19-7.31 (m, 1H), 5.38 (d, J=4.8 Hz, 1H), 4.78 (br. s., 1H), 4.67 (br. s., 1H), 3.41 (br. s., 4H), 3.30-3.38 (m, 4H), 3.27 (d, J=12.5 Hz, 1H), 3.21 (br. s., 2H), 3.00 (t, J=6.4 Hz, 2H), 2.90 (br. s., 1H), 2.53 (br. s., 1H), 2.10 (br. s., 4H), 1.84 (br. s., 3H), 1.75 (br. s., 7H), 1.54 (br. s., 8H), 1.36 (br. s., 3H), 1.20 (br. s., 5H), 1.11 (br. s., 3H), 1.07 (br. s., 3H), 0.98 (br. s., 3H), 0.94 (br. s., 3H). 19F NMR (376 MHz, MeOD) δ ppm −113.31 (s, 1 F).