tert-butyl N-(3-aminocyclohexyl)carbamate

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

Procedure: Dissolve racemic 3′, 5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (1.00 eq.) in dichloromethane (5-10 mL) and add 1,1′-carbonyl-diimidazole (1.50 eq.). Stir under argon atmosphere at room temperature and check reaction progress via TLC. Add (3-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.05-2.0 eq.) and continue to stir, checking progress via LC/MS. Once starting material has been fully consumed, dilute reaction with dichloromethane (50 mL) and wash with 1.0 N sodium hydroxide (30 mL) and brine (30 mL). Collect the organic phase, dry over anhydrous magnesium sulfate and concentrate under reduced pressure. Purify via flash chromatography by eluding with gradient of 100% dichloromethane to 10% ammonia methanol/90% dichloromethane to recover {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester. Dissolve the {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester (0.40, 0.65 mmol) in dioxane (20 mL), add 4N hydrochloric acid -dioxane (10 mL) and stir 30 min. Concentrate under vacuum, dilute in dichloromethane (100 mL) and add saturated aqueous sodium bicarbonate (50 mL). Dry the organic phase with magnesium sulfate and concentrate to a foam: MS (m/z): 528 (M+). reaction progress via TLC to stir Once starting material has been fully consumed dilute reaction with dichloromethane (50 mL) wash with 1.0 N sodium hydroxide (30 mL) and brine (30 mL) Collect the organic phase dry over anhydrous magnesium sulfate concentrate under reduced pressure Purify via flash chromatography to recover {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester stir 30 min Concentrate under vacuum dilute in dichloromethane (100 mL) add saturated aqueous sodium bicarbonate (50 mL) Dry the organic phase with magnesium sulfate concentrate to a foam

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

Procedure: Dissolve racemic 3′, 5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (1.00 eq.) in dichloromethane (5-10 mL) and add 1,1′-carbonyl-diimidazole (1.50 eq.). Stir under argon atmosphere at room temperature and check reaction progress via TLC. Add (3-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.05-2.0 eq.) and continue to stir, checking progress via LC/MS. Once starting material has been fully consumed, dilute reaction with dichloromethane (50 mL) and wash with 1.0 N sodium hydroxide (30 mL) and brine (30 mL). Collect the organic phase, dry over anhydrous magnesium sulfate and concentrate under reduced pressure. Purify via flash chromatography by eluding with gradient of 100% dichloromethane to 10% ammonia methanol/90% dichloromethane to recover {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester. Dissolve the {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester (0.40, 0.65 mmol) in dioxane (20 mL), add 4N hydrochloric acid -dioxane (10 mL) and stir 30 min. Concentrate under vacuum, dilute in dichloromethane (100 mL) and add saturated aqueous sodium bicarbonate (50 mL). Dry the organic phase with magnesium sulfate and concentrate to a foam: MS (m/z): 528 (M+). reaction progress via TLC to stir Once starting material has been fully consumed dilute reaction with dichloromethane (50 mL) wash with 1.0 N sodium hydroxide (30 mL) and brine (30 mL) Collect the organic phase dry over anhydrous magnesium sulfate concentrate under reduced pressure Purify via flash chromatography to recover {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester stir 30 min Concentrate under vacuum dilute in dichloromethane (100 mL) add saturated aqueous sodium bicarbonate (50 mL) Dry the organic phase with magnesium sulfate concentrate to a foam

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

Procedure: Dissolve racemic 3′, 5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (1.00 eq.) in dichloromethane (5-10 mL) and add 1,1′-carbonyl-diimidazole (1.50 eq.). Stir under argon atmosphere at room temperature and check reaction progress via TLC. Add (3-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.05-2.0 eq.) and continue to stir, checking progress via LC/MS. Once starting material has been fully consumed, dilute reaction with dichloromethane (50 mL) and wash with 1.0 N sodium hydroxide (30 mL) and brine (30 mL). Collect the organic phase, dry over anhydrous magnesium sulfate and concentrate under reduced pressure. Purify via flash chromatography by eluding with gradient of 100% dichloromethane to 10% ammonia methanol/90% dichloromethane to recover {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester. Dissolve the {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester (0.40, 0.65 mmol) in dioxane (20 mL), add 4N hydrochloric acid -dioxane (10 mL) and stir 30 min. Concentrate under vacuum, dilute in dichloromethane (100 mL) and add saturated aqueous sodium bicarbonate (50 mL). Dry the organic phase with magnesium sulfate and concentrate to a foam: MS (m/z): 528 (M+). reaction progress via TLC to stir Once starting material has been fully consumed dilute reaction with dichloromethane (50 mL) wash with 1.0 N sodium hydroxide (30 mL) and brine (30 mL) Collect the organic phase dry over anhydrous magnesium sulfate concentrate under reduced pressure Purify via flash chromatography to recover {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester stir 30 min Concentrate under vacuum dilute in dichloromethane (100 mL) add saturated aqueous sodium bicarbonate (50 mL) Dry the organic phase with magnesium sulfate concentrate to a foam

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

Procedure: The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using tert-butyl 3-aminocyclohexylcarbamate and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 496 (M+H).

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

Procedure: Dissolve racemic 3′, 5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (1.00 eq.) in dichloromethane (5-10 mL) and add 1,1′-carbonyl-diimidazole (1.50 eq.). Stir under argon atmosphere at room temperature and check reaction progress via TLC. Add (3-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.05-2.0 eq.) and continue to stir, checking progress via LC/MS. Once starting material has been fully consumed, dilute reaction with dichloromethane (50 mL) and wash with 1.0 N sodium hydroxide (30 mL) and brine (30 mL). Collect the organic phase, dry over anhydrous magnesium sulfate and concentrate under reduced pressure. Purify via flash chromatography by eluding with gradient of 100% dichloromethane to 10% ammonia methanol/90% dichloromethane to recover {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester. Dissolve the {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester (0.40, 0.65 mmol) in dioxane (20 mL), add 4N hydrochloric acid -dioxane (10 mL) and stir 30 min. Concentrate under vacuum, dilute in dichloromethane (100 mL) and add saturated aqueous sodium bicarbonate (50 mL). Dry the organic phase with magnesium sulfate and concentrate to a foam: MS (m/z): 528 (M+). reaction progress via TLC to stir Once starting material has been fully consumed dilute reaction with dichloromethane (50 mL) wash with 1.0 N sodium hydroxide (30 mL) and brine (30 mL) Collect the organic phase dry over anhydrous magnesium sulfate concentrate under reduced pressure Purify via flash chromatography to recover {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester stir 30 min Concentrate under vacuum dilute in dichloromethane (100 mL) add saturated aqueous sodium bicarbonate (50 mL) Dry the organic phase with magnesium sulfate concentrate to a foam