Tetrahydro-3-methyl-4H-pyran-4-one

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:

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: To a solution of (1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (73.8 mg, 0.152 mmol), 3-methyltetrahydro-4H-pyran-4-one (52.1 mg, 0.456 mmol) and triethylamine (0.0848 mL, 0.608 mmol) in dry methylene chloride (4.1 mL) was added sodium triacetoxyborohydride (96.7 mg, 0.456 mmol). After being stirred at room temperature under N2, the reaction was quenched with aqueous NaHCO3 and diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 three times. The organics were combined, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (Combi-Flash system, 0 to 40% MeOH in EtOAc, gradient, 12 gram column) to provide the desired product (9.1 mg, 12%). MS calculated for C26H37F3N4O3: (M+H) 511.3; found 511.3. the reaction was quenched with aqueous NaHCO3 diluted with CH2Cl2 The organic layer was separated the aqueous layer was extracted with CH2Cl2 three times dried over MgSO4 filtered concentrated purified by silica gel chromatography (Combi-Flash system, 0 to 40% MeOH in EtOAc, gradient, 12 gram column)

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

Procedure: To a solution of (1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (73.8 mg, 0.152 mmol), 3-methyltetrahydro-4H-pyran-4-one (52.1 mg, 0.456 mmol) and triethylamine (0.0848 mL, 0.608 mmol) in dry methylene chloride (4.1 mL) was added sodium triacetoxyborohydride (96.7 mg, 0.456 mmol). After being stirred at room temperature under N2, the reaction was quenched with aqueous NaHCO3 and diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 three times. The organics were combined, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (Combi-Flash system, 0 to 40% MeOH in EtOAc, gradient, 12 gram column) to provide the desired product (9.1 mg, 12%). MS calculated for C26H37F3N4O3: (M+H) 511.3; found 511.3. the reaction was quenched with aqueous NaHCO3 diluted with CH2Cl2 The organic layer was separated the aqueous layer was extracted with CH2Cl2 three times dried over MgSO4 filtered concentrated purified by silica gel chromatography (Combi-Flash system, 0 to 40% MeOH in EtOAc, gradient, 12 gram column)

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

Procedure: To a solution of (1R,3S)-3-(ethoxymethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (100.0 mg, 0.211 mmol), 3-methyltetrahydro-4H-pyran-4-one (72.3 mg, 0.634 mmol) and triethylamine (0.118 mL, 0.845 mmol) in dry methylene chloride (5 mL) was added sodium triacetoxyborohydride (134.3 mg, 0.634 mmol). After being stirred at room temperature under N2 overnight, the reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The organics were combined, dried over MgSO4, filtered, purified by silica gel Combi-Flash system (gradient, 0 to 40% MeOH in EtOAc, 12 gram column) to give the desired product (34 mg, 34%). MS calculated for C25H37F3N4O3: (M+H) 499.3; found 499.3. the reaction was quenched with aqueous NaHCO3 diluted with methylene chloride The organic layer was separated the aqueous layer was extracted with methylene chloride three times dried over MgSO4 filtered purified by silica gel Combi-Flash system (gradient, 0 to 40% MeOH in EtOAc, 12 gram column)

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

Procedure: To a solution of (1R,3S)-3-(ethoxymethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (100.0 mg, 0.211 mmol), 3-methyltetrahydro-4H-pyran-4-one (72.3 mg, 0.634 mmol) and triethylamine (0.118 mL, 0.845 mmol) in dry methylene chloride (5 mL) was added sodium triacetoxyborohydride (134.3 mg, 0.634 mmol). After being stirred at room temperature under N2 overnight, the reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The organics were combined, dried over MgSO4, filtered, purified by silica gel Combi-Flash system (gradient, 0 to 40% MeOH in EtOAc, 12 gram column) to give the desired product (34 mg, 34%). MS calculated for C25H37F3N4O3: (M+H) 499.3; found 499.3. the reaction was quenched with aqueous NaHCO3 diluted with methylene chloride The organic layer was separated the aqueous layer was extracted with methylene chloride three times dried over MgSO4 filtered purified by silica gel Combi-Flash system (gradient, 0 to 40% MeOH in EtOAc, 12 gram column)

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

Procedure: To a solution of (1S,3S)-3-ethyl-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (100 mg, 0.20 mmol), 3-methyltetrahydro-4H-pyran-4-one (96 mg, 0.71 mmol), and triethylamine (0.11 mL, 0.79 mmol) in methylene chloride (3 mL) was added sodium triacetoxyborohydride (96 mg, 0.45 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3 and extracted with methylene chloride three times. The combined organics were dried (MgSO4), filtered, concentrated, purified by flash column chromatography (NH4OH/MeOH/EtOAc) to yield the desired product (38 mg, 40%). MS calculated for C24H35F3N4O2: (M+H) 469.3; found 469.3. the reaction was quenched with saturated NaHCO3 extracted with methylene chloride three times The combined organics were dried (MgSO4) filtered concentrated purified by flash column chromatography (NH4OH/MeOH/EtOAc)