3-methoxydihydro-2H-pyran-4(3H)-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:; 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-methoxytetrahydro-4H-pyran-4-one (59.4 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 CH2C2. 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 (20 mg, 41%). MS calculated for C26H37F3N4O4: (M+H) 527.3; found 527.3. the reaction was quenched with aqueous NaHCO3 diluted with CH2C2 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-isopropyl-3-(4-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine (120 mg, 0.30 mmol), 3-methoxytetrahydro-4H-pyran-4-one (120 mg, 0.90 mmol), and triethylamine (0.12 mL, 0.90 mmol) in methylene chloride (20 mL) was added sodium triacetoxyborohydride (0.19 g, 0.90 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to provide the desired product as a mixture of cis/trans isomers. LCMS calculated for C26H40F3N4O3: (M+H) 513.3; found 513.2 for both isomers. washed with brine dried over sodium sulfate filtered concentrated The residue was purified by flash chromatography

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

Procedure: To a solution of (1R,3S)-3-isopropyl-3-(4-[6-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (110 mg, 0.24 mmol), 3-methoxytetrahydro-4H-pyran-4-one (80 mg, 0.61 mmol), and triethylamine (0.16 mL, 1.2 mmol) in methylene chloride (8 mL) was added sodium triacetoxyborohydride (190 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1) to give 123 mg of desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give isomer 1 (45 mg after converting to TFA salt) and isomer 2 (35 mg after converting to TFA salt). LCMS calculated for C25H37F3N4O3: (M+H) 498.2; found 498.2 for both isomers. the reaction was quenched with saturated NaHCO3 The resulting solution was extracted with EtOAc three times The combined organic layers were dried (MgSO4) concentrated The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1)

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

Procedure: To a solution of (1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine dihydrochloride (135.0 mg, 0.2945 mmol), 3-methoxytetrahydro-4H-pyran-4-one (110 mg, 0.88 mmol) and triethylamine (0.16 mL, 1.2 mmol) in methylene chloride (8 mL) was added sodium triacetoxyborohydride (190 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1) to give 123 mg of desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give isomer 1 (65 mg after converting to TFA salt) and isomer 2 (45 mg after converting to TFA salt). LCMS calculated for C24H36F3N5O3: (M+1) 500; found 500.1 for both isomers. the reaction was quenched with saturated NaHCO3 The resulting solution was extracted with EtOAc three times The combined organic layers were dried (MgSO4) concentrated The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1)

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

Procedure: To a solution of (1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine dihydrochloride (135.0 mg, 0.2945 mmol), 3-methoxytetrahydro-4H-pyran-4-one (110 mg, 0.88 mmol) and triethylamine (0.16 mL, 1.2 mmol) in methylene chloride (8 mL) was added sodium triacetoxyborohydride (190 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1) to give 123 mg of desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give isomer 1 (65 mg after converting to TFA salt) and isomer 2 (45 mg after converting to TFA salt). LCMS calculated for C24H36F3N5O3: (M+1) 500; found 500.1 for both isomers. the reaction was quenched with saturated NaHCO3 The resulting solution was extracted with EtOAc three times The combined organic layers were dried (MgSO4) concentrated The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1)

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

Procedure: To a solution of (1R,3S)-3-isopropyl-3-{[5-(trifluoromethyl)-3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (9.0 mg, 0.024 mmol), 3-methoxytetrahydro-4H-pyran-4-one (12.3 mg, 0.0709 mmol) and triethylamine (6.58 μL, 0.0472 mmol) in dry methylene chloride (2.0 mL) was added sodium triacetoxyborohydride (15.0 mg, 0.0708 mmol). After being stirred at room temperature 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 organic layers were combined, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product (45 mg) was purified by silica gel column (30:70 MeOH/EtOAc) to provide 1.6 mg (14%) of pure product. LC-MS calculated for C26H36F3N3O3: (M+H) 496; found 496.1. 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 evaporated under reduced pressure The crude product (45 mg) was purified by silica gel column (30:70 MeOH/EtOAc)

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

Procedure: To a solution of (1R,3S)-3-isopropyl-3-{[4-(trifluoromethyl)-3′,6′-dihydro-2,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (51.2 mg, 0.134 mmol), 3-methoxytetrahydro-4H-pyran-4-one (70 mg, 0.40 mmol) and triethylamine (0.0374 mL, 0.269 mmol) in dry methylene chloride (5.0 mL, 0.078 mol) was treated with sodium triacetoxyborohydride (85.4 mg, 0.403 mmol) 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 combined extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The crude product (90 mg) was passed through a short silica gel pad (30:70 MeOH/EtOAc). The filtrate was concentrated and separated by chiral HPLC to give two isomers: first isomer 26.3 mg; second isomer: 17.3 mg. LC-MS calculated for C26H36F3N3O3: (M+H) 496; found 496.2 for both isomers. 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 The combined extracts were dried over MgSO4 filtered evaporated under reduced pressure The filtrate was concentrated separated by chiral HPLC to give two isomers