N-methylcyclopentanamine

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:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 26 mg (0.26 mmol) N-methyl-cyclopentylamine in 2.5 mL NMP are added 80 mg (0.22 mmol) 2-{4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-N-ethyl-propion-amide (XII.1) and 110 (0.65 mmol) DIPEA. The mixture is stirred at 100° C. for 1 h and at 120° C. for 1 h under microwave irradiation. After that time, the mixture is directly purified by HPLC (XBridge 100; water, 0.3% NH4OH/MeOH) to yield the desired product. After that time, the mixture is directly purified by HPLC (XBridge 100; water, 0.3% NH4OH/MeOH)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2.70 g (7.81 mmol) {4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-acetic acid methyl ester (XII.2) in 20 mL ACN are added 2.64 mL (23.4 mmol) N-methyl-cyclopentylamine. The mixture is stirred for 2 h at 150° C. under microwave irradiation. After that time, the solvent is evaporated, the residue taken up in 60 mL ethanol and 30 mL 1N NaOH are added. The mixture is stirred for 1 h at rt and for 1 h at 40° C. Subsequently, 30 mL 1N HCl are added, the mixture is concentrated in vacuo and extracted with DCM. The organic layer is dried over sodium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silica gel; DCM:EtOH 80:20) to yield the desired product. After that time, the solvent is evaporated 30 mL 1N NaOH are added The mixture is stirred for 1 h at rt and for 1 h at 40° C Subsequently, 30 mL 1N HCl are added the mixture is concentrated in vacuo extracted with DCM The organic layer is dried over sodium sulphate the solvent is evaporated The residue is purified by column chromatography (silica gel; DCM:EtOH 80:20)

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

Procedure: The title compound was prepared from 1,3-dibromobenzene and N-methylcyclopentanamine using a similar procedure to that described for D43. LCMS (A): m/z (M+H)+ 254/256, Cl2H16BrN requires 253/255 (acidic).

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

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea (20 mg, 0.033 mmol), prepared as described in Procedure 3, 4, 5, 6 and 2, in DMSO/THF (0.1 mL/0.1 mL) was added N-methylcyclopentanamine (32 mg, 0.33 mmol). The resulting solution was stirred at 120° C. under microwave irradiation for 1800 sec. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was then washed with H2O, sat. NaCl and dried over Na2SO4. The organic solvent was evaporated under reduced pressure and the resulting residue was purified by prep HPLC (Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-1-methylurea (Example 246) as white lyophillate (13 mg, 65% yield). LCMS: [M+H] 619.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). The reaction mixture was filtered the solid was washed with EtOAc The filtrate was then washed with H2O, sat. NaCl dried over Na2SO4 The organic solvent was evaporated under reduced pressure the resulting residue was purified by prep HPLC (Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm)

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

Procedure: 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[[N-(cyclopentyl)methylamino]sulfonyl]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with N-(cyclopentyl)-methylamine. Yield=15%; MS (ESI+), 567 (M+H)+.

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.051 g, 0.123 mmol) and methylcyclopentylamine (0.050 mL, 0.44 mmol) in 1 mL of N-methyl pyrrolidinone in a sealed tube was stirred at 200° C. for 20 h. Additional methylcyclopentylamine (0.100 mL, 0.88 mmol) was added, and the solution stirred at 200° C. for 3 d. After cooling, the dark orange solution was partitioned between 10 mL of ethyl acetate and 10 mL of a 10% citric acid solution. The organic layer was sequentially washed with three 10 mL portions of water and 10 mL of a sat. aq. NaCl solution, dried over MgSO4, filtered and concentrated to an orange oil. Column chromatography (0-20% EtOAc/hexanes) afforded 0.030 g (58%) of impure 1-[2-(cyclopentyl-methyl-amino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one, which was used without further purification. After cooling the dark orange solution was partitioned between 10 mL of ethyl acetate and 10 mL of a 10% citric acid solution The organic layer was sequentially washed with three 10 mL portions of water and 10 mL of a sat. aq. NaCl solution dried over MgSO4 filtered concentrated to an orange oil