Piperidine derivatives as melanocortin-4 receptor agonists

Step A: Preparation of 1-(2-hydroxy-4,5-dimethylphenyl)propan-1-one (82)

[0647] A solution of n-butyllithium (134 mL of a 2.5 M solution in hexanes, 335 mmol) was added dropwise via syringe to a stirred solution of diisopropylamine (51.3 mL, 365 mmol) in THF (100 mL) at −78° C. After approximately 5 min, the reaction mixture was warmed to 0 IC and aged for another 5 min. After recooling to −78° C., a solution of the ketone 81 (25.0 g, 152 mmol) in THF (100 mL) was added dropwise via syringe and the resulting mixture was stirred at −78° C. for approximately 45 min. Iodomethane (47.5 mL, 762 mmol) was added and the solution allowed to warm to ambient temperature and stir overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride, then poured into saturated aqueous ammonium chloride and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo. Purification of the crude

Step A: Preparation of tert-butyl 4-{2-[(1R)-1-hydroxypropyl]-4,5-dimethylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (109)

[0655] Sodium borohydride (798 mg, 21.1 mmol) was added to a stirred solution of ketone 84 (6.58 g, 19.18 mmol) in THE / methanol (9:1, 100 mL) at −10° C. After 5 h, the reaction was quenched with water, poured into saturated aqueous sodium bicarbonate, and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo. Purification of the crude residue by plug filtration through silica gel eluting with 50:50 hexanes / EtOAc afforded racemic 109 as a colorless oil. The racemic title compound was resolved into its enantiomeric components using preparative chiral HPLC on CHIRACEL OD Phase (5% isopropanol / heptane as eluent) to give in order of elution: tert-butyl 4-{2-[(1S)-1-hydroxypropyl]4,5-dimethylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate as a colorless foam followed

Step A: Preparation of {(1S)-1-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5-chlorophenyl]ethyl}amine (127)

[0663] Compound 127 can be prepared from 1-(5-chloro-2-hydroxyphenyl)ethanone (126) following the procedures described in Schemes 3 and 4.

Step B: Preparation of (N-{(1S)-1-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}piperidin-4yl)-5-chlorophenyl]ethyl}-L-histidinamide trifluoroacetate (128)

[0664] DIEA (36.2 μL, 0.208 mmol), N,1-bis(tert-butoxycarbonyl)-L-histidine (29.6 mg, 0.085 mmol), HOAt (14.2 mg, 0.104 mmol) and HATU (39.6 mg, 0.104 mmol) were added to a solution of 127 (325 mg, 0.645 mmol) in DMF. After approximately 18 h, the reaction mixture was poured into water and extracted three times with DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo. The crude residue was treated with a saturated solution of HCl in EtOAc for 2