4-METHYLPIPERIDIN-4-OL

A mixture of the Cbz protected piperidine mt 3-1 (1.5 g, 6.02 mmol) and Pd/C (0.3 g) in methanol (30 mL) was degassed under reduce pressure and purged with hydrogen 358times. The reaction mixture was stirred under hydrogen (50 psi) at room temperature overnight. The reaction mixture was filtered through a pad of Celite and the filtrate wasconcentrated under reduce pressure to provide compound mt 3-2 (500 mg, 72percent), which was used for next step without further purification. MS-ES (m/z): 116.3(M+H) .4-methyl-piperidin-4-ol (Intermediate 79b)A solution of Intermediate 79a (5.50 g, 25.6 mmol) in TFA (20 mL) and DCM (40 mL) was stirred at RT for 1 h. The reaction mixture was applied to SCX- 2 cartridges (2 70 g) and washed with MeOH. The product was eluted with 2M NHSynthesis of compound 221.3. To a solution of 221.2 (1.3 g, 6.04 mmol, l .Oeq) in CHTo a stirred solution of 2- (5-amino-2- (furan-2-yl) -7H-pyrazolo [4, 3-e] [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yl) -2-phenylpropanoic acid (100 mg, 0.26 mmol) , HATU (108 mg, 0.28 mmol) and DIEA (100 mg, 0.78 mmol) in THF (15 ml) was added General procedure: Et3N (0.045 mL, 0.320 mmol) and 3-methylbutan-1-amine (0.037 ml, 0.320 mmol) were added to 5-((1, 2, 3, 5, 6, 7-hexahydro-s-indacen-4-yl)amino)-1-((2-(trimethylsilyl)- ethoxy)methyl)-1H-1, 2, 4-triazole-3-sulfonyl chloride (Intermediate B4) (100 mg, 0.213 mmol) in DCM (4 mL) at 0 C. The reaction was stirred for 1 h and concentrated in vacuo. TFA (1 mL) was added and the reaction was stirred at RT for 1 h. The product was purified by basic prep HPLC (5-50% MeCN in water) to afford the title compound (1.8 mg, 2% yield) as a pale white solid.LCMS m/z 390.2 (M+H)+ (ES+); 388.2 (M-H)- (ES-).1H NMR (DMSO-d6) d 8.77 (s, 1H), 7.72 (s, 1H), 6.94 (s, 1H), 2.94 (t, J = 7.4 Hz, 2H), 2.82 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.3 Hz, 4H), 1.97 (p, J = 7.4 Hz, 4H), 1.63 - 1.51 (m, 1H), 1.29 (q, J = 7.2 Hz, 2H), 0.82 (d, J = 6.6 Hz, 6H). One exchangeable proton not observedFormation of 1-[4-[(3S)-4-(2-amino-6-methyl-pyrimidin-4-yl)-1, 4-oxazepan-3-yl]-3-chloro-phenyl]-[0S21] To a stirred solution of 4-(2'-(tert-butyl)-[3, 4'-bipyridin]-5-yl)-3-chlorobenzoic acid (100 mg, 0.4098 mmol) in DMF(1 ml) was added HATU (622.8 mg, 1.639 mmol) and DIPEA (158.8 mg, 1.229 mmol). After stirring for 10 min, To a stirred solution of 2-(chloromethyl)-N-(2, 4-dimethoxybenzyl)imidazo[1, 2- c]quinazolin-5-amine (90 mg, 0.235 mmol) in acetonitrile (2351 mul) was added 4- methylpiperidin-4-ol (54.2 mg, 0.470 mmol) and potassium carbonate (97 mg, 0.705 mmol). The reaction mixture was heated to 80 C with stirring for 4 hrs, then cooled to ambient and filtered. The solvent was evaporated and the residue was redissolved in DCM and washed with NaHCO3 (aq) to give crude product which was used in the next step without purification, LC/MS = 462 [M+1].General procedure: To a round-bottomed flask equipped with a magnetic stir bar wereadded 20c or 20f (1.0 eq), 22a-d or 24a-b (1.2 eq), DIPEA (2.0 eq), and DMA (1.0 M). The reaction vessel was immersed in a 100 C preheatedoil bath for 12 h until the reaction was completed as determinedby TLC. After cooling, the reaction was diluted with water and extractedwith ethyl acetate. The ethyl acetate layer was washed withsaturated brine and dried over anhydrous MgSO4. After filtration andconcentration, the crude product was purified on a silica gel column toafford 25a-j.General procedure: To a round-bottomed flask equipped with a magnetic stir bar wereadded 20c or 20f (1.0 eq), 22a-d or 24a-b (1.2 eq), DIPEA (2.0 eq), and DMA (1.0 M). The reaction vessel was immersed in a 100 C preheatedoil bath for 12 h until the reaction was completed as determinedby TLC. After cooling, the reaction was diluted with water and extractedwith ethyl acetate. The ethyl acetate layer was washed withsaturated brine and dried over anhydrous MgSO4. After filtration andconcentration, the crude product was purified on a silica gel column toafford 25a-j. 4.1.14.1. 4-Hydroxy-4-methyl-N-(3-(4-(methylcarbamoyl)phenoxy)-5-(trifluoromethyl)phenyl)piperidine-1-carboxamide (25a). Coupling of20c (243 mg, 0.5 mmol) with 22a (69 mg, 0.6 mmol) in the presenceof DIPEA afforded 25a (160 mg, 62%), eluted with hexane/ethylacetate (1/5, V/V). White solid, M.P. 103-106 C. 1H NMR (400 MHz, CDCl3) delta 7.91 (d, J=8.8 Hz, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.27 (s, 1H), 7.12 (d, J=8.7 Hz, 2H), 6.98 (s, 1H), 6.61 (s, 1H), 3.79-3.72 (m, 2H), 3.42-3.32 (m, 2H), 3.06 (s, 3H), 1.67-1.61 (m, 4H), 1.31 (s, 3H).13C NMR (101 MHz, DMSO) delta 165.80, 158.15, 156.81, 154.07, 143.60, 130.51 (d, J=32.3 Hz), 130.16, 129.33, 123.79 (d, J=273.7 Hz), 118.42, 112.05, 110.59, 107.92, 66.02, 40.34, 38.21, 29.70, 26.23.HRMS (ESI) m/z [M+Na]+ calcd. for C22H25F3N3O4 452.1792, found452.1787.

Molecular Weight:115.17
XLogP3:-0.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Exact Mass:115.099714038
Monoisotopic Mass:115.099714038
Topological Polar Surface Area:32.3
Heavy Atom Count:8
Complexity:76.6
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes