Hydrochloric Acid → 6-(2-Hydroxypropan-2-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 629109Notes

Reaction equation

Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.C([O:48][C:49]([C:51]1C(C2C=NC=NC=2)=CC(C(NC2C=CC(OC(F)(F)F)=CC=2)=O)=CN=1)=[CH2:50])C.Cl.C([O-])([O-])=O.[Na+].[Na+].C(C1C(C2C=NC=NC=2)=CC(C(NC2C=CC(OC(F)(F)F)=CC=2)=O)=CN=1)(=O)C.C[Mg+].[Br-].C1COCC1.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[OH:48][C:49]([C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1)([CH3:51])[CH3:50]

Participants

Conditions

Temperature: 110 °C

Procedure

6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 56, 100 mg, 0.253 mmol), tributyl(1-ethoxyvinyl)stannane (0.103 mL, 0.304 mmol), Pd(Ph3P)4 (29.3 mg, 0.025 mmol) and dioxane (1 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 110° C. for 2 h. The solvent was evaporated off under reduced the crude 6-(1-ethoxyvinyl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (100 mg, 0.232 mmol) was treated with 4 M HCl in dioxane (2 mL, 8.00 mmol), stirred at RT for 2 h and then treated with excess aq. Na2CO3 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 24 g, EtOAc/n-hexane from 50% to 70% EtOAc). The 6-acetyl-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (25 mg, 0.062 mmol) was dissolved in DCM (3 mL), cooled to −60° C. and treated dropwise with a solution of MeMgBr 1.4 M in THF/toluene (1:3) (0.089 mL, 0.124 mmol) at The RM was stirred for 1.5 h at −60° C., then treated with a sat. aq. NH4Cl solution and extracted with DCM. The combined extracts were dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative SFC (Column NH2; gradient 12% to 17% in 6 min.) and lyophilized in water/MeCN to afford the title compound. UPLC-MS (Condition 2) tR 0.79-0.94 min, m/z=419.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.49 (s, 6H) 5.02 (br. s, 1H) 7.39 (d, J=8.40 Hz, 2H) 7.87 (d, J=9.10 Hz, 2H) 8.11 (d, J=2.19 Hz, 1H) 8.77 (s, 2H) 9.09 (d, J=2.20 Hz, 1H) 9.13 (s, 1H) 10.55 (s, 1H).

Workup

customwas sealed
customevacuated/purged with argon
customThe solvent was evaporated off
stirringstirred at RT for 2 h
customthe solvent was evaporated off under reduced pressure
customto give a residue which
customwas purified by flash chromatography (RediSep® Silica gel column, 24 g, EtOAc/n-hexane from 50% to 70% EtOAc)
temperaturecooled to −60° C.
stirringwas stirred for 1.5 h at −60° C.
extractionextracted with DCM
dry with materialThe combined extracts were dried over MgSO4
customthe solvent was evaporated off under reduced pressure
customto give the crude product which
customwas purified by preparative SFC (Column NH2; gradient 12% to 17% in 6 min.)

Sources & evidence

ORD record: ord-21662d908c964c0cb86d4180e9329072
Source dataset: uspto-grants-2016_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09315489B2

Reaction notes

Loading…