Potassium Carbonate → Tert-butyl (3-(4-fluoro-5-(3-(3-fluoro-3-methylbutyl)ureido)-2-methylphenyl)-2-methyl-1,6-naphthyridin-7-yl)carbamate

HRID 715139Notes

Reaction equation

HRID 715139 reaction equation
Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[C:14]([CH3:30])=[CH:15][C:16]([F:29])=[C:17]([NH:19][C:20]([NH:22][CH2:23][CH2:24][C:25]([F:28])([CH3:27])[CH3:26])=[O:21])[CH:18]=3)[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=1.C([NH:35][C:36](=[O:38])[O-:37])(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH3:45][C:46]1(C)[C:72]2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=C[C:47]1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:29][C:16]1[C:17]([NH:19][C:20]([NH:22][CH2:23][CH2:24][C:25]([F:28])([CH3:27])[CH3:26])=[O:21])=[CH:18][C:13]([C:7]2[C:8]([CH3:12])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([NH:35][C:36](=[O:38])[O:37][C:46]([CH3:72])([CH3:47])[CH3:45])[CH:11]=3)=[C:14]([CH3:30])[CH:15]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 21252905Tert-butylcarbamateHCID 898158151-(5-(7-Chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-fluoro-3-methylbutyl)urea

Product 1

HCID 89814429Tert-butyl (3-(4-fluoro-5-(3-(3-fluoro-3-methylbutyl)ureido)-2-methylphenyl)-2-methyl-1,6-naphthyridin-7-yl)carbamateYield 604.6%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
95 °C

Procedure

Combine 1-(5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-fluoro-3-methylbutyl)urea (8.1 g, 18.71 mmol), t-butylcarbamate (6.58 g, 56.1 mmol), potassium carbonate (7.76 g, 56.1 mmol), palladium (II) acetate (0.420 g, 1.871 mmol), and Xantphos (1.083 g, 1.871 mmol) in dioxane (100 mL). Sparge the mixture with argon and sonication for 10 min, then heat at 95° C. overnight. Dilute with EtOAc (100 mL), filter through diatomaceous earth, and wash the filter cake with EtOAc. Evaporate the filtrate and purify by silica gel chromatography (hexane/EtOAc) to yield the title compound (5.81 g, 60.5%). Dissolve the title compound (5.81 g, 11.31 mmol) in THF (100 mL), treat with Si-Thiol (Pd Scavenger) (1.3 mM/g, 9.4 mmol) and stir overnight at RT. Remove the solids via filtration, concentrate the filtrate and dry under high vacuum to afford the title compound (5.81 g, 100%). 1H NMR (400 MHz, DMSO-d6): δ 10.02 (s, 1H); 9.06 (d, J=0.8 Hz, 1H); 8.37 (s, 1H); 8.13 (d, J=24.9 Hz, 2H); 7.96 (d, J=8.5 Hz, 1H); 7.20 (d, J=12.3 Hz, 1H); 6.57 (t, J=5.7 Hz, 1H); 3.11-3.18 (m, 2H); 2.36 (s, 3H); 1.95 (s, 3H); 1.74 (dt, J=19.9, 7.5 Hz, 2H); 1.50 (s, 9H); 1.29 (d, J=22 Hz, 6H; MS (ESI) m/z: 514.3 (M+H+).

Workup

  1. customSparge the mixture
  2. customwith argon and sonication for 10 min
  3. additionDilute with EtOAc (100 mL)
  4. filtrationfilter through diatomaceous earth
  5. washwash the filter cake with EtOAc
  6. customEvaporate the filtrate
  7. custompurify by silica gel chromatography (hexane/EtOAc)

Sources & evidence

ORD record
ord-7c98af563dd44c37a3f69ea7151a2138
Source dataset
uspto-grants-2015_11
Patent number
US09187474B2

Reaction notes

Loading…