Potassium Phosphate, Tribasic → HCID 89907205, compound

HRID 924159Notes

Reaction equation

HRID 924159 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B(O)O)=[CH:32][N:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:33]3[C:34]([O:36][CH3:37])=[N:35][C:30]([O:29][CH3:28])=[N:31][CH:32]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1

Participants

4

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 2736209(2,4-Dimethoxypyrimidin-5-yl)boronic acidHCID 72545856(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Product 1

HCID 89907205HCID 89907205, compound

Conditions

Temperature
120 °C

Procedure

(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1, 150 mg, 0.324 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (71.6 mg, 0.389 mmol), PdCl2(dppf)-(CH2Cl2) (39.7 mg, 0.049 mmol) and K3PO4 (206 mg, 0.973 mmol) were added to a vial and flushed with argon. Dioxane (1.5 mL) was added and the mixture was stirred at 120° C. overnight. The solvent was evaporated off under reduced pressure, the residue was treated with Si-Thiol (Biotage, load: 1.3 mmol/g) in MeOH and purified by preparative SFC (Column DEAP, from 18% to 23% in 6 min) to afford the title compound as an off-white powder after lyophilization from water/MeCN. UPLC-MS (Condition 11), tR=1.05 min, m/z=522.3/524.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.92 (m, 2H) 2.89-3.43 (m, 4H) 3.91 (br. s, 3H) 3.95 (s, 3H) 4.21 (br. s, 1H) 4.74-5.00 (m, 1H) 7.33 (d, J=8.91 Hz, 2H) 7.83-7.90 (m, 3H) 8.32 (br. s, 1H) 8.74 (d, J=2.26 Hz, 1H) 10.11 (s, 1H).

Workup

  1. customflushed with argon
  2. additionDioxane (1.5 mL) was added
  3. customThe solvent was evaporated off under reduced pressure
  4. additionthe residue was treated with Si-Thiol (Biotage, load: 1.3 mmol/g) in MeOH
  5. custompurified by preparative SFC (Column DEAP, from 18% to 23% in 6 min)

Sources & evidence

ORD record
ord-9c67851c5a5e4215826dc6bdfbfd26e1
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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