N,N'-Dimethylethylenediamine → N-[3-[(3R)-5-Amino-3-(difluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-5-cyano-3-methyl-2-pyridinecarboxamide

HRID 2196360Notes

Reaction equation

HRID 2196360 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH:15]([F:17])[F:16])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.[C:19]([C:21]1[CH:22]=[C:23]([CH3:30])[C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=1)#[N:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[NH2:14][C:10]1[CH2:11][O:12][CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:29][C:27]([C:24]3[C:23]([CH3:30])=[CH:22][C:21]([C:19]#[N:20])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH:15]([F:17])[F:16])[N:9]=1

Participants

7

Reactant 4

HCID 8070N,N'-DimethylethylenediamineHCID 62657Potassium Phosphate, TribasicHCID 66665548(R)-5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamineHCID 666659355-Cyano-3-methyl-2-pyridinecarboxamide

Product 1

HCID 58118873N-[3-[(3R)-5-Amino-3-(difluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-5-cyano-3-methyl-2-pyridinecarboxamideYield 48.1%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
23 °C

Procedure

50 mg of (R)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine, 30 mg of 5-cyano-3-methyl-pyridine-2-carboxylic acid amide, 3.0 mg CuI and 65 mg K3PO4 was charged to the reactor under N2 atomosphere. 1.0 ml of dioxane was added. Followed by 3.0 mg of N1,N2-dimethylethane-1,2-diamine. The resulting reaction mixture was heated to reflux and hold for 23 h. Cooled down to 23° C. then dilute with 15 ml IPAc. The organic phase was washed with water (5 ml×2), concentrated to dry under reduced pressure, Purification via column chromatography on silica gel (IPAc-Heptane 2:1 to 3:1) gave 30 mg of white solid. ESIMS: [M+H]+=403.9, 1H NMR (400 MHz, DMSO-d6): 10.72 (s, 1H), 8.96 (s, 1H), 8.38 (s, 1H), 7.99 (dd, 1H), 7.81 (m, 1H), 7.18 (d, 1H), 6.17 (br s, 2H), 6.15 (t, 1H), 3.98 (m, 4H), 2.53 (s, 3H).

Workup

  1. customThe resulting reaction mixture
  2. temperaturewas heated
  3. temperatureto reflux
  4. additionthen dilute with 15 ml IPAc
  5. washThe organic phase was washed with water (5 ml×2)
  6. concentrationconcentrated
  7. customto dry under reduced pressure, Purification via column chromatography on silica gel (IPAc-Heptane 2:1 to 3:1)

Sources & evidence

ORD record
ord-1c77340c63914aceb0ae76365983ed13
Source dataset
uspto-grants-2012_12
Patent number
US08338413B1

Reaction notes

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