Formic Acid → (R)-6,6-Difluoro-5-(2-fluoro-5-pyrimidin-5-yl-phenyl)-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine formate

HRID 331133Notes

Reaction equation

HRID 331133 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[N:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22][CH:21]=1.[C:29](=O)([O-:31])[O-:30].[Cs+].[Cs+].C(O)=O>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:29]([OH:31])=[O:30].[F:15][C:14]1([F:16])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]([C:24]2[CH:25]=[N:20][CH:21]=[N:22][CH:23]=2)[CH:3]=[CH:4][C:5]=1[F:19])[CH3:18]

Participants

8

Reactant 4

HCID 284Formic AcidHCID 10796Cesium carbonateHCID 2795193(Pyrimidin-5-yl)boronic acid2×HCID 58563049(R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine

Product 1

HCID 68380467(R)-6,6-Difluoro-5-(2-fluoro-5-pyrimidin-5-yl-phenyl)-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine formate

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 962WaterSolvent2×HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

A degassed solution of (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (20 mg, 59.3 μmol (intermediate A7.1), pyrimidine-5-boronic acid (8.8 mg, 71.2 μmol), and cesium carbonate (77.3 mg, 237 μmol) in a mixture of dimethoxyethane (1 ml) and water (0.5 ml) was treated in a tube under an argon atmosphere with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS 72287-26-4) (2.2 mg, 3.0 μmol). The tube was sealed and heated to 80° C. for 70 minutes. In order to complete the reaction, pyrimidine-5-boronic acid (2.2 mg, 17.8 μmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (2.2 mg, 3.0 μmol) were added and stirring continued at 80° C. for 10 minutes. For the workup, the reaction mixture was cooled to room temperature and diluted with water (1.5 ml). After addition of formic acid (0.5 ml) the mixture was filtrated and the filtrate purified by preparative HPLC. The (R)-6,6-difluoro-5-(2-fluoro-5-pyrimidin-5-yl-phenyl)-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine was obtained as a light brown amorphous material (n off-white solid (14 mg, 59% yield). MS (ISP): m/z=337.2 [M+H]+.

Workup

  1. customThe tube was sealed
  2. additionwere added
  3. temperatureFor the workup, the reaction mixture was cooled to room temperature
  4. filtrationwas filtrated
  5. customthe filtrate purified by preparative HPLC

Sources & evidence

ORD record
ord-dacbfeec389d49e48cd330c4a0a65a75
Source dataset
uspto-grants-2014_11
Patent number
US08877744B2

Reaction notes

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