1,1,3,3-Tetramethylguanidine → (R)-5,5-difluoro-4-[5-fluoro-2-(4-methoxy-benzyl)-1H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine

HRID 1626141Notes

Reaction equation

HRID 1626141 reaction equation
[NH2:1][C:2]1[C:3](I)=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.CN(C)C(N(C)C)=N.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]#[CH:38])=[CH:32][CH:31]=1>CN(C)C=O.C(=O)([O-])O.[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:14][C:13]1([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]2[C:3]([CH:38]=[C:37]([CH2:36][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)[NH:1]2)=[CH:4][C:5]=1[F:18])[CH3:17]

Participants

8

Reactant 3

HCID 664601,1,3,3-TetramethylguanidineHCID 107731151-Methoxy-4-(prop-2-yn-1-yl)benzeneHCID 58304250HCID 58304250, compound

Product 1

HCID 71009041(R)-5,5-difluoro-4-[5-fluoro-2-(4-methoxy-benzyl)-1H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamineYield 33.4%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 6228DimethylformamideSolvent2×HCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
80 °C

Procedure

A solution of (R)-4-(5-amino-2-fluoro-4-iodo-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate B6.1) (100 mg, 260 μmol) N,N-dimethylformamide (0.5 ml) was purged with argon for 10 minutes. Thereafter, 1,1,3,3-tetramethylguanidine (74.8 mg, 81.3 μl, 649 μmol), bis-(triphenylphosphin)-palladium(II)dichlorid (9.11 mg, 13.0 μmol) and copper (I) iodide (7.42 mg, 38.9 μmol) were added. After 5 minutes at room temperature, a solution of 1-methoxy-4-prop-2-ynyl-benzene (CAS [13540-76-6]) (45.5 mg, 312 μmol) in N,N-dimethylformamide (0.2 ml) was added and the reaction mixture was stirred at 80° C. for 15 hours. For the workup, the reaction mixture was allowed to cool to room temperature, then it was diluted with a saturated solution of sodium hydrogencarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The crude product was purified by flash chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (R)-5,5-difluoro-4-[5-fluoro-2-(4-methoxy-benzyl)-1H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (35 mg, 33% yield) was obtained as a light green foam. MS (ISP): m/z=404.4 [M+H]+.

Workup

  1. temperatureto cool to room temperature
  2. extractionextracted with ethyl acetate
  3. dry with materialThe combined organic layers were dried over sodium sulphate
  4. customevaporated at reduced pressure
  5. customThe crude product was purified by flash chromatography on a silica-NH2 phase

Sources & evidence

ORD record
ord-fab20a470adc4b4b836413d3433a9f8d
Source dataset
uspto-grants-2014_07
Patent number
US08785436B2

Reaction notes

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