Toluene → HCID 86732230, compound

HRID 930397Notes

Reaction equation

HRID 930397 reaction equation
[NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][N:21]=3)[CH:13]=[C:14]([F:17])[C:15]=2[F:16])([CH2:8][F:9])[N:7]=1.[CH:32]1([C:35]#[CH:36])[CH2:34][CH2:33]1.C1(C)C=CC=CC=1.C(NCC)C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([C:36]#[C:35][CH:32]4[CH2:34][CH2:33]4)=[CH:22][N:21]=3)[CH:13]=[C:14]([F:17])[C:15]=2[F:16])([CH2:8][F:9])[N:7]=1

Participants

8

Reactant 4

HCID 1140TolueneHCID 8021DiethylamineHCID 138823CyclopropylacetyleneHCID 86732231HCID 86732231, compound

Product 1

HCID 86732230HCID 86732230, compoundYield 66.5%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Procedure

To a microwave vial were charged with N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-5-bromopicolinamide (0.144 g, 0.282 mmol, Example 157), cyclopropylacetylene, 70 wt. % solution in toluene (0.061 mL, 0.507 mmol), copper(I) iodide (8.05 mg, 0.042 mmol), tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol), diethylamine (0.175 mL, 1.690 mmol) and DMF (2.0 mL). The vial was purged with N2 for 5 min, and then microwaved at 90° C. for 50 min. LCMS indicated full conversion to the desired product with MS+=497 (M+1). The reaction mixture was partitioned between EtOAc and water. The separated organic layer was concentrated and the resulted residue was purified by Shimadzu HPLC to afford N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-5-(cyclopropylethynyl)picolinamide (0.093 g, 0.187 mmol, 66.5% yield) as light yellow solid. MS m/z=497.1 [M+H]+. Calculated for C23H18F6N4O2: 496.4

Workup

  1. customThe vial was purged with N2 for 5 min
  2. custommicrowaved at 90° C. for 50 min
  3. customThe reaction mixture was partitioned between EtOAc and water
  4. concentrationThe separated organic layer was concentrated
  5. customthe resulted residue was purified by Shimadzu HPLC

Sources & evidence

ORD record
ord-0f172099e9ea4ad7b78dd81c1d434db7
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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