Toluene → HCID 86732128, compound

HRID 930297Notes

Reaction equation

HRID 930297 reaction equation
[NH2:1][C:2]1[O:3][C@H:4]([C:27]([F:30])([F:29])[F:28])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=3)[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1.C(NCC)C.[CH:36]1([C:39]#[CH:40])[CH2:38][CH2:37]1.C1(C)C=CC=CC=1>CN(C=O)C.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.[Cu]I>[NH2:1][C:2]1[O:3][C@H:4]([C:27]([F:30])([F:29])[F:28])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([C:40]#[C:39][CH:36]4[CH2:38][CH2:37]4)=[CH:21][N:20]=3)[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1

Participants

8

Reactant 4

HCID 1140TolueneHCID 8021DiethylamineHCID 138823CyclopropylacetyleneHCID 78322077HCID 78322077, compound

Product 1

HCID 86732128HCID 86732128, compound

Reagents, catalysts & solvents 3

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

Procedure

N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-bromopicolinamide (Example 52) was transferred to a microwave vial followed by the addition of diethylamine (0.580 ml, 5.55 mmol), tetrakis(triphenylphosphine)palladium (0.053 g, 0.046 mmol), copper(I) iodide (0.021 g, 0.111 mmol), cyclopropylacetylene, 70 wt. % solution in toluene (0.179 ml, 1.480 mmol) and DMF (1.5 mL). The vial was sealed, purged with N2 and heated in microwaved at 90° C. for 45 min. The reaction went to completion, diluted in water (10 mL) and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-3% MeOH/DCM and 0-50% EtOAc/hexanes to afford a light yellow solid as N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-(cyclopropylethynyl)picolinamide. MS m/z=479 [M+H]+. Calculated for C23H19F5N4O2: 478.14

Workup

  1. customThe vial was sealed
  2. custompurged with N2
  3. temperatureheated
  4. customin microwaved at 90° C. for 45 min
  5. additiondiluted in water (10 mL)
  6. extractionextracted with EtOAc
  7. dry with materialThe combined organics were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customchromatographed on silica gel using 0-3% MeOH/DCM and 0-50% EtOAc/hexanes

Sources & evidence

ORD record
ord-f2da92df617d4b31927b7f570ae54b7f
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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