Pyridine → HCID 86685855, compound

HRID 1629764Notes

Reaction equation

HRID 1629764 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:34])[CH2:30][C:31]([OH:33])=O)=[CH:24][CH:23]=1.ClC(Cl)(Cl)C#N.[NH2:41][C@@:42]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]([F:70])([F:69])[F:68])=[CH:59][CH:58]=1)([C:53]([F:56])([F:55])[F:54])[CH2:43][C:44]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)=[O:45].N1C=CC=CC=1>C(Cl)Cl.CO>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:34])[CH2:30][C:31]([NH:41][C:42]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]([F:68])([F:69])[F:70])=[CH:59][CH:58]=2)([CH2:43][C:44](=[O:45])[C:46]2[CH:47]=[CH:48][C:49]([CH3:52])=[CH:50][CH:51]=2)[C:53]([F:56])([F:55])[F:54])=[O:33])=[CH:26][CH:27]=1

Participants

8

Reactant 5

HCID 1049PyridineHCID 11011TrichloroacetonitrileHCID 11776TriphenylphosphineHCID 116585393-(4-Methoxyanilino)-3-oxopropanoic acidHCID 86685849(S)-3-Amino-4,4,4-trifluoro-1-p-tolyl-3-(4-(4,4,4-trifluorobutoxy)phenyl)-butan-1-one

Product 1

HCID 86685855HCID 86685855, compoundYield 63.2%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent3×

Procedure

To triphenylphosphine (8.42 g, 32.1 mmol) in anhydrous CH2Cl2 (70 mL) was added Intermediate 6B (2.24 g, 10.7 mmol) in anhydrous CH2Cl2 (30 mL) followed by trichloroacetonitrile (1.86 g, 12.8 mmol). The mixture was stirred at rt for 3 h. The freshly prepared acid chloride was added to a solution of Intermediate 2F (1.13 g, 2.61 mmol) in anhydrous CH2Cl2 (20 mL), followed by the addition of pyridine (1.04 mL, 1.02 g, 12.85 mmol). The reaction was stirred at rt under argon overnight. The reaction was cooled to 0° C. and MeOH (40 mL) was added. The reaction was stirred at 0° C. for 10 min, then at rt for 30 min. The solvent was removed in vacuo and the crude product was purified by silica gel chromatography (120 g silica gel, eluted with EtOAc in hexanes). Product and triphenylphosphine oxide co-eluted. Fractions containing both were combined and evaporated to dryness. The solids were triturated with hexanes/EtOAc to remove most of the triphenylphosphine oxide. The product was again purified by silica gel chromatography (40 g silica gel, eluted with EtOAc in hexanes) to provide Intermediate 6C (1.03 g, 63%) as a brown oil. LCMS Anal. Calc'd for C31H30F6N2O5 624.57, found [M+H] 625.3.

Workup

  1. stirringThe reaction was stirred at rt under argon overnight
  2. temperatureThe reaction was cooled to 0° C.
  3. stirringThe reaction was stirred at 0° C. for 10 min
  4. waitat rt for 30 min
  5. customThe solvent was removed in vacuo
  6. customthe crude product was purified by silica gel chromatography (120 g silica gel, eluted with EtOAc in hexanes)
  7. additionFractions containing
  8. customevaporated to dryness
  9. customThe solids were triturated with hexanes/EtOAc
  10. customto remove most of the triphenylphosphine oxide
  11. customThe product was again purified by silica gel chromatography (40 g silica gel, eluted with EtOAc in hexanes)

Sources & evidence

ORD record
ord-0365e327601943c0a66bf86cec637501
Source dataset
uspto-grants-2014_07
Patent number
US08791091B2

Reaction notes

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