Potassium Carbonate → HCID 57488517, compound

HRID 1044396Notes

Reaction equation

HRID 1044396 reaction equation
C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH2:37]([O:44][CH2:45][C:46]([CH3:50])([CH3:49])[C:47]#[CH:48])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[NH2:51][C:52]1[C:57]([F:58])=[CH:56][C:55]([NH:59][CH2:60][C@@H:61]([OH:71])[CH2:62][O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[C:54](Br)[CH:53]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[NH2:51][C:52]1[C:57]([F:58])=[CH:56][C:55]([NH:59][CH2:60][C@@H:61]([OH:71])[CH2:62][O:63][CH2:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)=[C:54]([C:48]#[C:47][C:46]([CH3:50])([CH3:49])[CH2:45][O:44][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:53]=1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 821241,4-Bis(diphenylphosphino)butaneHCID 57488516[[(2,2-Dimethyl-3-butyn-1-yl)oxy]methyl]benzeneHCID 57516852HCID 57516852, compound

Product 1

HCID 57488517HCID 57488517, compound

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 167845palladium(II) acetateCatalystHCID 6342AcetonitrileSolvent3×

Conditions

Temperature
80 °C

Procedure

Palladium acetate (0.01 eq), dppb (0.015 eq), CuI (0.015 eq) and potassium carbonate (3 eq) are suspended in acetonitrile (1.2 vol). After stirring for 15 minutes, a solution of 4-benzyloxy-3,3-dimethylbut-1-yne (1.1 eq) in acetonitrile (0.2 vol) is added. The mixture is sparged with nitrogen gas for 1 h and then a solution of (R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol free base (1 eq) in acetonitrile (4.1 vol) is added. The mixture is sparged with nitrogen gas for another hour and then is heated to 80° C. Reaction progress is monitored by HPLC and the reaction is usually complete within 3-5 h. The mixture is cooled to room temperature and then filtered through Celite. The cake is washed with acetonitrile (4 vol). The combined filtrates are azeotroped to dryness and then the mixture is polish filtered into the next reactor. The acetonitrile solution of (R)-1-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol thus obtained is used directly in the next procedure (cyclization) without further manipulation.

Workup

  1. customThe mixture is sparged with nitrogen gas for 1 h
  2. customThe mixture is sparged with nitrogen gas for another hour
  3. customReaction progress
  4. waitthe reaction is usually complete within 3-5 h
  5. temperatureThe mixture is cooled to room temperature
  6. filtrationfiltered through Celite
  7. washThe cake is washed with acetonitrile (4 vol)
  8. customThe combined filtrates are azeotroped to dryness
  9. filtrationfiltered into the next reactor

Sources & evidence

ORD record
ord-ddbabbb3c2d2437f8c88f4e0a5733b9c
Source dataset
uspto-grants-2013_10
Patent number
US08563593B2

Reaction notes

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