2-Methyl-2-butanol → 5-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-({6-[(2-hydroxy-2-methylpropoxy)methyl]pyridin-2-yl}amino)thiophene-3-carboxamide

HRID 385849Notes

Reaction equation

HRID 385849 reaction equation
C(O)(CC)(C)C.[NH2:7][C:8]1[S:9][C:10]([C:16]2[C:21]([F:22])=[CH:20][C:19]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:18][C:17]=2[F:27])=[CH:11][C:12]=1[C:13]([NH2:15])=[O:14].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+].Br[C:69]1[N:74]=[C:73]([CH2:75][O:76][CH2:77][C:78]([CH3:81])([OH:80])[CH3:79])[CH:72]=[CH:71][CH:70]=1>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:22][C:21]1[CH:20]=[C:19]([C:23]([OH:26])([CH3:24])[CH3:25])[CH:18]=[C:17]([F:27])[C:16]=1[C:10]1[S:9][C:8]([NH:7][C:69]2[CH:70]=[CH:71][CH:72]=[C:73]([CH2:75][O:76][CH2:77][C:78]([OH:80])([CH3:79])[CH3:81])[N:74]=2)=[C:12]([C:13]([NH2:15])=[O:14])[CH:11]=1

Participants

8

Reactant 5

HCID 64052-Methyl-2-butanol2×HCID 11430Potassium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 583352721-[(6-Bromopyridin-2-yl)methoxy]-2-methylpropan-2-olHCID 595256192-Amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide

Product 1

HCID 251105985-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-({6-[(2-hydroxy-2-methylpropoxy)methyl]pyridin-2-yl}amino)thiophene-3-carboxamide

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolvent

Conditions

Temperature
105 °C

Procedure

t-Amyl alcohol (41 mL) was placed in a flask and argon was bubbled through it for several minutes. 2-Amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (2.50 g, 8.0 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (1.90 g, 4 mmol), Pd2(dba)3 (0.73 g, 0.8 mmol), and potassium carbonate (1.22 g, 8.8 mmol) were placed in a reaction vessel that was purged with argon. Degassed t-amyl alcohol (10 mL) was used to transfer 1-[(6-bromopyridin-2-yl)methoxy]-2-methylpropan-2-ol (2.08 g, 8.0 mmol) to the reaction vessel and the remaining t-amyl alcohol was added. Seven argon/vacuum cycles were performed. The solution was heated at 105° C. overnight. The reaction was then cooled to ambient temperature, diluted with methanol, and silica gel was added. The resulting mixture was concentrated in vacuo and then purified by column chromatography (silica, 0-5% methanol/ethyl acetate). Purification via mass guided reverse phase HPLC (Agilent 1100 HPLC-MSD, Phenomenex Gemeni-C18, 10 μM, 250 mm×50 mm i.d. column, 20-95% acetonitrile/water+0.01% formic acid modifier, 75-100 mL/min flow rate) afforded the title compound.

Workup

  1. customargon was bubbled through it for several minutes
  2. customthat was purged with argon
  3. temperatureThe reaction was then cooled to ambient temperature
  4. additionwas added
  5. concentrationThe resulting mixture was concentrated in vacuo
  6. custompurified by column chromatography (silica, 0-5% methanol/ethyl acetate)
  7. customPurification via mass

Sources & evidence

ORD record
ord-c4fcf8e82bee4947bdfec12ba5070c74
Source dataset
uspto-grants-2013_02
Patent number
US08367706B2

Reaction notes

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