2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → HCID 59506984, compound

HRID 1800481Notes

Reaction equation

HRID 1800481 reaction equation
Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:17][NH:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH:22]=[CH:23][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O[K])(C)(C)C>CC(O)(C)C.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]>[CH:14]1([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([N:18]([CH3:17])[C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=4)[CH:22]=[CH:23][CH:24]=2)[N:7]=3)=[O:13])[CH2:16][CH2:15]1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 58357240HCID 58357240, compoundHCID 68417573HCID 68417573, compoundHCID 178418922HCID 178418922, compound

Product 1

HCID 59506984HCID 59506984, compoundYield 16%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6386tert-ButanolSolvent

Conditions

Temperature
130 °C

Procedure

To a suspension of N-(5-bromo[1,3]thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide (298 mg, 1.00 mmol) in 2-methylpropan-2-ol (10 mL) were added N-[3-(methylamino)phenyl]-3-(trifluoromethyl)benzamide (306 mg, 1.04 mmol), tris(dibenzylideneacetone)dipalladium(0)(55.2 mg, 60.3 μmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (X-phos) (63.1 mg, 132 μmol) and t-butoxy potassium (283 mg, 2.52 mmol), and the mixture was stirred at 130° C. for 2.5 hr under microwave irradiation in a sealed tube. After the reaction solution was allowed to cool to room temperature, the insoluble material was filtered off, and washed with ethyl acetate, tetrahydrofuran and methanol. The filtrate and the washing solution were combined and diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride solution (100 mL×2), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→50/50), and further purified by reverse phase silica gel column chromatography (containing 0.1% TFA, water/acetonitrile=5/95→95/5), fractions containing the object product was concentrated, and the residue was dissolved in saturated aqueous sodium hydrogen carbonate solution. The aqueous solution was extracted with ethyl acetate (100 mL×2), the combined organic layer was dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was recrystallized from ethyl acetate and diisopropyl ether to give the title compound (81.2 mg, 16%) as colorless crystals.

Workup

  1. temperatureto cool to room temperature
  2. filtrationthe insoluble material was filtered off
  3. washwashed with ethyl acetate, tetrahydrofuran and methanol
  4. additiondiluted with ethyl acetate (200 mL)
  5. washwashed with saturated aqueous ammonium chloride solution (100 mL×2)
  6. dry with materialdried over anhydrous magnesium sulfate
  7. filtrationThe insoluble material was filtered off
  8. concentrationconcentrated
  9. customThe residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→50/50)
  10. customfurther purified by reverse phase silica gel column chromatography (containing 0.1% TFA, water/acetonitrile=5/95→95/5), fractions
  11. additioncontaining the object product
  12. concentrationwas concentrated
  13. dissolutionthe residue was dissolved in saturated aqueous sodium hydrogen carbonate solution
  14. extractionThe aqueous solution was extracted with ethyl acetate (100 mL×2)
  15. dry with materialthe combined organic layer was dried over anhydrous magnesium sulfate
  16. concentrationconcentrated
  17. customThe obtained crude product
  18. customwas recrystallized from ethyl acetate and diisopropyl ether

Sources & evidence

ORD record
ord-acf99b9cef8840998c19a3bb0c43f3fb
Source dataset
uspto-grants-2013_01
Patent number
US08344135B2

Reaction notes

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