Potassium Carbonate → 2-(4-Chlorophenyl)-5-{[5-(1-hydroxy-1-methylethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide

HRID 2060587Notes

Reaction equation

HRID 2060587 reaction equation
[NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]([NH2:16])=[O:15].Br[C:18]1[N:23]=[CH:22][C:21]([C:24]([OH:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)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]>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:18]3[CH:19]=[CH:20][C:21]([C:24]([OH:27])([CH3:26])[CH3:25])=[CH:22][N:23]=3)=[C:3]([C:14]([NH2:16])=[O:15])[N:4]=2)=[CH:12][CH:11]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 223919732-(6-Bromo-3-pyridyl)-2-propanolHCID 583352565-Amino-2-(4-chlorophenyl)-1,3-thiazole-4-carboxamide

Product 1

HCID 446025252-(4-Chlorophenyl)-5-{[5-(1-hydroxy-1-methylethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A sealed tube was charged with a stir bar, 5-amino-2-(4-chlorophenyl)-1,3-thiazole-4-carboxamide (150 mg, 0.59 mmol), 2-(6-bromopyridin-3-yl)propan-2-ol (for preparation, see WO 2004/050024 A2 Example 120 Step A) (128 mg, 0.59 mmol), Pd2(dba)3 (33 mg, 0.035 mmol), X-PHOS (85 mg, 0.177 mmol), and potassium carbonate (90 mg, 0.65 mmol). The tube was evacuated, and backfilled with argon three times. Fully degassed tert-amyl alcohol (1.2 mL) was added to the reaction vessel, which was sealed and left to stir at 100° C. overnight. The reaction vessel was removed then cooled to room temperature, and the crude reaction mixture was taken up in ethyl acetate and washed with 100 mL water. The water layer was treated with concentrated ammonium hydroxide and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, and filtered. To the filtrate was added 1.5 g of silica gel and the solvent was removed in vacuo. The compound on silica was purified via flash chromatography (silica, 0-3% methanol/ethyl acetate) to afford the title compound. 1H NMR (500 MHz, d6-DMSO): δ 11.26 (s, 1H), 8.24 (d, 1H), 7.98 (d, 2H), 7.82 (m, 2H), 7.73 (s, 1H), 7.35 (d, 2H), 7.17 (d, 1H), 5.14 (s, 1H), 1.44 (s, 6H). LRMS (APCI) calc'd for C18H18ClN4O2S [M+H]+: 389.1, found 389.0

Workup

  1. additionA sealed tube was charged with a stir bar
  2. customThe tube was evacuated
  3. additionFully degassed tert-amyl alcohol (1.2 mL) was added to the reaction vessel, which
  4. customwas sealed
  5. waitleft
  6. customThe reaction vessel was removed
  7. temperaturethen cooled to room temperature
  8. customthe crude reaction mixture
  9. washwashed with 100 mL water
  10. additionThe water layer was treated with concentrated ammonium hydroxide
  11. extractionextracted with ethyl acetate
  12. dry with materialThe combined organic extracts were dried over anhydrous magnesium sulfate
  13. filtrationfiltered
  14. additionTo the filtrate was added 1.5 g of silica gel
  15. customthe solvent was removed in vacuo
  16. customThe compound on silica was purified via flash chromatography (silica, 0-3% methanol/ethyl acetate)

Sources & evidence

ORD record
ord-85f4eef67a8c4372b881fd59389e2e0b
Source dataset
uspto-grants-2012_10
Patent number
US08278335B2

Reaction notes

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