Potassium Carbonate → 2-[4-(1-Hydroxy-1-methylethyl)phenyl]-5-{[6-(2-hydroxy-1-morpholin-4-ylethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide

HRID 2060598Notes

Reaction equation

HRID 2060598 reaction equation
[NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([NH2:19])=[O:18].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+].Br[C:61]1[N:66]=[C:65]([CH:67]([N:70]2[CH2:75][CH2:74][O:73][CH2:72][CH2:71]2)[CH2:68][OH:69])[CH:64]=[CH:63][CH:62]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:61]3[CH:62]=[CH:63][CH:64]=[C:65]([CH:67]([N:70]4[CH2:75][CH2:74][O:73][CH2:72][CH2:71]4)[CH2:68][OH:69])[N:66]=3)=[C:3]([C:17]([NH2:19])=[O:18])[N:4]=2)=[CH:12][CH:11]=1)([CH3:15])[CH3:14]

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 583352645-Amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamideHCID 583352752-(6-Bromopyridin-2-yl)-2-morpholin-4-ylethanol

Product 1

HCID 574828002-[4-(1-Hydroxy-1-methylethyl)phenyl]-5-{[6-(2-hydroxy-1-morpholin-4-ylethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Procedure

A sealed tube was charged with a stir bar, 5-amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 5, Step 3) (60 mg, 0.22 mmol), Pd2(dba)3 (5.9 mg, 6.5 μmol), X-PHOS (15.5 mg, 0.032 mmol), and potassium carbonate (33 mg, 0.24 mmol). The tube was evacuated and backfilled with argon three times. 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (Example 3, Step 1) (62 mg, 0.22 mmol) was placed in a separate vial which was also evacuated and backfilled with argon three times. Fully degassed tert-amyl alcohol (500 μl) was added to 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol and the resulting solution was transferred to the sealed tube via syringe. The tube was then sealed and placed in an oil bath at 100° C. and stirred overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate (2×) and brine (2×). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification was performed by reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier, monitoring at 230 nM). Desired fractions were poured into a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was extracted, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light yellow powder. 1H NMR (500 MHz, d6-DMSO) δ 11.25 (s, 1H), 7.84 (d, 2H), 7.70 (s, 1H), 7.68 (t, 1H), 7.59 (s, 1H), 7.55 (d, 2H), 7.05 (d, 1H), 6.92 (d, 1H), 5.08 (s, 1H), 4.51 (t, 1H), 3.98 (m, 2H), 3.65 (t, 1H), 3.53 (m, 4H), 3.75 (m, 4H), 3.42 (s, 6H). LRMS (APCI) calc'd for (C24H30N5O4S) [M+H]+, 484.2; found 484.1.

Workup

  1. additionA sealed tube was charged with a stir bar
  2. customThe tube was evacuated
  3. customwas also evacuated
  4. additionFully degassed tert-amyl alcohol (500 μl) was added to 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol
  5. customthe resulting solution was transferred to the sealed tube via syringe
  6. customThe tube was then sealed
  7. customplaced in an oil bath at 100° C.
  8. additiondiluted with ethyl acetate
  9. washwashed with saturated aqueous sodium bicarbonate (2×) and brine (2×)
  10. dry with materialThe organic layer was dried over magnesium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customPurification
  14. additionDesired fractions were poured into a mixture of ethyl acetate and saturated aqueous sodium bicarbonate
  15. extractionThe organic layer was extracted
  16. dry with materialdried over magnesium sulfate
  17. filtrationfiltered
  18. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-00aa7fb04f0e4dbe8a7df5a82fe10bef
Source dataset
uspto-grants-2012_10
Patent number
US08278335B2

Reaction notes

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