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

HRID 2060597Notes

Reaction equation

HRID 2060597 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]([CH2:67][N:68]2[CH2:73][CH2:72][O:71][CH2:70][CH2:69]2)[CH:64]=[CH:63][CH:62]=1>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]>[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]([CH2:67][N:68]4[CH2:73][CH2:72][O:71][CH2:70][CH2:69]4)[N:66]=3)=[C:3]([C:17]([NH2:19])=[O:18])[N:4]=2)=[CH:12][CH:11]=1)([CH3:15])[CH3:14]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 234381474-((6-Bromopyridin-2-yl)methyl)morpholineHCID 583352645-Amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide

Product 1

HCID 446238062-[4-(1-Hydroxy-1-methylethyl)phenyl]-5-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}-1,3-thiazole-4-carboxamide

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolvent

Procedure

A sealed tube was charged with a stir bar, 5-amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (150 mg, 0.54 mmol), Pd2(dba)3 (30 mg, 0.023 mmol), X-PHOS (77 mg, 0.16 mmol), and potassium carbonate (82 mg, 0.60 mmol). The tube was evacuated, and backfilled with argon three times. A second vial was charged with 4-[(6-bromopyridin-2-yl)methyl]morpholine (Example 2, Step 1) (139 mg, 0.54 mmol) and evacuated and backfilled with argon three times. Fully degassed tert-amyl alcohol (1.2 mL) was added to the vial containing 4-[(6-bromopyridin-2-yl)methyl]morpholine and the resulting solution was transferred by syringe to the tube containing the rest of the reagents. The reaction vessel was 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 (400 MHz CDCl3): δ 11.26 (s, 1H), 7.86 (d, 2H), 7.70 (s, 1H), 7.68 (d, 1H), 7.58 (s, 1H), 7.54 (d, 2H), 7.05 (d, 1H), 7.00 (d, 1H), 5.08 (s, 1H), 3.65 (s, 2H), 3.59 (m, 4H), 2.47 (m, 4H), 1.42 (s, 6H). LRMS (APCI) calc'd for C23H28N5O3S [M+H]+: 454.2, found 454.0.

Workup

  1. additionA sealed tube was charged with a stir bar
  2. customThe tube was evacuated
  3. customevacuated
  4. additionFully degassed tert-amyl alcohol (1.2 mL) was added to the
  5. additionvial containing 4-[(6-bromopyridin-2-yl)methyl]morpholine
  6. customthe resulting solution was transferred by syringe to the tube
  7. additioncontaining the rest of the reagents
  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-64989d9b13a2490d8f0cdb54525ffa68
Source dataset
uspto-grants-2012_10
Patent number
US08278335B2

Reaction notes

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