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

HRID 2060591Notes

Reaction equation

HRID 2060591 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].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:58]1[N:63]=[C:62]([CH:64]([N:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)[CH2:65][OH:66])[CH:61]=[CH:60][CH:59]=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]>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:58]3[CH:59]=[CH:60][CH:61]=[C:62]([CH:64]([N:67]4[CH2:72][CH2:71][O:70][CH2:69][CH2:68]4)[CH2:65][OH:66])[N:63]=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 583352565-Amino-2-(4-chlorophenyl)-1,3-thiazole-4-carboxamideHCID 583352752-(6-Bromopyridin-2-yl)-2-morpholin-4-ylethanol

Product 1

HCID 451011712-(4-Chlorophenyl)-5-{[6-(2-hydroxy-1-morpholin-4-ylethyl)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 (Example 1, Step 1) (247 mg, 0.97 mmol), Pd2(dba)3 (54 mg, 0.058 mmol), X-PHOS (139 mg, 0.29 mmol), and potassium carbonate (148 mg, 1.07 mmol). The tube was evacuated, and backfilled with argon three times. A second vial was charged with racemic 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (280 mg, 0.97 mmol) and evacuated and backfilled with argon three times. Fully degassed tert-amyl alcohol (2.3 mL) was added to the vial containing 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol and the resulting solution was transferred by syringe to the tube containing the rest of the reagents. This vial was sealed and left to stir at 100° C. overnight. 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 organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash chromatography (silica, 0-3% methanol/ethyl acetate) afforded the title compound. 1H NMR (600 MHz, d6-DMSO): δ 11.28 (s, 1H), 7.94 (d, 2H), 7.79 (s, 1H), 7.69 (t, 1H), 7.61 (s, 1H), 7.54 (d, 2H), 7.07 (d, 1H), 6.94 (d, 1H), 4.51 (t, 1H), 4.00 (m, 1H), 3.92 (m, 1H), 3.65 (t, 1H), 3.52 (m, 4H), 2.48 (m, 4H). LRMS (APCI) calcd for C21H22ClN5O3S [M+H]+: 460.1, found 460.0

Workup

  1. additionA sealed tube was charged with a stir bar
  2. customThe tube was evacuated
  3. customevacuated
  4. additionFully degassed tert-amyl alcohol (2.3 mL) was added to the
  5. additionvial containing 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol
  6. customthe resulting solution was transferred by syringe to the tube
  7. additioncontaining the rest of the reagents
  8. customThis vial was sealed
  9. waitleft
  10. temperatureThe reaction vessel was cooled to room temperature
  11. customthe crude reaction mixture
  12. washwashed with 100 mL water
  13. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo
  16. customPurification via flash chromatography (silica, 0-3% methanol/ethyl acetate)

Sources & evidence

ORD record
ord-106c6b46038a41538658dc8d2fa4a99a
Source dataset
uspto-grants-2012_10
Patent number
US08278335B2

Reaction notes

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