Pivalic acid → Methyl 4-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}-1-methylcyclohexanecarboxylate

HRID 928136Notes

Reaction equation

HRID 928136 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(O)(=O)C(C)(C)C.[OH:27][C:28]([CH:35]1[CH2:40][CH2:39][C:38]([CH3:45])([C:41]([O:43][CH3:44])=[O:42])[CH2:37][CH2:36]1)([C:30]1[S:31][CH:32]=[CH:33][N:34]=1)[CH3:29]>CC(N(C)C)=O.C(OCC)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].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:27][C:28]([CH:35]1[CH2:40][CH2:39][C:38]([CH3:45])([C:41]([O:43][CH3:44])=[O:42])[CH2:37][CH2:36]1)([C:30]1[S:31][C:32]([C:2]2[CH:3]=[C:4]([NH:9][C:10]3[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=2)=[CH:33][N:34]=1)[CH3:29]

Participants

9

Reactant 3

HCID 6417Pivalic acidHCID 58456396N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amineHCID 70982839HCID 70982839, compound

Product 1

HCID 86720198Methyl 4-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}-1-methylcyclohexanecarboxylate

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 3283Diethyl EtherSolventHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A solution of N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (41 mg, 0.123 mmol), Cataxium A (8.9 mg, 0.025 mmol), tris(dibenzylideneacetone)dipalladium(0) (5.7 mg, 0.0062 mmol), pivalic acid (0.006 mL, 0.049 mmol) and methyl 4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-methylcyclohexanecarboxylate (peak 3) (51.2 mg, 0.370 mmol) in dimethylacetamide (0.55 mL) was heated at 125° C. for 24 hours. The reaction mixture was then allowed to cool to room temperature and diluted with diethyl ether (10 mL), ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The layers were separated and the organic layer was washed with water (3×10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (20-50% ethyl acetate/hexanes) to provide methyl 4-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}-1-methylcyclohexanecarboxylate. MS ESI calc'd. for C26H30F3N4O3S [M+H]+ 535. found 535. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=4.9 Hz, 1H), 7.91 (s, 1H), 7.87 (s, 1H), 7.34 (s, 1H), 7.27 (s, 1H), 7.10 (s, 1H), 7.06 (d, J=4.9 Hz, 1H), 3.76 (s, 3H), 3.06 (s, 1H), 2.40 (s, 3H), 1.83-1.66 (m, 6H), 1.65 (s, 3H), 1.50-1.42 (m, 2H), 1.39-1.33 (m, 1H), 1.17 (s, 3H).

Workup

  1. customThe layers were separated
  2. washthe organic layer was washed with water (3×10 mL) and brine (10 mL)
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by chromatography on silica gel (20-50% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-9c322bdedd1a4df1b33dbf27d3276931
Source dataset
uspto-grants-2016_03
Patent number
US09290490B2

Reaction notes

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