Cesium carbonate → Tert-butyl 4-{1-hydroxy-1-[5-(3-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}piperidine-1-carboxylate

HRID 1040009Notes

Reaction equation

HRID 1040009 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[S:23][C:22]([C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)([OH:26])[CH3:25])=[N:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:26][C:24]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)([C:22]1[S:23][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=3)[CH:14]=2)=[CH:20][N:21]=1)[CH3:25]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27739122-Chloro-4-(trifluoromethyl)pyrimidineHCID 67433207Tert-butyl 4-(1-[5-(3-aminophenyl)-1,3-thiazol-2-yl]-1-hydroxyethyl)piperidine-1-carboxylate

Product 1

HCID 67431059Tert-butyl 4-{1-hydroxy-1-[5-(3-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}piperidine-1-carboxylateYield 66.2%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Procedure

2-Chloro-4-(trifluoromethyl)pyrimidine (0.030 mL, 0.245 mmol), the product of Step 3 (82.4 mg, 0.204 mmol), Cs2CO3 (133 mg, 0.408 mmol), palladium(II) acetate (2.292 mg, 10.21 μmol) and Xantphos (17.72 mg, 0.031 mmol) were stirred in Dioxane (4.0 mL) at 105° C. overnight under N2. The reaction mixture was filtered through a celite pre-pack column with CH2Cl2 and small amount of 2-MeTHF. The filtrate was concentrated and the residue was purified by flash chromatography to give tert-butyl 4-{1-hydroxy-1-[5-(3-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}piperidine-1-carboxylate (Example 15(1), 74 mg, 0.135 mmol, 66%). APCI: [M-Boc+H]+ m/z 450.1. 1H NMR (CDCl3): δ 8.67 (d, J=4.91, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.66 (s, 1H), 7.52 (d, J=8.22, 1H), 7.39 (t, J=7.91, 1H), 7.30-7.25 (m, 1H), 7.08 (d, J=4.91, 1H), 4.19-4.09 (m, 2H), 3.31 (s, 1H), 2.75-2.57 (m, 2H), 1.95 (td, J=12.01, 3.49, 1H), 1.87-1.73 (m, 1H), 1.67 (s, 3H), 1.60-1.49 (m, 1H), 1.45 (s, 9H), 1.50-1.32 (m, 1H). rhSYK activity=++

Workup

  1. filtrationThe reaction mixture was filtered through a celite pre-pack column with CH2Cl2 and small amount of 2-MeTHF
  2. concentrationThe filtrate was concentrated
  3. customthe residue was purified by flash chromatography

Sources & evidence

ORD record
ord-e3337f337e34495f9a47b0426738a7e0
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

Loading…