Cesium carbonate → Dicyclopropyl{5-[3-(morpholin-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}methanol

HRID 1040025Notes

Reaction equation

HRID 1040025 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:25]2[S:29][C:28]([C:30]([CH:35]3[CH2:37][CH2:36]3)([CH:32]3[CH2:34][CH2:33]3)[OH:31])=[N:27][CH:26]=2)[CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[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.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH:35]1([C:30]([CH:32]2[CH2:33][CH2:34]2)([C:28]2[S:29][C:25]([C:15]3[CH:14]=[C:13]([NH:12][C:2]4[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=4)[CH:18]=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=3)=[CH:26][N:27]=2)[OH:31])[CH2:37][CH2:36]1

Participants

8

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 67433244(5-[3-Amino-5-(morpholin-4-yl)phenyl]-1,3-thiazol-2-yl)(dicyclopropyl)methanol

Product 1

HCID 58456174Dicyclopropyl{5-[3-(morpholin-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}methanolYield 54%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
125 °C

Procedure

To a solution of 2-chloro-4-(trifluoromethyl)pyrimidine (0.079 mL, 0.654 mmol) and the product of Step 5 (221 mg, 0.595 mmol) in dioxane (4.0 mL) was added cesium carbonate (388 mg, 1.190 mmol), Pd(OAc)2 (6.68 mg, 0.030 mmol) and XantPhos (51.6 mg, 0.089 mmol) and the mixture was heated to 125° C. for 2 hours. After cooling to room temperature, 1.5 mL of water was added and the reaction mixture was filtered through a celite column with dichloromethane. The filtrate was concentrated and the residue was purified by chromatography on silica gel (0-100% ethyl acetate in hexanes). The yellow residue was triturated in diethyl ether (with trace dichloromethane) to give dicyclopropyl{5-[3-(morpholin-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}methanol (165 mg, 0.319 mmol, 54% yield) as an off-white solid. MS APCI: [M+H]+ m/z 518.1. 1H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H); 8.84 (d, J=4.9 Hz, 1H); 7.98 (s, 1H); 7.57 (s, 1H); 7.40 (s, 1H); 7.28 (d, J=4.9 Hz, 1H); 6.89 (s, 1H); 5.38 (s, 1H); 3.77 (t, J=4.3 Hz, 4H); 3.17 (t, J=4.4 Hz, 4H); 1.41-1.33 (m, 2H); 0.54-0.38 (m, 6H); 0.32-0.24 (m, 2H). rhSYK activity=+++

Workup

  1. temperatureAfter cooling to room temperature
  2. filtrationthe reaction mixture was filtered through a celite column with dichloromethane
  3. concentrationThe filtrate was concentrated
  4. customthe residue was purified by chromatography on silica gel (0-100% ethyl acetate in hexanes)
  5. customThe yellow residue was triturated in diethyl ether (with trace dichloromethane)

Sources & evidence

ORD record
ord-3f39d60e5bab4e93a87bfb9817fc152d
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

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