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

HRID 410535Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 410535
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

Komponenten

8

Edukt 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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 167845palladium(II) acetateKatalysatorHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
125 °C

Versuchsvorschrift

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=+++

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-3ed96aa9ffe44192b212000af3dfa848
Quelldatensatz
uspto-grants-2014_06
Patentnummer
US08759366B2

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