Potassium Carbonate → HCID 71812193, Verbindung

HRID 531269

Reaktionsgleichung

Reaktionsgleichung von HRID 531269
[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:33][CH3:34])=[N:28][CH:29]=[C:30](Cl)[CH:31]=4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:43][C:44]1[S:45][C:46](B2OC(C)(C)C(C)(C)O2)=[C:47]([CH3:49])[N:48]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1.O>C(#N)C>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:33][CH3:34])=[N:28][CH:29]=[C:30]([C:46]5[S:45][C:44]([CH3:43])=[N:48][C:47]=5[CH3:49])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Komponenten

6

Edukt 4

HCID 11430Potassium CarbonateHCID 185257002,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazoleHCID 218864351,4-Dioxane--water (1/1)HCID 90009178HCID 90009178, Verbindung

Produkt 1

HCID 71812193HCID 71812193, VerbindungAusbeute 8,9 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6342AcetonitrileLösungsmittel

Reaktionsbedingungen

Temperatur
130 °C

Versuchsvorschrift

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 1, 100 mg, 0.161 mmol), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (38.6 mg, 0.161 mmol) and K2CO3 (66.9 mg, 0.484 mmol) were mixed with 1.5 mL of 4/1 dioxane/water. The mixture was evacuated and charged with nitrogen three times, then {2-[2-(amino-κN)ethyl]phenyl-κC1}(chloro)[di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine]palladium (tert-Butyl X-Phos Precatalyst) (8.3 mg, 0.016 mmol) was added. The reaction was sealed and then heated for 25 minutes at 130° C. in a microwave reactor. The reaction was diluted with 5 mL acetonitrile and filtered through a 1 g RP C18 silica cartridge, eluting with 15 mL acetonitrile until the filtrate was colorless. The filtrate was concentrated prior to RP Prep purification on a X-Bridge 21.2×150 mm RP column. The sample was loaded in 7:3:1 CH3CN/water/DMSO (5 mL), then eluted with 10-100% acetonitrile/water (0.1% NH4OH) linear gradient over 20 minutes. The product of interest eluted in 80% portion of above gradient. Pure fractions (rich cut; impure discarded) were concentrated and lyophilized to give 10 mg product. LCMS (M+H)+: 697.4. 1H NMR (CDCl3, 500 MHz): δ 8.33 (d, J=2.3 Hz, 1H), 8.23 (s, 1H), 7.94 (s, 1H), 7.80 (s, 2H), 7.55 (d, J=2.1 Hz, 1H), 5.71 (d, J=8.5 Hz, 1H), 5.58 (m, 0.5H) 5.47 (m, 0.5H), 4.78 (d, J=17.1 Hz, 1H), 4.54 (m, 2H), 4.37 (m, 3H), 4.06 (d, J=18.4 Hz, 1H), 4.04 (s, 3H), 2.75 (s, 3H), 2.51 (s, 3H), 0.79 (d, J=6.5 Hz, 3H). RTA IC50: 3 nM

Aufarbeitung

  1. customThe mixture was evacuated
  2. additioncharged with nitrogen three times
  3. customThe reaction was sealed
  4. filtrationfiltered through a 1 g RP
  5. washsilica cartridge, eluting with 15 mL acetonitrile until the filtrate
  6. concentrationThe filtrate was concentrated
  7. customto RP Prep purification on a X-Bridge 21.2×150 mm RP column
  8. washeluted with 10-100% acetonitrile/water (0.1% NH4OH) linear gradient over 20 minutes
  9. washThe product of interest eluted in 80% portion of above gradient
  10. concentrationPure fractions (rich cut; impure discarded) were concentrated

Quellen und Nachweise

ORD-Eintrag
ord-5ebf55cba6224ea2998ffeff43e7d1e4
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09353101B2

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