2-Bromo-4-phenylpyridine → HCID 86695082, Verbindung

HRID 574356

Reaktionsgleichung

Reaktionsgleichung von HRID 574356
Br[C:2]1[CH:29]=[C:5]2[N:6]=[C:7]([CH3:28])[C:8]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21]C)=[O:20])=[C:9]([N:10]3[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]3)[N:4]2[N:3]=1.Br[C:31]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][N:32]=1.C([Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC)CCC.O[Li].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CO>[C:24]([O:23][C@@H:18]([C:8]1[C:7]([CH3:28])=[N:6][C:5]2[N:4]([N:3]=[C:2]([C:31]3[CH:36]=[C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:34]=[CH:33][N:32]=3)[CH:29]=2)[C:9]=1[N:10]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]1)[C:19]([OH:21])=[O:20])([CH3:27])([CH3:25])[CH3:26]

Komponenten

9

Edukt 4

HCID 1047002-Bromo-4-phenylpyridineHCID 168937Lithium hydroxide, monohydrateHCID 86695081HCID 86695081, VerbindungHCID 178448238HCID 178448238, Verbindung

Produkt 1

HCID 86695082HCID 86695082, VerbindungAusbeute 6,2 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 887MethanolLösungsmittelHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

To a solution of (S)-methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.050 g, 0.107 mmol, 1 equiv) in dioxane (1.0 mL) was added 2-bromo-4-phenylpyridine (0.030 g, 0.128 mmol, 1.2 equiv), hexabutyldistannane (0.12 mL, 0.235 mmol, 2.2 equiv), and Pd(PPh3)4 (0.012 g, 0.011 mmol, 0.1 equiv). The reaction was heated at 85° C. for 72 h. The reaction temperature was then lowered to 60° C. Methanol (1 mL), water (0.3 mL), and LiOH.H2O (26 mg, 1.07 mmol, 10 equiv) added and heating was continued for 2 h. Upon completion of the saponification, the reaction was removed from heat and filtered through a syringe filter. The crude reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column. Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 45-85% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min, to provide (S)-2-(tert-butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-(4-phenylpyridin-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (3.5 mg, 6%). 1H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J=4.9 Hz, 1H), 8.48 (s, 1H), 7.83 (d, J=7.6 Hz, 2H), 7.75 (d, J=4.0 Hz, 1H), 7.60-7.49 (m, 3H), 7.06 (s, 1H), 5.72 (br. s., 1H), 3.61-3.55 (m, 4H), 2.53 (s, 3H), 1.65 (br. s., 2H), 1.50 (br. s., 2H), 1.18 (s, 9H), 1.11 (br. s., 6H). LCMS (ESI, M+1): 528.3.

Aufarbeitung

  1. customwas then lowered to 60° C
  2. temperatureheating
  3. customUpon completion of the saponification, the reaction was removed
  4. temperaturefrom heat
  5. filtrationfiltered through a syringe
  6. filtrationfilter
  7. customThe crude reaction mixture
  8. customwas purified via preparative LC/MS with the following conditions
  9. waitGradient: 45-85% B over 20 minutes
  10. customa 5-minute hold

Quellen und Nachweise

ORD-Eintrag
ord-f36eb0c14cf1460ca5a10e052d2c48f1
Quelldatensatz
uspto-grants-2015_05
Patentnummer
US09034882B2

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