Potassium Phosphate, Tribasic → 4-((3R,4S)-1-(5-cyanopyrimidin-2-yl)-4-methoxypyrrolidin-3-ylamino)-6-(4-(cyclopropylcarbamoyl)phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877827Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 877827
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([O:16][CH3:17])[CH2:14][N:13]([C:18]4[N:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=4)[CH2:12]3)=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH:30]1([NH:33][C:34]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[O:35])[CH2:32][CH2:31]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[C:24]([C:21]1[CH:20]=[N:19][C:18]([N:13]2[CH2:14][C@H:15]([O:16][CH3:17])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:29]=[C:2]([C:39]5[CH:38]=[CH:37][C:36]([C:34](=[O:35])[NH:33][CH:30]6[CH2:32][CH2:31]6)=[CH:41][CH:40]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:26]([NH2:28])=[O:27])[CH2:12]2)=[N:23][CH:22]=1)#[N:25]

Komponenten

5

Edukt 3

HCID 62657Potassium Phosphate, TribasicHCID 2773359(4-(Cyclopropylcarbamoyl)phenyl)boronic acidHCID 682907596-bromo-4-((3R,4S)-1-(5-cyanopyrimidin-2-yl)-4-methoxypyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide

Produkt 1

HCID 682919074-((3R,4S)-1-(5-cyanopyrimidin-2-yl)-4-methoxypyrrolidin-3-ylamino)-6-(4-(cyclopropylcarbamoyl)phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamideAusbeute 35,5 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
140 °C

Versuchsvorschrift

A solution of 6-bromo-4-(((3R,4S)-1-(5-cyanopyrimidin-2-yl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.022 mmol) in 1,4-dioxane (0.5 mL), was added [1,1′-[bis(diphenylphosphino)ferrocene]-dicholorpalladium (II) (1.601 mg, 2.187 μmol), [4-(cyclopropylcarbamoyl)phenyl]-boronic acid (6.73 mg, 0.033 mmol) and potassium phosphate (2M, 0.033 mL, 0.066 mmol). The reaction vial was purged with nitrogen, sealed and heated at 140° C. for 1 h. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (4.2 mg, 35% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.57 (br. s., 1H), 8.51 (d, J=3.0 Hz, 1H), 8.13 (d, J=3.5 Hz, 1H), 7.95 (br. s., 1H), 7.87-7.75 (m, 2H), 7.73-7.66 (m, 2H), 7.62-7.55 (m, 2H), 7.18 (br. s., 1H), 5.09 (br. s., 1H), 4.33-4.22 (m, 2H), 4.02-3.94 (m, 1H), 3.93-3.84 (m, 1H), 3.77-3.69 (m, 1H), 3.52 (d, J=3.5 Hz, 3H), 2.89-2.80 (m, 1H), 0.80 (m, 4H). MS (ES+) m/z: 538.22 (M+H); LC retention time: 1.31 min (analytical HPLC Method I).

Aufarbeitung

  1. customThe reaction
  2. customvial was purged with nitrogen
  3. customsealed
  4. customThe crude material was purified via preparative LC/MS with the following conditions
  5. customa 5-minute hold
  6. additionFractions containing the desired product
  7. customdried via centrifugal evaporation

Quellen und Nachweise

ORD-Eintrag
ord-ae0bfa1ef9bc43c4ac4b9bd687b1a333
Quelldatensatz
uspto-grants-2015_03
Patentnummer
US08987268B2

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