1,2-Dichloroethane → (3S,4S)-tert-butyl 3-((3-carbamoyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate

HRID 877795Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 877795
[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27](O)=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.ON1C2C=CC=CC=2N=N1.O/[N:45]=[C:46](\[NH2:48])/[CH3:47]>CN(C=O)C>[C:21]([C:20]1[CH:19]=[N:18][N:17]2[CH:24]=[C:25]([C:27]3[O:28][N:48]=[C:46]([CH3:47])[N:45]=3)[CH:26]=[C:16]2[C:15]=1[NH:14][C@H:10]1[C@@H:11]([CH3:13])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]1)(=[O:23])[NH2:22]

Komponenten

6

Edukt 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 5487681(E)-N'-HydroxyacetimidamideHCID 682909544-(((3S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid

Produkt 1

HCID 68291042(3S,4S)-tert-butyl 3-((3-carbamoyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylateAusbeute 37 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

A mixture of 4-(((3S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (120 mg, 0.297 mmol), EDC (68.4 mg, 0.357 mmol) and 1-hydroxybenzotriazole (54.7 mg, 0.357 mmol) in DMF (2 mL) was stirred at rt for 30 minutes. (Z)—N′-hydroxyacetimidamide (48.5 mg, 0.654 mmol) was added and the reaction mixture was stirred for 30 min at rt and 3 hr at 125° C. for 5 hr. After cooling to rt, The reaction mixture was partitioned between EtOAc (30 ml) and saturated NaHCO3 solution (30 ml). The organic layer was washed with saturated NaHCO3 solution (30 ml), 10% LiCl solution (2×30 ml) and brine (30 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow oil that was chromatographed on a 12 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford (3S,4S)-tert-butyl 3-((3-carbamoyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate (50 mg, 0.110 mmol, 36.9% yield) as an off-white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.27 (s, 2H), 7.48 (s, 1H), 3.88-3.50 (m, 4H), 3.21 (td, J=10.3, 4.4 Hz, 1H), 2.72 (d, J=6.4 Hz, 1H), 2.43 (s, 3H), 1.45 (d, J=13.6 Hz, 9H), 1.18 (d, J=6.8 Hz, 3H). MS (ES+) m/z: 442.2 (M+H); LC retention time: 2.991 min (analytical HPLC Method O).

Aufarbeitung

  1. stirringthe reaction mixture was stirred for 30 min at rt and 3 hr at 125° C. for 5 hr
  2. temperatureAfter cooling to rt
  3. customThe reaction mixture was partitioned between EtOAc (30 ml) and saturated NaHCO3 solution (30 ml)
  4. washThe organic layer was washed with saturated NaHCO3 solution (30 ml), 10% LiCl solution (2×30 ml) and brine (30 ml)
  5. customAfter drying
  6. filtration(MgSO4) and filtration
  7. concentrationthe organic layer was concentrated to a yellow oil that
  8. customwas chromatographed on a 12 gm ISCO silica gel cartridge
  9. washeluting with a 0-100% EtOAc/Hex gradient
  10. concentrationThe pure fractions were concentrated

Quellen und Nachweise

ORD-Eintrag
ord-78944531c1314e52b62be22c816dca2d
Quelldatensatz
uspto-grants-2015_03
Patentnummer
US08987268B2

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