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 877795ノート

反応式

HRID 877795 の反応式
[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]

参加物

6

反応物 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

生成物 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-carboxylate収率 37%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-78944531c1314e52b62be22c816dca2d
出典データセット
uspto-grants-2015_03
特許番号
US08987268B2

反応ノート

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