Diisopropylethylamine → (3aS,4R,5R,6aS)-tert-butyl 5-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

HRID 877733Notes

Reaction equation

HRID 877733 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][CH:16]1[CH2:30][CH:19]2[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH:18]2[CH:17]1[CH3:31].C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]3[CH2:30][C@@H:19]4[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:22][C@@H:18]4[C@H:17]3[CH3:31])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 682911926-Bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide2×HCID 68291516tert-butyl 5-amino-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate2×

Product 1

HCID 68291216(3aS,4R,5R,6aS)-tert-butyl 5-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 5.05 g, 18.40 mmol), crude tert-butyl 5-amino-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Intermediate 7, 7.07 g) and N,N-diisopropylethylamine (12.85 mL, 73.6 mmol) in N-methylpyrrolidinone (80 mL) was heated to 95° C. for 5 h. The mixture was diluted with ethyl acetate (600 mL), washed with water, brine, dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes, gave the desired product as a racemic mixture (3.1 g). This mixture was resolved using preparative SFC using the following conditions: Column: ChiralPak AD-H 25×3 cm, 5 μm; Column Temp: 40° C.; Flow rate: 130 mL/min; Mobile Phase: CO2/methanol=50/50; Injection Volume: 5 mL (22.2 mg/mL, 3 g solid in 75 mL methanol and 60 mL chloroform); Detector Wavelength: 263 nm. The first eluted enantiomer was the desired (3aS,4R,5R,6aS)-tert-butyl 5-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.35 g). 1H NMR (400 MHz, chloroform-d) δ ppm 10.40 (1 H, d, J=8.36 Hz), 7.88 (1 H, s), 7.58 (1 H, d, J=1.76 Hz), 6.83 (1 H, d, J=1.76 Hz), 5.64 (2 H, br. s.), 3.86-4.08 (1 H, m), 3.49-3.67 (1 H, m), 3.38-3.50 (2 H, m), 3.14-3.34 (1 H, m), 2.74-2.82 (1 H, m), 2.55-2.68 (1 H, m), 2.18-2.40 (1 H, m), 1.59-1.90 (2 H, m), 1.51 (9 H, s), 1.08-1.19 (3 H, m); MS (ES+) m/z: 478.2, 480.2 (M+H).

Workup

  1. washwashed with water, brine
  2. dry with materialdried (MgSO4)
  3. concentrationconcentrated
  4. washSilica gel chromatography, eluting with 0-60% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-4fee577bc7884870a901507625e628ef
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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