Tetrahydrofuran → (3S,4S)-benzyl 3-((6-(6-(aminomethyl)pyridin-3-yl)-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate

HRID 877780Notes

Reaction equation

HRID 877780 reaction equation
[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([CH2:19][N:20]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:17][CH:18]=3)[CH:12]=[C:6]2[C:5]=1[NH:31][C@H:32]1[C@@H:36]([CH2:37][CH3:38])[CH2:35][N:34]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:33]1)(=[O:3])[NH2:2].O.NN.C1COCC1>CCO>[NH2:20][CH2:19][C:16]1[N:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:6]3[C:5]([NH:31][C@H:32]4[C@@H:36]([CH2:37][CH3:38])[CH2:35][N:34]([C:39]([O:41][CH2:42][C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)=[O:40])[CH2:33]4)=[C:4]([C:1](=[O:3])[NH2:2])[CH:9]=[N:8][N:7]3[CH:10]=2)=[CH:18][CH:17]=1

Participants

5

Reactant 3

HCID 8028TetrahydrofuranHCID 24654Hydrazine hydrate (1:1)2×HCID 68350391(3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate

Product 1

HCID 68350398(3S,4S)-benzyl 3-((6-(6-(aminomethyl)pyridin-3-yl)-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylateYield 66%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (57 mg, 0.089 mmol) and hydrazine, hydrate (8.29 μl, 0.266 mmol) in EtOH (2 mL) was heated to 70° C. for 10 minutes. THF (0.5 ml) was added to obtain homogeneity and heating was continued for 1.5 hr. Additional hydrazine, hydrate (8.29 μl, 0.266 mmol) (times 4; total of 12 equivalents) was added and heating was continued for 1.5 hr. A precipitation was observed. After cooling to rt, the reaction mixture was filtered and the filtrate was concentrated to a residue that was triturated with EtOAc. Filtration and drying afforded (3S,4S)-benzyl 3-((6-(6-(aminomethyl)pyridin-3-yl)-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (30 mg, 0.058 mmol, 66.0% yield) as a tan solid. The material is contaminated with the hydrazide by-product and will be used as is in the next step. MS (ES+) m/z: 514.4 (M+H); LC retention time: 2.303 min (analytical HPLC Method O).

Workup

  1. customto obtain homogeneity
  2. temperatureheating
  3. temperatureheating
  4. waitwas continued for 1.5 hr
  5. customA precipitation
  6. temperatureAfter cooling to rt
  7. filtrationthe reaction mixture was filtered
  8. concentrationthe filtrate was concentrated to a residue that
  9. customwas triturated with EtOAc
  10. filtrationFiltration
  11. customdrying

Sources & evidence

ORD record
ord-82e623fb195d4e7a9bab16d8d851d2cf
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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