Acetic Acid → (S)-Methyl 2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate

HRID 132416Notes

Reaction equation

HRID 132416 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:5]([CH2:11]Cl)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.Cl.Cl.[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][NH2:32].C(N(CC)CC)C.C(O)(=O)C>C(#N)C.ClCCl>[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][N:32]1[C:15](=[O:17])[C@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:4]2[CH:3]=[C:2]([Cl:1])[C:10]3[NH:9][N:8]=[CH:7][C:6]=3[C:5]=2[CH2:11]1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 8471TriethylamineHCID 124178631H-imidazol-2-ylmethanamine dihydrochlorideHCID 59731905(S)-Dimethyl 2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate

Product 1

HCID 59731852(S)-Methyl 2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetateYield 24%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

(S)-Dimethyl 2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (250 mg, 0.63 mmol) and (1H-imidazol-2-yl)methanamine dihydrochloride (170 mg, 1.0 mmol) were combined and suspended in acetonitrile (10 mL). Triethylamine (800 μL, 5.7 mmol) was added to the mixture. Reaction was warmed to reflux for 3 hours. Acetic acid (1.5 mL) was added to the mixture. Reaction was heated at reflux for 20 hours. Mixture was cooled to room temperature then diluted with dichloromethane. Mixture was extracted twice with water. Aqueous layer was concentrated in vacuo. Residue was purified by preparatory HPLC. Water was lyophilized off. Remaining residue was passed through a column of Dowex 1×4-200 ion exchange resin eluting methanol. Title compound was recovered as amber residue in 24% yield. MS m/e (M+H)+=388.1.

Workup

  1. customReaction
  2. temperaturewas warmed
  3. temperatureto reflux for 3 hours
  4. customReaction
  5. temperaturewas heated
  6. temperatureat reflux for 20 hours
  7. extractionMixture was extracted twice with water
  8. concentrationAqueous layer was concentrated in vacuo
  9. customResidue was purified by preparatory HPLC
  10. washeluting methanol
  11. customTitle compound was recovered as amber residue in 24% yield

Sources & evidence

ORD record
ord-49b21671298e45cfb59d27a983765b9d
Source dataset
uspto-grants-2008_06
Patent number
US07384931B2

Reaction notes

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