1,2-Dichloroethane → 2-[(7S)-4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]-N-(3-methyl-2,5-dioxo-1',3'-dihydrospiro[imidazolidine-4,2'-inden]-5'-yl)acetamide

HRID 552563Notes

Reaction equation

HRID 552563 reaction equation
Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](O)=[O:20])[CH2:17][C:6]=2[CH:5]=1.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH2:36][C:35]1([C:43](=[O:44])[NH:42][C:41](=[O:45])[N:40]1[CH3:46])[CH2:34]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[CH2:36][C:35]3([C:43](=[O:44])[NH:42][C:41](=[O:45])[N:40]3[CH3:46])[CH2:34]4)=[O:20])[CH2:17][C:6]=2[CH:5]=1

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 18440306(-)-5'-Amino-3-methyl-spiro[imidazolidine-4,2'-indane]-2,5-dioneHCID 67202381(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride

Product 1

HCID 249870692-[(7S)-4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]-N-(3-methyl-2,5-dioxo-1',3'-dihydrospiro[imidazolidine-4,2'-inden]-5'-yl)acetamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of (S)-2-[4-chloro-8-oxo-9-(pyridine-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]acetic acid dihydrochloride (105 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-5′-amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (65 mg, 0.28 mmol) [Bell et al. WO 2004/082605], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.

Workup

  1. customThe reaction mixture is purified directly by HPLC
  2. washeluting with a gradient of H2O
  3. additionThe pure, product-containing fractions
  4. extractionThe resulting mixture is extracted with EtOAc (2×20 mL)
  5. washthe combined organic extracts are washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-94a82c69e9ae48e49bceaab14ebca5a4
Source dataset
uspto-grants-2011_05
Patent number
US07951795B2

Reaction notes

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