1,2-Dichloroethane → 2'-Oxo-N-{(7R)-8-oxo-9-[4-(trifluoromethyl)benzyl]-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl}-1',2',5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide

HRID 552566Notes

Reaction equation

HRID 552566 reaction equation
[NH2:1][C@H:2]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:13][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[CH:11]=[CH:12][C:4]=2[CH2:3]1.[O:28]=[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]21[CH2:48][C:40]1[CH:41]=[N:42][C:43]([C:45](O)=[O:46])=[CH:44][C:39]=1[CH2:38]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:28]=[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]21[CH2:48][C:40]1[CH:41]=[N:42][C:43]([C:45]([NH:1][C@H:2]3[C:15](=[O:16])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=4)[CH2:13][C:5]4[C:6]5[CH:7]=[N:8][NH:9][C:10]=5[CH:11]=[CH:12][C:4]=4[CH2:3]3)=[O:46])=[CH:44][C:39]=1[CH2:38]2

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 57974027(+/-)-2'-Oxo-1',2',5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid2×HCID 597318587-(R)-amino-9-(4-trifluoromethylbenzyl)-6,7,9,10-tetrahydro-3H-2,3,9-triazacyclohepta[e]inden-8-one

Product 1

HCID 249870682'-Oxo-N-{(7R)-8-oxo-9-[4-(trifluoromethyl)benzyl]-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl}-1',2',5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 7-(R)-amino-9-(4-trifluoromethylbenzyl)-6,7,9,10-tetrahydro-3H-2,3,9-triazacyclohepta[e]inden-8-one (86 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (79 mg, 0.28 mmol, described in Intermediate 5), 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-96afd459da864c978f67aaa4905211ac
Source dataset
uspto-grants-2011_05
Patent number
US07951795B2

Reaction notes

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