Dimethylformamide → (R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate

HRID 2378998Notes

Reaction equation

[C:1](=[O:34])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:15][C:6]2[C:7]3[CH:8]=[N:9][NH:10][C:11]=3[C:12]([Cl:14])=[CH:13][C:5]=2[CH2:4]1.CN(C=O)C.C(N(CC)CC)C.[NH:47]1[CH2:52][CH2:51][CH:50]([N:53]2[C:61]3[C:56](=[N:57][CH:58]=[CH:59][CH:60]=3)[NH:55][C:54]2=[O:62])[CH2:49][CH2:48]1>>[O:62]=[C:54]1[NH:55][C:56]2=[N:57][CH:58]=[CH:59][CH:60]=[C:61]2[N:53]1[CH:50]1[CH2:51][CH2:52][N:47]([C:1]([O:2][C@H:3]2[C:17](=[O:18])[N:16]([CH2:19][C:20]([F:23])([F:21])[F:22])[CH2:15][C:6]3[C:7]4[CH:8]=[N:9][NH:10][C:11]=4[C:12]([Cl:14])=[CH:13][C:5]=3[CH2:4]2)=[O:34])[CH2:48][CH2:49]1

Participants

Reactant 4

HCID 6228Dimethylformamide

HCID 8471Triethylamine

HCID 22293182Bms-973013

HCID 59732082(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-nitrophenyl carbonate

Product 1

HCID 59006334(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylateYield 80%

Procedure

(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-nitrophenyl carbonate (115 mg, 0.23 mmol) in DMF (10.00 mL, 129 mmol) was added triethylamine (0.128 mL, 0.920 mmol) followed by 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one, 1.00HCl (70.3 mg, 0.276 mmol). After 12 h, the solvent was removed and the product was purified by flash chromatography using 5% methanol in dichloromethane to give (R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (106 mg, 0.183 mmol, 80% yield). 1H NMR (500 MHz, CD3OD): in δ 8.29 (s, 1H), 8.03 (br, 1H), 7.96 (d, J=5.5 Hz, 1H), 7.71 (m, 1H), 7.27 (s, 1H), 7.13-7.12 (m, 1H), 6.10 (m, 1H), 5.44 (d, J=17 Hz, 1H), 4.88 (d, J=17 Hz, 1H), 4.72-4.60 (m, 2H), 4.50-4.39 (m, 1H), 4.38-4.22 (m, 1H), 4.21-4.02 (m, 1H), 3.40-3.40 (m, 1H), 3.39-3.27 (m, 2H), 3.23-2.97 (m, 2H), 2.71-2.23 (m, 2H), 1.95-1.74 (m, 2H); MS (ESI) 578 (M+H); Rf=2.15.

Workup

customthe solvent was removed
customthe product was purified by flash chromatography

Sources & evidence

ORD record: ord-09489415075f4db1bddfbcc1b4241876
Source dataset: uspto-grants-2008_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07470680B2

Reaction notes

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