1-Hydroxybenzotriazole → N-((3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydro-3H-spiro[furo[2,3-b]pyridine-2,3'-pyrrolo[2,3-b]pyridine]-5-carboxamide

HRID 931402Notes

Reaction equation

HRID 931402 reaction equation
[O:1]=[C:2]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[O:29][C:21]1=[N:22][CH:23]=[C:24]([C:26]([OH:28])=O)[CH:25]=[C:20]1[CH2:19]2.[NH2:30][C@H:31]1[CH2:36][C@@H:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:34]([CH3:43])[N:33]([CH2:44][C:45]([F:48])([F:47])[F:46])[C:32]1=[O:49].Cl.N[C@H]1C[C@@H](C2C=CC=CC=2)[C@@H](C)N(CC(F)(F)F)C1=O.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:43][C@H:34]1[N:33]([CH2:44][C:45]([F:48])([F:46])[F:47])[C:32](=[O:49])[C@@H:31]([NH:30][C:26]([C:24]2[CH:25]=[C:20]3[CH2:19][C:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[C:2]4=[O:1])[O:29][C:21]3=[N:22][CH:23]=2)=[O:28])[CH2:36][C@H:35]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1

Participants

8

Reactant 6

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68749751(3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochlorideHCID 68749752(3S,5S,6R)-3-Amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-oneHCID 900505402'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydro-3H-spiro[furo[2,3-b]pyridine-2,3'-pyrrolo[2,3-b]pyridine]-5-carboxylic acid

Product 1

HCID 131735169N-((3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydro-3H-spiro[furo[2,3-b]pyridine-2,3'-pyrrolo[2,3-b]pyridine]-5-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 2′-oxo-1′-((2-(trimethylsilyl)ethoxy)methyl)-1′,2′-dihydro-3H-spiro[furo[2,3-b]pyridine-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid, (described in Intermediate 5) (0.095 g, 0.23 mmol), (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one, (described in Intermediate 1) (0.098 g, 0.35 mmol), N,N-diisopropylethylamine (0.12 mL, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.065 g, 0.35 mmol) and HOBT (0.015 g, 0.12 mmol) in DMF (3 mL) was stirred initially at 0° C. for 15 min, then gradually warmed to 23° C. and stirred for 3 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in petroleum ether to give the title compounds as a 1:1 mixture of isomers. MS: m/z=682.5 (M+1).

Workup

  1. temperaturegradually warmed to 23° C.
  2. stirringstirred for 3 h
  3. customThe reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate
  4. dry with materialThe organic layer was dried over sodium sulfate
  5. concentrationconcentrated
  6. customThe residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in petroleum ether

Sources & evidence

ORD record
ord-fc3574ec31384f328832f5a0a2da9470
Source dataset
uspto-grants-2016_03
Patent number
US09296750B2

Reaction notes

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