Triethylamine → (6S)-N-[(3S,5S,6R)-6-Methyl-5-(2-methylphenyl)-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide

HRID 406572Notes

Reaction equation

HRID 406572 reaction equation
Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[NH:22][C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[C@@:15]21[CH2:33][C:25]1=[N:26][CH:27]=[C:28]([C:30](O)=[O:31])[CH:29]=[C:24]1[CH2:23]2.Cl.[NH2:35][C@H:36]1[CH2:41][C@@H:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[CH3:48])[C@@H:39]([CH3:49])[N:38]([CH2:50][C:51]([F:54])([F:53])[F:52])[C:37]1=[O:55].N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>CN(C=O)C>[CH3:49][C@H:39]1[N:38]([CH2:50][C:51]([F:53])([F:54])[F:52])[C:37](=[O:55])[C@@H:36]([NH:35][C:30]([C:28]2[CH:29]=[C:24]3[CH2:23][C@@:15]4([C:16]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:22][C:14]4=[O:13])[CH2:33][C:25]3=[N:26][CH:27]=2)=[O:31])[CH2:41][C@H:40]1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68746980(S)-2'-oxo-1',2',5,7-tetrahydrospiro(cyclopenta(b)pyridine-6,3'-pyrrolo(2,3-b)-bipyridine)-3-carboxylic acid2×HCID 68754170(3S,5S,6R)-3-amino-6-methyl-5-(2-methylphenyl)-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride2×

Product 1

HCID 68751311(6S)-N-[(3S,5S,6R)-6-Methyl-5-(2-methylphenyl)-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
23 °C

Procedure

N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.10 g, 0.53 mmol) was added to a solution of (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 1) (111 mg, 0.39 mmol), (3S,5S,6R)-3-amino-6-methyl-5-(2-methylphenyl)-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride (described in Intermediate 6) (127 mg, 0.38 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol(HOAt, 15 mg, 0.11 mmol), and triethylamine (0.16 mL, 0.91 mmol) in DMF (3 mL), and the resulting mixture was stirred at 23° C. for 18 h. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (2×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 1% methanol→7% methanol/dichloromethane to afford the title compound. HRMS: m/z=564.2219 (M+1), calculated m/z=564.2234 for C30H28F3N5O3. 1H NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 8.56 (s, 1H), 8.17 (dd, 1H, J=5.0, 1.5 Hz), 8.05 (s, 1H), 7.30 (d, 1H, J=5.0 Hz), 7.20 (m, 3H), 7.12 (m, 2H), 6.89 (dd, 1H, J=7.5, 5.0 Hz), 5.00-4.94 (m, 1H), 4.55 (m, 1H), 3.93-3.90 (m, 1H), 3.81-3.76 (m, 2H), 3.68 (d, 1H, J=16.5 Hz), 3.31-3.23 (m, 2H), 3.17 (d, 1H, J=16.5 Hz), 2.75-2.67 (m, 2H), 2.41 (s, 3H), 1.11 (d, 3H, J=6.5 Hz).

Workup

  1. customThe reaction mixture was then partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (2×30 mL)
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated
  5. customThe residue was purified by flash column chromatography on silica gel
  6. washeluting with 1% methanol

Sources & evidence

ORD record
ord-6e1c1403797e4b3086155c0b100f2d13
Source dataset
uspto-grants-2014_06
Patent number
US08754096B2

Reaction notes

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