Acetonitrile → (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 706386Notes

Reaction equation

HRID 706386 reaction equation
CC1C=CC([C:6]([O-])=[O:7])=CC=1.[CH3:11][C@H:12]1[N:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:23])[C@@H:15]([NH3+:24])[CH2:14][C@H:13]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].[O-:32]P([O-])([O-])=O.[K+].[K+].[K+].[CH:40]1[CH:41]=[CH:42][C:43]2N(O)N=[N:46][C:44]=2[CH:45]=1.[CH3:50][CH2:51][N:52]=[C:53]=[N:54][CH2:55][CH2:56][CH2:57]N(C)C.Cl.[CH3:62][C:63]#N>O>[CH3:11][C@H:12]1[N:17]([CH2:18][C:19]([F:21])([F:22])[F:20])[C:16](=[O:23])[C@@H:15]([NH:24][C:6]([C:41]2[CH:42]=[C:43]3[CH2:57][C@@:56]4([C:63]5[C:53](=[N:52][CH:51]=[CH:50][CH:62]=5)[NH:54][C:55]4=[O:32])[CH2:45][C:44]3=[N:46][CH:40]=2)=[O:7])[CH2:14][C@H:13]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]

Participants

7

Reactant 5

HCID 6342AcetonitrileHCID 62657Potassium Phosphate, TribasicHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 118023940(3S,5S,6R)-6-Methyl-2-oxo-5-(o-tolyl)-1-(2,2,2-trifluoroethyl)piperidin-3-aminium 4-methylbenzoate

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-carboxamideYield 89%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

Salt 39 (0.25 g, 0.58 mmol) was partitioned between IPAC (2.5 mL) and 5 wt % aqueous solution of K3PO4 (2.5 mL), and washed twice with 5 wt % aqueous K3PO4. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give a crude 40. Crude 40 was dissolved in MeCN (1.75 mL) and H2O (1.0 mL). To this was added acid 14 (0.17 g, 0.53 mmol), HOBT (0.11 g, 0.70 mmol) and EDC.HCl (0.17 g, 0.87 mmol). The heterogeneous mixture was aged at 20-25° C. for 16 h. The homogeneous reaction was partitioned between IPAC and saturated aqueous NaHCO3, and washed twice with saturated aqueous NaHCO3. The organic layer was washed with 15 wt % aqueous citric acid solution, saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated to give product 41 (0.29 g, 89% yield). 1H NMR (400 MHz, CD3OD): δ 8.88 (d, J=1.9 Hz, 1H), 8.15 (d, J=1.9 Hz, 1H), 8.08 (dd, J=5.3, 1.6 Hz, 1H), 7.35 (dd, J=7.4, 1.6 Hz, 1H), 7.15-7.18 (m, 4H), 6.95 (dd, J=7.4, 5.3 Hz, 1H), 4.59 (dd, J=11.5, 7.0 Hz, 1H), 3.89-3.92 (m, 1H), 3.81 (dt, J=13.4, 3.2 Hz, 1H), 3.61-3.63 (m, 4H), 3.31-3.32 (m, 2H), 2.93-2.95 (m, 1H), 2.40 (s, 3H), 2.14-2.17 (m, 1H); 1.14 (d, J=6.5 Hz, 3H); 1H NMR (500 MHz, CDCl3): δ 8.91 (s, 1H), 8.56 (s, 1H), 8.17 (dd, J=5.0, 1.5 Hz, 1H), 8.05 (s, 1H), 7.30 (d, J=5.0 Hz, 1H), 7.20 (m, 3H), 7.12 (m, 2H), 6.89 (dd, J=7.5, 5.0 Hz, 1H), 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, J=16.5 Hz, 1H), 3.31-3.23 (m, 2H), 3.17 (d, J=16.5 Hz, 1H), 2.75-2.67 (m, 2H), 2.41 (s, 3H), 1.11 (d, J=6.5 Hz, 3H); 13C NMR (100 MHz, CD3OD): δ 182.8, 171.8, 168.0, 166.7, 157.5, 148.7, 148.2, 139.5, 137.5, 136.8, 133.4, 132.0, 131.6, 130.8, 130.6, 128.4, 128.3, 127.4, 126.6 (q, J=283 Hz), 119.9, 58.1, 53.7, 53.0, 46.7 (q, J=33.4 Hz), 45.2, 42.1, 40.2, 28.8, 19.0, 13.6; HRMS: m/z=564.2219 (M+1), calculated m/z=564.2234 for C30H28F3N5O3.

Workup

  1. washwashed twice with 5 wt % aqueous K3PO4
  2. washThe organic layer was washed with brine
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated
  5. customto give a crude 40
  6. customThe homogeneous reaction
  7. customwas partitioned between IPAC and saturated aqueous NaHCO3
  8. washwashed twice with saturated aqueous NaHCO3
  9. washThe organic layer was washed with 15 wt % aqueous citric acid solution, saturated aqueous NaHCO3 and brine
  10. dry with materialThe organic layer was dried over Na2SO4
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-fd323aec17374ef0bcf01b130683d2fb
Source dataset
uspto-grants-2015_11
Patent number
US09174989B2

Reaction notes

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