Triethylamine → N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

HRID 271953Notes

Reaction equation

HRID 271953 reaction equation
C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[C:10]1=[O:30].Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].Cl.Cl.[O:46]=[C:47]1[NH:55][C:50]2=[N:51][CH:52]=[CH:53][CH:54]=[C:49]2[N:48]1[CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>O1CCCC1.ClCCl>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[C:10](=[O:30])[C@H:9]([NH:8][C:32]([N:59]2[CH2:60][CH2:61][CH:56]([N:48]3[C:49]4[C:50](=[N:51][CH:52]=[CH:53][CH:54]=4)[NH:55][C:47]3=[O:46])[CH2:57][CH2:58]2)=[O:33])[CH2:15][CH2:14]1

Participants

7

Reactant 4

HCID 8471Triethylamine2×HCID 821294-Nitrophenyl chloroformateHCID 222931811-(piperidin-4-yl)-1H,2H,3H-imidazo[4,5-b]pyridin-2-one dihydrochlorideHCID 60037855(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(1,3-thiazol-2-ylmethyl)azepan-2-one

Product 1

HCID 11157497N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamideYield 76.8%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

Triethylamine (0.156 mL, 0.1.12 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(1,3-thiazol-2-ylmethyl)azepan-2-one (302 mg, 0.895 mmol) and 4-nitrophenyl chloroformate (217 mg, 1.074 mmol) in tetrahydrofuran (15 mL) at 0° C. After 30 min, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (782 mg, 2.685 mmol), triethylamine (5.37 mmol) and dichloromethane (15 mL) were added and the mixture allowed to warm to ambient temperature. The reaction was stirred overnight, concentrated, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% →8% methanol/dichloromethane) gave the title compound (400 mg). MS 582.2109 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J=4.5 Hz, 1H), 7.73 (d, J=3.4 Hz, 1H), 7.35 (m, 2H), 7.0 (m, 2H), 6.98 (dd, J=5.4, 7.8 Hz, 1H), 6.85 (m, 1H), 6.21 (d, J=5.3 Hz, 1H), 5.0 (app q, J=15 Hz, 2H), 4.85 (dd, J=5.0, 11.1 Hz, 1H), 4.58 (m, 1H), 4.27 (br dd, 2H), 4.00 (dd, J=10.6, 15.1 Hz, 1H), 3.50 (d, J=15.1 Hz, 1H), 3.0 (br dd, 1 h), 2.88 (dd, J=10.0, 10.0 Hz, 1H), 2.2-1.6 (m, 8H).

Workup

  1. concentrationconcentrated
  2. additiondiluted with saturated aqueous sodium bicarbonate
  3. extractionextracted with dichloromethane (2×)
  4. washThe organic layer was washed with water, saturated brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customPurification by silica gel chromatography (0% →8% methanol/dichloromethane)

Sources & evidence

ORD record
ord-de4845ccaa8c4a1b93bb1369523e2498
Source dataset
uspto-grants-2008_11
Patent number
US07452903B2

Reaction notes

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