Triethylamine → Telcagepant

HRID 20161Notes

Reaction equation

HRID 20161 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]([F:28])([F:27])[F:26])[C:10]1=[O:29].Cl[C:31](OC1C=CC([N+]([O-])=O)=CC=1)=[O:32].Cl.Cl.[O:45]=[C:46]1[NH:54][C:49]2=[N:50][CH:51]=[CH:52][CH:53]=[C:48]2[N:47]1[CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]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]([F:28])([F:26])[F:27])[C:10](=[O:29])[C@H:9]([NH:8][C:31]([N:58]2[CH2:59][CH2:60][CH:55]([N:47]3[C:48]4[C:49](=[N:50][CH:51]=[CH:52][CH:53]=4)[NH:54][C:46]3=[O:45])[CH2:56][CH2:57]2)=[O:32])[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 23653826(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one

Product 1

HCID 11319053TelcagepantYield 62.7%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

Triethylamine (0.038 mL, 0.276 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one (89 mg, 0.276 mmol) and 4-nitrophenyl chloroformate (56 mg, 0.276 mmol) in tetrahydrofuran (3 mL) at 0° C. After 30 min, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (88 mg, 0.304 mmol), triethylamine (0.152 mL, 1.104 mmol), and dichloromethane (5 mL) were added and the mixture allowed to warm to ambient temperature. After 48 h, the mixture was concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave the title compound (98 mg). The title compound was converted to the HCl salt with 2M HCl in ether. MS 567.2 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.11 (dd, J=7.8 Hz, 1.0 Hz, 1H), 8.00 (dd, J=5.9 Hz, 1.0 Hz, 1H), 7.34-7.31 (m, 1H), 7.19-7.13 (m, 3H), 4.86-4.83 (m, 1H), 4.62-4.57 (m, 1H), 4.49-4.41 (m, 1H), 4.33-4.25 (m, 3H), 4.12-4.04 (m, 1H), 3.51-3.46 (m, 1H), 3.18-3.14 (m, 1H), 3.09-2.96 (m, 2H), 2.51-2.44 (m, 1H), 2.33-2.25 (m, 1H), 2.22-2.10 (m, 3H), 1.90-1.81 (m, 3H).

Workup

  1. waitAfter 48 h
  2. concentrationthe mixture was concentrated
  3. customPurification by silica gel chromatography [100% dichloromethane→95% dichloromethane/methanol (10% ammonium hydroxide/methanol)]

Sources & evidence

ORD record
ord-e09a775319d24b67ab040f95ce8b25d7
Source dataset
uspto-grants-2010_06
Patent number
US07745427B2

Reaction notes

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