Triethylamine → (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-3-hydroxyazetidine-1-carboxamide

HRID 1809541Notes

Reaction equation

HRID 1809541 reaction equation
[CH:1]1N=[CH:4][N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.CCN(CC)CC.N[C@H]1C2[C:24](=[C:25]([C:30]3[N:34]=[C:33]([C:35]4[CH:36]=[CH:37][C:38]([O:43][CH:44]([CH3:46])[CH3:45])=[C:39]([CH:42]=4)[C:40]#[N:41])[O:32][N:31]=3)[CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.Cl.N1CC([OH:52])C1>C(Cl)Cl>[C:40]([C:39]1[CH:42]=[C:35]([C:33]2[O:32][N:31]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[C:10]4[C:24]=3[CH2:23][CH2:22][C@H:9]4[NH:8][C:6]([N:3]3[CH2:2][CH:1]([OH:52])[CH2:4]3)=[O:7])[N:34]=2)[CH:36]=[CH:37][C:38]=1[O:43][CH:44]([CH3:46])[CH3:45])#[N:41]

Participants

6

Reactant 4

HCID 8471Triethylamine3×HCID 682631,1'-CarbonyldiimidazoleHCID 27592903-Hydroxyazetidine hydrochlorideHCID 58344778(R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Product 1

HCID 58344692(R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-3-hydroxyazetidine-1-carboxamideYield 74.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

Prepared using General Procedure 21: To a stirred solution of CDI ((268.5 mg, 1.66 mmol) and Et3N (279.0 mg, 2.76 mmol) in DCM (10 mL) was added the solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (500.0 mg, 1.38 mmol) and Et3N (279.0 mg, 2.76 mmol) in DCM (10 mL) for 1 h at room temperature and then this solution was added to the preparative solution of azetidin-3-ol hydrochloride (453.54 mg, 4.14 mmol)) and Et3N (418.55 mg, 4.14 mmol) in DCM (10 mL) at room temperature. The reaction was stirred at room temperature for 4 h. The solvent was evaporated and the pure product was isolated after silica gel column chromatography (DCM/MeOH) to afford 474.32 mg (74.8%) of (R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-3-hydroxyazetidine-1-carboxamide 234. LCMS-ESI (m/z) calculated for C25H25N5O4: 459.5; found 460.2 [M+H]+, tR=3.20 min. Elemental analysis: C calc.=65.35%; found=65.07%; H calc.=5.48%; found=5.47%; N calc.=15.24%; found=15.14%. 1H NMR (400 MHz, DMSO3) δ 8.50 (d, J=2.3 Hz, 1H), 8.40 (dd, J=9.0, 2.3 Hz, 1H), 8.08-7.89 (m, 1H), 7.55 (d, J=9.2 Hz, 1H), 7.44 (dd, J=7.0, 5.9 Hz, 2H), 6.72 (d, J=8.7 Hz, 1H), 5.57 (d, J=6.5 Hz, 1H), 5.23 (q, J=8.3 Hz, 1H), 4.98 (hept, J=6.1 Hz, 1H), 4.39 (ddd, J=11.3, 6.6, 1.9 Hz, 1H), 4.10-3.91 (m, 2H), 3.60 (dt, J=8.6, 4.3 Hz, 2H), 3.39 (ddd, J=9.4, 7.8, 2.3 Hz, 1H), 3.05 (dt, J=8.4, 5.2 Hz, 1H), 2.47-2.35 (m, 1H), 1.95-1.74 (m, 1H), 1.37 (d, J=6.0 Hz, 6H). 13C NMR (101 MHz, DMSO) δ 173.10, 168.25, 162.48, 159.59, 147.03, 142.45, 134.57, 133.78, 127.32, 127.13, 126.97, 122.25, 115.98, 115.26, 114.86, 102.45, 72.52, 59.93, 59.08, 54.48, 32.86, 31.08, 21.48. Chiral HPLC: (R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-3-hydroxyazetidine-1-carboxamide 234 was eluted in 15% EtOH in hexane: >99.9% ee, tR=20.30 min (Chiral Method 1). Compound 235 was prepared in an analogous fashion from 50: >99.9% ee, tR for the (S)-enantiomer=23.61 min (Chiral Method 1).

Workup

  1. customPrepared
  2. customThe solvent was evaporated
  3. customthe pure product was isolated after silica gel column chromatography (DCM/MeOH)

Sources & evidence

ORD record
ord-aac1b197a69c43d5b0a0eb4ee2e73dde
Source dataset
uspto-grants-2013_01
Patent number
US08362048B2

Reaction notes

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