5-(3-((1R)-1-(3-chloro-2-hydroxypropylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile → (R)-5-(3-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

HRID 1809509Notes

Reaction equation

HRID 1809509 reaction equation
Cl[CH2:2][CH:3]([OH:32])[CH2:4][NH:5][C@H:6]1[C:14]2[C:9](=[C:10]([C:15]3[N:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([CH:27]=4)[C:25]#[N:26])[O:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>CC#N>[OH:32][CH:3]1[CH2:4][N:5]([C@H:6]2[C:14]3[C:9](=[C:10]([C:15]4[N:19]=[C:18]([C:20]5[CH:21]=[CH:22][C:23]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([CH:27]=5)[C:25]#[N:26])[O:17][N:16]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:2]1

Participants

3

Reactant 1

HCID 673140155-(3-((1R)-1-(3-chloro-2-hydroxypropylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Product 1

HCID 58344567(R)-5-(3-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrileYield 27%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
75 °C

Procedure

To a flask containing 5-(3-((1R)-1-(3-chloro-2-hydroxypropylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile INT-15 (77.0 mg, 0.17 mmol) in CH3CN (4 mL) was added TEA (44.5 μL, 0.32 mmol). The reaction mixture was heated at 75° C. overnight then concentrated in vacuo, dissolved in DCM and purified by chromatography (MeOH/DCM) to provide 19 mg (27%) of (R)-5-(3-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 83 as a white solid. LCMS-ESI (m/z) calculated for C24H24N4O3: 416.5; found 417.1 [M+H]+, tR=6.19 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 8.09 (dd, J=7.7, 0.7 Hz, 1H), 7.44 (d, J=7.4 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 4.79 (dt, J=12.2, 6.1 Hz, 1H), 4.46 (p, J=5.8 Hz, 1H), 3.99 (dd, J=7.0, 3.5 Hz, 1H), 3.70 (dt, J=19.2, 5.6 Hz, 2H), 3.47 (d, J=6.7 Hz, 1H), 3.41 (dd, J=16.6, 8.7 Hz, 1H), 3.28 (ddd, J=17.5, 8.8, 4.2 Hz, 1H), 3.20-3.13 (m, 1H), 3.13-3.05 (m, 1H), 2.13 (dddd, J=16.9, 12.6, 8.4, 5.5 Hz, 2H), 1.47 (d, J=6.1 Hz, 6H). (S)-5-(3-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 84 was prepared in an analogous fashion from (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50.

Workup

  1. concentrationthen concentrated in vacuo
  2. dissolutiondissolved in DCM
  3. custompurified by chromatography (MeOH/DCM)

Sources & evidence

ORD record
ord-3579c67975b643c285256088dd8bfdfc
Source dataset
uspto-grants-2013_01
Patent number
US08362048B2

Reaction notes

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