Ethylenediamine → (3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

HRID 929195Notes

Reaction equation

HRID 929195 reaction equation
[OH:1][C@@H:2]1[CH2:6][O:5][C@@H:4]2[C@H:7]([O:10][C:11]3[NH:12][C:13]4[C:14]([N:28]=3)=[N:15][C:16]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)=[C:17]([Cl:19])[CH:18]=4)[CH2:8][O:9][C@H:3]12.[CH2:29](N)[CH2:30][NH2:31].C(=S)=S>>[Cl:19][C:17]1[CH:18]=[C:13]2[NH:12][C:11]([O:10][C@H:7]3[C@H:4]4[O:5][CH2:6][C@@H:2]([OH:1])[C@H:3]4[O:9][CH2:8]3)=[N:28][C:14]2=[N:15][C:16]=1[C:20]1[CH:27]=[CH:26][C:23]([C:24]2[NH:31][CH2:30][CH2:29][N:25]=2)=[CH:22][CH:21]=1

Participants

4

Reactant 3

HCID 3301EthylenediamineHCID 6348Carbon DisulfideHCID 900425354-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydro-furo[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]benzonitrile

Product 1

HCID 118413219(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

Conditions

Temperature
50 °C

Procedure

A vial was charged with 4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydro-furo[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]benzonitrile (24.8 mg, 0.062 mmol), ethylenediamine (0.5 ml, 7.46 mmol), and carbon disulfide (5 μl, 0.083 mmol). The reaction mixture was heated to 50° C. for 19 h. The reaction mixture was cooled to room temperature before being concentrated under reduced pressure to 0.1 mL. The concentrated reaction mixture was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 0%-30% acetonitrile/water+0.05% TFA gradient, followed by a 30% acetonitrile/water+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C21H20ClN5O4 441.12 observed m/e: 442.19 (M+H)+ (Rt 0.25/2 min); 1H NMR δ (ppm) (CD3OD): 7.95 (s, 4H), 7.85 (s, 1H), 5.54 (qt, J=5.3 Hz, 1H), 4.96 (t, J=5.2 Hz, 1H), 4.46 (t, J=5.0 Hz, 1H), 4.26-4.30 (m, 1H), 4.16 (dd, J=5.7 Hz, J=10.3 Hz, 1H), 4.14 (s, 4H), 4.11 (dd, J=4.7 Hz, J=10.2 Hz, 1H), 3.89 (dd, J=6.8 Hz, J=8.1 Hz, 1H), 3.59 (t, J=8.6 Hz, 1H).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. concentrationbefore being concentrated under reduced pressure to 0.1 mL
  3. customThe concentrated reaction mixture
  4. customwas purified by preparative HPLC reverse phase (C-18)
  5. washeluting with a 0%-30% acetonitrile/water+0.05% TFA gradient
  6. customflush
  7. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-5eab560796004fba89390f7fa94bc810
Source dataset
uspto-grants-2016_03
Patent number
US09290517B2

Reaction notes

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