Diethyl Ether → HCID 90067331, compound

HRID 929207Notes

Reaction equation

HRID 929207 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[O:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH3:33][Mg]Br.C(OCC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C@:29]([CH3:33])([OH:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1

Participants

5

Reactant 3

HCID 3283Diethyl EtherHCID 90041963HCID 90041963, compoundHCID 178418573HCID 178418573, compound

Product 1

HCID 90067331HCID 90067331, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A stirred solution of (3R,3aR,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (21.4 mg, 0.048 mmol) in THF (0.5 ml) was degassed (3×) and placed under nitrogen after being cooled to 0° C. in an ice bath. Methylmagnesium bromide 3.0 M in diethyl ether (0.16 ml, 0.480 mmol) was added to the reaction mixture. After 20 minutes, the reaction mixture was removed from the bath and allowed to warm to room temperature. After 1 hour, the reaction mixture was transferred via pipette into saturated aqueous NaHCO3 (15 ml) before being partitioned between EtOAc (30 ml) and water (15 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, washed with brine (1×15 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a colorless residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient followed by a 80% 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 C25H22ClN3O4 463.13 observed m/e: 464.12 (M+H)+ (Rt 1.19/2 min); 1H NMR δ (ppm) (CD3OD): 8.00 (s, 1H), 7.74-7.78 (m, 4H), 7.71 (d, J=7.4 Hz, 2H), 7.49 (t, J=7.7 Hz, 2H), 7.39 (t, J=7.4 Hz, 1H), 5.60 (qt, J=5.1 Hz, 1H), 5.00 (t, J=5.2 Hz, 1H), 4.13-4.19 (m, 2H), 4.07 (d, J=4.8 Hz, 1H), 3.70 (d, J=8.1 Hz, 1H), 3.54 (d, J=8.1 Hz, 1H), 1.32 (s, 3H).

Workup

  1. customthe reaction mixture was removed from the bath
  2. temperatureto warm to room temperature
  3. waitAfter 1 hour
  4. custombefore being partitioned between EtOAc (30 ml) and water (15 ml)
  5. extractionThe aqueous layer was extracted with EtOAc (2×20 ml)
  6. washwashed with brine (1×15 ml)
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. customevaporated under reduced pressure
  10. customto give a colorless residue
  11. customThis material was purified by preparative HPLC reverse phase (C-18)
  12. washeluting with a 20%-80% acetonitrile/water+0.05% TFA
  13. customflush
  14. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-eebf2dc5611546af946a94c4a55c61d3
Source dataset
uspto-grants-2016_03
Patent number
US09290517B2

Reaction notes

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