Ethylene Glycol → HCID 66858789, compound

HRID 1803312Notes

Reaction equation

HRID 1803312 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=[O:30])[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.[CH2:41](O)[CH2:42][OH:43].O.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)(C(F)(F)F)=O>C1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27]5([CH2:28][CH2:29][N:23]4[N:22]=3)[O:43][CH2:42][CH2:41][O:30]5)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1

Participants

6

Reactant 4

HCID 174Ethylene GlycolHCID 6422Trifluoroacetic acidHCID 521998p-Toluenesulfonic acid monohydrateHCID 66860172HCID 66860172, compound

Product 1

HCID 66858789HCID 66858789, compoundYield 35%

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Procedure

A solution of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (84 mg, 0.180 mmol, from example 137) in benzene (1 mL) was treated with ethylene glycol (0.011 mL, 0.198 mmol), and 4-methylbenzenesulfonic acid, hydrate (34.2 mg, 0.180 mmol). The mixture was heated to reflux using a Dean-Stark trap for 6 h, the mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The aqueous phase was extracted twice more with ethyl acetate and the combined organic layers were combined and washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (39.4 mg, 34% yield) as a TFA salt. LC-MS (M+H)+ 511.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.75 (1 H, br. s.), 7.30-7.33 (1 H, m), 7.25-7.29 (2 H, m), 7.09-7.17 (3 H, m), 7.06 (1 H, br. s.), 7.02 (1 H, dd, J=8.5, 2.4 Hz), 4.45-4.54 (1 H, m), 4.32-4.42 (2 H, m), 4.02-4.11 (4 H, m), 3.83 (3 H, s), 2.32-2.40 (1 H, m), 2.23 (1 H, d, J=13.7 Hz), 2.08-2.19 (2 H, m).

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux
  3. customfor 6 h
  4. customquenched with saturated sodium bicarbonate
  5. extractionextracted with ethyl acetate
  6. extractionThe aqueous phase was extracted twice more with ethyl acetate
  7. washwashed with brine
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated in vacuo
  10. customThe crude product was purified

Sources & evidence

ORD record
ord-0e0142089db046b88e067781ed2a02c3
Source dataset
uspto-grants-2013_01
Patent number
US08349880B2

Reaction notes

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