Hydrochloric Acid → HCID 178519926, compound

HRID 1846791Notes

Reaction equation

HRID 1846791 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]([O:8][CH:9]2[CH2:12][CH:11]([C:13]([C:15]3[N:19](COC)[C:18]4[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=4[N:16]=3)=[O:14])[CH2:10]2)=[N:6][CH:7]=1.Cl>C1COCC1>[NH:16]1[C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[N:19]=[C:15]1[C:13]([C@H:11]1[CH2:10][C@@H:9]([O:8][C:5]2[C:4]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[CH2:12]1)=[O:14].[NH:16]1[C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[N:19]=[C:15]1[C:13]([C@H:11]1[CH2:10][C@H:9]([O:8][C:5]2[C:4]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[CH2:12]1)=[O:14]

Participants

5

Reactant 2

HCID 313Hydrochloric AcidHCID 67481419{3-[5-Fluoro-3-(tetrahydro-pyran-4-YL)-pyridin-2-yloxy]-cyclobutyl}-(1-methoxymethyl-1H-benzoimidazol-2-YL)-methanone

Product 2

HCID 178519925HCID 178519925, compoundHCID 178519926HCID 178519926, compoundYield 36.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of {3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutyl}-(1-methoxymethyl-1H-benzoimidazol-2-yl)-methanone (1.2 g) in THF (20 mL) at RT was added concentrated HCl (20 mL). The reaction mixture was stirred at RT for 1 h and then heated to 60° C. for 6 h. The mixture was partially concentrated, neutralized with saturated NaHCO3 and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×10 mL) and the combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to get a residue, which was purified by flash column chromatography on silica gel (5% to 30% EtOAc in DCM) gave cis-(1H-benzoimidazol-2-yl)-{3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutyl}-methanone and trans-(1H-benzoimidazol-2-yl)-{3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutyl}-methanone (196 mg) as white solid. [M+1] 396 each. IC50 (uM) 0.00003 (cis) and 0.0005 (trans).

Workup

  1. temperatureheated to 60° C. for 6 h
  2. concentrationThe mixture was partially concentrated
  3. additiondiluted with EtOAc
  4. extractionThe aqueous phase was extracted with EtOAc (2×10 mL)
  5. washthe combined organic extracts were washed with brine (10 mL)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto get a residue, which
  10. customwas purified by flash column chromatography on silica gel (5% to 30% EtOAc in DCM)

Sources & evidence

ORD record
ord-8a99d43cdefe4b0b9d794485447722c3
Source dataset
uspto-grants-2015_02
Patent number
US08952037B2

Reaction notes

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