Cyclobutanone → 1-{[6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl](hydroxy)methyl}cyclobutanol

HRID 1882111Notes

Reaction equation

HRID 1882111 reaction equation
[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:34]1(=[O:38])[CH2:37][CH2:36][CH2:35]1.C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]([OH:33])[C:34]5([OH:38])[CH2:37][CH2:36][CH2:35]5)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1

Participants

7

Reactant 3

HCID 14496CyclobutanoneHCID 516892Sodium BicarbonateHCID 593314196-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde

Product 1

HCID 593315641-{[6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl](hydroxy)methyl}cyclobutanolYield 6.9%

Reagents, catalysts & solvents 3

HCID 10313229titanium(III) trichlorideCatalystHCID 176Acetic AcidSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (940 mg) in acetic acid (10 mL) were added cyclobutanone (2.1 g) and 20% aqueous titanium trichloride solution (3.1 g), and the mixture was stirred under argon at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, and neutralized with saturated aqueous sodium hydrogen carbonate solution, and filtered through celite to remove the insoluble material. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. The obtained pale-yellow amorphous solid was purified by preparative HPLC to give the title compound (75 mg, yield 6.9%) as a colorless amorphous solid. MS: 537 (MH+).

Workup

  1. filtrationfiltered through celite
  2. customto remove the insoluble material
  3. extractionThe filtrate was extracted with ethyl acetate
  4. washThe ethyl acetate layer was washed with saturated brine
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. customto give a pale-yellow amorphous solid from a fraction
  8. washeluted with ethyl acetate
  9. customThe obtained pale-yellow amorphous solid was purified by preparative HPLC

Sources & evidence

ORD record
ord-fe7155c561b045fbb6fc75c239a347b1
Source dataset
uspto-grants-2012_11
Patent number
US08318746B2

Reaction notes

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