Isobutyronitrile → 3-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-(3,5-difluorophenyl)-3-hydroxy-2,2-dimethylpropanenitrile

HRID 602666Notes

Reaction equation

HRID 602666 reaction equation
[C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C([Li])CCC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[N:19]2[CH2:22][CH:21]([C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)=[O:24])[CH2:20]2)=[CH:14][CH:13]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[N:19]2[CH2:22][CH:21]([C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)([OH:24])[C:2]([CH3:4])([CH3:3])[C:1]#[N:5])[CH2:20]2)=[CH:14][CH:13]=1

Participants

7

Reactant 4

HCID 6559IsobutyronitrileHCID 25517Ammonium ChlorideHCID 22506671{1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)methanoneHCID 178418339Butyllithium

Product 1

HCID 670658733-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-(3,5-difluorophenyl)-3-hydroxy-2,2-dimethylpropanenitrile

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 84 uL (0.928 mmol) of isobutyronitrile in 2 mL of THF was added a solution of 370 uL (0.928 mmol) of butyllithium (2.5M solution in hexanes), followed by stirring for 50 minutes at −55° C. to 40° C. Then a solution of 334 mg (0.773 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)methanone (as in Preparation 6) in THF was added at −78° C. and the solution was stirred for 5 h at −60° C. to −50° C. A solution of 2 mL of saturated NH4Cl was added to quench the reaction and the reaction mixture was poured into 30 mL of ether and washed with 5 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate=4:1 to afford the title compound. 1NMR (CDCl3) δ 1.24 (s, 3H), 1.34 (S, 3H), 2.58 (br, 1H), 3.12 (br, 1H), 3.40 (br, 2H), 3.60 (br, 1H), 4.26 (m, 1H), 4.43 (s, 1H), 6.76 (m, 1H), 7.06 (m, 2H), 7.25-7.34 (m, 8H); Mass Spectrum: m/e=501 (M+1 35Cl, 35Cl) and 503 (M+1 35Cl, 37Cl).

Workup

  1. stirringthe solution was stirred for 5 h at −60° C. to −50° C
  2. customto quench
  3. customthe reaction
  4. washwashed with 5 mL of aq NaHCO3
  5. dry with materialThe organic layer was dried over Na2SO4
  6. concentrationconcentrated
  7. customThe residue was purified by silica gel chromatography with hexanes/ethyl acetate=4:1

Sources & evidence

ORD record
ord-370d505c98a54802abadbb9397c94af5
Source dataset
uspto-grants-2011_03
Patent number
US07906503B2

Reaction notes

Loading…