3-azetidinecarboxylic Acid → HCID 46846917, compound

HRID 1804516Notes

Reaction equation

HRID 1804516 reaction equation
[CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C([BH3-])#N.[Na+]>CO.ClC(Cl)C.C(O)(=O)C.ClCCl>[CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:16]=3[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1

Participants

8

Reactant 3

HCID 931923-azetidinecarboxylic AcidHCID 5003444Sodium cyanoborohydrideHCID 86659947HCID 86659947, compound

Product 1

HCID 46846917HCID 46846917, compoundYield 52%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 63651,1-DichloroethaneSolvent

Conditions

Temperature
60 °C

Procedure

To a mixture of 2-methyl-4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (0.050 g, 0.125 mmol) and azetidine-3-carboxylic acid (0.015 g, 0.150 mmol) in methanol (0.5 mL) and dichloroethane (0.5 mL) at room temperature was added 3 drops of acetic acid via a pasteur pipette. The reaction mixture was heated at 60° C. for 1 h. The reaction was cooled to room temperature, sodium cyanoborohydride (9.59 mg, 0.150 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a white solid which was triturated with methanol with sonication and filtered. The resulting white solid was purified by flash silica gel chromatography using a mixture of methanol, dichloromethane, and ammonium hydroxide (10:90:0-20:80:1) to give 1-(2-methyl-4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (0.032 g, 0.065 mmol, 52% yield) as a white solid. The compound had an HPLC ret. time=2.82 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=485.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.38 (s, 3H), 3.17 (s, 2H), 3.22-3.24 (m, 1H), 3.46 (br. s., 2H), 3.63 (s, 2H), 7.51 (d, J=7.77 Hz, 1H), 7.57-7.73 (m, 5H), 7.86-7.94 (m, 2H), and 12.33 (br. s., 1H).

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. washwashed with water
  3. washwashed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationConcentration under reduced pressure
  6. customafforded a white solid which
  7. customwas triturated with methanol with sonication
  8. filtrationfiltered
  9. customThe resulting white solid was purified by flash silica gel chromatography
  10. additiona mixture of methanol, dichloromethane, and ammonium hydroxide (10:90:0-20:80:1)

Sources & evidence

ORD record
ord-db16381962804917984f6c8d9b752180
Source dataset
uspto-grants-2013_01
Patent number
US08354398B2

Reaction notes

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