Acetic Acid → HCID 24824725, compound

HRID 1172930Notes

Reaction equation

HRID 1172930 reaction equation
[NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C(O)(=O)C.[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[N:27]=[C:26]([C:28]3[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=3)[O:25][N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:22])[CH3:21].C([BH3-])#N.[Na+]>CO>[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[N:27]=[C:26]([C:28]3[CH:29]=[CH:30][C:31]([CH2:32][N:1]4[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]4)=[CH:34][CH:35]=3)[O:25][N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:21])[CH3:22]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 931923-azetidinecarboxylic AcidHCID 5003444Sodium cyanoborohydrideHCID 59556538HCID 59556538, compound

Product 1

HCID 24824725HCID 24824725, compoundYield 55.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent3×

Procedure

Azetidine-3-carboxylic acid (3.72 g, 36.8 mmol) (Synchem) was dissolved in acetic acid (16.03 ml, 280 mmol) and methanol (2 ml). This was added to a stirred suspension of 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (12 g, 35.0 mmol) in MeOH (600 ml). The reaction was stirred for about 18 h. Sodium cyanoborohydride (5.50 g, 88 mmol) was added and the reaction stirred for about 4 h. The reaction was cooled with an ice bath and the precipitate was collected by vacuum filtration and washed with ice cold methanol and then ether. TLC showed impurities still present. The solid was dissolved in 1:1 EtOAc /(6:3:1 CHCl3/MeOH/NH4OH) with a little extra added NH4OH. Chromatography over silica gel in a mixture of 1:1 EtOAc/(6:3:1 CHCl3/MeOH/NH4OH) increasing to all 6:3:1 CHCl3/MeOH/NH4OH eluted the product. The fractions were evaporated to dryness to afford a colorless film/oil. Methanol was added and the mixture swirled but this gave low recovery on filtration. The mixture was dissolved in methanol. and the filtrate evaporated to dryness. The residue was resuspended in the minimum amount of methanol, water was added and the mixture filtered, washed with water and then ether. The residue was dried under vacuum at ambient temperature and then under vacuum at about 60° C. to remove trace methanol to afford 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)azetidine-3-carboxylic acid (8.3 g, 19.40 mmol, 55.4% yield) as a white solid: LCMS (Table 1, Method a) Rt=2.94 min.; MS m/z: 428.31, 430.27 (M+H)+; mp 194.8-195.9° C.; 1H NMR (400 MHz, DMSO) δ ppm 8.12 (d, J=8.34 Hz, 2H), 8.06 (d, J=2.13 Hz, 1H), 8.00 (dd, J=8.67, 2.15 Hz, 1H), 7.54 (d, J=8.36 Hz, 2H), 7.39 (d, J=9.06 Hz, 1H), 4.88-4.77 (m, 1H), 3.67 (s, 2H), 3.48-3.38 (m, 2H), 3.29-3.19 (m, 3H), 1.35 (d, J=6.02 Hz, 6H).

Workup

  1. stirringthe reaction stirred for about 4 h
  2. temperatureThe reaction was cooled with an ice bath
  3. filtrationthe precipitate was collected by vacuum filtration
  4. washwashed with ice cold methanol
  5. dissolutionThe solid was dissolved in 1:1 EtOAc /(6:3:1 CHCl3/MeOH/NH4OH) with a little
  6. additionextra added NH4OH
  7. additionChromatography over silica gel in a mixture of 1:1 EtOAc/(6:3:1 CHCl3/MeOH/NH4OH)
  8. temperatureincreasing to all 6:3:1 CHCl3/MeOH/NH4OH
  9. washeluted the product
  10. customThe fractions were evaporated to dryness
  11. customto afford a colorless film/oil
  12. filtrationthis gave low recovery on filtration
  13. dissolutionThe mixture was dissolved in methanol
  14. customand the filtrate evaporated to dryness
  15. additionwas added
  16. filtrationthe mixture filtered
  17. washwashed with water
  18. customThe residue was dried under vacuum at ambient temperature
  19. customunder vacuum at about 60° C. to remove trace methanol

Sources & evidence

ORD record
ord-32afc8754ad8441d937f18d99e50ee94
Source dataset
uspto-grants-2010_11
Patent number
US07834039B2

Reaction notes

Loading…