3-azetidinecarboxylic Acid → 1-(4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid

HRID 1941889Notes

Reaction equation

HRID 1941889 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=3)[N:17]=2)[CH:9]=[N:8]1.[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:25][N:29]4[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]4)=[CH:27][CH:28]=3)[N:17]=2)[CH:9]=[N:8]1

Participants

6

Reactant 3

HCID 931923-azetidinecarboxylic AcidHCID 5003444Sodium cyanoborohydrideHCID 866590394-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde

Product 1

HCID 468649261-(4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acidYield 62.4%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 702EthanolSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of 4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (21 g, 54.5 mmol) and azetidine-3-carboxylic acid (6.61 g, 65.4 mmol) in ethanol (750 mL) and acetic acid (20 mL) was stirred at RT for 30 min. The reaction was cooled to 0° C. and a solution of sodium cyanoborohydride (caution: potential source of cyanide generation) (1.17 g, 27.3 mmol) in ethanol was added slowly. The reaction was warmed to RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The solids were collected by filtration and washed with water. The product was purified by triturating once each with DCM:methanol (98:2), DCM:methanol (96:4) and ethyl acetate to afford 1-(4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (16 g, 34 mmol). The compound had an HPLC retention time=8.48 min.−Column: XbridgeA 4.6×150 mm Flow rate=1.0 mL/min. Buffer=0.05% TFA in water pH2.5. Solvent A=Buffer:Acetonitrile (95:5), Solvent B=Acetonitrile:Buffer (95:5). 0-100% B over 12 minutes. LC/MS M+1=471.2.

Workup

  1. temperatureThe reaction was warmed to RT
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. additionthe residue was diluted with water
  4. filtrationThe solids were collected by filtration
  5. washwashed with water
  6. customThe product was purified
  7. customby triturating once each with DCM:methanol (98:2), DCM:methanol (96:4) and ethyl acetate

Sources & evidence

ORD record
ord-46e0e95e21b344d0bb7f6af81d8a1aa6
Source dataset
uspto-grants-2013_03
Patent number
US08389509B2

Reaction notes

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