3-azetidinecarboxylic Acid → Trifluoroacetic acid

HRID 1506422Notes

Reaction equation

HRID 1506422 reaction equation
[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[S:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:31]1[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]1.C([BH3-])#N.[Na+].CC#N.[OH2:45]>CO.ClCCCl.CC(O)=O>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]3[S:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH2:29][N:31]6[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]6)=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:11]([OH:36])([C:12]([F:15])([F:14])[F:13])=[O:45]

Participants

9

Reactant 4

HCID 931923-azetidinecarboxylic AcidHCID 5003444Sodium cyanoborohydrideHCID 18373917Acetonitrile--water (1/1)HCID 866699012-(3-Phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazole-7-carbaldehyde

Product 2

HCID 6422Trifluoroacetic acidYield 2.279%HCID 671703321-((2-(3-Phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl)methyl)azetidine-3-carboxylic acid

Reagents, catalysts & solvents 3

HCID 176Acetic AcidCatalystHCID 111,2-DichloroethaneSolventHCID 887MethanolSolvent

Conditions

Temperature
80 °C

Procedure

To a stirring solution of 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazole-7-carbaldehyde (Preparation 56F, 352 mg, 0.825 mmol) and azetidine-3-carboxylic acid (100 mg, 0.990 mmol) in MeOH (5 mL) and 1,2-dichloroethane (5.00 mL) was added at room temperature about 3-4 drops of AcOH. The reaction mixture was immersed in an oil bath heated at 80° C. and stirred for 1 h. It was cooled to room temperature and was treated with sodium cyanoborohydride (62.2 mg, 0.990 mmol), which was added in one portion. The reaction mixture was stirred at room temperature for 1 h, concentrated, and half of the material was purified by prep. HPLC (HPLC conditions: Phenomenex Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min.) to yield 1-((2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl)methyl)azetidine-3-carboxylic acid, TFA (12 mg, 0.019 mmol, 2.279% yield) as a fluffy light yellow solid. The product had an LC ret. time=3.155 min. (condition: Start % B=0, Final % B=100, Gradient Time=4 min, Flow Rate=4 ml/min, Wavelength=220, Solvent Pair=MeOH−H2O−TFA; Solvent A=10% MeOH−90% H2O−0.1% TFA; Solvent B=90% MeOH−10% H2O−0.1% TFA; Column 1=1: Waters Sunfire C18 4.6×50 mm (4 min. grad)); LC/MS M+1=512.12. 1H NMR (400 MHz, CD3OD) δ ppm 7.65 (1H, s), 7.63 (1H, d, J=1.32 Hz), 7.53-7.62 (4H, m), 7.46 (1H, s), 7.41 (1H, dd, J=7.92, 1.76 Hz), 4.42 (2H, s), 4.34 (2H, d, J=3.08 Hz), 4.32 (2H, d, J=1.10 Hz), 3.60-3.70 (1H, m), 3.21 (4H, s).

Workup

  1. customThe reaction mixture was immersed in an oil bath
  2. temperatureIt was cooled to room temperature
  3. additionwas added in one portion
  4. stirringThe reaction mixture was stirred at room temperature for 1 h
  5. concentrationconcentrated
  6. customhalf of the material was purified by prep

Sources & evidence

ORD record
ord-cd70cfc33d334bfea5c23f89d3928f73
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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