Acetic Acid → Trifluoroacetic acid

HRID 1506529Notes

Reaction equation

HRID 1506529 reaction equation
[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]4[C:18]5[C:23]([CH2:24][CH2:25][C:14]=34)=[CH:22][C:21]([CH:26]=O)=[CH:20][CH:19]=5)=[CH:9][C:8]=2[C:28]([F:31])([F:30])[F:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1.C(O)(=[O:41])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:57][OH:58]>ClCCCl>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]4[C:18]5[C:23]([CH2:24][CH2:25][C:14]=34)=[CH:22][C:21]([CH2:26][N:32]3[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]3)=[CH:20][CH:19]=5)=[CH:9][C:8]=2[C:28]([F:31])([F:30])[F:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[C:57]([OH:41])([C:28]([F:31])([F:30])[F:29])=[O:58]

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 887MethanolHCID 931923-azetidinecarboxylic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 866699333-(4-Cyclohexyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde

Product 2

HCID 6422Trifluoroacetic acidYield 52.3%HCID 671703911-((3-(4-Cyclohexyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 3-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 118E, 20 mg, 0.047 mmol), 1,2-dichloroethane (0.4 mL), MeOH (0.4 mL), azetidine-3-carboxylic acid (14.26 mg, 0.141 mmol) and acetic acid (0.016 mL, 0.282 mmol) was heated at 50° C. (oil bath temp.) for 1 h under nitrogen. The mixture was cooled to room temperature and sodium triacetoxyborohydride (29.9 mg, 0.141 mmol) was added in one lot. The contents were stirred at room temperature for 3 hr. The mixture was concentrated and dissolved in methanol (1.8 mL) and dichloromethane (0.2 mL). Purification using reverse phase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization gave 1-((3-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, TFA (16 mg, 0.025 mmol, 52.3% yield) as a white solid. The compound had an HPLC retention time=3.77 min. (condition C); LC/MS M+1=511.2; 1H NMR (400 MHz, MeOD) δ ppm 7.99-8.05 (3H, m), 7.78 (1H, d, J=8.6 Hz), 7.51 (1H, d, J=1.1 Hz), 7.47 (1H, dd, J=7.9, 1.8 Hz), 4.46 (2H, s), 4.33-4.38 (4H, m), 3.63-3.74 (1H, m), 3.09-3.15 (4H, m), 3.00 (1H, t, J=11.7 Hz), 1.77-1.96 (5H, m), 1.54-1.67 (2H, m, J=12.0, 12.0, 11.9, 2.1 Hz), 1.35-1.53 (3H, m).

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. concentrationThe mixture was concentrated
  3. dissolutiondissolved in methanol (1.8 mL)
  4. customPurification
  5. concentrationphase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization

Sources & evidence

ORD record
ord-f4a9c925aee94144b0ec42dbcdf246e7
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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