Methanol → Trifluoroacetic acid

HRID 1506370Notes

Reaction equation

HRID 1506370 reaction equation
[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=O)=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])[CH:2]([CH3:4])[CH3:3].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C([BH3-])#N.[Na+].[CH3:41][OH:42]>ClC(Cl)C.CC(O)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH2:24][N:30]2[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]2)=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])[CH:2]([CH3:4])[CH3:3].[C:41]([OH:35])([C:26]([F:29])([F:28])[F:27])=[O:42]

Participants

8

Reactant 4

HCID 887MethanolHCID 931923-azetidinecarboxylic AcidHCID 5003444Sodium cyanoborohydrideHCID 866698863-(4-Isobutyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde

Product 2

HCID 6422Trifluoroacetic acidYield 32.5%HCID 671720391-((3-(4-Isobutyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 63651,1-DichloroethaneSolvent

Conditions

Temperature
80 °C

Procedure

To 3-(4-isobutyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 23D, 0.3 g, 0.751 mmol) in dichloroethane (2 mL) and methanol (2 mL) was added azetidine-3-carboxylic acid (0.091 g, 0.901 mmol) followed by 8 drops of AcOH. The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature and sodium cyanoborohydride was added in one lot. The contents were stirred at room temperature for 30 min., concentrated, dissolved in acetonitrile (1.5 mL) and subjected to prep. HPLC purification PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Fractions corresponding to the product were collected and concentrated. The oily residue was freeze dried to yield 1-((3-(4-isobutyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, TFA (0.146 g, 0.244 mmol, 32.5% yield) as a tan solid. The compound had an HPLC retention time=3.55 min. (condition C); LC/MS M+1=485.4. 1H NMR (500 MHz, MeOD) δ ppm 7.83-7.94 (m, 3H) 7.50 (d, J=8.32 Hz, 1H) 7.38 (s, 1H) 7.34 (dd, J=8.05, 1.66 Hz, 1H) 4.33 (s, 2H) 4.18-4.28 (m, 3H) 3.58 (qd, J=8.37, 8.18 Hz, 1H) 3.15 (1H, hidden under CD3OD peak) 2.96-3.01 (m, 4H) 2.62 (d, J=6.94 Hz, 2H) 1.85-1.94 (m, 1H) 0.84 (d, J=6.66 Hz, 6H).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. concentrationconcentrated
  3. dissolutiondissolved in acetonitrile (1.5 mL)
  4. customHPLC purification PHENOMENEX® Luna Axia 30×100 mm
  5. custom10 min.
  6. customFractions corresponding to the product were collected
  7. concentrationconcentrated
  8. customdried

Sources & evidence

ORD record
ord-bfe8de15c8b6402da58736010394daea
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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