Methanol → HCID 131734359, compound

HRID 1506465Notes

Reaction equation

HRID 1506465 reaction equation
[CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=O)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]1.C([BH3-])#N.[Na+].[CH3:42][OH:43]>ClCCCl.C(O)(=O)C>[OH:43][C:42]([C:27]([F:30])([F:29])[F:28])=[O:36].[CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH2:25][N:31]3[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]3)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:29])([F:28])[F:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

7

Reactant 4

HCID 887MethanolHCID 931923-azetidinecarboxylic AcidHCID 5003444Sodium cyanoborohydrideHCID 86669917HCID 86669917, compound

Product 1

HCID 131734359HCID 131734359, compoundYield 44%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 111,2-DichloroethaneSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.015 g, 0.036 mmol) in methanol (2.0 mL) and 1,2-dichloroethane (2.0 mL) was added azetidine-3-carboxylic acid (3.64 mg, 0.036 mmol) followed by 3 drops of acetic acid (2.16 mg, 0.036 mmol). The reaction mixture was heated at 60° C. for 1.5 h. The reaction mixture was cooled to room temperature, and sodium cyanoborohydride (4.83 mg, 0.077 mmol) was added. The reaction mixture was then stirred at room temperature for 15 minutes, concentrated under vacuum, and the crude residue was partitioned between dichloromethane and water. The dichloromethane extract was concentrated, and the residue was chromatographed using reverse-phase preparative HPLC (Column: LUNA 5 u C18, 21×100 mm:Solvent MeOH(B)—H2O(A), 0.1% TFA: 0% B-100% B, Gradient Time 12 min, Stop Time 20 min, Flow Rate 20 ml/min, Wavelength 220 nM) to give 1-((3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid TFA (0.008 g, 0.016 mmol, 44%) as a white solid. The product had an HPLC ret. time=3.78 min. (condition B). LC/MS M+1=502.07. 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (1H, d, J=7.70 Hz), 7.52 (2H, m), 4.41 (2H, s), 4.05-4.34 (4H, m), 3.43-3.62 (1H, m), 2.90-3.21 (4H, m), 2.71 (1H, s), 2.01 (2H, br. s.), 1.76 (4H, br. s.), and 1.28-1.57 (4H, m).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. concentrationconcentrated under vacuum
  3. customthe crude residue was partitioned between dichloromethane and water
  4. extractionThe dichloromethane extract
  5. concentrationwas concentrated
  6. customthe residue was chromatographed
  7. customreverse-phase preparative HPLC (Column: LUNA 5 u C18, 21×100 mm:Solvent MeOH(B)—H2O(A), 0.1% TFA: 0% B-100% B, Gradient Time 12 min, Stop Time 20 min, Flow Rate 20 ml/min, Wavelength 220 nM)

Sources & evidence

ORD record
ord-033dcfe579bc41df9abd48993f61a749
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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