3-azetidinecarboxylic Acid → 1-((3-(2-(1-(4-Fluorophenyl)cyclohexyl)ethyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid

HRID 1506374Notes

Reaction equation

HRID 1506374 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=O)=[CH:23][CH:22]=5)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:31]1[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]1.C([BH3-])#N.[Na+]>CO.ClC(Cl)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH2:29][N:31]3[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]3)=[CH:23][CH:22]=5)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1

Participants

7

Reactant 3

HCID 931923-azetidinecarboxylic AcidHCID 5003444Sodium cyanoborohydrideHCID 866698873-(2-(1-(4-Fluorophenyl)cyclohexyl)ethyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde

Product 1

HCID 671706111-((3-(2-(1-(4-Fluorophenyl)cyclohexyl)ethyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acidYield 4.2%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidCatalystHCID 887MethanolSolventHCID 63651,1-DichloroethaneSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of the 3-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 26C, 89 mg, 0.22 mmol) and the azetidine-3-carboxylic acid (26.7 mg, 0.264 mmol) in methanol (1.5 mL) and dichloroethane (1.5 mL) at room temperature was added 4 to 5 drops of glacial acetic acid. The reaction mixture was heated at 60° C. for 1 hr, cooled to room temperature, and then treated with sodium cyanoborohydride (16.59 mg, 0.264 mmol). The reaction was stirred overnight at room temperature, quenched with ˜1 ml of saturated. aq. sodium bicarbonate, stirred for 30 min, concentrated under reduced pressure and partitioned between dichloromethane and water. The organic layer was washed with brine, dried over anhyd. sodium sulfate, concentrated, dried in vacuo and purified by preparative HPLC using the following conditions: Column. Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.) to yield 4.5 mgs (4.14% over three steps) of 1-((3-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid. The compound had a HPLC retention time=2.53 min. (condition F); LC/MS M+1=489.16; 1H NMR (400 MHz, MeOD) δ ppm 7.84 (1H, d, J=7.78 Hz), 7.36-7.44 (4H, m), 7.05 (2H, t, J=8.78 Hz), 4.34 (2H, s), 4.19 (2H, s), 4.17 (2H, s), 3.42 (1H, quin, J=8.34 Hz), 2.91 (2H, t, J=7.15 Hz), 2.51 (2H, t, J=7.15 Hz), 2.38-2.45 (2H, m), 2.14 (2H, br. s.), 1.92-1.99 (2H, m), 1.35-1.70 (8H, m).

Workup

  1. temperaturecooled to room temperature
  2. customquenched with ˜1 ml of saturated
  3. stirringaq. sodium bicarbonate, stirred for 30 min
  4. concentrationconcentrated under reduced pressure
  5. custompartitioned between dichloromethane and water
  6. washThe organic layer was washed with brine
  7. customdried over anhyd
  8. concentrationsodium sulfate, concentrated
  9. customdried in vacuo
  10. custompurified by preparative HPLC
  11. waitGradient: 50-100% B over 25 minutes
  12. customa 5-minute hold
  13. additionFractions containing the desired product
  14. customdried via centrifugal evaporation
  15. customThe material was further purified via preparative LC/MS with the following conditions
  16. waitGradient: 30-100% B over 25 minutes
  17. customa 5-minute hold
  18. additionFractions containing the desired product
  19. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-ece9edc7aaed47888f4e8a5a7becd06c
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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