(R)-3-Pyrrolidinol → (3R)-1-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)pyrrolidin-3-ol

HRID 1506523Notes

Reaction equation

HRID 1506523 reaction equation
[C: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])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]1[C@@H:35]([OH:36])[CH2:34][NH:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C: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:33]3[CH2:32][CH2:31][C@@H:35]([OH:36])[CH2:34]3)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:29])([F:30])[F:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

5

Reactant 3

HCID 2759337(R)-3-PyrrolidinolHCID 5049666Sodium triacetoxyborohydrideHCID 866698753-(5-Phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde

Product 1

HCID 67170524(3R)-1-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)pyrrolidin-3-olYield 80%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 88A, 20 mg, 0.049 mmol), 3R-Pyrrolidinol (21.23 mg, 0.244 mmol), sodium triacetoxyborohydride (31.0 mg, 0.146 mmol) and dichloromethane (1 mL) was stirred at room temperature overnight. The mixture was concentrated and dissolved in methanol. HPLC purification (Column: Waters XBridge C18, 19×250 mm, 5-nm 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: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) and concentration gave the titled compound (18.8 mg, 0.039 mmol, 80% yield) as a solid. The compound had an HPLC retention time=2.15 min. (Column: Supelco Ascentis Express C-18, 4.6×50 mm, 2.7 um; Solvent A=0.05% TFA in H2O:MeCN (95:5); Solvent B=0.05% TFA in H2O:MeCN (5:95)); LC/MS M+1=482.1; 1H NMR (400 MHz, MeOD) δ ppm 7.95 (1H, d, J=7.7 Hz), 7.73 (2H, d, J=7.3 Hz), 7.53-7.66 (3H, m), 7.36-7.43 (2H, m), 4.39-4.47 (1H, m), 3.87-4.01 (2H, m), 2.97-3.14 (6H, m), 2.83 (2H, d, J=19.6 Hz), 2.14-2.27 (1H, m), 1.81-1.93 (1H, m, J=13.6 Hz).

Workup

  1. concentrationThe mixture was concentrated
  2. dissolutiondissolved in methanol
  3. customHPLC purification (Column
  4. waitGradient: 25-100% B over 25 minutes
  5. customa 5-minute hold
  6. concentrationFlow: 20 mL/min) and concentration

Sources & evidence

ORD record
ord-e84b75a132a04c128ffed4b243242eb1
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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