4-Methylmorpholine → n-((r)-1-(3-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamide
Reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.CN1CCOCC1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:62][C:63]([F:79])([F:78])[C:64]([CH:70]1[O:74][N:73]=[C:72]([C:75]([OH:77])=[O:76])[CH2:71]1)([OH:69])[C:65]([F:68])([F:67])[F:66]>CN(C=O)C.CO>[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[F:68][C:65]([F:66])([F:67])[C:64]([CH:70]1[O:74][N:73]=[C:72]([C:75]([OH:77])=[O:76])[CH2:71]1)([OH:69])[C:63]([F:79])([F:78])[F:62].[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:23][C:75]([C:72]2[CH2:71][CH:70]([C:64]([OH:69])([C:63]([F:79])([F:78])[F:62])[C:65]([F:66])([F:67])[F:68])[O:74][N:73]=2)=[O:76])([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1Participants
Reactant 4
Product 3
HCID 113234795-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxylic acid
HCID 59458474n-((r)-1-(3-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamideYield 6.2%
HCID 59458485(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamineReagents, catalysts & solvents 2
Procedure
(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine was prepared by the methods described in Procedure 3, 4, 5 and 6. 5-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxylic acid was prepared as described in Journal of Medicinal Chemistry, 2006, 49, 14, 4055. To a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (60 mg, 0.14 mmol), in anhydrous DMF (1 mL) was added N-methylmorpholine (26 mg, 0.28 mmol), PyBrOP (73 mg, 0.14 mmol) and 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxylic acid (40 mg, 0.14 mmol). The resulting solution was stirred at rt for 16 h. The resulting solution was diluted with MeOH (0.5 mL) and purified by preparative HPLC (YMC Sunfire 30×100 mm column, eluting with 10-90% MeOH/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm). (N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamide (Example 321, 3 mg, 3% yield) was isolated as a colorless oil at a retention time of 11.29 min. LCMS: RT=2.18 min [M+H] 689.45 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.14 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400 MHz 1H (CDCl3) Diastereomeric ratio is 1:1; 7.28-6.86 ppm, 24H, m; 6.64 ppm, 1H, m; 6.61 ppm, 1H, m; 5.88 ppm, 2H, t, J=60.0 Hz; 5.16 ppm, 2H, t, J=16.0 Hz; 3.94 ppm, 1H, d, J=12.0 Hz; 3.88 ppm, 1H, d, J=12.0 Hz; 3.75 ppm, 1H, d, J=12.0 Hz; 3.68 ppm, 1H, d, J=12.0 Hz; 3.61 ppm, 2H, m; 3.40 ppm, 1H, dm, J=12.0 Hz; 3.33 ppm, 1H, dm, J=12.0 Hz.
Workup
- custompurified by preparative HPLC (YMC Sunfire 30×100 mm column, eluting with 10-90% MeOH/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm)
Sources & evidence
- ORD record
- ord-dfacacd04146422bb9bbb4bef01be1bc
- Source dataset
- uspto-grants-2012_11
- Patent number
- US08304403B2
Reaction notes
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