Ethanolamine → (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide

HRID 77238Notes

Reaction equation

HRID 77238 reaction equation
[OH:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C[N:61]1CC[O:64][CH2:63][CH2:62]1.NCCO>CN(C=O)C>[OH:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:19]=3[C:29]([F:30])([F:32])[F:31])[O:15][N:14]=2)=[CH:11][CH:12]=1)([CH3:6])[C:3]([NH:61][CH2:62][CH2:63][OH:64])=[O:5]

Participants

6

Reactant 4

HCID 700EthanolamineHCID 79724-MethylmorpholineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 131731880HCID 131731880, compound

Product 1

HCID 67458356(R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamideYield 14.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (Int-XV, 30 mg, 0.067 mmol), BOP (29.8 mg, 0.067 mmol), 4-methylmorpholine (27.3 mg, 0.269 mmol), and 2-aminoethanol (6.17 mg, 0.101 mmol) were added to DMF (1 mL). The reaction mixture was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=30.0 min) to provide (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide (6 mg, 9.83 μmol, 14.59% yield): LCMS=489.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.21 (2 H, m), 7.53-7.92 (7 H, m), 3.60 (2 H, td, J=5.61, 3.74 Hz), 3.33-3.43 (2 H, m), 1.80 (3 H, s); HPLC peak RT=9.0 min (Method A).

Workup

  1. custompurified by prep HPLC (PHENOMENEX® 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=30.0 min)

Sources & evidence

ORD record
ord-58e0dd949a774796b84b734a0374d81b
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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