4-Methylmorpholine → (R/S)-2-hydroxy-N-(2-hydroxy-2-methylpropyl)-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide

HRID 77177

Reaction equation

HRID 77177 reaction equation
[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:21]=3[C:22]([F:25])([F:23])[F:24])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]([OH:36])([CH3:37])[CH3:35])=[O:5]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 951022-Propanol, 1-amino-2-methyl-HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67460691(R/S)-2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid

Product 1

HCID 53495666(R/S)-2-hydroxy-N-(2-hydroxy-2-methylpropyl)-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamideYield 39.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 40 mg, 0.093 mmol), 1-amino-2-methylpropan-2-ol (12.43 mg, 0.139 mmol), 4-methylmorpholine (37.6 mg, 0.372 mmol), and HATU (45.9 mg, 0.121 mmol) were dissolved in DMF (1 mL). It was stirred for 20 min and was then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% methanol to 100% methanol over 10 min, 20 mL/min, 220 nM, product retention=11.2 min) to provide (R/S)-2-hydroxy-N-(2-hydroxy-2-methylpropyl)-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.036 mmol, 39.2% yield): LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.48 (1 H, s), 8.13 (2 H, d, J=8.35 Hz), 7.52-7.76 (7 H, m), 5.16 (1 H, s), 3.25 (2 H, s), 1.17 (3 H, s), 1.14 (3 H, s); HPLC peak RT=7.3 min (Method A).

Workup

  1. customwas then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% methanol to 100% methanol over 10 min, 20 mL/min, 220 nM, product retention=11.2 min)

Sources & evidence

ORD record
ord-d54183e22a3148aa8915803a1b41ac99
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Linked notes

Loading…