Dimethylformamide → (R/S)-N-(3-(1H-imidazol-1-yl)propyl)-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide TFA

HRID 77187Notes

Reaction equation

HRID 77187 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[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[N:32]1([CH2:37][CH2:38][CH2:39][NH2:40])[CH:36]=[CH:35][N:34]=[CH:33]1.CN(C([O:48]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN([CH:75]=[O:76])C>>[N:32]1([CH2:37][CH2:38][CH2:39][NH:40][C:3](=[O:5])[CH:2]([OH:1])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]=[C:15]([C:17]4[C:21]([C:22]([F:23])([F:25])[F:24])=[C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:19][N:18]=4)[O:14][N:13]=3)=[CH:10][CH:11]=2)[CH:36]=[CH:35][N:34]=[CH:33]1.[C:75]([OH:76])([C:22]([F:25])([F:24])[F:23])=[O:48]

Participants

6

Reactant 5

HCID 6228DimethylformamideHCID 79724-MethylmorpholineHCID 787361H-Imidazole-1-propanamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67458660(R/S)-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid

Product 1

HCID 53495939(R/S)-N-(3-(1H-imidazol-1-yl)propyl)-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide TFAYield 42.3%

Procedure

(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), 3-(1H-imidazol-1-yl)propan-1-amine (13.06 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were dissolved in DMF (1 mL). This was stirred for 1 h and then was 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% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=10.5 min) to provide (R/S)-N-(3-(1H-imidazol-1-yl)propyl)-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide-TFA (20 mg, 0.029 mmol, 42.3% yield): LCMS=539.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.90 (1 H, s), 8.13-8.19 (2 H, m), 7.52-7.83 (9 H, m), 5.16 (1 H, s), 4.23 (2 H, td, J=6.88, 3.41 Hz), 3.26-3.31 (2 H, m), 2.12 (2 H, dq, J=6.82, 6.68 Hz); HPLC peak RT=7.8 min (Method A).

Workup

  1. customwas 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% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=10.5 min)

Sources & evidence

ORD record
ord-35ebbfae2c8c4fc6936d071a2f4cc037
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

Loading…