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

HRID 77140Notes

Reaction equation

HRID 77140 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[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CC[O:36]CC1.[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH:47]=[CH:46][N:45]=[CH:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN([CH:75]=[O:76])C>>[N:43]1([CH2:42][CH2:41][CH2:40][NH:39][C:3](=[O:5])[CH:2]([OH:1])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:8][CH:7]=2)[CH:47]=[CH:46][N:45]=[CH:44]1.[C:75]([OH:76])([C:28]([F:31])([F:30])[F:29])=[O:36]

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 674589572-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid

Product 1

HCID 53496730(R/S)-N-(3-(1H-imidazol-1-yl)propyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide TFAYield 19.61%

Procedure

(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.061 mL, 0.556 mmol), 1-(3-aminopropyl)imidazole (9.96 μL, 0.083 mmol), and HATU (39.7 mg, 0.104 mmol). The reaction mixture was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 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 time=10.6 min) to give (R/S)-N-(3-(1H-imidazol-1-yl)propyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide-TFA (10 mg, 0.014 mmol, 19.61% yield): LCMS=539.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.90 (1 H, s), 8.52 (1 H, t, J=6.15 Hz), 8.19 (2 H, d, J=8.35 Hz), 7.47-7.80 (9 H, m), 5.16 (1 H, s), 4.23 (2 H, td, J=6.81, 3.52 Hz), 3.22-3.29 (2 H, m), 2.12 (2 H, dq, J=6.81, 6.66 Hz). HPLC Peak RT=6.3 min (Analytical Method A).

Workup

  1. customwas then purified by preparative HPLC (PHENOMENEX® Luna 5u
  2. washC18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid
  3. customover 10 min

Sources & evidence

ORD record
ord-fb90402981dc478ba9bcdf8675adbc84
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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