4-Methylmorpholine → (R/S)-N-(1-cyano-2-phenylethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide

HRID 77226Notes

Reaction equation

HRID 77226 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](O)=[O:4].Cl.[NH2:33][CH:34]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:35]#[N:36].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:35]([CH:34]([NH:33][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)#[N:36]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 133524422-Amino-3-phenylpropanenitrile hydrochlorideHCID 674589572-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid

Product 1

HCID 53496736(R/S)-N-(1-cyano-2-phenylethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamideYield 26.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 20 mg, 0.046 mmol), (R/S)-2-amino-3-phenylpropanenitrile hydrochloride (8.47 mg, 0.046 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (2 mL). This was stirred for 1 h before it 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=12.2 min) to provide (R/S)-N-(1-cyano-2-phenylethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8 mg, 0.012 mmol, 26.2% yield) as a mixture of diastereomers: LCMS=546.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.05-8.17 (2 H, m), 7.18-7.72 (12 H, m), 5.08-5.15 (1 H, m), 5.02 (1 H, t, J=7.70 Hz), 3.11-3.27 (2 H, m); HPLC peak RT=11.0 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=12.2 min)

Sources & evidence

ORD record
ord-3b8a1dde552a4491944615f68c465d31
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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