4-Methylmorpholine → 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N,N-dimethylpropanamide

HRID 77196Notes

Reaction equation

HRID 77196 reaction equation
[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24](C4C=CC=CC=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.[CH3:38][NH:39][CH3:40].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[C:23]=3[C:33]([F:35])([F:36])[F:34])[O:19][N:18]=2)=[CH:15][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([N:39]([CH3:40])[CH3:38])=[O:9])=[O:4]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 10473Dimethylamine, hydrochlorideHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 534964603-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid

Product 1

HCID 534960943-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N,N-dimethylpropanamideYield 42.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 4, 35 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of dimethylamine-HCl (11.36 mg, 0.139 mmol), 4-methylmorpholine (0.046 mL, 0.418 mmol), and BOP (61.6 mg, 0.139 mmol). This was stirred for 1 h and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention time=33.5 min) to give 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N,N-dimethylpropanamide (16.1 mg, 0.030 mmol, 42.8% yield) as a single enantiomer. LCMS=530.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.69 (4 H, d, J=8.14 Hz), 7.49-7.65 (3 H, m), 5.11 (1 H, s), 3.51 (2 H, t, J=6.49 Hz), 2.98 (3 H, s), 2.92 (3 H, s), 2.60 (2 H, t, J=6.60 Hz). HPLC Peak RT=9.6 min (Analytical Method D).

Workup

  1. customwas then purified by preparative HPLC (PHENOMENEX® Luna 5u
  2. washC18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid
  3. customover 30 min

Sources & evidence

ORD record
ord-f191e3f5834a4853b0e8a017c97c7a90
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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