4-Methylmorpholine → 2-hydroxy-N-(2-(methylamino)-2-oxoethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide

HRID 77142Notes

Reaction equation

HRID 77142 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].CN1CCOCC1.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH3:45])=[O:43].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[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:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:40][CH2:41][C:42]([NH:44][CH3:45])=[O:43])=[O:4]

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 138422022-amino-N-methylacetamide 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 534964572-hydroxy-N-(2-(methylamino)-2-oxoethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamideYield 46.4%

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-Vb, 60 mg, 0.139 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.092 mL, 0.835 mmol), 2-amino-N-methylacetamide-HCl (31.2 mg, 0.250 mmol), and HATU (95 mg, 0.250 mmol). This was stirred overnight 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=33.0 min) to give single enantiomer 2-hydroxy-N-(2-(methylamino)-2-oxoethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (33 mg, 0.064 mmol, 46.4% yield): LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.23 (2 H, m), 7.66-7.79 (4 H, m), 7.52-7.66 (3 H, m), 5.20 (1 H, s), 3.88-4.00 (2 H, m), 3.78-3.88 (2 H, m), 2.75 (3 H, s); HPLC Peak RT=9.1 min (Analytical Method B).

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-67980fff405446138f12759b0f23386e
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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