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

HRID 77219Notes

Reaction equation

HRID 77219 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.Cl.[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][NH2:39].CN1CCOCC1.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: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:29])[F:30])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:39][CH2:38][C:34]1[S:33][CH:37]=[CH:36][N:35]=1)=[O:5]

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 42614216(1,3-Thiazol-2-yl)methanamine 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 53496607(R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(thiazol-2-ylmethyl)acetamideYield 62.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

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, 23 mg, 0.053 mmol), thiazol-2-ylmethanamine-HCl (12.05 mg, 0.080 mmol), 4-methylmorpholine (21.57 mg, 0.213 mmol), and HATU (26.4 mg, 0.069 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (YMC S5 20×100 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=11.8 min) to provide (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(thiazol-2-ylmethyl)acetamide (19 mg, 0.033 mmol, 62.3% yield): LCMS=528.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.22 (2 H, m), 7.46-7.78 (9 H, m), 5.22 (1 H, s), 4.67-4.82 (2 H, m); HPLC peak RT=9.5 min (Method A).

Workup

  1. customwas purified by prep HPLC (YMC S5 20×100 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=11.8 min)

Sources & evidence

ORD record
ord-920dc1640c234b8f8897b48fa192f0f4
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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