4-Methylmorpholine → HCID 53497284, compound

HRID 77157Notes

Reaction equation

HRID 77157 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.CN1CCOCC1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][NH2:46].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>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:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:46][CH2:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=1)=[O:5]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 195092-PyridinemethanamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 674589572-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid

Product 1

HCID 53497284HCID 53497284, compoundYield 41.3%

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, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), pyridin-2-ylmethanamine (9.03 mg, 0.083 mmol), and BOP (36.9 mg, 0.083 mmol). This was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(pyridin-2-ylmethyl)acetamide (9.9 mg, 0.019 mmol, 40.5% yield): LCMS=522.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.47 (1H, dd, J=5.40, 1.88 Hz), 8.11-8.23 (2 H, m), 7.62-7.77 (5 H, m), 7.48-7.61 (3 H, m), 7.21-7.32 (2 H, m), 5.20 (1 H, s), 4.44-4.62 (2 H, m); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.05% TFA; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.1 min.

Workup

  1. customwas then purified via preparative LCMS with the following conditions
  2. waitGradient: 50-100% B over 25 minutes
  3. customa 5-minute hold
  4. additionFractions containing the desired product
  5. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-093d5987eba0486585e1a777896d063c
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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