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Lithium Hydroxide → 2-(4-(4-(5-(2-Methyl-5-(trifluoromethyl)oxazole-4-carboxamido)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid

HRID 881737
Notes
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Reaction equation

HRID 881737 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][C:23]([O:25]C)=[O:24])([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:27][C:28]1[O:29][C:30]([C:36]([F:39])([F:38])[F:37])=[C:31]([C:33](O)=[O:34])[N:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-]>CN(C=O)C.O.C1COCC1.C(O)(=O)C.CCN(CC)CC>[CH3:27][C:28]1[O:29][C:30]([C:36]([F:39])([F:37])[F:38])=[C:31]([C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]45[CH2:21][CH2:20][C:17]([CH2:22][C:23]([OH:25])=[O:24])([CH2:18][CH2:19]4)[O:16][CH2:15]5)=[CH:10][CH:9]=3)=[N:6][CH:7]=2)=[O:34])[N:32]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

10

Reactant 4

HCID 3939Lithium HydroxideHCID 27756512-methyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxylic AcidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 86700825Methyl2-(4-(4-(5-aminopyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate

Product 1

HCID 72188429
2-(4-(4-(5-(2-Methyl-5-(trifluoromethyl)oxazole-4-carboxamido)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid
Yield 19%

Reagents, catalysts & solvents 5

HCID 176Acetic AcidSolventHCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Procedure

To a solution of methyl 2-(4-(4-(5-aminopyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (212 mg, 0.602 mmol) in DMF (3 ml) at rt under N2 was added 2-methyl-5-(trifluoromethyl)oxazole-4-carboxylic acid (141 mg, 0.722 mmol) and Et3N (0.167 ml, 1.203 mmol. The mixture was stirred for 5 minutes before the addition of HATU (274 mg, 0.722 mmol) at room temperature. Upon completion of reaction, the mixture was diluted with H2O (25 ml) and extracted with EtOAc (50 ml). The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude methyl ester. LC/MS, ESI-MS (+): 530.0, RT: 1.37 (Condition E). The crude methylester was suspended in THF (4 ml) and treated with 1N LiOH (0.722 ml, 0.722 mmol). Upon completion of reaction, the mixture was diluted with H2O and brought to pH 5 with acetic acid. The resulting slurry was filtered, washed with H2O and dried at 80° C. for several hours. The crude solid was triturated with hot EtOH, AcN, and Et2O to give the title compound as off-white solid after drying (65 mg, 19% yield). HR/MS (M+H)+ found 516.1749. calc. 516.1735, RT: 2.76 (Condition L). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.08 1 (s, 1H), 10.92 (s, 1H), 9.03 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.99 (d, J=16.0 Hz, 2H), 7.94 (d, J=16.0 Hz, 1H), 7.44 (d, J=8.00 Hz, 2H), 3.91 (s, 2H), 2.63 (s, 3H), 2.33 (s, 2H), 2.08-1.85 (m, 8H).

Workup

  1. customUpon completion of reaction
  2. extractionextracted with EtOAc (50 ml)
  3. washThe organic portion was washed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto afford the crude methyl ester
  8. custom530.0, RT
  9. customUpon completion of reaction
  10. filtrationThe resulting slurry was filtered
  11. washwashed with H2O
  12. customdried at 80° C. for several hours
  13. customThe crude solid was triturated with hot EtOH, AcN, and Et2O

Sources & evidence

ORD record
ord-2aa64aea4f9647a7b027849084783530
Source dataset
uspto-grants-2015_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08993619B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes