Triethylamine → 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-phenyl}-amide

HRID 1510287Notes

Reaction equation

HRID 1510287 reaction equation
[C:1]1([C:7]2[O:8][C:9]([C:30]([F:33])([F:32])[F:31])=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=O)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[OH:47][NH:48][C:49](=[NH:53])[CH:50]([CH3:52])[CH3:51]>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[CH:50]([C:49]1[N:53]=[C:27]([CH:24]2[CH2:23][CH2:22][N:21]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]4[N:11]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[O:8][C:9]=4[C:30]([F:32])([F:31])[F:33])=[O:13])=[CH:20][CH:19]=3)[CH2:26][CH2:25]2)[O:47][N:48]=1)([CH3:52])[CH3:51]

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 576521231-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acidHCID 178449908HCID 178449908, compound

Product 1

HCID 468320632-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-phenyl}-amide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a mixture of 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid (200 mg, 0.435 mmol) in 2 mL of CH2Cl2 was added a drop of DMF and approximately 2 mL of oxalyl chloride dropwise (gas evolution observed). The resulting mixture was stirred at room temperature for 72 hours, then concentrated to produce a solid, which was triturated with ether, then suspended in 5 mL of THF. To this suspension was added triethylamine (110 mg, 151 μL, 1.088 mmol), followed by N-hydroxy-isobutyramidine (54 mg, 0.529 mmol). The resulting reaction mixture was stirred at room temperature overnight, then diluted with EtOAc, and washed twice with saturated NH4Cl solution. The organic phase was then dried over Na2SO4, filtered, and concentrated. The residue was re-dissolved in 5 mL of THF, and treated with 4 N TBAF solution in THF (excess, ca. 2 mL). The mixture was stirred at room temperature overnight, and then diluted with EtOAc. The organic phase was washed with water, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel (gradient elution with 10-50% ethyl acetate in hexanes) to produce 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-phenyl}-amide as an off-white solid. HRMS calcd for C27H26F3N5O3 (M+H) 526.2061, obsd 526.2059.

Workup

  1. concentrationconcentrated
  2. customto produce a solid, which
  3. customwas triturated with ether
  4. customThe resulting reaction mixture
  5. stirringwas stirred at room temperature overnight
  6. washwashed twice with saturated NH4Cl solution
  7. dry with materialThe organic phase was then dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. dissolutionThe residue was re-dissolved in 5 mL of THF
  11. additiontreated with 4 N TBAF solution in THF (excess, ca. 2 mL)
  12. stirringThe mixture was stirred at room temperature overnight
  13. additiondiluted with EtOAc
  14. washThe organic phase was washed with water
  15. dry with materialdried over Na2SO4
  16. filtrationfiltered
  17. concentrationconcentrated
  18. customThe crude product was purified by chromatography on silica gel (gradient elution with 10-50% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-09421f4f581f4422ac8fb59da784fc17
Source dataset
uspto-grants-2012_07
Patent number
US08211914B2

Reaction notes

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