Diisopropylcarbodiimide → HCID 136078764, compound

HRID 714266Notes

Reaction equation

HRID 714266 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O/[N:21]=[C:22](/[C:24]1[C:25](=[O:31])[NH:26][C:27]([CH3:30])=[CH:28][CH:29]=1)\[NH2:23].C(N=C=NC(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C2C(C3ON=C(N)N=3)CN(C2)C1>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]3[O:19][N:23]=[C:22]([C:24]4[C:25](=[O:31])[NH:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[N:21]=3)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[C:6]([F:8])[CH:7]=1

Participants

8

Reactant 5

HCID 12734DiisopropylcarbodiimideHCID 1639383-(3-Amino-1,2,4-oxadiazol-5-yl)-1-azabicyclo(2.2.1)heptaneHCID 2724141Tetrabutylammonium Fluoride2×HCID 66824535HCID 66824535, compoundHCID 135607271468067-84-7

Product 1

HCID 136078764HCID 136078764, compoundYield 26.7%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 3-(1-(3,5-difluorophenyl)cyclohexyl)propanoic acid (20 mg, 0.075 mmol) and (Z)—N′-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3-carboximidamide (12.46 mg, 0.075 mmol) in acetonitrile (1 mL) was added N,N′-diisopropylcarbodiimide (0.013 mL, 0.082 mmol), and the mixture was stirred for 2.5 hrs at room temp. TBAF (0.112 mL, 0.112 mmol) was added and the mixture was stirred at room temperature. The oxadiazole formation was very slow. After 1 day of stirring, an additional 0.112 mL of 1M TBAF was added and the mixture was stirred for 5 more days. The mixture was diluted with EtOAc and washed with water and brine. The organic extract was dried over Na2SO4 and evaporated to give an oily residue which was purified by Combiflash (12 g silica gel). Elution with 7:93 MeOH—CH2Cl2 afforded a white solid which was repurified by prep HPLC to give pure 3-(5-(2-(1-(3,5-difluorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)-6-methylpyridin-2(1H)-one (8.0 mg, 26.7% yield) as a white solid. HPLC: tR=3.95 min, Waters Sunfire C18 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH-0.1% TFA; Final solvent: 90% aq. MeOH-0.1% TFA. LC/MS: m/e 400.12 (M+H)+. 1H NMR (400 MHz, CDCl3): δ ppm 8.19 (1 H, d), 6.84-6.86 (2 H, m), 6.65 (1H, m), 6.21 (1H, d), 2.44-2.54 (5 H, m), 2.04-2.06 (4 H, m), 1.39-1.61 (8 H, m).

Workup

  1. stirringthe mixture was stirred at room temperature
  2. stirringAfter 1 day of stirring
  3. stirringthe mixture was stirred for 5 more days
  4. washwashed with water and brine
  5. extractionThe organic extract
  6. dry with materialwas dried over Na2SO4
  7. customevaporated
  8. customto give an oily residue which
  9. customwas purified by Combiflash (12 g silica gel)
  10. washElution with 7:93 MeOH—CH2Cl2
  11. customafforded a white solid which
  12. customwas repurified by prep HPLC

Sources & evidence

ORD record
ord-b7d3fe455a3d465599bee0a50f849ab6
Source dataset
uspto-grants-2015_11
Patent number
US09187437B2

Reaction notes

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