Triethylamine → 5-cyclopropyl-N-(1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-4-(1-fluoropropan-2-yloxy)picolinamide

HRID 1480342Notes

Reaction equation

HRID 1480342 reaction equation
[CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[CH:48]1([CH2:51][C:52]([C:55]2[N:59]=[C:58]([CH3:60])[O:57][N:56]=2)([NH2:54])[CH3:53])[CH2:50][CH2:49]1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([NH:54][C:52]([C:55]3[N:59]=[C:58]([CH3:60])[O:57][N:56]=3)([CH3:53])[CH2:51][CH:48]3[CH2:49][CH2:50]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 710877902-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine hydrochlorideHCID 902040445-Cyclopropyl-4-(1-fluoropropan-2-yloxy)picolinic acid

Product 1

HCID 902036905-cyclopropyl-N-(1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-4-(1-fluoropropan-2-yloxy)picolinamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 5-cyclopropyl-4-(1-fluoropropan-2-yloxy)picolinic acid (enantiomer A) (example 287e, 0.08 g, 334 μmol) in dry DMF (2 ml) was added TBTU (113 mg, 351 μmol) and triethylamine (102 mg, 140 μl, 1.00 mmol). The reaction was stirred at room temperature for 30 minutes followed by addition of 1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (example 66e, 72.8 mg, 334 μmol). The reaction was then stirred at room temperature overnight. The reaction was diluted with ethyl acetate and extracted with a 1M aqueous solution of sodium bicarbonate. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of heptane and ethyl acetate to give a mixture of epimers. The epimers was then separated by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the first epimer collected (26 mg, 19%); MS (ESI, m/z): 403.4 (M+H+).

Workup

  1. stirringThe reaction was then stirred at room temperature overnight
  2. extractionextracted with a 1M aqueous solution of sodium bicarbonate
  3. customThe organic phase was collected
  4. extractionthe aqueous phase was back-extracted with ethyl acetate
  5. dry with materialCombined organic phases were dried over sodium sulfate
  6. customevaporated down to dryness
  7. customThe crude material was purified by flash chromatography on silica eluting with a gradient of heptane and ethyl acetate
  8. customto give
  9. additiona mixture of epimers
  10. customThe epimers was then separated by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane)
  11. customcollected (26 mg, 19%)

Sources & evidence

ORD record
ord-e36493f52fa7416d8875db8d16f5c6f8
Source dataset
uspto-grants-2016_08
Patent number
US09409866B2

Reaction notes

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