Potassium Phosphate, Tribasic → (3S)-1-[(2S,3S)-2-Amino-3-[4-([1,2,4]triazolo[4,3-alpha]pyridin-6-yl)phenyl]-1-oxobutanyl]-3-fluoropyrrolidine

HRID 1372467Notes

Reaction equation

HRID 1372467 reaction equation
I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.C(OC([NH:18][C@@H:19]([C@H:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:29])[C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([F:27])[CH2:23]1)=[O:21])=O)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:18][C@@H:19]([C@H:28]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[N:9][N:10]=3)[CH:7]=2)=[CH:32][CH:31]=1)[CH3:29])[C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([F:27])[CH2:23]1)=[O:21]

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 69371253Tert-butyl{(1s,2s)-1-{[(3s)-3-fluoropyrrolidin-1-yl]carbonyl}-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamateHCID 693715596-Iodo-[1,2,4]triazolo[4,3-a]pyridine

Product 1

HCID 10451602(3S)-1-[(2S,3S)-2-Amino-3-[4-([1,2,4]triazolo[4,3-alpha]pyridin-6-yl)phenyl]-1-oxobutanyl]-3-fluoropyrrolidine

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

To a stirred solution of the product (48.0 mg, 0.195 mmol) from Step B in 0.75 mL of ethylene glycol dimethyl ether and 0.75 mL of water was added 62.0 mg (0.13 mmol) of (3S)-1-[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-oxobutanyl]-3-fluoropyrrolidine from Example 10, Step B, 1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride (21.0 mg, 0.26 mmol) and potassium phosphate (83 mg, 0.39 mmol). The reaction mixture was heated at 90° C. for 16 h, and then allowed to cool to room temperature. The mixture was diluted with ethyl acetate, and the solution was washed sequentially with water and saturated aqueous brine, dried (magnesium sulfate), and concentrated under reduced pressure in vacuo to yield the crude coupled product, which was purified by preparative thin layer chromatography (silica gel, 5% methanol/dichloromethane eluant). The resultant product was dissolved in 1 mL of dichloromethane and was treated with 1 mL of trifluoroacetic acid. The reaction was stirred at room temperature for 1 h, and was then concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel, 10% methanol/1% ammonium hydroxide/dichloromethane eluant) to afford the title compound. LC/MS 368.2 (M+1).

Workup

  1. temperatureto cool to room temperature
  2. washthe solution was washed sequentially with water and saturated aqueous brine
  3. dry with materialdried (magnesium sulfate)
  4. concentrationconcentrated under reduced pressure in vacuo
  5. customto yield the crude
  6. customwas purified by preparative thin layer chromatography (silica gel, 5% methanol/dichloromethane eluant)
  7. dissolutionThe resultant product was dissolved in 1 mL of dichloromethane
  8. additionwas treated with 1 mL of trifluoroacetic acid
  9. concentrationwas then concentrated under reduced pressure
  10. customThe residue was purified by preparative thin layer chromatography (silica gel, 10% methanol/1% ammonium hydroxide/dichloromethane eluant)

Sources & evidence

ORD record
ord-cd374eb264394065945a5ca975db0abd
Source dataset
uspto-grants-2007_01
Patent number
US07157490B2

Reaction notes

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