1,2-Dichloroethane → 6-fluoro-2-{(1R,5S)-6-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.2]non-3-yl}quinazoline

HRID 1916161Notes

Reaction equation

HRID 1916161 reaction equation
[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C@@H:17]3[CH2:19][CH2:20][C@@H:14]([CH2:15][N:16]3C3C=CC(OC)=CC=3)[CH2:13]1)[N:6]=[CH:5]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:50]1[N:51]([C:55]2[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][C:56]=2[C:57](O)=[O:58])[N:52]=[CH:53][CH:54]=1.C([O-])(O)=O.[Na+]>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C@@H:17]3[CH2:19][CH2:20][C@@H:14]([CH2:15][N:16]3[C:57](=[O:58])[C:56]3[CH:60]=[C:61]([CH3:64])[CH:62]=[CH:63][C:55]=3[N:51]3[N:52]=[CH:53][CH:54]=[N:50]3)[CH2:13]1)[N:6]=[CH:5]2

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 516892Sodium BicarbonateHCID 532601655-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acidHCID 689989426-fluoro-2-[(1S,5S)-6-(4-methoxyphenyl)-3,6-diazabicyclo[3.2.2]non-3-yl]quinazoline

Product 1

HCID 689959736-fluoro-2-{(1R,5S)-6-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.2]non-3-yl}quinazoline

Reagents, catalysts & solvents 1

HCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
70 °C

Procedure

To a solution of 6-fluoro-2-[(1S,5S)-6-(4-methoxyphenyl)-3,6-diazabicyclo[3.2.2]non-3-yl]quinazoline (E-5, 0.020 g, 0.053 mmol, 1.0 equiv) in acetonitrile/water (0.3 mL total; 2:1) at 0° C. was added ceric ammonium nitrate (0.043 g, 0.079 mmol, 1.5 equiv) and the reaction was stirred 1 h. At 1 h, added more ceric ammonium nitrate (0.0 43 g, 0.079 mmol, 1.5 equiv) and the reaction was complete after 2 h. The reaction mixture was quenched with 10% aqueous sodium thiosulfate and concentrated directly. The resulting residue was azeotroped with methanol (2×10 mL) and toluene (2×20 mL). The oily residue was dissolved in DMF (0.3 mL) and to this solution was added EDC (0.030 g, 0.16 mmol, 3.0 equiv), HOBt (0.024 g, 0.16 mmol, 3.0 equiv), triethylamine (0.037 mL, 0.26 mmol, 5.0 equiv), and 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid (0.032 g, 0.16 mmol, 3.0 equiv). The reaction mixture was heated to 70° C. for 1 h and cooled to ambient temperature. The reaction was partitioned between ethyl acetate (20 mL) and saturated NaHCO3 (20 mL) and the organic phase was washed with water (4×10 mL). The combined organic phase was dried over MgSO4, concentrated and purified by column chromatography on silica gel (0 to 100% ethyl acetate in hexanes). The resulting product was further purified by reverse phase column chromatography (15 to 85% acetonitrile in water, 0.1% TFA buffer) to afford, after free-basing with saturated NaHCO3, E-6 as a yellow foam. HRMS [M+H] C25H24FN7O calc'd 458.2104, found 458.2115.

Workup

  1. waitAt 1 h
  2. waitthe reaction was complete after 2 h
  3. customThe reaction mixture was quenched with 10% aqueous sodium thiosulfate
  4. concentrationconcentrated directly
  5. customThe resulting residue was azeotroped with methanol (2×10 mL) and toluene (2×20 mL)
  6. dissolutionThe oily residue was dissolved in DMF (0.3 mL) and to this solution
  7. temperaturecooled to ambient temperature
  8. customThe reaction was partitioned between ethyl acetate (20 mL) and saturated NaHCO3 (20 mL)
  9. washthe organic phase was washed with water (4×10 mL)
  10. dry with materialThe combined organic phase was dried over MgSO4
  11. concentrationconcentrated
  12. custompurified by column chromatography on silica gel (0 to 100% ethyl acetate in hexanes)
  13. customThe resulting product was further purified by reverse phase column chromatography (15 to 85% acetonitrile in water, 0.1% TFA buffer)
  14. customto afford

Sources & evidence

ORD record
ord-4a2b5e8075ea4505a3c3a71e41f4e2e5
Source dataset
uspto-grants-2013_12
Patent number
US08618102B2

Reaction notes

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