Dichloromethane → (R)-8-fluoro-9-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide

HRID 575434Notes

Reaction equation

HRID 575434 reaction equation
[F:1][C:2]1[C:19](I)=[CH:18][C:5]2[C:6]3[N:10]=[C:9]([C:11]([NH2:13])=[O:12])[NH:8][C:7]=3[CH:14]3[CH2:17][CH:16]([C:4]=2[CH:3]=1)[CH2:15]3.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[CH:23]=1.C(Cl)Cl>N1CCCCC1.C(OCC)(=O)C.CO.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH3:8].[F:1][C:2]1[C:19]([C:30]#[C:29][C@@:27]([OH:31])([C:24]2[CH:23]=[C:22]([CH3:21])[O:26][N:25]=2)[CH3:28])=[CH:18][C:5]2[C:6]3[N:10]=[C:9]([C:11]([NH2:13])=[O:12])[NH:8][C:7]=3[CH:14]3[CH2:17][CH:16]([C:4]=2[CH:3]=1)[CH2:15]3

Participants

10

Reactant 3

HCID 6344DichloromethaneHCID 58221468(R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-olHCID 866934908-Fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide

Product 2

HCID 222AmmoniaHCID 86693492(R)-8-fluoro-9-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamideYield 62.9%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 887MethanolSolventHCID 8082PiperidineSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
40 °C

Procedure

Into a pressure tube containing a solution of 8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (80 mg, 0.21 mmol) in piperidine (2 mL) was introduced (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (158 mg, 1.04 mmol) and copper(I) iodide (2 mg, 0.01 mmol). The resulting solution was de-oxygenated by nitrogen bubbling for five minutes following which tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) was added. Nitrogen bubbling was continued for a further two minutes and the pressure tube closed under an atmosphere of nitrogen. The reaction mixture was warmed to 40° C. for 2 hr. After concentration of the reaction mixture in vacuo, the residue was slurried in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate (5 mL), water (5 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered and the filtrate evaporated onto silica gel (−1.0 g) in vacuo. The dry-loaded material was purified by silica gel flash column chromatography (eluent: DCM containing a 0-4% gradient of 7M ammonia in methanol) to furnish the title compound (27 mg, 0.066 mmol, 31%) as a rusty-brown solid: 1H NMR (500 MHz, d4-methanol) δ 1.63 (d, J=11.03 Hz, 2H), 1.90 (s, 3H), 2.45 (s, 3H), 2.91-3.00 (m, 2H), 3.46 (td, J=7.09, 4.10 Hz, 1H), 3.66 (td, J=8.12, 3.94 Hz, 1H), 6.33 (s, 1H), 6.94 (d, J=10.09 Hz, 1H), 8.31 (d, J=7.25 Hz, 1H); M+1=407.

Workup

  1. additionwas added
  2. waitNitrogen bubbling was continued for a further two minutes
  3. customthe pressure tube closed under an atmosphere of nitrogen
  4. washwashed with saturated aqueous sodium bicarbonate (5 mL), water (5 mL) and brine (5 mL)
  5. extractionThe organic extract
  6. dry with materialwas dried over sodium sulfate
  7. filtrationfiltered
  8. customthe filtrate evaporated onto silica gel (−1.0 g) in vacuo
  9. customThe dry-loaded material was purified by silica gel flash column chromatography (eluent

Sources & evidence

ORD record
ord-5fd060851def4be7810a8b8f264bdef7
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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