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

HRID 575435Notes

Reaction equation

HRID 575435 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.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C@:27]([OH:31])([C:29]#[CH:30])[CH3:28].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:22]2[N:23]=[CH:24][CH:25]=[CH:26][N:21]=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 86693464(2R)-2-pyrimidin-2-ylbut-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 86693493(R)-8-fluoro-9-(3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl)-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamideYield 91.6%

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 (73 mg, 0.19 mmol) in piperidine (2 mL) was introduced (2R)-2-(pyrimidin-2-yl)but-3-yn-2-ol (140 mg, 0.95 mmol) and copper(I) iodide (2 mg, 0.01 mmol). The resulting solution was de-oxygenated by nitrogen bubbling for five minutes then tetrakis(triphenylphosphine)palladium(0) (11 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 6 hr. After concentration of the reaction mixture in vacuo, the residue was slurried in ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate (2×5 mL), water (2×5 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. Purification of the dry-loaded material by silica gel flash column chromatography (eluent: DCM containing a 0-8% gradient of 7M ammonia in methanol) furnished the title compound (35 mg, 0.087 mmol, 46%) as a colorless solid: 1H NMR (500 MHz, d4-methanol) 61.64 (d, J=9.77 Hz, 2H), 1.97 (s, 3H), 2.96 (qd, J=7.88, 2.84 Hz, 2H), 3.43-3.50 (m, 1H), 3.66 (td, J=8.12, 4.26 Hz, 1H), 6.91 (d, J=10.09 Hz, 1H), 7.46 (t, J=4.89 Hz, 1H), 8.32 (d, J=7.57 Hz, 1H), 8.86 (d, J=5.04 Hz, 2H); M+H=404.

Workup

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

Sources & evidence

ORD record
ord-23597bc604a04ab683e196eea3ee0451
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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