N-Iodosuccinimide → [3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)cyclobutyl]-methanol

HRID 386307Notes

Reaction equation

HRID 386307 reaction equation
C1C(=O)N([I:8])C(=O)C1.[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20]3)=[N:17][CH:18]=2)[CH:13]=[CH:14][N:15]=1>CN(C=O)C.C(Cl)Cl>[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:20][CH:21]([CH2:23][OH:24])[CH2:22]3)=[N:17][C:18]=2[I:8])[CH:13]=[CH:14][N:15]=1

Participants

5

Reactant 2

HCID 120273N-IodosuccinimideHCID 57681011(3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl)methanol2×

Product 1

HCID 57681020[3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)cyclobutyl]-methanol

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent3×HCID 6344DichloromethaneSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of NIS (6.31 g, 28.0 mmol) in anh DMF (100 mL) under Ar was added dry [3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol (6.67 g) dissolved in anh DMF (30 mL). The flask containing [3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol was rinsed with another portion of anh DMF (20 mL) and the rinse was added to the reaction mixture. The reaction was heated to 60° C. (rt→60° C.˜30 min) and the stirred at this temperature for 3 h. The mixture was then cooled to rt, partitioned between 1 M aq Na2S2O3 (60 mL), brine (60 mL) and DCM (160 mL). The aq layer was extracted with DCM (3×100 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and purified by flash chromatography on SiO2 (0-8% MeOH in DCM) to provide a material, homogenous by UV on both TLC and HPLC, still containing DMF. The material was dissolved in DCM (200 mL) and washed with water (3×40 mL), dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a pale yellow solid; HPLC (polar—5 min) 2.52 min; MS (ES+): m/z (rel. int.) 364.0 (100, M4+1); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=4.8 Hz, 1 H), 7.49 (d, J=4.8 Hz, 0.22 H, minor isomer), 7.29 (d, J=4.8 Hz, 1 H), 7.28 (d, J=5.2 Hz, 0.23 H, minor isomer), 3.83-3.80 (m, 0.7 H), 3.72-3.62 (m, 3 H), 2.75-2.55 (m, 4 H), 2.42-2.32 (m, 1-2H).

Workup

  1. washwas rinsed with another portion of anh DMF (20 mL)
  2. additionthe rinse was added to the reaction mixture
  3. temperatureThe mixture was then cooled to rt
  4. custompartitioned between 1 M aq Na2S2O3 (60 mL), brine (60 mL) and DCM (160 mL)
  5. extractionThe aq layer was extracted with DCM (3×100 mL)
  6. dry with materialThe combined organics were dried (Na2SO4)
  7. concentrationconcentrated under reduced pressure
  8. custompurified by flash chromatography on SiO2 (0-8% MeOH in DCM)
  9. customto provide a material
  10. washwashed with water (3×40 mL)
  11. dry with materialdried (Na2SO4)
  12. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-b71934ad6fe449f3b2add0f217429c58
Source dataset
uspto-grants-2013_02
Patent number
US08367826B2

Reaction notes

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