Diisopropylethylamine → N-[(1S)-1-(7-bromo-6-fluoro-1-methyl-benzimidazol-2-yl)ethyl]-9H-purin-6-amine

HRID 243504Notes

Reaction equation

HRID 243504 reaction equation
[Br:1][C:2]1[C:7]2[N:8]([CH3:14])[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CC(O)C>[Br:1][C:2]1[C:7]2[N:8]([CH3:14])[C:9]([C@@H:11]([NH:13][C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][NH:21]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 977406-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineHCID 204431481,4-Dioxane hydrochlorideHCID 68157037(S)-1-(7-Bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamine

Product 1

HCID 178461925N-[(1S)-1-(7-bromo-6-fluoro-1-methyl-benzimidazol-2-yl)ethyl]-9H-purin-6-amineYield 63%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of (S)-1-(7-Bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamine, (0.50 g, 1.84 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.61 g, 2.57 mmol) and DIPEA (0.60 mL, 3.31 mmol) in IPA (7 mL) was stirred at 85° C. in a sealed tube for 21 h. After cooling, the was mixture partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4), concentrated in vacuo and the residue purified by chromatography (SiO2, 0-5% (2M ammonia in methanol) in DCM). The product was dissolved in methanol (15 mL), treated with HCl/dioxane (4M, 2.0 mL, 8.0 mmol) then stirred for 10 minutes. The reaction mixture was concentrated in vacuo and the residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo to give 430 as a white solid (0.45 g, 63%). LCMS (Method K): RT 3.12 min [M+H]+ 390.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.99 (1H, s), 8.27-7.97 (3H, m), 7.62 (1H, dd, J=8.72, 4.66 Hz), 7.23-7.16 (1H, m), 5.76 (1H, m), 4.09 (3H, s), 1.67 (3H, d, J=6.76 Hz). Signals split due to presence of tautomers

Workup

  1. temperatureAfter cooling
  2. customthe was mixture partitioned between DCM (3×) and saturated aqueous NaHCO3
  3. dry with materialThe combined DCM extracts were dried (Na2SO4)
  4. concentrationconcentrated in vacuo
  5. customthe residue purified by chromatography (SiO2, 0-5% (2M ammonia in methanol) in DCM)
  6. dissolutionThe product was dissolved in methanol (15 mL)
  7. stirringthen stirred for 10 minutes
  8. concentrationThe reaction mixture was concentrated in vacuo
  9. washwas washed with MeOH
  10. washthe product eluted with 2M NH3/MeOH
  11. concentrationthen concentrated in vacuo

Sources & evidence

ORD record
ord-bd73ce2dcbe644648e59e2a517c9dfef
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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