Ammonia → 1-Iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine

HRID 2402625Notes

Reaction equation

[NH3:1].C1COCC1.Cl[C:8]1[C:9]2[N:10]([C:14]([CH:18]3[CH2:21][CH:20]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:19]3)=[N:15][C:16]=2[I:17])[CH:11]=[CH:12][N:13]=1>C(O)(C)C>[I:17][C:16]1[N:15]=[C:14]([CH:18]2[CH2:21][CH:20]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:19]2)[N:10]2[CH:11]=[CH:12][N:13]=[C:8]([NH2:1])[C:9]=12

Participants

Conditions

Temperature: -78 °C

Procedure

A solution of 2N ammonia in isopropyl alcohol (350 mL) and THF (30 mL, 0.4 mol) was added to 8-chloro-1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazine (19.91 g, 0.04612 mol) in a Parr bomb and cooled to −78° C. Ammonia was bubbled into the solution for 8-10 min. The bomb was sealed, stirred and heated to at 110° C. over 3 d. The solvent was then evaporated in vacuo and purified by flash silica gel chromatography (wetted with CHCl3, dried loaded with silica, and eluted with 8% (7N NH3) MeOH in CHCl3), which afforded the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.31 (1H, d, J=5.01), 7.16 (1H, d, J=6.25), 5.83 (2H, s), 3.49 (1H, m), 3.06 (1H, m), 2.76 (4H, m), 2.64 (8H, m), 2.46 (3H, s); MS (ES+): m/z 412.89/413.91 (50/10) [MH+]; HPLC: tR=0.31 min. (OpenLynx, polar—5 min.).

Workup

customAmmonia was bubbled into the solution for 8-10 min
customThe bomb was sealed
temperatureheated to at 110° C. over 3 d
customThe solvent was then evaporated in vacuo
custompurified by flash silica gel chromatography (wetted with CHCl3, dried loaded with silica, and eluted with 8% (7N NH3) MeOH in CHCl3), which

Sources & evidence

ORD record: ord-c4e139379a1d4df785f6867623c70604
Source dataset: uspto-grants-2014_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08796455B2

Reaction notes

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