Phosphorus oxychloride → 8-(Piperazin-1-yl)-5-(thiophen-2-yl)imidazo[1,5-a]pyrazine

HRID 1045761Notes

Reaction equation

[CH:1]([NH:3][CH2:4][C:5]1[C:6]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[N:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=O.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[N:16]1([C:6]2[C:5]3[N:10]([CH:1]=[N:3][CH:4]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][N:7]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1

Participants

Conditions

Temperature: 90 °C

Procedure

A 50 mL round bottom flask was charged with tert-butyl 4-(3-(formamidomethyl)-5-(thiophen-2-yl)pyrazin-2-yl)piperazine-1-carboxylate (0.40 g, 1.0 mmol) and toluene (20 mL). To the above mixture was added dropwise POCl3 (0.76 g, 5.0 mmol). The resulting mixture was heated at 90° C. for 1 h. Work-up: the reaction mixture was poured into saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 5% MeOH in dichloromethane, to afford 0.25 g (85%) of the product. 1H NMR (300 MHz, CDCl3) δ: 8.41 (s, 1H), 7.74 (s, 1H), 7.46 (dd, J=5.1, 1.2 Hz, 1H), 7.37 (dd, J=3.6, 1.2 Hz, 1H), 7.25 (s, 1H), 7.19 (dd, J=5.1, 3.6 Hz, 1H), 3.89 (t, J=5.1 Hz, 4H), 3.08 (t, J=5.1 Hz, 4H). MS m/z: 286 (M+H+).

Workup

extractionextracted with dichloromethane
washThe combined organic layers were washed with brine
dry with materialdried over anhydrous Na2SO4
concentrationconcentrated in vacuo
customThe residue was further purified by flash column chromatography on silica gel with 5% MeOH in dichloromethane

Sources & evidence

ORD record: ord-ceb7eff5ff9d4da4992b229d258543a9
Source dataset: uspto-grants-2013_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08569300B2

Reaction notes

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