6-Bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one → HCID 178518663, compound

HRID 388110Notes

Reaction equation

HRID 388110 reaction equation
Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]=[C:15]4[N:17]([CH2:21][CH:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[C:18](=[O:20])[NH:19][C:14]4=[N:13][CH:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1.C[Sn](C)(C)C1C=CC2NC(C(OC(C)(C)C)=O)=NC=2C=1.BrC1N=C2N(CC3CCOCC3)C(=O)NC2=NC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]=[C:15]4[N:17]([CH2:21][CH:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[C:18](=[O:20])[NH:19][C:14]4=[N:13][CH:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1

Participants

6

Reactant 3

HCID 866263956-Bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-oneHCID 178450790HCID 178450790, compoundHCID 178479657HCID 178479657, compound

Product 1

HCID 178518663HCID 178518663, compoundYield 10%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Procedure

6-(1H-Benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride. tert-Butyl 5-(trimethylstannyl)-1H-benzo[d]imidazole-2-carboxylate (640 mg, 1.7 mmol), 6-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (See Example 101.B) (420 mg, 1.3 mmol), dichlorobis(triphenylphosphine)palladium(II) (90 mg, 0.13 mmol) in DMF (25 mL) were reacted for 1.5 h at 90° C. The product was purified by reverse-phase semi-preparatory HPLC (30-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). The desired fractions were concentrated, treated with 4N hydrochloric acid in diethyl ether (few drops), and sonicated. This procedure was repeated twice more to provide 6-(1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (48 mg, 10% yield) as the hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.55 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.06 (dd, J=8.0, 1.6, 1H), 7.80 (d, J=8.8, 1H), 3.81 (m, 2H), 3.80 (d, J=7.2, 2H), 3.27 (d, J=11.6, 2H), 2.14 (m, 1H), 1.59 (m, 2H), 1.33 (m, 2H); MS (ESI) m/z 351.2 [M+1]+.

Workup

  1. customThe product was purified by reverse-phase semi-preparatory HPLC (30-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min)
  2. concentrationThe desired fractions were concentrated
  3. additiontreated with 4N hydrochloric acid in diethyl ether (few drops)
  4. customsonicated

Sources & evidence

ORD record
ord-db1e076f62f54f4a886f717d7d8498f0
Source dataset
uspto-grants-2013_02
Patent number
US08372976B2

Reaction notes

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