6-Methoxy-3-pyridinylamine → 4'-Cyclopropylmethyl-N2-(6-methoxy-pyridin-3-yl)-N2'-methyl-[4,5]bipyrimidinyl-2,2'-diamine

HRID 1397139Notes

Reaction equation

[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](S(C)=O)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH3:40])[N:25]=2)[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:9][C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH3:40])[N:25]=2)[CH2:21][CH2:22]1

Participants

Conditions

Temperature: -78 °C

Procedure

To a solution of 6-methoxypyridin-3-amine (61.4 mg, 0.494 mmol) in THF (5 mL) cooled to −78° C., lithium bis(trimethylsilyl)amide (1M in THF, 0.494 mL, 0.494 mmol) was added dropwise under nitrogen. After the reaction was stirred at −78° C. for 10 minutes, a solution of 4′-(cyclopropylmethyl)-N-methyl-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (5-1) (30 mg, 0.099 mmol) in THF (1 mL) was added to the reaction at −78° C. The reaction was slowly warmed up to rt, then the reaction was allowed to stir for 1 hour. The reaction was quenched with saturated ammonium chloride solution, then concentrated in vacuo. The reaction was taken up in acetonitrile, purified by reverse-phase HPLC [10-90% organic phase over 15 minutes], then further purified by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 7% MeOH/DCM] to afford the title compound as a white solid (19.49 mg, 46.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.04 (br. s., 2 H) 0.34 (d, J=7.58 Hz, 2 H) 1.01 (br. s., 1 H) 2.77 (d, J=6.57 Hz, 2 H) 2.86 (d, J=4.55 Hz, 3 H) 3.74-3.86 (m, 3 H) 6.78 (d, J=9.09 Hz, 1 H) 6.97 (d, J=5.05 Hz, 1 H) 7.36 (d, J=4.04 Hz, 1 H) 7.99 (dd, J=8.59, 2.53 Hz, 1 H) 8.35-8.50 (m, 3 H) 9.46 (s, 1 H). HRMS (ES+) for C19 H21N7O.H+ [MH+]: calcd, 364.1886. found, 364.1891. UV-LC: 94.60/100% UV purity at 254/214 nm; tR=5.08 minutes over 7.75 minutes.

Workup

temperatureThe reaction was slowly warmed up to rt
stirringto stir for 1 hour
customThe reaction was quenched with saturated ammonium chloride solution
concentrationconcentrated in vacuo
custompurified by reverse-phase HPLC [10-90% organic phase over 15 minutes]
customfurther purified by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 7% MeOH/DCM]

Sources & evidence

ORD record: ord-085b4cfa63a043229fce9423b97f32f1
Source dataset: uspto-grants-2014_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08901147B2

Reaction notes

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