Hydrogen Bromide → (R)-4-(piperidin-2-ylmethoxy)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile

HRID 60302Notes

Reaction equation

[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:9]1[C:17]2[C:16]3[CH:18]=[C:19]([C:22]#[N:23])[N:20]=[CH:21][C:15]=3[N:14](COCC[Si](C)(C)C)[C:13]=2[N:12]=[CH:11][CH:10]=1.Br.[OH-].[Na+].Cl>O1CCOCC1>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:9]1[C:17]2[C:16]3[CH:18]=[C:19]([C:22]#[N:23])[N:20]=[CH:21][C:15]=3[NH:14][C:13]=2[N:12]=[CH:11][CH:10]=1

Participants

Conditions

Temperature: 75 °C

Procedure

(R)-4-(piperidin-2-ylmethoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (467 mg, 1.1 mmol) was dissolved in 1,4-dioxane (0.5 mL) and then treated with 48% HBr(aq) (0.5 mL) and heated at 75° C. for 15 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (122 mg, 37%). 1H NMR (400 MHz, d6-DMSO) δ 8.97 (d, J=0.7, 1H), 8.54 (m, 2H), 7.05 (d, J=5.8, 1H), 4.30-4.18 (m, 2H), 3.11 (m, 1H), 3.03 (m, 1H), 2.69-2.60 (m, 1H), 1.79 (m, 2H), 1.58 (m, 1H), 1.45-1.33 (m, 2H), 1.33-1.21 (m, 1H). LCMS (Method D): RT=7.41 min, M+H+=308.1.

Workup

customThe cooled reaction mixture
customproducing a cloudy precipitate
customThe solid was collected by centrifugation
dissolutiondissolved in dimethylsulfoxide (2 mL)
custompurified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min]

Sources & evidence

ORD record: ord-4a2f0861f34648dfbd73369396ab5604
Source dataset: uspto-grants-2016_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09440976B2

Reaction notes

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