Hydrogen Bromide → (S)-4-(3-(ethylamino)piperidin-1-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile

HRID 60264Notes

Reaction equation

HRID 60264 reaction equation
[C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8](COCC[Si](C)(C)C)[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([N:30]([CH2:38][CH3:39])C(=O)OC(C)(C)C)[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].Br.[OH-].[Na+].Cl>O1CCOCC1>[CH2:38]([NH:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:23]2[C:6]3[C:5]4[CH:4]=[C:3]([C:1]#[N:2])[N:11]=[CH:10][C:9]=4[NH:8][C:7]=3[N:20]=[CH:21][CH:22]=2)[CH2:25]1)[CH3:39]

Participants

6

Reactant 4

HCID 260Hydrogen BromideHCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 58365157(S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-4-yl)piperidin-3-yl(ethyl)carbamate

Product 1

HCID 53250248(S)-4-(3-(ethylamino)piperidin-1-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrileYield 62.4%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
75 °C

Procedure

(S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)piperidin-3-yl(ethyl)carbamate (90 mg, 0.15 mmol) was dissolved in 1,4-dioxane (0.3 mL) and then treated with 48% HBr(aq) (0.3 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 (30 mg, 40% over two steps). 1H NMR (500 MHz, d6-DMSO) δ 8.94 (s, 1H), 8.45-8.39 (m, 2H), 6.87 (d, J=5.6, 1H), 3.71 (d, J=11.1, 1H), 3.51 (d, J=12.0, 1H), 3.08-2.99 (m, 1H), 2.99-2.90 (m, 1H), 2.80-2.72 (m, 1H), 2.72-2.66 (m, 1H), 2.62 (m, 1H), 2.01 (m, 1H), 1.93 (m, 1H), 1.78 (m, 1H), 1.37 (m, 1H), 1.05 (t, J=7.1, 3H), NH signal not observed. LCMS (Method E): RT=2.576 min, M+H+=321.1.

Workup

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

Sources & evidence

ORD record
ord-057bb928678b4de695629927b1c92d3e
Source dataset
uspto-grants-2016_09
Patent number
US09440976B2

Reaction notes

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