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

HRID 60304Notes

Reaction equation

HRID 60304 reaction equation
[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:9][O:10][C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([C:24]#[N:25])[N:22]=[CH:23][C:17]=3[N:16](COCC[Si](C)(C)C)[C:15]=2[N:14]=[CH:13][CH:12]=1)[CH3:2].Br.[OH-].[Na+].Cl>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:9][O:10][C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([C:24]#[N:25])[N:22]=[CH:23][C:17]=3[NH:16][C:15]=2[N:14]=[CH:13][CH:12]=1)[CH3:2]

Participants

6

Reactant 4

HCID 260Hydrogen BromideHCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 67247602(R)-4-((1-ethylpiperidin-2-yl)methoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile

Product 1

HCID 58365001(R)-4-((1-ethylpiperidin-2-yl)methoxy)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrileYield 32%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
75 °C

Procedure

(R)-4-((1-ethylpiperidin-2-yl)methoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (64 mg, 0.14 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 solid (15 mg, 32%). 1H NMR (500 MHz, d6-DMSO) δ 12.81 (s, 1H), 8.98 (s, 1H), 8.55 (d, J=5.7, 1H), 8.43 (s, 1H), 7.05 (d, J=5.8, 1H), 4.27 (m, 3H), 3.05 (m, 1H), 2.77 (m, 1H), 2.36 (m, 1H), 2.25 (m, 1H), 1.99 (m, 1H), 1.83 (m, 1H), 1.70 (m, 1H), 1.57 (m, 1H), 1.23 (m, 1H), 1.03 (t, J=7.1, 3H), 0.92 (d, J=6.6, 1H). LCMS (Method D): RT=6.63 min, M+H+=336.2.

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-7c88b60feba04bd184e4069c9ca37b6f
Source dataset
uspto-grants-2016_09
Patent number
US09440976B2

Reaction notes

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