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

HRID 60261Notes

Reaction equation

HRID 60261 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][O:9][C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[N:15](COCC[Si](C)(C)C)[C:14]=3[N:13]=[CH:12][CH:11]=2)[CH2:3]1.Br.[OH-].[Na+].Cl>O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][O:9][C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[NH:15][C:14]=3[N:13]=[CH:12][CH:11]=2)[CH2:3]1

Participants

6

Reactant 4

HCID 260Hydrogen BromideHCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 58365084HCID 58365084, compound

Product 1

HCID 53251532(R)-4-((1-methylpiperidin-3-yl)methoxy)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrileYield 80.9%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
75 °C

Procedure

(R)-4-(1-methylpiperidin-3-ylmethoxy)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (45 mg, 0.1 mmol) was dissolved in 1,4-dioxane (0.2 mL) and then treated with 48% HBr(aq) (0.2 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 pale yellow solid (26 mg, 70% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.97 (d, J=0.7, 1H), 8.54 (d, J=5.7, 1H), 8.44 (s, 1H), 7.04 (d, J=5.8, 1H), 4.28 (d, J=6.4, 2H), 2.88 (m, 1H), 2.65 (m, 1H), 2.27 (m, 1H), 2.19 (s, 3H), 1.97 (m, 2H), 1.83 (m, 1H), 1.74-1.66 (m, 1H), 1.59 (m, 1H), 1.28-1.18 (m, 1H), NH signal not observed. LCMS (method D): RT=7.182 min, M+H+=322.1.

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-36bfaee5e9b24fa2aadde87b2ae6030d
Source dataset
uspto-grants-2016_09
Patent number
US09440976B2

Reaction notes

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