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

HRID 60278Notes

Reaction equation

HRID 60278 reaction equation
[Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6](COCC[Si](C)(C)C)[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[C:3]=1[N:25]1[CH2:29][CH2:28][C@H:27]([N:30]([CH2:38][CH3:39])C(=O)OC(C)(C)C)[CH2:26]1.Br.[OH-].[Na+].Cl>O1CCOCC1>[Br:1][C:2]1[CH:24]=[N:23][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[C:3]=1[N:25]1[CH2:29][CH2:28][C@H:27]([NH:30][CH2:38][CH3:39])[CH2:26]1

Participants

6

Reactant 4

HCID 260Hydrogen BromideHCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 58365177(S)-tert-butyl 1-(3-bromo-6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-4-yl)pyrrolidin-3-yl(ethyl)carbamate

Product 1

HCID 53234599(S)-3-Bromo-4-(3-(ethylamino)pyrrolidin-1-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrileYield 59.7%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
55 °C

Procedure

(S)-tert-butyl 1-(3-bromo-6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)pyrrolidin-3-yl(ethyl)carbamate (65 mg, 0.1 mmol) was dissolved in 1,4-dioxane (0.3 mL) and then treated with 48% HBr(aq) (0.3 mL) and heated at 55° C. for 20 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 (23 mg, 26% over two steps). 1H NMR (500 MHz, d6-DMSO) δ 8.97 (s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 3.79-3.73 (m, 2H), 3.62-3.51 (m, 3H), 3.43 (m, 1H), 2.72-2.59 (m, 2H), 2.26 (m, 1H), 1.97 (m, 1H), 1.14 (t, J=7.1, 3H), NH signal not observed. LCMS (Method D): RT=7.535 min, M+H+=385.0/387.0.

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-d70067216c8f42df8f76b47f9c6cade4
Source dataset
uspto-grants-2016_09
Patent number
US09440976B2

Reaction notes

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