Hydrogen Bromide → (R)-4-(Piperidin-3-yloxy)-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole

HRID 60320Notes

Reaction equation

HRID 60320 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:15]=[CH:14][C:13]3[N:12](COCC[Si](C)(C)C)[C:11]4[N:24]=[CH:25][CH:26]=[C:27]([O:28][C@@H:29]5[CH2:34][CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]5)[C:10]=4[C:9]=3[CH:8]=2)[CH:4]=[N:3]1.Br.[OH-].[Na+].Cl>O1CCOCC1>[NH:31]1[CH2:32][CH2:33][CH2:34][C@@H:29]([O:28][C:27]2[C:10]3[C:9]4[CH:8]=[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)[N:15]=[CH:14][C:13]=4[NH:12][C:11]=3[N:24]=[CH:25][CH:26]=2)[CH2:30]1

Participants

6

Reactant 4

HCID 260Hydrogen BromideHCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 58365130(R)-tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-4-yloxy)piperidine-1-carboxylate

Product 1

HCID 53251837(R)-4-(Piperidin-3-yloxy)-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrroleYield 31.9%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
75 °C

Procedure

(R)-tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yloxy)piperidine-1-carboxylate (50 mg, 0.09 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 5 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 (10 mg, 30% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 11.95 (s, 1H), 8.77 (s, 1H), 8.39 (d, J=5.7, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 6.95 (d, J=5.9, 1H), 4.77-4.67 (m, 1H), 3.91 (s, 3H), 3.10-3.25 (m, 1H), 2.90-2.83 (m, 2H), 2.67 (m, 1H), 2.19 (m, 1H), 1.91-1.78 (m, 2H), 1.67-1.53 (m, 1H), piperidine NH not observed. LCMS (Method D): RT=5.567 min, M+H+=349.1.

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-19c468a8d2884347acea61d79a718827
Source dataset
uspto-grants-2016_09
Patent number
US09440976B2

Reaction notes

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