Trifluoroacetic acid → (4R)-4-((1R)-1-((6-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)phenyl)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one

HRID 2209107Notes

Reaction equation

HRID 2209107 reaction equation
[CH:1]1([N:4]2[C:8]3[C:9]([O:33][C@@H:34]([C@@H:36]4[CH2:40][C:39](=[O:41])[NH:38][CH2:37]4)[CH3:35])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH:23]6[CH2:25][CH:21]([N:22]6C(OC(C)(C)C)=O)[CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH:23]12[CH2:25][CH:21]([NH:22]1)[CH2:20][N:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]3[N:10]=[C:9]([O:33][C@@H:34]([C@H:36]4[CH2:37][NH:38][C:39](=[O:41])[CH2:40]4)[CH3:35])[C:8]4[N:4]([CH:1]5[CH2:3][CH2:2]5)[CH:5]=[N:6][C:7]=4[CH:12]=3)=[CH:18][CH:17]=1)[CH2:24]2

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 516892Sodium BicarbonateHCID 117843474tert-butyl 3-(4-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

Product 1

HCID 117843098(4R)-4-((1R)-1-((6-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)phenyl)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-oneYield 100.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a round-bottomed, 100-mL, single-necked flask was placed tert-butyl 3-(4-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (200.0 mg, 0.27 mmol) in dichloromethane (1 mL). To this was added trifluoroacetic acid (3.1 ml, 40.81 mmol). The mixture was stirred at room temperature for 3 h. Then, it was neutralized with sat. NaHCO3 and the organic layers were extracted with dichloromethane (3×5 mL). The combined organic layers were washed with water (2×5 mL) and brine (1×5 mL), dried (Na2SO4), concentrated, and purified by flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane) to give 124.8 mg (71%) of (4R)-4-((1R)-1-((6-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)phenyl)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.61 (s, 1H), 7.57 (s, 1H), 6.78 (d, J=9.1 Hz, 2H), 5.57 (m, 1H), 3.57 (m, 8H), 2.84 (m, 2H), 2.57 (m, 1H), 2.39 (m, 3H), 1.53 (m, 1H), 1.41 (d, J=6.3 Hz, 3H), 1.18 (m, 4H). MS (ESI+) m/z 459.1 (M+H).

Workup

  1. extractionthe organic layers were extracted with dichloromethane (3×5 mL)
  2. washThe combined organic layers were washed with water (2×5 mL) and brine (1×5 mL)
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated
  5. custompurified by flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane)

Sources & evidence

ORD record
ord-84721773ab0a4bd886fee6b5f5d1393a
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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