(R)-4-((R)-1-((3-cyclopropyl-6-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one → 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

HRID 2209106Notes

Reaction equation

HRID 2209106 reaction equation
[CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16](C5CCN(C6COC6)CC5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.CC1(C)C(C)(C)OB(C2C=CC([N:52]3[CH2:57][CH:56]4[CH2:58][CH:54]([N:55]4[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:53]3)=CC=2)O1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@@H:32]4[CH2:33][C:34](=[O:37])[NH:35][CH2:36]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:14]=[CH:15][C:16]([N:52]5[CH2:53][CH:54]6[CH2:58][CH:56]([N:55]6[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:57]5)=[CH:17][CH:18]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1

Participants

6

Reactant 2

HCID 117843603(R)-4-((R)-1-((3-cyclopropyl-6-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-oneHCID 123316145Tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

Product 1

HCID 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-carboxylateYield 59%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 10340Sodium CarbonateSolvent

Procedure

Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:, using instead tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (289.4 mg, 0.72 mmol), and Pd(PPh3)4 (34.8 mg, 0.030 mmol) in DME (3 mL) and 2N Na2CO3 (2 mL). The reaction mixture was sonicated for 30 sec and degassed with nitrogen gas for 30 sec, and heated at 100 C for 1 h. Then it was cooled to room temperature, directly loaded on the pre-packed silica cartridge, and purified by flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane) to give 200.0 mg (59%) of 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.

Workup

  1. customPrepared by Suzuki
  2. customreaction procedure
  3. customThe reaction mixture was sonicated for 30 sec
  4. customdegassed with nitrogen gas for 30 sec
  5. temperatureheated at 100 C for 1 h
  6. custompurified by flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane)

Sources & evidence

ORD record
ord-0c017e5b365d41b4b093ba3bbd9bb4d2
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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