Propargyl alcohol → N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-hydroxyprop-1-ynyl)pyrrolo[1,2-a]pyrazine-3-carboxamide tartrate

HRID 25164

Reaction equation

HRID 25164 reaction equation
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]3[N:16]([C:18](Br)=[CH:19][CH:20]=3)[CH:17]=1)=[O:11])[CH2:2]2.C(N(CC)CC)C.[CH2:29]([OH:32])[C:30]#[CH:31].[C:33]([OH:42])(=[O:41])[C@H:34]([C@@H:36]([C:38]([OH:40])=[O:39])[OH:37])[OH:35]>O1CCOCC1.[I+].[Cu+].Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:38]([CH:36]([CH:34]([C:33]([OH:42])=[O:41])[OH:35])[OH:37])([OH:40])=[O:39].[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]3[N:16]([C:18]([C:31]#[C:30][CH2:29][OH:32])=[CH:19][CH:20]=3)[CH:17]=1)=[O:11])[CH2:2]2

Participants

8

Reactant 4

HCID 7859Propargyl alcoholHCID 8471TriethylamineHCID 439655D-Tartaric acidHCID 10247203N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromopyrrolo[1,2-a]pyrazine-3-carboxamide

Product 1

HCID 69772344N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-hydroxyprop-1-ynyl)pyrrolo[1,2-a]pyrazine-3-carboxamide tartrateYield 24%

Reagents, catalysts & solvents 3

HCID 178418903HCID 178418903, compoundCatalystHCID 178505377HCID 178505377, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To an argon sparged solution of N-[(3R)— 1-azabicyclo[2.2.2]oct-3-yl]-6-bromopyrrolo[1,2-a]pyrazine-3-carboxamide (0.230 g, 0.92 mmol), triethylamine (3.2 mL, 23.0 mmol) in dioxane (5 mL) is added copper (I) iodine (0.054 g, 0.28 mmol), propargyl alcohol (0.22 mL, 3.68 mmol), and dichlorobis(triphenylphosphino)-palladium (II) (0.063 g, 0.09 mmol). The reaction vessel is purged with argon, and stirred at 80° C. for 20 h at which point it is filtered through a plug of celite, concentrated to dryness, and the residue dissolved in CHCl3 (150 mL) that is washed with a solution containing 1:1 NH4OH/brine (5×35 mL). The residue is purified using silica gel chromatography (5% MeOH/CH2Cl2 gradient up to 10% MeOH/CH2Cl2) to give a pale orange colored oil that is salted with d-tartaric acid, and crystallized from EtOH/Et2O to give a tan solid. Yield 24%. HRMS (FAB) calcd for C18H20N4O2+H 325.1664, found 325.1664.

Workup

  1. customThe reaction vessel is purged with argon
  2. filtrationis filtered through a plug of celite,
  3. concentrationconcentrated to dryness
  4. dissolutionthe residue dissolved in CHCl3 (150 mL) that
  5. washis washed with a solution
  6. additioncontaining 1:1 NH4OH/brine (5×35 mL)
  7. customThe residue is purified
  8. customto give a pale orange colored oil that
  9. customcrystallized from EtOH/Et2O
  10. customto give a tan solid

Sources & evidence

ORD record
ord-0ee1fb5b7808414d8920f6aced541af2
Source dataset
uspto-grants-2005_02
Patent number
US06858613B2

Linked notes

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