Sodium hydride → AQW-051

HRID 882809Notes

Reaction equation

HRID 882809 reaction equation
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[H-].[Na+].Cl[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[N:17][CH:18]=1>CN(C=O)C.C1(C)C=CC=CC=1>[C:22]1([CH3:25])[CH:23]=[CH:24][C:19]([C:16]2[N:17]=[CH:18][C:13]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:14][CH:15]=2)=[CH:20][CH:21]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 914043-Quinuclidinol, (-)-HCID 671210225-Chloro-2-(4-methylphenyl)pyridine

Product 1

HCID 50914822AQW-051

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Procedure

Bromine (18.0 ml, 353.7 mmol) is slowly added to a soln. of 2-amino-5-chloropyridine (15.0 g, 116.7 mmol) in 47% aq. HBr (75.0 ml) at −10° C. An aq. soln. of NaNO2 (28.1 g, 407.3 mmol) is slowly added. The mixture is stirred for 1 h at −10 to −5° C., then for 1 h at 5° C. The mixture is neutralised with 5M aq. NaOH soln. maintaining the temperature below 25° C. The precipitate is filtered and recrystallized from pentane to give 2-bromo-5-chloropyridine. 2-Bromo-5-chloropyridine (5.0 g, 26.0 mmol), p-tolylboronic acid (4.0 g, 29.4 mmol) and tetrakis(triphenylphosphine)palladium (1.44 g, 1.2 mmol) are dissolved in toluene:EtOH 9:1 (1375 ml). A 2M aq. Na2CO3 soln. (62.5 ml) is added to the reaction mixture. The mixture is stirred at 90° C. for 24 h, cooled to rt and filtered over celite. The toluene layer is separated and washed with brine. The aq. layers are extracted with AcOEt. The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown solid which is purified by FC (silica gel, eluent toluene) to give 5-chloro-2-p-tolyl-pyridine. (R)-3-Quinuclidinol (2.97 g, 23.4 mmol) is added to a suspension of NaH (0.96 g of a 60% dispersion in mineral oil, 22.8 mmol) in DMF (90 ml). The mixture is stirred for 1 h at rt. 5-Chloro-2-p-tolyl-pyridine (4.00 g, 19.6 mmol) is added and the mixture is heated for 135 h at 135° C. The reaction mixture is diluted with toluene and washed with 1 M aq. NaOH soln. and brine. The aq. layers are re-extracted with toluene (3×). The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown oil which is purified by FC (silica gel, eluents: AcOEt, then AcOEt/MeOH/NEt3 87:10:3) and recrystallized from CH3CN to give (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane; mp ° C.: 110-112; [α]Drt=+21.2° (0.50, MeOH), M+H+ 295.2.

Workup

  1. temperaturethe mixture is heated for 135 h at 135° C
  2. washwashed with 1 M aq. NaOH soln
  3. extractionThe aq. layers are re-extracted with toluene (3×)
  4. dry with materialThe combined organic extracts are dried over MgSO4
  5. filtrationfiltered
  6. customThe filtrate is evaporated
  7. customto give a brown oil which
  8. customis purified by FC (silica gel, eluents
  9. customAcOEt, then AcOEt/MeOH/NEt3 87:10:3) and recrystallized from CH3CN

Sources & evidence

ORD record
ord-63363cb2bdf944f58b04b6d38f1727a6
Source dataset
uspto-grants-2012_08
Patent number
US08236803B2

Reaction notes

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