Sodium Carbonate → (-)-5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane

HRID 44456Notes

Reaction equation

HRID 44456 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3]1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]23[CH2:24][N:21]([CH2:22][CH2:23]2)[CH2:20][CH2:19][CH2:18]3)=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:1][N:2]1[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]34[CH2:24][N:21]([CH2:22][CH2:23]3)[CH2:20][CH2:19][CH2:18]4)=[CH:13][N:12]=2)[CH:4]=[N:3]1

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 112635011-Methyl-1H-pyrazole-4-boronic acidHCID 862593785-(2-Bromopyrid-5-yl)-1-azabicyclo[3.2.1]octane

Product 1

HCID 16005053(-)-5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octaneYield 93.2%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 702EthanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
105 °C

Procedure

0.162 g (0.78 mmol) of 1-methyl-4-pyrazolylboronic acid, 0.160 g (0.6 mmol) of (−)-5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]octane (obtained by reacting 5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]octane (−)-hydrobromide (1:1), prepared in step 1.2, with saturated aqueous sodium carbonate solution) are successively introduced into a 10 ml three-necked round-bottomed flask, as a solution in 3 ml of toluene and 0.3 ml of ethanol. 0.035 g (0.03 mmol) of tetrakis(triphenylphosphine)palladium and 0.6 ml of aqueous 2M sodium carbonate solution are then added and the mixture is heated at 105° C. for 18 hours. It is cooled to room temperature, the solvent is evaporated off under reduced pressure and the residue is taken up in 10 ml of chloroform and filtered through diatomaceous earth. The solvent is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 95/5/0.5 proportions. 0.15 g of (−)-5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane is obtained, and is dissolved in 2 ml of isopropyl alcohol to add 0.196 ml of a 5.7N solution of hydrobromic acid in acetic acid. The crystals obtained are collected by filtration and dried under vacuum. 0.163 g of product is obtained.

Workup

  1. temperatureIt is cooled to room temperature
  2. customthe solvent is evaporated off under reduced pressure
  3. filtrationfiltered through diatomaceous earth
  4. concentrationThe solvent is concentrated under reduced pressure
  5. customthe residue is purified by chromatography on a column of silica gel
  6. washeluting with a mixture of chloroform, methanol and aqueous ammonia in 95/5/0.5 proportions

Sources & evidence

ORD record
ord-530aeacf8f964050ac69ac25383d834a
Source dataset
uspto-grants-2013_09
Patent number
US08541440B2

Reaction notes

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