(R)-Quinuclidin-3-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetate → (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide

HRID 1920569Notes

Reaction equation

HRID 1920569 reaction equation
[Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][N:7]=1)=[O:4].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([O:20][C:21](=[O:34])[C:22]([OH:33])([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:13]2>C(Cl)(Cl)Cl.C(#N)C>[Br-:1].[OH:33][C:22]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[C:21]([O:20][C@@H:14]1[CH:15]2[CH2:18][CH2:19][N+:12]([CH2:2][C:3](=[O:4])[NH:5][C:6]3[CH:11]=[CH:10][N:9]=[CH:8][N:7]=3)([CH2:17][CH2:16]2)[CH2:13]1)=[O:34]

Participants

4

Reactant 2

HCID 44232927(R)-Quinuclidin-3-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetateHCID 445419272-Bromo-N-pyrimidin-4-yl-acetamide

Product 1

HCID 86611384(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide

Reagents, catalysts & solvents 1

HCID 22555007Acetonitrile chloroformSolvent

Procedure

A solution of 2-Bromo-N-pyrimidin-4-yl-acetamide (0.90 g, 4.17 mmol) and hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 70(ii)) (1.32 g, 3.79 mmol) in dry chloroform-acetonitrile (20 ml+4 ml) are heated at 50° C. for 3 hours. The mixture is then cooled to room temperature and concentrated. Purification by reverse phase C18 column chromatography (gradient elution 100% water to 100% acetonitrile) gives after concentration a light brown solid. The solid was triturated with hot acetonitrile then dissolved in hot acetonitrile containing a few drops of water. After standing at 5° C. for several hours crystals are formed which are filtered and dried to give the title compound.

Workup

  1. concentrationconcentrated
  2. customPurification
  3. washby reverse phase C18 column chromatography (gradient elution 100% water to 100% acetonitrile)
  4. customgives
  5. concentrationafter concentration a light brown solid
  6. customThe solid was triturated with hot acetonitrile
  7. dissolutionthen dissolved in hot acetonitrile containing a few drops of water
  8. waitAfter standing at 5° C. for several hours
  9. customcrystals are formed which
  10. filtrationare filtered
  11. customdried

Sources & evidence

ORD record
ord-00d1a659282244e481c0f059ceed3b18
Source dataset
uspto-grants-2012_05
Patent number
US08168654B2

Reaction notes

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