1-Hydroxybenzotriazole → (R)-Quinuclidin-3-yl 2-(4-fluorobenzylamino)-2-phenylacetate

HRID 77009Notes

Reaction equation

HRID 77009 reaction equation
Cl.[F:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23]([O:11][C:10](=[O:12])[CH:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:20][CH:19]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:22]2

Participants

5

Reactant 3

HCID 757711-HydroxybenzotriazoleHCID 914043-Quinuclidinol, (-)-HCID 67425426(4-Fluoro-benzylamino)-phenyl-acetic acid hydrochloride

Product 1

HCID 59401102(R)-Quinuclidin-3-yl 2-(4-fluorobenzylamino)-2-phenylacetateYield 21%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A mixture of (4-fluoro-benzylamino)-phenyl-acetic acid hydrochloride (233 mg, 0.79 mmol), (R)-quinuclidin-3-ol (200 mg, 1.57 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (596 mg, 1.57 mmol), TEA (0.22 mL, 1.57 mmol) and HOBT (241 mg, 1.57 mmol) in acetonitrile (10 mL) is stirred at RT for 48 hours. THF is removed under vacuum and the crude is partitioned between EtOAc and water. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The crude is purified by preparative HPLC. The combined fractions are dried and partitioned between EtOAc and 2M K2CO3. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness to achieve the title compound as colorless oil (61 mg, 21% yield, mixture of diastereoisomers).

Workup

  1. customTHF is removed under vacuum
  2. customthe crude is partitioned between EtOAc and water
  3. dry with materialThe organic phase is dried over sodium sulphate
  4. filtrationfiltered
  5. customevaporated to dryness
  6. customThe crude is purified by preparative HPLC
  7. customThe combined fractions are dried
  8. custompartitioned between EtOAc and 2M K2CO3
  9. dry with materialThe organic phase is dried over sodium sulphate
  10. filtrationfiltered
  11. customevaporated to dryness

Sources & evidence

ORD record
ord-ae5add85318f48a489b0faa1aa081ebe
Source dataset
uspto-grants-2014_09
Patent number
US08835682B2

Reaction notes

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