Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate → (R)-1-[[2-(3,4-difluoroPhenyl)-4-quinoliny]carbonyl]-2-hydroxymethyl-pyrrolidine

HRID 411515

Reaction equation

HRID 411515 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:33]2[CH:34]=[CH:35][CH:36]=C[C:32]=2[N:31]=N1.C([O-])(O)=[O:50].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:18]=[C:17]([C:19]([N:31]3[CH2:32][CH2:33][CH2:34][C@@H:35]3[CH2:36][OH:50])=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

5

Reactant 3

HCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 516892Sodium BicarbonateHCID 46116332-(3,4-Difluorophenyl)-4-quinolinecarboxylic acid

Product 1

HCID 9799393(R)-1-[[2-(3,4-difluoroPhenyl)-4-quinoliny]carbonyl]-2-hydroxymethyl-pyrrolidine

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 2-(3,4-difluoroPhenyl)-4-quinoline carboxylic acid (100 mg), BOP (220 mg) and (R)-(−)-pyrrolidine methanol (0.1 mL) in 1 ml of DMF is stirred at room temperature for 18 hours. The mixture is added to saturated aqueous NaHCO3 solution and extracted three times with EtOAc. The combined EtOAc layers are washed with brine and water, dried over Na2SO4, filtered and concentrated to afford a foam. The foam is purified by preparative silica gel thin layer chromatography, using 10% methanol in methylene chloride as the developing solvent. The desired product is obtained as a free base. 1H NMR (CDCl3) d 1.77 -1.87(3H, m), 2.16-2.22 (1H, m), 3.18-3.26 (2H, m), 3.83-3.95 (2H, m), 4.52-4.56 (1H, m), 7.23-7.30 (1H, m), 7.57 (1H, m), 7.73-7.78 (2H, m), 7.83 (1H, d), 7.87 (1H, m), 8.03-8.10 (1H, m), 8.15 (1H, d). The hydrochloride salt was prepared by treating the free base in EtOAc with a solution of hydrogen chloride in ether and collecting the resulting solid by filtration.

Workup

  1. extractionextracted three times with EtOAc
  2. washThe combined EtOAc layers are washed with brine and water
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto afford a foam
  7. customThe foam is purified by preparative silica gel thin layer chromatography

Sources & evidence

ORD record
ord-c38a426b38c0429fab38b282dfe34620
Source dataset
uspto-grants-2003_05
Patent number
US06559163B2

Linked notes

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