Hydrochloric Acid → 6-Butyl-8-[((3R)-1-{3-[(1,1-dimethylethyl)sulfonyl]propyl}-3-pyrrolidinyl)oxy] quinoline, dihydrochloride salt

HRID 1363024Notes

Reaction equation

HRID 1363024 reaction equation
[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][C@@H:16]3[CH2:20][CH2:19][NH:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[CH3:21][C:22]([S:25]([CH2:28][CH2:29][CH2:30]Br)(=[O:27])=[O:26])([CH3:24])[CH3:23].CC(S(CCC[Cl:42])(=O)=O)(C)C.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[ClH:51]>CN(C=O)C.CO>[ClH:42].[ClH:51].[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][C@@H:16]3[CH2:20][CH2:19][N:18]([CH2:30][CH2:29][CH2:28][S:25]([C:22]([CH3:24])([CH3:23])[CH3:21])(=[O:27])=[O:26])[CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 5238Sodium IodideHCID 11430Potassium CarbonateHCID 2424061-Chloro-3-(2-methylpropane-2-sulfonyl)propane2×HCID 434445061-Bromo-3-(2-methylpropane-2-sulfonyl)propaneHCID 669217306-Butyl-8-[(3R)-3-pyrrolidinyloxy]quinoline2×

Product 1

HCID 1317286556-Butyl-8-[((3R)-1-{3-[(1,1-dimethylethyl)sulfonyl]propyl}-3-pyrrolidinyl)oxy] quinoline, dihydrochloride salt

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent3×HCID 6228DimethylformamideSolvent

Conditions

Temperature
150 °C

Procedure

To a solution of 6-butyl-8-[(3R)-3-pyrrolidinyloxy]quinoline (for example, as prepared for Intermediate 10) (0.130 g, 0.481 mmol), in DMF (3 ml) was added a mixture of 3-bromopropyl 1,1-dimethylethyl sulfone and 3-chloropropyl 1,1-dimethylethyl sulfone (for example, as prepared for Intermediate 17) (1:1, 0.215 g, 0.96 mmol), sodium iodide (0.144 g, 0.96 mmol), then potassium carbonate (0.133 g, 0.96 mmol). The suspension was heated to 150° C. for 15 min in a Smith Creator™ microwave oven with fixed hold time on. The mixture was applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and the cartridge washed with methanol (2 column volumes). The cartridge was eluted with 10% 0.88 s.g. ammonia in methanol (2 column volumes) and the basic fraction concentrated in vacuo. The residue (0.2 g) was purified by MDAP and the appropriate fractions combined and concentrated in vacuo. The residue (0.113 g) was further purified by Flashmaster II chromatography (50 g cartridge) eluting with 0-25% methanol in DCM over 40 min. The appropriate fractions were combined and the solvent removed in vacuo (70 mg, 33%). To a portion of this material (29 mg, 0.067 mmol) in methanol (0.5 ml) was added 1.25 M hydrogen chloride in methanol (0.3 ml). The solvent was removed using a stream of nitrogen to leave the title compound as white solid (34 mg). LCMS RT=2.97 min, ES+ve m/z 433 (M+H)+.

Workup

  1. washthe cartridge washed with methanol (2 column volumes)
  2. washThe cartridge was eluted with 10% 0.88 s
  3. concentrationammonia in methanol (2 column volumes) and the basic fraction concentrated in vacuo
  4. customThe residue (0.2 g) was purified by MDAP
  5. concentrationconcentrated in vacuo
  6. customThe residue (0.113 g) was further purified by Flashmaster II chromatography (50 g cartridge)
  7. washeluting with 0-25% methanol in DCM over 40 min
  8. customthe solvent removed in vacuo (70 mg, 33%)
  9. customThe solvent was removed

Sources & evidence

ORD record
ord-c45fc555d162421d958bcc7ddcb90c99
Source dataset
uspto-grants-2011_02
Patent number
US07884114B2

Reaction notes

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