Water → (2,3-Dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol

HRID 2055853Notes

Reaction equation

HRID 2055853 reaction equation
O.S(=O)(=O)(O)O.[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:17]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][CH2:20]1)[OH:18].[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:17]([CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:24]1)[OH:18]

Participants

6

Reactant 4

HCID 962WaterHCID 1118Sulfuric Acid2×HCID 14798Sodium HydroxideHCID 11953651(S)-(2,3-Dimethoxyphenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol

Product 1

HCID 60858(2,3-Dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanolYield 80%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

The concentrated resolution mother liquors from Scheme B, step b, (302.3 g, assayed 38.5 wt % diastereomeric salt (116 g, 147 mmol of salt)) were concentrated on the rotary evaporator to a solution which was approximately 0.67 g/mL. This solution was added dropwise to a suspension of toluene (250 mL), water (175 mL) and potassium carbonate (25.58 g, 0.185 mol). The mixture was stirred for about 30 minutes at 40° C. (The organic phase contained 14.1 wt %, 49.8 g (S)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3c) by assay. The aqueous phase1 contained 1.3 wt %, 5 g of (S)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3c) by assay). The toluene was removed by evaporation to give a white solid (60 g). This residue was dissolved in tetrahydrofuran (174 mL), water (75 mL) and sulphuric acid (47.6 g, 0.48 mol). (The pale yellow solution was assayed, 14.8 wt %, 50.3 g of (S)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3c)). The mixture was heated at reflux for 32 hours. After 16 hours, an additional portion (6.5 g, 66 mmol) of sulphuric acid was added. The reaction mixture was cooled to ambient temperature and carefully neutralized with 50% aqueous sodium hydroxide (87.92 g, 1.1 mol). The tetrahydrofuran was removed by vacuum distillation on the rotary evaporator, toluene (175 mL) and water (55 mL) were added and the mixture was stirred at 60-70° C. for about 30 minutes. The phases were decanted at 60° C. and the aqueous phase was extracted a second time with toluene (80 mL). The toluene phases were combined and concentrated on the rotary evaporator to remove water. The solution was assayed (29.7%, 43.2 g α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol) (5), heated to reflux and slowly cooled. Seeding at 50° C. was required. The slurry was digested at 50° C. prior to cooling to 0-5° C. prior to isolation by filtration. The filter cake was washed with chilled toluene (30 mL) and dried to a constant weight to obtain α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (5) (40.25 g, 81%, 97.5% assay). 1The aqueous phase which contained the (2S,3S)-(+)-di-(p-anisoyl)tartaric acid was added dropwise to a solution of 32% HCl (42.57 g, 0.37 mol) and water (234 mL) at 40° C. The (2S,3S)-(+)-di-(p-anisoyl)tartaric acid precipitated as a white solid. The solution was cooled to room temperature overnight and in an ice bath for 45 minutes prior to isolation by filtration. The recovered solid was washed with cold water, suction filtered, and finally dried to a constant weight in a vacuum oven to give 47.55 g of product (77% recovery).

Workup

  1. temperatureThe mixture was heated
  2. temperatureat reflux for 32 hours
  3. customThe tetrahydrofuran was removed by vacuum distillation on the rotary evaporator, toluene (175 mL) and water (55 mL)
  4. additionwere added
  5. customThe phases were decanted at 60° C.
  6. extractionthe aqueous phase was extracted a second time with toluene (80 mL)
  7. concentrationconcentrated on the rotary evaporator
  8. customto remove water
  9. temperatureheated
  10. temperatureto reflux
  11. temperatureslowly cooled
  12. customSeeding at 50° C.
  13. customwas digested at 50° C.
  14. temperatureto cooling to 0-5° C.
  15. filtrationto isolation by filtration
  16. washThe filter cake was washed with chilled toluene (30 mL)
  17. customdried to a constant weight

Sources & evidence

ORD record
ord-66a5076c6545424cac7648c94fb583d0
Source dataset
uspto-grants-2008_02
Patent number
US07332607B2

Reaction notes

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