Water → Fexofenadine Hydrochloride

HRID 1445535Notes

Reaction equation

HRID 1445535 reaction equation
O.[ClH:2].[OH:3][C:4]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:18][CH:17]=2)[OH:15])[CH2:7][CH2:6]1.O>CC(C)=O>[ClH:2].[OH:3][C:4]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:18][CH:17]=2)[OH:15])[CH2:7][CH2:6]1

Participants

4

Reactant 2

HCID 962WaterHCID 116137484-[(4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid hydrochloride hydrate

Product 1

HCID 63002Fexofenadine HydrochlorideYield 97%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Conditions

Temperature
80 °C

Procedure

Place 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride hydrate (Form IV) (54.35 g, 0.0970 mol, having 4% water present) in a pressure bottle along with water (4.16 g) and acetone (38.1 g). Seal the bottle tightly and heat to approximately 80° C. Cool to less then 60° C., filter through filter aid in a coarse sintered glass funnel and rinse the filter cake with acetone (32.4 g). Place acetone (215 g) in a 1 L three necked flask fitted with a mechanical stirrer, thermometer, a reflux condenser and containing a small amount of Form I crystals and heat to reflux. Add a portion of the acetone/water solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride hydrate (Form IV) (47.65 g) to the refluxing, acetone over about 10 minutes. Slowly add ethyl acetate (157.5 g) over 45 minutes then add the remaining portion of the acetone/water solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride hydrate (Form IV), rinsed in with about 20 mL of acetone. Add additional ethyl acetate (157.5 g) over 45 minutes to 1 hour, maintaining the slurry at reflux. Stir for 15 minutes, cool to −15° C. and vacuum filter the white solid on a 350 mL coarse sintered glass funnel. Wash the solids with ethyl acetate (2×50 mL) and vacuum dry overnight to give the title compound (50.36 g, 97%); mp 198-199.5° C.

Workup

  1. customSeal the bottle tightly
  2. temperatureCool to less then 60° C.
  3. filtrationfilter
  4. filtrationthrough filter aid in a coarse sintered glass funnel
  5. washrinse the filter cake with acetone (32.4 g)
  6. customPlace acetone (215 g) in a 1 L three necked flask fitted with a mechanical stirrer
  7. additionthermometer, a reflux condenser and containing a small amount of Form I crystals
  8. temperatureheat to reflux
  9. additionAdd a portion of the acetone/water solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride hydrate (Form IV) (47.65 g) to the refluxing, acetone over about 10 minutes
  10. additionSlowly add ethyl acetate (157.5 g) over 45 minutes then add the remaining portion of the acetone/water solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride hydrate (Form IV)
  11. washrinsed in with about 20 mL of acetone
  12. additionAdd additional ethyl acetate (157.5 g) over 45 minutes to 1 hour
  13. temperaturemaintaining the slurry
  14. temperatureat reflux
  15. temperaturecool to −15° C.
  16. filtrationvacuum filter the white solid on a 350 mL coarse sintered glass funnel
  17. washWash the solids with ethyl acetate (2×50 mL) and vacuum
  18. customdry overnight

Sources & evidence

ORD record
ord-8cee760d1b7946b6b04638083db0e4e9
Source dataset
uspto-grants-2010_02
Patent number
US07666881B2

Reaction notes

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