Hydrochloric Acid → 4-[(4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid hydrochloride hydrate

HRID 722697Notes

Reaction equation

HRID 722697 reaction equation
[ClH:1].[OH:2][C:3]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.[OH-].[Na+].[BH4-].[Na+].Cl>O.CC(C)=O.CO>[OH2:2].[ClH:1].[OH:2][C:3]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)[OH:14])[CH2:6][CH2:5]1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 4311764Sodium borohydrideHCID 12939646Ethyl 4-{4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl}-alpha,alpha-dimethylbenzeneacetate hydrochloride

Product 1

HCID 116137484-[(4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid hydrochloride hydrateYield 196.7%

Reagents, catalysts & solvents 3

HCID 180AcetoneSolventHCID 887MethanolSolventHCID 962WaterSolvent2×

Conditions

Temperature
73 °C

Procedure

Place ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate, hydrochloride (60.01 g, 0.106 mol) in a 1-L three necked round-bottom flask and fit the flask with a mechanical stirrer, a Claisen head, a thermometer and a reflux condenser with a nitrogen bubbler on top. Add methanol (300 mL) and turn the stirrer on. Dilute the slurry with water (6 mL) and heat to 52–54° C. over 15–20 minutes. Hold at 52° C. for 2 hours and then add 50% sodium hydroxide (42.54 g, 0.532 mol). Heat at 73° C. for approximately 1 hour, 45 minutes, cool to less than 35° C. using a water bath and then add sodium borohydride (2.02 g, 0.0534 mol). Stir overnight at 35° C., treat with acetone (15.5 mL) and stir for 2 hours at 35° C. Acidify the mixture to a pH of 1.85 with 28% hydrochloric acid (75.72 g), dilute with water (282 mL), stir for about 30 minutes and cool over about 2 hours to −15° C. Filter the solids off and wash with water (2×75 mL) and ethyl acetate (2×75 mL). Vacuum dry the solid and allow to stand for 2 days to give 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (57.97 g, 91.5%) as a fine powder.

Workup

  1. temperatureheat to 52–54° C. over 15–20 minutes
  2. temperaturecool to less than 35° C.
  3. stirringstir for 2 hours at 35° C
  4. stirringstir for about 30 minutes
  5. temperaturecool over about 2 hours to −15° C
  6. filtrationFilter the solids off and
  7. washwash with water (2×75 mL) and ethyl acetate (2×75 mL)
  8. customVacuum dry the solid
  9. waitto stand for 2 days

Sources & evidence

ORD record
ord-8bdaf02642934cc8a49d45e9a57fc4ab
Source dataset
uspto-grants-2006_11
Patent number
US07138524B2

Reaction notes

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