Potassium Iodide → Haloperidol hydrochloride

HRID 2083663Notes

Reaction equation

HRID 2083663 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[I-].[K+].[OH-].[K+].C1CO[C:21]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([CH2:22][CH2:23][CH2:24]Cl)[O:20]1>C1(C)C=CC=CC=1.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:24][CH2:23][CH2:22][C:21]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:20])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 4875Potassium IodideHCID 14797Potassium HydroxideHCID 382824-(4-Chlorophenyl)-4-hydroxypiperidineHCID 27237782-(3-Chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane

Product 1

HCID 11495267Haloperidol hydrochlorideYield 75.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

Under a nitrogen atmosphere 4.87 parts of 4-(4-chlorophenyl)piperidin-4-ol, 1.91 parts of potassium iodide and 25 parts of deionized water is combined and gently warmed. 1.65 Parts of potassium hydroxide, followed by 6.12 parts of 1,1-ethylenedioxy-1-(4-fluorophenyl)-4-chlorobutane is added, and the mixture is heated to reflux. After refluxing for 3.75 hours, the reaction mixture is cooled to room temperature, and 55 parts of toluene is added. The aqueous and organic layers are separated, and the aqueous layer discarded. 5.1 Parts of methanol is added to the organic layer and the mixture cooled to about 25° C. While stirring vigorously, 3.1 parts of concentrated hydrochloric acid is added. The resultant precipitate is filtered and washed twice with 22 parts by volume portions of a 10:9:1 mixture of acetone-toluene-methanol. The filtrate, after standing for about 18 hours, affords additional precipitate. This is filtered and combined with the initially isolated precipitate. The solid is then washed twice with 22 parts by volume portions of a 10:9:1 mixture of acetone-toluene-methanol and twice with 22 parts by volume portions of a 10:1 mixture of acetone-methanol. The solid is air-dried to give, in 75.5% yield, 4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyrophenone hydrochloride as a white solid melting at about 226° - 228° C., and identical to the product of Example 2.

Workup

  1. temperaturegently warmed
  2. additionis added
  3. temperaturethe mixture is heated to reflux
  4. temperatureAfter refluxing for 3.75 hours
  5. customThe aqueous and organic layers are separated
  6. addition5.1 Parts of methanol is added to the organic layer
  7. temperaturethe mixture cooled to about 25° C
  8. addition3.1 parts of concentrated hydrochloric acid is added
  9. filtrationThe resultant precipitate is filtered
  10. washwashed twice with 22 parts by volume portions of a 10:9:1 mixture of acetone-toluene-methanol
  11. customaffords additional precipitate
  12. filtrationThis is filtered
  13. washThe solid is then washed twice with 22 parts by volume portions of a 10:9:1 mixture of acetone-toluene-methanol and twice with 22 parts by volume portions of a 10:1 mixture of acetone-methanol
  14. customThe solid is air-dried

Sources & evidence

ORD record
ord-36f3e6179fb54916a63d0bc0e5b71bb0
Source dataset
uspto-grants-1978_04
Patent number
US04086234

Reaction notes

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