GB1596874A

GB1596874A - Synthesis of haloperidol

Info

Publication number: GB1596874A
Application number: GB15642/78A
Authority: GB
Original assignee: GD Searle LLC
Current assignee: GD Searle LLC
Priority date: 1978-04-20
Filing date: 1978-04-20
Publication date: 1981-09-03
Also published as: FR2423470B1; JPS54145675A; FR2423470A1; DE2915596A1; CA1129424A; BE875699A; NL7903086A; IT7948783A0; IT1120411B

Description

(54) IMPROVED SYNTHESIS OF HALOPERIDOL (71) We, G.D. SEARLE & CO., a corporation organised under the Laws of Delaware, U.S.A. of P.O. Box 5110, Chicago, Illinois 60680, United States of America do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to an improved synthesis of haloperidol and also to an intermediate used therein. The formula of haloperidol is as follows:

It is therapeutically useful as a tranquilising agent.

In the past, haloperidol has been produced by a process comprising the direct coupling of y-chloro-4-fluorobutyrophenone to 4-p-chlorophenyl-4-hydroxypiperidine hydrochloride and the isolation of the thus-obtained haloperidol. The purity and yield of product obtained in this way is not entirely satisfactory.

It has become necessary to produce haloperidol of greater purity than is convenientlv possible using the known synthesis.

It has now been found that haloperidol may be prepared in good yield and of a purity not previously conveniently obtainable by reacting a mixture of two isomeric enol ethers:

wherein R represents C1-C3 alkyl; and X represents chlorine or bromine; with 4-pchlorophenyl-4-hydroxypiperidine in aqueous basic solution, acidifying the reaction mixture and isolating the haloperidol.

The enol ether (II) is a novel compound which may be prepared by reacting trimethyl orthoformate, methanol and y-chloro or -bromo-4-fluorobutyrophenone at an elevated temperature not exceeding 145"C, under anhydrous conditions and in the presence of acid, preferably concentrated sulphuric acid, and separating the thus-obtained enol ether of y-chloro or -bromo -4-fluorobutyrophenone.

Accordingly, the present invention also provides, as a novel compound, a compound corresponding to the following general formula:

RO CH-CH2-CH2-X (lye) (cis and trans) F wherein R and X are as defined above.

In another embodiment, the present invention provides a process for the preparation of a compound corresponding to general formula (II) which comprises heating together, at an elevated temperature not exceeding 145"C, under anhydrous conditions and in the presence of acid, a tri- C1-C3 alkyl, e.g. trimethyl, orthoformate, methanol and the appropriate y-halo-4-fluorobutyrophenone and isolating the thus-obtained compound.

The reaction is preferably carried out using concentrated sulphuric acid, in the presence of methanol, under a nitrogen atmosphere to ensure anhydrous conditions. The reaction scheme may be represented as follows:

Furthermore, the present invention provides a process for the preparation of haloperidol which comprises reacting a compound corresponding to general formula (II) with 4-p-chlorophenyl-4-hydroxypiperidine in aqueous basic solution, acidifying the reaction mixture and isolating the thus-obtained haloperidol. The reaction is generally carried out at an elevated temperature.

The reaction scheme may be represented as follows:

H CI CH3Q CI OH F H + other isomer HCI KOH/KI 0 N OH F 143 (I) CI The invention is further illustrated by the following Examples: EXAMPLE 1 Preparation of the y-chloro-4-fluorobutyrophenone enol ether 45 litres of trimethyl orthoformate, 30 Kg of y-chloro-4-fluorobutyrophenone, 12.5 1.

methanol and 200 mls of concentrated sulphuric acid were placed in a 50 gal glass-lined reactor, covered with nitrogen and heated to reflux for 2 hours while stirring. Excess solvent was stripped off under vacuum giving 34 Kg of y-chloro-4-fluorobutyrophenone ketal in the form of a brown mobile oil. The ketal was transferred to a 50 litre still and refluxed under vacuum using an oil pump. Dry ice solvent traps were provided to deal with the gaseous solvent evolved. When efferescence had subsided, the vessel was heated to, and maintained at, 1200C until efferescence again died down. The vessel temperature was then increased to from 130 to 140"C and further solvent collected. When no more solvent was evolved the apparatus was switched from reflux to distillation. The enol ether product was collected until the vessel temperature rose above 145"C. At this point the distillation was stopped. A yield of 25 Kg (77.8% of the theoretical yield) was obtained.

EXAMPLE 2 Preparation of haloperidol 6 Kg of 4-p-chlorophenyl-4-hydroxypiperidine hydrochloride, 2.0 Kg of potassium iodide and 25 litres of water were placed in a 40 gal stainless steel reactor and covered with nitrogen. The reaction mixture was stirred, warmed slightly and 3.50 Kg of potassiulll hydroxide was added. The mixture was stirred for 5 minutes, 5.95 Kg of y-chloro-4 fluorobutyrophenone enol ether (Example 1) was added and the mixture refluxed gently for from 3 to 5 hours. The mixture was then cooled and 63 litres of toluene added, the mixture was stirred for 5 minutes and then separated. 6.4 litres of methanol were added to the toluene layer and the mixture transferred to a glass-lined vessel. 2.5 litres of concentrated hydrochloric acid was added while stirring vigorously, and a flocculent precipitate of haloperidol hydrochloride separated out. The mixture was stirred vigorously for 5 minutes, cooled and filtered. The residue was slurried with a mixture of acetone: toluene: methanol and the slurry sucked dry. The residue was again washed with an acetone: toluene: methanol mixture. The residue was washed twice with an acetone: methanol mixture and the residue sucked dry. The solid was placed in a stainless steel vessel and dissolved in 80 litres of methanol, heated to reflux and filtered through a pad of "Hyflo" into a glass-lined vessel. 160 litres of water containing 800 mls of concentrated hydrochloric acid was added, and the mixture heated to reflux for from 15 to 20 minutes. The mixture was cooled and 15 litres of 0.88 ammonia solution added. The slurry was refluxed with stirring for 1.5 hours, cooled, filtered, the residue washed with 2 x 30 litres of a water: methanol mixture, and the residue dried at from 60 to 75"C to constant weight. Yield 7.1 kg (78So of the theoretical yield).

WHAT WE CLAIM IS: 1. A compound corresponding to the following general formula (II):

wherein R represents Cl-C3 alkyl; and X represents chlorine or bromine.

2. A process for the preparation of a compound as claimed in claim 1 which comprises reacting a tri-C,-Cq alkyl orthoformate, methanol and y-chloro- or -bromo-4fluorobutyrophenone at an elevated temperature of not more than 145"C under anhydrous conditions in the presence of acid and isolating the product.

3. A process as claimed in claim 2 substantially as herein described with particular reference to Example 1.

4. A compound as claimed in claim 1 when prepared by a process as claimed in claim 2

Claims

or claim 3.

5. A process for the preparation of haloperidol which comprises reacting a compound as claimed in claim 1 or claim 4 with 4-p-chlorophenyl-4-hydroxypiperidine in a basic aqueous solution, acidifying the reaction mixture and isolating the product.

6. A process as claimed in claim 5 substantially as herein described with particular reference to Example 2.

7. Haloperidol when prepared by a process as claimed in claim 5 or claim 6.