Synthesis of Melperone

Introduction

Melperone is an antipsychotic, useful in the treatment of amphetamine schizophrenia. It can be used with combination of beta blockers to combat amphetamine overdose.

All reagents are non-controlled, except gamma-butyrolactone, which is used in step 1. But the product from that step, 4-chlorobutyryl chloride, is non-controlled and commercially available.

4-chlorobutyryl chloride

86 g gamma-butyrolactone (1 mol) and 100 mL thionyl chloride are mixed together with 1 g water-free zinc chloride, and refluxed 30 hrs with moisture protection. After recooling, the mass is vacuum-fractionated, the fraction boiling between 60-80°C at 15 mmHg contains the product. Yield about 100 g.

4-chloro-p-fluorobutyrophenone

100 g (80 mL) 4-chlorobutyryl chloride are added dropwise to a well stirred suspension of 100 g anhydrous aluminium chloride in 500 mL fluorobenzene. With cooling, the internal temperature is kept at 25°C. After the addition, the whole is stirred 4 hrs and poured on 500 g ice. Precipated salts are dissolved by adding hydrochloric acid, the organic layer is separated, washed twice with water, and dried over sodium sulfate. The excess fluorobenzene (expensive!) is distilled off carefully and is recycled. The residue is vacuum fractionated to give 66 g (43% yield) of 4-chloro-p-fluorobutyrophenone, boiling at 150-175°C at 15-20 mmHg.

Melperone, N-(4-(p-fluorophenyl)-4-oxobutyl)-4-methylpiperidine

66 g 4-chloro-p-fluorobutyrophenone, 80 mL 4-methylpiperidine, and 1 g powdered potassium iodide are refluxed 20 hrs in 500 mL dry toluene. Thereafter, the precipated 4-methylpiperidine is suction filtered, and washed with 2x100 mL toluene. The combined filtrate is extracted twice with 300 mL 20% hydrochloric acid. The toluene layer is then discarded, and the acid layer is extracted three times with 200 mL chloroform. The combined chloroform extracts are evapoated to complete dryness (rotary evaporator), and the residue is suspended in 300 mL anhydrous acetone, all lumps are broken up manually. The white precipate is filtered of and washed twice with 100 mL anhydrous acetone. The filter cake, dry weight 85 g (86% of theory) consists of pure melperone hydrochloride.

The dosage of melperone to treat amphetamine schizophrenia: 100-300 mg, depending on the severity of the case. It will not really supress tachycardia, so beta blockers should be additionally used.