Abstract
Herein, a significantly improved synthesis and purification of synthesis of Baclofen via dissolving β-(para-chlorophenyl)-glutaric acid imide into basic solution and further amount of bromine to access Baclofen with high purity is reported. pH of the reaction solution was adjusted with concentrated hydrochloric acid. Finally, the 4-amino-3-(4- chlorophenyl) butanoic acid was filtered and recrystallized. It is demonstrated that the present synthetic protocol doesnot need any hazardous or harmful solvents, has operational simplicity, and shows high yields and short synthetic route with simple work-up. As an advantage, this method includes a convenient approach for synthesis of Baclofen with ultrasound irradiation as the convenient energy source at the first step of reaction Followed by leading to good production yeilds. The product was characterized by M.p, IR, and NMR.
Introduction
4-Amino-3-(4-chlorophenyl) butanoic acid (Baclofen) is a derivative of γ-amino butyric acid and its β-substituted derivatives play an important role in a number of central nervous systems [1, 2]. It is also an inhibitor of monosynaptic and polysynaptic transmission in the spinal cord [3]. There are three different receptor subtypes: a ligand-gated chloride channel GABAA and GABAC receptors and G-protein-coupled metabotropic (GPCRs) GABAB receptors [4]. Baclofen has been chemicaly explained and given five names: β-(Aminomethyl)-4-chloro benzene propionic acid, 4-Amino-3(p-chlorophenyl) butyric acid, β-(Aminomethyl)-p-chlorohydrocinnamic acid, β-(4-Chlorophenyl) GABA, and γ-Amino-β-(p-chloropheny1) butyric acid [5]. It is primarily used for the treatment of spastic movement disorders, especially in instances of spinal cord injury, cerebral palsy, and multiple sclerosis [6, 7].
Because of its biological and pharmacological importance, much attention has been devoted to the synthesis of Baclofen. It was synthesized for the first time in 1962 by the Swiss chemist Heinrich Keberle [8]. Numerous methods have been reported for the synthesis of Baclofen [9–12]. Ibuka et al. preparation of Baclofen during five steps and key step involved a regio selective ring opening of 2-phenylaziridine with allyl magnesium bromide and they obtained good yield but the reagents used are expensive, [9] Coelho et al. synthesized Baclofen during four steps based on the application of a [2 + 2] cyclo addition reaction, but the yield was low [13, 14]. However, in spite of their potential utility, many of these methods involve expensive reagents, strong acidic conditions,long reaction times and the yield is low [15]. At present, with the quick development in the fields of synthetic and catalytic chemistry, researchers have started to develop environmentally benign processes to avoid or minimize the harmful effects. Recently, sonochemistry as a new trend in organic chemistry has offered a versatile and more environmentally friendly conditions for a large variety of syntheses. It has been used as an efficient heating source for the organic reactions. Shorter reaction time is the main advantage of ultrasound-assisted reactions [16–19]. In this paper, an alternative approach to the synthesis of Baclofen is described which gives the product with ultrasound irradiation as the convenient energy source at the first step of reaction Followed by leading to good production yeilds.
Materials and mehtods
Materials
All reactants were obtained from Sigma-Aldrich, and freshly distilled prior to use. Melting points were determined with a TG (Rheometric Scientific STA 1500) apparatus and are uncorrected. 1HNMR spectra was recorded at 300 MHz in CDCl3 with TMS as the internal standard (Bruker). IR spectra were determined directly (Bruker Victor22). Ultrasonic irradiation was carried out with a Misoui X3000 (35 KHz, 54 w). TLC analysis was performed on glass plate pre-coated silica gel (10–40 μm). Spots were visualized using UV light or iodine. Column chromatography was performed on a silica gel (200–300 mesh) column with a mixture of petroleum ether and ethyl acetate as the eluent. Dichloromethane was refluxed with calcium hydride and freshly distilled prior to use.
Procedure for the synthesis of γ-Amino-β-(p-chloropheny1) butyric acid 2
The solution of sodium hydroxide (0.844 g) in water (20 mL) was added to β-(para-chlorophenyl)-glutaric acid imide (4.2 g), and the solution was stirred. The reaction mixture was stirred for 10 minutes (under ultrasound irradiation at 50°C), and then the solution was cooled to 10–15°C. At this temperature, a solution of sodium hydroxide (4.1 g) in water (20 mL) was added dropwise to the reaction mixture. Then, bromine (3.82 g) was added dropwise to the solution with an interval period of 10 minutes with stirred. When all bromine was added, the batch stirring continued for 5 hours at 20–25°C. The reaction solution was then cautiously adjusted with concentrated hydrochloric acid to pH = 7, finnaly crystalline γ-Amino-β-(p-chloropheny1) butyric acid was filtered and the organic layer was dried and melting point was obtained at 205–207°C. The compound was purified by column chromatography using petroleum ether or recrystallized from water. IR (KBr) n/cm-1 3415, 3183, 3088, 1723, 1672, 1486, 1382, 1275, 1192, 808 cm-1; 1HNMR (300 MHz, CDCl3) δ 2.55 (dd, J = 16.5, 8.7 Hz, 1H), 2.82 (dd, J = 16.5, 5.7 Hz, 1H), 2.93–3.50 (m, 3H), 7.34 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.94 (bs, 3H, NH3+), 12.23 (bs, 1H, COOH).
Herein, an experimental procedure for a high yield synthesis of Baclofen with increased selectivity via dissolving of β-(p-chlorophenyl)-glutaric acid imide into basic solution and further amount of bromine to access Baclofen with ultrasound, and one-pot synthetic route under semi Hoffman rearrangement reaction is reported [20, 21].
Results and discussion
The synthetic pathway for the preparation of Baclofen is illustrated in Fig. 1 [22–25]. To begin the study, γ-Amino-β-(p-chloropheny1) butyric acid (
Reagents and conditions: (a) NaOH, H2O, 50°C, 10 min; (b) NaOH, H2O, 10–15°C; (C) (i) Br2, 10 min; (ii) 5 h, 20–25°C.
It could be found that with the increase of the ultrasound power from 10W to 45W, the yield of
Effects of ultrasound power and irradiation time on the formation of
aIsolated yields
Baclofen as a target product was successfully synthesized. The protocol offers several advantages such as mild reaction conditions, short reaction times and step, easy isolation and leading to good production yeilds. It was also revealed that the proposed method is more economical, if the reaction is exposed to ultrasounds instead of using conventional heating methods. Hence, the process doesnot need any hazardous or harmful solvents, and thus it is a simple, environmentally friendly technique. In short, this paper presents an alternative approach towards the synthesis of baclofen which involves with new and convenient energy source and ecofriendly procedure.
Footnotes
Acknowledgments
The authors gratefully acknowledge support from the Jaber Ibn Hayyan Laboratory Foundation of NSTRI. We are greatful to Dr. N. Zarsav for his valuable comments and technically editing of the manuscript.