An efficient and simple ultrasound-assisted approach to synthesis of Baclofen

1 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 GABA_A and GABA_C receptors and G-protein-coupled metabotropic (GPCRs) GABA_B 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.

2 Materials and mehtods

3 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 (2) was prepared via the reaction of β-(para-chlorophenyl)-glutaric acid imide and sodium hydroxide, under one-pot at 50°C. After heating, the solution was cooled, a solution of sodium hydroxide and bromide was dropwise added into the reaction system. pH was adjusted to 7 by addition of concentrated hydrochloric acid. Finally, 4-amino-3-(4- chlorophenyl) butanoic acid was filtered and recrystallized (Fig. 1). The advantages of this novel protocol include cheap reagents, high yields, fewer steps, available reagents and short time and the avoidance of the use of organic solvents. Baclofen prepared by this method has a yield of 87%. The product structure was characterized by IR, and ¹H and spectra.

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Fig.1

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 (2) showed a linear increase from 15% to 65% for an irradiation time of 5 minutes. However, with the ultrasound power of 45W, when the ultrasound irradiation time we increased to 10 minutes, the yield of (2) increased first, then showed a slight decrease for periods longer than 10 minutes (Table 1, entry 6). when the optimized ultrasound power and the irradiation time were found to be 45W and 10 minutes, respectively (Table 1, entry 7). The results are presented in Table 1.

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.