An Efficient Synthesis of Anti-spasmodic Drug Mebeverine Hydrochloride

An efficient synthetic process for an antispasmodic drug and active pharmaceutical ingredient of Mebeverine hydrochloride 1 is reported in this communication. It is used for stomach cramps and irritable bowel syndrome (IBS). The treatment for irritable bowel syndrome involves lot of drugs like (Dicyclomine hydrochloride, Linaclotide.etc) available in market, but Mebeverine hydrochloride (1) is most effective than any other drug. Earlier manufacturing 1 process reported yield < 46% and used high volumes of reagents and expensive catalyst. We developed new commercial process for 1 with economically, environmentally favored conditions. Proposed synthetic route contains three stages with overall yield of 77% and Purity by HPLC NLT 99.7%.


INTRODUCTION
Heterocyclic compounds play a significant role in the discovery of new drugs and drug like substances. Organic Synthesis is extensively used in the new drug discovery programs and new processes for already known drug substances using green and eco-friendly methodologies. In this context, we have been working in our laboratory to develop novel and commercially feasible synthetic methodologies for important drugs with a particular focus on Original Research Article environmentally benign conditions. Mebeverine.HCl is a heterocyclic compound which belongs to a group of medicines called Antispasmodics. This is used to treat symptoms of irritable bowel syndrome (IBS), the very common condition which causes spasms. There is a great demand for both developments of new antispasmodics agents and new manufacturing process for existing antispasmodic agents. Extensive literature search revealed that there is not much literature available for commercial synthesis of Mebeverine hydrochloride (1) hence we showed interest in developing a commercially feasible synthetic route. The reported method for preparation of Mebeverine hydrochloride(1) suffers from many disadvantages which include (i) overall low yield,(ii) inadequate optimization of reaction conditions, (iii) expensive reagents like Pt, hence there is a need to overcome the above mentioned drawbacks and also to develop an industrially viable process. The first synthesis of Mebeverine hydrochloride (1)  Interesting biological activities for relevant compounds were also reported. 2 Synthesis starts with Veratric acid [2]. as a key starting material. It was reacted with sodium methoxide to form sodium salt of Veratric acid [3] further reacted with 1,4 dibromobutane to get the compound [4] Reductive amination of 4methoxy phenyl acetone [5] with aqueous ethylamine in presence of Pt/C and hydrogen pressure gives [6]. Further reaction between compounds [4,6]. in the presence MEK and i-PrOH HCl provides [1]. The major disadvantages associated with this process are formation of dimer impurity of about 8-12% by HPLC during synthesis of [4] and use of highly expensive catalyst like Pt/C used for reductive amination with an overall yield of 34.0%. MVR Raju et.al. have recently disclosed commercial manufacturing process of Mebeverine hydrochloride (1).(Scheme -2). 3 Synthesis starts with 4-methoxy phenyl acetone []5 reacted with aqueous ethylamine in the presence of sodium borohydride to obtain [6] which was reacted with 4-bromo butyl acetate [7] followed by hydrolysis to get compound [7], esterification between [9] and Veratric acid [2] in the presence of Para toluene sulphonic acid (p-TsOH) at 100-110°C followed by hydrochloride salt formation provided the target molecule Mebeverine hydrochloride (1). Disadvantages include formation of alcohol impurity by about 6-10 % by HPLC during reductive amination with an overall yield of 46.0%. Besides, there has been a great deal of interest on Mebeverine as revealed by recent litrerature [8][9][10][11]. We report herein the results of our efforts to improve the process and overall yield of Mebeverine hydrochloride.

MATERIALS AND METHODS
All the Chemicals, reagents and solvents used are of commercial grade. 1 HNMR and 13 C NMR data were recorded in SA-Varian 400MHz NMR. TMS as a reference standard, Chemical shifts values are reported in δ PPM and deteriorated solvents CDCl 3 and DMSO. Elemental analysis for C, H and N used instrument vario EL.
HPLC: Method of analysis of Mebeverine hydrochloride adopted from European pharmacopeia.

RESULTS AND DISCUSSION
Based on the earlier reports that have shortcomings and limitations as described above and in order to overcome the drawback, we have pursued an alternative synthetic strategy which has resulted the final product in high yields and purity as shown in the scheme 3. Hence, we report an improved synthetic route for Mebeverine hydrochloride (1) with high purity (≥99.7%), improved yields (77% of overall yield), easy workup and simple isolation of the product with commercial feasibility.

Improved Process of Mebeverine Hydrochloride [1]
A modified process was designed and developed to achieve the improved yield of Mebeverine hydrochloride drug compared to existing processes as shown in scheme-3. Synthesis of target Mebeverine hydrochloride (1) starts with compound 2, it was reacted with 4-bromo butanol to provide compound 4, reductive amination of compound5 with aqueous ethylamine in the presence of Raney Ni, Hydrogen gas provided compound 6. Dehydrohalogenation by the reaction of compound 4 and 6 provided final Mebeverine hydrochloride (1). With an objective to develop a commercially viable process for the manufacture of Mebeverine hydrochloride (1) the reaction conditions were well optimized in each and every step as discussed below.

Improved Process Conditions for of 4bromobutyl 3,4-dimethoxybenzoate [4]
Synthesis of compound 4 involves the esterification of compound 3. The method reported by GB 1009082A involves use of high volumes of 1,4-dibromobutaneto react with compound 3 at 150°C. 1,10 This method suffers from formation of dimer. Hence, we conducted some experiments with different volumes of 1,4dibromo butane and the obtained results are presented in Table 1.
In order to avoid the formation of dimer and to increase the yield, we have used 4bromobutanol (1.2 eq) catalytic amount of p-TsOH(0.27 eq) and 5.0 v of toluene to get the compound with a dramatic improvement in the yield. The results obtained by using different dehydrating reagents are shown in the following Table 2.

Improved Process Conditions for N-Ethyl-1-(4-methoxyphenyl) propan-2amine [6]
Reported synthesis of compound 6 involves reductive amination between 4-methoxy phenyl acetone 5 and aqueous ethylamine (Scheme 1) is highly expensive for commercial manufacturing. 8 So we have focused our attention to develop the condition that is economically favorable for commercial application. The results obtained under different conditions are presented in Table 3.

Improved Process Conditions for Mebeverine hydrochloride [1]
The reaction between compounds 4 and 6 as reported in scheme 1 was tried under different conditions to improve the yield and quality and the results obtained are tabulated as shown in the following Table 4.

Preparation of N-Ethyl-1-(4methoxyphenyl) propan-2-amine [6]
1.0 kg of 4-methoxy phenyl acetone and 100.0 g of Raney Ni were taken in 4.0 L of methanol in a pressure vessel. Resulting mixture was cooled to 10-15°C. At 10-15°C temperature slowly added the 1.5 L of aqueous mono ethylamine (70 %) into the reaction mass and maintained the reaction mass for 1h at 10-15°C. After completion of 1h maintenance applied 3-4 kg of hydrogen pressure then again maintained the reaction mass for 4h at 25-35°C under 2-3 kg of hydrogen pressure. Checked the 4-methoxy phenyl acetone content by HPLC or TLC (limit NMT 1.0 %). After Removing the hydrogen gas reaction mass filtered through hyflo and washed the hyflo bed with 5.0 L of methanol and evaporated methanol completely to get N-Ethyl-1-(4-methoxyphenyl) propan-2-amine(6).

CONCLUSION
In the present work, we have reported an efficient process for Mebeverine hydrochloride and practically demonstrated as disclosed in the experimental part. All the intermediates were characterized by 1 HNMR,13 CNMR and Mass. The major advantages of present process include (i) improved overall yield, (ii) well optimized conditions and economically favorable reagents.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.