Non-Infringing Efficient One-Pot Process for the Preparation of Pure Entacapone

Abstract A new and non-infringing efficient one-pot process for the preparation of catechol-O- methyltransferase (COMT) enzyme inhibitors, entacapone 1 under mild condition, initially reaction of 3-methoxy-4-hydroxy-5-nitro-benzaldehyde 5 with 2-cyano acetic acid 13 in presence of new organic base benzyl Trimethyl ammonium hydroxide, i.e. Triton-B which undergo Knoevenagel condensation to get intermediate 22 which is then react with SOCl2 to get chloride intermediate 23 and which undergo condensation with diethylamine to get 6 and finally deprotection in presence of HBr-AcOH to get economically efficient and industrially feasible entacapone 1 with higher purity and yield without isolation of any intermediate as compared to conventional batch wise process. Graphical Abstract


Introduction
Parkinson's disease (PD) is a long-term neurological disorder. The disorder affects several regions of the brain especially an area called the 'substania nigra' these cells produce a chemical messenger called dopamine that controls balance and movement. Generally, Parkinson's disease begins after age 50. Parkinson's disease affects more than 1 million people in North America 1 and more than 10 million people globally. In the US 60,000 new cases are identified each year. The combined direct and indirect cost of Parkinson's including treatment, social security payment is estimated to be nearly $52 billion per year in the US. Medications cost an average of $2,500 a year and therapeutic surgery can cost up to $100,000 per person. 2 During such treatment catechol-Omethyltransferase (COMT) enzyme inhibitors have been developed and increase the bioavailability of L-DOPA. Among them, Entacapone 1 is a COMT inhibitor. Chemically it is known as (2E)-2-cyano-3-(3, 4-dihydroxy-5-nitro-phenyl)-N,N-diethyl-2-propanamide. 3,4 Entacapone 1 is approved under the trademark Comtan by US FDA for the treatment of Parkinson's disease. 5,6 Many synthetic approaches have been reported for the synthesis of entacapone 1. [7][8][9][10][11][12][13][14][15] The first process for the synthesis of entacapone 1 was disclosed by Backstrom et al. 7,8 They prepared entacapone 1 along with a mixture of two geometric isomers 4 wherein the ratio of E/Z isomers is approximately 70:30 through the condensation reaction between 3,4-dihydroxy-5-nitrobenzaldehyde 2 and N, N-diethyl-2-cyano acetamide 3 (Scheme 1).
Further, Pippuri et al. [9] also prepared entacapone but crystallized the mixture of isomers 4 from lower aliphatic carboxylic acid, such as HCOOH and CH 3 COOH in the presence of catalytic amounts of HCl or HBr to obtain pure entacapone 1 (Scheme 2).
The main disadvantage of the processes is the use of hazardous and corrosive reagents, longer reaction time needs for purification to obtain pure entacapone 1 hence reducing the yield.
Cziaky et al. [11] vanillin 7 is reacted with N, N-diethyl-2-cyano acetamide 3. The resulting enamide 8 is nitrated to get intermediate 6 which after demethylation get crude entacapone (Scheme 4). This crude product was further purified from isopropyl alcohol and then with acetone-acetic acid to get pure entacapone 1.
Sanmarti et al. [12] reported another method for synthesis of entacapone 1 as shown (Scheme 5).In this method, acid 9 was reacted with SOCl 2 to get their acid chloride 10, which is then treated with N, N-diethyl-2-cyano acetamide to get enamide 11. Then this 12 react with NaHB(OAc) 3 results in dimethoxy entacapone 12, which is then demethylated to give entacapone 1 (Scheme 5).
In this process there are some drawbacks, i.e. hazardous chemicals such as AlCl 3 and NaH have been used and multistep synthesis hence commercially not feasible process.
More recently Attimogae et al. [15] reported another process by condensation of 5-nitro vanillin with ethyl cyanoacetate by subsequent demethylation with triethylamine and dil.HI to get entacapone 1 with only 45% yield as shown (Scheme 8).
The above process also uses hazardous chemicals, longer reaction time, use of a costly catalyst such as Pd(Ph 3 P) 4 , moderate yield hence industrially not feasible process.
Therefore there is a need for an economical and industrially feasible process for the preparation of pure Entacapone 1 with a high yield. We report here an economical and industrially feasible efficient one-pot process for the preparation of entacapone 1 with high purity and yield without isolation of any intermediate.

Results and discussion
Initially, Knoevenagel condensation was tried with 5-nitro vanillin 5 with cyanoacetic acid 13 with a new organic base, i.e. benzyl trimethyl ammonium hydroxide (Triton B) to get intermediate 22 which is then in situ converted into the corresponding chloride by reaction with thionyl chloride to get intermediate 23. Which is then in situ condensed with diethylamine to get ¼162-163 C [14] was identical with an authentic sample and was characterized extensively by IR and NMR studies. This one-pot process proceeds through novel intermediate 22 and 23 in situ.
All reported processes have some drawbacks such as the use of corrosive and hazardous chemicals, longer reaction time, due isolation of intermediate in each step this will increase the waste and impact on the environment, need of crystallization hence reduce the yield of the product. Hence, reported processes were not economically good for industrial production and also not ecologically feasible. To overcome these problems, we have developed an industrially feasible efficient one-pot process for the preparation of pure entacapone 1.
For the synthesis of entacapone screening of different bases (step i) for the one-pot process was carried out and examine yield of entacapone 1. Triton-B is also used as a base and phase transfer catalyst (PTC) and which is the best for achieving a higher yield of the desired product ( Figure 1). [16] It is used in aldol condensation reactions and base-catalyzed dehydration reactions. [17] We used pyridine, piperidine, diethylamine, sodium hydride, pyrrolidine, potassium terbutoxide and Triton-B (benzyl trimethyl ammonium hydroxide) in different suitable solvents (Table 1) we got 45%, 55%, 62%, 50%, 60%, 45% and 80% yield, respectively. Due to the high reactivity of Triton-B, we got maximum yield.
We study the effect of the amount of Triton-B on the yield of entacapone 1. We carried out several experiments by using different amounts of Triton-B from 0-2 equivalent of Triton-B. In absence of Triton-B, there was no progress of reaction. We used different amount of Triton-B as shown in Table 2 by use of ethanol as a solvent and maintain the reaction at 80 C and isolate entacapone 1 yield by use of different amount of Triton-B. We got following observations. By use of 1.0 eq. of Triton-B after 18 h of stirring reaction was completed and we got 35% of yield. By use of 1.15 eq. of Triton-B after 12 h of stirring reaction was completed and we got 40% of yield. By use of 1.25 eq. of Triton-B after 8 h stirring reaction was completed and we got 52% of yield. By use of 1.35 eq. of Triton-B after 6 h stirring reaction was completed and we got 60% of yield. By use of 1.45 eq. of Triton-B after 5 h stirring reaction was completed and we got 62% of yield. By use of 1.55 eq. of Triton-B after 4 h stirring reaction was completed and we got 65% of yield. By use of 1.65 eq. of Triton-B after 4 h stirring reaction was completed and we got 70% of yield. By use of 1.75 eq. of Triton-B after 4 h stirring reaction was completed and we got 75% of yield. By use of 1.85 eq. of Triton-B after 4 h stirring reaction was completed and we got 80% of yield. By use of 1.90 eq. of Triton-B after 4 h stirring reaction was completed and we got same yield, i.e. 80% of yield. By use of 2.0 eq. of Triton-B after 4 h stirring reaction was completed and we got 80% of yield.
Hence by use of 1.85 eq. of Triton-B, and 4 h stirring, we got maximum yield. Further increasing the amount of Triton-B there was no any change on the yield of final entacapone 1.
For screening of reaction condition (step i) we study the progress of the reaction and monitor the reaction in situ by Thin layer chromatography (TLC) ( Table 3). We monitor the reaction from R.T. to 80 C. For this, we carried out different experiments in ethanol as a solvent and use 1.85 eq. of Triton-B. We observed that at 80 C temperature and 4 h maintaining starting material spot is completely disappear. In our one-pot process, pH of reaction mass in different stages (in situ) at the stage (i), (ii), (iii), and (iv) was 10.5, 2.1, 11.4, and 2.5 respectively. From the industrial point of view, correct reactor MOC is important. For acidic reagents, a glass line reactor is used and for basic reagents, stainless steel reactor is used.
There are some advantages of our one-pot process: i. Without isolation of any intermediate final product obtained hence, minimizing step, reduce waste. ii. It will minimize equipment energy. iii. It minimizes the cost. iv. Due to the one-pot process we got a high yield, i.e. >80%, v. We got high purity (>99%) without any purification. However, the industry is also starting to see the benefit of conducting multiple steps in one reactor, vi. As compared to conventional batch-wise process one-pot synthesis is ecologically and economically efficient way. vii. It helps to reduce the effort and separation methods. viii. It reduces the environmental impact because environmental sustainability is a global issue in organic chemistry.  Reaction condition: 5-nitro vanillin (0.0253), 2-cyano acetic acid, (0.0328 mol), ethanol, base (0-2 eq.). aIsolated yield at 80 C.
All reagents were obtained from commercial sources with the greatest quality hence used without further purification. Solvents freshly were distilled and then used. Melting points were determined in open capillaries and are uncorrected. TLC was routinely checked for completion of the reaction and process optimization purpose. We have done several experiments to optimize the one-pot process by changing reaction conditions and stoichiometric amounts of reagents and reactants. The IR spectra were recorded in solid state as KBr dispersion between 4000 and 400 cm À1 using SHIMADZU Fourier Transform (FT)-IR spectrometer. The 1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra were recorded in DMSO/CDCl 3 using a Brucker instrument. The chemical shift is reported in parts per million (d ppm) relative to tetramethylsilane.

One-Pot process for preparation of entacapone (1)
A mixture of 4-hydroxy-3-methoxy benzaldehyde 5 (1.0 g, 0.0050 mol),2-cyano-acetic acid 13 (0.64 g, 0.0076 mole),benzyl trimethyl ammonium hydroxide, i.e. Triton-B (1.56 g, 0.0093 mole), acetic acid (0.39 g, 0.0065 mole) and ethanol (10 mL) were heated to reflux for 4 h. Monitor the progress of the reaction on TLC. The reaction mixture was concentrated under reduced pressure to get residue 22. Add DCM and water (10 mL þ 10 mL). Stir for 10-15 min. Remove aq. layer. Then add SOCl 2 (1.78 g, 0.015 moles) in the organic layer at R.T. and heat for 4 h at 40 C. The reaction mass is then concentrated under reduced pressure to get residue 23. In crude 23 DCM (10 mL) was added and in that add diethylamine (0.92 g, 0.0126 moles) at À5 to 0 C in 15 min and stir for 2 h at the same temp. Thereafter reaction mass was concentrated to get residue 6. Then add Toluene (10 mL), 48% HBr-AcOH (2 mL) reaction mass was heated at 100 C for 3 h and cool to R.T. Then it was concentrated and diluted with ethyl acetate (10 mL) and water (10 mL). The solution was stirred for 30 min at 5-10 C. Concentrate ethyl acetate layer under reduced pressure. Ethyl acetate (10 mL) was added to the residue and stirred for 30 min at 0-5 C.

Conclusion
In conclusion, we have developed here an economical, ecological and industrially feasible efficient non-infringing one-pot process for the preparation of pure entacapone 1 without isolation of any intermediate. Entacapone with higher purity and yield as compared to conventional batch-wise process will be prepared by this process without doing any extensive purification. Reaction condition: 5-nitro vanillin (0.0253), 2-cyano acetic acid, (0.0328 mol), ethanol, Triton-B (1.85 eq.), reaction progress.