Synthesis and Green Metric Evaluation of 2-( Chloromethyl )-3-Methyl-4-( Methylsulfonyl ) Pyridine

2-[[(2-pyridinyl) methyl] sulfinyl]-1H-benzimidazoles are the prominent motif’s that belong to the class of prazoles. These are used in the treatment of gastroesophageal reflux disease (GERD) ulcers and other gastric acid related diseases. The present article describes the modified synthesis of 2-chloromethyl-4-methanesulfonyl-3-methyl pyridine (an intermediate utilized in the synthesis of Dexlansoprazole). The advantages of this modification involves (i) N-oxidation of 2,3-lutidine with catalytic quantity of RuCl3 in presence of oxygen (ii) One pot synthesis of 2,3-dimethyl-4-(methylthio) pyridine-N-oxide using 30% NaSH, methyl iodide and tetra butyl ammonium hydroxide (iii) Oxidation of methythio pyridine–N-oxide with 30% H2O2 followed by N-deoxygenation with RuCl3.H2O to produce 2,3-dimethyl-4-(methylsulfonyl)pyridine (iv) Chlorination of the penultimate step using trichloroisocyanuric acid to obtain the desired 2-chloromethyl-4-methanesulfonyl-3-methyl pyridine. Furthermore, green metrics assessment was calculated for the above modified scheme based on the parameters viz., atom economy (AE), reaction mass efficiency (RME) and E-factor. It was observed that, in case of step 4 (oxidation of thiomethyl pyridine-N-oxide), the E-factor value is very less 3.2 which is indicative of less waste generation, when compared to the various steps that are involved in the synthesis.


INTRODUCTION
A prominent class of drugs that bring out distinctive and enduring pharmacological effect by reducing the gastric acid production are the Proton pump inhibitors (PPIs).Due to their outstanding efficacy and safety, these drugs are included in list of the most expansively marketed drugs in the world.

2-[[(2-pyridinyl) methyl
] sulfinyl]-1H-benzimidazoles are the prominent motif's that belong to the class of prazoles.These are used in the treatment of gastroesophageal reflux disease (GERD) ulcers and other gastric acid related diseases. 1 Some of the examples of the proton pump inhibitors with pyridine ring nucleus (Figure 1) that are the top selling classes of pharmaceuticals and have populated this area 2 are omeprazole (1, Losec), rabeprazole (3, Aciphex), pantoprazole (2, Protonix), lansoprazole (4, Prevacid) and dexlansoprazole (5).All these PPI drugs (API's) contain the distinguishing benzimidazole unit flanked with a sulfoxide substituent at the 2-position.
A new inclusion to the proton pump inhibitor (PPI) class is Lansoprazole, which is acceptable for the treatment of heartburn related with non-erosive gastroesophageal reflux disease (GERD) and remedial for all grades of erosive esophagitis (EE) 3,4 .Another prominent class of PPI is the 'Dexlansoprazole (dex)', it is a dextrorotatory enantiomer of lansoprazole that was developed by Takeda Pharmaceutical Co., Ltd and got approved in 2009 by US Food and Drug Administration (FDA).Later on this drug (dex) was accepted by Canada and Mexico in 2010 and 2011, respectively 5 .In the clinical administration, Dex exhibited lower elimination rate, excellent dominance in higher efficacy and less side effects than S-(-)-lansoprazole (levo) 6 .
Evaluation of the greenness of chemical processes is the outmost significance in green chemistry.In general, it is well known that in order to measure the efficiency of the process, it has to be first optimized and controlled.Managing the process in green chemistry should be implicit as a choice to select the greenest option.The improvement and application of measurable procedures allows us to differentiate the greenness of existing solutions with newly developed ones.
In the early 1990s, U.S. Environmental Protection Agency, has introduced the concept of green chemistry which is defined as ''the utilization of a set of principles that minimizes or eliminates the use or production of unsafe substances in the design, manufacture and application of chemical products''.2] Thus the concept of atom economy paved the way to green chemistry by emphasizing the significance of the incorporation of all the atoms in the reaction product 13 .Atom economy (molecular weight ratio of the final product divided by the sum of all reactants, Eq.1) is not solely sufficient to determine the material economy of the reaction, though it useful to choose a synthetic pathway.A precise method to evaluate the material economy is the reaction mass efficiency (RME) which is the percentage of the mass of the reactants that remains in the product (Eq.2) 14,15 .It is understood that in a chemical reaction/process, the formation of the product requires, use of reactants along with the additional required materials such as solvents, catalysts and acids and bases used in the work-up.These are the essential material in the process, though these materials does not appear in the balanced chemical equation.The Sheldon E-factor, 16 which is defined according to equation (3), respectively, permits a best measurement of the material economy.The calculation of E factor is solely depends on mass (E factor) and presents a global standpoint and is calculated as the ratio of the total mass of all waste to the mass of the desired product 16 .During the E-factor calculations, apart from considering the amount of the by-products (i.e amount of waste), it also take into consideration of the amount of (i) non-reacting starting materials, (ii) auxiliaries, (iii) catalysts or any additives such as acids, bases, salts, (iv) solvents of the reaction or solvents required in the work-up (extraction, washing, separation, recrystallisation, chromatographic support if not recycled, etc.).Sheldon 17 has suggested one exception during the calculation of E-factor, as inclusion of water in the E-factor equation leads to exceptionally high E-factor value (aqueous waste stream), it is expelled from the calculation of E-factor.

RESULTS AND DISCUSSIONS
The traditional method for the synthesis of 2-chlromethyl-pyridine precursor are prepared from the starting materials 19,20 viz., 2,3,5-trimethyl pyridine, 2,3-dimethyl pyridine (for the synthesis of omeprazole, rabeprazole, lansoprazole and dexlansoprazole), which is nitrated in the 4th position to form the 4-nitropyridine derivative.The 4-nitro pyridine precursor is treated with sodium methoxide and acetic anhydride to generate methoxide ion which replaces the nitro group.The methyl group at the second position is converted to the acetoxymethyl group using acetic anhydride.This acetoxy methyl group in turn is hydrolysed and chlorinated using thionyl chloride to generate the 2-chloromethyl pyridine precursor.

S y n t h e s i s o f 2 -c h l o r o m e t h y l -4 -
methanesulfonyl-3-methyl pyridine 7, is depicted in scheme-1 is the modified version of the previously reported literature method 18 .N-oxidaton of 2,3lutidine in presence of 5 mol% of RuCl 3 X3H 2 O 21 and bubbling of oxygen in dichloromethane at room temperature for 8h yielded 2,3-Dimethyl-pyridine-N-oxide 2 in 93% yield.This method of N-oxidation of pyridine substrate catalyzed by ruthenium with molecular oxygen as the prime oxidant, resulted in the high yield under optimal reaction conditions.The advantage of this method is (i) the easy separation of the catalysts, (ii) simple workup and environmentally acceptable makes this method a convenient approach.Chlorination of N-oxide 2 was carried out by bubbling chlorine gas 22 in dichloromethane at 25 o C for 3h (in two equal intervals of 1.5 h) resulted in the desired 4-chloro-2,3-dimethyl-pyridine-Noxide 3 in 49% yield.Nucleophillic substitution with NaSH followed by alkylation with MeI in presence of 40% tetra butyl ammonium hydroxide 23 resulted in the formation of 2,3-dimethyl-4-(methylthio) pyridine-N-oxide 4 in 85% yield.In this method, the aqueous tetra-n-butyl ammonium hydroxide solution (TBAOH) was applied as a strong base, as a reaction medium and as a phase transfer catalyst.Oxidation of methythio-pyridine 4 was achieved in presence of 30% H 2 O 2 24 (portion wise addition in intervals of 2h, 6h and 10h) at 75 o C for 24h gave 4-Methanesulfonyl-2,3-dimethyl-pyridine-1-oxide 5 in 85% yield.This method of oxidation with 30% H 2 O 2 is measured as a highly atom-economic, solvent and catalyst free oxidation.N-deoxygenation of 5 in presence of RuCl3x3H 2 O 25 in acetonitrile at 85 o C for 1h resulted in the formation of 2,3-dimethyl-4-(methylsulfonyl)pyridine 6 in 85% yield.This method is mild, competent and avoidance of harsh reagents and is of reasonably a broad scope for the deoxygenation of N-oxides.Allylic chlorination of 6 with trichloroisocyanuric acid 26 in chloroform at reflux for 1h gave the desired 2-(chloromethyl)-3methyl-4-(methylsulfonyl)pyridine 7 in 82% yield.As trichloroisocyanuric acid (TCCA) is safe in handling and due to its efficient expulsion of chlorine (for use in reactions all three chlorine atoms are active) in the chemical process, it is used as a chlorination and oxidation reactions also on large scale.TCCA is more atom economical and is also highly soluble in organic solvents and is more economical, when compared to N-Chlorosuccinamide (the most-used N-haloamide), thus making it the better reagent for large-scale use.The structural elucidation of the intermediates and the final 2-chloromethyl-4-methanesulfonyl-3methyl pyridine 7 was characterized by the various spectroscopic techniques like 1 H NMR, mass and IR data.As an example, the 1 H NMR of 2-(chloromethyl)-3-methyl-4-(methylsulfonyl)pyridine7 is described here, the protons resonating at d 8.68 ppm and 7.90 ppm as doublets with two proton integration is assigned to the pyridine ring protons and the proton resonating d 4.82 ppm as singlet is assigned to the methylene proton (-CH 2 Cl) while the singlet signals at 3.15 ppm and 2.83 ppm is assigned to the groups -SO 2 CH 3 and -CH 3 flanked to the pyridine ring nucleus.The molecular ion of the compound in the mass spectra with m/z, 220.1 (M+1) further supports the confirmation of the desired product.

Reaction Conditions
In view of the significant importance of green metrics evaluation, we have calculated the atom economy (AE), reaction mass efficiency (RME) and E-factor for the various steps that are involved in the synthesis of 2-(chloromethyl)-3-methyl-4-(methylsulfonyl)pyridine 7. The calculation of these parameters is tabulated in Table-1.In general, the % of AE is less than 100% due to the formation of various by-products involved in the individual steps, while the variation in RME is recognized to the factors such as number of reactants involved in the reaction, usage of excess molar equivalents of reactants and poor yields of the products.
Among the various steps, step 1 indicates, higher % of yield, AE and RME values i.e., 99, 97, 93% respectively, though these parameters measures the effectiveness of the reaction but in terms of E-factor value (12.48) it is less efficient.The high value of E-factor value is attributed to the usage of voluminous amounts of solvent (during work up of the reactions), purification techniques (crystallization / column chromatography) and drying agents.In case of step 4, even though the values of AE, RME and yield (74%, 62% and 85%) are at lower end when compare to step 1, the E-factor value is 3.2, the lower value of E-factor is indicative of the less waste generation when compared to step 1.Similarly, the variation of AE, RME and E-factor for the remaining steps (Table 1) is explained based on the above criteria.The E-factor value for the various steps involved in the synthesis is observed in the Scheme 1: Modified synthesis of 2-chloromethyl-4-methanesulfonyl-3-methyl pyridine 7 Step 1 Step 2 Step 3 Step 4 Step 5 Step 6  ).Thus, the E-factor value clearly gives information on the waste generation involved in the various steps on a laboratory scale.Based on this information, a process chemist can explore to modify the technology before going further for much higher batch size.

MATERIALS AND METHODS
All the chemical and solvents used for the synthesis were analytical standard from Fluka or Merck.For thin-layer chromatography (TLC) analysis, E.Merck AL silica gel 60 F254 plates were utilized and spots were visualized under UV light.The mass spectrawas recorded on Agilent ion trap MS and Infrared (IR) spectra were recorded on a Perkin Elmer FT-IR spectrometer. 1 H NMR spectra was recorded in CDCl 3 and DMSO-d6 with a 400 MHz (Varian Mercury plus) instrument.TMS was used as an internal standard and the chemical shift values were reported in ´ (ppm) and the signals were reported as s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), m (multiplet) and coupling constants are measured in Hz.Melting point (mp) determinations were performed by using Mel-temp apparatus and are uncorrected.

CONCLUSION
In summary, the present article describes the modified synthesis of 2-chloromethyl-4methanesulfonyl-3-methyl pyridine 7. The merits of the synthesis involves, N-oxidation reaction 2,3lutidine under mild conditions using RuCl 3 .3H 2 O, one pot synthesis of 4-methylthio-pyridine-Noxide, formation of 4-(methylsulfonyl)pyridine-Noxide using H 2 O 2 and chlorination reaction using trichloroisocyanuric acid.Based on the E-factor assessment, it is concluded that E-factor in step 4 (oxidation of thiomethyl pyridine-N-oxide) is 3.2, which is indicative of less waste generation, when compared to the various steps involved in the synthesis.The increasing pattern of E-factor values, " step 4 (E-factor-3.2) > step 1 (E-factor-12.48)> step 2 (E-factor-14.14)>step 3 (E-factor-16.35)>step 6 (E-factor-27.04)>step5 (E-factor-28.5)"clearly demonstrates that E-factor value is least in the case of step 4 while for the remaining steps it varied between 12.48-28.5.Based on this information, a process chemist can explore to modify the technology before going further for much higher batch size.
mass reactants -mass product -