INTRODUCTION:

Pyridinylmethyl sulphinyl benzimidazole compounds are known to have H⁺/K⁺-ATPase inhibitory action in parietal cells^1-5 and therefore have considerable importance in the therapy of diseases associated with an increased secretion of gastric acid or used as anti-ulcerative agent^6-7. Many sulphoxide compounds of closely related structure are known, for example Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole and Tenatoprazole. These compounds are also referred to as proton pump inhibitors (PPI) due to their mechanism of action.

2- Chloromethyl pyridine compounds of formula 6 (Scheme 1) are important intermediates for preparation of the above pharmaceutically valuable sulphoxide compounds. A general and convenient method for the deoxygenation and subsequent side chain functionalization of 2-methyl pyridine 1-oxides of formula 2, involves initial treatment with 4-toluenesulfonyl chloride in boiling dichloromethane or dioxane in the presence of Triethylamine. (Scheme 1) or with phosphoryl chloride and lithium chloride. Such chemistry has been reported by E. Matsumura^8-9 and described in patents¹⁰. Similar chemistry has been reported by Rane et al^11-15.

Our main objective of the present study was to prepare 2- Chloromethyl pyridine intermediate 6 from N- oxide intermediate of structural formula 2 and condense with 2-Mercapto benzimidazole to get finally Rabeprazole sodium in high yield and purity.

Another objective was to demonstrate the shorter route of synthesis of Rabeprazole and reduce overall cost of manufacturing of Active Pharmaceutical Ingredient(API).

RESULTS AND DISCUSSION:

General route of synthesis for Proton pump inhibitors.

Scheme 1

Synthesis of Rabeprazole is a multi step synthesis task involving various organic transformations^[11,
15]. In a typical sequence, pyridine derivative 1 is treated with suitably substituted alcohol in presence of strong base to get corresponding 4-alkoxy intermediate 2. This intermediate 2 on further reaction with acetic anhydride yields O-acetyl intermediate 3, which on further heating provides intermediate 4. Alkaline hydrolysis of intermediate 4 generates intermediate 5. This is chlorinated using thionyl choride to furnish chloro intermediate 6 . Condensation of 6 with 2-Mercapto benzimidazole in presence of base gives 7 and finally sulphoxide 8 is prepared by employing mild oxidizing agent like metachloroperbenzoic acid or sodium hypochlorite to get final Rabeprazole Active pharmaceutical ingredient (API).

Our present approach for synthesis of Rabeprazole:

Scheme 2

In our modification of process, we converted intermediate 2 directly into intermediate 6 by employing p-toluene sulphonyl chloride and triethyl amine in dichloromethane at reflux for 2 hours to get intermediate 6. Thus obviating synthesis of intermediate 3,4 and 5. This reduced total synthesis by three steps and also significantly improved the overall yield and cost of the crucial intermediate 6 for Rabeprazole manufacturing on large scale.

EXPERIMENTAL:

The ¹H NMR spectra were recorded on Varian Mercury plus at 400 MHz. The infrared spectra were recorded in the solid state as KBr dispersion medium using a Perkin-Elmer One Fourier transform infrared( FT-IR) spectrophotometer. The mass analysis was performed on AB- 4000 Q-trap LC-MS/MS mass spectrometer MDS SCIEX, Applied Bio systems, California, USA using dilute methanolic solutions of compounds in direct injection mode. Melting points were determined on a Büchi melting point apparatus and are uncorrected. The solvents and reagents were used without further purification.

4-Chloro- 2,3 Dimethyl pyridine N-Oxide (Chloro Intermediate 1) was commercially available and used without any purification.

Synthesis of 4-(3-methoxypropoxy-2,3-Dimethyl pyridine N-Oxide (Methoxy propoxy intermediate 2):¹⁴

In a 500 ml lit RB Flask, 60 ml DMSO was charged and KOH flakes( 12.9g, 230 mmoles) were added under stirring 3-methoxy propanol (14.0 g 153 mmoles) was charged slowly at 30-36 ^oC. Temperature was raised to 50-55^oC and maintained for 1 hour. Reaction mass was cooled to 40-42^oC and Chloro intermediate 1 (11.6 g, 55 mmoles) was charged at 40-42^oC and temperature was raised to 75-80 ^oC and maintained for 3 hours. Reaction was monitored by TLC using CHCl₃: MeOH ( 15:1) as mobile phase. After disappearance of Chloro intermediate 1 on TLC, reaction mixture was cooled to 25-30^oC and 120 ml of distilled water was added. Product was extracted with 50 ml Chloroform, layers were separated and aqueous layer was extracted with 20 ml chloroform. Combined organic layer was washed with distilled water 15 ml x 3 times and dried over anhydrous sodium sulphate. Chloroform was recovered under vacuum to get brown oily compound. Wt: 11.2 g( HPLC Purity: 96.60%) and characterized by ¹H NMR, MS and IR.

IR (KBr, cm^-1) 3373 (Ar-H), 2878(Ali-H), 1566 (aromatic C=C),1455(N-O), 1296 (C-N), 1100 (C-O arylalkylether), 752 (Ar-H bending); MS( EI)+ve ES-MS: 211 (M⁺);¹H NMR (400MHz, DMSO-d₆: δ 8.05 (d, J=7.2 Hz, 1H), 6.74 (d, J=7.2 Hz, 1H),4.01 (t, 2H), 3.45 (t, 2H), 3.23 (s, 3H), 2.37 (s, 3H),1.96 (qn, J=6, 2H).

Synthesis of “in situ”2-(Chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine intermediate 6 and condensation with 2-Mercapto benzimidazole:^9,12

In a 3 lit RB flask, above Methoxypropoxy intermediate 2 (11.2 g 53 mmoles) was dissolved in 25 ml dichlomethane and p-toluene sulphonyl chloride( 11.2 g, 58 mmoles) was added and heated to 40^oC and maintained for 2 hours. Triethyl amine( 8.4 g , 83 mmoles) was mixed with 50 ml dichloromethane and added to reaction mixture through dropping funnel slowly over 1 hour. pH of the reaction mixture was checked and adjusted to 7-8 by addition of Triethyl amine and maintained for 3 hours at 40-42^oC. NaHCO₃solid ( 5.3 g) was charged and stirred for 10 minutes. MDC was recovered under vacuum and residue was dissolved in 70 ml Methanol.

A small portion of above MDC solution was passed through small SiO₂bed and MDC filtrate was evaporated under vacuum. White solid obtained (Intermediate 6) was characterized by ¹H NMR, MS and IR. ( HPLC Purity: 99.50%).

IR (KBr, cm^-1) 3433 (Are-H), 2868 (Ali-H), 1543 (aromatic C=C), 1311 (C-N), 1097 (C-O arylalkylether), 764 (Ar-H bending); MS( EI)+ve ES-MS: 230 (M⁺+1);¹H NMR (400MHz, DMSO-d₆: δ 8.58 (d, J=7.2 Hz, 1H), 7.33 (d, J=7.2 Hz, 1H),5.06 (s, 2H),4.38 (t, 2H), 3.54 (t, 2H), 3.32 (s, 3H), 2.34 (s, 3H),2.15 (qn , J=6, 2H).

Sodium hydroxide( 4.7g, 118 mmoles) was dissolved in 120 ml distilled water. 2-Mercapto benzimidazole (8.3 g, 55 mmoles) was charged to above solution and heated to 45-50°C . Above methanolic solution of “in situ” 2-(Chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine intermediate 6 was added slowly over 2-3 hours and after addition was complete stirred further for 4 hours. Reaction mixture was cooled to 30-35^oC and Methanol was recovered under vacuum. Residue was dissolved in 70 ml ethyl acetate and washed with 5% NaOH solution( 20 ml) and distilled water ( 20 ml) and dried over anhydrous sodium sulphate. Ethyl acetate was recovered under vacuum to get crude sulphide intermediate 7( wt: 13.1 g ).

Above crude intermediate 7 was suspended in 50 ml Diisopropyl ether and stirred to 30 minutes and filtered on Buchner funnel and washed with 10 ml DIPE. Material was dried in vacuum till constant weight. Dry Wt: 9.9 g ( HPLC purity: 87-88%)

Purification of above crude sulphide compound: Above crude ( 9.9 g) was dissolved in 40 ml ethyl acetate at 60-65^oC. Solution was treated with activated charcoal and filtered hot to get clear solution. About 20 ml of Ethyl acetate was recovered under vacuum. It was then cooled to 10-15^oC to get white solid and stirred for 45 minutes. Solid was filtered on Buchner funnel and washed with 10 ml cold ethyl acetate. Material was dried at 40-45^oC under vacuum till constant weight. Dry wt.: 8.0 g ( HPLC Purity: 99.93%)

Mp: 116-118^oC; IR (KBr, cm^-1) 3049 (Ar-H), 2890(Ali-H), 1587 (aromatic C=C), 1304 (C-N), 1092 (C-O arylalkylether), 747 (Ar-H bending); MS( EI)+ve ES-MS: 344 (M⁺+1); ¹H NMR (400MHz, DMSO-d₆: δ 13.04 (brs, NH), 8.36 (d, J=5.6 Hz, 1H), 7.20-7.28 (m, 2H), 7.18-7.19 (m, 2H), 6.78 (d, J= 5.6Hz, 1H). 4.39 (s, 2H), 4.15 (t, J=6.4 Hz, 2H), 3.58 (t, J=6.4Hz, 2H), 3.37 (s, 3H), 2.28 (s, 3H), 2.11 (qn, J=6, 2H).

Synthesis of Rabeprazole 8:¹⁶

Intermediate 7 (3 g, 8.73 mmol) was dissolved in 7.5 ml Methanol and cooled to 0-5^oC. NaOCl solution( 1.2- 1.5% wt/wt, about 55 ml) was added slowly drop wise over 1-2 hours at 0-5^oC and temperature was maintained for 1 hour. TLC was done (in Toluene: Acetone: Methanol 8:8:2 mobile phase) to check completion of reaction. After disappearance of starting intermediate 7, pH was adjusted to 10.6 by adding ammonium acetate solution and product was extracted in 15 ml Chloroform and characterized by ¹H NMR, MS and IR.

IR (KBr, cm^-1) 3064 (Ar-H), 2898(Ali-H), 1581 (aromatic C=C), 1300 (C-N), 1095 (C-O arylalkylether),1060 (S-O, sulphoxide), 753 (Ar-H bending); MS( ESI)+ve: 360 (M⁺+1); ¹H NMR (400MHz, DMSO-d₆: δ 12.98 (brs, NH), 8.28 (d, J=5.6 Hz, 1H), 7.69-7.61 (m, 3H), 6.70 (d, 2H), 4.69-4.82 (dd, J=13.6, 2H), 4.05 (t, J=6.4 Hz, 2H), 3.51 (t, J=6.4Hz, 2H), 3.38 (s, 3H), 2.13 (s, 3H), 2.05 (qn, J=6.4, 2H).¹³C NMR (100 MHz, DMDO-d₆) δ163.68, 153.14, 149.12, 148.22, 122.87, 119.74, 117.40, 110.50, 106.19, 68.74, 65.12, 58.75, 36.27, 29.21, 11.05.

Synthesis Rabeprazole Sodium:¹⁶

Above chloroform layer was extracted with 10% NaOH solution ( 2 g, 50 mmoles in 20 ml distilled water). Layers were separated and pH of aqueous layer was adjusted with ammonium acetate to 9.3-9.5. Aqueous layer was extracted once again with 15 ml chloroform. Organic layer was separated. Product goes in aqueous layer as sodium salt. Aqueous layer was acidified with acetic acid upto 8.0-8.5. Product becomes free base and simultaneously extracted in chloroform 15 ml x 2 times. Combined organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum to get free base i.e. an oily compound(2.7g). It was dissolved completely in Isopropyl alcohol and NaOH (0.2 g, 5 mmoles AR grade) in 1 ml distilled water was added. Product becomes sodium salt. Reaction mixture was stirred for 30 minutes. IPA was recovered under vacuum completely and residue was suspended in 21 ml ethyl acetate and 9 ml n-heptane was slowly added at 25-30^oC. White solid was stirred for 1 hour and filtered on Buchner funnel and washed with 5 ml n-heptane. It was dried under vacuum at 35-40^oC till constant weight. Dry wt: 2.0 g (HPLC Purity: 98.9%) and characterized by ¹H NMR, MS and IR.

IR (KBr, cm^-1) 3047 (Ar-H), 2881(Ali-H), 1583 (aromatic C=C), 1298 (C-N), 1093 (C-O arylalkylether),1027 (S-O, sulphoxide), 745 (Ar-H bending); MS( ESI)+ve: 382 (M⁺+Na); ¹H NMR (400MHz, DMSO-d₆: δ 8.44 (d, J=5.6 Hz, 1H), 7.64-7.66 (m, 2H), 7.08-7.10 (m, 3H), 4.60-4.86 (dd, J=13.6, 2H), 4.25 (t, J=6.4 Hz, 2H), 3.64 (t, J=6.4Hz, 2H), 3.40 (s, 3H), 2.31 (s, 3H), 2.13 (qn, J=6.4, 2H). ¹³C NMR (100 MHz, DMDO-d₆) δ162.67, 154.68, 150.35, 147.69, 121.40, 119.79, 117.38, 110.49, 106.27, 68.31, 65.09, 57.95, 36.25, 28.68, 10.36.

CONCLUSION:

In conclusion, we have developed an efficient and commercially viable process for 2-Chloromethyl pyridine intermediate useful for preparation of pyridinylmethyl sulphinyl benzimidazoles like Rabeprazole sodium. We have also demonstrated a shorter route of synthesis for 2-Chloromethyl pyridine intermediate and in situ condensation with 2-Mercaptobenzimidazole to get Rabeprazole. This strategy is extremely advantageous for commercial scale up (5-100 kg) and would help in reducing the overall timeline and cost for the large scale manufacture of Rabeprazole sodium.

ACKNOWLEDGEMENTS:

We are grateful to the Management and Principal of Patkar-Varde College and Dr. A G Gadre, Head, Department of Chemistry for guidance, constant encouragement and support to carry out this research work.

REFERENCES:

1. (i)Morri, M.; Takeguchi, N. Different biochemical modes of action of two irreversible H⁺-K⁺ ATPase inhibitors, omeprazole and E3810. J. Biol. Chem, 1993,268, 21553-21559.

(ii)James M. Mullin, Melissa Gabello, Lisa J. Murray, Christopher P. Farrell, Jillan Bellows, Kevin R. Wolov, Keith R. Kearney, David Rudolph and James J. Thornton, Proton pump inhibitors: actions and reactions, Drug Discovery Today 2009,14, (13/14) 647-660.

2. Nakai, H.; Shimamura, Y.; Kanazawa, T.; Yasuda, S.; Kayano, M. Determination of a new H⁺-K⁺ ATPase inhibitors(E3810) and its four metabolites in human plasma by high performance liquid chromatography. J.Chrom. B: Biomed Appl., 1994, 660,211-220.

3. Fujisaki, H.; Shibata, H. Oketani, K.; Murakami, M. Inhibitions of acid secretion by E3810 and omeprazole and their reversal by glutathine. Biochem. Pharmacol., 1991, 42,321-328.

4. Takeguchi, N.; Yamanouchi, T.; Sakai, H.; Mora, M. New Fluorescent probes E3810 and E3810 methoxy for determining distributions of the apical membrane and the acidic compartment of gastric acid secreting cells. Jpn. J. Physiol., 1992, 42, 75-88.

5. Carswel, C.I.; Goa, K.L. Rabeprazole: An update of its use in acid related disorders. Drugs 2001,61,2327-2356.

6. Barth, J.; Hahne , W. Rabeprazole- based therapy in helicobacter pylori eradication. Ailment. Pharmacol. Ther, 2002, 16 ,31-33.

7. Garcia, C. V. Nudelman N. S.; Steppe, M.; Schapoval, E. E. S. Structural elucidation of Rabeprazole sodium photodegradation products. J. Pharm. Biomed. Anal, 2008, 46, 88-93.

8. E. Matsumara, Preparation of monochloropyridines. J.Chem. Soc. ( Japan), 1953,74, 363. Chemical.Abstracts. 1954 48:6,422b .

9. Spitzner, D., Deoxygenation and side chain halogenation in Science of Synthesis, 2004, 15, 192.

10. R. Garth Pews, Mezzie L. Ash, The Dow Chemical Co. Preparation of chloromethylpyridines. US Patent 4211873.

11. Souda Shigeru, Ueda Nirohiro, Mezon Gakuen, Eisai Co. Pyridine derivatives, pharmaceutical compositions comprising the same, the use of the same for the manufacture of medicaments having therapeutic or preventive value and a process for preparing the same. EP Patent 268956.

12. Rane, R.A.; Pathak, R.K.; Kaushik, C.P.; Rao, K. V. V.P.; Kumar, A. A practical one pot synthesis of 2-[2-(Pyridylmethyl)-thio]-1H-Benzimidazoles Synth. Commun., 2002, 32, 1211.

13. Barnes, J.H.; Hartley, F.R.; Jones,C.E.L. The preparation of 4- and 6-chloro-2-chloromethylpyridine Tetrahedron, 1982, 38, 3277.

14. Cameron, D.W., Deutscher, K.R.; Feutrill, G.I.; Hunt,D.E. Synthesis of azaanthraquinones: homolytic substitution of pyridines Aust. J. Chem., 1982, 35,1451.

15. Thomas C.Kühler, Jan Fryklund, Nils-Åke Bergman, Jessica Weilitz, Adrian Lee and Håkan Larsson, Structure-activitiy relationship of Omeprazole and analogues as Helicobacter pylori ureas inhibitors. J. Med. Chem. 1995, 38,4906-4916.

16. Om Dutta Tyagi,Purna Chandra Ray, Madhuresh Kumar Sethi, Bhausaheb Chavhan, Process for the preparation of pure Rabeprazole, US Patent 2010/0190989.

Received on 19.02.2011 Accepted on 12.03.2011

Asian J. Pharm. Res. 1(1): Jan.-Mar. 2011; Page 13-16