Jou rn al of Scicntific & Industri al Research Vol. 62 , Apri l 2003 , pp 334-33 H

Novel Synthesis of Non-steroidal Anti-inflammatory Drugs by Electrocatalytic Hydrogenation

R Ramesh Raju, S Krishna Mohan and S Jayarama Reddy '" Electrochemi cal Research Lahoratories, Department of Chemi stry, Sri v enk ateswara University, Tirupati 51 7502. Ind ia.

Received: 05 August 2002; accepted : 07 October 2002

Aryl-2- group of non-steroidal anti-innammatory drugs (NSAIDs), such as pro tiz inic ac id , , carp ro fen, and pranoprofen have been synthesised in hi gh yields by using an undivided cell at a ni ckel cathode in th e presence of sulphuri c ac id.

Introduction cathode at an apparent current density under moderate Non-steroidal, anti-i nfl ammatory drugs temperatures. The reaction sequence is given in (NSAIDs) are a class of medi cations that possess Scheme I. analges ic and anti-pyretic activities 1-5. These are used Materials and Methods for reducin g fever and inflammation in vari ous mu scui os keleta di sorders, menstrual cramps, and Precursors of drugs were prepared according to body pains 6- 12. NSAIDs are perhaps the commonly the avai lable procedures IR-2 1. Analytical grade used new group of avai lable today, reagents of ethanol and sulphuric acid were used as whi ch are frequ entl y used, domestically and in solvent and electrolyte. For the preparative healthcare facilities for diversifi ed medi cal di sorders. electrolys is th e electrochemical undivided cell of Conventional synthesis of non-steroidal , anti­ 100mL vo lume was equipped with Raney ni ckel 2 infl ammatory drugs, like proti zinic acid, cathode (3x4cm ) and lead anode Ox4cm\ The two benoxaprofen, , and pranoprofen has already electrodes were connected to a 0 C power supply. been reported 1.\-16 But, formati on of hazardous Controll ed potential electrolys is was carri ed out, chemicals , like cyanides, low yield s du e to high us in g the potentiostat (Model: PS-603, Techn o­ temperatures and hi gh stereoselectivity, makes thi s Electroni cs, Lucknow, India). Melt ing points were method ineffi cient. Hence, attempts were focused determined by Mel-Temperature apparatus. I H NMR toward s electrochemical approach of these drugs. was recorded on a Varian EM-360 spectrometer in j. Electrochemica ll y generated hydrogen is an CDCI, in the presence of SiMe4 as an internal attractive process, which avoids the necessity for the standard. IR spectra were determined with a Perkin­ suppl y of hydrogen gas. It also offers the advantage Elmer 1600. of givin g th e product, which can be easil y isolated in Experimental Procedure pure form and avoid s th e side products and isomeri c forms. Thus, it was pl ann ed to synthesise those drugs The electrochemical reaction was carri ed out by by electrochemical hydrogenation from their dissol ving 2-(7 -methoxy-I O-methyl-2-phenothazi nyl) precursors. In thi s paper, we report first propene-I-oic ac id (4.5 g) in eth anol (50 mL) electrochemi cal synthesis c f protizinic acid, containing 10 per cent su lphuric ac id ( 15 mL) at a benoxaprofen, carprofen, and pranoprofen at a high constant current density of 100A/m2 in an undivided ~. surface area, low hydrogen overvolt age of ni ckel cell equipped with ni ckel cathode and lead anodc. The cell was kept under th e nitrogen atmos phere and '" Author for corres pond ence th e contents were stirred, usin g magneti c stirrer at Fax: +9 1-H574-48499, E-mail: j reddy_s@ya hoo.co l11 50 DC. The extent of reaction was fo ll owecl by regular RAJU el al.: NOVEL SYNTHESIS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS 335

~ e CH2 ry N~ COOH Meo ~ s ~

2-(7-n~thoxy-1 0-~thyl-2-phenothiazinyl) propene- l-oic acid Protizinic acid

I + .~ Ni Pb ~ -Q-<0=(JXl CI ~ J ":: N ~ I COOH CI -Q-<~ J "::0N =(JX'~ I COOH H+

2-(4-chlor ophenyl)-a -methyl-S-benzoxazole- Benoxaprofen ethene- I-oie acid

H H I I N H:~ - I Ni Pb+ COOH ~ I f COOH CI H+ CI ~~

Carprofen 6-Chloro-a-methyl-9H-carbazole-2-ethene- I-oic acid

I N 0 N 0 - :?' -;::? CH3 :?' -;::? CH2 Ni Pb+

~ H+ ~ ~ COOH ~ ~ COOH

2-(SH- [1 ]benzopyrino[2,3-b ]pyridin-7 -yl)propene-l-oic acid Pronoprofe n

Scheme I

sampling through thin layer chromatography. At the Benoxaprofen - mp 188-1890C, IH NMR end of the reaction the electrolyte solution was (CDCI,): 8 = 1.45 (d, 3H), 3.68 (q, IH), 7.20-7.90 diluted with water and the product was extracted into (m, 7H, Ar-H), I 1.63 (s, I H) ; IR (neat): u = 1730 diisopropyl ether (or) acetonitrile (or) chloroform (or) em· 1. dioxane, washed with water, dried over MgS04. and o the evaporation of solvents gave 3.6g protizinic acid Carprofen - mp 196-197 C, IH NMR (COCl ,,): in 80 per cent of isolated yield, mp 124-1250C, 8 =1 .44(d, 3H), 3.82 (q, IH), 7.95 (m, 6H, Ar-H), IHNMR (CDC!.,): = 1.43 (d, 3H), 3.62 (q, I H) , 3.42 8.21 (s, 5H, NH), 11.65 (s, I H); IR: (neat): u = 1720 8 ·1 (s, 3H, N-CH .~), 3.69 (s, 3H, OCH,), 7.15-7.54 (m, cm . l 6H,Ar-H), 11.58 (s, I H). IR (neat): u = 1725 cm· . Pranoprofen - mp 183-184oC, IH NMR The synthesis of benoxaprofen, carprofen, and (CDCI): 8 = 1.46(d, 3H), 3.85 (q, I H), 4.23 (s, 2H, - pranoprofen has also been achieved by the similar CHr ), 7.98 (m, 6H, Ar-H), 11.66 (s , I H); fR (neat): l method. u = 1735 cm· . 336 J SCI IND RES VOL 62 APR IL 2003

Results and Discussion An increase in the bulk catho lyte concentration of precursors leads to an increase in the amount of The electrochemical hydrogenation on the precursors at the catalyst surface w hi c h, in turn, precursors of protlZII11C acid, benoxaprofen, increased the efficiency of hydrogen addition to th e carprofen, and pranoprofen in ethanol at nickel >C=C< in precursors. An increase in the reactant cathode in the presence of sulphuric acid has been concentration gave selectivity in favour of the product carried out at different concentrations, current and also an increased mass conversion relative to the densities,and reaction temperatures. The experimental given amount of charge passed . At high substrate results are presented in Table I which demonstrates concentration the evolution of hydrogen at the th e variation in th e product yield due to the change in 17 cathode was suppressed . To test thi s hypoth esis, th e initial concentration of the substrate reduced at a electrocatalytic hydrogen experiments were carri ed fixed current density and also from the change of out with initial concentration of precursors rangin g temperature at a given substrate concentration. The J from 2.0 to 8.0 mol dm- conditi ons favouring the formation of better product yield s are low concentration and hi gh current density In order to study the effect of temperature on the (Table 2). product the electrolysis is performed at four different temperatures, rangin g from 15 to 50°C, in an initial The products were confirmed by 'H NMR concentration of 2.0 mol dm-'. A change in tempe­ spectral studies. The presence of doublet in the region rature has significant effect on the reaction effic iency. o 1.43- 1.46 and quartet in the region 0 3.62-3.85 for However the hi gher temperature increases the methine proton (adj acent to carboxylic group) hydrogenation rate. The results suggest that elevated indicates the formation of the product. temperatures accelerate th e reacti on of adsorbed

Tahlc 1- Elcc trocatalyti c rcducti on o i" 2-(7-meth oxy-1 O-mcth yl -2-ph eno thi az inyl) propenoic ac id . 2-(4-chlorophcnyl)-o:-mcth yl-5- be nzoxazole eth enc-I-oic ac id , 6-cloro-o:-meth yl-9H-carbozo lc-2- eth cne- I-oic ac id and 2-(5 H-[ I] benzopyronor2.3- -r b]pyridin-7-yl)propene -I -oic ac id"

Exp. Tcmpcrature Su bstrate Current efficiency (per ce nt ) Yield (per cen t) No. (1lC) concentration (g/dm' ) Proti zi nic Bcnoxaproi"en Carproi"en Pranoprofen Proti zinic Benoxaproi"en Carproi"cn Pran oprolCn acid acid

15 2.0 85 83 82 8 1 62 8 1 64 82

20 83 82 8 1 79 64 83 66 80

30 8 1 79 80 72 65 84 67 8 1

50 80 78 76 7 1 78 86 79 83

2 30 4.0 75 71 74 72 70 62 71 67

50 66 64 63 62 8 1 73 82 78

3 30 6.0 68 66 67 65 77 76 74 74

50 63 62 64 6 1 84 85 79 83

4 30 8.0 69 68 67 70 76 78 74 72

50 62 64 63 68 85 84 82 83

"At current dcnsity oi" 100 A/m2 RAJU et al.: NOVEL SYNTH ES IS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS 337

X Table 2 - Effect of cu rrent dcnsit y on 2-(7-meth oxy- 10-methy l-2-phenothiazin yl) propenoic ac id , 2-(4-chl orophcnyl)-a-meth yl-5 - benzoxazole ethene- I-o ic acid, 6-cloro-a-meth yl-9 H-carbozole-2- eth ene-I-oic ac id and 2-(5 H-[ I] benzopyrono[2,3 -b]pyridin-7-yl) propene- I-oic ac id"

Experiment No. Curren t de nsity (A/m2) Yield (per ce nt )

Protizinic ac id Benoxaprofen Carprofen Pranoprofen

10 6 1 59 54 56

2 50 63 6 1 58 53

3 100 69 66 63 62

" Concentrati on = 4.0 g/d m' at 30 "C

hydrogen with substrate to a greater extent than the 6 Dunwell D W, Evans D, Hi cks T A, Cashin C H & Kit chen normal te mperatures. A, 2 - Ary l - 5 - benzoxazolealkanoic ac id derivati ves with notab le anti-in fl ammatory ac ti vi ty, } Med Chelll, 18 ( 1975) All the parametres were optimised for the 53. hyd rogenati on of precursors to near completi on, over 7 Cash in C 1-1 , Dawson W & Kitchen E A, The pharmacology a reacti on ti me of 10-1 2 h. In a ll these reactions the of benoxaprofen (2- [4-ch lorophenyIJ -a-methyl- 5-benzo­ required non-steroidal anti-inflammatory drugs were xazole acet ic ac id ), LR CL 3794, a new co mpound with ant i­ infl amm atory activity apparently unrelated to inhi bition of th e only products found on the ni ckel catalyst. prostag landin sy nthesis, } Pharlll Ph{//wcol. 29 (1977 ) 330. Conclusions 8 Chart J J & Maier R, A brief rev iew or thc pre-clini cal Pharmacology of , Chem Abstr, 96 ( 1982) I 10 I 08r. The electrochemi cal hydrogenati on of aryl-2- 9 Randall L 0 & Baruth H, and an ti-inflammato ry propionic acid s could be achi eved over a ni ckel ac ti vit y of 6- ch loro-a-meth yl carbozole -2-acetic ac id . Arch cathode in good yields than the conventional method . lilt PharllIaeodvn , 220 ( 1976) 94. This electrochemi cal hydrogenation is an alternate 10 Rames h Raju R, Damodar J & Jayarama Redd y S. The route for th e synthesis of drugs, whi c h does not electrocatalyti c hydroge nation of a-aryl ac ryli c ac id s. Eleetrochem CO Il1I1I1/I/ , 4 (2002) 115. require th e external supply of hydrogen gas. The II Maruyama Y, Anam i K. Imayos i T & Imamura H, effect of substrate concentrati on, temperature, and Pharmacological studi es of 2-(5 H-[ I]-benzopyrano [2.3 -b 1 current density greatl y influences the yields obtained . pyridin-7-yl) propianic aci d, Yakugakll Zasshi, 97 ( 1977 ) The product yields and the experimental results 343. obtained are in good agreement with the usual 12 Damodar J, Kri shn a Mohan S & Jaya rama Reddy S, expectations. Synthesis of 2-aryl propionic acids by electrocarboxylati on of benzyl ch lorides catalysed by PdCI 2 (PPh,h.. Electroehem References Comlllun, 3 (200 1) 762. 13 Messer M & Farge D, Acid derivati ves of phenothiazine, Skid more I F, Antagonism of analog induccd preparation and stud y of the relati on between chemical vasoconstriction by non-steroidal ant i-i nfl am matory agent s, st ru cture and an ti-infl ammatory ac ti vity. C R Aead Sei Ser. Mulec A.li)('cts Mer/, 4 ( 19 8 1) 303. 265 (1967) 758. 2 Dav id P G Hamon, Ralph A Massy-Westropp & Joscphine L Newton, Enanti oselective sy ntheses of 2-aryl propanoic acid 14 Dunwell D W & Evans D, Synthesis and ant i-inflammatory non steroidal anti-i nfl ammatory drugs and rel ated activity of some 2- heteroaryl-a-methyl-5-benzoxazole acetic co mpou nds , Tetrahedrol/ , 51 (1995) 12645. acids, } Med Chelll , 18 (1975) I 158. 3 Litter T R. Stabi li zat ion of cardiaclysosomal and cellu lar 15 Maeda M. Tanaka Y. Suzuki T & akamura K. membran es in protection of isc hemi c myocardium due to Pharmaco logical st udi es on ca rprofen, a new non-steroid al coronary acciusion: effi cacy of th e non-stcroidal anti­ anti-inflammatory drug in animals, ChI'lli Abstr. 88 ( 1978 ) infl am matory drugs, Pharlll Th er, 15 (1981) 45. 69038c. 4 Anastassides T P, The effect of ce ll densi ty on net rates of 16 Castaner J & Roberts P, Synt hes is and properties or 4- glycosaminoglycon sy nthesis and secretion by cultu red rat am ino-2, 3. 5, 6- tetra-chlorobenzene diazonium dibromo­ fibrobl asts, Call Med Assoe }, 122 ( 19 80) 405. iodide, Drugs Flltllre, 2 ( 1977) 217. 5 Arrigoni Martelli E, An tirhcumatic drugs, Drugs Tor/ay, 18 17 Robin D, Comtois M, Mart el A. Lemieux R, Cheon y A K & (1982) 461. Lessard L, The electrocatal yti c hydroge ntat ioll of fu sed 338 J SCIIND RES VOL 62 APRIL 2003

polycycli c aromati c co mpoun ds at Raney ni ckel electrodes: 20 Nakani shi M, Oe T, Tsuru da M. Matsuo H. Saku ragi S & the influence of catalyst activ ati on and electrolysis Maruyama Y, Studies on th e synthesis and anti­ conditi on, Can} Clr em 68 ( 1990) 121 8. infl ammatory ac ti vity of xanthenyl and benzo­ 18 Farge D, Jean Ma rt C, Messer M & Mayer N, 2-(7-Methoxy- pyranopyridinyl acetic ac id deri vati ves . Cirelli Abstr, 84 3-phenothi az in yl) propi oni c acids, Chem Abstr, 70 (1969) ( 1976) 135515b. 68394g. 21 Dunwell D W, Evans D, Smith C E & Will iamso n W R N, 19 Kemmerer J M & Rubi o F, Electrochemi cal behaviour and Synthesis and anti-intlammatory ac ti vity of so me 2- solubilit y stud y of hydrogen and aceti c acid in molten alkali su bstituted-a-meth yl- 5-benzimidazole acetic acids, } Med acetates, } Pharm Sci. 68 ( 1979) 1274. Chem. 18 (1975) 692.