Efficient Synthesis of 5Alkyl Amino and Thioether Substituted Pyrazoles

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  TETRAHEDRONLETTERSTetrahedron Letters 44 (2003) 7629–7632 Pergamon Efficient synthesis of 5-alkyl amino and thioether substitutedpyrazoles Subas M. Sakya* and Bryson Rast Veterinary Medicine Research and Development ,  Pfizer Inc .,  Groton ,  CT   06340  ,  USA Received 16 June 2003; revised 11 August 2003; accepted 13 August 2003 Abstract—  Nucleophilic substitution reactions of 1-(4-methylsulfonyl-2-pyridyl)-5-chloro pyrazoles with various substitutions atthe 4 position with amine nucleophiles and thiols occur under mild conditions to provide the 5-alkyl amino and thioetherpyrazoles in high yields.© 2003 Elsevier Ltd. All rights reserved. 1. Introduction Many vicinal bis-aryl substituted aryl, heteroaryl,cycloalkyl or heterocyclic templates have been disclosedas cyclooxygenase-2 (COX-2) selective agents. 1a Twosuccessful templates have been the 1,5-disubstitutedpyrazoles and 3,4-disubstituted furanones which haveresulted in the commercial products celecoxib (Cele-brex ® ) and rofecoxib (Vioxx ® ), respectively. A thirdCOX-2 selective agent to come on the market is valde-coxib (Bextra ® ), which belongs to the isoxazole class.Several other classes of compounds with COX-2 selec-tivity are still under development. 1b We started to look at 1,5-diarylpyrazole analogs asselective COX-2 inhibitors for veterinary use. 2 While wewere initiating our efforts in this area, Merck disclosedsome phenoxy and alkoxy lactones with improvedactivity against the COX-2 enzyme. 3 That reportprompted us to look at 5-amino, ether and thioetherpyrazoles as alternatives to the well known 1,5-diarylpyrazoles as selective COX-2 inhibitors (Fig. 1). In thispaper we report our development of an efficient synthe-sis of the 5-alkyl amino pyrazoles for our anti-inflam-matory program.Some scattered reports are available where the displace-ment of the 5-chloro pyrazole seems feasible withhydrazines, thiols, azide, and amines when an electronwithdrawing group is present at the 4-position. 4 Littlehas been investigated on the scope of the amino substi-tution reaction with the 4-nitrile or ester derivatives. 5 Thus, we decided to explore the amino substitution of the 1-(4-methylsulfonyl-2-pyridyl)-5-chloro-4-cyanopyrazoles with variety of amines to enable us to rapidlysynthesize and purifiy analogs. 2. Results and discussion The desired 5-chloro pyrazoles were synthesized asshown in Scheme 1. The condensation of the 2-pyridylhydrazine  1 5 with ethyl trifluoromethyl acetoacetate inethanol under reflux overnight followed by treatmentwith sodium hydroxide to effect complete ring closureprovided the 5-hydroxy pyrazole  2  in greater than 80%yield. This alcohol resisted complete conversion to the5-chloro pyrazole  3  (37%) even after prolonged heatingwith POCl 3 . Use of literature conditions (POCl 3 , DMF) Figure 1.  Lead COX-2 inhibitors and synthetic targets. * Corresponding author.0040-4039 / $ - see front matter © 2003 Elsevier Ltd. All rights reserved.doi:10.1016 /  j.tetlet.2003.08.054  S  .  M  .  Sakya ,  B  .  Rast  /   Tetrahedron Letters  44 (2003) 7629–7632  7630 Scheme 1.  Reagents and conditions : (a) EtOH, reflux,  16 h;2 equiv. NaOH, EtOH, 30 min,  > 90%; (b) POCl 3 , 120°C,37%; (c) POCl 3 , 4 equiv. DMF, 80°C, 4 h; (d) HONH 2 ·HCl,TFE, reflux, 2 h, 90%; Cl 3 CCOCl, Et 3 N, CH 2 Cl 2 , 0°C, 4–6 h, > 90% methoxide and ammonia to give the methyl ester  7 (80%) and amide  8  (67%), respectively.We initially explored the substitution reaction on  4  withvarious piperazines at room temperature in methylenechloride. To our surprise, the reaction was facile andgave clean products in excess of 95% after aqueouswork-up (Scheme 3, Table 1). Similarly, thiophenolreacted at room temperature to provide the product in98% yield. Imidazole required a temperature of 40°C toprovide a 76% yield of the product. For alkyl amines,the temperature had to be increased to 80°C indichloroethane before complete reaction was seen. Noreaction of the amines with the aldehyde was detectedunder these conditions (Table 1). Reaction of   3  with cis -dimethylmorpholine (80°C, DCE) also gave the sub-stitution product in 93% yield (Scheme 3).For the purposes of studying the scope of the reactionand to make useful analogs as COX-2 inhibitors, thesesame conditions were extended to make amino analogsof   5  (Scheme 4, Table 2). For the parallel synthesis, wedid reactions in 0.2 mM scale with 2 equiv. each of theamine and triethylamine at 80°C for 16–20 h indichloroethane. Rapid purification was done usingbatch preparative TLC, washing and filtration of desired product silica bands, followed by solvent evapo-ration. More than 200 amino analogs were maderapidly following this parallel reaction / purification pro-tocol. Almost all primary amines and most of thesecondary cyclic amines underwent the displacementreaction in high yields (Table 2). Dialkyl amines gavevariable yields depending on the substituent size andsteric bulk. Scheme 2.  Reagents and conditions : (a) 2 equiv. KMnO 4 , 2 h,84%; (b) oxalyl chloride, cat. DMF, DCM, 2 h; (c) for  7 : 1.4equiv. NaOMe, THF, rt, 30 min, 79%; (d) for  8 : NH 3 ,MeOH, rt, 16 h, 67%. Table 1.  Reactions with chloro aldehyde pyrazole  4 % YieldEntry ConditionsReactant95 N  -Ethylpiperazine1 rt, 1 h93rt, 2 h2  N  -Phenylpiperazine94 N  -Acetylpiperazine3 rt, 2 hThiophenol4 rt, 2 h 987640°C, 16 h5 ImidazoleIsopropyl amine6 40°C, 16 h 147 Aminomethyl 80°C, 20 h 66cyclopropaneCyclohexanethiol 80°C, 20 h 7382-Mercaptopyridine9 80°C, 20 h 9510 9280°C, 20 h N  -Methyl benzylamine Scheme 3.  Reagents and conditions : (a) 1.1–2.0 equiv. of reactant, 1.2–2.0 equiv. of Et 3 N, DCM for rt and 40°C; DCEfor 80°C. Scheme 4.  Reagents and conditions : (a) 1.2–2.0 equiv. amines,2 equiv. Et 3 N, DCE, 80°C, 0–99%. gave the 4-formyl-5-chloro pyrazole  4  in  > 90% yields. 6 The aldehyde was reacted with hydroxylamine hydro-chloride salt in refluxing trifluoroethanol (TFE) to givethe oxime (90%) which was then converted to thedesired nitrile  5  (90%) with trichloroacetylchloride inthe presence of triethylamine.The aldehyde was further oxidized with potassium per-manganate to give the acid  6  in 84% yield (Scheme 2).The acid was converted to the acid chloride (oxalylchloride, catalytic DMF) and trapped with sodium  S  .  M  .  Sakya ,  B  .  Rast  /   Tetrahedron Letters  44 (2003) 7629–7632   7631 Table 2.  Amino substitution reaction on 5-chloro-4-nitrilepyrazole  5Table 3.  Reactions with 5-chloro 4-methylester  7  andamide  8 Entry RReactant % YieldCO 2 CH 3 2-Methylbutylamine 4612 3-Amylamine CO 2 CH 3  42CO 2 CH 3 2-Methylpiperidine 443Neopentylamine4 CO 2 CH 3  49CO 2 CH 3 5 19Aminomethyl cyclopropaneCO 2 NH 2 Aminomethyl cyclopropane 176 cis -2,6-Dimethylmorpholine7 CO 2 NH 2  50CO 2 NH 2  338 Cyclohexane methylamineCO 2 NH 2 endo -2-Amino norbornane 329Piperidine10 CO 2 NH 2  17 Several analogs of   7  and  8  were also prepared using thesame procedure as described above, which indicates abroad generality of this procedure (Table 3). DMF aswell as other solvents could be used in the displacementreactions but we chose dichloroethane because of con-venience for rapid analog purification and isolation.Since the compounds were synthesized in a smalllibrary fashion, none of the reactions have beenoptimized.Thus, we have developed a convenient and efficient wayof introducing alkyl amines and aryl and alkyl thiols tothe 5-position of 1-(4-methylsulfonyl 2-pyridyl) 4-sub-stituted pyrazoles to enable generation of large num-bers of analogs for rapid biological screening. 7 Acknowledgements We would like to thank Mr. Jason Dutra and Dr.Henry Cheng for their suggestion to use sodiumhydroxide to facilitate the cyclization to the pyrazolone 2 . Thanks to our managers Dr. Carl Ziegler and Dr.Burton Jaynes for their support of our efforts andextensive suggestions on our manuscript (Dr. Jaynes). References 1. (a) Dannhardt, G.; Laufer, S.  Curr .  Med  .  Chem .  2000 ,  7  ,1101–1112; (b) Carty, T. J.; Marfat, A.  Curr .  Opin .  Anti  - Inflamm .  Immunomod  .  Invest .  Drugs  1999 ,  1 , 89.2. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J.S.; Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.;Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier,D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn,J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.;Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P.C.  J  .  Med  .  Chem .  1997 ,  40  , 1347.3. (a) Leblanc, Y.; Roy, P.; Boyce, S.; Brideau, C.; Chan, C.C.; Charleson, S.; Gordon, R.; Grimm, E.; Guay, J.;Leger, S.; Li, C. S.; Riendeau, D.; Visco, D.; Wang, Z.;Webb, J.; Xu, L. J.; Prasit, P.  Bioorg  .  Med  .  Chem .  Lett . 1999 ,  9  , 2207; (b) Li, C.-S.; Black, W. C.; Brideau, C.;Chan, C. C.; Charleson, S.; Cromlish, W. A.; Claveau, D.;Gauthier, J. Y.; Gordon, R.; Greig, G.; Grimm, E.; Guay, Although aryl thiols readily reacted even at room tem-perature, aryl amines either gave no product or verylow yields under these conditions. Even alkyl substi-tuted aryl amines failed to provide products (item 16)  S  .  M  .  Sakya ,  B  .  Rast  /   Tetrahedron Letters  44 (2003) 7629–7632  7632 J.; Lau, C. K.; Riendeau, D.; Therien, M.; Visco, D. M.;Wong, E.; Xu, L.; Prasit, P.  Bioorg  .  Med  .  Chem .  Lett . 1999 ,  9  , 3181; (c) Lau, C. K.; Brideau, C.; Chan, C. C.;Charleson, S.; Cromlish, W. A.; Ethier, D.; Gauthier, J.Y.; Gordon, R.; Guay, J.; Kargman, S.; Li, C.-S.; Prasit,P.; Riendeau, D.; Therien, M.; Visco, D. M.; Xu, L. Bioorg  .  Med  .  Chem .  Lett .  1999 ,  9  , 3187.4. (a) Khan, M. A.; Freitas, A. C. C.  J  .  Heterocyclic Chem . 1983 ,  20  , 277; (b) Bakhite, E. A.; Geies, A. A.; El-Kashef,H. S.  Phosphorus Sulfur Silicon Rel  .  Elem .  2000 ,  157  , 107;(c) Molina, P.; Arques, A.; Vinader, M. V.; Becher, J.;Brondum, K.  J  .  Org  .  Chem .  1988 ,  53  , 4654; (d) Svenstrup,N.; Simonsen, K. B.; Thorup, N.; Brodersen, J.; Dehaen,W.; Becher, J.  J  .  Org  .  Chem .  1999 ,  64  , 2814–2820; (e)Weinges, A.; Balzer, W. R.; Gerstung, S.; Gerstung, S. D.In Ger. Offen.; (Wella AG, Germany). De, 1996, p 8 pp;(f) Gehring, R.; Schallner, O.; Stetter, J.; Santel, H. J.;Schmidt, R. R. In Ger. Offen.; (Bayer A.-G., Fed. Rep.Ger.). De, 1986, p 79 pp; (g) Neunhoeffer, H.; Gerstung,S.; Clausen, T.; Balzer, W. In Ger. Offen.; (Wella AG,Germany). De, 1994, p 14 pp; (h) Dickore, K.; Gehring,R.; Sasse, K.; Santel, H. J.; Schmidt, R. R. In Ger. Offen.;(Bayer A.-G., Fed. Rep. Ger.). De, 1986, p 88 pp.5. Cheng, H.; Li, J.; Lundy, K. M.; Minich, M. L.; Sakya, S.M.; Uchida, C. In PCT Int. Appl. (Pfizer Products Inc.,USA) WO, 2001, p 130 pp.6. Lee, L. F.; Schleppnik, F. M.; Schneider, R. W.; Camp-bell, D. H.  J  .  Heterocyclic Chem .  1990 ,  27  , 243.7. Sample reaction procedure (example 10, Table 2): A sus-pension of   5  (200 mg, 0.570 mmol) in 2 ml dichloroethane(DCE) was treated with triethylamine (0.684 mmol, 1.2equiv.) and piperidine (0.627 mmol, 1.1 equiv.) and heatedthe mixture at 80°C for 16 h. TLC shows completion.Water was added to the mixture, shaken and separatedusing an organic selective membrane filtration cartridge.Solvent was evaporated to give a crude residue. Theproduct (771 mg, 97%) was purified using preparative thinlayer chromatography, utilizing 1:1 EtOAc / hexanes forelution.  1 H NMR (400 MHz, CDCl 3 )    9.07 (d, 1H,  J  = 2.5Hz), 8.40–8.37 (dd, 1H,  J  = 2.5, 5.8 Hz), 8.02–8.00 (d, 1H, J  = 8.7 Hz), 3.35–3.32 (t, 4H,  J  = 5.2 Hz), 3.16 (s, 3H),1.72–1.56 (m, 6H). MS ( m / z ) 400.1 (M + H). All the com-pounds run in parallel synthesis manner were character-ized by LC–MS and are consistent with the structures.Compounds that were scaled up are characterized by  1 HNMR and LC–MS. Data for select compounds: entry 9,Table 1:  1 H NMR (400 MHz, CDCl 3 )    9.97 (s, 1H),8.93–8.92 (t, 1H  J  = 1.45 Hz), 8.39–8.36 (dd, 1H,  J  = 2.3,7.3 Hz), 8.23–8.22 (m, 1H), 8.11–8.08 (d, 1H,  J  = 8.3 Hz),7.62–7.57 (m, 1H), 7.31–7.29 (d, 1H,  J  = 7.9 Hz), 7.09–7.06(m, 1H), 3.11 (s, 3H); MS ( m / z ) 429.3 (M + H); entry 10,Table 1:  1 H NMR (400 MHz, CDCl 3 )    9.96 (s, 1H), 9.04(d, 1H,  J  = 2.5 Hz), 8.35–8.33 (dd, 1H,  J  = 2.5, 5.8 Hz),7.88–7.86 (t, 1H,  J  = 8.3 Hz), 7.29–7.20 (br, 5H), 4.39 (s,2H), 3.15 (s, 3H), 2.84 (s, 3H); MS ( m / z ) 439.2 (M + H);entry 7, Table 2:  1 H NMR (400 MHz, CDCl 3 )    9.07–9.08(d, 1H,  J  = 1.6 Hz), 8.41–8.39 (dd, 1H,  J  = 2.3, 8.5 Hz),7.98–7.95 (d, 1H,  J  = 8.5 Hz), 3.3–3.2 (m, 2H), 3.15 (s,3H), 3.15 (m, 1H), 2.0–1.0 (m, 13H); MS ( m / z ) 442.1(M + H); entry 13, Table 2:  1 H NMR (400 MHz, CDCl 3 )   9.06–9.05 (d, 1H,  J  = 2.5 Hz), 8.40–8.38 (dd, 1H,  J  = 2.5,8.3 Hz), 7.99–7.96 (d, 1H,  J  = 8.7 Hz), 3.15 (s, 3H), 2.81 (s,3H), 1.30–1.28 (d, 6H,  J  = 6.6 Hz); MS ( m / z ) 388.1 (M + H).
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