An improved and scalable process for 3,8-diazabicyclo [3.2.1]-octane analogues

Available online at www.sciencedirect.comCHINES E。ScienceDirectC HEMICAL. L ETTERSEL SEVIERChinese Chemical Letters 22 (2011) 523- -526www.elsevier.com/locate/ccletAn improved and scalable process for 3,8-diazabicyclo[3.2.1]-octane analoguesLong Jiang Huang, Da Wei TengCollege of Chemical Engineering, Qingdao University of Science & Technology. Qingdao 266042. ChinaReceived 23 August 2010Available online 1 March 201 IAbstractAn improved and scalable process for substituted 3,8-diazabicyclo[3.2. I]octane was developed. N-Benzy1-2.5-dicarbethoxy-pyrrolidine 2 was reduced to N-benzyl-2,.5 dihydroxymethylpyrolidine 9 and subsequently debenzylated to afford N-Boc-2,5-dihydroxymethylpyrrolidine 10. After mesylation of the diol 10 and cyclization with benzylamine, a diversity of scaffold, 3,8-diazabicylol3.2.1loctane analogue 12 was obtained in a total yield of 42% in five steps.心2010 Da Wei Teng. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.Keywords: 3.8-Dazabicyelo13.2.1 loctane; Scaffold; Process developmentThe piperazine nucleus is often found embedded in chemotherapic agents exhibiting a wide range of biologicalactivities [1,2]. As an analogue and alternative of piperizine in drug discovery, compounds based on 3,8-diazabicyclo[3.2.1]octanyl ring system received great interest for their biological acativities such as anti-tumoractivity [3], antiarrhythmic activity [4], antinociceptive activity [5], analgetic activity [5,6], as μ-opioid receptor [7],neuronal nicotinic acetylcholine receptor [8] as well as novel amide CCR5 antagonist [9].Cignarella et al. [10] first reported the synthesis of 3,8-diazabicyclo[3.2.1 ]octane derivatives. Several 3-substituted-8-methyl-3,8-diazabicyclo[3.2. l]octanes were synthesized starting from 2,5-dicarbethoxypyrrolidine, which wasconverted into N-carbobenzoxy-2,5-pyrrolidine dicarboxylic acid anhydride in three steps. The latter reacted withappropriate amines to give 3-substituted-8-carbobenzoxy-3,8-diazabicyclo[3.2. I ]octanes-2,4-diones from which thecorresponding bicyclic bases were obtained by reduction with lithium aluminium hydride. The process suffers fromseveral disadvantages such as long steps, tedious and labrious isolation of intermediates and low overall yields. A moreefficient synthesis of 3-benzyl-3,8-diazabicyclo[3.2.1 ]octanes was subsequently reported soon and has being usedtoday (Scheme I) [3.5,9,1 I]. The key intermediate, 2-benzylcarbamyl-5- carbethoxy pyrrolidine 4 was obtained in anoverall yield of 87% based on the recovery of starting materials by refluxing 3 with benzylamine in xylene. 4 was thenheated at 200 -210 C to afford intermediate 5 from which the 3-benzyl-3,8- diazabicyclo[3.2.1 ]octane was obtained byreduction with lithium aluminiun hydride. The modified synthesis is much shorter and efficient than the original one.But it still has some drawbacks. The intermediates need to be isolated in each step, which result in labrious work-upand isolation. The cyclization of the key intermediate 4 was carried out at high temperature. The total yield is only 17%* Corresponding author.中国煤化工E-mail udress: dteng@qus.edu.cn (D.W. Teng).MHCNMHG.1001-84175 - see front matter C 2010 Da Wei Teng. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.doi;10.1016j.cclet.2010.1 1.030524LJ. Huang, D.W. Teng/Chinese Chemical Letters 22 (2011) 523 -526CHzO2CCO2C2HsHyO2CNCO2C:Hs3n3CH2O2CCONHCH2CHs➢出N- -BnScheme I. Cignerella's synthesis of mono substituted 3.8 diazabiclol3.2.loctane. Reagents and conditions: (a) BnNH2, benzene, refux; (b) H2,Pd/C, ethanol; (c) benzylamine, xylene, refux; (d) 210 'C; (e) LiAlH4, ether, 0 'C r.t.(23% based on the conversion) in five steps. In our course to synthesize this intermediate, an improved and scalableprocess of diverse substituted 3,8 diazabicyclo [3.2.1 ]octane was developed. The synthetic route was illustrated asScheme 3.1. Results and discussionIn our effort to search for novel antitumor compounds in drug discovery, we need to synthesize this scaffold inkilogram quantities. We tried to use the same procedures as described by Cignarella [1 la,b]. After mono-amidation ofethyI 2,5-pyrrolidine dicarboxylate 3, the isolation of unreacted starting materials and product was difficult and theyield is unsatisfactory, the subsequent cyclization is also not worked well in our hand. After several attempts to thecyclization of the second ring, we found (Scheme 2) that when ethyl 2.5-pyrrolidine dicarboxylate 3 was reduced andmesylated, the dimesylate 8 could be cylizated smoothly by refluxing with primary amines. This process is much easerand the yield is reasonable. But it still has some drawbacks: the diol 7 was water soluble and hard to isolate, which alsoresult in tedious work up. It is also necessary to isolate the intermediates 7 and 8. The 3-benzyl-3,8-diazabicyclo[3.2.l]octane 6 needs to be distillated at high vacuum.Inspired by this result, we examined the same strategy from 2 without debenzylation. The results are as well asexpected. The yield of reduction of 2 is much better than that of reduction of 3 by lithium aluminium hydride. Thereaction is easy to work up. Based on those results, we proposed a modifed synthesis of the bicyclic ring system(Scheme 3). In order to maximize the diversity of the scaffold, we synthesized the di-substituted 3,8-diazabicyclo-C:HsO2C-Co,C;Hs_ a . HO~OH b MsOBnScheme 2. alternative synthesis of mono-substituted 3,8-diazabicyclo[3.2. l]octane. Reagents and conditions: (a) LiAIH4, ether, 0 °C-rt; (b) MsCl,El;N, r.t. CH2Cl2; (c) BnNH2, CHzCN, refux.CHsO2CCO2C;Hs_ aHb，29Boc中国煤化工3oeTYHCNMHGScheme 3. Synthesis of substituted 3.8 diazabicyclo|3.2.1 loctane. Reagents and conditions: (a) LiAlH, THF, 0 °C- tu; (b) H2, Pd/C, Boc2O,MeOH. 40 C; (c) MsCI, ElzN, rL. CH2Cl2; (d) BnNH2, CH;CN, refux.LJ. Huang, D.W. Teng/Chinese Chemical Ltters 22 (2011) 523- -526525[3.2.1 ]octane 12, which could be either de- Boc to modify the amine in 3-position or debenzylated to modify the aminein 8-position and/or both.The 2.5 dicarbethoxypyrrolidine 2 was synthesized frommeso a, ar dibrormoadipate 1 by modifying the Braun andSeeman's method [12]. In our hand, starting with one kilogram of ethylmeso a; a-dibromoadipate 1, we obtained the2.5-dicarbethoxypyrrolidine 2 (888 g) quantitively by refuxing with equimolar benzylamine in toluene for 4hcompared a yield of 82.5% in benzene for 24 h [12]. Reduction of 2 by lithium aluminium hydride in tetrahydrofurangives N-benzyl-2,5-dihydroxymethylpyrrolidine 9. Debenzylation of 9 in the mixture of di-tert -butyl dicarbonate andmethanol by hydrogenation using Pd/C catalyst afford N-Boc 2,5- dihydroxymethylpyrrolidine 10. Mesylation of thediol 10 with methanesulfonyl chloride in dichloromethane, we obtained tert-butyl 2,5-bis((methylsulfonyI)ox-y)methyl)pyrrolidine- I-carboxylate 11. Refuxing 11 with benzylamine in acetonitrile afford the desired compound 3-benzyl-8- Boc-3,8-diazabicyclo[3.2.1]octane 12. We also found by optimization that it is unnecessary to isolate theintermediates in each step. After regular work up, the intermediates (2, 9, 10. and 11) were obtained and used in nextstep. The 3-benzyl-8 Boc -3,8 diazabicyclo[3.2. l]octane 12 (370 g) was obtained by recrystallization in petroleumether [13-16]. The total yield is 42% in five steps.2. ConclusionWe developed an improved simple and scalable process for the synthesis of 3,8 diazabicyclo[3.2.1]octaneanalogues, which can be used in the synthesis of diverse 3,8-diazabicyclo[3.2. l]octane derivatives.AcknowledgmentThis research was partially supported by the program of research fund for retuming scholars of Ministry ofEducation of China (No. 200812053).References[1] J.W. Tracy. LT. Webster, HF. Chambers, et al.. The Pharmacological Basis of Therapeutics, 10h ed. 2001，p. 1059.[2] (a) YJ. Shaw. YT. Yang. J.B. Garrison, et al. J. Med. Chem. 47 (2004) 4453;(b) LJ. Lombardo. F.Y. Lee, P. Chen, D. Norris, et al. J. Med. Chem.47 (2004) 6658.(31 R. Filosa, A. Peduto, P. de Capraris, et al. Eur. J. Med. Chem.42 (2007) 293.[4] s. Villa, D. Barlocco, G. Cignerlla, et al. Eur. J. Med. Chem. 36 (2001) 495.|5| D. Barlocco, C. Cignerell, D. Tondi, et al. J. Med. Chem. 41 (1998) 674.{61 G. Cignarlla, E. Testa, J. Med. Chem. 11 (1968) 592.[7] (a) D. Barlocco, G. Cignerella, C. Giovanni. et al. J. Comput. Aided Mol. Des. 7 (1993) 557;(b) D. Barlocco, G. Cignarella. P. Vianello, et al. Farmaco 53 (1998) 557;(c) D. Barlocco, F. Paola, F. Waler. Farmaco 48 (1993) 387.[81 L. Toma. P. Quadreli, W.H. Bunnelle, et al. J. Med. Chem. 45 (2002) 4011.[91 D.C. Pryde, M. Corless, D.R. Fenwick, et al. Bioog, Med. Chem. Lett. 19 (2009) 1084.[10] (a) G. Cignarella. N. Gianciancomo. J. Org. Chem. 25 (1961) 1500;(b) G. Cigrarlla, N. Gianciancomo, E. Ocelli. J. Org. Chem. 26 (1961) 2747.[1] (a) E. Ccelli, L. Fontanella A. Diena. et al. Farmaco, Edizione Scicntifica 40 (1985) 86;(b) E. Ocelli, L. Fontanella, A. Diena, et al. Farmaco. Edizione Scienifica 33 (1978) 401;(C) E. Occelli, L. Fontanella, A. Diena, et al. Farmaco, Edizione Scienifica 24 (1969) 418;(d) G. Cignarella. T. Emilio. J. Med. Chem. l1 (1968) 592;(e) s.C. Smith, P.D. Bentley. Tetrahedron Lett. 43 (2002) 899;(I) H. Liu, T.M. Cheng. H.M. Zhang. et al. Pham. Med. Chem. 336 (2003) 510.[121 J. von Braun. J. Seeman, Ber 56 (1923) 1840.[13] Spectral data of compound 2: 'H NMR (500 MHz. CDCI): 87.32 (m, 2H), 7.27 (m, 2H).7.23 (m, IH), 4.05 (dd, 4H,J= 10.5 Hz. J=7.5 H2),3.96(s. 2H).2.08 (m, 4H), 1.19 (t., 6H,J= 7.5 Hz); "3C NMR (125 MHz, CDC):8173.4(2C). 137.5. 129.5(2C), 128.0(2C), 127.2.77.4(2C),60.6. 57.8 (2C). 28.7 (2C), 14.1 (2C): LRMS: MS (ES") mk= 306.2 (M+1中国煤化工、).2.78 (d. 2H.J= 12.0Hz),[14] Spectral data of compound 6: 'H NMR (500 MHz, CDCI;): 87.26 (m. SH), 62.71 (d, 2H,J= 12.5 Hz). 2.13 (m, 2H), 2.06 (m.2H); "C NMR (125 MHz,iYHC N M H G2C), 127.2.6.0, 64.3 (2C).58.8 (2C). 29.3 (2C): LRMS: MS (ES) m/z = 203.1 (M+1)*.[15] Spectral da of compound 10: 'H NMR (500 MHz, CDCl3): 83.94 (s, 2H), 3.82 (s. 4H). 3.51 (d. 2H, J= 7.5 Hz), 1.98 (m, 4H), 1.46 (s, 9H);“C NMR (25 MHz.CDCls): 8 156.5, 80.7. 65.5, 64.4. 60.6 (2C), 28.4 (3C), 26.9 (2C); LRMS: MS (ES") m/z= 232.1 (M+1)*.526LJ. Huang, D.W. Teng/Chinese Chemical Letters 22 (2011)523 -526[16] Typical procedure: To a suspension of LiAIH4 (198 g, 5.21 mol) in THF (400 mL), was added a solution of 2 (888 g, 2.912 mo) in THF(900 mL) at 0 'C dropwise. The mixture was sirred for five minutes. Then water (200 mL) and a solution of 10% NaOH (200 mL) were addeddropwise at 0 °C. The mixture was filtered and the cake was washed with dichloromethane. The filtrate was combined and evaporated to obtain9 (600 g, impure). It was dissolved in ethanol (3500 mL) and di-ten buty dicarbonate (600 g, 2.75 mol) and Pd/C (10 g) was added. Themixture was hydrogenated at 40。C and 60 psi hydrogen pressure for four hours, The mixture was cooled and fltered. The fitrate wasevaporated to obtain 10 (630 g, impure). It was dissolved in dichloromethane (1000 mL) and triethylamine (700 g, 6.92 mol)was added, thenmethanesulfonyl chloride (550 g, 4.80 mol) was added dropwise at 0 °C. The mixture was alowed to warm to room temperature and siredoveright. The mixture was washed sequenially with water, a solution of 10% citric acid and brine. The organic phase was dried overanhydrous sodium sulfale and evaporated to obtain 11 (800 g, impure). It was dissolved in actonitrile (1000 mL) and benzylamine (762 g,7.12 mo) was added. The mixture was heated to refux overmight. The mixture was evaporated and the residue was disolved in ethyl acetate,filtered through a silica pad, washed with water, a solution of 10% citric acid and brine. The organic phase was dried over anhydrous sodiumsulfate and evaporated. The compound 12 was obtained by recrystallization from petroleum ether as whie solid (370 g. 42.1% in five steps). 'HNMR (S00 MHz, CDCl3): 87.31 (m, 4H), 7.26 (m, IH),4.20(s, 1H), 4.09 (s, 1H), 3.47 (s, 2H).2.61 (d, 2H,J= 10.0 Hz),2.31 (s, 1H),2.24(s,lH), 1.90(s, 2H), 1.83(s, 2H), 1.47 (s, 9H); 13C NMR(125 MHz, CDCl): δ 153.7, 138.9, 128.7 (2C), 128.2(2C), 127.0,79.2, 61.9, 58.2,57.7,54.7, 53.8, 28.5 (3C), 27.8; LRMS: MS (ES*) mz = 303.2 (M+1)*.中国煤化工MYHCNMHG