- Email: [email protected]
Novel methods for the synthesis of 1,5,2-diazaphosphinines as potential inhibitors of HCV polymerase
Accepted Manuscript Novel methods for the synthesis of 1,5,2-diazaphosphinines as potential inhibitors of HCV polymerase Daniel Da Costa, Arlène Roland, Cyril B. Dousson PII: DOI: Reference:
S0040-4039(16)31531-3 http://dx.doi.org/10.1016/j.tetlet.2016.11.063 TETL 48349
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
26 September 2016 10 November 2016 15 November 2016
Please cite this article as: Da Costa, D., Roland, A., Dousson, C.B., Novel methods for the synthesis of 1,5,2diazaphosphinines as potential inhibitors of HCV polymerase, Tetrahedron Letters (2016), doi: http://dx.doi.org/ 10.1016/j.tetlet.2016.11.063
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Tetrahedron Letters
Novel methods for the synthesis of 1,5,2-diazaphosphinines as potential inhibitors of HCV polymerase Daniel Da Costa a,, Arlène Roland b,† and Cyril B. Dousson a a
Idenix-an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France.
b
elementary School Former Idenix employee.
†
A RT I C L E I N F O
A BS T RA C T
Article history: Received Received in revised form Accepted Available online
Two new methods for the preparation of 1,5,2-diazaphosphinines are described. The first approach involves the reaction between an amidine and an alkynylphosphonate in basic media. The second route involves the reaction between an amidine and a dithioketene acetal phosphonate in basic media. The 1,5,2-diazaphosphinines targets were synthesised for a HCV polymerase inhibitor program. 2016 Elsevier Ltd. All rights reserved .
Keywords: Hepatitis C virus 1,5,2-Diazaphosphinines NS5B Non-nucleoside inhibitors Thiadiazine bioisostere Allosteric inhibitors
Introduction Structural modification in medicinal chemistry is commonly used to refine the efficiency of a drug. One of the most efficient tool in drug design is the concept of bioisosteres1. Bioisosteres are constituted by different functions compared to the original group but they show close biological response allowing different selectivity, potency and physical properties such as polarity, pKa or solubility. These differences may drive the improvement of biological activity and lead to new intellectual properties. A lot of functions or components were exploited as bioisosteres and phosphorus based ones proved the potential of such derivatives. In this context, several phosphorus derivatives led to original drugs with improved biological response as already reported in antiviral medecines. Consequently, different Non-Nucleoside Reverse Transcriptase Inhibitors programs were developed replacing sulfonyl2 group by a phosphonyl bioisostere3. In this context, the purpose of our work was to substitute the sulfur atom in benzothiadiazines4 (Scheme 1), well known as Hepatitis C virus (HCV) polymerase inhibitors, by a phosphonyl group to form phosphadiazines or 1,5,2-diazaphosphinines analogues. Hepatitis C virus (HCV) has been known as a flaviviridae virus family since 19895 and causes at least a substantial proportion of post-transfusion hepatitis and of sporadic acute hepatitis. HCV has infected approximately 170 million people worldwide and 10,000 people die annually in the United States from HCV liver diseases, such as liver failure, cirrhosis and
———
hepatocellular carcinoma6. This virus became a major public health problem with around four more million infected people each year. Furthermore, morbidity and mortality rates from chronic HCV infection are projected to double in this decade and may surpass those of human immunodeficiency virus 7. Thus, with the potential emergence of a resistant virus and the side effects related to treatment, new potent and safe therapies are still useful to help eradicate this disease. The key step for the synthesis of 1,5,2-diazaphosphinines 1 is the formation of the P-N intracyclic bond. Different previously published procedures were evaluated to obtain the desired scaffold8,9. The cyclisation methods (Figure 1) were realised by different reactions from primary enamine phosphonates and from nitriles or isocyanates (Figure 1: route a and route b), from phosphite and from o-bromoarylamidine (Figure 1: route c), from primary enamine phosphonates and from dithioketene acetal (Figure 1: route f), from 1-alkynylphosphonate and from amidine (Figure 1: route e), and finally from dithioketene acetal phosphonate and from amidine (Figure 1: route d). The last two methods have not yet been described but have been developed in spite of all the previous methods in order to access a greater diversity on these phosphorylated heterocycles. The first synthesis of 1,5,2-diazaphosphinines 1 was reported by Palacios et al.8 through a reaction from primary enamine phosphonates obtained from phosphonates, and nitriles (Figure 1: route a and route b). The phosphonyl group was used to replace a carbonyl group in a heterocycle. Thus, initially 1,5,2-
Corresponding author. Tel.: +33(0)499522252; fax: +33(0)499522250; e-mail: [email protected]
2
Tetrahedron Letters
diazaphosphinines were synthesised to mimic pyrimidone and pyrimidine rings which are frequently used in medicinal chemistry.
a
b
f
c
1
Benzothiadiazines
e
This work
d
Figure 1. General structure of benzothiadiazines and general retrosynthetic pathways for making 1,5,2-diazaphosphinines and derivatives.
Synthesis of phosphadiazines Recently, three syntheses were described in patents9. All of them used phosphonoaniline derivatives to synthesize phosphadiazines (Figure 1: route a, route c and route f). The first reported route was the addition of bromoanilines 3 to nitriles 2 in the presence of trimethyl aluminium. Then, the amidinoaryl bromide 4 was coupled with trialkyl phosphite in the presence of palladium acetate in acetonitrile to give phosphonate 5. Phosphadiazines 6 were obtained by intramolecular cyclisation which occurred while heating in dimethylacetamide under microwave irradiation at 200°C for 4.5 hours (Scheme 1).
(Scheme 3). First, phosphonoaniline 11 reacted with dithioketene acetal 10 in dioxane at 80°C giving the intermediate 12. Then, ammonia (gas) was added and the reaction mixture was heated at 100°C in a sealed tube to afford the amidine 13 which cyclised to the final phosphadiazine 14. i, ii
10
14
11
i
ii
12 2
3
i
13
Scheme 3. Synthesis of phosphadiazines. Conditions and reagents: (i) dioxane, 80°C; (ii) NH3 gas, 100°C, 5%-32%.
6
iii
Using this methodology, the dithioketene acetal 15 and the aniline phosphonate 16 were handled to accomplish the synthesis of the phosphadiazine 17 in 32% yield (Scheme 4).
ii
4
5
Scheme 1. Synthesis of phosphadiazines. Conditions and reagents: (i) AlMe3, dioxane, 80°C; (ii) P(OR)3, Pd(OAc)2, CH3CN, 160°C, microwave irradiation; (iii) dimethylacetamide, 200°C, microwave irradiation, 7%-60%.
i, ii
15
Another reported method was the condensation between the tetramic nitrile 7 and the phosphonoanilines 8 in the presence of trimethyl aluminium (Scheme 2). The presence of amidine 5 as a by-product suggested a two-step mechanism. The first step was the addition of aniline to nitrile to form amidine 5 followed by the cyclisation to obtain phosphadiazine 9 in 60% yield.
16
17
Scheme 4. Example of synthesis. Conditions and reagents: (i) dioxane, 80°C; (ii) NH3 gas, 100°C, 32%.
Synthesis of 1,5,2-diazaphosphinines Two original methods (Figure 1: route d and route e) consist in the reaction of amidine11 and 1-alkynylphosphonates12 or dithioketene phosphonates13. These methods were developed to introduce more diversity to the chemical structure of the targets as the other ways were not efficient enough.
i
7
8
9
Scheme 2. Synthesis of phosphadiazines from nitrile. Conditions and reagents: (i) AlMe3, dioxane, 80°C, 60%.
In some case, nitriles were not reactive enough to give the desired compound. To overcome this issue, a more reactive starting material such as a dithioketene acetal 10 4f,g,i,10 was used. The two-step reaction was carried out in one pot reaction
The 1-alkynylphosphonate 19 was synthesised12 by addition of ethynylmagnesium bromide to diisopropylphosphochloridate 18 in THF at 0°C with a yield of 30%. The amidine 20 was obtained11 by reaction of the nitrile derivative 7 with trimethylaluminium and ammonium chloride in dioxane at 85°C with a yield of 58%. The reaction of amidine 20 and 1alkynylphosphonate 19 was performed in dioxane with potassium tert-butoxide giving the Michael-type adduct which undergoes cyclisation to give the diazaphosphinine 21 (Scheme 5). Compound 21 was obtained in a 35% yield (Scheme 5) with no
substitution, but this compound can still be fonctionalized. In this case, huge chemical diversity can be introduced by activating the vinylic proton in different reactions such as halogenation and palladium-catalyzed reactions.
Acknowledgments D.D.C. thanks Drs. Jean-Laurent PAPARIN and David DUKHAN for the guidance in the writing of the article and also Sylvie CAPPELLE for editing assistance.
18
References and notes i
1.
19 ii iii
7
21
20
Scheme 5. Example of Synthesis. Conditions and reagents: (i) HC≡CMgBr, THF, 0°C, 30%; (ii) AlMe3, NH4Cl, dioxane, 80°C, 58%; (iii) tBuOK, dioxane, 80°C, 35%.
2. 3.
The last experiment to make the 1,5,2-diazaphosphinines 24 was the reaction between an amidine 20 and a dialkyl (1-cyano2,2-bismethylsulfanylvinyl)phosphonate such as the diethyl (1cyano-2,2-bismethylsulfanylvinyl)phosphonate 23 (Scheme 6). The amidine 20 was made as described in Scheme 5 and the diethyl (1-cyano-2,2-bismethylsulfanylvinyl)phosphonate 23 was prepared from the diethyl cyanomethylphosphonate 22 as described in the literature13. The reaction between the amidine 20 and the diethyl (1-cyano2,2-bismethylsulfanylvinyl)phosphonate 23 was carried out in dioxane with potassium tert-butoxide at room temperature overnight to synthetise 24 in a 40% yield (Scheme 6). In this case, chemical diversity can be introduced by using different reactions to the cyano group or the methylthio group.
22
i
23 ii
20
24
Scheme 6. Example of synthesis. Conditions and reagents: (i) NaH, CS2, MeI, THF, room temperature, 64%; (ii) tBuOK, dioxane, 80°C, 40%.
Conclusion In conclusion, two new strategies for the syntheses of 1,5,2diazaphosphinines were successfully developed from amidine and 1-alkynylphosphonate or diethyl (1-cyano-2,2bismethylsulfanylvinyl)phosphonate. These novel syntheses give access to higher diversity on the 1,5,2-diazaphosphinines scaffolds which may prove useful for future design of HCV polymerase inhibitors.
4.
(a) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529-2591. (b) Virieux, D.; Volle, J.-N.; Balalara, N.; Pirat, J.-L. Top. Curr. Chem. 2015, 360, 39-114. (c) Elliot, T. S.; Slowey, A.; Ye, Y.; Conway, S. J. Med. Chem. Commun. 2012, 3, 735-751. (d) Pierra-Rouviere, C.; Amador, A.; Badaroux, E.; Convard, T.; Da Costa, D.; Dukhan, D.; Griffe, L.; Griffon, J-F.; LaColla, M.; Leroy, F.; Liuzzi, M.; Loi, A.G.; McCarville, J.; Mascia, V.; Milhau, J.; Onidi, L.; Paparin, J-L.; Rahali, R.; Sais, E.; Seifer, M.; Surleraux, D.; Standring, D.; Dousson, C. Bioorg. & Med. Chem. Let. 2016, 26, 4536-4541. (e) for more interest in phosphorus molecules see: Smith, B. R.; Eastman, C. M.; Njardarson, J. T. J. Med. Chem. 2014, 57, 9764-9773. Silvestri, R.; Artico, M.; De Martino, G., La Regina, G.; Loddo, R.; La Colla, M.; La Colla J. Med. Chem. 2004, 47, 3892-3896. (a) Alexandre, F.-R.; Amador, A.; Bot, S.; Caillet, C.; Convard, T.; Jakubik, J.; Musiu, C.; Poddesu, B.; Vargiu, L.; Liuzzi, M. ; Roland, A. ; Seifer, M. ; Standring, D. ; Storer, R. ; Dousson, C. B. J. Med. Chem. 2014, 54, 392-395. (b) Dousson, C.; Alexandre, F.-R.; Amador, A.; Bonaric, S.; Bot, S.; Caillet, C.; Convard, T.; Da Costa, D.; Lioure, M.-P.; Roland, A.; Rosinovsky, E.; Maldonado, S.; Parsy, C.; Trochet, C.; Storer, R.; Stewart, A.; Wang, J.; Mayes, B.A.; Musiu, C.; Poddesu, B.; Vargiu, L.; Liuzzi, M.; Moussa, A.; Jakubik, J.; Hubbard, L.; Seifer, M.; Standring, D. J. Med. Chem. 2016, 59, 18911898. (a) Hendricks, R. T.; Spencer, S. R.; Blake, J. F.; Fell, J. B.; Fischer, J. P.; Stengel, P. J.; Leveque, V. J.P.; LePogam, S.; Rajyaguru, S.; Najera, I.; Josey, J. A.; Swallow, S. Bioorg. and Med. Chem. Lett. 2009, 19, 410-414. (b) Wang, G.; Zhang, L.; Wu, X.; Das, D.; Ruhrmund, D.; Hooi, L.; Misialek, S.; Ravi R.; Buckman, B. O.; Kossen, K.; Seiwert, S. D.; Beigelman, L. Bioorg. and Med. Chem. Lett. 2009, 19, 4484-4487. (c) Wang, G.; Lei, H.; Wang, X.; Das, D.; Hong, J.; Mackinnon, C. H.; Coulter, T. S.; Montalbetti, C. A. G. N.; Mears, R.; Gai, X.; Bailey, S. E.; Ruhrmund, D.; Hooi, L.; Misialek, S.; Rajagopalan, P. T. R.; Cheng, R. K.Y.; Barker, J. J.; Felicetti, B.; Schoenfeld, D. L.; Stoycheva, A.; Buckman, B. O.; Kossen, K.; Seiwert, S. D.; Beigelman, L. Bioorg. and Med. Chem. Lett. 2009, 19, 4480-4483. (d) Wang, G.; He, Y.; Sun, J.; Das, D.; Hu, M.; Huang, J.; Ruhrmund, D.; Hooi, L.; Misialek, S.; Ravi, R.; Stoycheva, A.; Buckman, B. O.; Kossen, K.; Seiwert, S. D.; Beigelman, L. Bioorg. and Med. Chem. Lett. 2009, 19, 44764479. (e) Shaw, A. N.; Tedesco, R.; Bambal, R.; Chai, D.; Concha, N. O.; Darcy, M. G.; Dhanak, D.; Duffy, K. J.; Fitch, D. M.; Gates, A.; Johnston, V. K.; Keenan, R. M.; Lin-Goerke, J.; Liu, N.; Sarisky, R. T.; Wiggall, K. J.; Zimmerman, M. N. Bioorg. and Med. Chem. Lett. 2009, 19, 4350-4353. (f) Randolph, J. T.; Flentge, C. A.; Huang, P. P.; Hutchinson, D. K.; Klein, L. L.; Lim, H. B.; Mondal, R.; Reisch, T.; Montgomery, D. A.; Jiang, W. W.; Masse, S. V.; Hernandez, L. E.; Henry, R. F.; Liu, Y.; Koev, G.; Kati, W. M.; Stewart, K. D.; Beno, D. W. A.; Molla, A.; Kempf, D. J. J. of Med. Chem. 2009, 52, 3174-3183. (g) Wagner, R.; Larson, D. P.; Beno, D. W. A.; Bosse, T. D.; Darbyshire, J. F.; Gao, Y.; Gates, B. D.; He, W.; Henry, R. F.; Hernandez, L. E.; Hutchinson, D. K.; Jiang, W. W.; Kati, W. M.; Klein, L. L.; Koev, G.; Kohlbrenner, W.; Krueger, A. C.; Liu, J.; Liu, Y.; Long, M. A.; Maring, C. J.; Masse, S. V.; Middleton, T.; Montgomery, D. A.; Pratt, J. K.; Stuart, P.; Molla, A.; Kempf, D. J. J. Med. Chem. 2009, 52, 1659-1669. (h) Li, L.-S.; Zhou, Y.; Murphy, D. E.; Stankovic, N.; Zhao, J.; Dragovich, P. S.; Bertolini, T.; Sun, Z.; Ayida, B.; Tran, C. V.; Ruebsam, F.; Webber, S. E.; Shah, A. M.; Tsan, M.; Showalter, R. E.; Patel, R.; LeBrun, L. A.; Bartkowski, D. M.; Nolan, T. G.; Norris, D. A.; Kamran, R.; Brooks, J.; Sergeeva, M. V.; Kirkovsky, L.; Zhao, Q.; Kissinger, C. R. Bioorg. and Med. Chem. Lett. 2008, 18, 34463455. (i) Hutchinson, D. K.; Rosenberg, T.; Klein, L. L.; Bosse,
4
Tetrahedron Letters
5. 6.
7. 8.
9.
10.
11.
12.
13.
T. D.; Larson, D.l P.; He, W.; Jiang, W. W.; Kati, W. M.; Kohlbrenner, W. E.; Liu, Y.; Masse, S. V.; Middleton, T.; Molla, A.; Montgomery, D. A.; Beno, D. W. A.; Stewart, K. D.; Stoll, V. S.; Kempf, D. J. Bioorg. and Med. Chem. Lett. 2008, 18, 3887-3890. Choo, Q. L.; Kuo, G.; Weiner, A. J.; Overby, L. R.; Bradley, D. W.; Houghton, M. Science 1989, 244, 359-362. Cohen, J. Science 1999, 285, 27. CDC hepatitis C Fact Sheet 2003 http://www.cdc.gov/ncidod/diseases/hepatitis/c/cfact.pdf. Saito, I.; Miyamura, T.; Ohbayashi, A.; Harada, H.; Katayama, T.; Kikuchi, S.; Watanabe, Y., Koi, S.; Onji, M. Proc. Natl. Acad. Sci. USA, 1990, 87, 6547-6549. Burke, K. P.; Cox, A. L. Immunol. Res. 2010, 47, 216-217. (a) Palacios, F.; Ochoa de Retana , A. M.; Pascual, S.; López de Munain, R.; Oyarzabal, J.; Ezpeleta, J. M. Tetrahedron 2005, 61, 1087-1094. (b) Palacios, F.; Ochoa de Retana , A. M.; Pascual, S.; López de Munain, R.; Tetrahedron Lett. 2002, 53, 5917-5919. (a) Dousson, C.; Surleraux, D.; Paparin, J.-L.; Pierra, C.; Roland, A. U.S. Patent 20090081158, 2009. (b) Dousson, C.; Surleraux, D.; Roland, A.; Pierra, C.; Da Costa, D. U.S. Patent 20090060866, 2009. (a) Krueger, A. C.; Madigan, D. L.; Green, B. E.; Hutchinson, D. K.; Jiang, W. W.; Kati, W. M.; Liu, Y.; Maring, C. J.; Masse, S. V.; McDaniel, K. F.; Middleton, T. R.; Mo, H.; Molla, A.; Montgomery, D. A.; Ng, T. I.; Kempf, D. J. Bioorg. and Med. Chem. Lett. 2007, 17, 2289-2292. (b) Bosse, T. D.; Larson, D. P.; Wagner, R.; Hutchinson, D. K.; Rockway, T. W.; Kati, W. M.; Liu, Y.; Masse, S.; Middleton, T.; Mo, H.; Montgomery, D.; Jiang, W.; Koev, G.; Kempf, D. J.; Molla, A. Bioorg. and Med. Chem. Lett. 2008, 18, 568-570. (c) Donner, P. L.; Xie, Q.; Pratt, J. K.; Maring, C. J.; Kati, W.; Jiang, W.; Liu, Y.; Koev, G.; Masse, S.; Montgomery, D.; Molla, A.; Kempf, D. J. Bioorg. and Med. Chem. Lett. 2008, 18, 27352738. (d) Hutchinson, D. K.; Bellettini, J. R.; Betebenner, D. A.; Bishop, R.; Borchardt, T. B.; Bosse, T. D.; Cink, R. D.; Flentge, C. A.; Gates, B. D.; Green, B. E.; Hinman, M. M.; Huang, P. P.; Klein, L. L.; Krueger, A. C.; Larson, D. P.; Leanna, M. R.; Liu, D.; Madigan, D. L.; McDaniel, K. F. Randolph, J. T.; Rockway, T. W.; Rosenberg, T. A.; Stewart, K. D.; Stoll, V. S.; Wagner, R.; Yeung, M. C. W.O. Patent 2005019191, 2005. Darcy, M.; Dhanak, D.; Duffy, K. J.; Fitch, D. M.; Sarisky, R. T.; Shaw, A. N.; Tedesco, R.; Zimmerman, M. N. W.O. Patent 03059356, 2003. McAllister, T. E.; Nix, M. G.; Webb, M. E. Chem. Commun. 2011, 47, 1297-1299. Baumann, K.; Billich, A.; Oberhauser, B.; Voegeli-Lange, R. W.O. Patent 2008022771, 2008. Krug, H. G.; Neidlein, R.; Boese, R.; Kramer, W. Heterocycles 1995, 41, 721-740.
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Novel methods for the synthesis of 1,5,2-diazaphosphinines as potential inhibitors of HCV polymerase Daniel Da Costa, Arlène Roland and Cyril B. Dousson
Leave this area blank for abstract info.
6
Tetrahedron Letters
Highlights
Two new methods for the preparation of the 1,5,2-diazaphosphinines are described. The 1,5,2-diazaphosphinines are new HCV NS5B non-nucleoside inhibitors. The 1,5,2-diazaphosphinines are thiadiazine bioisostere.
S0040-4039(16)31531-3 http://dx.doi.org/10.1016/j.tetlet.2016.11.063 TETL 48349
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
26 September 2016 10 November 2016 15 November 2016
Please cite this article as: Da Costa, D., Roland, A., Dousson, C.B., Novel methods for the synthesis of 1,5,2diazaphosphinines as potential inhibitors of HCV polymerase, Tetrahedron Letters (2016), doi: http://dx.doi.org/ 10.1016/j.tetlet.2016.11.063
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Tetrahedron Letters
Novel methods for the synthesis of 1,5,2-diazaphosphinines as potential inhibitors of HCV polymerase Daniel Da Costa a,, Arlène Roland b,† and Cyril B. Dousson a a
Idenix-an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France.
b
elementary School Former Idenix employee.
†
A RT I C L E I N F O
A BS T RA C T
Article history: Received Received in revised form Accepted Available online
Two new methods for the preparation of 1,5,2-diazaphosphinines are described. The first approach involves the reaction between an amidine and an alkynylphosphonate in basic media. The second route involves the reaction between an amidine and a dithioketene acetal phosphonate in basic media. The 1,5,2-diazaphosphinines targets were synthesised for a HCV polymerase inhibitor program. 2016 Elsevier Ltd. All rights reserved .
Keywords: Hepatitis C virus 1,5,2-Diazaphosphinines NS5B Non-nucleoside inhibitors Thiadiazine bioisostere Allosteric inhibitors
Introduction Structural modification in medicinal chemistry is commonly used to refine the efficiency of a drug. One of the most efficient tool in drug design is the concept of bioisosteres1. Bioisosteres are constituted by different functions compared to the original group but they show close biological response allowing different selectivity, potency and physical properties such as polarity, pKa or solubility. These differences may drive the improvement of biological activity and lead to new intellectual properties. A lot of functions or components were exploited as bioisosteres and phosphorus based ones proved the potential of such derivatives. In this context, several phosphorus derivatives led to original drugs with improved biological response as already reported in antiviral medecines. Consequently, different Non-Nucleoside Reverse Transcriptase Inhibitors programs were developed replacing sulfonyl2 group by a phosphonyl bioisostere3. In this context, the purpose of our work was to substitute the sulfur atom in benzothiadiazines4 (Scheme 1), well known as Hepatitis C virus (HCV) polymerase inhibitors, by a phosphonyl group to form phosphadiazines or 1,5,2-diazaphosphinines analogues. Hepatitis C virus (HCV) has been known as a flaviviridae virus family since 19895 and causes at least a substantial proportion of post-transfusion hepatitis and of sporadic acute hepatitis. HCV has infected approximately 170 million people worldwide and 10,000 people die annually in the United States from HCV liver diseases, such as liver failure, cirrhosis and
———
hepatocellular carcinoma6. This virus became a major public health problem with around four more million infected people each year. Furthermore, morbidity and mortality rates from chronic HCV infection are projected to double in this decade and may surpass those of human immunodeficiency virus 7. Thus, with the potential emergence of a resistant virus and the side effects related to treatment, new potent and safe therapies are still useful to help eradicate this disease. The key step for the synthesis of 1,5,2-diazaphosphinines 1 is the formation of the P-N intracyclic bond. Different previously published procedures were evaluated to obtain the desired scaffold8,9. The cyclisation methods (Figure 1) were realised by different reactions from primary enamine phosphonates and from nitriles or isocyanates (Figure 1: route a and route b), from phosphite and from o-bromoarylamidine (Figure 1: route c), from primary enamine phosphonates and from dithioketene acetal (Figure 1: route f), from 1-alkynylphosphonate and from amidine (Figure 1: route e), and finally from dithioketene acetal phosphonate and from amidine (Figure 1: route d). The last two methods have not yet been described but have been developed in spite of all the previous methods in order to access a greater diversity on these phosphorylated heterocycles. The first synthesis of 1,5,2-diazaphosphinines 1 was reported by Palacios et al.8 through a reaction from primary enamine phosphonates obtained from phosphonates, and nitriles (Figure 1: route a and route b). The phosphonyl group was used to replace a carbonyl group in a heterocycle. Thus, initially 1,5,2-
Corresponding author. Tel.: +33(0)499522252; fax: +33(0)499522250; e-mail: [email protected]
2
Tetrahedron Letters
diazaphosphinines were synthesised to mimic pyrimidone and pyrimidine rings which are frequently used in medicinal chemistry.
a
b
f
c
1
Benzothiadiazines
e
This work
d
Figure 1. General structure of benzothiadiazines and general retrosynthetic pathways for making 1,5,2-diazaphosphinines and derivatives.
Synthesis of phosphadiazines Recently, three syntheses were described in patents9. All of them used phosphonoaniline derivatives to synthesize phosphadiazines (Figure 1: route a, route c and route f). The first reported route was the addition of bromoanilines 3 to nitriles 2 in the presence of trimethyl aluminium. Then, the amidinoaryl bromide 4 was coupled with trialkyl phosphite in the presence of palladium acetate in acetonitrile to give phosphonate 5. Phosphadiazines 6 were obtained by intramolecular cyclisation which occurred while heating in dimethylacetamide under microwave irradiation at 200°C for 4.5 hours (Scheme 1).
(Scheme 3). First, phosphonoaniline 11 reacted with dithioketene acetal 10 in dioxane at 80°C giving the intermediate 12. Then, ammonia (gas) was added and the reaction mixture was heated at 100°C in a sealed tube to afford the amidine 13 which cyclised to the final phosphadiazine 14. i, ii
10
14
11
i
ii
12 2
3
i
13
Scheme 3. Synthesis of phosphadiazines. Conditions and reagents: (i) dioxane, 80°C; (ii) NH3 gas, 100°C, 5%-32%.
6
iii
Using this methodology, the dithioketene acetal 15 and the aniline phosphonate 16 were handled to accomplish the synthesis of the phosphadiazine 17 in 32% yield (Scheme 4).
ii
4
5
Scheme 1. Synthesis of phosphadiazines. Conditions and reagents: (i) AlMe3, dioxane, 80°C; (ii) P(OR)3, Pd(OAc)2, CH3CN, 160°C, microwave irradiation; (iii) dimethylacetamide, 200°C, microwave irradiation, 7%-60%.
i, ii
15
Another reported method was the condensation between the tetramic nitrile 7 and the phosphonoanilines 8 in the presence of trimethyl aluminium (Scheme 2). The presence of amidine 5 as a by-product suggested a two-step mechanism. The first step was the addition of aniline to nitrile to form amidine 5 followed by the cyclisation to obtain phosphadiazine 9 in 60% yield.
16
17
Scheme 4. Example of synthesis. Conditions and reagents: (i) dioxane, 80°C; (ii) NH3 gas, 100°C, 32%.
Synthesis of 1,5,2-diazaphosphinines Two original methods (Figure 1: route d and route e) consist in the reaction of amidine11 and 1-alkynylphosphonates12 or dithioketene phosphonates13. These methods were developed to introduce more diversity to the chemical structure of the targets as the other ways were not efficient enough.
i
7
8
9
Scheme 2. Synthesis of phosphadiazines from nitrile. Conditions and reagents: (i) AlMe3, dioxane, 80°C, 60%.
In some case, nitriles were not reactive enough to give the desired compound. To overcome this issue, a more reactive starting material such as a dithioketene acetal 10 4f,g,i,10 was used. The two-step reaction was carried out in one pot reaction
The 1-alkynylphosphonate 19 was synthesised12 by addition of ethynylmagnesium bromide to diisopropylphosphochloridate 18 in THF at 0°C with a yield of 30%. The amidine 20 was obtained11 by reaction of the nitrile derivative 7 with trimethylaluminium and ammonium chloride in dioxane at 85°C with a yield of 58%. The reaction of amidine 20 and 1alkynylphosphonate 19 was performed in dioxane with potassium tert-butoxide giving the Michael-type adduct which undergoes cyclisation to give the diazaphosphinine 21 (Scheme 5). Compound 21 was obtained in a 35% yield (Scheme 5) with no
substitution, but this compound can still be fonctionalized. In this case, huge chemical diversity can be introduced by activating the vinylic proton in different reactions such as halogenation and palladium-catalyzed reactions.
Acknowledgments D.D.C. thanks Drs. Jean-Laurent PAPARIN and David DUKHAN for the guidance in the writing of the article and also Sylvie CAPPELLE for editing assistance.
18
References and notes i
1.
19 ii iii
7
21
20
Scheme 5. Example of Synthesis. Conditions and reagents: (i) HC≡CMgBr, THF, 0°C, 30%; (ii) AlMe3, NH4Cl, dioxane, 80°C, 58%; (iii) tBuOK, dioxane, 80°C, 35%.
2. 3.
The last experiment to make the 1,5,2-diazaphosphinines 24 was the reaction between an amidine 20 and a dialkyl (1-cyano2,2-bismethylsulfanylvinyl)phosphonate such as the diethyl (1cyano-2,2-bismethylsulfanylvinyl)phosphonate 23 (Scheme 6). The amidine 20 was made as described in Scheme 5 and the diethyl (1-cyano-2,2-bismethylsulfanylvinyl)phosphonate 23 was prepared from the diethyl cyanomethylphosphonate 22 as described in the literature13. The reaction between the amidine 20 and the diethyl (1-cyano2,2-bismethylsulfanylvinyl)phosphonate 23 was carried out in dioxane with potassium tert-butoxide at room temperature overnight to synthetise 24 in a 40% yield (Scheme 6). In this case, chemical diversity can be introduced by using different reactions to the cyano group or the methylthio group.
22
i
23 ii
20
24
Scheme 6. Example of synthesis. Conditions and reagents: (i) NaH, CS2, MeI, THF, room temperature, 64%; (ii) tBuOK, dioxane, 80°C, 40%.
Conclusion In conclusion, two new strategies for the syntheses of 1,5,2diazaphosphinines were successfully developed from amidine and 1-alkynylphosphonate or diethyl (1-cyano-2,2bismethylsulfanylvinyl)phosphonate. These novel syntheses give access to higher diversity on the 1,5,2-diazaphosphinines scaffolds which may prove useful for future design of HCV polymerase inhibitors.
4.
(a) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529-2591. (b) Virieux, D.; Volle, J.-N.; Balalara, N.; Pirat, J.-L. Top. Curr. Chem. 2015, 360, 39-114. (c) Elliot, T. S.; Slowey, A.; Ye, Y.; Conway, S. J. Med. Chem. Commun. 2012, 3, 735-751. (d) Pierra-Rouviere, C.; Amador, A.; Badaroux, E.; Convard, T.; Da Costa, D.; Dukhan, D.; Griffe, L.; Griffon, J-F.; LaColla, M.; Leroy, F.; Liuzzi, M.; Loi, A.G.; McCarville, J.; Mascia, V.; Milhau, J.; Onidi, L.; Paparin, J-L.; Rahali, R.; Sais, E.; Seifer, M.; Surleraux, D.; Standring, D.; Dousson, C. Bioorg. & Med. Chem. Let. 2016, 26, 4536-4541. (e) for more interest in phosphorus molecules see: Smith, B. R.; Eastman, C. M.; Njardarson, J. T. J. Med. Chem. 2014, 57, 9764-9773. Silvestri, R.; Artico, M.; De Martino, G., La Regina, G.; Loddo, R.; La Colla, M.; La Colla J. Med. Chem. 2004, 47, 3892-3896. (a) Alexandre, F.-R.; Amador, A.; Bot, S.; Caillet, C.; Convard, T.; Jakubik, J.; Musiu, C.; Poddesu, B.; Vargiu, L.; Liuzzi, M. ; Roland, A. ; Seifer, M. ; Standring, D. ; Storer, R. ; Dousson, C. B. J. Med. Chem. 2014, 54, 392-395. (b) Dousson, C.; Alexandre, F.-R.; Amador, A.; Bonaric, S.; Bot, S.; Caillet, C.; Convard, T.; Da Costa, D.; Lioure, M.-P.; Roland, A.; Rosinovsky, E.; Maldonado, S.; Parsy, C.; Trochet, C.; Storer, R.; Stewart, A.; Wang, J.; Mayes, B.A.; Musiu, C.; Poddesu, B.; Vargiu, L.; Liuzzi, M.; Moussa, A.; Jakubik, J.; Hubbard, L.; Seifer, M.; Standring, D. J. Med. Chem. 2016, 59, 18911898. (a) Hendricks, R. T.; Spencer, S. R.; Blake, J. F.; Fell, J. B.; Fischer, J. P.; Stengel, P. J.; Leveque, V. J.P.; LePogam, S.; Rajyaguru, S.; Najera, I.; Josey, J. A.; Swallow, S. Bioorg. and Med. Chem. Lett. 2009, 19, 410-414. (b) Wang, G.; Zhang, L.; Wu, X.; Das, D.; Ruhrmund, D.; Hooi, L.; Misialek, S.; Ravi R.; Buckman, B. O.; Kossen, K.; Seiwert, S. D.; Beigelman, L. Bioorg. and Med. Chem. Lett. 2009, 19, 4484-4487. (c) Wang, G.; Lei, H.; Wang, X.; Das, D.; Hong, J.; Mackinnon, C. H.; Coulter, T. S.; Montalbetti, C. A. G. N.; Mears, R.; Gai, X.; Bailey, S. E.; Ruhrmund, D.; Hooi, L.; Misialek, S.; Rajagopalan, P. T. R.; Cheng, R. K.Y.; Barker, J. J.; Felicetti, B.; Schoenfeld, D. L.; Stoycheva, A.; Buckman, B. O.; Kossen, K.; Seiwert, S. D.; Beigelman, L. Bioorg. and Med. Chem. Lett. 2009, 19, 4480-4483. (d) Wang, G.; He, Y.; Sun, J.; Das, D.; Hu, M.; Huang, J.; Ruhrmund, D.; Hooi, L.; Misialek, S.; Ravi, R.; Stoycheva, A.; Buckman, B. O.; Kossen, K.; Seiwert, S. D.; Beigelman, L. Bioorg. and Med. Chem. Lett. 2009, 19, 44764479. (e) Shaw, A. N.; Tedesco, R.; Bambal, R.; Chai, D.; Concha, N. O.; Darcy, M. G.; Dhanak, D.; Duffy, K. J.; Fitch, D. M.; Gates, A.; Johnston, V. K.; Keenan, R. M.; Lin-Goerke, J.; Liu, N.; Sarisky, R. T.; Wiggall, K. J.; Zimmerman, M. N. Bioorg. and Med. Chem. Lett. 2009, 19, 4350-4353. (f) Randolph, J. T.; Flentge, C. A.; Huang, P. P.; Hutchinson, D. K.; Klein, L. L.; Lim, H. B.; Mondal, R.; Reisch, T.; Montgomery, D. A.; Jiang, W. W.; Masse, S. V.; Hernandez, L. E.; Henry, R. F.; Liu, Y.; Koev, G.; Kati, W. M.; Stewart, K. D.; Beno, D. W. A.; Molla, A.; Kempf, D. J. J. of Med. Chem. 2009, 52, 3174-3183. (g) Wagner, R.; Larson, D. P.; Beno, D. W. A.; Bosse, T. D.; Darbyshire, J. F.; Gao, Y.; Gates, B. D.; He, W.; Henry, R. F.; Hernandez, L. E.; Hutchinson, D. K.; Jiang, W. W.; Kati, W. M.; Klein, L. L.; Koev, G.; Kohlbrenner, W.; Krueger, A. C.; Liu, J.; Liu, Y.; Long, M. A.; Maring, C. J.; Masse, S. V.; Middleton, T.; Montgomery, D. A.; Pratt, J. K.; Stuart, P.; Molla, A.; Kempf, D. J. J. Med. Chem. 2009, 52, 1659-1669. (h) Li, L.-S.; Zhou, Y.; Murphy, D. E.; Stankovic, N.; Zhao, J.; Dragovich, P. S.; Bertolini, T.; Sun, Z.; Ayida, B.; Tran, C. V.; Ruebsam, F.; Webber, S. E.; Shah, A. M.; Tsan, M.; Showalter, R. E.; Patel, R.; LeBrun, L. A.; Bartkowski, D. M.; Nolan, T. G.; Norris, D. A.; Kamran, R.; Brooks, J.; Sergeeva, M. V.; Kirkovsky, L.; Zhao, Q.; Kissinger, C. R. Bioorg. and Med. Chem. Lett. 2008, 18, 34463455. (i) Hutchinson, D. K.; Rosenberg, T.; Klein, L. L.; Bosse,
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5. 6.
7. 8.
9.
10.
11.
12.
13.
T. D.; Larson, D.l P.; He, W.; Jiang, W. W.; Kati, W. M.; Kohlbrenner, W. E.; Liu, Y.; Masse, S. V.; Middleton, T.; Molla, A.; Montgomery, D. A.; Beno, D. W. A.; Stewart, K. D.; Stoll, V. S.; Kempf, D. J. Bioorg. and Med. Chem. Lett. 2008, 18, 3887-3890. Choo, Q. L.; Kuo, G.; Weiner, A. J.; Overby, L. R.; Bradley, D. W.; Houghton, M. Science 1989, 244, 359-362. Cohen, J. Science 1999, 285, 27. CDC hepatitis C Fact Sheet 2003 http://www.cdc.gov/ncidod/diseases/hepatitis/c/cfact.pdf. Saito, I.; Miyamura, T.; Ohbayashi, A.; Harada, H.; Katayama, T.; Kikuchi, S.; Watanabe, Y., Koi, S.; Onji, M. Proc. Natl. Acad. Sci. USA, 1990, 87, 6547-6549. Burke, K. P.; Cox, A. L. Immunol. Res. 2010, 47, 216-217. (a) Palacios, F.; Ochoa de Retana , A. M.; Pascual, S.; López de Munain, R.; Oyarzabal, J.; Ezpeleta, J. M. Tetrahedron 2005, 61, 1087-1094. (b) Palacios, F.; Ochoa de Retana , A. M.; Pascual, S.; López de Munain, R.; Tetrahedron Lett. 2002, 53, 5917-5919. (a) Dousson, C.; Surleraux, D.; Paparin, J.-L.; Pierra, C.; Roland, A. U.S. Patent 20090081158, 2009. (b) Dousson, C.; Surleraux, D.; Roland, A.; Pierra, C.; Da Costa, D. U.S. Patent 20090060866, 2009. (a) Krueger, A. C.; Madigan, D. L.; Green, B. E.; Hutchinson, D. K.; Jiang, W. W.; Kati, W. M.; Liu, Y.; Maring, C. J.; Masse, S. V.; McDaniel, K. F.; Middleton, T. R.; Mo, H.; Molla, A.; Montgomery, D. A.; Ng, T. I.; Kempf, D. J. Bioorg. and Med. Chem. Lett. 2007, 17, 2289-2292. (b) Bosse, T. D.; Larson, D. P.; Wagner, R.; Hutchinson, D. K.; Rockway, T. W.; Kati, W. M.; Liu, Y.; Masse, S.; Middleton, T.; Mo, H.; Montgomery, D.; Jiang, W.; Koev, G.; Kempf, D. J.; Molla, A. Bioorg. and Med. Chem. Lett. 2008, 18, 568-570. (c) Donner, P. L.; Xie, Q.; Pratt, J. K.; Maring, C. J.; Kati, W.; Jiang, W.; Liu, Y.; Koev, G.; Masse, S.; Montgomery, D.; Molla, A.; Kempf, D. J. Bioorg. and Med. Chem. Lett. 2008, 18, 27352738. (d) Hutchinson, D. K.; Bellettini, J. R.; Betebenner, D. A.; Bishop, R.; Borchardt, T. B.; Bosse, T. D.; Cink, R. D.; Flentge, C. A.; Gates, B. D.; Green, B. E.; Hinman, M. M.; Huang, P. P.; Klein, L. L.; Krueger, A. C.; Larson, D. P.; Leanna, M. R.; Liu, D.; Madigan, D. L.; McDaniel, K. F. Randolph, J. T.; Rockway, T. W.; Rosenberg, T. A.; Stewart, K. D.; Stoll, V. S.; Wagner, R.; Yeung, M. C. W.O. Patent 2005019191, 2005. Darcy, M.; Dhanak, D.; Duffy, K. J.; Fitch, D. M.; Sarisky, R. T.; Shaw, A. N.; Tedesco, R.; Zimmerman, M. N. W.O. Patent 03059356, 2003. McAllister, T. E.; Nix, M. G.; Webb, M. E. Chem. Commun. 2011, 47, 1297-1299. Baumann, K.; Billich, A.; Oberhauser, B.; Voegeli-Lange, R. W.O. Patent 2008022771, 2008. Krug, H. G.; Neidlein, R.; Boese, R.; Kramer, W. Heterocycles 1995, 41, 721-740.
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Novel methods for the synthesis of 1,5,2-diazaphosphinines as potential inhibitors of HCV polymerase Daniel Da Costa, Arlène Roland and Cyril B. Dousson
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6
Tetrahedron Letters
Highlights
Two new methods for the preparation of the 1,5,2-diazaphosphinines are described. The 1,5,2-diazaphosphinines are new HCV NS5B non-nucleoside inhibitors. The 1,5,2-diazaphosphinines are thiadiazine bioisostere.