Article pubs.acs.org/OPRD
Practical Synthesis of A Benzophenone-Based NNRT Inhibitor of HIV-1 Xiao-jun Wang,*,† Li Zhang,† Xiufeng Sun,† Heewon Lee,† Dhileepkumar Krishnamurthy,† Jeff A. O’Meara,‡ Serge Landry,‡ Christiane Yoakim,‡ Bruno Simoneau,‡ Nathan K. Yee,† and Chris H. Senanayake† †
Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877, United States Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard Street, Laval, Québec H7S 2G5, Canada
‡
S Supporting Information *
ABSTRACT: A convergent synthesis of NNRTI 1 is described. The key step involves a direct coupling of acid chloride 4 with Grignard reagent 11 in the presence of bis[2-(N,N-dimethylamino)ethyl] ether that moderates the reactivity of the Grignard reagent to give benzophenone 7. An efficient 2-step process for the preparation of 2-fluoro-3-methyl-4-aminobenzoic acid (3) is also described.
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INTRODUCTION Non-nucleoside reverse transcriptase inhibitors (NNRTI) represent an important class of agents for the treatment of HIV infections and AIDS.1 Benzophenone-based NNRTIs have emerged as effective second generation inhibitors exhibiting high potency against both wild-type and resistant strains of the virus.2 Recently, our drug discovery program produced a series of novel and potent benzophenone-based NNRTIs such as candidate 1 (Scheme 1), and we were interested in developing an efficient process for 1 on pilot plant scale.
Scheme 2. Initial Synthesis of 1
Scheme 1. Retrosynthetic Analysis of 1
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RESULTS AND DISCUSSION We investigated several approaches for the construction of benzophenone 7. Friedel−Crafts reaction between 4-chloroanisole and acid chloride 4 in the presence of various Lewis acids gave 7 only in low yield. Similarly, Fries reaction of benzoate 10 produced phenolic benzophenone 2 in 200 °C (decomposed); 1H NMR (400 MHz, DMSO-d6) 9.52 (s, 1H), 7.66 (t, J = 8.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 2.72 (m, 1H), 2.11 (d, J = 2.4 Hz, 3H), 1.12 (d, J = 6.8 Hz, 6H); 13C NMR (400 MHz, DMSOd6) 175.6, 165.0 (d, J = 3.0 Hz), 159.6 (d, J = 253.0 Hz), 142.1 (d, J = 7.0 Hz), 128.6 (d, J = 2.0 Hz), 119.7 (d, J = 3 0.0 Hz), 119.4 (d, J = 18.0 Hz), 115.0 (d, J = 2.0 Hz), 34.4, 19.4, 9.6 (d, J = 6.0 Hz); HRMS calcd for C12H14FNO3 [M + H]+: 240.1030, Found: 240.1033. A small amount of 18b was isolated by flash chromatography on silica gel: mp 129−130 °C; 1 H NMR (400 MHz, MeOD-d4) 7.17 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 8.4 Hz, 1H), 2.71 (m, 1H), 2.14 (d, J = 2.0 Hz, 3H), 1.24 (d, J = 6.8 Hz, 6H); 13C NMR (400 MHz, MeOD-d4) 179.1, 162.8 (d, J = 241.0 Hz), 138.8 (d, J = 6.0 Hz), 127.7 (d, J = 10.0 Hz), 123.0 (d, J = 3 0.0 Hz), 122.3 (d, J = 18.0 Hz), 113.8 (d, J = 13.0 Hz), 36.5, 20.0, 9.9 (d, J = 5.0 Hz); HRMS calcd for C11H14FNO [M + H]+: 196.1132, Found: 196.1140. 565
dx.doi.org/10.1021/op200301h | Org. Process Res. Dev. 2012, 16, 561−566
Organic Process Research & Development
Article
2-methyl-3-fluoroaniline (19) (81%) and the 4-deuterium analogue of 19 (19%) was obtained which evidenced the internal quench of the resulting magnesium species by the active acetyl protons. (11) A gelatinous mixture was formed once the analogues trimethylacetamide and benzamide of 17, both lacking acidic αprotons, were treated with p-tolMgCl in THF. The insufficient stirring of the mixture was considered to be not scalable. (12) For an example, see: Beinker, P.; Hanson, J. R.; Meindl, N.; Rodriguez Medina, I. C. J. Chem. Res., Synop. 1998, 204−205. (13) For an example, see: Ma, D.; Xia, C.; Jiang, J.; Zhang, J.; Tang, W. J. Org. Chem. 2003, 68, 442−451. (14) Zhang, L.; Wang, X.-j.; Wang, J.; Grinberg, N.; Krishnamurthy, D.; Senanayake, C. H. Tetrahedron Lett. 2009, 50, 2964−2966.
(d, J = 7.4 Hz), 140.8, 140.7 (d, J = 6.8 Hz), 133.7, 131.0, 130.9 (dq, J = 7.9, 33.0 Hz), 129.8 (d, J = 2.8 Hz), 128.5, 126.3, 124.4, 122.7 (dq, J = 2.6, 270.1 Hz), 120.9 (m), 119.3 (d, J = 22.5), 116.3 (dd, J = 3.1, 25.2 Hz), 113.6 (d, J = 19.0 Hz), 111.1, 110.8 (d, J = 11.2 Hz), 8.5 (d, J = 11.8 Hz); HRMS calcd for C22H13F5ClNO3 [M + H]+: 470.0582, Found: 470.0582.
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ASSOCIATED CONTENT
S Supporting Information *
1
H/13C NMR spectra for 1−3, 7, 9, 9a−b, 14−16, 17, 17a−b, 18, 18a−b, and 21−26. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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REFERENCES
(1) (a) Koup, R. A.; Merluzzi, V. J.; Hargrave, K. D.; Adams, J.; Grozinger, K.; Eckmer, R. J.; Sullivan, J. L. J. Infect. Dis. 1991, 163, 966−970. (b) Freimuth, W. W. Adv. Exp. Med. Biol. 1996, 394, 279− 289. (c) Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.; Lumma, W. C.; Lyle, T. A.; Huff, J. R.; Anderson, P. S.; Olsen, D. B.; Carroll, S. S.; Pettibone, D. J.; O’Brien, J. A.; Ball, R. G.; Balani, S. K.; Lin, J. H.; Chen, I.-W.; Schleif, W. A.; Sardana, V. V.; Long, W. J.; Byrnes, V. W.; Emini, E. A. Antimicrob. Agents Chemother. 1995, 39, 2602−2605. (2) (a) Wyatt, P. G.; Bethell, R. C.; Cammack, N.; Charon, D.; Dodic, N.; Dumaitre, B.; Evans, D. N.; Green, D. V. S.; Hopewell, P. L.; Humber, D. C.; Lamont, R. B.; Orr, D. C.; Plested, S. J.; Ryan, D. M.; Sollis, S. L.; Storer, R.; Weingarten, G. G. J. Med. Chem. 1995, 38, 1657−1665. (b) Romines, K. R.; Freeman, G. A.; Schaller, L. T.; Cowan, J. R.; Gonzales, S. S.; Tidwell, J. H.; Andrews, C. W. III; Stammers, D. K.; Hazen, R. J.; Ferris, R. G.; Short, S. A.; Chan, J. H.; Boone, L. R. J. Med. Chem. 2006, 49, 727−739. (c) Chan, J. H.; Freeman, G. A.; Tidwell, J. H.; Romines, K. R.; Schaller, L. T.; Cowan, J. R.; Gonzales, S. S.; Lowell, G. S.; Andrews, C. W. III; Reynolds, D. J.; St. Clair, M.; Hazen, R. J.; Ferris, R. G.; Creech, K. L.; Roberts, G. B.; Short, S. A.; Weaver, K.; Koszalka, G. W.; Boone, L. R. J. Med. Chem. 2004, 47, 1175−1182. (3) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815− 3818. (b) O’Meara, J. A.; Yoakim, C.; Simoneau, B. US 2006/ 0025480A1. (4) For examples of Fries rearrangement, see: (a) Olah, G. A.; Arvanaghi, M.; Krishnamurthy, V. V. J. Org. Chem. 1983, 48, 3359− 3360. (b) Khanum, S. A.; Murari, S. K.; Vishwanth, B. S.; Shashikanth, S. Bioorg. Med. Chem. Lett. 2005, 15, 4100−4104. (c) Martin, R.; Demerseman, P. Synthesis 1992, 738−740. (5) Wang, X.-j.; Zhang, L.; Sun, X.; Xu, Y.; Krishnamurthy, D.; Senanayake, C. H. Org. Lett. 2005, 7, 5593−5595. (6) Leazer, J. L. Jr.; Cvetovich, R.; Tsay, F.-R.; Dolling, U.; Vickery, T.; Bachert, D. J. Org. Chem. 2003, 68, 3695−3698 and references cited therein. (7) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3th ed.; Wiley-Interscience: 1999; pp 23−27. (8) Varchi, G.; Kofink, C.; Lindsay, D. M.; Ricci, A.; Knochel, P. Chem. Commun. 2003, 396−397. (9) For a review of halogen-metal exchange with iPrMgCl, see: Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302−4320. (10) The trideuterium-acetamide of 9 was subjected to the successive addition of p-tolMgCl (10 min) and iPrMgCl (20 min) followed by MeOH quench. After saponification with aqueous NaOH, a mixture of 566
dx.doi.org/10.1021/op200301h | Org. Process Res. Dev. 2012, 16, 561−566
