Letter pubs.acs.org/OrgLett
A Highly Concise and Convergent Synthesis of HCV Polymerase Inhibitor Deleobuvir (BI 207127): Application of a One-Pot Borylation−Suzuki Coupling Reaction Yongda Zhang,*,† Bruce Z. Lu,*,⊥ ,† Guisheng Li,† Sonia Rodriguez,† Jonathan Tan,† Han-Xun Wei,† Jianxiu Liu,† Frank Roschangar,† Fei Ding,† Wenyi Zhao,† Bo Qu,† Diana Reeves,† Nelu Grinberg,† Heewon Lee,† Golo Heckmann,‡ Oliver Niemeier,‡ Michael Brenner,‡ Youla Tsantrizos,§ Pierre L. Beaulieu,§ Azad Hossain,† Nathan Yee,† Vittorio Farina,⊥ and Chris H. Senanayake† †
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States ‡ Boehringer Ingelheim GmbH & Co KG, Binger Strasse 173, 55216 Ingelheim am Rhein, Germany § Research and Development, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada S Supporting Information *
ABSTRACT: A highly concise and convergent synthesis of HCV polymerase inhibitor Deleobuvir (BI 207127, 1) was achieved, featuring efficient Pd-catalyzed one-pot borylation−Suzuki coupling where TFP was identified as the unique ligand effective for these transformations.
T
he Hepatitis C virus (HCV) is a major global public health problem. It is estimated that approximately 3% of the global population are chronically infected with HCV.1 Chronic HCV infections2 are responsible for an estimated 96 000 deaths per year and also are the leading cause of liver transplantation in industrialized nations. To address this growing medical need, significant efforts have been directed, over the past two decades, to the development of novel chemotherapies for treatment of HCV infections. Deleobuvir (BI 207127, 1, Figure 1), a highly effective HCV polymerase inhibitor, is currently in phase III clinical trials at Boehringer Ingelheim.3 In order to support the clinical trials and potential market demands, an efficient and scalable
chemical synthesis is required. Herein we report a concise and convergent synthesis 1 featuring the Pd-catalyzed one-pot sequential borylation−Suzuki coupling. Our retrosynthetic analysis of 1 is outlined in Scheme 1. We envisioned that 1 could be accessed from cyclobutyl amine 2 and indole carboxylic acid 3 through amide bond formation. The amine 2 could be assembled from diamine 4 and cyclobutyl amino acid 5 via benzimidazole formation. The key intermediate 2,3-disubstituted indole 3 could be derived from indole 6, which could be accessible from readily available indole carboxylic acid 7 and cyclopentanone. Functionalized indoles exist in abundant natural products and synthetic compounds with vital medicinal value.4 Given their prevalence and importance, numerous elegant methodologies for their synthesis have been constantly emerging over the past few decades.5 However, there are still some challenges in achieving the regioselective synthesis of 2,3-disubstituted indoles such as 3 in a practical and efficient manner.
Figure 1. Polymerase inhibitor Deleobuvir (BI 207127, 1).
Received: July 17, 2014 Published: August 8, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol5021114 | Org. Lett. 2014, 16, 4558−4561
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Scheme 1. Retrosynthetic Analysis of 1
Scheme 3. Synthesis of Indole Bromide 15
The most widely used borylating agents are B2(pin)2 and PinB-H (4,4,5,5-tetramethyl-1,3,2-dioxaborolane).13 Considering that PinB-H is less expensive, atom-economical, and easily available, PinB-H was chosen for borylation. Using the literature conditions, the borylation of 15 with PinB-H gave 12 in 93% yield (Scheme 4).14 Only a small amount of Scheme 4. Initial Attempt of One-Pot Borylation−Suzuki Coupling Protocol Originally, 2,3-disubstituted indole 8 was prepared in a low yield via Stille coupling of 9 (Scheme 2).6 Alternatively, classical Scheme 2. Synthesis of 2,3-Disubstituted Indole 8
desbromo product 6 was observed in the borylation. Unfortunately, subsequent one-pot direct Suzuki coupling with 13 only furnished 2,3-substituted indole 8 in 17% yield. The major product was 16 together with a very small amount of dimer 17. Obviously, the C−Br of the desired product 8 formed in situ is more reactive than the C−I in 13 leading to the formation of 16 under these conditions.15 In order to avoid the undesired oxidative addition of Pd(0) to the C−Br bond of the desired product 8, we investigated the ligand effect on the Suzuki coupling of indole boronate 12 (Table 1). In all the cases, stable Pd(OAc)2 was employed as the Pd source. The use of t-Bu3P, Cy3P, CyJohnPhos, DtBPPF, Ph3As, and TPPTS [3,3′,3″-phosphanetriyltris(benzenesulfonic acid) trisodium salt] gave the protodeboronation product 6 predominately (Table 1, entries 1−6). With Ph3P or (p-tol)3P, 8 formed in moderate yields together with a significant amount of 6 (Table 1, entries 7−8). TFP (tri-2-furyl phosphine) as the weakly donating ligand has been widely used in the Pdcatalyzed reactions since it was identified as an exceptional ligand for the Stille coupling reactions.16 We found that TFP worked reasonably well in our case, giving a 73:22 ratio of 8 and 6 (Table 1, entry 9). Notably, the formation of 16 was negligible. Encouraged by these results, we attempted different bases to reduce the amount of 6 (Table 1, entries 10−12). Only K3PO4 gave a slightly better result. To further improve the Suzuki coupling especially with the indole boronate 12 as the limiting reagent, we investigated the
Fisher indolization unavoidably brought up the regioselectivity issues due to the 6-carboxylate substituent.7 When Larock’s indolization protocol was applied with iodoaniline 10 and alkyne 11,8 no desired product 8 was observed because Pd(0) was prone to insert across the C−Br bond in the electrondeficient pyrimidine 11 competitively with the C−I bond of 10.9 At this stage, we focused on the synthesis of 8 via the Suzuki coupling of indolyl boronate 12 and iodide 13.10 Since aryl iodides are generally more reactive than aryl bromides in Pd-catalyzed reactions, the use of 13 should enable us to prepare 5-bromo-pyrimidin-2-yl indole 8.11 In addition, the potential one-pot sequential borylation−Suzuki coupling protocol is very attractive to us with its significant advantages of potentially avoiding the isolation and purification of organoboron reagents and utilizing the same catalyst for both borylation and Suzuki coupling.12 Our work commenced from the synthesis of the bromide 15, which was efficiently prepared with a 53% overall yield from commercially available indole acid 7 (Scheme 3). Condensation of 7 with cyclopentanone followed by hydrogenation allowed us to regiospecifically introduce the cyclopentane ring at the 3position of 14. One-pot N,O-methylation with Me2CO3 produced methyl ester 6, which underwent bromination with Br2 to produce bromide 15 in 93% yield. 4559
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Table 1. Ligand Effect on the Suzuki Couplinga
Table 2. Effect of Pd/TFP Ratio on the Couplinga
entry
ligand
base
time (h)
conv
8:6:(16+17)b
1 2 3 4 5 6 7 8 9 10 11 12
t-Bu3P Cy3P CyJohnPhos DtBPPF Ph3As TPPTS Ph3P (p-tol)3P TFP TFP TFP TFP
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 Na2CO3 KOH K3PO4
1 2 1 1 4 2 14 12 4 4 2 1
99 99 92 99 99 45 72 92 98 99 99 99
1:99:0 3:95:2 3:97:0 8:92:0 13:85:2 16:83:1 50:36:14 60:30:10 73:22:5 73:23:4 25:61:14 76:17:7
entry
Pd:TFP
yield of 6b
yield of 8b
1 2 3 4 5
1:100 1:12 1:8 1:4 1:3
5 7 10 11 14
93 87 88 77 69
a Conditions: 12 (1.0 mmol), 13 (1.1 mmol), Pd(OAc)2 (3 mol %), TFP, K3PO4 (3.0 equiv, 1.67 M in H2O), DME (2.0 mL). bHPLC assay yield.
Pd(OAc)2 (Table 2, entry 4), the yield of 8 was improved from 77% to 85%. Meanwhile, the level of 6 dropped from 11% to 7%. Likewise, the use of 1.5 mol % of Pd2(dba)3 as the Pd(0) source gave an 86% yield of 8 and a 6% yield of 6. As mentioned previously, we intended to develop a one-pot borylation−Suzuki coupling. Due to the instability of methyl ester 15 upon storage,20 we switched to the more stable isopropyl ester 18. Gratifyingly, TFP also worked in the borylation of 18, affording 19 in 97% yield.21 Our studies indicated a ratio of 4:1 TFP/Pd was optimal for the borylation.22 In our one-pot borylation−Suzuki coupling, the borylation was performed with 3 mol % of Pd(OAc)2 and 12 mol % of TFP in CH3CN (Scheme 5). Once the borylation was
a
Conditions: 12 (1.0 mmol), 13 (1.1 mmol), Pd(OAc)2 (5 mol %), ligand (20 mol %), base (3.0 equiv, 1.67 M in H2O), DME (2.0 mL). b Determined by HPLC at 220 nm.
root cause of the undesired competitive reaction leading to the protodeboronation product 6. In the presence of K3PO4, 12 was relatively stable at 23 °C without Pd(OAc)2 and TFP. However, at elevated temperature, the formation of 6 increased; 25% of 6 was observed at 80 °C in 40 min. Initial results indicated that the protodeboronation seemed unavoidable under the current conditions of the Suzuki coupling. Surprisingly, complete conversion of 12 to 6 was observed in 15 min even at 23 °C in the presence of Pd(OAc)2 without TFP. Control experiments indicated that Pd(OAc)2 and the base had a synergistic effect on protodeboronation. Without the base K3PO4 and TFP, the formation of 6 was slow; the ratio of 6 and 12 was 52:48 after 8 h.17 It is known that the reduction rate of Pd(II) to Pd(0) by phosphines is highly dependent on the nature of phosphines.18 It is likely that Pd(OAc)2 is reduced very quickly to Pd(0) by TFP, which minimizes the Pd(II)-catalyzed protodeboronation.19 In the case of CyJohnPhos and other electron-rich phosphines (Table1, entries 1−4), the slow reduction of Pd(OAc)2 in their presence could be contributing to the substantial level of protodeboronation (Table 1, entry 3). At the same time, the use of a high ratio of TFP/Pd(OAc)2 might slow down Pd(II)-catalyzed protodeboronation by facilitating the reduction of Pd(II) species. Interestingly, we found that even with up to 100:1 TFP/Pd(OAc)2, the subsequent Suzuki reaction was not shut down; all Suzuki reactions were complete in 1 h (Table 2, entries 1−5). As expected, the level of 6 was reduced from 14% to 5%. Meanwhile, the formation of the dimer 17 was reduced to less than 2% and the yield of 8 was improved from 69% to 93% accordingly (Table 2, entry 1). We believe the base-promoted protodeboronation is responsible for the formation of 6. Based on our observations above, the use of preformed Pd(0) should minimize the formation of 6 in the Suzuki coupling. To verify that, we performed the Suzuki coupling with Pd(0), generated in situ by heating a mixture of 3 mol % of Pd(OAc)2 and 12 mol % of TFP in DME at 60 °C for 1 h. Upon addition of 12, 13, and aq. K3PO4, the Suzuki reaction was complete in 30 min at 80 °C. In comparison with the use of
Scheme 5. Synthesis of 3 via One-Pot Sequential Borylation−Suzuki Coupling Process
complete, the excess PinB-H was quenched with 1.0 equiv of H2O followed by the addition of a slurry of 13 in aqueous K3PO4. Under our optimized conditions, the ester 20 was isolated in 79% yield. Saponification of 20 gave 3 in 95% yield with >99% purity. The amine 2 was prepared efficiently from commercially available 2,4-dichloro-1-nitrobenzene 21 (Scheme 6). Siteselective amination with MeNH2 gave 22. Phosphine-free Pdcatalyzed Heck coupling with n-butyl acrylate in the presence of LiCl provided 23,23 which was selectively hydrogenated to give diamine 4 in 87% yield. The stable amino acid salt 5 was converted to acyl chloride 24 with PCl5 in the presence of 2oxazolidone. Direct addition of diamine 4 produced the amide intermediate, which underwent cyclization upon heating to generate the benzimidazole 2 in one pot with an 83% yield. With 2 and 3 in hand, 1 was assembled efficiently in two steps (Scheme 7). In situ generation of acyl chloride 25 from indole acid 3 with SOCl2 followed by addition of i-Pr2NEt and 4560
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Thavonekham, B.; Beaulieu, P. L.; Kukolj, G.; Tsantrizos, Y. S. J. Med. Chem. 2014, 57, 1845. (4) Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155. (b) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175. (c) KochanowskaKaramyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489. (5) (a) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Perboni, A.; Sferrazza, A.; Stabile, P. Org. Lett. 2010, 12, 3279. (b) Subba Reddy, B. V.; Reddy, M. R.; Rao, Y. G.; Yadav, J. S.; Sridhar, B. Org. Lett. 2013, 15, 464. (c) Wei, Y.; Deb, I.; Yoshikai, N. J. Am. Chem. Soc. 2012, 134, 9098. (d) Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195. (e) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (f) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215. (6) Beaulieu, P. L.; Bös, M.; Cordingley, M. G.; Chabot, C.; Fazal, G.; Garneau, M.; Gillard, J. R.; Jolicoeur, E.; LaPlante, S.; McKercher, G.; Poirier, M.; Poupart, M.-A.; Tsantrizos, Y. S.; Duan, J.; Kukolj, G. J. Med. Chem. 2012, 55, 7650. (7) (a) Fischer, E.; Jourdan, F. Chem. Ber. 1883, 16, 6. (b) Park, I.-K.; Suh, S.-E.; Lim, B.-Y.; Cho, C.-G. Org. Lett. 2009, 11, 5454. (8) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689. (b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652. (c) Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.; Farina, V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129. (d) Liu, J. X.; Shen, M.; Zhang, Y. D.; Li, G.; Khodabocus, A.; Rodriguez, S.; Qu, B.; Farina, V.; Senanayake, C. H.; Lu, B. Z. Org. Lett. 2006, 8, 3573. (e) Lu, B. Z.; Zhao, W.; Wei, H.-X.; Dufour, M.; Farina, V.; Senanayake, C. H. Org. Lett. 2006, 8, 3271. (9) Indeed, the addition of phenyl acetylene gave the Sonogashira coupling product derived from 11. Moreover, using the des-bromo analog of 11, the indolization with 10 gave a 64% yield of the expected Larock product. Conditions: (i) 5-(cyclopentylethynyl)pyrimidine (6.5 mmol), 10 (6.8 mmol), Pd(OAc)2 (5 mol %), DiPPF (10 mol %), K2CO3 (2.5 equiv), NMP (2 mL), 130 °C, 15 min; (ii) dimethyl carbonate, 100 °C, 5 h. (10) Example of Pd-catalyzed Suzuki coupling with indole boronate: (a) Cai, X.; Snieckus, V. Org. Lett. 2004, 6, 2243. (b) Tobisu, M.; Fujihara, H.; Koh, K.; Chatani, N. J. Org. Chem. 2010, 75, 4841. (11) Example of Pd-catalyzed coupling with 13: Wong, K.-T.; Lu, Y.R.; Liao, Y.-L. Tetrahedron Lett. 2001, 42, 6341. (12) Examples of one-pot sequential borylation−Suzuki reactions: (a) Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am. Chem. Soc. 2002, 124, 8001. (b) Martin, T.; Laguerre, C.; Hoarau, C.; Marsais, F. Org. Lett. 2009, 11, 3690. (c) Zhang, Y.; Gao, J.; Li, W.; Lee, H.; Lu, B. Z.; Senanayake, C. H. J. Org. Chem. 2011, 76, 6394. (13) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. (b) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62, 6458. (14) Billingsley, K. L.; Buchwald, S. L. J. Org. Chem. 2008, 73, 5589. (15) Dong, C.-G.; Hu, Q.-S. J. Am. Chem. Soc. 2005, 127, 10006. (16) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585. (b) Andersen, N. G.; Keay, B. A. Chem. Rev. 2001, 101, 997. (17) (a) The use of other Pd(II) salts including PdCl2, PdBr2, and Pd(OCOCF3)2 gave similar results. Although protodeboronation facilitated by metal ions such as Cu(II), Ag(I), and Ni(II) is reported in the literature, Pd(II)-catalyzed protodeboronation is not well documented. (b) Kuivila, H. G.; Reuwer, J. F., Jr.; Mangravite, J. A. J. Am. Chem. Soc. 1964, 86, 2666. (18) Amatore, C.; Carré, E.; Jutand, A.; M’Barki, M. A. Organometallics 1995, 14, 1818. (19) Amatore, C.; Jutand, A.; Khalilb, F. ARKIVOC 2006, iv, 38. (20) No hydrolysis of methyl ester was observed during Suzuki coupling. (21) (a) During our process development, the decomposition of 15 was extensive upon storage while the stability of 18 met our criteria. (b) The use of other solvents such as THF, 2-MeTHF, and CH3CN gave similar results. CH3CN was chosen for further optimization. (22) The use of 1:1 Pd/TFP gave a less than 5% conversion after 4 h while only a 52% conversion was observed with 1:8 Pd/TFP after 7 h. (23) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
Scheme 6. Synthesis of Amine 2
Scheme 7. Synthesis of 1
amine 2 afforded the amide 26 in 97% yield. Saponification of n-butyl ester 26 gave 1 with a 96% yield as an off-white solid. In summary, a highly concise and convergent synthesis of HCV polymerase inhibitor 1 was achieved in six chemical steps with a 70% overall yield starting from 18. The practicality and efficiency of the syntheses enabled us to produce metric tons of 1 to support a clinical program. During the course of our studies, TFP was identified as the best ligand for the one-pot sequential borylation−Suzuki coupling.
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ASSOCIATED CONTENT
S Supporting Information *
Experimental details and scanned NMR spectra of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. Present Address ⊥
Janssen Pharmaceutical, Turnhoutseweg 30, 2340 Beerse, Belgium.
Notes
The authors declare no competing financial interest.
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REFERENCES
(1) (a) Gravitz, L. Nature 2011, 474, 7350. (b) Mohd Hanafiah, K.; Groeger, J.; Flaxman, A. D.; Wiersma, S. T. Hepatology (Baltimore, Md.) 2013, 57, 1333. (2) Recently, two drugs were approved by FDA for treatment of patients with chronic hepatitis C. (a) Sovaldi was approved by US FDA on December 2013. (b) OLYSIO/Simeprevir was approved by US FDA on November 2013. (3) LaPlante, S. L.; Bös, M.; Brochu, C.; Chabot, C.; Coulombe, R.; Gillard, J. R.; Jakalian, A.; Poirier, M.; Rancourt, J.; Stammers, T.; 4561
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