Highly Regioselective and Practical Synthesis of 5-Bromo-4-chloro-3

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Highly Regioselective and Practical Synthesis of 5-Bromo-4-Chloro-3-Nitro-7-Azaindole Chong Han, Keena Green, Eugen Pfeifer, and Francis Gosselin Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00060 • Publication Date (Web): 28 Mar 2017 Downloaded from http://pubs.acs.org on March 30, 2017

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Organic Process Research & Development

Highly Regioselective and Practical Synthesis of 5Bromo-4-chloro-3-nitro-7-azaindole Chong Han,*,†, Keena Green,† Eugen Pfeifer,‡ and Francis Gosselin† †

Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San

Francisco, California 94080, United States ‡

Department of Pharma Technical Development, F. Hoffmann-La Roche AG, Grenzacherstrasse

124, CH-4070 Basel, Switzerland

ACS Paragon Plus Environment

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Abstract

We report an efficient and highly regiocontrolled route to prepare a functionalized 7-azaindole derivative– 5-bromo-4-chloro-3-nitro-7-azaindole from readily available parent 7-azaindole featuring a highly regioselective bromination of 4-chloro-3-nitro-7-azaindole intermediate. In addition to the high efficiency and excellent control of regioisomeric impurities, the process is operationally simple by isolating each product via direct crystallization from the reaction mixture with no liquid-liquid extractions or distillation steps needed. We demonstrated the route on >50 kilogram scale and 46% overall yield to provide the target product in 97% purity by HPLC, which can serve as a useful building block for the preparation of a series of 3,4,5-substituted-7azaindole derivatives.

Keywords: 7-azaindole; nitration; bromination; 3,4,5-substituted-7-azaindole; 5-bromo-4chloro-3-nitro-7-azaindole; regiocontrolled.


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Introduction Azaindoles are privileged scaffolds in drug discovery as bioisosteres for indoles and their derivatives have attracted broad interest in the pharmaceutical industry.1 7-Azaindole, in particular, has emerged as a valuable framework in the design of new kinase inhibitors for the treatment of cancer.2 In addition to the numerous 7-azaindole containing drug candidates, this heterocyclic moiety is found in approved therapeutic agents such as the B-Raf inhibitor ZelborafTM (vemurafenib)3 and B-cell lymphoma 2 (BCL2) inhibitor VenclextaTM (venetoclax)4 (Figure 1). In the course of chemical development of a kinase inhibitor in our laboratories,5 we became interested in devising an efficient synthesis of 3,4,5-substituted-7-azaindole compounds.6 We identified 5-bromo-4-chloro-3-nitro-7-azaindole (1) as a useful intermediate for the preparation of a series of 3,4,5-functionalized 7-azaindole derivatives. Examination of the literature on synthesis of 7-azaindole derivatives revealed that 5-bromo-4-chloro-7-azaindole (2) could be a readily available precursor for which two synthetic routes had been reported: one starting from 5-bromo-7-azaindole (3)7 and the other starting from 4-chloro-7-azaindole (4)8 (Scheme 1). In route I, chlorination of the corresponding N-oxide of 3 gave 2 in a modest 34% yield over 2 steps.9 In route II, 4-chloro-7-azaindole (4) was protected with N-triisopropylsilyl group prior to lithiation at C-5 under cryogenic condition followed by electrophilic bromination using carbon tetrabromide (CBr4) to afford 2 in 44% yield over 3 steps. The route required use of a protecting group, cryogenic conditions, and toxic reagents such as CBr4, which rendered itself unsuitable for synthesis on kilogram scale. Aiming to develop a robust and regiocontrolled synthesis towards 1 amenable to multi-kilogram scale, we envisioned a selective bromination of 4-chloro-3-nitro-7-azaindole (5) that can be prepared by nitration of 4 (Scheme 2). Herein, we


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report the development of the proposed route leading to 1 that has been demonstrated on over 50 kilogram scale.10

Figure 1. Chemical Structures of Marketed Drugs Containing a 7-Azaindole Framework Scheme 1. Literature Routes via 5-Bromo-4-chloro-7-azaindole (2)

Scheme 2. Proposed Synthetic Route Featuring a Regioselective Functionalization


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Results and Discussion N-oxide Formation and Chlorination Reaction. We commenced our study by identifying a reliable route to 4-chloro-7-azaindole (4) precursor (Scheme 3). Chlorination of 7-azaindole Noxide (7) has been reported using neat phosphorus oxychloride (POCl3)11 or methanesulfonyl chloride (MsCl)12 in DMF. With minor modifications implemented based on the literature,11,12a we were able to produce 4-chloro-7-azaindole (4) reliably on >50 kg scale through a sequence of N-oxide formation with meta-chloroperoxybenzoic acid (m-CPBA) in EtOAc,13 followed by freebasing of the corresponding meta-chlorobenzoic acid salt using aqueous potassium phosphate, and regioselective chlorination of 7 using MsCl in DMF. It is noteworthy that although the nucleophilic chlorination was deemed highly regioselective at the C-4 position over C-6 with only small amounts of the corresponding 3-chloro regioisomer 4b reported in the literature,11 we did observe small amounts of the corresponding 6-chloro regioisomer 4a (2–3 A % HPLC) in the crude reaction mixture that could be purged to 30 min

93

HNO3:H2SO4 (1:3)

A or B

>30 min

86

3

HNO3:H2SO4 (1:4)

B

>30 min

90

4

HNO3:H2SO4 (1:4)

A

98% conversion, an excess amount of NBS (150–160 mol %) was needed and attempts to reduce the charge was not successful. To further improve the yield, we evaluated a variety of additives. The reaction was found to be sensitive to water with a lower yield obtained in the presence of 100 mol % of water (54%; Table 2, entry 2). We observed no negative impact upon addition of neutral (K2SO4) or acidic (KHSO4) inorganic salts under anhydrous conditions (Table 2, entries 3–4). Gratifyingly, use of a weakly basic additive such as K2HPO4, KOAc, or NaOAc in a stoichiometric amount (100 mol %) gave a much cleaner reaction profile and improved the reaction yield by approximately 20% (Table 2, entries 5–7). The reaction gave comparable yield using 50 mol % of NaOAc (Table 2, entry 8) but lower yield when 200 mol % of NaOAc was used (Table 2, entry 9). It is noteworthy that the reaction was not sensitive to water in the presence of NaOAc and no diminished yield was observed even with 100 mol % of water added (Table 2, entry 10 vs. entry 7). We developed a quench procedure using an aqueous sodium sulfite solution to completely reduce any remaining oxidants and convert small amounts (50 kg scale and obtained 1 in 46% yield and 97% purity over 4 steps starting from 7-azaindole 6 (Scheme 5). The process is concise, operationally simple and efficient since every single product is crystallized directly from the reaction mixture upon the addition of an aqueous solution and as such no liquid-liquid extraction or distillation steps are involved. Moreover, the process can be considered environmentally friendly as water contributes to approximately 70% of the total mass of solvents used for these four steps. From an impurity control standpoint, a key feature of the synthesis is that the sequence provides excellent robustness with respect to control of process-related regioisomeric impurities that may often raise purging issues in the synthesis of active pharmaceutical ingredient due to their similarity to the parent structure. Additionally, compound 1 has been shown to be non-mutagenic by Ames test, which poses no risks for its use in drug candidate development from a genotoxic impurity perspective.


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Scheme 5. Preparation of 5-Bromo-4-chloro-3-nitro-7-azaindole (1) from 7-Azaindole (6)


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Conclusion In summary, we developed a robust and highly regioselective route to prepare a useful 7-azaindole building block– 5-bromo-4-chloro-3-nitro-7-azaindole, and demonstrated on >50 kg scale to produce the product in good yield and high purity. Further functionalization of azaindole 1 into pharmaceutically active 3,4,5-substituted 7-azaindole derivatives will be reported in due course.


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Experimental Section General Information. All reactions were performed under a nitrogen atmosphere unless otherwise stated. NMR spectra were recorded on a Bruker 300 MHz instrument at ambient temperature. All 1H NMR spectra were measured in parts per million (ppm) relative to the residual solvent peak in the deuterated solvent (δ 2.50 for DMSO-d6). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz), and integration. All

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C NMR

spectra are reported in ppm relative to the deuterated solvent peak (δ 39.5 ppm for DMSO-d6) and were obtained with complete 1H decoupling unless otherwise stated. HRMS data was obtained on a LTQ Orbitrap Discovery (Thermo Fisher Scientific) at Genentech, Inc. Melting points were measured by differential scanning calorimetry (DSC, TA Instruments Q2000) and reported as onset temperature. 1H-Pyrrolo[2,3-b]pyridine 7-oxide (7).12a To a solution of 1H-pyrrolo[2,3-b]pyridine 6 (65.3 kg, 553 mol, 100 mol %) in EtOAc (655 kg) was added m-CPBA (85 wt %, 146 kg, 130 mol %) in portions below 20 °C. The resulting suspension was stirred at 25 °C for 2 h and filtered. The resulting solids were washed with EtOAc/petroleum ether (40/60, w/w, 243 kg × 2) and dried at below 40 °C under reduced pressure to provide 7-hydroxy-1H-pyrrolo[2,3-b]pyridin-7-ium 3chlorobenzoate (148 kg, 92% yield) as a light yellow solid. To a mixture of 7-hydroxy-1Hpyrrolo[2,3-b]pyridin-7-ium 3-chlorobenzoate and water (528 kg) was added 2 M aqueous K3PO4 solution (317 kg) to adjust the pH to 10 at 10–15 °C. The suspension was stirred at 0 °C for 1 h and filtered. The solid was washed with cold water (176 kg) and dried under reduced pressure at 50 °C to afford 1H-pyrrolo[2,3-b]pyridine 7-oxide 6 as a light pink solid (63.3 kg, 85% yield, >99.0 A % HPLC). mp 100 °C; 1H NMR (300 MHz, DMSO-d6) δ 1H NMR (300


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MHz, DMSO-d6) δ 12.50 (s, 1H), 8.14 (d, J = 6.1 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 3.3 Hz, 1H), 7.08 (dd, J = 8.0, 6.1 Hz, 1H), 6.59 (d, J = 3.3 Hz, 1H);

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C NMR (75 MHz,

DMSO-d6) δ 138.4, 131.3, 126.7, 124.2, 120.3, 116.2, 102.4. 4-Chloro-1H-pyrrolo[2,3-b]pyridine (4).11 To a solution of 1H-pyrrolo[2,3-b]pyridine 7-oxide 7 (63.0 kg, 470 mol, 100 mol %) in DMF (302 kg) was added MsCl (179 kg, 333 mol %) at 60– 75 °C over 1 h. The reaction mixture was stirred at 70 °C for 5 h, cooled to 40 °C, and transferred into cold water (1280 kg) over 1 h while maintaining the batch temperature below 15 °C. To the resulting suspension was added aqueous NaOH solution (500 kg, 30 wt %).17 The suspension was stirred at 10 °C for 0.5 h and filtered. The resulting solids were washed with water (380 kg) and dried under reduced pressure at 50 °C to afford 4-chloro-1H-pyrrolo[2,3b]pyridine 4 as a light yellow solid (52.0 kg, 73% yield, 97.5 A % HPLC; 3-chloro isomer 4a18a: 1.8 A % HPLC; 6-chloro isomer 4b18b: 0.7 A % HPLC). mp 175 °C (lit. mp 175–177 °C); 1H NMR (300 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.18 (d, J = 5.2 Hz, 1H), 7.60 (t, J = 3.0 Hz, 1H), 7.20 (d, J = 5.1 Hz, 1H), 6.51 (dd, J = 3.3, 2.0 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 149.1, 143.2, 134.1, 127.2, 118.7, 115.3, 98.0. 4-Chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (5).10,14 Into a solution of H2SO4 (363 kg, 98 wt %) was charged 4-chloro-1H-pyrrolo[2,3-b]pyridine 4 (50.0 kg, 93.3 wt %, 306 mol, 100 mol %) in portions at 0–10 °C. HNO3 (36.2 kg, 120 mol %, 65 wt %) was added over 3 h while maintaining the internal temperature at 0–10 °C, followed by cold (5 ºC) water (72.8 kg). The reaction mixture was stirred at 5 °C for 30 min. Cold water (5 ºC) (624 kg) was then slowly added at 0–15 °C. The resulting suspension was filtered. The solid was washed with water (180 kg), 20 wt % K2HPO4 solution (300 kg), and water (400 kg), sequentially. The removal of residual salts in the final cake wash was monitored using a conductivity meter (target 300 °C; 1H NMR (300 MHz, DMSO-d6) δ 13.39 (br s, 1H), 8.92 (s, 1H), 8.37 (d, J = 5.2 Hz, 1H), 7.49 (d, J = 5.2 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 148.2, 145.7, 134.7, 132.7, 127.2, 120.9, 110.1. HRMS calcd for C7H3ClN3O2 [M-H]-: 199.9919, found 199.9921. 5-Bromo-4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (1).10 Into a suspension of 4-chloro-3nitro-1H-pyrrolo[2,3-b]pyridine 5 (53.2 kg, 94.5 wt %, 254 mol, 100 mol %) and sodium acetate (11.0 kg, 50 mol %) in acetic acid (336.1 kg) was added NBS (73.8 kg, 160 mol %) in portions19 at 25 °C. The reaction mixture was stirred at 25 °C for 18 h. Into the reaction mixture was added 5 wt % aqueous sodium sulfite solution (694 kg) over 1 h. The suspension was stirred at 25 °C for 2 h and filtered. The resulting solid was washed with water (347 kg) and dried under reduced pressure at 70 °C to afford 5-bromo-4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine 1 as a tan solid (66.4 kg, 96.2 wt %, 90% yield, 96.9 A % HPLC; unreacted starting material 5: 0.99 A% HPLC; impurity 8: 0.95 A% HPLC): mp 269 °C dec; 1H NMR (300 MHz, DMSO-d6) δ 13.68 (s, 1H), 8.93 (s, 1H), 8.66 (s, 1H);

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C NMR (75 MHz, DMSO-d6) δ 146.9, 146.4, 133.9, 133.2, 127.0,

116.7, 111.2. HRMS calcd for C7H2BrClN3O2 [M-H]-: 273.9024, found 273.9031.


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Associated Contents Supporting Information. The supporting information is available free of charge on the ACS Publications website. 1

H and 13C NMR spectra of compounds 7, 4, 5, and 1

Author Information Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest.

Acknowledgements We thank Dr. Haiming Zhang for helpful discussion, Dr. Chunang Gu for collecting HRMS data, Ms. Tina Nguyen for analytical support, and Ms. Rebecca Rowe for collecting mp data.


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References (1) Fang, Y.-Q.; Yuen, J.; Lautens M. J. Org. Chem. 2007, 72, 5152−5160 and references therein. (2) For a review, see: Mérour, J.-Y.; Buron, F.; Plé, K.; Bonnet, P.; Routier, S. Molecules, 2014, 19, 19935−19979. (3) Tsai, J.; Lee, J. T.; Wang, W.; Zhang, J.; Cho, H.; Mamo, S.; Bremer, R.; Gillette, S.; Kong, J.; Haass, N. K.; Sproesser, K.; Li, L.; Smalley, K. S. M.; Fong, D.; Zhu, Y.-L.; Marimuthu, A.; Nguyen, H.; Lam, B.; Liu, J.; Cheung, I.; Rice, J.; Suzuki, Y.; Luu, C.; Settachatgul, C.; Shellooe, R.; Cantwell, J.; Kim, S.-H.; Schlessinger, J.; Zhang, K. Y. J.; West, B. L.; Powell, B.; Habets, G.; Zhang, C.; Ibrahim, P. N.; Hirth, P.; Artis, D. R.; Herlyn, M.; Bollag, G. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 3041−3046. (4) Souers A. J.; Leverson J. D.; Boghaert E. R.; Ackler, S. L.; Catron, N. D.; Chen, J.; Dayton, B. D.; Ding, H.; Enschede, S. H.; Fairbrother, W. J.; Huang, D. C. S.; Hymowitz, S. G.; Jin, S.; Khaw, S. L.; Kovar, P. J.; Lam, L. T.; Lee, J.; Maecker, H. L.; Marsh, K. C.; Mason, K. D.; Mitten, M. J.; Nimmer, P. M.; Oleksijew, A.; Park, C. H.; Park, C.-M.; Phillips, D. C.; Roberts, A. W.; Sampath, D.; Seymour, J. F.; Smith, M. L.; Sullivan, G. M.; Tahir, S. K.; Tse, C.; Wendt, M. D.; Xiao, Y.; Xue, J. C.; Zhang, H.; Humerickhouse, R. A.; Rosenberg, S. H.; Elmore, S. W. Nat. Med. 2013, 19, 202−210. (5) Blake, J. F.; Guanawardana, I. W.; Huerou, Y. L.; Mohr, P. J.; Wallace, E. M; Wang, B. Pyrrolopyridines as Kinase Inhibitors. U.S. Patent 8,841,304, Sep 23, 2014.


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(6) For reviews on the synthesis of azaindole derivatives, see: (a) Mérour, J.-Y.; Joseph, B. Curr. Org. Chem. 2001, 5, 471−506. (b) Popowycz, F.; Routier, S.; Joseph, B.; Mérour, J.-Y. Tetrahedron 2007, 63, 1031−1064. (c) Mérour, J.-Y.; Routier, S.; Suzenet, F.; Joseph, B. Tetrahedron 2013, 69, 4767−4834. For selected publications on 7-azaindole functionalization, see: (d) Henderson, J. L.; McDermott, S. M.; Buchwald, S. L. Org. Lett. 2010, 12, 4438−4441. (e) Schneider, C.; David, E.; Toutov, A. A.; Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 2722−2726. (f) Barl, N. M.; Sansiaume-Dagousset, E.; Karaghiosoff, K.; Knochel, P. Angew. Chem., Int. Ed. 2013, 52, 10093−10096. (7) Blaney, J. M.; Gosberg, A.; Gradl, S. N.; Hirst, G.; Hopkins, S. A.; Sprengeler, P. A.; Steensma, R. W.; Uy, J. Substituted Pyrrolopyridines and Pyrazolopyridines as Kinase Modulators. U.S. Patent 8,158,647, Apr 17, 2012. (8) (a) L’Heureux, A.; Thibault, C.; Ruel, R. Tetrahedron Lett. 2004, 45, 2317−2319. (b) Dong, H.-Q.; Foreman, K.; Li, A.-H.; Mulvihill, M. J.; Panicker, B.; Steinig, A. G.; Stolz, K. M.; Weng, Q.; Jin, M.; Volk, B.; Wang, J.; Wang, T.; Beard, J. D. Pyrrolopyridine Kinase Inhibiting Compounds. US 20070129364, Jun 7, 2007. (9) The regioselectivity of the chlorination step was not reported in ref. 7. In our hands, we obtained at best a 10:1 ratio of the desired 4-chloroazaindole vs the corresponding 6chloroazaindole regioisomer using either POCl3 or MsCl in DMF. (10) Han, C. Intermediates and Processes for Preparing Compounds. U.S. Patent 9,221,813, Dec 29, 2015. (11) Wang, X.; Zhi, B.; Baum, J.; Chen, Y.; Crockett, R.; Huang, L.; Eisenberg, S.; Ng, J.; Larsen, R.; Martinelli, M.; Reider, P. J. Org. Chem. 2006, 71, 4021−4023.


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(12) (a) Thibault, C.; L’Heureux, A.; Bhide, R. S.; Ruel, R. Org. Lett. 2003, 5, 5023−5025. (b) Soundararajan, N.; Benoit, S.; Gingres, S. Processes for the Preparation of Antiviral 7-Azaindole Derivatives. U.S. Patent 7,105,677, Sep 12, 2006. (13) Reaction calorimetry analysis indicated an adiabatic temperature rise of 47 °C for the Noxide formation step performed at 20 °C using m-CPBA in EtOAc, which would result in a maximum temperature of the synthesis reaction (MTSR) of 67 °C that is 10 °C lower than the boiling point of EtOAc. Although the reaction is considered safe under these conditions, portionwise addition of m-CPBA and appropriate cooling are strongly preferred to ensure the safety of the process. (14) Kumaran, K.; Kamil, S. R. M.; Jaisankar, K. R. Int. J. PharmTech Res. 2012, 4, 169−175. (15) Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2007; pp 685−690. (16) Reaction calorimetry analysis showed no accumulation (

Highly Regioselective and Practical Synthesis of 5-Bromo-4-chloro-3

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