A Practical and Efficient Approach to the Preparation of Bioactive

Jan 10, 2017 - The whole procedure gives the target product in a 38% overall yield with >99% purity. Key steps in this process including oxidation and...
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A Practical and Efficient Approach to the Preparation of Bioactive Natural Product Wogonin Tinghan Li, Tianwei Weng, Jubo Wang, Zhihui Wei, Lu Zhao, and Zhiyu Li Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00249 • Publication Date (Web): 10 Jan 2017 Downloaded from http://pubs.acs.org on January 10, 2017

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A Practical and Efficient Approach to the Preparation of Bioactive Natural Product Wogonin

Tinghan Li,†,‡ Tianwei Weng,†,‡ Jubo Wang,†,‡ Zhihui Wei,†,‡ Lu Zhao,†,‡ and Zhiyu Li*,†,‡



Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University,

Nanjing, 210009, China ‡

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University,

Nanjing, 210009, China *Corresponding author: Tel: +86 139 5167 8592 E-mail: [email protected]

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Table of Contents graphic:

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ABSTRACT: A scalable and practical route to wogonin, a bioactive natural product with multiple pharmacological activities which is currently under phase I/II clinical studies, is described. Wogonin was obtained via a four-step process starting from commercially available chrysin and including the Elbs oxidation, benzylation, methylation and the final debenzylation. The whole procedure gives the target product in a 38% overall yield with >99% purity. Key steps in this process including oxidation and methylation are discussed in detail. The optimized process has been successfully demonstrated on kilogram scale to support ongoing clinical development of wogonin.

KEYWORDS: Natural product, Large-scale synthesis, Elbs oxidation, Reaction condition optimization.

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INTRODUCTION Wogonin (1, Figure 1) is a natural phytochemical flavones isolated from the roots of Chinese herbal Huang-Qin (Scutellaria baicalensis Georgi).1 It has been shown to exhibit a wide range of significant biological activities such as anti-oxidation,2 anti-inflammatory,3 neuroprotective,4 especially antitumor activity.5 Substantial efforts from several research groups have been devoted to explore the antitumor mechanisms of 1.6 Unlike other natural flavones, 1 has been reported to selectively kill cancer with little to no toxicity to normal cells at concentrations that are lethal to tumor cells.7 Significantly, 1 has been approved by the China Food and Drug Administration (CFDA) for phase I/II clinical studies since 2014. The content of 1 in Scutellaria baicalensis Georgi is very low with the ratio of active to dry material about 1.3%.8 The compound supply for development cannot be met simply via isolation and purification. Thus, it is not surprising that the synthesis of this pharmaceutically important natural product has triggered great efforts in recent years.

Figure 1. Structure of bioactive flavone wogonin

RESULTS AND DISCUSSION Original and Revised Routes to 1. Three synthetic approaches toward 1 have been reported.9 Rao’s route in 1947 selected chrysin (2) as starting material to obtain 1 through O7-benzylation, oxidation, methylation and debenzylation (Scheme 1, Route A).9a Although the route is short and simple, the overall isolated yield of 1 is 5% due to the low yielding oxidation step (less than 15% yield from 3 to 4). In 2003, Huang et al reported that 1 could be synthesized by three steps from a relative expensive starting material 3,4,5-trimethoxyphenol (5) (Route B).9b Additionally, since the two hydroxyl groups of intermediate 6 were competing for the ring closure reaction, this process was accompanied by the structurally similar by-product oroxylin A (7) which was difficult to separate. In 2009, Li et al disclosed another method (Route C) based on Route B by utilizing intermediate 9 which has only one reactive position in order to avoid the competitive addition while forming the flavone nucleus.9c In this method, 9 was procured from pyrogallic acid (8) sequentially via benzylation, oxidation, reduction, methylation, debenzylation and Friedel-Crafts acylation. Subsequently, 9 was converted to 1 through cyclization and selective

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demethylation. Although this method can produce ten-gram scale of 1 in a single batch, there are two shortcomings limiting the large-scale synthesis: (1) long synthetic procedure and laborious work-ups; (2) the relatively low 14.9% overall yield. The drawbacks of the above routes urged us to find an alternative synthetic route to 1 with simplified procedure and improved yield ready for large-scale manufacture. We envisioned that the most expeditious route to 1 was to select a compound with 2-phenylchromone as starting material and avoid the cumbersome ring closure reaction. Therefore, Rao’s route was taken as reference, in which the Elbs oxidation was the key step needed to be improved. A review of the literature revealed that the yields of the Elbs oxidations are closely related to the starting materials, e.g. 5,7-dihydroxyflavones always give higher yields than 5-hydroxy-7-benzyloxyflavones.10 Thus, in order to improve yield, chrysin (2) which is at the same time inexpensive and commercially available was selected as starting material and the substrate of the Elbs oxidation. Direct O7-benzylation of the sulfate 10 followed by hydrolysis, methylation and debenzylation finally generated 1 (Scheme 2).

Scheme 1. Initial Routes to Wogonin

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Scheme 2. An Improved Route to Wogonin

Oxidation of Chrysin (2). The Elbs oxidation, generally applied in synthesis of flavone with low yield and long reaction time,11 is a nucleophilic displacements reaction in which the nucleophile is a phenolate anion and the product is an aromatic sulfate whose orientation relative to the phenolic group is preferentially para. According to the literature procedure,12 the Elbs oxidation is typically carried out by dissolving the substrate in an alkaline aqueous medium, and then adding a peroxydisulfate salt at room temperature. Tetramethylammonium hydroxide was chosen as the alkali because the ammonium salt of phenol was found to be much more soluble than the sodium and potassium salts, and potassium persulfate was chosen as the oxidant because it is mild and cheap. The reaction concentration reported in the literature was 120 L solvent mix/kg of starting material. Optimization of the reaction concentration showed that the yield of oxidation was closely related to the solvent volume and the highest yield was obtained when the reaction concentration being 20−30 L solvent mix/kg of starting material. 25 L solvent mix/kg of starting material was eventually chosen as the reaction concentration. The oxidation is known to be highly exothermic. Although potassium persulfate is a mild oxidant, an exotherm from ~24 to ~36 ○C was observed during this reaction when potassium persulfate was added in one portion. Subsequent experiments identified the addition rate of potassium persulfate as an important parameter for achieving safety profile of this reaction. It was found that adding potassium persulfate in 12 equal portions (2 equiv in total) every 20 minutes exhibited very slight exotherm (temperature rise of ~6 ○C) between each addition. The improved operation has been successfully applied to the kilogram manufacture of compound 10. Based on the literature report,13 after stirred for 3 hours, the pH of the reaction solution was neutralized to 6 by addition of monopotassium phosphate and extracted with n-butanol. Considering that n-butanol is expensive with a high boiling point, the workup was improved with adding a large amount of sodium

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chloride to the neutral solution to precipitate the product relying on the salting out effect.14 The improved workup procedure which was more environmentally friendly and cost-efficient circumvented the inconvenient extraction and purification, as well as increased the yield to a considerable extent.

Benzylation and hydrolysis. Gratifyingly, a prior substitution on 7-hydroxy of compound 10 was observed during the benzylation and nearly no 5-substitued product was obtained probably due to the intra-molecular hydrogen bond on this position. A brief screen of reaction conditions for O7-benzylation of 10 was performed. It was determined that N,N-Dimethylformamide (DMF) was a suitable solvent because of the good solubility of 10 in it and potassium carbonate (K2CO3) delivered the highest conversion as base. It was also found that using fine powder K2CO3 was favourable for the rate of the benzylation. Further optimization with varying amounts (1−2 equiv) of benzyl bromide (BnBr) was undertaken (Figure 2). The results showed that the conversion was low (~50%) when the amount of BnBr was below 1.5 equiv, and a larger amount of BnBr (1.7−2 equiv) accelerated the formation of the undesired di-benzylated byproduct 13 (Scheme 3). As a result, 1.5 equiv of BnBr was adopted as a standard. In order to streamline the synthetic procedure and simplify the workups, we envisaged that the hydrolysis could be telescoped into the prior step. After the benzylation was deemed complete by HPLC, the reaction slurry was filtered to remove K2CO3, and the stream of 12 in DMF was taken directly into the hydrolysis step with 6 M hydrochloric acid (HCl) (Scheme 3). Precipitation from the hydrolysis mixture by addition of water gave crude 4 in a 90% yield, contaminated with ~4 area % of 14 which was derived from the byproduct 13 (Scheme 3). Subsequent experiments showed that recrystallization of crude 4 from tetrahydrofuran (THF)/water could remove the undesired impurity 14 efficiently to a 99%) effectively. The yield of eventual debenzylation was about 92−93% and a recrystallization from ethanol can give pure 1 with >99% purity.

CONCLUSION In summary, we have demonstrated a practical and efficient process for the synthesis of wogonin, a bioactive natural product with multiple pharmacological activities. Notable improvement was the development of a telescoped four-step procedure that obviated building the flavone core with a relatively high (38%) overall yield, comparing with the initial synthetic routes in literatures. The process from commercially available chrysin to wogonin was significantly optimized with easy workups and high yields. More importantly, the improved Elbs oxidation made it possible to be applied to large-scale production. All steps were run on more than 500 gram scale, and no chromatography was needed even at the final step. This scalable process has allowed multiple batches of 1 with high purity (>99.8%) for clinical studies.

EXPERIMENTAL SECTION General Information. All reagents and solvents purchased from commercial suppliers were used without further purification. 1HNMR and 13CNMR spectra were collected on a Bruker AVANCE 300 MHz spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) from tetramethylsilane (TMS) using the residual solvent resonance. Multiplicities are abbreviated as: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br s (broad singlet). HR-MS was recorded on Agilent technologies 6520 Accurate-Mass LC/MS Q-TOF instruments. The procedures outlined in this section are those employed for the reactions run at the largest scale. Unless specified otherwise, all compounds were ≥95% pure.

Preparation of tetramethylammonium 5,7-dihydroxy-4-oxo-2-phenyl-4H-chromen-8-yl sulfate

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(10). A 50 L reactor was charged with tetramethylammonium hydroxide (2184 g, 24 mol, 6 equiv) and water (28.58 L). Chrysin (2, 1016 g, 4 mol, 1 equiv) was added over 20 minutes, and the mixture was stirred at room temperature for an additional 20 minutes. Then, potassium persulfate (2160 g g, 8 mol, 2 equiv) was added every 20 minutes in 12 equal portions. An exotherm from 24 to 30 ○C was observed between each addition. After the final portion was added, the resulting homogeneous dark solution was stirred at 25 ± 2 ○C for 2.5 hours, after which time HPLC showed that all starting material was consumed. The reaction soluti8on was neutrallized to pH 6−7 by adding monopotassium phosphate (1360 g, 10 mol, 2.5 equiv) in 6 portions every 10 minutes, resulting in the formation of dark brown precipitate. Sodium chloride (2340 g, 40 mol, 10 equiv) was added into the batch in 5 portions every 5 minutes and the resulting mixture was stirred at room temperature for 4 hours. The precipitate was collected by filtration, and the viscous cake was washed with 2 × 5 L of MeOH (manually stirring the viscous cake on the filter then filtrating) and dried in vacuo at 45 ± 2 ○C until constant weight to give 10 as a brown solid (1032.3 g, 91.7 area% by HPLC purity, 56% corrected yield). 1H NMR (300 MHz, DMSO-d6): δ = 12.61 (s, 1H, 5-OH), 10.12 (s, 1H, 7-OH), 8.18 (m, 2H, Ar-H), 7.61 (m, 3H, Ar-H), 7.01 (s, 1H, CHCO), 6.32 (s, 1H, Ar-H), 3.09 (s, 12H, N+(CH3)4) ppm. 13C NMR (75 MHz, DMSO-d6): 182.0, 163.3, 157.4, 157.0, 149.8, 132.1, 130.8, 129.0 (2 × C), 126.6 (2 × C), 121.5, 104.9, 104.1, 99.7, 54.4 (4 × C) ppm.

Preparation of 7-benzyloxy-5,8-dihydroxy-2-phenyl-4H-chromen-4-one (4). To a 20 L reactor was added 10 (1057.7 g, 2.5 mol, 1 equiv), K2CO3 (690 g, 5 mol, 2 equiv) and anhydrous DMF (10 L). After stirring for 20 minutes, benzyl bromide (641.3 g, 3.8 mol, 1.5 equiv) was added to the mixture. The resulting homogeneous dark solution was warmed to 50 ○C and held at this temperature for 8 hours, at which time HPLC analysis indicated reaction completion. The reaction mixture was then cooled to 20 ○C and filtered. The filtrate was acidified to pH 2 by adding 1.5 L of 6 M HCl slowly (exothermic) and agitated vigorously at room temperature overnight. Water (45 L) was added to the resulting mixture slowly to precipitate the product. The suspension was filtered, and the filter cake was washed with 1 L of water and dried in vacuum to get 840.6 g (93% yield, uncorrected) of crude 4 as an orange solid. Recrystallization: Crude 4 (125 g, 0.35 mol) was suspended in THF (960 mL) and then heated to 40 ○C until the solution was homogeneous. An equivalent amount of water (960 mL) was added slowly at 40 ○C over 20 minutes, and the solution was naturally cooled down to room temperature. The suspension was further chilled to 5 ○C for 1 hour and filtered. The filter cake was washed with 100 mL cold THF/water (1:5) and dried in vacuum at ambient temperature, providing 118.8 g of pure 4 (90% yield, 97.6 area% by HPLC purity). 1H NMR (300 MHz, CDCl3): δ = 12.36 (s, 1H, 5-OH), 7.96 (m, 2H, Ar-H), 7.52 (m, 3H, Ar-H),

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7.42 (m, 5H, Ar-H), 6.66 (s, 1H, CHCO), 6.52 (s, 1H, Ar-H), 5.20 (s, 2H, ArOCH2) ppm.

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C NMR (75

MHz, CDCl3): 182.9, 164.0, 154.1, 151.2, 143.4, 135.2, 131.9, 131.3, 129.1 (2 × C), 128.9 (2 × C), 127.9 (3 × C), 126.4 (2 × C), 105.3 (2 × C), 96.3, 71.6 ppm. HRMS (ESI), [M + H]+ calculated for C22H17O5 361.1071, found 361.1077.

Preparation of 7-benzyloxy-5-hydroxy-8-methoxy-2-phenyl-4H-chromen-4-one (11). 4 (900 g, 2.5 mol, 1 equiv), K2CO3 (690 g, 5 mol, 2 equiv), anhydrous DMF (8 L) and THF (8 L) were charged to a 50 L reactor, and the mixture was stirred for 20 minutes. Dimethyl sulfate (378 g, 3 mol, 1.2 equiv) was added to the solution at room temperature slowly over 30 minutes, maintaining the reaction temperature between 25 and 30 ○C. The resulting slurry was then held at this temperature for an additional 3 hours. After the reaction was deemed complete by HPLC analysis, 16 L water was added slowly to quench the reaction (exothermic). The resulting mixture was stirred for 30 minutes and filtered. The filter cake was washed with 1 L of water and dried in vacuum to give 841.5 g (90% yield, uncorrected) of crude 11 as a yellow solid. Recrystallization: Crude 11 (100 g, 0.27 mol) was dissolved in NMP (1.5 L), and then 500 mL water was added to the solution slowly while stirring. The resulting suspension was stirred at room temperature for 12 hours and filtered. The filter cake was washed with 100 mL NMP/water (4:1) and dried in vacuum at ambient temperature, providing 94.5 g of pure 11 (94.5% yield, 99.5 area% by HPLC purity). 1H NMR (300 MHz, CDCl3): δ = 12.53 (s, 1H, 5-OH), 7.95 (m, 2H, Ar-H), 7.54 (m, 3H, Ar-H), 7.39 (m, 5H, Ar-H), 6.68 (s, 1H, CHCO), 6.48 (s, 1H, Ar-H), 5.23 (s, 2H, ArOCH2), 3.97 (s, 3H, ArOCH3) ppm. 13C NMR (75 MHz, CDCl3): 181.7, 162.9, 156.8, 156.3, 148.6, 134.8, 130.9, 130.3, 128.1 (2 × C), 127.7 (3 × C), 127.3, 126.2 (2 × C), 125.3 (2 × C), 104.4, 104.2, 96.2, 69.9, 60.7 ppm. HRMS (ESI), [M + H]+ calculated for C23H19O5 375.1227, found 375.1233.

Preparation of 5,7-dihydroxy-8-methoxy-2-phenyl-4H-chromen-4-one (1). Compound 11 (748 g, 2 mol, 1 equiv) was dissolved in THF (12 L). The solution was charged into a 20 L flask containing Pd/C (74.8 g, 10 wt % loading). The flask was first purged with nitrogen and then replaced by hydrogen. The resulting solution was hydrogenated for 4 hours at ambient temperature and pressure. The mixture was filtered through Celite to remove catalyst and the filter cake was washed with THF (2.4 L × 2). The combined filtrates were evaporated to give 550 g (97% yield, uncorrected) of crude debenzylation product 1. Recrystallization: Crude 1 (142 g, 0.5 mol) was suspended in ethanol (700 mL) and then heated to 70 ○C.

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The homogeneous mixture was filtered through Celite immediately without cooling. After the filtrate was naturally cooled down for 15 minutes, seed crystals (1.7 g, 1.2 wt %) were added. The suspension was further chilled to room temperature for 5 hours and filtered. The filter cake was washed with 200 mL cold ethanol and once again recrystallized with the same procedure to provide 135 g of pure 1 as a yellow solid (95% yield, 99.8 area% by HPLC purity, Pd level < 5 ppm). 1H NMR (300 MHz, DMSO-d6): δ = 12.52 (s, 1H, 5-OH), 10.83 (s, 1H, 7-OH), 8.07 (m, 2H, Ar-H), 7.62 (m, 3H, Ar-H), 6.99 (s, 1H, CHCO), 6.33 (s, 1H, Ar-H), 3.88 (s, 3H, ArOCH3) ppm.

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C NMR (75 MHz, DMSO-d6): 182.0, 162.9, 157.3, 156.2, 149.6,

132.0, 130.8, 129.2 (2 × C), 127.7, 126.2 (2 × C), 105.0, 103.7, 99.1, 61.0 ppm. HRMS (ESI), [M + H]+ calculated for C16H13O5 285.0757, found 285.0756.

ASSOCIATED CONTENT Supporting Information 1

HNMR and 13C NMR spectra for compounds 10, 4, 11 and 1, HPLC conditions and chromatograms.

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (No. 21372260).

REFERENCES (1) Li-Weber, M. Cancer Treat. Rev. 2009, 35, 57−68. (2) Pietta, P. G. J. Nat. Prod. 2000, 63, 1035−1042. (3) Park, B. K.; Heo, M. Y.; Park, H.; Kim, H. P. Eur. J. Pharmacol. 2001, 425, 153−157. (4) Son, D.; Lee, P.; Lee, J.; Kim, H.; Kim, S. Y. Eur. J. Pharmacol. 2004, 493, 99−102. (5) (a) Wang, W.; Guo, Q. L.; You, Q. D.; Zhang, K.; Yang, Y.; Yu, J.; Liu, W.; Zhao, L.; Gu, H.-Y.; Hu, Y.; Tan, Z.; Wang, X.-T. Biol. Pharm. Bull. 2006, 29, 1132−1137. (b) Lu, N.; Gao, Y.; Ling, Y.; Chen, Y.; Yang, Y.; Gu, H. Y.; Qi, Q.; Liu, W.; Wang, X. T.; You, Q. D.; Guo, Q. L. Life Sci. 2008, 82, 956−963. (6) (a) Polier, G.; Ding, J.; Konkimalla, B. V; Eick, D.; Ribeiro, N.; Köhler, R.; Giaisi, M.; Efferth, T.; Desaubry, L.; Krammer, P. H.; Li-Weber, M. Cell Death Dis. 2010, 2, e182−e182. (b) Ding, J.; Polier, G.; Koḧler, R.; Giaisi, M.; Krammer, P. H.; Li-Weber, M. J. Biol. Chem. 2012, 287, 641−649. (7) Baumann, S.; Fas, S. C.; Giaisi, M.; Muller, W. W.; Merling, A.; Gulow, K.; Edler, L.; Krammer, P. H.; Li-Weber, M. Blood 2008, 111, 2354−2363.

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(8) Wang H. Z.; Yu C. H.; Gao J.; Zhao G. R. China J. Chinese materia medica 2007, 32, 1637−1640. (9) (a) Venkateswara Rao K.; Visweswara Rao K.; Seshadri T. R. Proc. Indian Acad. Sci. 1947, 26, 13−17. (b) Huang, W. H.; Chien, P. Y.; Yang, C. H.; Lee, A. R. Chem. Pharm. Bull. 2003, 51, 339−340. (c) Li, Z.Y.; Cao, X.; Wang, X.; Guo, Q.L.; You, Q.D. Org. Prep. Proced. Int. 2009, 41, 327–330. (10) Behrman, E. J. Beilstein J. Org. Chem. 2006, 2, 22. (11) Martin-Benlloch, X.; Elhabiri, M.; Lanfranchi, D. A.; Davioud-Charvet, E. Org. Process Res. Dev. 2014, 18, 613–617. (12) Behrman, E. J. Organic Reactions; Wiley: New Jersey, 2004. (13) Barron, D.; Jolivet, S.; Crouzet, J. M.; Mariotte, A. M. Tetrahedron Lett. 1992, 33, 7137–7140. (14) Mezei, T.; Mesterházy, N.; Bakó, T.; Porcs-Makkay, M.; Simig, G.; Volk, B. Org. Process Res. Dev. 2009, 13, 567–572.

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