Concise Synthesis of Key Intermediate of Mirabegron via a Mixed

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Concise Synthesis of Key Intermediate of Mirabegron via a Mixed Anhydride Method Qilong Zhang, Zhiyuan Zhuang, Qingdong Liu, Zhanming Zhang, Fuxu Zhan, and Gengxiu Zheng Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00231 • Publication Date (Web): 13 Oct 2016 Downloaded from http://pubs.acs.org on October 13, 2016

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Organic Process Research & Development

Concise Synthesis of Key Intermediate of Mirabegron via a Mixed Anhydride Method Qi-Long Zhang, Zhi-Yuan Zhuang, Qing-Dong Liu, Zhan-Ming Zhang, Fu-Xu Zhan,* and GengXiu Zheng* School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, Shandong P.R. China.

ACS Paragon Plus Environment

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Table of Contents Graphic:


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ABSTRACT: An efficiently scalable synthesis of key intermediate towards mirabegron has been developed via a mixed anhydride method, employing PivCl instead of EDCI and HOBt. The developed process produced (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (10) in 91.5-92.3% yield and > 99.0% HPLC purity under a mild condition. During this process, a side reaction induced by triethylamine hydrochloride was discovered and investigated, which was ultimately avoided by executing the reaction in a biphasic solvent system. KEYWORDS: mirabegron, intermediate, mixed anhydride method, PivCl


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INTRODUCTION Overactive bladder (OAB) is characterized by symptoms of urinary urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia.1,2,3 Current guidelines recommend oral antimuscarinics drugs as the first-line pharmacologic therapy in the management of OAB despite the companion adverse effects.4,5 Mirabegron is an orally active β3 adrenoceptor agonist approved by the FDA for treatment of OAB in 2012, which is an important step towards the better treatment options for the management of OAB.6 (R)-Styrene oxide 1 and 4-nitrophenethylamine 2 were exploited as starting materials in the first synthesis of mirabegron (Scheme 1). Heating 1 and 2 in i-propanol afforded amino alcohol 3, and then the amino group was protected by di-tert-butyl dicarbonate (Boc2O), followed by a condensation with 2-aminothiazol-4-acetic acid. Deprotection of the condensation product 7 finally afforded mirabegron.7-10 Although reactions in the whole process were all conventional reactions, optically pure 1 was not industrial available, which restricted its application in industry. Scheme 1 1st generation synthetic route of mirabegron


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(R)-Mandelic 8 and 4-nitrophenethylamine hydrochloride 9 were exploited as starting materials in an alternate route (Scheme 2). Condensation of 8 and 9 in the presence of 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt) and triethylamine in N,N-dimethylformamide (DMF) furnished the corresponding amide 10, which was further reduced in the presence of borane-tetrahydrofuran complex in a mixed solution of 1,3-dimethyl-2-imidazolidinone (DMI) and tetrahydrofuran (THF), affording amine 11. The nitro group of 11 was then reduced by hydrogenation affording aniline 12 which was further amidated by an aqueous EDCI coupling affording mirabegron. This route was rather concise with only 4 steps, in which the sole stereogenic center was introduced via a bulk starting material 8.11-13 However, usage of the costly EDCI twice, especially in the first step, led to a high cost and more impurities. Scheme 2 2nd generation synthetic route of mirabegron


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Aiming to find an economical and suitable process for scale-up production of mirabegron, we decided to develop a new method for the formation of the key amido bond. Herein we report an efficient and concise synthesis of a key intermediate (10) of mirabegron. RESULTS AND DISCUSION The 2nd generation synthetic route using (R)-mandelic instead of (R)-styrene oxide made it possible for industrial application. However, the large consumption of EDCI increased the cost dramatically. An ideal way to avoid using of EDCI was to find alternatives for carboxylic acid activation. We intended to utilize a mixed anhydride method, which traditionally would require 3 steps involving hydroxyl protection, amidation and deprotection, compared to the one step route employing EDCI. Thus, in order to solve the issue of step economy, we designed a one-pot mixed anhydride method based on the kinetic differences between the carboxylate anion and hydroxyl. Several acyl chlorides and sulfonyl chlorides14,15 were investigated. Considering that anhydride intermediates were not stable enough for thorough

characterization, 4-


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nitrophenethylamine 15 was used to capture the anhydride intermediates. Unfortunately, none of these attempts gave satisfactory results. Better results were obtained via tosyl chloride (TsCl) and mesyl chloride (MsCl) with conversions of 10 being 35% and 47% respectively, which were still not satisfactory (Table 1). Table 1. The 1st generation synthesis design for intermediate 10

Entry

R1

R2Cl

Temp. ºC

1 2 3

H H H

TsCl MsCl PivCl

reflux 25 0

K2CO3 K2CO3 Et3N

30 45 0

4

Na

TsCl

reflux

—

35

5

Na

MsCl

25

—

47

6

Na

PivCl

0

—

0

Base

10 （%））

Reaction conditions: 13 (40 mmol), R2Cl (40 mmol), CH3CN (50 mL), base (48 mmol). Conversion was calculated from the HPLC area. A further study of the PivCl mediated reaction uncovered that the acylation product was 19, which was not able to be attacked by 4-nitrophenethylamine 15. A plausible mechanism was proposed for the formation of 19. Initial formation of 16 was accompanied by intramolecular


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trapping of the benzyl hydroxyl group, forming a five-membered ring which ultimately collapsed to form 19 (Figure 1).

Figure 1. Proposed mechanism for the formation of compound 19 Facing the disappointing results, we had to give up our original design to seek another one. The hydroxyl had to be protected before amidation based on the proposed mechanism. However, protection-deprotection would be rather tedious. Considering that PivCl can act as a hydroxyl protective group, we proposed that adding excess PivCl might result in in situ protection of the hydroxyl group, followed by amidation. To ensure that all of the PivCl was consumed, water was added to consume excess PivCl followed by further refluxing. A moderate conversion to product 10 was observed when 1.6 eq of PivCl was added. However, byproduct 21 was also found in 8.2% conversion. Increasing the equivalent of PivCl led to higher amount of 10. Table 2. The 2nd generation synthesis design for intermediate 10


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OH

OPiv

OH PivCl, Et N 3 then H O 2 O

OPiv

15, Et3N,DCM

O

then NaOH

20 OH

H N

H N +

O 10

Entry 1

O

NO2 O2N 21

PivCl (equiv) 1.6

10 (%) 55.0

21 (%) 8.2

2

1.7

76.7

8.7

3

1.8

82.8

8.0

4

1.9

83.1

8.7

5

2.0

83.0

8.8

Reaction conditions: (R)-mandelic (6.09 g, 40 mmol), Et3N (8.90 g, 88 mmol), in DCM (50 mL), PivCl (amount was as indicated); H2O (10 mL), triethylamine (4.45 g, 44 mmol), 4nitrophenethylamine (6.31 g, 38 mmol), NaOH (1.76 g, 44 mmol), addition temperature 0-5 °C, reaction temperature 40-50 °C. Conversion was calculated from the HPLC area. At firstly, it may seem that 21 was produced from 15 and excess PivCl. However, only trace PivCl was detected by GC after refluxing implying 21 was formed via 20. The only Lewis acid triethylamine hydrochloride came into view. A proposed mechanism indicated the effect of triethylamine hydrochloride in the formation of the byproduct 21.


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Figure 2. Proposed mechanism for the formation of compound 21 The triethylamine hydrochloride produced in the first step was removed by washing with water, and the triethylamine used as an acid scavenger in the successive acylation process was also avoided. This improved sequence provided much better access to 10. After careful investigation, the optimized condition was established. PivCl was added to a solution of (R)-mandelic and triethylamine in DCM at 0-5 °C with further stirring for 0.5 h, after which water was added and the reaction mixture was reflux for 1.5-2.0 h. The organic layer was separated from the aqueous phase, to which 4-nitrophenethylamine was added and then stirred for 2-3 h. DCM was then replaced with ethanol and a followed up hydrolysis afforded intermediate 10. A 30 g scale experiment was performed, which after crystallization in ethanol-water delivered 10 in 92.0% yield and 99.4% purity. The 1H NMR and 13C NMR of 10 matched with that of reported. Most importantly, the specific rotation of 10 matched with that of a commercial product, which demonstrated that the stereogenic center was not affected under the developed acylation condition. This acylation condition was further applied on the large-scale production for multiple batches (from 50 g to a maximum of 500 g), and all gave the same results as the lab scale (91.5-


10

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92.3% yield, > 99.0 purity). The resulted product was used for the synthesis of mirabegron API following the above mentioned 2nd generation route on a 50 g scale (Scheme 3). Scheme 3 Preparation of 10

CONCLUSIONS In conclusion, an efficient and robust process for the synthesis towards a key intermediate 10 of mirabegron has been developed using mixed anhydride method. The optimized process was conducted under a mild condition affording the desired product 10 in 91.5-92.3% yield and > 99% purity, which was further utilized in the production of mirabegron API (50 g). Meanwhile, a side reaction caused by triethylamine hydrochloride was discovered and studied, which was ultimately avoided by executing the reaction in a biphasic solvent system. EXPERIMENTAL SECTION General. All the reagents and solvents were obtained from commercial suppliers and used without further purification. 1H and

13

C NMR spectra were recorded on a Bruker AVANCE

AV400 spectrometer in CDCl3, chemical shift data are reported in δ (ppm) from the internal standard TMS. Reaction monitoring and purity (area percentage) were analyzed by highperformance liquid chromatography (HPLC). It was performed by a standard method on a Shimadzu C18 column, 250 mm × 4.6 mm (5 µm); λ = 254 nm; mobile phase: MeOH/0.05 mol/L


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aq KH2PO4 buffer = 40/60. The HPLC analysis data is reported in area % and is not adjusted to weight %. GC conditions: column, HP-5, 30.0 m × 250 µm, 0.25-µm-thick coating; carrier gas, N2, 20 psi; injection, 240 °C, split ratio of 1:30; temperature, 50-240 at 10 °C/min. The GC analysis data is reported in area % and is not adjusted to weight %. The 1st generation synthesis design for intermediate 10. To a solution of 13 (40 mmol) and base (48 mmol) in the CH3CN (50 mL) was added PivCl (40 mmol) slowly at 0-5 °C, and the mixture was stirred for 1 h. Then the reaction mixture was raised to room temperature and stirred for 1 h. 4-Nitrophenethylamine (40 mmol) was added dropwise to the solution over a period of 15 min, the resulting solution was stirred at indicated temperature for 1.5-2.0 h. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (15 mL), then water (100 mL) was added dropwise and the mixture was stirred for 1 h. The precipitated solids were filtered, washed with water (10 mL), and dried at 50 °C affording 10 in the yield given in Table 1. The 2nd generation synthesis for intermediate 10. To a solution of 13 (6.09 g, 40 mmol) and triethylamine (8.90 g, 88 mmol) in DCM (50 mL) was added PivCl (amount was indicated in Table 2) at 0-5 °C, and the mixture was stirred for 0.5 h. Then the reaction mixture was raised to room temperature and stirred for 1 h. When the reaction was completed monitored by HPLC, the reaction mixture was washed with water (10 mL) and the DCM layer was separated. 4Ntrophenethylamine (6.64 g, 40 mmol) was added dropwise to the separated DCM solution at room temperature over a period of 15 min in the presence of triethylamine (4.45 g, 44 mmol), and the resulting solution was stirred for 2-3 h. The mixture was washed with hydrochloric acid (1M, 10 mL), the organic layer was concentrated under vacuum, then ethanol (50 mL) was added. To the mixture was added a solution of NaOH (1.76 g, 44 mmol) in water (6 mL) under 5 °C.


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When the reaction was completed checked by HPLC, the solvent was concentrated in vacuo to 20 mL. Then water (100 mL) was added dropwise and the mixture was stirred for 1 h. The precipitated solids were filtered, washed with water (10 mL), and dried at 50 °C to afford 10 and 21. Yield given in Table 2 was calculated from the HPLC area. Preparation of 10. To a solution of 13 (500.0 g, 3.29 mol) and triethylamine (681.7 g, 6.74 mol) in DCM (4.0 L) was added PivCl (792.4 g, 6.57 mol) slowly at 0-5 °C, and the mixture was stirred for 0.5 h. Then the mixture was raised to 20-30 °C and H2O (0.4 L) was added. After that, the reaction mixture was heated to reflux for 1.5-2.0 h until complete consumption of 13 which was monitored by HPLC. Then the mixture was cooled to room temperature. The DCM was separated from the aqueous phase, and 4-nitrophenethylamine (518.4 g, 3.12 mol) was added dropwise to the solution of DCM layer at room temperature over a period of 15 min, and the solution was stirred for 2-3 h. The mixture was washed with hydrochloric acid (1 M, 800 mL), after which the DCM layer was concentrated under vacuum, then ethanol (4.0 L) was added. To the mixture was added a solution of NaOH (144.6 g, 3.61 mol in 0.8 L H2O) under 5 °C in 2 h. The resulting mixture was stirred until complete consumption of the intermediate which was monitored by HPLC. The solvent was concentrated in vacuo until it was saturation. Whereupon water (8.0 L) was added dropwise and the mixture was stirred for 1 h. The precipitated solids were filtered, washed with water (0.8 L), and dried at 50 °C affording 10 as a light yellow solid (860.0 g, yield of 91.8 % based on 4-nitrophenethylamine). The HPLC purity was 99.4 %. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.6 Hz, 2H), 7.31 (ddd, J = 7.2, 5.9, 3.4 Hz, 5H), 7.15 (d, J = 8.6 Hz, 2H), 6.34 (s, 1H), 4.95 (d, J = 3.4 Hz, 1H), 3.75 (d, J = 3.5 Hz, 1H), 3.62–3.42 (m, 2H), 2.95–2.77 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 172.52, 146.77, 146.48, 139.60, 129.72,


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20 128.78, 128.61, 126.66, 123.82, 74.12, 40.01, 35.52. [α ]589 = -5.40 (c = 1.0, DCM; the specific

rotation of a commercial product is -5.43 in the same condition).

ASSOCIATED CONTENT Supporting Information. Copies of relevant NMR spectra and chromatograms. AUTHOR INFORMATION Corresponding Author E-mail: [email protected], [email protected]. Tel.: +8653182765841 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources Funding was partially provided by the National Science Foundation of China (21402064), the startup fund of University of Jinan, the Doctoral Fund of University of Jinan (160080304) and the Science Foundation for Post Doctorate Research from the University of Jinan (1003814). Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We thank the National Natural Science Foundation of China for financial support.


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ABBREVIATIONS OAB,

Overactive

bladder;

EDCI,

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

hydrochloride; PivCl, pivaloyl chloride; HOBt, 1-hydroxybenzotriazole; TsCl, tosyl chloride; MsCl, mesyl chloride. REFERENCES (1) Abrams, P.; Cardozo, L.; Fall, M.; Griffiths, D.; Rosier, P.; Ulmsten, U.; Kerrebroeck, P. V.; Victor, A.; Wein, A. UROLOGY 2003, 61, 37. (2) Abrams, P.; Chapple, C.; Khoury, S.; Roehrborn, C.; Rosette J. D. L. J Urol. 2009, 181, 1779. (3) Jaiprakash, H.; Benglorkar, G. M. RJPBCS 2014, 5(3), 213. (4) Malcolm G. Lucas, M. G.; Ruud J. L.; Bosch, R. J. L.; Burkhard, F. C.; Cruz, F.; Madden, T. B.; Nambiar, A. K.; Neisius, A.; Ridder, D. J. M. K.; Tubaro, A.; Turner, W.; Pickard, R. EUROPEAN UROLOGY 2012, 62, 1130. (5) Gormley, E. A.; Lightner, D. J.; Burgio, K. L.; Toby C. Chai, T. C.; Clemens, J. Q.; Culkin, D. J.; Das, A. K.; Foster, H. E.; Scarpero, H. M.; Tessier, C. D.; Vasavada, S. P. J Urol. 2012, 188, 2455. (6) Sacco, E.; Bientinesi, R. World J Obstet Gynecol 2013, 2(4), 65. (7) Maruyama, T.; Suzuki, T.; Onda, K.; Hayakawa, M.; Moritomo, H.; Kimizuka, T.; Matsui, T. US6346532, 2002. (8) Kawazoe, S.; Sakamoto, K.; Awamura, Y.; Maruyama, T.; Suzuki, T.; Onda, K.; Takasu, T. EP144096A1, 2004.


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(9) Takasu, T.; Sato, S.; Ukai, M.; Maruyama, T. EP1559427A1, 2005. (10) Zhang, H.; Li, Y.; Chen, S.; Shen, M.; Wang, X. CN103896872A, 2014. (11) Kawazoe, S.; Sakamoto, K.; Awamura, Y.; Maruyama, T.; Suziki, T.; Onda, K.; Takasu, T. US7982049B2, 2011. (12) Takasu, T.; Sato, S.; Ukai, M.; Maruyama, T.; Shibasaki, M. US8835474B2, 2014. (13) Ge, D.; Wu, Q. CN104230840A, 2014. (14) Hajipour, A. R.; Mazloumi, G. Phosphorus, Sulfur and Silicon 2003, 178, 137. (15) Jászay, Z. M.; Petneházy, I.; Tókc, L. Synthesis 1989, 745.


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Concise Synthesis of Key Intermediate of Mirabegron via a Mixed

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