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 Qi-Long Zhang, Zhi-Yuan Zhuang, Qing-Dong Liu, Zhan-Ming Zhang, Fu-Xu Zhan,* and Geng-Xiu Zheng* School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, Shandong, P. R. China

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S Supporting Information *

by an aqueous EDCI coupling affording mirabegron. This route was rather concise with only four 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. Aiming to find an economical and suitable process for scaleup 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.

ABSTRACT: An efficiently scalable synthesis of key intermediate toward mirabegron has been developed via a mixed anhydride method, employing PivCl instead of EDCI and HOBt. The developed process produced (R)-2hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (10) in 91.5−92.3% yield and >99.0% HPLC purity under mild conditions. 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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RESULTS AND DISCUSSION The second-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 three steps involving hydroxyl protection, amidation, and deprotection, compared to the onestep 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 the hydroxyl. Several acyl chlorides and sulfonyl chlorides14,15 were investigated. Considering that anhydride intermediates were not stable enough for thorough characterization, 4-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). 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. The initial formation of 16 was accompanied by intramolecular trapping of the benzyl hydroxyl group, forming a five-membered ring which ultimately collapsed to form 19 (Figure 1). 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.

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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.1−3 Current guidelines recommend oral antimuscarinics drugs as the firstline 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 toward 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 industrially available, which restricted its application in industry. (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 1ethyl-3-(3-(dimethylamino)propyl)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 boranetetrahydrofuran complex in a mixed solution of 1,3-dimethyl-2imidazolidinone (DMI) and tetrahydrofuran (THF), affording amine 11. The nitro group of 11 was then reduced by hydrogenation affording aniline 12 which was further amidated © 2016 American Chemical Society

Received: July 6, 2016 Published: October 13, 2016 1993

DOI: 10.1021/acs.oprd.6b00231 Org. Process Res. Dev. 2016, 20, 1993−1996

Organic Process Research & Development

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Scheme 1. First-Generation Synthetic Route of Mirabegron

Scheme 2. Second-Generation Synthetic Route of Mirabegron

Table 1. First-Generation Synthesis Design for Intermediate 10a

entry

R1

R2Cl

temp. (°C)

base

10 (%)

1 2 3 4 5 6

H H H Na Na Na

TsCl MsCl PivCl TsCl MsCl PivCl

reflux 25 0 reflux 25 0

K2CO3 K2CO3 Et3N

30 45 0 35 47 0

Figure 1. Proposed mechanism for the formation of compound 19.

in 8.2% conversion. Increasing the equivalent of PivCl led to higher amount of 10. At first, 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 (Figure 2) indicated the effect of triethylamine hydrochloride in the formation of the byproduct 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

a Reaction conditions: 13 (40 mmol), R2Cl (40 mmol), CH3CN (50 mL), base (48 mmol). Conversion was calculated from the HPLC area.

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 1994



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Figure 2. Proposed mechanism for the formation of compound 21.

Scheme 3. Preparation of 10

Shimadzu C18 column, 250 mm × 4.6 mm (5 μm); λ = 254 nm; mobile phase: MeOH/0.05 mol/L aq KH2PO4 buffer = 40/60. The HPLC analysis data are 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 are reported in area % and are not adjusted to weight %. First-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. Second-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. 4-Nitrophenethylamine (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 (1 M, 10 mL); the organic layer was concentrated under vacuum, and 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. When the reaction was completed checked by HPLC, the solvent was

refluxed 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 (91.5−92.3% yield, >99.0 purity). The resulted product was used for the synthesis of mirabegron API following the above-mentioned second generation route on a 50 g scale (Scheme 3).

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CONCLUSIONS In conclusion, an efficient and robust process for the synthesis toward 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.

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EXPERIMENTAL SECTION

General. All of the reagents and solvents were obtained from commercial suppliers and used without further purification. 1H and 13C 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 high-performance liquid chromatography (HPLC). It was performed by a standard method on a 1995



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Table 2. Second-Generation Synthesis Design for Intermediate 10a

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.6b00231. Copies of relevant NMR spectra and chromatograms (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel.: +8653182765841. *E-mail: [email protected]. entry

PivCl (equiv)

10 (%)

21 (%)

1 2 3 4 5

1.6 1.7 1.8 1.9 2.0

55.0 76.7 82.8 83.1 83.0

8.2 8.7 8.0 8.7 8.8

Funding

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

a

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), 4-nitrophenethylamine (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.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China for financial support. ABBREVIATIONS OAB, overactive bladder; EDCI, 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride; PivCl, pivaloyl chloride; HOBt, 1-hydroxybenzotriazole; TsCl, tosyl chloride; MsCl, mesyl chloride

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. The 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 saturated, 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). 13 C NMR (100 MHz, CDCl3) δ 172.52, 146.77, 146.48, 139.60, 129.72, 128.78, 128.61, 126.66, 123.82, 74.12, 40.01, 35.52. [α]20 589 = −5.40 (c = 1.0, DCM; the specific rotation of a commercial product is −5.43 in the same condition).

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REFERENCES

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Concise Synthesis of Key Intermediate of Mirabegron via a Mixed

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