One-Flow Operation via 4-Bromopyridine Enables Flash Synthesis of AChE Inhibitor

Hiroki Soutome; Yusuke Kimuro; Tomoko Kawaguchi; Dong-eun Yoo; Yiyue Yao; Shuto Oshida; Hiroki Nakayama; Masatomo Iwata; Ruka Ebisawa; Ryuhei Kikuchi; Kyosuke Tomite; Shuto Wada; Yosuke Ashikari; Aiichiro Nagaki

doi:10.1055/a-2218-9048

Synthesis, Table of Contents

Synthesis 2024; 56(05): 821-827
DOI: 10.1055/a-2218-9048

paper

Special Issue Flow Chemistry

One-Flow Operation via 4-Bromopyridine Enables Flash Synthesis of AChE Inhibitor

Hiroki Soutome

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

^bYokohama Technical Center, AGC Inc., Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan

,

Yusuke Kimuro

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

^cResearch and Development Center, Juzen Chemical Corp., 1-10 Kiba-cho, Toyama 930-0806, Japan

,

Tomoko Kawaguchi

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

,

Dong-eun Yoo

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

,

Yiyue Yao

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

,

Shuto Oshida

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

,

Hiroki Nakayama

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

,

Masatomo Iwata

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

,

Ruka Ebisawa

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

,

Ryuhei Kikuchi

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

,

Kyosuke Tomite

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

,

Shuto Wada

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

,

Yosuke Ashikari

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

,

Aiichiro Nagaki ∗

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

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Abstract

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Abstract

4-Bromopyridine is a building block that can be converted into valuable compounds, but due to its low stability, it is commercially available in the form of hydrochloride salt. Therefore, the hydrochloride salt is usually desalted with a basic aqueous solution and dried before organic reaction. In this study, to simplify the preparation and reaction procedure of 4-bromopyridine, multiple operations, desalting with a base, separation of the aqueous layer, and subsequent halogen–lithium exchange reaction were integrated into a single flow reaction. The reaction sequence was completed within 20 seconds and the yields were higher than the conventional methods. This is because the subsequent reaction can be performed immediately after the generation of 4-bromopyridine, which is unstable under ambient conditions.

Key words

one flow operation - flow microreactors - flash chemistry - integrated flow reactions - bromopyridine hydrochloride - liquid-liquid separate membrane - AChE inhibitors

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References

References
1 Sheldon RA. Chem. Soc. Rev. 2012; 41: 1437

2a Trost BM. Science 1991; 254: 1471
2b Trost BM. Angew. Chem., Int. Ed. Engl. 1995; 34: 259
2c Newhouse T, Baran PS, Hoffmann RW. Chem. Soc. Rev. 2009; 38: 3010

3a Wender PA, Verma VA, Paxton TJ, Pillow TH. Acc. Chem. Res. 2008; 41: 40
3b Wender PA. Tetrahedron 2013; 69: 7529

4a Hayashi Y. Chem. Sci. 2016; 7: 866
4b Hayashi Y. Acc. Chem. Res. 2021; 54: 1385

5 Li C.-J, Trost BM. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 13197

6a Matsumoto Y, Tsuzuki R, Matsuhisa A, Takayama K, Yoden T, Uchida W, Asano M, Fujita S, Yanagisawa I, Fujikura T. Chem. Pharm. Bull. 1996; 44: 103
6b Choi-Sledeski YM, McGarry DG, Green DM, Mason HJ, Becker MR, Davis RS, Ewing WR, Dankulich WP, Manetta VE, Morris RL, Spada AP, Cheney DL, Brown KD, Colussi DJ, Chu V, Heran CL, Morgan SR, Bentley RG, Leadley RJ, Maignan S, Guilloteau JP, Dunwiddie CT, Pauls HW. J. Med. Chem. 1999; 42: 3572
6c Russo O, Alami M, Brion J.-D, Sicsic S, Berque-Bestel I. Tetrahedron Lett. 2004; 45: 7069

7a Savanor PM, Jathi K, Bhat SK, Tantry RN. Res. J. Chem. Sci. 2013; 3: 38
7b Dutta B, Dey A, Sinha C, Ray PP, Mir MH. Dalton Trans. 2019; 48: 11259
7c Heitz W, Rehder A, Nießner N. Makromol. Chem. 1991; 12: 637

8a Mayer N, Schweiger M, Fuchs E, Migglautsch AK, Doler C, Grabner GF, Romauch M, Melcher M.-C, Zechner R, Zimmermann R, Breinbauer R. Bioorg. Med. Chem. 2020; 28: 115610
8b Kadri M, Hou J, Dorcet V, Roisnel T, Bechki L, Miloudi A, Bruneau C, Gramage-Doria R. Chem. Eur. J. 2017; 23: 5033
8c Li J.-Y, Lee C, Chen C.-Y, Lee W.-L, Ma R, Wu C.-G. Inorg. Chem. 2015; 54: 10483

9a Berlin AA, Razvodovskii EF. J. Polym. Sci. C, Polym. Symp. 2007; 16: 369
9b Wibaut JP, Broekman FW. Recl. Trav. Chim. Pays-Bas 1959; 78: 593

10a Anand P, Singh B, Singh N. Bioorg. Med. Chem. 2012; 20: 1175
10b Eckroat TJ, Manross DL, Cowan SC. Int. J. Mol. Sci. 2020; 21: 5965

11a Nagaki A, Ashikari Y, Takumi M, Tamaki T. Chem. Lett. 2021; 50: 485
11b Gutmann B, Cantillo D, Kappe CO. Angew. Chem. Int. Ed. 2015; 54: 6688
11c Capaldo L, Wen Z, Noël T. Chem. Sci. 2023; 14: 4230
11d Hartman RL, McMullen JP, Jensen KF. Angew. Chem. Int. Ed. 2011; 50: 7502
11e Tonhauser C, Natalello A, Löwe H, Frey H. Macromolecules 2012; 45: 9551

12 Bailey WF, Luderer MR, Jordan KP. J. Org. Chem. 2006; 71: 2825

13a Nagaki A, Yamada S, Doi M, Tomida Y, Takabayashi N, Yoshida J. Green Chem. 2011; 13: 1110
13b Nagaki A, Yamada D, Yamada S, Doi M, Ichinari D, Tomida Y, Takabayashi N, Yoshida J. Aust. J. Chem. 2013; 66: 199
13c Wakabayashi S, Takumi M, Kamio S, Wakioka M, Ohki Y, Nagaki A. Chem. Eur. J. 2023; 29: e202202882

14a Harenberg JH, Weidmann N, Knochel P. Synlett 2020; 31: 1880
14b Hessel V, Kralisch D, Kockmann N, Noël T, Wang Q. ChemSusChem 2013; 6: 746
14c Fuse S, Otake Y, Nakamura H. Chem. Asian J. 2018; 13: 3818
14d Ramanjaneyulu BT, Vishwakarma NK, Vidyacharan S, Adiyala PR, Kim D.-P. Bull. Korean Chem. Soc. 2018; 39: 757

15a Sagmeister P, Lebl R, Castillo I, Rehrl J, Kruisz J, Sipek M, Horn M, Sacher S, Cantillo D, Williams JD, Kappe CO. Angew. Chem. Int. Ed. 2021; 60: 8139
15b Jaman Z, Sobreira TJ. P, Mufti A, Ferreira CR, Cooks RG, Thompson DH. Org. Process Res. Dev. 2019; 23: 334

The direct use of arylborates generated in flow microreactors for cross-coupling reactions has been reported, see:

16a Nagaki A, Moriwaki Y, Yoshida J. Chem. Commun. 2012; 48: 11211
16b Ashikari Y, Kawaguchi T, Mandai K, Aizawa Y, Nagaki A. J. Am. Chem. Soc. 2020; 142: 17039

17 Baharloo F, Moslemin MH, Nadri H, Asadipour A, Mahdavi M, Emami S, Firoozpour LR, Mohebat L, Shafiee A, Foroumadi A. Eur. J. Med. Chem. 2015; 93: 196
18 Tong Z, Garry OL, Smith PJ, Jiang Y, Mansfield SJ, Anderson EA. Org. Lett. 2021; 23: 4888
19 Jiang Q, Fang L.-Q, Li Y.-H, Wang J, Li J.-H. ChemistrySelect 2023; 8: e202300780

20a Zhou H.-J, Huang J.-M. J. Org. Chem. 2022; 87: 5328
20b Sterckx H, Sambiagio C, Médran-Navarrete V, Maes BU. W. Adv. Synth. Catal. 2017; 359: 3226

21 DeBerardinis AM, Turlington M, Ko J, Sole L, Pu L. J. Org. Chem. 2010; 75: 2836

22a Zhang X, Yang C, Gao H, Wang L, Guo L, Xia W. Org. Lett. 2021; 23: 3472
22b Zhang X, Yang C, Gao H, Wang L, Guo L, Xia W. Org. Lett. 2021; 23: 3472
22c Wang G, Cao J, Gao L, Chen W, Huang W, Cheng X, Li S. J. Am. Chem. Soc. 2017; 139: 3904

23a Fargeas V, Favresse F, Mathieu D, Beaudet I, Charrue P, Lebret B, Piteau M, Quintard J.-P. Eur. J. Org. Chem. 2003; 1711
23b Nicolaou KC, Hepworth D, King NP, Finlay MR, Scarpelli R, Pereira MM, Bollbuck B, Bigot A, Werschkun B, Winssinger N. Chemistry 2000; 6: 2783

24a Yang L, Semba K, Nakao Y. Angew. Chem. Int. Ed. 2017; 56: 4853
24b Cook MJ, Fernandes I. Patent WO 2002096913 A1, 2002

25a Lansakara AI, Farrell DP, Pigge FC. Org. Biomol. Chem. 2014; 12: 1090
25b Wu G, Yin W, Shen HC, Huang Y. Green Chem. 2012; 14: 580

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