Development of In-Water Scalable Process for the Preparation of [2-(3-Bromo-2-methylphenyl)-7-chloro-1,3-benzoxazol-5-yl]methanol, a Key Intermediate in the Synthesis of Potent PD-1/PD-L1 Inhibitors

Abstract

We propose a synthetic process for the preparation of a benzoxazole building block for a programmed death-ligand 1 inhibitor that is a candidate currently under clinical investigation for cancer treatment. Our research focused on searching for mild, scalable, and ecofriendly conditions for the synthesis of benzoxazoles. To reduce the use of toxic reagents or solvents and to minimize the production of organic wastes, the cyclization reaction was performed in an aqueous micellar medium. This in-water benzoxazole synthesis gave comparable yields to previously reported processes, and was applied to a broad range of benzoxazoles with various substitution patterns, showcasing its effectiveness in ecofriendly benzoxazole cyclization reactions.

Key words

benzoxazoles - cyclization - in-water reaction - micelles - surfactants

Publication History

Received: 15 May 2024

Accepted after revision: 10 June 2024

Article published online:
01 July 2024

• References and Notes

• 1 Hili R, Yudin AK. Nat. Chem. Biol. 2006; 2: 284
• 2 Pozharskii AF, Soldatenkov AT, Katritzky AR. In Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry and Biochemistry and the Role of Heterocycles in Science, Technology, Medicine, and Agriculture, 2nd ed. Wiley; Chichester: 2011
• 3 Kerru N, Gummidi L, Maddila S, Gangu KK, Jonnalagadda SB. Molecules 2020; 25: 1909
• 4 Walsh CT. ACS Infect. Dis. 2018; 4: 1283
• 5 Abu-Hashem AA. J. Heterocycl. Chem. 2021; 58: 74
• 6 Šlachtová V, Brulíková L. ChemistrySelect 2018; 3: 4653
• 7 Seth K, Garg SK, Kumar R, Purohit P, Meena VS, Goyal R, Banerjee UC, Chakraborti AK. ACS Med. Chem. Lett. 2014; 5: 512
• 8 Şener E, Yalçin I.-s, Sungur E. Quant. Struct.-Act. Relat. 1991; 10: 223
• 9 Singh R, Nagori BP. Trop. J. Pharm. Life Sci. 2018; 4: 56
• 10 Shibata K, Kashiwada M, Ueki M, Taniguchi M. J. Antibiot. 1993; 46: 1095
• 11 Wu L, Li L, Yao W. WO 2019191707 2019
• 12 Wong XK, Yeong KY. ChemMedChem 2021; 16: 3237
• 13 Abdullahi A, Yeong KY. Med. Chem. Res. 2024; 33: 406
• 14 El Alami A, El Maraghi A, Sdassi H. Synth. Commun. 2024; 54: 769
• 15 Soni S, Sahiba N, Teli S, Teli P, Agarwal LK, Agarwal S. RSC Adv. 2023; 13: 24093
• 16 Nguyen TT, Nguyen X.-TT, Nguyen T.-LH, Tran PH. ACS Omega 2019; 4: 368
• 17 Wang D, Carper D, Jia Z, Shen B, Sclafani JA, Wilson R, Zhou J, Suleiman O, Wright M. WO 2022099071 2022
• 18a Clarke CJ, Tu W.-C, Levers O, Bröhl A, Hallett JP. Chem. Rev. 2018; 118: 747
• 18b Shen T, Zhou S, Ruan J, Chen X, Liu X, Ge X, Qian C. Adv. Colloid Interface Sci. 2021; 287: 102299
• 18c Sheldon RA. ACS Sustainable Chem. Eng. 2018; 6: 32
• 19 Zhou F, Hearne Z, Li C.-J. Curr. Opin. Green Sustain. Chem. 2019; 18: 118
• 20 Lajoie L, Fabiano-Tixier A.-S, Chemat F. Pharmaceuticals 2022; 15: 1507
• 21a Lipshutz BH. Curr. Opin. Green Sustainable Chem. 2018; 11: 1
• 21b Lipshutz BH, Huang S, Leong WW. Y, Isley NA. J. Am. Chem. Soc. 2012; 134: 19985
• 21c Andersson MP, Gallou F, Klumphu P, Takale BS, Lipshutz BH. Chem. Eur. J. 2018; 24: 6778
• 21d Klumphu P, Desfeux C, Zhang Y, Handa S, Gallou F, Lipshutz BH. Chem. Sci. 2017; 8: 6354
• 21e Handa S, Jin B, Bora PP, Wang Y, Zhang X, Gallou F, Reilly J, Lipshutz BH. ACS Catal. 2019; 9: 2423
• 21f Jin B, Gallou F, Reilly J, Lipshutz BH. Chem. Sci. 2019; 10: 3481
• 22a Dwars T, Paetzold E, Oehme G. Angew. Chem. Int. Ed. 2005; 44: 7174
• 22b Zhang K, Suh JM, Choi J.-W, Jang HW, Shokouhimehr M, Varma RS. ACS Omega 2019; 4: 483
• 22c Ohtaka A, Kawase M, Aihara S, Miyamoto Y, Terada A, Nakamura K, Hamasaka G, Uozumi Y, Shinagawa T, Shimomura O, Nomura R. ACS Omega 2018; 3: 10066
• 22d Yamada YM. A, Arakawa T, Hocke H, Uozumi Y. Angew. Chem. Int. Ed. 2007; 46: 704
• 22e Osako T, Srisa J, Torii K, Hamasaka G, Uozumi Y. Synlett 2019; 31: 147
• 22f Srisa J, Tankam T, Sukwattanasinitt M, Wacharasindhu S. Chem. Asian J. 2019; 14: 3335
• 23 Erythropel HC, Zimmerman JB, de Winter TM, Petitjean L, Melnikov F, Lam CH, Lounsbury AW, Mellor KE, Janković NZ, Tu Q, Pincus LN, Falinski MM, Coish P, Plata DL, Anastas P. Green Chem. 2018; 20: 1929
• 24 Anastas P, Eghbali N. Chem. Soc. Rev. 2010; 39: 301
• 25 Lipshutz BH, Subir G. Aldrichimica Acta 2008; 41: 59
• 26 Benzoxazole 8–16; General Procedure (Procedure A)A mixture of the appropriate aminophenol 1 (1.0 equiv) and benzaldehyde 5 (1.3 equiv) in 5 wt% aq Triton X-100 (2.0 mL) was stirred at 800 rpm at rt for 1 h, then DDQ (1.2 equiv) was added and the mixture was stirred at rt for a further 5 min. The resulting mixture was concentrated by rotary evaporation, and the crude product was purified by column chromatography (silica gel). 2-(3-Bromo-2-methylphenyl)-1,3-benzoxazole-5-carbonitrile (8) Synthesized according to General Procedure A from 3-amino-4-hydroxybenzonitrile (4b; 134.1 mg, 1.0 mmol) and 3-bromo-2-methylbenzaldehyde (5a; 258.7 mg, 1.3 mmol) to give a white solid; yield: 68%. ¹H NMR (500 MHz, CDCl₃): δ = 8.12 (t, J = 1.2 Hz, 1 H), 8.05 (dd, J = 7.9, 1.3 Hz, 1 H), 7.78 (dd, J = 8.0, 1.3 Hz, 1 H), 7.69 (d, J = 1.2 Hz, 2 H), 7.23 (t, J = 7.9 Hz, 1 H), 2.87 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 164.6, 152.7, 142.4, 138.9, 136.2, 129.8, 129.6, 127.7, 127.4, 127.3, 125.10, 118.8, 112.1, 108.7, 21.5. HRMS (method: Kinetex C18, 1.7 um, LC column 50 x 2.1 mm (phenomenex). Oven temperature 45 °C. Gradient solvent: 0.1% HCOOH in water: 0.1% HCOOH in acetonitrile = 80/20 to 0.1% HCOOH in water: 0.1% HCOOH in acetonitrile = 5/95 run time 10 minutes with flowrate 0.2 mL/min. Sciex exion LCTM and Q-TOF (X500B)): m/z [M + H]⁺ calcd for C₁₅H₁₀BrN₂O: 312.9977; found: 312.9974.