Crisaborole synthesis

Crisaborole, also known as AN-2728, is a topically administered, boron-containing, anti-inflammatory compound that inhibits PDE4 activity and thereby suppresses the release of TNFalpha, IL-12, IL-23 and other cytokines. At the time of publication, three phase Ib clinical trials, a IIa trial and a IIb trial of AN-2728 in patients with psoriasis had been completed; the compound was also undergoing phase II development for atopic dermatitis, but no data were available for this indication. Synthetic Description Reference: Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V, Freund Y, Kimura R, Maples KR, Plattner JJ. Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2129-32. doi: 10.1016/j.bmcl.2009.03.007. Epub 2009 Mar 9. PubMed PMID: 19303290. Synthetic Description Reference: Baker, Stephen J.; Sanders, Virginia; Akama, Tsutomu; Bellinger-Kawahara, Carolyn; Freund, Yvonne; Maples, Kirk R.; Plattner, Jacob J.; Zhang, Yong-Kang; Zhou, Huchen; Hernandez, Vincent S. Boron-containing small molecules as anti-inflammatory agents. WO 2007095638. (Assignee Anacor Pharmaceuticals, Inc., USA) Synthetic Description Reference: Ceric, Helena; Malenica, Marica; Ratkaj, Marina; Landeka, Ivana; Jegorov, Alexandr. Solid state forms of crisaborole. US 20170305936. Synthetic Description Reference: Li, Peijie; Sun, Yuanchao; Zhang, Muqun; Du, Heng; Gao, Suwan; Hu, Zhenyu; Krivonos, Sonia; Khashper, Arkady; Shteinman, Vitaly; Sery, Yana; Ben-Daniel, Revital. Crisaborole production process. WO 2018150327. (Assignee Wavelength Enterprises Ltd., Israel) Synthetic Description Reference: Baker, Stephen J.; Akama, Tsutomu; Alley, Michael Richard Kevin; Benkovic, Stephen J.; Dipierro, Michael; Hernandez, Vincent S.; Hold, Karin M.; Kennedy, Isaac; Likhotvorik, Igor; Mao, Weimin; Maples, Kirk R.; Plattner, Jacob J.; Rock, Fernando; Sanders, Virginia; Stemphoski, Aaron M.; Yiannikouros, George Petros; Zegar, Siead; Zhang, Yong-Kang; Zhou, Huchen. Preparation of boron-containing small molecules and nucleosides for treating fungal infections. WO 2007078340. (Assignee Anacor Pharmaceuticals, Inc., USA) Synthetic Description Reference: Zhao, Xinhua. Synthetic method of crisaborole from 4-halogenated benzonitrile. CN 106928264. (Assignee Hunan Zhongzhi Youku Technology Co., Ltd., Peop. Rep. China) Synthetic Description Reference: Huguet Clotet, Juan; Ozores Viturro, Lidia; Rodriguez Ropero, Sergio; Dalmases Barjoan, Pere. Process for preparing 4-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole). WO 2018115362. (Assignee Laboratorios Lesvi, SL, Spain) Synthetic Description Reference: Pullagurla, Manik Reddy; Pitta, Bhaskar Reddy; Namana, Suresh Babu; Rangisetty, Jagadeesh Babu. Novel process for the preparation of 4-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole). WO 2018207216. (Assignee Biophore India Pharmaceuticals Pvt. Ltd., India) Synthetic Description Reference: Srinivasan, Thirumalai Rajan; Sajja, Eswaraiah; Ghojala, Venkat Reddy; Bekkam, Markandeya. Process for the preparation of 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-[2,1]-benzoxaborole and polymorphs thereof. WO 2018216032. (Assignee MSN Laboratories Private Limited, R&D Center, India) Synthetic Description Reference: Bhirud, Shekhar Bhaskar; Naik, Samir; Tewari, Amit; Kajale, Yogesh Baburao; Choraghe, Mahendra Joma; Pawar, Sanjay Sakharam. Process for preparation of crisaborole. WO 2018224923. (Assignee Glenmark Pharmaceuticals Limited, India)

• ROUTE 1



Reference: Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V, Freund Y, Kimura R, Maples KR, Plattner JJ. Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2129-32. doi: 10.1016/j.bmcl.2009.03.007. Epub 2009 Mar 9. PubMed PMID: 19303290.

• ROUTE 2



Reference: Baker, Stephen J.; Sanders, Virginia; Akama, Tsutomu; Bellinger-Kawahara, Carolyn; Freund, Yvonne; Maples, Kirk R.; Plattner, Jacob J.; Zhang, Yong-Kang; Zhou, Huchen; Hernandez, Vincent S. Boron-containing small molecules as anti-inflammatory agents. WO 2007095638. (Assignee Anacor Pharmaceuticals, Inc., USA)

• ROUTE 3



Reference: Ceric, Helena; Malenica, Marica; Ratkaj, Marina; Landeka, Ivana; Jegorov, Alexandr. Solid state forms of crisaborole. US 20170305936.

• ROUTE 4



Reference: Li, Peijie; Sun, Yuanchao; Zhang, Muqun; Du, Heng; Gao, Suwan; Hu, Zhenyu; Krivonos, Sonia; Khashper, Arkady; Shteinman, Vitaly; Sery, Yana; Ben-Daniel, Revital. Crisaborole production process. WO 2018150327. (Assignee Wavelength Enterprises Ltd., Israel)

• ROUTE 5



Reference: Baker, Stephen J.; Akama, Tsutomu; Alley, Michael Richard Kevin; Benkovic, Stephen J.; Dipierro, Michael; Hernandez, Vincent S.; Hold, Karin M.; Kennedy, Isaac; Likhotvorik, Igor; Mao, Weimin; Maples, Kirk R.; Plattner, Jacob J.; Rock, Fernando; Sanders, Virginia; Stemphoski, Aaron M.; Yiannikouros, George Petros; Zegar, Siead; Zhang, Yong-Kang; Zhou, Huchen. Preparation of boron-containing small molecules and nucleosides for treating fungal infections. WO 2007078340. (Assignee Anacor Pharmaceuticals, Inc., USA)

• ROUTE 6



Reference: Zhao, Xinhua. Synthetic method of crisaborole from 4-halogenated benzonitrile. CN 106928264. (Assignee Hunan Zhongzhi Youku Technology Co., Ltd., Peop. Rep. China)

• ROUTE 7



Reference: Huguet Clotet, Juan; Ozores Viturro, Lidia; Rodriguez Ropero, Sergio; Dalmases Barjoan, Pere. Process for preparing 4-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole). WO 2018115362. (Assignee Laboratorios Lesvi, SL, Spain)

• ROUTE 8



Reference: Pullagurla, Manik Reddy; Pitta, Bhaskar Reddy; Namana, Suresh Babu; Rangisetty, Jagadeesh Babu. Novel process for the preparation of 4-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole). WO 2018207216. (Assignee Biophore India Pharmaceuticals Pvt. Ltd., India)

• ROUTE 9



Reference: Srinivasan, Thirumalai Rajan; Sajja, Eswaraiah; Ghojala, Venkat Reddy; Bekkam, Markandeya. Process for the preparation of 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-[2,1]-benzoxaborole and polymorphs thereof. WO 2018216032. (Assignee MSN Laboratories Private Limited, R&D Center, India)

• ROUTE 10



Reference: Bhirud, Shekhar Bhaskar; Naik, Samir; Tewari, Amit; Kajale, Yogesh Baburao; Choraghe, Mahendra Joma; Pawar, Sanjay Sakharam. Process for preparation of crisaborole. WO 2018224923. (Assignee Glenmark Pharmaceuticals Limited, India)