Novel and Practical Industrial Process Scale-Up of 5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid, a Key Intermediate in the Manufacturing of Therapeutic SGLT2 Inhibitors
Abstract 5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid (1) is a key intermediate for the synthesis of a family of promising SGLT2 inhibitors currently in preclinical and phase I studies for diabetes therapy. In this investigation, cheap, easily available dimethyl terephthalate was used...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Georg Thieme Verlag KG
2022-12-01
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| Series: | Pharmaceutical Fronts |
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| Online Access: | http://www.thieme-connect.de/DOI/DOI?10.1055/s-0042-1755195 |
| _version_ | 1797976616507277312 |
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| author | Yi Zhang Xiao Ma Xiao-Hui Shan Xiao-Wen Zhang Jian-Qi Li Yu Liu |
| author_facet | Yi Zhang Xiao Ma Xiao-Hui Shan Xiao-Wen Zhang Jian-Qi Li Yu Liu |
| author_sort | Yi Zhang |
| collection | DOAJ |
| description | Abstract
5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid (1) is a key intermediate for the synthesis of a family of promising SGLT2 inhibitors currently in preclinical and phase I studies for diabetes therapy. In this investigation, cheap, easily available dimethyl terephthalate was used as the raw starting material, and compound 1 was prepared effectively in six steps, including nitration, hydrolysis, hydrogenation, esterification, bromination, and diazotization. The preparation was run successfully on approximately 70 kg/batch with the total yield of 24%. This practical process was demonstrated to be scalable with a great yield and significant cost reduction. |
| first_indexed | 2024-04-11T04:53:45Z |
| format | Article |
| id | doaj.art-d6f2a753e5184d3398c532816a59749f |
| institution | Directory Open Access Journal |
| issn | 2628-5088 2628-5096 |
| language | English |
| last_indexed | 2024-04-11T04:53:45Z |
| publishDate | 2022-12-01 |
| publisher | Georg Thieme Verlag KG |
| record_format | Article |
| series | Pharmaceutical Fronts |
| spelling | doaj.art-d6f2a753e5184d3398c532816a59749f2022-12-26T23:50:06ZengGeorg Thieme Verlag KGPharmaceutical Fronts2628-50882628-50962022-12-010404e244e24910.1055/s-0042-1755195Novel and Practical Industrial Process Scale-Up of 5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid, a Key Intermediate in the Manufacturing of Therapeutic SGLT2 InhibitorsYi Zhang0Xiao Ma1Xiao-Hui Shan2Xiao-Wen Zhang3Jian-Qi Li4Yu Liu5Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of ChinaNovel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of ChinaShandong Shenghua New Material Technology Co., Ltd., Laiyang, People's Republic of ChinaNovel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of ChinaNovel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of ChinaNovel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of ChinaAbstract 5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid (1) is a key intermediate for the synthesis of a family of promising SGLT2 inhibitors currently in preclinical and phase I studies for diabetes therapy. In this investigation, cheap, easily available dimethyl terephthalate was used as the raw starting material, and compound 1 was prepared effectively in six steps, including nitration, hydrolysis, hydrogenation, esterification, bromination, and diazotization. The preparation was run successfully on approximately 70 kg/batch with the total yield of 24%. This practical process was demonstrated to be scalable with a great yield and significant cost reduction.http://www.thieme-connect.de/DOI/DOI?10.1055/s-0042-17551955-bromo-2-chloro-4-(methoxycarbonyl)benzoic acidsglt2 inhibitorspractical processscale up |
| spellingShingle | Yi Zhang Xiao Ma Xiao-Hui Shan Xiao-Wen Zhang Jian-Qi Li Yu Liu Novel and Practical Industrial Process Scale-Up of 5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid, a Key Intermediate in the Manufacturing of Therapeutic SGLT2 Inhibitors Pharmaceutical Fronts 5-bromo-2-chloro-4-(methoxycarbonyl)benzoic acid sglt2 inhibitors practical process scale up |
| title | Novel and Practical Industrial Process Scale-Up of 5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid, a Key Intermediate in the Manufacturing of Therapeutic SGLT2 Inhibitors |
| title_full | Novel and Practical Industrial Process Scale-Up of 5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid, a Key Intermediate in the Manufacturing of Therapeutic SGLT2 Inhibitors |
| title_fullStr | Novel and Practical Industrial Process Scale-Up of 5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid, a Key Intermediate in the Manufacturing of Therapeutic SGLT2 Inhibitors |
| title_full_unstemmed | Novel and Practical Industrial Process Scale-Up of 5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid, a Key Intermediate in the Manufacturing of Therapeutic SGLT2 Inhibitors |
| title_short | Novel and Practical Industrial Process Scale-Up of 5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid, a Key Intermediate in the Manufacturing of Therapeutic SGLT2 Inhibitors |
| title_sort | novel and practical industrial process scale up of 5 bromo 2 chloro 4 methoxycarbonyl benzoic acid a key intermediate in the manufacturing of therapeutic sglt2 inhibitors |
| topic | 5-bromo-2-chloro-4-(methoxycarbonyl)benzoic acid sglt2 inhibitors practical process scale up |
| url | http://www.thieme-connect.de/DOI/DOI?10.1055/s-0042-1755195 |
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