• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

用于合成DNDI-VL-2098的可扩展工艺开发：一种治疗内脏利什曼病的潜在临床前候选药物。

Development of a Scalable Process for the Synthesis of DNDI-VL-2098: A Potential Preclinical Drug Candidate for the Treatment of Visceral Leishmaniasis.

作者信息

Satam Vijay S, Pedada Srinivasa Rao, Kamaraj Pasumpon, Antao Nakita, Singh Apoorva, Hindupur Rama Mohan, Pati Hari N, Thompson Andrew M, Launay Delphine, Martin Denis

机构信息

Process Chemistry Division, Advinus Therapeutics Ltd., 21 & 22, Phase II, Peenya Industrial Area, Bangalore 560058, Karnataka, India.

Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

出版信息

Org Process Res Dev. 2017 Jan 20;21(1):52-59. doi: 10.1021/acs.oprd.6b00331. Epub 2016 Dec 6.

DOI:10.1021/acs.oprd.6b00331
PMID:28539754
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5437808/
Abstract

A process suitable for kilogram-scale synthesis of (2)-2-methyl-6-nitro-2-{[4-(trifluoromethoxy)phenoxy]methyl}-2,3-dihydroimidazo[2,1-][1,3]oxazole (DNDI-VL-2098, ), a preclinical drug candidate for the treatment of visceral leishmaniasis, is described. The four-step synthesis of the target compound involves the Sharpless asymmetric epoxidation of 2-methyl-2-propen-1-ol, . Identification of a suitable synthetic route using retrosynthetic analysis and development of a scalable process to access several kilograms of are illustrated. The process was simplified by employing in situ synthesis of some intermediates, reducing safety hazards, and eliminating the need for column chromatography. The improved reactions were carried out on the kilogram scale to produce in good yield, high optical purity, and high quality.

摘要

描述了一种适用于千克级合成(2)-2-甲基-6-硝基-2-{[4-(三氟甲氧基)苯氧基]甲基}-2,3-二氢咪唑并[2,1-][1,3]恶唑(DNDI-VL-2098，一种用于治疗内脏利什曼病的临床前候选药物)的方法。目标化合物的四步合成涉及2-甲基-2-丙烯-1-醇的夏普莱斯不对称环氧化反应。阐述了通过逆合成分析确定合适的合成路线以及开发可扩展工艺以制备数千克该化合物的过程。该工艺通过采用一些中间体的原位合成得以简化，降低了安全风险，并且无需柱色谱法。改进后的反应在千克规模上进行，以良好的产率、高光学纯度和高质量制备该化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/1c904e1c06f5/op-2016-00331a_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/5c827f308310/op-2016-00331a_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/34955a46a66e/op-2016-00331a_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/912e715aa91a/op-2016-00331a_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/76b3d3312852/op-2016-00331a_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/fe5bd4bacd28/op-2016-00331a_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/a7dc3891cc1c/op-2016-00331a_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/1c904e1c06f5/op-2016-00331a_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/5c827f308310/op-2016-00331a_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/34955a46a66e/op-2016-00331a_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/912e715aa91a/op-2016-00331a_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/76b3d3312852/op-2016-00331a_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/fe5bd4bacd28/op-2016-00331a_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/a7dc3891cc1c/op-2016-00331a_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3412/5437808/1c904e1c06f5/op-2016-00331a_0003.jpg

相似文献

1
Development of a Scalable Process for the Synthesis of DNDI-VL-2098: A Potential Preclinical Drug Candidate for the Treatment of Visceral Leishmaniasis.用于合成DNDI-VL-2098的可扩展工艺开发：一种治疗内脏利什曼病的潜在临床前候选药物。
Org Process Res Dev. 2017 Jan 20;21(1):52-59. doi: 10.1021/acs.oprd.6b00331. Epub 2016 Dec 6.
2
Nitroimidazo-oxazole compound DNDI-VL-2098: an orally effective preclinical drug candidate for the treatment of visceral leishmaniasis.硝咪唑并恶唑类化合物 DNDI-VL-2098：一种治疗内脏利什曼病的有效口服前临床候选药物。
J Antimicrob Chemother. 2015 Feb;70(2):518-27. doi: 10.1093/jac/dku422. Epub 2014 Nov 10.
3
DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc.DNDI-6174 是一种针对细胞色素 bc 的内脏利什曼病的临床前候选药物。
Sci Transl Med. 2023 Dec 13;15(726):eadh9902. doi: 10.1126/scitranslmed.adh9902.
4
Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis.重新定位抗结核 6-硝基-2,3-二氢咪唑并[2,1-b][1,3]恶唑类药物治疗被忽视热带病：内脏利什曼病临床前候选药物的结构活性研究。
J Med Chem. 2016 Mar 24;59(6):2530-50. doi: 10.1021/acs.jmedchem.5b01699. Epub 2016 Mar 8.
5
Practical Synthesis of 6-Amino-1-hydroxy-2,1-benzoxaborolane: A Key Intermediate of DNDI-6148.6-氨基-1-羟基-2,1-苯并硼氧烷的实用合成：DNDI-6148的关键中间体
Org Process Res Dev. 2024 Mar 29;28(4):1213-1223. doi: 10.1021/acs.oprd.4c00031. eCollection 2024 Apr 19.
6
7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis.7-取代的2-硝基-5,6-二氢咪唑并[2,1-b][1,3]恶嗪：新型抗结核药物成为内脏利什曼病的新临床前候选药物。
J Med Chem. 2017 May 25;60(10):4212-4233. doi: 10.1021/acs.jmedchem.7b00034. Epub 2017 May 11.
7
DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis.DNDI-6148：一种用于治疗内脏利什曼病的新型苯并恶硼烷临床前候选药物。
J Med Chem. 2021 Nov 11;64(21):16159-16176. doi: 10.1021/acs.jmedchem.1c01437. Epub 2021 Oct 28.
8
In vitro metabolism, disposition, preclinical pharmacokinetics and prediction of human pharmacokinetics of DNDI-VL-2098, a potential oral treatment for Visceral Leishmaniasis.DNDI-VL-2098（一种用于内脏利什曼病的潜在口服治疗药物）的体外代谢、处置、临床前药代动力学及人体药代动力学预测
Eur J Pharm Sci. 2014 Dec 18;65:147-55. doi: 10.1016/j.ejps.2014.09.006. Epub 2014 Sep 27.
9
Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis.（6R）-2-硝基-6-[4-（三氟甲氧基）苯氧基]-6,7-二氢-5H-咪唑并[2,1-b][1,3]恶嗪（DNDI-8219）的开发：一种新的内脏利什曼病治疗先导化合物。
J Med Chem. 2018 Mar 22;61(6):2329-2352. doi: 10.1021/acs.jmedchem.7b01581. Epub 2018 Mar 6.
10
Pharmacokinetics and Pharmacodynamics of the Nitroimidazole DNDI-0690 in Mouse Models of Cutaneous Leishmaniasis.硝咪唑类化合物 DNDI-0690 在皮肤利什曼病小鼠模型中的药代动力学和药效学研究。
Antimicrob Agents Chemother. 2019 Aug 23;63(9). doi: 10.1128/AAC.00829-19. Print 2019 Sep.

引用本文的文献

1
Study on Reaction Mechanism and Process Safety for Epoxidation.环氧化反应机理及过程安全研究
ACS Omega. 2023 Nov 29;8(49):47254-47261. doi: 10.1021/acsomega.3c07461. eCollection 2023 Dec 12.
2
A recent update on new synthetic chiral compounds with antileishmanial activity.最近有关具有抗利什曼原虫活性的新型合成手性化合物的最新进展。
Chirality. 2022 Oct;34(10):1279-1297. doi: 10.1002/chir.23494. Epub 2022 Aug 10.
3
Functionalized Nitroimidazole Scaffold Construction and Their Pharmaceutical Applications: A 1950-2021 Comprehensive Overview.

本文引用的文献

1
Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis.重新定位抗结核 6-硝基-2,3-二氢咪唑并[2,1-b][1,3]恶唑类药物治疗被忽视热带病：内脏利什曼病临床前候选药物的结构活性研究。
J Med Chem. 2016 Mar 24;59(6):2530-50. doi: 10.1021/acs.jmedchem.5b01699. Epub 2016 Mar 8.
2
Visceral leishmaniasis prevalence and associated risk factors in the saran district of Bihar, India, from 2009 to July of 2011.2009 年至 2011 年 7 月印度比哈尔邦萨拉恩区内脏利什曼病的流行情况及相关危险因素。
Am J Trop Med Hyg. 2013 Apr;88(4):778-84. doi: 10.4269/ajtmh.12-0442. Epub 2013 Feb 4.
3
功能化硝基咪唑支架的构建及其药物应用：1950 - 2021年综述
Pharmaceuticals (Basel). 2022 Apr 30;15(5):561. doi: 10.3390/ph15050561.
4
A concise and sequential synthesis of the nitroimidazooxazole based drug, Delamanid and related compounds.基于硝基咪唑并恶唑的药物地拉米韦及相关化合物的简洁且连贯的合成。
RSC Adv. 2020 May 1;10(29):17085-17093. doi: 10.1039/d0ra01662d. eCollection 2020 Apr 29.
5
Recent Progress in the Discovery and Development of 2-Nitroimidazooxazines and 6-Nitroimidazooxazoles to Treat Tuberculosis and Neglected Tropical Diseases.新型 2-硝基咪唑并恶嗪和 6-硝基咪唑并恶唑类化合物在抗结核和治疗被忽视热带病药物研发中的研究进展
Molecules. 2020 Sep 10;25(18):4137. doi: 10.3390/molecules25184137.
6
Competing Pathways in O-Arylations with Diaryliodonium Salts: Mechanistic Insights.二芳基碘鎓盐参与的O-芳基化反应中的竞争途径：机理见解
Chemistry. 2017 Sep 21;23(53):13249-13258. doi: 10.1002/chem.201703057. Epub 2017 Sep 5.
7
Dichlorotrifluoromethoxyacetic Acid: Preparation and Reactivity.二氯三氟甲氧基乙酸：制备与反应活性
Molecules. 2017 Jun 9;22(6):966. doi: 10.3390/molecules22060966.
Assessing the essentiality of Leishmania donovani nitroreductase and its role in nitro drug activation.
评估杜氏利什曼原虫硝基还原酶的必需性及其在硝基药物激活中的作用。
Antimicrob Agents Chemother. 2013 Feb;57(2):901-6. doi: 10.1128/AAC.01788-12. Epub 2012 Dec 3.
4
Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles.新型系列光学活性6-硝基-2,3-二氢咪唑并[2,1-b]恶唑的合成及其抗结核活性
J Med Chem. 2006 Dec 28;49(26):7854-60. doi: 10.1021/jm060957y.
5
The increase in risk factors for leishmaniasis worldwide.全球范围内利什曼病风险因素的增加。
Trans R Soc Trop Med Hyg. 2001 May-Jun;95(3):239-43. doi: 10.1016/s0035-9203(01)90223-8.