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[1]何灵敏,周开扬,王 璨,等.替卡格雷关键中间体合成工艺研究 [J].武汉工程大学学报,2026,48(04):406-411,417.[doi:10.19843/j.cnki.CN42-1779/TQ.202506004]
　HE Lingmin,ZHOU Kaiyang,WANG Can,et al.Optimization of synthetic process of a key intermediate for ticagrelor [J].Journal of Wuhan Institute of Technology,2026,48(04):406-411,417.[doi:10.19843/j.cnki.CN42-1779/TQ.202506004]
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替卡格雷关键中间体合成工艺研究
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《武汉工程大学学报》[ISSN:1674-2869/CN:42-1779/TQ]

卷:
48
期数:
2026年04期
页码:
406-411,417
栏目:
现代大化工
出版日期:
2026-08-30

文章信息/Info

Title:
Optimization of synthetic process of a key intermediate for ticagrelor
文章编号:
1674 - 2869（2026）04 - 0406 - 06
作者:
何灵敏1; 周开扬2; 王 璨2; 林 丰*2; 陈云峰*2
1.浙江燎原药业有限公司，浙江 临海 317016；
2.武汉工程大学化学与环境工程学院，湖北 武汉 430205
Author(s):
HE Lingmin1;  ZHOU Kaiyang2;  WANG Can2;  LIN Feng*2; CHEN Yunfeng*2
1. Zhejiang Liaoyuan Pharmaceutical Co., Ltd, Linhai 317016, China;
2. School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430205, China
关键词:
替卡格雷; 药物中间体; 抗血栓; 工业化生产
Keywords:
ticagrelor;  drug intermediate;  antithrombosis;  industrial synthesis
分类号:
TQ460.6
DOI:
10.19843/j.cnki.CN42-1779/TQ.202506004
文献标志码:
A
摘要:
为优化替卡格雷的关键中间体2-[[(3AR,4S,6R,6AS)-6-氨基四氢-2,2-二甲基-4H-环戊并-1,3-二恶茂-4-基]氧基]-乙醇(2R,3R)-2,3-二羟基丁二酸盐的合成工艺，选择了一条以D-核糖为起始原料的合成路线，通过优化反应条件以及后处理方案，达到降低合成成本，简化操作流程的目的，提升工艺工业应用价值。相较于传统工艺，本工艺采用硫酸铜去除吡啶，使第二步反应收率从文献报道的68%提升至80%；同时采用一锅法的开环/缩合/分子内环加成序列反应合成关键中间体7，减少了后处理的步骤，三步反应总收率达到41%；对第8步反应溶剂进行了筛选，将该步收率提升至90%；在第9步反应中加入相转移催化剂四丁基溴化铵，使此步反应收率由60%提升至99%。经工艺优化，该合成路线整体收率可达41%。
Abstract:
To optimize the synthetic process of 2-[[(3AR,4S,6R,6AS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopentano-1,3-dioxamo-4-yl]oxy]-ethanol(2R,3R)-2,3-dihydroxysuccinate, a key intermediate for Ticagrelor, a synthetic route utilizing D-ribose as the starting material was adopted, and the reaction conditions and post-treatment protocols were systematically optimized to reduce production costs, simplify operational procedures, and improve the industrial applicability of the process. In contrast to the conventional synthetic route, copper sulfate was used to remove pyridine in the second step, increasing the reaction yield from the reported 68% to 80%. Meanwhile，a one-pot sequential reaction strategy involving ring-opening，condensation and intramolecular cycloaddition was developed to synthesize the key intermediate 7, effectively simplifying post-treatment operations and achieving a three-step total yield of 41%. Solvent screening was performed for the eighth reaction step, raising the corresponding yield to 90%. Furthermore, tetrabutylammonium bromide, a phase-transfer catalyst, was introduced in the ninth step, significantly improving the reaction yield from 60% to 99%. The overall yield of the optimized synthetic route reached 41%.

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备注/Memo

备注/Memo:
收稿日期：2025-06-05
基金项目：国家自然科学基金（22105150）
作者简介：何灵敏，工程师。Email: helinming77@sina.com
*通信作者：林 丰，工程师。Email: 478562807@qq.com
陈云峰，博士，教授。Email: yfchen@wit.edu.cn
更新日期/Last Update: 2026-09-05