[1]周玥莹,曾皓月,裘京晓,等.半富马酸替诺福韦艾拉酚胺的合成工艺优化[J].华侨大学学报(自然科学版),2019,40(4):527-534.[doi:10.11830/ISSN.1000-5013.201806034]
　ZHOU Yueying,ZENG Haoyue,QIU Jingxiao,et al.Improved Synthesis of Tenofovir Alafenamide Hemifumarate[J].Journal of Huaqiao University(Natural Science),2019,40(4):527-534.[doi:10.11830/ISSN.1000-5013.201806034]
点击复制

半富马酸替诺福韦艾拉酚胺的合成工艺优化()
分享到：

《华侨大学学报（自然科学版）》[ISSN:1000-5013/CN:35-1079/N]

卷:
第40卷
期数:
2019年第4期
页码:
527-534
栏目:
出版日期:
2019-07-10

文章信息/Info

Title:
Improved Synthesis of Tenofovir Alafenamide Hemifumarate
文章编号:
1000-5013(2019)04-0527-08
作者:
周玥莹1;  曾皓月1;  裘京晓2;  黄程勇3;  吴振4;  王立强1
1. 华侨大学 生物医学学院, 福建 泉州 362021;2. 北京第二外国语学院 校医院, 北京 100024;3. 福建国脉生物科技有限公司, 福建 泉州 362006;4. 厦门大学 药学院, 福建 厦门 361102
Author(s):
ZHOU Yueying1;  ZENG Haoyue1;  QIU Jingxiao2; HUANG Chengyong3;  WU Zhen4;  WANG Liqiang1
1. School of Biomedical Sciences, Huaqiao University, Quanzhou 362021, China; 2. School Hospital, Beijing International Studies University, Beijing 100024, China; 3. Fujian Guomai Biological Technology Limited Company, Quanzhou 362006, China; 4. College of Pharmacy, Xiamen University, Xiamen 361102, China
关键词:
半富马酸替诺福韦艾拉酚胺;  腺嘌呤;  (R)-碳酸丙烯酯;  工艺改进
Keywords:
tenofovir alafenamide hemifumarate;  adenine;  (R)-propylene carbonate;  process improvement
分类号:
R914.5
DOI:
10.11830/ISSN.1000-5013.201806034
文献标志码:
A
摘要:
对最新抗乙肝药物半富马酸替诺福韦艾拉酚胺(TAF)的合成工艺进行优化研究.以腺嘌呤(1)为原料,与(R)-碳酸丙烯酯反应得到(R)-9-(2-羟丙基)腺嘌呤.然后,将产物经磷叶立德取代,水解反应得到(R)-9-((2-磷酸单苯酯基)甲氧基)丙基)-腺嘌呤.最后,将所得产物经取代、酰化、缩合、成盐反应得到目标产物TAF,并对各步反应条件进行优化.结果表明:总收率达32.1%(以腺嘌呤计),较原工艺提高23.1%,目标化合物及主要中间体经电子轰击质谱(EI-MS)、核磁共振氢谱(1H-NMR)、核磁共振碳谱(13C-NMR)确证结构;与现有文献报道的TAF合成工艺相比,优化后的工艺总收率大幅提高,反应成本降低,反应时间缩短,可避免生产过程中的安全隐患,适合工业化生产.
Abstract:
The synthesis process of a new anti-hepatitis B drug, tenofovir alafenamide(TAF)hemifumarate, was optimized. Adenine(1)was used as a raw material to react with(R)-propylene carbonate to give(R)-9-(2-hydroxypropyl)adenine, followed by phosphorus ylide substitution and hydrolysis to obtain(R)-9-((2-phenylphenyl)methoxy)propyl)-adenine. Finally, the product obtained in the previous step was substituted, acylated, condensed and salt-formed to obtain the target product TAF, and the reaction conditions of each step were optimized. The results shows that the total yield reached 32.1%(as calculated on adenine), which was 23.1% higher than the original process, and the product and main intermediates were confirmed by electron impact mass spectrometry(EI-MS), proton nuclear magnetic resonance(1H-NMR)and carbon 13 nuclear magnetic resonance(13C-NMR). Compared with the TAF synthesis technology reported in the existing literature, the total yield of the process after optimization improved significantly, the reaction cost reduced, and the reaction time shortened. In addition, the security threats in the production process were avoided, which indicates that the synthesis process is suitable for industrial production.

参考文献/References:

[1] HAMPEL A,SOLBACH P,CORNBERG M,et al.Current seroprevalence, vaccination and predictive value of liver enzymes for hepatitis B among refugees in Germany[J].Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz,2016,59(5):578-583.DOI:10.1007/s00103-016-2333-8.
[2] IQBAL K,KLEVENS R M,KAINER M A,et al.Epidemiology of acute hepatitis B in the United States from population-based surveillance, 2006-2011[J].Clinical Infectious Diseases,2015,61(4):584-592.DOI:10.1093/cid/civ332.
[3] OTT J J,HORN J,KRAUSE G,et al.Time trends of chronic HBV infection over prior decades: A global analysis[J].Journal of Hepatology,2016,66(1):48-54.DOI:10.1016/j.jhep.2016.08.013.
[4] MARKOWITZ M,ZOLOPA A,SQUIRES K,et al.Phase Ⅰ/Ⅱ study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults[J].J Antimicrob Chemother,2014,69(5):1362-1369.DOI:10.1093/jac/dkt532.
[5] AGARWAL K,FUNG S K,NGUYEN T T,et al.Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection[J].Journal of Hepatology,2015,62(3):533-540.DOI:10.1016/j.jhep.2014.10.035.
[6] SAX P E,ZOLOPA A,BRAR I,et al.Tenofovir alafenamide vs tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: A randomized phase 2 study[J].Journal of Acquired Immune Deficiency Syndromes,2014,67(1):52-58.DOI:10.1097/QAI.0000000000000225.
[7] ZHANG Qian,MA Baiwei,WANG Qianqian,et al.The synthesis of tenofovir and its analogues via asymmetric transfer hydrogenation[J].Organic Letters,2014,16(7):2014-2017.DOI:10.1021/ol500583d.
[8] 郑庆泉,黄世福,曹徐涛.半富马酸替诺福韦艾拉酚胺关键中间体的合成工艺: 中国 104817593B[P].2016-11-16.
[9] BECKER M W,CHAPMAN H H,CIHLAR T,et al.Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same: US 20000220021[P].2000-07-21.
[10] OCAMPO C E, LEE D, JAMISON T F. Selective Lewis acid catalyzed assembly of phosphonomethyl ethers: Three-step synthesis of tenofovir[J].Organic Letters,2015,17(4):820-823.DOI:10.1021/ol503612h.
[11] ROUX L,PRIET S,PAYROT N,et al.Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: Synthesis, antiviral activity and decomposition study[J].European Journal of Medicinal Chemistry,2013,63(4/5/6):869-881.DOI:10.1016/j.ejmech.2013.02.039.
[12] LARROW J F,AND S E S,JACOBSEN E N.Kinetic resolution of terminal epoxides via highly regioselective and enantioselective ring opening with TMSN3: An efficient, catalytic route to 1,2-amino alcohols[J].Journal of the American Chemical Society,1996,118(31):7420-7421.DOI:10.1002/chin.199647029.
[13] HOLV A,MASOJíDKOVáM.Synthesis of enantiomeric N-(2-phosphonomethoxypropyl)derivatives of purine and pyrimidine bases(Ⅰ): The stepwise approach[J].Cheminform,1995,27(1):1196-1212.DOI:10.1135/cccc19951196.
[14] LIU Dazhan,SHI Bing,WANG Fang,et al.Tenofovir alafenamide hemifumarate: US 8754065 B2[P].2014-06-01.
[15] JANSA P,BASZCZY?SKI O,PROCHáZKOVá E,et al.Microwave-assisted hydrolysis of phosphonate diesters: An efficient protocol for the preparation of phosphonic acids[J].Green Chemistry,2012,43(51):2282-2288.DOI:10.1002/chin.201251161.

备注/Memo

备注/Memo:
收稿日期: 2018-06-13
通信作者: 王立强(1970-),男,教授,博士,主要从事药剂学和创新药物研发的研究.E-mail:wlq1599@163.com.
基金项目: 国家重点研发计划项目(2016YFE0101700)
更新日期/Last Update: 2019-07-20