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CN105503705B - 一种阿扎那韦相关物质及其制备方法 - Google Patents

一种阿扎那韦相关物质及其制备方法 Download PDF

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CN105503705B
CN105503705B CN201410487188.7A CN201410487188A CN105503705B CN 105503705 B CN105503705 B CN 105503705B CN 201410487188 A CN201410487188 A CN 201410487188A CN 105503705 B CN105503705 B CN 105503705B
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atazanavir
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CN105503705A (zh
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叶美其
钱建强
贺志
高红军
李原强
徐建康
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Jiangsu Ruike Medical Science And Technology Co ltd
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Abstract

本发明涉及医药化工技术领域，具体涉及一种阿扎那韦相关物质及其制备方法，本发明提供了一种化合物W：其中R为并与其邻位羟基环合成结构或为具有如下式(M)结构的基团，

Description

一种阿扎那韦相关物质及其制备方法
技术领域
本发明涉及医药化工技术领域，具体涉及一种阿扎那韦相关物质及其制备方法。
背景技术
硫酸阿扎那韦用于与其他抗逆转录病毒药物联合使用治疗HIV-1感染，该药物商品名为锐艾妥(Reyataz)，是一种蛋白酶抑制剂，其化学名称为：(3S,8S,9S,12S)-3,12-双(1,1-二甲基乙基)-8-羟基-4,11-二氧代-9-(苯甲基)-6-[[4-(2-嘧啶)苯基]甲基]-2,5,6,10,13-五氮杂十四烷二酸二甲酯硫酸盐(1:1)，化学结构如下：
在阿扎那韦的合成过程中往往会混有一些杂质，任何影响药物纯度的物质，称之为杂质，其包括有机杂质，无机杂质，残留溶剂，来源有工艺杂质和降解产物等。杂质研究是药学研究的重要内容，同时也直接涉及到药品的安全有效性。因此，合成和得到潜在杂质，对建立检测方法，分析杂质含量，并确定合理的杂质限度起到至关重要的作用。
发明内容
为实现本发明的目的，本发明提供了一种化合物W：
其中R为并与其邻位羟基环合成结构或为具有如下式(M)结构的基团，
具体的化合物W选自如下结构：
另一方面，本发明提供了所述化合物A的制备方法：由化合物I与N,N'-二琥珀酰亚胺基碳酸酯进行反应制备得到，
另一方面，本发明提供了所述化合物B的制备方法，由式II化合物在三乙胺和N,N'-二琥珀酰亚胺基碳酸酯存在下得到化合物III，化合物III在四丁基氟化胺存在下得到化合物B，
附图说明
图1为实施例1制备得到的式A化合物的纯度HPLC分析图谱；
图2为实施例3制备得到的式B化合物的纯度HPLC分析图谱。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
HPLC分析仪器及方法：
仪器型号：Agilent 1260
色谱柱：Agilent Eclipse XDB-C18150*4.6mm/5um
流动相A：纯水
流动相B：乙腈
流速：1.0mL/min
波长：250nm
柱温：30℃
进样量：10μL
实施例1：化合物A的制备
将化合物I(0.16g，0.30mmol)溶于5ml二氯甲烷，再加入N,N'-二琥珀酰亚胺基碳酸酯(0.15g,0.60mmol)，室温搅拌3h。减压除溶，经柱层析分离(淋洗剂:Hex/EtOAc＝1/4)，得白色固体化合物A 1.60g，收率95.3％，100％。
1H NMR(400 MHz,DMSO):δ9.06(s,1H),8.66(d,J＝4.0 Hz,1H),8.06(d,J＝8.4Hz,2H),7.97–7.86(m,3H),7.42(d,J＝8.4 Hz,2H),7.36–7.33(m,1H),7.22–7.15(m,5H),6.79(d,J＝9.6Hz,1H),4.81(d,J＝10.4 Hz,1H),4.17(brs,1H),3.95(dd,J1＝13.2 Hz,J2＝23.6 Hz,2H),3.84(d,J＝9.6 Hz,1H),3.52(s,3H),3.02–2.72(m,4H),0.74(s,9H)；
13C NMR(100 MHz,DMSO):δ170.4,156.4,155.7,151.1,149.5,138.2,137.9,137.2,137.1,129.4,129.0,127.9,126.4,126.0,122.5,120.1,73.3,62.9,60.9,51.4,50.6,48.0,35.9,33.3,26.5；
LC-HRMS(ESI)calcd for[M+H,C31H38N5O5]+:560.2873,Found 560.2869.
实施例2：化合物III的制备
将化合物II(0.15g，0.23mmol)溶于5ml二氯甲烷，再依次加入0.2ml三乙胺和N,N'-二琥珀酰亚胺基碳酸酯(58.9mg，0.23mmol)。室温搅拌6h，减压除溶，经柱层析分离(淋洗剂:Hex/EtOAc＝1/1)，得白色固体化合物III 0.10g，收率65.8％。
1H NMR(400 MHz,DMSO):δ8.57–8.48(m,2H),7.92–6.86(m,30H),4.45–3.52(m,16H),2.76–2.34(d,8H),0.85–0.82(m,36H),0.01–-0.13(m,12H)；
LC-HRMS(ESI)calcd for[M+Na,C73H104N10O9NaSi2]+:1343.7424,Found1343.7486.
实施例3：化合物B的制备
将化合物III(0.20g,0.15mmol)溶于5ml四氢呋喃，再加入四丁基氟化胺(1mol/L的四氢呋喃溶液，0.6ml,0.60mmol)。室温搅拌12h，加入5ml水淬灭反应，再以2×10ml乙酸乙酯萃取有机相，5ml饱和氯化钠水溶液洗涤，无水硫酸钠干燥。减压除溶，经柱层析分离(淋洗剂:DCM/MeOH＝30/1)，得白色固体化合物B 0.14g，收率85.4％，100％。
1H NMR(400 MHz,DMSO):δ8.61–8.52(m,2H),7.94–6.70(m,30H),5.23–4.82(m,2H),4.19–3.50(m,16H),2.75–2.50(m,8H),0.79–0.59(m,18H)；
LC-HRMS(ESI)calcd for[M+H,C61H77N10O9]+:1093.5875,Found 1093.5897.
尽管已经结合了具体实施方式对本发明进行了充分的描述，应当注意的是对于本领域技术人员来说其各种变化和修改是显而易见的。这样的变化和修改将可以理解为包括在由所附权利要求所定义的本发明的范围内。

Claims (2)

1.一种化合物A，结构式如下：
2.权利要求1所述化合物(A)的制备方法，由化合物(I)与N,N'-二琥珀酰亚胺基碳酸酯进行反应制备得到，
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010132663A1 (en) * 2009-05-13 2010-11-18 Concert Pharmaceticals, Inc. Pegylated azapeptide derivatives as hiv protease inhibitors
EP2272830A1 (en) * 2009-06-18 2011-01-12 Esteve Química, S.A. Preparation process of an antivirally heterocyclic azahexane derivative
WO2011107843A2 (en) * 2010-03-01 2011-09-09 Lupin Limited Process for the preparation of atazanavir sulfate substantially free of diastereomers
WO2013014633A1 (en) * 2011-07-27 2013-01-31 Ranbaxy Laboratories Limited Process for preparation of atazanavir or its bisulfate salt
CN102911113A (zh) * 2011-08-05 2013-02-06 浙江九洲药业股份有限公司 一种阿扎那韦的制备方法
WO2014125270A1 (en) * 2013-02-12 2014-08-21 Cipla House Process for preparing atazanavir sulphate

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8461347B2 (en) * 2011-08-05 2013-06-11 Scinopharm Taiwan, Ltd. Process for preparing form A of atazanavir sulfate

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010132663A1 (en) * 2009-05-13 2010-11-18 Concert Pharmaceticals, Inc. Pegylated azapeptide derivatives as hiv protease inhibitors
EP2272830A1 (en) * 2009-06-18 2011-01-12 Esteve Química, S.A. Preparation process of an antivirally heterocyclic azahexane derivative
WO2011107843A2 (en) * 2010-03-01 2011-09-09 Lupin Limited Process for the preparation of atazanavir sulfate substantially free of diastereomers
WO2013014633A1 (en) * 2011-07-27 2013-01-31 Ranbaxy Laboratories Limited Process for preparation of atazanavir or its bisulfate salt
CN102911113A (zh) * 2011-08-05 2013-02-06 浙江九洲药业股份有限公司 一种阿扎那韦的制备方法
WO2014125270A1 (en) * 2013-02-12 2014-08-21 Cipla House Process for preparing atazanavir sulphate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Gradient RP-HPLC method for the determination of potential impurities in atazanavir sulfate;Sreenivasa Rao Chitturi，等;《Journal of Pharmaceutical and Biomedical Analysis》;20110119;第55卷(第1期);第31-47页

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