盐酸伐昔洛韦中间体 | 502421-44-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 盐酸伐昔洛韦中间体
• 中文别名: 盐酸伐昔洛韦中间体BVG
• 英文名称: Boc-L-valacyclovir
• 英文别名: N-t-Boc Valacyclovir；2-[(2-amino-6-oxo-1H-purin-9-yl)methoxy]ethyl (2S)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate
• CAS: 502421-44-5
• 化学式: C₁₈H₂₈N₆O₆
• 分子量: 424.457
• InChiKey: FGLBYLSLCQBNHV-NSHDSACASA-N

物化性质

• 熔点：
  193-195oC
• 沸点：
  603.96℃
• 密度：
  1.39±0.1 g/cm3(Predicted)
• 溶解度：
  醋酸（微溶）、DMSO（微溶）、甲醇（微溶）
• LogP：
  1.83

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  30
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  159
• 氢给体数：
  3
• 氢受体数：
  8

安全信息

• WGK Germany：
  3

反应信息

• 作为反应物：
  描述：

  盐酸伐昔洛韦中间体 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 伐昔洛韦
  参考文献：
  名称：

  Topical iontophoretic delivery of ionizable, biolabile aciclovir prodrugs: A rational approach to improve cutaneous bioavailability

  摘要：

  The objective was to investigate the topical iontophoretic delivery of a series of amino acid ester prodrugs of aciclovir (ACV-X, where ACV = aciclovir and X = Arg, Gly, Ile, Phe, Trp and Val) as a means to enhance cutaneous delivery of ACV. The newly synthesized prodrugs were characterized by H-1 NMR and high resolution mass spectrometry. Analytical methods using HPLC-UV were developed for their quantification and each method was validated. Investigation of solution stability as a function of pH showed that all ACV-X prodrugs were relatively stable in acid conditions at pH 2.0 and pH 5.5 for up to 8 h but susceptible to extensive hydrolysis at pH 7.4 and under alkaline conditions (pH 10). No ACV-X hydrolysis was observed after contact for 2 h with the external surface of porcine stratum corneum. However, there was significant hydrolysis following contact with the dermal surface of dermatomed porcine skin, in particular, for ACV-Arg. Passive transport of ACV and ACV-X prodrugs from aqueous solution after 2 h was below the limit of detection. Iontophoresis of ACV at 0.5 mA/cm(2) for 2 h led to modest ACV skin deposition (Q(DEP,ACV)) of 4.6 +/- 0.3 nmol/cm(2). In contrast, iontophoresis of ACV-X prodrugs under the same conditions produced order of magnitude increases in cutaneous deposition of ACV species, that is, Q(DEP,TOTAL) = Q(DEP,ACV) + Q(DEP,ACV-X). Q(DEP,TOTAL) for ACV-Gly, ACV-Val, ACV-Ile, ACV-Phe, ACV-Trp and ACV-Arg was 412.8 +/- 44.0, 358.8 +/- 66.8, 434.1 +/- 68.2, 249.8 +/- 81.4, 156.1 +/- 76.3, 785.9 +/- 78.1 nmol/cm(2), respectively. The extent of bioconversion of ACV -X to ACV in the skin was high and the proportion of ACV present ranged from 81% to 100%. The skin retention ratio, a measure of the selectivity of ACV species for deposition over permeation after iontophoretic delivery of ACV -X prodrugs, was dependent on both the rate of transport and the susceptibility to hydrolysis of the prodrugs. Skin deposition of ACV and its six prodrugs were investigated further as a function of current density (0.125, 0.25 and 0.5 mA/cm(2)); the effect of duration of current application (5,10, 30, 60 and 120 min) was evaluated using ACV-Arg and ACV-Ile. Iontophoresis of ACV-Arg and ACV-Ile at 0.25 mA/cm(2) for only 5 min resulted in the deposition of appreciable amounts of ACV (36.4 +/- 5.7 nmol/cm(2) and 40.3 +/- 6.1 nmol/cm(2), respectively), corresponding to supra-therapeutic average concentrations in skin against HSV-1 or HSV-2. The results demonstrated that cutaneous bioavailability of ACV could be significantly improved after short duration iontophoresis of ionizable, biolabile ACV -X prodrugs. (C) 2015 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejpb.2015.12.002
• 作为产物：
  描述：

  阿昔洛韦 、 N-Boc-L-缬氨酸 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 吡啶 、 二氯甲烷 为溶剂， 反应 50.0h， 生成 盐酸伐昔洛韦中间体
  参考文献：
  名称：

  阿昔洛韦二肽前药的构效关系：对前药设计的启示

  摘要：

  评估了一系列抗病毒阿昔洛韦（ACV）的水溶性二肽酯前药的化学稳定性，细胞毒性以及对几种单纯疱疹-1型和-2型，牛痘，水疱性口腔炎，巨细胞病毒和水痘带状疱疹病毒的抗病毒活性。ACV二肽酯对疱疹病毒非常有活性，而与它们释放母体药物的速率无关。它们的最低细胞毒性浓度超过100μM，且产生的MCC / EC 50值低于ACV。当比较pH 7.4缓冲液中Phe-Gly酯和酰胺（ACV，齐多夫定，对乙酰氨基酚，卡托普利和伯氨喹）的反应性时，发现药物释放速率随药物离去基团能力的增加而增加。母体药物在人血浆中从Phe-Gly释放的速度明显比在pH 7.4缓冲液中释放快，因此表明基于二肽的前药方法可以成功地应用于含有硫醇，苯酚和胺官能团的生物活性剂。

  DOI：

  10.1016/j.ejmech.2008.08.009

文献信息

• Synthesis and characterization of novel dipeptide ester prodrugs of acyclovir
  作者：Yasser E Nashed、Ashim K Mitra

  DOI：10.1016/s1386-1425(03)00007-6

  日期：2003.7

  Four dipeptide (Gly-Gly, Gly-Val, Val-Val, Val-Gly) ester prodrugs of 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir, ACV) were synthesized. LC/MS was used to characterize the new prodrugs. Both 1H NMR and 13C NMR spectra of the four prodrugs of ACV were measured and assigned based on spectral comparison with compounds of similar structures.

  合成了9-[（2-羟基乙氧基）甲基]鸟嘌呤（无环鸟苷，ACV）的四个二肽（Gly-Gly，Gly-Val，Val-Val，Val-Gly）酯前药。LC / MS用于表征新的前药。测量了ACV的四种前药的1H NMR和13C NMR光谱，并根据与相似结构化合物的光谱比较进行了分配。
• [EN] PROCESS FOR THE PREPARATION OF VALACYCLOVIR<br/>[FR] PROCÉDÉ DE PRÉPARATION DE VALACYCLOVIR
  申请人：AUROBINDO PHARMA LTD

  公开号：WO2017149420A1

  公开（公告）日：2017-09-08

  The present invention relates to an improved process for the preparation of Valacyclovir or pharmaceutically acceptable salts thereof, which comprises reaction of amine -protected Valacyclovir or its salt with deprotecting agent in a continuous flow reactor.

  本发明涉及一种改进的制备Valacyclovir或其药用可接受盐的工艺，包括在连续流反应器中用去保护试剂对胺保护Valacyclovir或其盐进行反应。
• [EN] SYNTHESIS AND PURIFICATION OF VALACYCLOVIR<br/>[FR] SYNTHESE ET PURIFICATION DE VALACYCLOVIR
  申请人：TEVA PHARMA

  公开号：WO2003041647A2

  公开（公告）日：2003-05-22

  The present invention relates to protected valacyclovir, N-tert-butoxycarbonyl-L-valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy] ethyl ester, and a method of making it. The present invention further relates to a method of making valacyclovir including the steps of coupling an amine protected valine selected from N-tbutoxycarbonyl valine and N-formyl valine with acyclovir using a coupling agent to form a protected valacyclovir, and deprotecting the protected valacyclovir to form valacyclovir or a pharmaceutically acceptable salt thereof. The present invention further relates to valacyclovir in pure form, a method of making pure valacyclovir, and to compositions containing pure valacyclovir.

  本发明涉及保护的瓦拉西韦，N-叔丁氧羰基-L-缬氨酸2-[(2-氨基-1,6-二氢-6-氧代-9H-嘌呤-9-基)甲氧基]乙酯及其制备方法。本发明还涉及一种制备瓦拉西韦的方法，包括以下步骤：使用偶联剂将N-叔丁氧羰基缬氨酸或N-甲酰缬氨酸中选择的氨基保护缬氨酸与阿昔洛韦偶联，形成保护的瓦拉西韦，然后去保护得到瓦拉西韦或其药用可接受盐。本发明还涉及纯形式的瓦拉西韦，制备纯瓦拉西韦的方法，以及含有纯瓦拉西韦的组合物。
• Synthesis and purification of valacyclovir
  申请人：——

  公开号：US20030153757A1

  公开（公告）日：2003-08-14

  The present invention relates to protected valacyclovir, N-tert-butoxycarbonyl-L-valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy] ethyl ester, and a method of making it. The present invention further relates to a method of making valacyclovir including the steps of coupling an amine protected valine selected from N-t-butoxycarbonyl valine and N-formyl valine with acyclovir using a coupling agent to form a protected valacyclovir, and deprotecting the protected valacyclovir to form valacyclovir or a pharmaceutically acceptable salt thereof. The present invention further relates to valacyclovir in pure form, a method of making pure valacyclovir, and to compositions containing pure valacyclovir.

  本发明涉及保护的瓦拉西酷vir、N-叔丁氧羰基-L-缬氨酸2-[(2-氨基-1,6-二氢-6-氧基-9H-嘌呤-9-基)甲氧基]乙酯以及其制备方法。本发明还涉及一种制备瓦拉西酷vir的方法，包括以下步骤：使用偶联剂将选择自N-叔丁氧羰基缬氨酸和N-甲酰缬氨酸的氨基保护缬氨酸与阿昔洛韦偶联形成保护的瓦拉西酷vir，然后去保护使保护的瓦拉西酷vir形成瓦拉西酷vir或其药学上可接受的盐。本发明还涉及纯形式的瓦拉西酷vir、制备纯瓦拉西酷vir的方法，以及含有纯瓦拉西酷vir的组合物。
• Process for the preparation of valacyclovir
  申请人：AUROBINDO PHARMA LTD

  公开号：US10836765B2

  公开（公告）日：2020-11-17

  The present invention relates to an improved process for the preparation of Valacyclovir or pharmaceutically acceptable salts thereof, which comprises reaction of amine-protected Valacyclovir or its salt with deprotecting agent in a continuous flow reactor.

  本发明涉及一种制备伐昔洛韦或其药学上可接受的盐类的改进工艺，该工艺包括在连续流反应器中使受胺保护的伐昔洛韦或其盐类与脱保护剂反应。