sofosbuvir | 1190307-88-0

• 物质功能分类: 生物化工 - 氨基酸及其衍生物 - 丙氨酸类衍生物
• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: sofosbuvir
• 英文别名: (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate；PSI-7977；GS-7977；isopropyl ((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate；isopropyl (2S)-2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)aminopropanoate；sovaldi；propan-2-yl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate
• CAS: 1190307-88-0
• 化学式: C₂₂H₂₉FN₃O₉P
• 分子量: 529.459
• InChiKey: TTZHDVOVKQGIBA-IQWMDFIBSA-N

物化性质

• 熔点：
  122-124°C
• 密度：
  1.41
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 颜色/状态：
  White to off-white crystalline solid
• 蒸汽压力：
  1.78X10-10 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable if stored as directed; avoid strong oxidizing agents
• 分解：
  Thermal decomposition may produce toxic gases such as carbon monoxide, carbon dioxide, and nitrogen oxides.
• 解离常数：
  pKa1= 9.38 (amide); pKa2 = 10.30 (phosphonamide) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  153
• 氢给体数：
  3
• 氢受体数：
  11

ADMET

代谢

在体外研究中，使用人肝微粒体进行的实验表明，索非布韦是组织蛋白酶A（Cat A）和羧酸酯酶1（CES1）的有效底物。索非布韦被CatA和CES1切割，随后的活化步骤包括通过组氨酸三聚体核苷酸结合蛋白1（HINT1）去除氨基酸，以及通过尿苷一磷酸-胞苷一磷酸（UMP-CMP）激酶和核苷二磷酸（NDP）激酶进行磷酸化。体外数据显示，Cat A优先水解索非布韦（S-对映体），而CES1没有表现出对映选择性。[A19628, A19631]。

In vitro studies in human liver microsomes showed that sofosbuvir was an efficient substrate for Cathepsin A (Cat A) and carboxyl esterase 1 (CES1). Sofosbuvir was cleaved by CatA and CES1 and subsequent activation steps included amino acid removal by histidine triad nucleotide-binding protein 1 (HINT1) and phosphorylation by uridine monophosphate-cytidine monophosphate (UMP-CMP) kinase and nucleoside diphosphate (NDP) kinase. In vitro data indicated that Cat A preferentially hydrolysed sofosbuvir (the S-diastereomer) while CES1 did not exhibit stereoselectivity [A19628, A19631].

来源:DrugBank

代谢

体外研究在人类肝脏微粒体中显示，索非布韦是组织蛋白酶A（Cat A）和羧酸酯酶1（CES1）的有效底物。没有迹象表明通过尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）或含黄素的单加氧酶（FMO）进行代谢。索非布韦被CatA和CES1裂解，随后的活化步骤包括通过组氨酸三聚体核苷酸结合蛋白1（HINT1）去除氨基酸，以及通过尿苷单磷酸-胞苷单磷酸（UMP-CMP）激酶和核苷二磷酸（NDP）激酶进行磷酸化。体外数据显示，Cat A优先水解索非布韦（S-对映体），而CES1没有表现出对映选择性。这与使用GS-9851的研究一致，该研究表明在含有Clone A复制子的肝源性细胞系中对三磷酸的代谢效率较低，并且与原代人类肝细胞相比显示出较低的CES 1活性，但具有较高的Cat A活性。在大鼠、狗、猴子和人类的肝细胞培养后，GS-9851被转化为三磷酸GS-461203，其中在人细胞中最有效。索非布韦在口服给药后也容易在狗肝脏中转化为三磷酸，并在所有评估的时间点上是主要的代谢物，具有约18小时的长半衰期。在猴子中无法检测到活性代谢物GS-461203。此外，尽管在大鼠肝脏中检测到GS-461203，但在小鼠肝脏中无法测量到。

In vitro studies in human liver microsomes showed that sofosbuvir was an efficient substrate for Cathepsin A (Cat A) and carboxyl esterase 1 (CES1). There were no indications of metabolism via urdine diphosphate glucuronosyltransferases (UGTs) or flavin-containing monooxygenase (FMO). Sofosbuvir was cleaved by CatA and CES1 and subsequent activation steps included amino acid removal by histidine triad nucleotide-binding protein 1 (HINT1) and phosphorylation by uridine monophosphate-cytidine monophosphate (UMP-CMP) kinase and nucleoside diphosphate (NDP) kinase. In vitro data indicated that Cat A preferentially hydrolysed sofosbuvir (the S-diastereomer) while CES1 did not exhibit stereoselectivity. This would be consistent with studies using GS-9851 showing a less efficient metabolism to the triphosphate in the hepatically-derived cell line containing the Clone A replicon and shown to exhibit low CES 1 activity, but high Cat A activity compared with primary human hepatocytes. Following incubation of hepatocytes from rat, dog, monkey and human GS-9851 was converted to the triphosphate GS-461203 in all species, most efficiently in human. Sofosbuvir was also readily converted to the triphosphate in dog liver after oral doses and was the dominant metabolite at all time points assessed with a long half-life of approx. 18 hours. The active metabolite GS-461203 could not be detected in monkey. Further while GS-461203 was detected in rat liver, it could not be measured in liver from mouse.

来源:Hazardous Substances Data Bank (HSDB)

代谢

索菲布韦在肝脏中被广泛代谢，形成具有药理活性的核苷类似物三磷酸GS-461203。代谢激活途径涉及人类组织蛋白酶A（CatA）或羧酸酯酶1（CES1）催化的羧酸酯基团的顺序水解，以及组氨酸三聚体核苷酸结合蛋白1（HINT1）催化的磷酰胺键的断裂，随后通过嘧啶核苷酸生物合成途径进行磷酸化。去磷酸化导致形成核苷代谢物GS-331007，该代谢物不能有效地再磷酸化，且在体外缺乏抗HCV活性。

Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro.

来源:Hazardous Substances Data Bank (HSDB)

代谢

GS-331007 和 GS-566500 在所有物种中均有检测到，其中 GS-331007 是所有物种和所有基质中的主要药物相关物质。在给予索非布韦的所有物种的血浆、尿液和粪便中，检测到的主要代谢物是 GS-331007，占总暴露量的>80%。在大鼠肝脏和血浆中也检测到了 GS-566500。非妊娠、妊娠和产后大鼠以及产后大鼠乳汁中的代谢物轮廓总体上是相似的，其中 GS-331007 和 GS-331007 的2个硫酸结合物是主要的代谢物。

GS-331007 and GS-566500 were detected in all species with GS-331007 being the major drug related material in all species and all matrices. In plasma, urine and feces of all species administered sofosbuvir the primary metabolite detected was GS-331007 accounting for >80% of total exposure. In rat liver and plasma GS-566500 was also detected. The metabolite profile was overall comparable between non-pregnant, pregnant and postpartum rats and in milk of postpartum rats with GS-331007 and 2 sulfate conjugates of GS-331007 being the major metabolites.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在狗单次口服20 mg/kg的索非布韦后，血浆中鉴定出三种代谢物，GS-331007、GS-566500和M4（GS-606965的假定葡萄糖苷酸化产物），分别占总血浆AUC的93.4%、1.6%和0.5%。母体化合物占总量的4.5%。在狗（和鼠）中，大部分放射性剂量在8到12小时内通过尿液回收。

In dog following a single oral dose of 20 mg/kg of sofosbuvir three metabolites in plasma were identified, GS-331007, GS-566500 and M4 (proposed glucuronidation product of GS-606965), accounting for 93.4%, 1.6% and 0.5%, respectively of total plasma AUC. Parent compound amounted to 4.5%. In dog (and mouse) the majority of a radioactive dose was recovered in urine within 8 to 12 hours.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在大规模随机对照试验中，尽管接受索非布韦治疗的患者患有慢性肝病，但血清酶升高的情况并不常见。在大多数情况下，开始索非布韦治疗时，血清转氨酶水平迅速改善，而且新的、晚期ALT升高超过正常上限3倍的情况并不常见，比安慰剂或不治疗的情况要少。在多个大型临床试验中，索非布韦并未与黄疸的临床明显肝损伤病例有关联。因为索非布韦总是与其他抗病毒药物一起使用，所以不可能总是将索非布韦与其他药物在引起不良反应中的相对作用区分开来。 有两种罕见且不寻常的与索非布韦关系不明的肝损伤形式在用抗病毒治疗丙型肝炎的患者中被描述：突然肝功能衰竭的患者有预先存在的肝硬化，以及在有预先存在的HBV感染证据的患者中乙型肝炎的再激活。 与索非布韦（也许还有其他对HCV有效的强效药物）相关的一种罕见但显著的肝损伤是在预先存在肝硬化的患者中发生的肝功能衰竭。在几个实例中，肝功能衰竭在开始治疗后的2到6周内发生（案例1），而在其他情况下，它发生在治疗晚期或治疗结束后的立即期。发病的典型模式是胆红素逐渐升高，伴有肝衰竭的迹象，如凝血酶原时间延长、血清白蛋白下降和腹水和肝性脑病的出现。在许多（但不是所有）实例中，与治疗前相比，血清酶水平没有变化或仅略有升高。在所有实例中，索非布韦是与其他抗病毒药物（如聚乙二醇干扰素、西美瑞韦、达卡他韦或雷迪帕韦）联合使用的，索非布韦的具体作用一直难以界定。这种衰竭通常与快速病毒清除同时发生，而经历这一事件的幸存患者通常会有持续的病毒学应答。这种衰竭的原因尚不清楚，但它可能代表了对HCV病毒根除的反应（靶上效应），而不是所给予抗病毒剂的毒性（对肝脏的靶外效应）。或者，这种损伤可能是巧合的，与治疗无关。 第二种可能在索非布韦治疗中发生的肝损伤形式，也可能发生在其他强效抗HCV药物中，是乙型肝炎的再激活。在HBsAg阳性且HBV DNA水平低、不被认为是慢性肝病原因的慢性丙型肝炎患者中，已经报告了具有临床明显肝炎和血清HBV DNA水平升高的实例（案例2）。在血清中没有HBsAg而只有抗-HBc的患者中，也已经描述了再激活，这种情况表明之前从乙型肝炎中恢复。HBV再激活通常在开始治疗丙型肝炎后的2到8周内出现，并且可以表现为急性肝炎的症状、血清转氨酶水平和胆红素的显著升高。已经有报道称在使用索非布韦治疗期间因HBV再激活而死亡的实例。再激活的原因尚不清楚，但它可能反映了HCV复制的根除，HCV复制对HBV复制具有非特异性的抑制作用。或者，随着HCV的突然清除或由于抗病毒剂的直接作用，免疫反应性的改变可能改变HBV的复制状态。 可能性评分：E*（在易感个体中未证实但怀疑是临床明显肝损伤的原因）。

In large randomized controlled trials, serum enzymes elevations were uncommon in patients treated with sofosbuvir despite the fact that the patients being treated had chronic liver disease. In most situations, serum aminotransferase levels improved rapidly upon initiating sofosbuvir therapy, and de novo, late elevations of ALT above 3 times the upper limit of normal (ULN) were uncommon and less frequent than with placebo or no therapy. In multiple, large clinical trials sofosbuvir has not been linked to instances of clinically apparent liver injury with jaundice. Because sofosbuvir is always used with other antiviral agents, it is not always possible to separate the relative role of sofosbuvir from other drugs in causing adverse reactions. Two rare and unusual forms of liver injury of uncertain relationship to sofosbuvir have been described in patients with receiving antiviral therapy for hepatitis C: sudden hepatic decompensation in patients with preexisting cirrhosis and reactivation of hepatitis B in patients with preexisting evidence of HBV infection. A rare, but striking liver injury associated with sofosbuvir (and perhaps other potent agents active against HCV) is hepatic decompensation occurring in patients with preexisting cirrhosis. In several instances, decompensation occurred within 2 to 6 weeks of starting therapy (Case 1), while in others it occurred late during therapy or in the immediate posttreatment period. The typical pattern of onset was a progressive rise in bilirubin with signs of hepatic failure such as prolongation of the prothrombin time, decrease in serum albumin and appearance of ascites and hepatic encephalopathy. In many (but not all) instances, serum enzyme levels did not change or increased only slightly in comparison to pretreatment values. In all instances, sofosbuvir was being used in combination with other antiviral agents, such as peginterferon, simeprevir, daclatasvir or ledipasvir, and the specific role of sofosbuvir has been difficult to define. The decompensation usually coincided with rapid viral clearance and patients who survived the episode often had a sustained virological response. The cause of this decompensation is not clear, but it may represent a response to HCV viral eradication (on-target effect) rather than toxicity of the administered antiviral agents (off-target effect on the liver). Alternatively, the injury may be coincidental and unrelated to therapy. A second form of liver injury that can occur with sofosbuvir therapy and perhaps other potent anti-HCV agents is reactivation of hepatitis B. Instances of clinically apparent hepatitis with rises in serum HBV DNA levels have been reported in patients with chronic hepatitis C who were HBsAg positive and had low levels of HBV DNA which were not thought to be the cause of the chronic liver disease (Case 2). Reactivation has also been described in patients who have anti-HBc without HBsAg in serum, a pattern that suggests previous recovery from hepatitis B. HBV reactivation typically arises within 2 to 8 weeks of starting therapy for hepatitis C and it can be clinically manifest with symptoms of acute hepatitis and marked elevations in serum aminotransferase levels and bilirubin. Instances of death from HBV reactivation have been reported with sofosbuvir therapy. The cause of reactivation is unclear, but it may reflect the eradication of HCV replication which has a nonspecific suppressive effect on HBV replication. Alternatively, the change in immune reactivity with sudden clearance of HCV or as a result of a direct activity of the antiviral agents may alter the replicative status of HBV. Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury in susceptible individuals).

来源:LiverTox

毒理性

• 相互作用

利福平和SOFOSBUVIR同时使用可能会导致SOFOSBUVIR和GS-331007的血浆浓度降低，从而降低SOFOSBUVIR的疗效。利福平和SOFOSBUVIR不应同时使用。

Concomitant use of rifampin, a potent inducer of P-gp in the intestine, and sofosbuvir may cause decreased plasma concentrations of sofosbuvir and GS-331007 and may lead to decreased therapeutic effect of sofosbuvir. Rifampin and sofosbuvir should not be used concomitantly.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

利福布汀预计会导致索非布韦和GS-331007的血浆浓度降低，这可能会导致索非布韦的治疗效果降低。不建议同时使用利福布汀和索非布韦。

Rifabutin is expected to cause decreased plasma concentrations of sofosbuvir and GS-331007, which may lead to decreased therapeutic effect of sofosbuvir. Concomitant use of rifabutin and sofosbuvir is not recommended.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与索非布韦同时使用时，某些抗惊厥药（即，卡马西平、氧卡马西平、苯巴比妥、苯妥英）可能会降低索非布韦和GS-331007的血浆浓度，这可能导致索非布韦的治疗效果降低。不推荐同时使用这些抗惊厥药和索非布韦。

When used concomitantly with sofosbuvir, certain anticonvulsants (i.e., carbamazepine, oxcarbazepine, phenobarbital, phenytoin) are expected to decrease plasma concentrations of sofosbuvir and GS-331007, which may lead to decreased therapeutic effect of sofosbuvir. Concomitant use of these anticonvulsants and sofosbuvir is not recommended.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

Sofosbuvir是乳腺癌耐药蛋白（BCRP）的底物；GS-331007不是BCRP的底物。BCRP的抑制剂可能会导致sofosbuvir的血浆浓度增加，而不增加GS-331007的血浆浓度。Sofosbuvir和GS-331007不是BCRP的抑制剂；与BCRP底物的药物发生药代动力学相互作用的可能性不大。

Sofosbuvir is a substrate of breast cancer resistance protein (BCRP); GS-331007 is not a BCRP substrate. Inhibitors of BCRP may cause increased plasma concentrations of sofosbuvir without increasing plasma concentrations of GS-331007. Sofosbuvir and GS-331007 are not BCRP inhibitors; pharmacokinetic interactions are unlikely with drugs that are BCRP substrates.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

当口服时，索非布韦在大约0.5到2小时内达到最大血浆浓度，最大浓度（Cmax）为567 ng/mL [FDA标签]。

When given orally, sofosbuvir reaches its maximum plasma concentration in about 0.5 to 2 hours with a maximal concentration (Cmax) of 567 ng/mL [FDA Label].

来源:DrugBank

吸收、分配和排泄

• 消除途径

索非布韦通过三种途径消除：尿液（80%）、粪便（14%）和呼吸（2.5%）；然而，通过肾脏的消除是主要的途径[FDA标签]。

Sofosbuvir is eliminated by three routes: urine ( 80%), feces (14%), and respiration (2.5%); however, elimination through the kidneys is the major route [FDA Label].

来源:DrugBank

吸收、分配和排泄

• 分布容积

尚未确定索非布韦的分布体积 [FDA 标签]。

The volume of distribution for sofosbuvir has yet to be determined [FDA Label].

来源:DrugBank

吸收、分配和排泄

• 清除

"索非布韦的清除率尚未确定 [FDA 标签]。"

The clearance of sofosbuvir has yet to be determined [FDA Label].

来源:DrugBank

吸收、分配和排泄

索非布韦大约有61-65%与人类血浆蛋白结合，且这种结合在1微克/毫升到20微克/毫升的药物浓度范围内是独立的。GS-331007在人类血浆中的蛋白结合是最小的。在健康受试者单次服用400毫克(14)C-索非布韦后，(14)C放射性物质的血液与血浆比率大约为0.7。

Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 ug/mL to 20 ug/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of (14)C-sofosbuvir in healthy subjects, the blood to plasma ratio of (14)C-radioactivity was approximately 0.7.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  29339900
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  -20°C

制备方法与用途

索非布韦 用途

索非布韦是一种前药，可代谢为活性抗病毒药2'-脱氧-2'-α-氟-β-C-甲基尿苷-5'-单磷酸酯。它目前正处于3期临床试验阶段，用于治疗丙型肝炎。研究表明，索非布韦是丙型肝炎病毒的核苷酸抑制剂，并对HCV NS5B聚合酶具有选择性的抑制作用。

口服治疗丙肝药物

索非布韦又称为索菲布韦或索氟布韦，是全球首个口服治疗丙型肝炎的药物。它于2013年在美国获得批准，成为该年度最重要的新药之一。索非布韦由美国吉利德科学公司研发，其英文名称为Sofosbuvir、Sovaldi，可能达到超过100亿美元的全球销售峰值。

美国食品药品管理局（FDA）批准

2013年12月6日，美国FDA批准索非布韦用于治疗慢性丙型肝炎病毒感染。这是首款无需同时使用干扰素(IFN)即可安全、有效地治疗某些类型HCV感染的药物。

丙型肝炎概述

丙型肝炎是一种病毒性疾病，可导致肝脏炎症，并可能引发肝功能减弱或肝衰竭。许多患者在出现明显症状之前已有几年时间的肝脏损伤。长期慢性HCV感染可能会导致瘢痕及肝硬化，进而引起出血、黄疸（眼睛或皮肤变黄）、肝腹水、感染或肝癌等并发症。据美国疾病控制与预防中心统计，大约有320万美国人感染了丙型肝炎病毒。

治疗方案

索非布韦是一种核苷酸类似物抑制剂，能阻断丙型肝炎病毒复制所需的一种特异性蛋白质。它通常作为慢性HCV感染的抗病毒联合治疗方案的一部分，用于特定基因型的患者。治疗方案可能包括索非布韦与利巴韦林或聚乙二醇干扰素α的组合。

突破性治疗药物资格

索非布韦是第三个以FDA授予的突破性治疗药物资格获批的药物。该资格适用于初步临床研究证明比现有疗法为严重或危及生命疾病患者提供实质性改善的药物申请者。

美国专利信息

索非布韦在美国的专利有效期至2029年3月26日（美国专利号：7964580和8334270），2025年4月3日（美国专利号：7429572和8415322）。

生物活性

Sofosbuvir (PSI-7977, GS-7977) 是一种HCV的NS5B聚合酶抑制剂，用于治疗慢性丙型肝炎病毒感染。

靶点

靶点：

• NS5B聚合酶

体外研究

作为HCV NS5B聚合酶抑制剂，PSI-7977比PSI-7976更有效，EC50分别为92 nM和1.07 μM，EC90分别达到0.29 μM 和2.99 μM。克隆A细胞与 PSI-7977温育产生的浓度高于与 PSI-7976温育的细胞。PSI-7977是CatA的有效底物，比PSI-7977抗S96T突变型，EC90从0.42 μM提高到7.8 μM。在长达8天的细胞毒性检测中，PSI-7977没有对Huh7、HepG2、BxPC3和CEM细胞产生毒性，即使浓度高达100 μM。处理HepG2细胞14天后，IC90抑制mtDNA为72.1 μM，rDNA为68.6 μM。PSI-7977有效抑制基因型1a、1b和2a复制，以及含有GT 2a、2b 和3a NS5B聚合酶的嵌合体复制。

JFH-1 NS5B区序列分析表明，选择在S282T出现前后的其他氨基酸变化（如T179A, M289L, I293L, M434T和H479P）是抗PSI-7977必需的。

反应信息

• 作为反应物：
  描述：

  sofosbuvir 在 5%-palladium/activated carbon 、 氢气 、 N,N'-二异丙基碳二亚胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.83h， 生成
  参考文献：
  名称：

  核苷氨基磷酸酯衍生物及其应用

  摘要：

  本发明提供了一种核苷氨基磷酸酯衍生物及其应用，其具体为式I化合物，或其药学可接受的酸式盐、溶剂化物或水合物；其中：R1为C1～4烷基；R2为任意取代的苯基或萘基，其取代基选自C1～4烷基、C1～4烷氧基；R3为氨基酸酰基或多肽酰基。本发明的化合物可用于制备预防或治疗哺乳动物感染性疾病药物，特别是用于制备预防或治疗丙型肝炎、肝硬化、肝癌的药物中。

  公开号：

  CN105254695B
• 作为产物：
  描述：

  bromo sofosbuvir 在 5%-palladium/activated carbon 作用下， 以 异丙醇 为溶剂， 20.0~25.0 ℃ 、300.01 kPa 条件下， 反应 10.0h， 以1.8 g的产率得到sofosbuvir
  参考文献：
  名称：

  [EN] PROCESS FOR THE PREPARATION OF PURE SOFOSBUVIR
  [FR] PROCÉDÉ DE PRÉPARATION DE SOFOSBUVIR PUR

  摘要：

  本发明提供了纯度为索非布韦的制备方法及其中间体。

  公开号：

  WO2017093973A1

文献信息

• [EN] PROCESS FOR THE PREPARATION OF (Sp)-SOFOSBUVIR AND INTERMEDIATES THEREOF<br/>[FR] PROCÉDÉ DE PRÉPARATION DU (SP)-SOFOSBUVIR ET DE SES INTERMÉDIAIRES
  申请人：ALEMBIC PHARMACEUTICALS LTD

  公开号：WO2018025195A1

  公开（公告）日：2018-02-08

  The present invention is directed towards process for preparation of an optically pure (Sp)-Sofosbuvir of Formula-(I) and its intermediate namely (Sp)-isomer of isopropyl alanyl phosphoramidate of Formula (III) thereof.

  本发明涉及一种制备光学纯(Sp)-索非布韦（化学式(I)）及其中间体即异丙基丙氨基磷酰胺的(Sp)-异构体（化学式(III)）的方法。
• Macroheterocyclic nucleoside derivatives and their analogues, production and use thereof
  申请人：Ivachtchenko Alexandre Vasilievich

  公开号：US20180099989A1

  公开（公告）日：2018-04-12

  Nucleosides and nucleotides (nucleos(t)ides) have been in clinical use for almost 50 years and have become cornerstones of treatment for patients with viral infections or cancer. The approval of several additional drugs over the past decade demonstrates that this family still possesses strong potential. Therefore nucleos(t)ide are of great interest as promising chemotherapeutic agents, including: 2′-deoxy-L-uridine (CAS No 31501-19-6), 2′-deoxy-D-uridine (CAS No 951-78-0), telbivudine (CAS No 3424-98-4), zidovudine (AZT, CAS No 30516-87-1), trifluridine (CAS No 70-00-8), clevudine (CAS No 163252-36-6), PSI-6206 (CAS No 863329-66-2), 2′-(5)-2′-chloro-2′-deoxy-2′-fluorouridine (CAS No 1673560-41-2), ND06954 (CAS No 114248-23-6), stavudine (CAS No 3056-17-5), 5-ethynyltavudine (Festinavir, CAS No 634907-30-5), torcitabine (CAS No 40093-94-5), (−)-beta-D-(2R,4R)-dioxolane-thymine (DOT, 1-((2R,4R)-2-(hydroxymethyl)-1,3-dioxolan-4-yl)-5-methyl-2,4 (1H,3H)-pyrimidinedione, CAS No. 127658-07-5), 2-(6-amino-purin-9-yl)-ethanol (CAS No 707-99-3), 2′-C-methylcytidine (CAS No 20724-73-6), PSI-6130 (CAS No 817204-33-4), gemcitabine (CAS No 95058-81-4), 2′-chloro-2′-deoxy-2′-fluorocytidine (CAS No 1786426-19-4), 2′,2′-dichloro-2′-deoxycytidine (CAS No 1703785-65-2), 2′-C-methylcytidine (CAS No 20724-73-6), PSI-6130 (CAS No 817204-33-4), lamivudine (3TC, CAS No 134678-17-4), emtricitabine (CAS No 143491-57-0), 2′-deoxyadenosine (CAS No 958-09-8), 2′-deoxy-β-L-adenosine (CAS No 14365-45-8), 2′-deoxy-4′-C-ethynyl-2-fluoroadenosine (CAS No 865363-93-5), didanosine (CAS No 69655-05-6), entecavir (CAS No 209216-23-9), FMCA (CAS No 1307273-70-6), dioxolane-G (DOG, CAS No 145514-01-8), β-D-2′-deoxy-2′-(R)-fluoro-2′-β-C-methylguanosine (CAS No 817204-45-8), abacavir (ABC, CAS No 136470-78-5), dioxolane-A (DOA, CAS #145514-02-9), [(2R,4R)-4-(6-cyclopropylamino-purin-9-yl)-[1,3]dioxolan-2-yl]-methanol (CAS No 1446751-04-7), amdoxovir (AMDX, CAS No 145514-04-1), (R)-1-(6-amino-purin-9-yl)-propan-2-ol (CAS No 14047-28-0), and [(2S,5R)-5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yl]-methanol. Macroheterocyclic nucleoside derivative and its analogue of the general formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, wherein: Ar is aryl or hetaryl; R 1 and R 2 are not necessarily the same substituents selected from H, F, Cl, CH 3 , OH; R 3 is H or CH 3 ; X is oxygen or ethanediyl-1,1 (C═CH 2 ); Y is CH(R 4 )(CH 2 ) k , CH(R 4 )(CH 2 ) m C(O)O(CH 2 ) n ; R 4 is H or CH 3 ; k has a value from zero to six; m has a value from zero to two; n has a value of one to four; Q is a radical selected from Q1-Q4; wherein: R 5 is the substituent selected from H, F, Cl, CH 3 , OH; the arrow (→) indicates the location, joined by Q1-Q4.

  核苷和核苷酸（核苷（t）酸）已经在临床上使用了近50年，已成为治疗病毒感染或癌症患者的治疗基石。过去十年批准了几种额外的药物，表明这个家族仍然具有强大的潜力。因此，核苷（t）酸作为有前途的化疗药物具有很大的吸引力，包括：2'-脱氧-L-尿苷（CAS号31501-19-6）、2'-脱氧-D-尿苷（CAS号951-78-0）、替比夫定（CAS号3424-98-4）、阿司匹林（AZT，CAS号30516-87-1）、三氟胸苷（CAS号70-00-8）、克雷胸苷（CAS号163252-36-6）、PSI-6206（CAS号863329-66-2）、2'-(5)-2'-氯-2'-脱氧-2'-氟尿苷（CAS号1673560-41-2）、ND06954（CAS号114248-23-6）、司他夫定（CAS号3056-17-5）、5-乙炔基司他夫定（费司那韦，CAS号634907-30-5）、托西他滨（CAS号40093-94-5）、（-）-β-D-(2R,4R)-二氧杂环己嘧啶（DOT，1-((2R,4R)-2-(羟甲基)-1,3-二氧杂环己-4-基)-5-甲基-2,4(1H,3H)-嘧啶二酮，CAS号127658-07-5）、2-(6-氨基嘌呤-9-基)-乙醇（CAS号707-99-3）、2'-C-甲基胞苷（CAS号20724-73-6）、PSI-6130（CAS号817204-33-4）、吉西他滨（CAS号95058-81-4）、2'-氯-2'-脱氧-2'-氟胞苷（CAS号1786426-19-4）、2',2'-二氯-2'-脱氧胞苷（CAS号1703785-65-2）、2'-C-甲基胞苷（CAS号20724-73-6）、PSI-6130（CAS号817204-33-4）、拉米夫定（3TC，CAS号134678-17-4）、恩替卡韦（CAS号143491-57-0）、2'-脱氧腺苷（CAS号958-09-8）、2'-脱氧-β-L-腺苷（CAS号14365-45-8）、2'-脱氧-4'-C-乙炔基-2-氟腺苷（CAS号865363-93-5）、地达诺辛（CAS号69655-05-6）、恩替卡韦（CAS号209216-23-9）、FMCA（CAS号1307273-70-6）、二氧杂环己胞苷（DOG，CAS号145514-01-8）、β-D-2'-脱氧-2'-(R)-氟-2'-β-C-甲基鸟苷（CAS号817204-45-8）、阿巴卡韦（ABC，CAS号136470-78-5）、二氧杂环己-A（DOA，CAS号145514-02-9）、[(2R,4R)-4-(6-环丙基氨基嘌呤-9-基)-[1,3]二氧杂环己-2-基]-甲醇（CAS号1446751-04-7）、阿姆多氧韦（AMDX，CAS号145514-04-1）、(R)-1-(6-氨基嘌呤-9-基)-丙醇（CAS号14047-28-0）、和[(2S,5R)-5-(6-氨基嘌呤-9-基)-4-氟-2,5-二氢呋喃-2-基]-甲醇。 宏环核苷衍生物及其一般式1或一般式2的类似物，立体异构体，同位素富集类似物，药学上可接受的盐，水合物，溶剂合物，或其结晶或多形式， 其中： Ar是芳基或杂芳基； R 1 和R 2 不一定相同，选自H，F，Cl，CH 3 ，OH的取代基； R 3 是H或CH 3 ； X是氧或乙烯二基-1,1（C═CH 2 ）； Y是CH(R 4 )(CH 2 ) k ，CH(R 4 )(CH 2 ) m C(O)O(CH 2 ) n ； R 4 是H或CH 3 ； k的值从零到六； m的值从零到二； n的值从一到四； Q是从Q1-Q4中选择的基团； 其中：R 5 是选自H，F，Cl，CH 3 ，OH的取代基； 箭头（→）表示位置，由Q1-Q4连接。
• [EN] SELECTIVE PROCESS FOR SYNTHESIS OF NUCLEOSIDE PHOSPHORAMIDATES<br/>[FR] PROCÉDÉ SÉLECTIF POUR LA SYNTHÈSE DE PHOSPHORAMIDATES DE NUCLÉOSIDE
  申请人：SANDOZ AG

  公开号：WO2016189040A1

  公开（公告）日：2016-12-01

  A process for preparing a nucleoside phosphoramidate, in particular to a process for preparing sofosbuvir, wherein a phosphoramidate derivative is used as starting material.

  一种用于制备核苷磷酰亚胺，特别是用于制备索非布韦的过程，其中使用磷酰亚胺衍生物作为起始材料。
• [EN] NUCLEOSIDE PHOSPHORAMIDATES USEFUL FOR THE TREATMENT OF VIRAL INFECTIONS AND PREPARATION THEREOF<br/>[FR] PHOSPHORAMIDATES DE NUCLÉOSIDES UTILES POUR LE TRAITEMENT D'INFECTIONS VIRALES ET PRÉPARATION DE CEUX-CI
  申请人：QUIM SINTETICA S A

  公开号：WO2016151542A1

  公开（公告）日：2016-09-29

  The present invention relates to an industrially applicable process for the preparation of phosphoramidates useful for the treatment of viral infections, such as sofosbuvir, and to intermediates useful for the preparation thereof. Formula (I):

  本发明涉及一种工业上可应用的制备磷酰胺酸酯的方法，用于治疗病毒感染，如索非布韦，以及用于制备该类化合物的中间体。公式（I）:
• [EN] AN IMPROVED PROCESS FOR THE PREPARATION OF SOFOSBUVIR<br/>[FR] PROCÉDÉ AMÉLIORÉ DE SYNTHÈSE DE SOFOSBUVIR
  申请人：OPTIMUS DRUGS (P) LTD

  公开号：WO2018015821A1

  公开（公告）日：2018-01-25

  The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Sofosbuvir. The present invention involves use of reagents that are less expensive, easier to handle and eco-friendly process.

  本发明涉及一种改进的、具有商业可行性和工业优势的索非布韦制备方法。本发明涉及使用价格较低、易于处理且环保的试剂。