CN101367834B - 用于制备醇和酚的水溶性膦酰氧基甲基衍生物的方法 - Google Patents
用于制备醇和酚的水溶性膦酰氧基甲基衍生物的方法 Download PDFInfo
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- CN101367834B CN101367834B CN200810145160XA CN200810145160A CN101367834B CN 101367834 B CN101367834 B CN 101367834B CN 200810145160X A CN200810145160X A CN 200810145160XA CN 200810145160 A CN200810145160 A CN 200810145160A CN 101367834 B CN101367834 B CN 101367834B
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
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Abstract
本发明涉及用于制备醇和酚的水溶性膦酰氧基甲基衍生物的方法。该方法包括化学式(i)和化学式(ii)的步骤；R-OH代表含醇或酚的药物，n代表整数1或2，R1是H、碱金属离子或药学上可接受的阳离子，并且R2是H、碱金属离子或药学上可接受的阳离子。第一步第二步
Description
本申请是申请号为02825882.7、申请日为2002年12月20日、发明名称为“用于制备醇和酚的水溶性膦酰氧基甲基衍生物的方法”的中国专利申请的分案申请。
技术领域
本发明涉及一种用于制备含有芳香受阻羟基药物的水溶性前体药物的新方法。具体而言，本发明涉及一种用于制备含有受阻醇和酚的药物，如喜树碱、普鲁泊福、依托泊苷，维生素E和环孢菌素A的水溶性膦酰氧基甲基醚的方法。
背景技术
药物向患者的成功送递对于疾病的治疗十分重要。然而，很多性质已知的临床药物的使用会受到它们水溶性非常低的限制。由于水溶性较低，必须将这些药物与助溶的药物载体，包括表面活性剂一起配制。已经显示这些表面活性剂在人类中导致了严重的副作用，限制了这些药物的临床安全性并因此限制了它们对严重疾病的治疗。
例如，喜树碱是一种从中国喜树，旱莲木(Camptothecaaccuminata)的树皮中分离出来的天然产物。已经显示它在若干体内动物模型，包括多数肿瘤类型，如肺、乳腺、卵巢、胰腺、结肠和胃癌以及恶性黑色素瘤中具有较强的抗肿瘤活性。喜树碱的重要缺点在于其非常有限的水溶性。进行生物学研究时，必需将该化合物溶解在强有机溶剂(DMSO)中，或将药物在吐温80：盐水中配制成悬液，但悬液对于人类疗法而言属于不良的药物制剂。近来，美国已经批准了将2种具有中等水溶性的喜树碱类似物用于治疗晚期卵巢癌(盐酸拓扑替康(Hycamtin))和结肠直肠癌(伊立替康(Camptosar))。
具有像喜树碱一样类似问题的其它药物是环孢菌素A(CsA)、普鲁泊福、依托泊苷和维生素E(α-生育酚)。像喜树碱一样，CsA在其结构内具有空间位阻醇，一种仲醇。CsA是在CremophorEL/乙醇混合物中配制的。
空间位阻的、水溶性较差酚的例子是普鲁泊福，一种麻醉剂。静脉内临床应用时，将普鲁泊福配制成o/w乳状液。普鲁泊福不仅水溶性差，而且可引起注射部位的疼痛。这种疼痛必须用利多卡因缓解。此外，因为普鲁泊福被配制成乳状液，因此很难且怀疑能否向该制剂中加入其它药物并且该制剂的物理改变，如增加油滴大小，会导致肺栓塞等。
美国专利US6,204,257描述了含有醇和酚的药物，如喜树碱和普鲁泊福的水溶性形式。关于喜树碱，化合物是以游离酸及其药学上可接受盐形式存在的喜树碱的膦酰氧基甲基醚。酸和盐的水溶性可帮助制备药物制剂。
然而，在美国专利US6,204,257中描述的制备含有醇和酚药物的水溶性形式的方法十分复杂，而且使用了昂贵且致癌的试剂。例如，O-膦酰氧基甲基普鲁泊福的合成需要6步，正如在下面的反应流程中概括的那样。
因此，需要一种较简短而且不使用致癌或昂贵试剂的方法。
发明内容
本发明涉及制备含醇和酚的药物的水溶性膦酰氧基甲基衍生物，尤其是膦酰基-O-甲基2，6-二异丙基苯酚二钠盐的新方法。
本发明具体涉及制备水溶性膦酰氧基甲基衍生物，包括下列步骤：
第一步
第二步
其中R-OH代表含醇或酚的药物，n代表整数1或2，R1是H、碱金属离子或药学上可接受的阳离子，并且R2是H、碱金属离子或药学上可接受的阳离子。
在优选实施方案中，2，6-二异丙基苯酚与溴氯甲烷反应，产生O-氯甲基-二异丙基苯酚。
O-氯甲基-二异丙基苯酚与磷酸反应，产生膦酰基-O-甲基2，6-二异丙基苯酚二钠盐。
本发明涉及一种制备含醇和酚的药物的水溶性膦酰氧基甲基衍生物，尤其是膦酰基-O-甲基2，6-二异丙基苯酚二钠盐的新方法。这种膦酰氧基甲基衍生物已经在美国专利US6,204,257中描述，该美国专利申请全部引入此处作为参考。本发明的方法仅需2步，而且不需要现有技术方法的致癌且昂贵的原料。此外，无需层析。该方法可产生高达85％，通常约40-85％的产率。
这里所述的本发明涉及用于制备由通式I代表的含醇和酚药物的水溶性膦酰氧基甲基衍生物的新方法：
通式I是ROH的衍生物，其中ROH代表含醇或酚的药物，如喜树碱、普鲁泊福、依托泊苷、维生素E和环孢菌素A。ROH优选是含酚的药物，如普鲁泊福。此外还包括某些由于本身水溶性较差而不能配制成可注射形式的药物。这些包括，但不限制于，达那唑、甲睾酮、双碘喹啉、阿托夸酮和fluconale。
术语n代表整数1或2，优选1。R1是氢或碱金属离子，包括钠、钾或锂或质子化胺或质子化氨基酸或任何其它药学上可接受的阳离子。R2是氢或碱金属离子，包括钠、钾或锂或质子化胺或质子化氨基酸或任何其它药学上可接受的阳离子。
通式I的衍生物可按照下列反应流程制备：
第一步
第二步
其中R-OH代表含有醇或酚的药物，n代表整数1或2，R1是H、碱金属离子或药学上可接受的阳离子，并且R2是H、碱金属离子或药学上可接受的阳离子。
在第1步中，R-OH与过量溴氯甲烷在有碱和四氢呋喃(THF)存在的条件下反应。然后使所得产物与过量磷酸和碱在适宜的溶剂中反应。
上述流程的实施可用2，6-二异丙基苯酚作为起始物质举例说明。在第1步中，2，6-二异丙基苯酚与溴氯甲烷反应，产生O-氯甲基-二异丙基苯酚。
在第2步中，O-氯甲基-二异丙基苯酚与磷酸反应，产生O-甲基2，6-二异丙基苯酚二钠盐。
更具体而言，在第1步中，2，6-二异丙基苯酚与过量溴氯甲烷在有碱和适宜溶剂，优选四氢呋喃(THF)存在的条件下反应，产生O-氯甲基-2，6-二异丙基苯酚。反应温度可以为约20至约100℃，优选约25至约65℃。
所述碱优选为碱金属氢氧化物或碱金属氢化物。适宜的碱金属氢氧化物和氢化物包括，但不限制于，氢化钠和氢氧化钠。
碱的用量为1摩尔2，6-二异丙基苯酚使用至少约1.5摩尔碱。溴氯甲烷的用量为1摩尔2，6-二异丙基苯酚使用至少约10摩尔，优选约10-30摩尔溴氯甲烷。预期溴氯甲烷可用碘氯甲烷代替。
THF可用其它适宜的溶剂，如具有较强溶解力、含有非质子性氧的溶剂，如乙二醇醚替换。
在第2步中，O-氯甲基-2，6-二异丙基苯酚与摩尔过量的磷酸和碱在适宜的溶剂中反应。至少约3，优选约3-10，通常约6摩尔的磷酸和碱与1摩尔O-氯甲基-2，6-二异丙基苯酚结合。反应温度低于100℃，通常约25-80℃。
适宜的溶剂包括极性的质子惰性溶剂，如乙腈、二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)或N-甲基吡咯烷酮(NMP)。所述溶剂应当能够溶解产品的三乙铵盐。所述碱优选为烷基胺或吡啶或取代的吡啶衍生物。更优选，所述碱是三乙胺。
然后除去溶剂，将残余物溶于水中，用例如HCl酸化至约pH1-2，优选约pH1.5。将游离酸形式的产物萃取到MTBE中。
然后除去溶剂，如在真空内。将残余物溶于水中，用适宜的试剂，如NaOH调节至约pH8-11.5，然后用适宜的溶剂，如甲苯萃取该溶液。接着可将溶液浓缩。可加入异丙醇或其它适宜溶剂，然后使产物沉淀或重结晶。适宜的溶剂包括极性、可与水混溶的有机溶剂，如丙酮、乙腈、醇、THF或二噁烷，从而产生膦酰基-O-甲基2，6-二异丙基苯酚二钠盐。
具体实施方式
实施例1
步骤1：在有4个颈口的500mL圆底烧瓶上装备机械搅拌器、氮气进口、冷凝器和温度计。向烧瓶中填装17.8g(0.10摩尔)2，6-二异丙基苯酚、200mL THF、8.0g(0.20摩尔)氢氧化钠颗粒和387g(3.0摩尔，194mL)溴氯甲烷。将反应混合物加热至64℃，持续2-3小时，直到通过GC测量不再有2，6-二异丙基苯酚存在。冷却至25℃后，将悬液过滤，用THF洗涤滤饼。旋转蒸发除去THF，在真空(0-1托，b.p.＝80℃)下蒸馏所得的油，产生16.9g(0.074摩尔，75％产率)的O-氯甲基2，6-二异丙基苯酚。
步骤2：将4个颈口的1L圆底烧瓶放在加热套中，烧瓶上装备有控制温度的热电偶。向烧瓶中填装300mL乙腈，接着是三乙胺(48.7mL，0.349mol)和85％磷酸(18.7mL，0.318mol)。然后加入O-氯甲基2，6-二异丙基苯酚(12g，0.0529mol)，将反应溶液加热至65℃达2小时。通过TLC和HPLC测定起始物质消失而判断反应是否完全。将溶液冷却，并在减压下浓缩混合物。将残余物溶于500mL水中，用8N HCl酸化至pH＝1.5。用500mL MTBE萃取该溶液3次。用盐水洗涤合并的有机萃取液1次，通过C盐过滤有机层。向残余物中加入60mL水，并加入20％NaOH溶液至pH＝8.6。用50mL甲苯洗涤该溶液2次。在减压下将水溶液浓缩至原体积的一半，加入315mL异丙醇。加热混合物至70℃以溶解产物，然后冷却至0℃。通过吸滤分离结晶的白色固体，用45mL异丙醇洗涤1次，并在真空炉(30英寸Hg，45℃)中干燥48小时，产生13.1g(0.039摩尔，75％产率)白色固体。
实施例2
步骤1：使2，6-二异丙基苯酚(20kg，FW(分子量)＝178，112mol，1个当量)与溴氯甲烷(347kg，FW＝129，2,682mol，24个当量)和氢氧化钠(11kg，FW＝40，280mol，2.5个当量)在四氢呋喃(108kg，FW＝72，1,498mol，13.3个当量)中回流反应约1.5小时。冷却至20℃后，用水(87kg)将反应混合物淬灭。收集有机层，并用15％氯化钠水溶液(78kg)洗涤2次。层分离后再次收集有机层，并将有机层中的溶剂蒸馏出来，产生粗油。简单蒸馏粗油，产生淡黄色油状的纯氯甲基(2，6-二异丙基苯基)醚(FW＝227)。
步骤2：约75℃时，使氯甲基(2，6-二异丙基苯基)醚(20kg，FW＝227，88.20mol，1个当量)与磷酸(81kg，85％，FW＝98，705mol，8个当量)和三乙胺(89kg，FW＝101，883mol，10个当量)在乙腈(200kg，FW＝41，4,872mol，55个当量)中反应3小时。冷却反应混合物，并在真空下浓缩。将所得浆液溶于水中。用浓盐酸调节混合物的pH值至1.5。用甲苯萃取酸化的混合物2次。合并2次的有机萃取液，并用水洗涤1次。在真空下浓缩有机溶液。将所得油与净化水、USP混合。用50％氢氧化钠水溶液调节混合物至pH11。用甲苯洗涤含水混合物2次。然后在真空下部分浓缩含水混合物至原体积的约40-50％。70℃时，将异丙醇(525kg)加入到浓缩的水溶液中，然后冷却至0℃，使产物结晶出来。过滤收集固体，并在真空下干燥，从而产生膦酰基-O-甲基2，6-二异丙基苯酚二钠盐(C13H19Na2O5P，FW＝332)。
实施例3
步骤1：在4个颈口的500mL圆底烧瓶上装备机械搅拌器、氮气进口、冷凝器和温度计。向烧瓶中填装8.9g(0.05摩尔)2，6-二异丙基苯酚、100mL THF、4.0g(0.10摩尔)氢氧化钠颗粒。将所得绿色悬液加热至60-65℃，持续1小时。将反应混合物冷却至30℃，并加入100mL(199g，1.54摩尔)溴氯甲烷，重新开始加热。将反应混合物在64℃维持2-3小时，直到通过GC测量不再有2，6-二异丙基苯酚存在。冷却至25℃后，通过C盐过滤悬液，用THF洗涤滤饼。旋转蒸发除去THF，在真空(0-1托，b.p.＝80℃)下蒸馏所得的油，产生9.6g(0.042摩尔，85％产率)的O-氯甲基2，6-二异丙基苯酚。
步骤2：将4个颈口的1L圆底烧瓶放在加热套中，烧瓶上装备有控制温度的热电偶。向烧瓶中填装300mL乙腈，接着是三乙胺(48.7mL，0.349mol)和85％磷酸(18.7mL，0.318mol)。然后加入O-氯甲基2，6-二异丙基苯酚(12g，0.0529mol)，将反应溶液加热至65℃达2小时。通过TLC和HPLC测定起始物质消失而判断反应是否完全。将溶液冷却，并在减压下浓缩混合物。将残余物溶于500mL水中，用8N HCl酸化至pH＝1.5。用500mL MTBE萃取该溶液3次。用盐水洗涤合并的有机萃取液1次，并通过C盐过滤有机层。加入1个当量的TEA，在减压下浓缩溶液。向残余物中加入60mL水，并加入20％NaOH溶液至pH＝8.6。用50mL甲苯洗涤该溶液2次。在减压下浓缩水溶液。加入水(30ml)，将溶液在冰浴中冷却。滴加丙酮(300mL)。将所得混合物在冰箱中冷却过夜。然后将混合物在冰浴中冷却1小时，过滤固体。将白色固体在真空炉(30英寸Hg，45℃)中干燥48小时，产生7.50g(0.023摩尔，43％产率)白色固体。
实施例4
在有氢氧化钠和THF存在的条件下，用溴氯甲烷处理2，6-二异丙基苯酚，产生85％产率的O-氯甲基-2，6-二异丙基苯酚，将其通过真空蒸馏纯化。在乙腈中用磷酸和三乙胺处理O-氯甲基-2，6-二异丙基苯酚，之后除去溶剂，在甲醇中溶解，调节pH并用丙酮析出沉淀，产生85％产率的膦酰基-O-甲基2，6-二异丙基苯酚二钠盐。
当已经通过具体实施例，包括目前实施本发明的优选方式描述了本发明后，本领域那些技术人员应认识到，上述系统和技术的若干改变和置换也落在本发明的精神和范围内。
Claims (18)
1.制备膦酰基-o-甲基2，6-二异丙基苯酚二钠盐的方法，包括下列步骤：
第一步
第二步
其中R-OH代表普鲁泊福，n代表1，R1是钠，并且R2是钠；其中第二步包括
(i)使R-O-CH2Cl与摩尔过量的磷酸和三乙胺在合适的溶剂中反应；
(ii)从(i)的产物中除去溶剂以形成残余物，将该残余物溶于水，并且酸化至pH 1-2；
(iii)用MTBE萃取(ii)的产物；
(iv)从(iii)的产物中除去溶剂以形成残余物，将该残余物溶于水以形成溶液，并且将该溶液的pH调节至8至11.5；
(v)用适当的溶剂萃取所述溶液；
(vi)任选地浓缩所述溶液；以及
(vii)沉淀或重结晶以获得所述膦酰基-O-甲基2，6-二异丙基苯酚二钠盐。
2.根据权利要求1的方法，其中在第一步中，使R-OH与摩尔过量的溴氯甲烷在有氢氧化钠和适宜溶剂存在的条件下反应。
3.根据权利要求1的方法，其中在第一步中，使R-OH与摩尔过量的碘氯甲烷在有氢氧化钠和适宜溶剂存在的条件下反应。
4.根据权利要求2或3的方法，其中在第一步中所用溶剂是乙二醇醚。
5.根据权利要求2或3的方法，其中在第一步中所用溶剂是四氢呋喃。
6.根据权利要求2或3的方法，其中对于每1摩尔R-OH存在至少1.5摩尔氢氧化钠。
7.根据权利要求2的方法，其中对于每1摩尔R-OH存在至少10摩尔溴氯甲烷。
8.根据权利要求1的方法，其中第1步的反应温度为25℃至65℃。
9.根据权利要求1的方法，其中(i)中的所述溶剂是极性质子惰性溶剂。
10.根据权利要求9的方法，其中将至少3摩尔磷酸与1摩尔R-O-CH2Cl结合。
11.根据权利要求10的方法，其中对于每摩尔R-O-CH2Cl存在3至10摩尔磷酸。
12.根据权利要求1的方法，其中第2步的反应温度低于100℃。
13.根据权利要求12的方法，其中所述反应温度是25℃至80℃。
14.根据权利要求9的方法，其中所述极性质子惰性溶剂选自乙腈、二甲基甲酰胺、二甲基亚砜或N-甲基吡咯烷酮。
15.根据权利要求3的方法，其中对于每1摩尔R-OH存在至少10摩尔碘氯甲烷。
16.根据权利要求1的方法，其中(v)的所述溶剂是甲苯。
17.权利要求7的方法，其中每1摩尔2，6-二异丙基苯酚存在10-30摩尔溴氯甲烷。
18.权利要求15的方法，其中每1摩尔2，6-二异丙基苯酚存在10-30摩尔碘氯甲烷。
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Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA04010527A (es) | 2002-04-26 | 2004-12-13 | Gilead Sciences Inc | Acumulacion celular de analogos de fosfonato de los compuestos inhibidores de la proteasa del virus de inmunodeficiencia humana (vih). |
| WO2005002626A2 (en) | 2003-04-25 | 2005-01-13 | Gilead Sciences, Inc. | Therapeutic phosphonate compounds |
| WO2004096285A2 (en) | 2003-04-25 | 2004-11-11 | Gilead Sciences, Inc. | Anti-infective phosphonate conjugates |
| US7452901B2 (en) | 2003-04-25 | 2008-11-18 | Gilead Sciences, Inc. | Anti-cancer phosphonate analogs |
| MXPA05011289A (es) * | 2003-04-25 | 2006-01-24 | Gilead Sciences Inc | Compuestos de fosfato que tienen actividad inmunomoduladora. |
| US7407965B2 (en) | 2003-04-25 | 2008-08-05 | Gilead Sciences, Inc. | Phosphonate analogs for treating metabolic diseases |
| US7470724B2 (en) | 2003-04-25 | 2008-12-30 | Gilead Sciences, Inc. | Phosphonate compounds having immuno-modulatory activity |
| EP1628685B1 (en) | 2003-04-25 | 2010-12-08 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
| US7432261B2 (en) | 2003-04-25 | 2008-10-07 | Gilead Sciences, Inc. | Anti-inflammatory phosphonate compounds |
| US7417055B2 (en) | 2003-04-25 | 2008-08-26 | Gilead Sciences, Inc. | Kinase inhibitory phosphonate analogs |
| US7427636B2 (en) | 2003-04-25 | 2008-09-23 | Gilead Sciences, Inc. | Inosine monophosphate dehydrogenase inhibitory phosphonate compounds |
| US20040225022A1 (en) * | 2003-05-09 | 2004-11-11 | Desai Neil P. | Propofol formulation containing reduced oil and surfactants |
| US7427624B2 (en) | 2003-10-24 | 2008-09-23 | Gilead Sciences, Inc. | Purine nucleoside phosphorylase inhibitory phosphonate compounds |
| CA2543144A1 (en) | 2003-10-24 | 2005-05-12 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds |
| US7432273B2 (en) | 2003-10-24 | 2008-10-07 | Gilead Sciences, Inc. | Phosphonate analogs of antimetabolites |
| US20080287471A1 (en) | 2003-12-22 | 2008-11-20 | Maria Fardis | 4'-Substituted Carbovir And Abacavir-Derivatives As Well As Related Compounds With Hiv And Hcv Antiviral Activity |
| PL216369B1 (pl) | 2004-07-27 | 2014-03-31 | Gilead Sciences | Pochodne fosfonianowe, kompozycje farmaceutyczne zawierające te pochodne oraz zastosowanie tych pochodnych do wytwarzania leku do hamowania wirusa HIV |
| PE20110219A1 (es) | 2008-07-08 | 2011-03-31 | Gilead Sciences Inc | Sales del compuesto n-[(s)({[(2r,5r)-5-(6-amino-9h-purin-9-il)-4-fluoro-2,5-dihidrofuran-2-il]oxi}metil)fenoxifosfinoil]-l-alaninato de etilo como inhibidores de vih |
| KR20100032803A (ko) * | 2008-09-18 | 2010-03-26 | 씨제이제일제당 (주) | 아데포비어디피복실의 개선된 제조방법 |
| CN101845057B (zh) * | 2009-03-27 | 2013-10-23 | 四川大学 | 取代苯酚的甲缩醛磷酸盐麻醉镇静药用化合物及制备方法 |
| US9150600B2 (en) | 2009-05-07 | 2015-10-06 | Regents Of The University Of Minnesota | Triptolide prodrugs |
| MX2011011776A (es) * | 2009-05-07 | 2012-08-03 | Univ Minnesota | Nuevos profarmacos de triptolite. |
| JP2012140330A (ja) * | 2010-12-28 | 2012-07-26 | Tosoh Corp | 水溶性リン酸エステルの精製方法 |
| ITMI20110580A1 (it) * | 2011-04-08 | 2012-10-09 | Chemelectiva S R L | Iintermedi utili per la preparazione di fospropofol e processo per la loro preparazione |
| UY34072A (es) | 2011-05-17 | 2013-01-03 | Novartis Ag | Derivados sustituidos de indol |
| CN102351895A (zh) * | 2011-08-08 | 2012-02-15 | 陕西合成药业有限公司 | 甲磷丙泊酚二钠水合物及其制备方法和用途 |
| CN102516099B (zh) * | 2011-12-02 | 2013-07-17 | 成都苑东药业有限公司 | 一种水溶性三醇胺的衍生物 |
| CN102382133B (zh) * | 2011-12-02 | 2016-03-23 | 陕西合成药业股份有限公司 | 一种磷丙泊酚钠的制备及纯化方法 |
| CN102399236A (zh) * | 2011-12-27 | 2012-04-04 | 上海立科药物化学有限公司 | 磷丙泊酚钠的合成方法 |
| CN102603798A (zh) * | 2012-02-14 | 2012-07-25 | 陕西合成药业有限公司 | 一种唑系化合物水溶性前药的制备方法 |
| PT2995604T (pt) * | 2013-05-09 | 2019-10-11 | Sichuan Haisco Pharmaceutical Co Ltd | Derivado de fenol e seu processo de preparação e utilização em medicina |
| WO2017205632A1 (en) | 2016-05-27 | 2017-11-30 | The Johns Hopkins University | Buccal, sublingual and intranasal delivery of fospropofol |
| EP3960740B1 (en) | 2017-08-01 | 2023-11-15 | Gilead Sciences, Inc. | Crystalline forms of ethyl ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-l-alaninate (gs-9131) vanillate for treating viral infections |
| CN109456360B (zh) * | 2018-12-17 | 2021-05-14 | 河南中医药大学 | 一种磷丙泊酚钠的制备方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6204257B1 (en) * | 1998-08-07 | 2001-03-20 | Universtiy Of Kansas | Water soluble prodrugs of hindered alcohols |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2833827A (en) * | 1955-01-17 | 1958-05-06 | Bayer Ag | Tri (3, 5-di lower alkyl-4-hydroxy phenyl)-sulfonium chlorides and method of preparing same |
| GB814278A (en) | 1956-11-13 | 1959-06-03 | Bataafsche Petroleum | Process for the preparation of 2.4.6 trialkylated phenols |
| JPS56131594A (en) * | 1980-03-17 | 1981-10-15 | Mitsui Toatsu Chem Inc | Preparation of alkyl phosphate |
| JPH04282337A (ja) * | 1991-03-08 | 1992-10-07 | Fuji Photo Film Co Ltd | ２−アリールオキシ−１−クロルプロパンの製造方法 |
| US6201257B1 (en) * | 1996-10-10 | 2001-03-13 | Advanced Scientific Concepts, Inc. | Semiconductor X-ray photocathodes devices |
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