CN102199181A - 烷基取代的2-脱氧-2-氟代-d-呋喃核糖基嘧啶和嘌呤及其衍生物的制备 - Google Patents
烷基取代的2-脱氧-2-氟代-d-呋喃核糖基嘧啶和嘌呤及其衍生物的制备 Download PDFInfo
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- CN102199181A CN102199181A CN2011100790463A CN201110079046A CN102199181A CN 102199181 A CN102199181 A CN 102199181A CN 2011100790463 A CN2011100790463 A CN 2011100790463A CN 201110079046 A CN201110079046 A CN 201110079046A CN 102199181 A CN102199181 A CN 102199181A
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
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Abstract
本发明提供(i)一种制备2-脱氧-2-氟代-2-甲基-D-核糖内酯衍生物的方法，(ii)内酯向具有有效抗HCV活性的核苷及其类似物的转化，和(iii)由预形成的(优选天然产的)核苷制备含2-脱氧-2-氟代-2-C-甲基-β-D-呋喃核糖基核苷的抗HCV核苷。
Description
本发明专利申请是国际申请日为2005年7月21日、国际申请号为PCT/US2005/025916、进入中国国家阶段的申请号为200580031530.1、发明名称为“烷基取代的2-脱氧-2-氟代-D-呋喃核糖基嘧啶和嘌呤及其衍生物的制备”的发明专利申请的分案申请。
该申请于2005年7月21日作为PCT国际专利申请提交，除美国以外的所有指定国家的申请人为美国国有公司Pharmasset，Inc.，在美国的全部申请人为Pieyang Wang(中国公民)、Wojciech Stec(波兰公民)、Jeremy Clark(美国公民)、Byoung-Kown Chun(韩国公民)、Junxing Shi(中国公民)和Jinfa Du(美国公民)，该申请要求于2004年7月21日提交的美国临时专利申请第60/589866号的优先权。
发明领域
本发明提供(i)一种制备2-脱氧-2-氟代-2-甲基-D-核糖内酯(ribonolactone)衍生物的方法；(ii)将所述内酯转化为具有有效抗HCV活性的核苷及其类似物；(iii)由预形成的、优选天然产核苷制备含有2′-脱氧-2′-氟代-2′-C-甲基-β-D-呋喃核糖基核苷的抗HCV核苷。
发明背景
HCV感染已经在世界范围内流行，受感染病患承受巨大的痛苦。目前，还没有普遍有效地治疗该感染的措施，仅有的用于治疗慢性丙型肝炎的药物是各种形式的α干扰素(IFN-α)，它们单独使用或与三氮唑核苷组合使用。但是，这些治疗措施的治疗价值由于副作用而被大大减低，因此迫切需要开发其它用于治疗的供选择方案。
HCV是黄病毒科(Flaviviridae)的一种小的，有包膜的病毒，其在核衣壳中具有约9.6kb的阳性单链RNA基因组。该基因组含有一个编码刚大于3,000个氨基酸的多蛋白的开放读框(ORF)，切割该多蛋白可得到成熟的结构与非结构病毒蛋白质。ORF的侧翼是对RNA翻译和复制重要的长度为几百个核苷酸的5’和3’非翻译区(NTR)。翻译的多蛋白在N末端含有结构核心(C)与包膜蛋白(E1、E2、p7)，其后是非结构蛋白(NS2、NS3、NS4A、NS4B、NS5A、NS5B)。利用宿主信号肽酶切割得到成熟的结构蛋白。NS2/NS3蛋白酶自催化切割NS2与NS3之间的连接处，而与NS4A形成复合体的NS3的N-末端丝氨酸蛋白酶结构域切割其余四个连接处。NS3蛋白也具有能在复制期间使双螺旋RNA解旋的NTP依赖性的解旋酶活性。NS5B蛋白具有对病毒复制关键的RNA依赖性的RNA聚合酶(RDRP)活性。与HBV或HIV不同，本文强调的是HCV的复制不涉及DNA。
美国专利申请(序列号10/828,753)揭示了1-(2-脱氧-2-氟代-2-C-甲基-β-D-呋喃核糖基)胞嘧啶(14)是有效的且选择性的抗HCV剂。最初的合成步骤(方案1-3)的效率非常低，总产率等于或小于4％，不能适应大规模生产。
方案1
方案2
方案3
需要一种新颖且廉价的合成具有抗HCV活性的2-C-烷基-2-脱氧-2-取代-D-吡喃核糖基核苷的方法。
发明概述
文中揭示的本发明涉及通式[I]和[II]的化合物的组合物和合成方法，
式中：
X是卤素(F、Cl、Br)，
Y是N或CH，
Z是卤素、OH、OR′、SH、SR′、NH2、NHR′或R′，
R2′是C1-C3烷基、乙烯基或乙炔基；
R3′和R5′可相同或不同，是H、烷基、芳烷基、酰基、环缩醛，诸如2′，3′-O-异亚丙基或2′，3-O-苯亚甲基或2′，3′-环碳酸基；
R2、R4、R5和R6各自独立地是H、卤素(包括F、Cl、Br、I)、OH、OR′、SH、SR′、N3、NH2、NHR′、NR′2、NHC(O)OR′、C1-C6低级烷基、卤化的(F、Cl、Br、I)C1-C6低级烷基如CF3和CH2CH2F、C2-C6低级烯基如CH＝CH2、卤化的(F、Cl、Br、I)C2-C6低级烯基如CH＝CHCl、CH＝CHBr和CH＝CHI、C2-C6低级炔基如C≡CH、卤化的(F、Cl、Br、I)C2-C6低级炔基、C1-C6低级羟烷基如CH2OH和CH2CH2OH、卤化的(F、Cl、Br、I)C1-C6低级烷基、C1-C6低级烷氧基如甲氧基和乙氧基、CO2H、CO2R′、CONH2、CONHR′、CONR′2、CH＝CHCO2H、CH＝CHCO2R′；和
R′是任选取代的C1-C12烷基(特别是当烷基是氨基酸残基时)、环烷基、任选取代的C2-C6炔基、任选取代的C2-C6低级烯基或任选取代的酰基。
在其它方面，本发明提供制备通式为III和IV的含有2-脱氧-2-氟代-2-C-甲基-D-呋喃核糖基部分的核苷的方法，
该方法包括：(i)合成结构式V的3，5-保护的2-脱氧-2-氟代-2-C-甲基-D-核糖(ribono)-γ-内酯中间体，(ii)将结构式V的中间体转化为结构式III和IV的嘌呤和嘧啶核苷，(iii)通过预形成的核苷(优选天然核苷)制备结构式III和IV的核苷。
关于上述III、IV和V，R4和R5如上文R3和R5中所定义，可以独立的是H、Me、酰基(诸如Ac、Bz、取代Bz)、苄基、取代苄基、三苯甲基、三烷基甲硅烷基、叔丁基二烷基甲硅烷基、叔丁基二苯基甲硅烷基、TIPDS、THP、MOM、MEM，或者R3和R5通过-SiR2-O-SiR2-或-SiR2-连接，其中R是低级烷基，诸如Me、Et、n-Pr或i-Pr。
本发明的另一方面是通式V的新型内酯中间体，以及该内酯中间体的制备方法，包括前体酯中间体，这些制备方法和中间体将在下文中详细描述。
发明详述
目前没有抵抗黄病毒(包括丙型肝炎病毒(HCV)、登革热病毒(DENV)、西方尼罗河病毒(MNV)或黄热病病毒(YFV))感染的方法。唯一被认可的治疗方法是单独使用α干扰素或使用α干扰素和核苷三氮唑核苷的组合来治疗HCV感染，但是这些治疗措施的治疗价值由于副作用而大大降低。最近发现一类核苷，包括2′-脱氧-2′-氟代-2′-C-甲基胞苷(14)，对抵抗复制体系中复制HCV表现出有效且有选择的活性。但是，这类核苷以及类似核苷化合物合成的难度阻碍了开发治疗黄病毒感染的临床药物所必需进行的生物物理、生物化学、药理学评估。
本发明提供一种有效地制备含有2-脱氧-2-氟代-2-C-甲基-D-呋喃核糖基部分III和IV的方法，该方法包括：(i)合成结构式V的3，5-保护的2-脱氧-2-氟代-2-C-甲基-D-核糖(ribono)-γ-内酯中间体，(ii)将结构式V的中间体转化为结构式III和IV的嘌呤和嘧啶核苷，(iii)通过预形成的核苷(优选天然核苷)制备结构式III和IV的核苷。
定义
文中所用的术语“独立地”是指独立应用的变量可以根据应用的不同而独立地变化。因此，在如RaXYRa之类的化合物中，其中Ra“独立地是碳或氮”，则两个Ra都可以是碳，两个Ra都可以是氮，或者一个Ra可以是碳而另一个Ra是氮。
文中所用的术语“对映异构体纯的”或“对映异构体增强的”是指一种核苷组合物，该组合物中所述核苷的一种对映异构体的含量至少约为95％，优选约为97％、98％、99％或100％。
文中所用的术语“基本上不含”或“基本上不存在”是指一种核苷组合物，该组合物中所述核苷的指定对映异构体的含量至少为85-90重量％，优选为95-98重量％，甚至更优选为99-100重量％。在一个优选的实施方式中，在本发明的方法和化合物中，所述化合物基本上不含有对映异构体。
除非另有指示，文中所用的术语“烷基”是指通常为C1-C10的饱和直链或支链烃链，具体包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基、异己基、环己基、环己基甲基、3-甲基戊基、2，2-二甲基丁基和2，3-二甲基丁基等。该术语包括取代和未取代的烷基。烷基可任选被一个或多个选择以下的部分取代：羟基、氨基、烷基氨基、芳基氨基、烷氧基、芳氧基、硝基、氰基、磺酸、硫酸酯、膦酸、磷酸酯或膦酸酯。连接在烷基碳原子上的一个或多个氢原子可以被一个或多个卤素原子(例如，氟或氯，或氟和氯)替代，诸如三氟甲基、二氟甲基、氟氯甲基等。烃链还可以被如N、O或S之类的杂原子中断。
除非另有指示，文中所用的术语“低级烷基”是指C1-C4饱和直链或支链烷基，包括如上所定义的取代和未取代形式。除非在本申请中另有具体说明，当烷基是合适部分时，优选低级烷基。同样，当烷基或低级烷基是合适部分时，优选未取代的烷基或低级烷基。
除非另有指示，文中所用的术语“环烷基”是指具有3-8个、优选3-6个碳原子的饱和烃环，诸如环丙基、环丁基、环戊基和环己基。环烷基的环原子也可以被烷基取代，诸如环丙基甲基等。
术语“烷基氨基”或“芳基氨基”分别指具有一个或两个烷基或芳基取代基的氨基。
除非另有指示，文中所用的术语“保护的”是指添加到氧、氮或磷原子上以防止该原子进一步反应或出于其它目的的基团。有机合成领域的技术人员已经知道了许多氧和氮保护基团。非限制性的例子包括：C(O)-烷基、C(O)Ph、C(O)芳基、CH3、CH2-烷基、CH2-烯基、CH2Ph、CH2-芳基、CH2O-烷基、CH2O-芳基、SO2-烷基、SO2-芳基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基和1，3-(1，1，3，3-四异丙基二亚硅烷基(disiloxanylidene))。
除非另有指示，文中所用的术语“芳基”指苯基、联苯基或萘基，优选的是苯基。该术语包括取代和未取代的部分。芳基可以被一个或多个取代基取代，所述取代基包括但不限于：羟基、卤代、氨基、烷基氨基、芳基氨基、烷氧基、芳氧基、硝基、氰基、磺酸、硫酸酯、膦酸、磷酸酯或膦酸酯，这些取代基可以是未保护的，或者根据需要用本领域技术人员已知方法进行保护，例如参见T.W.Greene和P.G.M.Wuts在″Protective Groupsin Organic Synthesis，″第三版，John Wiley & Sons，1999中所述。
术语“烷芳基”或“烷基芳基”指具有芳基取代基的烷基。术语“芳烷基”或“芳基烷基”指具有烷基取代基的芳基，例如，苄基。
文中所用的术语“卤代”包括氯代、溴代、碘代和氟代。
术语“酰基酯”或“O-连接的酯”指通式为C(O)R′的羧酸酯，其中酯基的非羰基部分R′是直链或支链烷基或环烷基或低级烷基；烷氧基烷基，包括甲氧基甲基；芳烷基，包括苄基；芳氧基烷基，诸如苯氧基甲基；芳基，包括任选地被卤素(F、Cl、Br、I)、C1-C4烷基或C1-C4烷氧基取代的苯基；磺酸酯，诸如烷基或芳烷基磺酰基，包括甲磺酰基；单磷酸酯、二膦酸酯或三磷酸酯；三苯甲基或一甲氧基三苯甲基；取代苄基；三烷基甲硅烷基(例如二甲基叔丁基甲硅烷基)或二苯基甲基甲硅烷基。酯基中的芳基最好包括苯基。
术语“酰基”指通式为R″C(O)-的基团，其中R″是直链或支链烷基或环烷基；氨基酸；芳基，包括苯基；烷基芳基；芳烷基，包括苄基；烷氧基烷基，包括甲氧基甲基；芳氧基烷基，诸如苯氧基甲基；或任选地被氯、溴、氟、碘、C1-C4烷基或C1-C4烷氧基取代的烷基(包括低级烷基)、芳基(包括苯基)；磺酸酯，诸如烷基或芳烷基磺酰基，包括甲磺酰基；一磷酸酯、二磷酸酯或三磷酸酯；三苯甲基或一甲氧基三苯甲基；取代苄基；烷芳基；芳烷基，包括苄基；烷氧基烷基，包括甲氧基甲基；芳氧基烷基，诸如苯氧基甲基。酯中的芳基最好包括苯基。特别地，酰基包括乙酰基、三氟乙酰基、甲基乙酰基、环丙基乙酰基、环丙基羧基、丙酰基、丁酰基、己酰基、庚酰基、辛酰基、新庚酰基、苯基乙酰基、2-乙酰氧基-2-苯基乙酰基、二苯基乙酰基、α-甲氧基-α-三氟甲基-苯基乙酰基、溴乙酰基、2-硝基-苯乙酰基、4-氯-苯乙酰基、2-氯-2，2-二苯基乙酰基、2-氯-2-苯基乙酰基、三甲基乙酰基、氯代二氟乙酰基、全氟乙酰基、氟乙酰基、溴代二氟乙酰基、甲氧基乙酰基、2-噻吩乙酰基、氯磺酰基乙酰基、3-甲氧基苯基乙酰基、苯氧基乙酰基、叔丁基乙酰基、三氯乙酰基、一氯乙酰基、二氯乙酰基、7H-十二氟庚酰基、全氟庚酰基、7H-十二氟庚酰基、7-氯-十二氟庚酰基、7-氯-十二氟庚酰基、7H-十二氟庚酰基、7H-十二氟庚酰基、九氟-3，6-二氧杂庚酰基、九氟-3，6-二氧杂庚酰基、全氟庚酰基、甲氧基苯甲酰基、甲基3-氨基-5-苯基噻吩-2-羧基、3，6-二氯-2-甲氧基-苯甲酰基、4-(1，1，2，2-四氟-乙氧基)-苯甲酰基、2-溴-丙酰基、ω-氨基辛酰基(capryl)、癸酰基、正十五烷酰基、硬脂酰基、3-环戊基-丙酰基、1-苯-羧基、O-乙酰基扁桃基(mandelyl)、新戊酰基乙酰基、1-金刚烷-羧基、环己烷-羧基、2，6-吡啶二羧基、环丙烷-羧基、环丁烷-羧基、全氟环己基羧基、4-甲基苯甲酰基、氯甲基异
唑基羰基、全氟环己基羧基、巴豆酰基、1-甲基-1H-吲唑-3-羰基、2-丙烯基、异戊酰基、1-吡咯烷羰基、4-苯基苯甲酰基。当使用术语酰基时，具体指乙酰基、三氟乙酰基、甲基乙酰基、环丙基乙酰基、丙酰基、丁酰基、己酰基、庚酰基、辛酰基、新庚酰基、苯基乙酰基，二苯基乙酰基、ct-三氟甲基-苯基乙酰基、溴乙酰基、4-氯-苯乙酰基、2-氯-2，2-二苯基乙酰基、2-氯-2-苯基乙酰基、三甲基乙酰基、氯代二氟乙酰基、全氟乙酰基、氟乙酰基、溴代二氟乙酰基、2-噻吩乙酰基、叔丁基乙酰基、三氯乙酰基、一氯乙酰基、二氯乙酰基、甲氧基苯甲酰基、2-溴-丙酰基、癸酰基、正十五烷酰基、硬酯酰基、3-环戊基-丙酰基、1-苯-羧基、新戊酰基乙酰基、1-金刚烷-羧基、环己烷-羧基、2，6-吡啶二羧基、环丙烷-羧基、环丁烷-羧基、4-甲基苯甲酰基、巴豆酰基、1-甲基-1H-吲哚-3-羰基、2-丙烯基、异戊酰基、4-苯基苯甲酰基。
术语“低级酰基”指其中如上所定义的R″是低级烷基的酰基。
术语“嘌呤”或“嘧啶”碱包括，但不限于，腺嘌呤、N6-烷基嘌呤、N6-酰基嘌呤(其中酰基是C(O)(烷基、芳基、烷基芳基或芳基烷基))、N6-苄基嘌呤、N6-卤代嘌呤、N6-乙烯基嘌呤、N6-乙炔嘌呤、N6-酰基嘌呤、N6-羟烷基嘌呤、N6-烯丙基(allcyl)氨基嘌呤、N6-硫代烯丙基(thioallcyl)嘌呤、N2-烷基嘌呤、N2-烷基-6-硫代嘌呤、胸腺嘧啶、胞嘧啶、5-氟代胞嘧啶、5-甲基胞嘧啶、6-氮杂嘧啶(包括6-氮杂胞嘧啶)、2-和/或4-巯基嘧啶、尿嘧啶、5-卤代尿嘧啶(包括5-氟尿嘧啶)、C5-烷基嘧啶、C5-苄基嘧啶、C5-卤代嘧啶、C5-乙烯基嘧啶、C5-乙炔嘧啶、C5-酰基嘧啶、C5-羟烷基嘌呤、C5-酰氨基嘧啶、C5-氰基嘧啶、C5-碘代嘧啶、C6-碘代嘧啶、C5-Br-乙烯基嘧啶、C6-Br-乙烯基嘧啶、C5-硝基嘧啶、C5-氨基-嘧啶、N2-烷基嘌呤、N2-烷基-6-硫代嘌呤、5-氮杂胞苷基、5-氮杂尿嘧啶基、三唑并吡啶基、咪唑并吡啶基、吡咯并嘧啶基和吡唑并嘧啶基。嘌呤碱包括，但不限于，鸟嘌呤、腺嘌呤、次黄嘌呤、2，6-二氨基嘌呤和6-氯嘌呤。可以按需要对所述碱上的氧和氮官能团进行保护。合适的保护基团是本领域技术人员所熟知的，其包括三甲基甲硅烷基、二甲基己基甲硅烷基、叔丁基二甲基甲硅烷基和叔丁基二苯基甲硅烷基、三苯甲基、烷基和酰基，诸如乙酰基和丙酰基、甲磺酰基和对甲苯磺酰基。
术语“氨基酸”包括天然和合成的α、β、γ或δ氨基酸，包括但不限于，蛋白质中发现的氨基酸，即甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸、苯基丙氨酸、色氨酸、脯氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、天冬氨酸盐、谷氨酸盐、赖氨酸、精氨酸和组氨酸。在一个优选的实施方式中，氨基酸是L-构型。或者，氨基酸可以是以下物质的衍生物：丙氨酰、缬氨酰、亮氨酰、异亮氨酰、脯氨酰、苯基丙氨酰、色氨酰、甲硫氨酰、甘氨酰、丝氨酰、苏氨酰、半胱氨酰、酪氨酰、天冬酰胺酰、谷氨酰胺酰、天冬氨二酰、戊二酸单酰(glutaroyl)、赖氨酰、精氨酰、组氨酰、β-丙氨酰、β-缬氨酰、β-亮氨酰、β-异亮氨酰、β-脯氨酰、β-苯基丙氨酰、β-色氨酰、β-甲硫氨酰、β-甘氨酰、β-丝氨酰、β-苏氨酰、β-半胱氨酰、β-酪氨酰、β-天冬酰胺酰、β-谷氨酰胺酰、β-天冬氨二酰、β-戊二酸单酰、β-赖氨酰、β-精氨酰或β-组氨酰。当使用术语氨基酸时，认为该术语具体指D和L-构型的a、β、γ或δ甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸、苯基丙氨酸、色氨酸、脯氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、天冬氨酸盐、谷氨酸盐、赖氨酸、精氨酸和组氨酸的酯。
在说明书中使用术语“药学上可接受的盐或药物前体”来描述在对病患给药后提供活性化合物的化合物的任何药学上可接受的形式(例如，酯、磷酸酯、酯或相关基团的盐)。药学上可接受的盐包括衍生自药学上可接受的无机或有机碱和酸的物质。合适的盐包括衍生自碱金属(诸如钾和钠)、碱土金属(诸如钙和镁)以及药学领域中众所周知的许多其它酸的盐。当形成包含氮原子时，药学上可接受的盐还可以是酸加成盐。这类盐还可以衍生自药学上可接受的无机或有机酸，诸如盐酸、硫酸、磷酸、乙酸、柠檬酸、酒石酸等。药学上可接受的药物前体指能在寄主中发生代谢变化(例如水解或氧化)形成本发明化合物的化合物。药物前体的典型例子包括在活性化合物的官能部分具有生物学上易变化的保护基团的化合物。药物前体包括能够氧化、还原、氨化、脱氨化、羟基化、脱羟基化、水解、脱水、烷基化、脱烷基化、酰化、脱酰化、磷酸化、脱磷酸化产生活性化合物的化合物。
化合物的制备
(i)3，5-二-O-保护的-D-核糖-γ-内酯的合成
2，3-O-异亚丙基-D-甘油醛39(方案4)与商购的40发生维蒂希反应(Wittig reaction)，得到主产物(E)-产物41。使用AD-混合-β作为二羟基化试剂进行Sharpless二羟基化反应(J.Org.Chem.1992，57，2768-2771)，以高产率得到所需产物42。通过HCl/MeOH处理使42高产率地内酯化为2-C-甲基-D-阿拉伯(arabino)-γ-内酯(46)。伯OH基和仲OH基进行选择性O-苯甲酰化反应，以高产率生产3，5-二-O-苯甲酰衍生物47。用DAST或Deoxofluor，三氟化[二(2-甲氧基乙基)氨基]硫在各种不同条件下处理47，得到痕量所需2′-氟代-核糖-γ-内酯49，但主要是能从其中分离出未氟化的核糖内酯(48)的混合物。但是，用过量(优选3当量的)叔胺(优选是二异丙基乙胺)和过量(优选5当量的)DAST或Deoxofluor处理47，可以约50％的产率得到49。还发现，使用3，5-O-MOM替代苯甲酰基保护，48的产率可以接近90％。因此，在如三氟甲基磺酸之类的强酸存在下用二甲氧基甲烷处理46，得到50，50在碱存在下与DAST或Deoxofluor反应后，产生分离产率为87％的49。
还发现，在用DAST或Deoxofluor对开链单苯甲酸酯43进行处理后，可以发生平稳的氟化反应，得到所需的2-脱氧-2-氟代-2-C-甲基-3-O-苯甲酰基-4，5-O-异亚丙基-D-核糖酸乙酯44，其中开链单苯甲酸酯43容易通过42的选择性苯甲酰化反应得到。44的内酯化只得到γ-内酯45，45的进一步苯甲酰化得到二苯甲酸酯49。
方案4
在本发明的一个实施方式中，提供一种合成中间体49的方法，该方法通过以下步骤实现：39与2-溴丙酸烷基酯如53在活性锌存在下、在醚溶剂如二乙醚或四氢呋喃(或两种溶剂的混合物)中进行Reformatsky缩合反应(方案5)，得到54，54通过氧化反应转化为55。可以使用的氧化剂是：活性二甲亚砜，诸如二甲亚砜、三氟乙酸酐或乙酸酐的混合物(Swern/Moffat氧化)；三氧化铬或其它铬酸盐试剂；Dess-Martin过碘烷(periodinane)；或具有或不具有分子筛的过钌酸四丙铵(TPAP)。该氧化生成C-3酮的反应优选在不影响C-4立体化学的情况下进行。
55的氟化在2-位通过亲电子氟化(″F+″)在合适的溶剂中进行，得到56，所述溶剂是例如二甲基甲酰胺、四氢呋喃、乙醇、叔丁醇或二乙醚，或本领域技术人员已知的这些溶剂的任意组合(Rozen等，J.Org.Chem.，2001，66，7646-7468；Jun-An Ma and Dominique Cahard，Journal of Fluorine Chemistry，2004，出版中，以及其参考文献)。亲电子氟化试剂的一些非限制性例子是
N-氟代磺酰亚胺(NFSI)和AcOF。可通过使用如Sodeoka等人(JP2004010555)所描述的不对称过渡金属络合物催化剂之类的催化剂或其它催化剂来实现立体选择性氟化。起始β-酮醚55可以在氟化之前首先转化为烯酮甲硅烷基乙缩醛(Rozen等，J.Org.Chem.，2001，66，7646-7468)。
使用三苯基硅烷在如AlCl3之类的路易斯酸存在下或在如三氟乙酸之类的有机酸存在下对C-3酮56进行选择性还原(Kitazume等，J.Org.Chem.，1987，52，3218-3223)，得到两种2，3位结构相反(anti)的产物57和58。但是，通过使用立体选择性氟化结合选择性还原，可以良好的产率得到58(高非对映异构体过量)。58的苯甲酰化得到44，44转化为前文中描述的内酯45。
方案5
(ii)通过缩合制备含有2-脱氧-2-氟代-3-甲基-D-呋喃核糖基部分的核苷。
使用DIBAL-H可以将如49之类的内酯还原为相应的糖。在端羟基乙酰化后，以高产率得到59(方案12)。59与甲硅烷基化碱(例如，甲硅烷基化N4-苯甲酰基胞嘧啶在Vorbrüggen条件下)缩合，得到端基保护的核苷60和60-a的混合物。在端基异构体(anomer)分离后，通过用金属醇盐在醇、优选NaOMe/MeOH或甲醇铵(methanolic ammonia)中进行脱保护来制备所需的β-核苷14。
方案6
化合物59可以转化为溴代糖61(方案7)，溴代糖61与嘌呤的钠盐(例如钠-N6-苯甲酰基腺嘌呤)缩合，得到相应的被保护的嘌呤核苷65。通过皂化容易得到所需的游离核苷63。
方案7
(iii)由预形成的核苷合成：
使用预形成的核苷作为原料来制备所需的2′-C-烷基-2′-脱氧-2′-氟代-β-D-核糖核苷具有一些优点，例如可以避免形成端基异构体以及随后对它们的分离，而得到高产率的目标核苷。
已经描述了两种由核苷原料制备所需核苷14的步骤(方案2和3)。但是，如上文所述，这些步骤也产生两种不希望得到的产物22和23，后者是由于如方案8所示的相邻基团的参与所产生的。从所述混合物中分离所需核苷14相当麻烦。因此，本发明通过在3′-OH基团处使用非参与保护基团如THP、甲基、乙基、苄基、对甲氧基苄基、苄氧基甲基、苯氧基甲基、甲氧基甲基、乙氧基甲基、甲磺酰基、甲苯磺酰基、三氟乙酰基、三氯乙酰基来防止生成23。
方案8
一个例子示于方案17中。当用DAST或Deoxofluor处理N4，5′-O-二苯甲酰基-3′-O-甲磺酰基-2′-脱氧-2′-C-甲基-β-D-阿拉伯呋喃糖基胞嘧啶(64)时，以54％的产率得到所需氟化产物65，同时以39％的产率得到烯烃66。如同预期的，没有形成可检测量的未氟化胞苷衍生物67。有若干种方法将65脱保护为14。方案9表示了一个例子，该例子需要3′-构型的双反转(double inversion)。
方案9
当3′-O-取代基是非参与(non-participating)和非离去基团如甲氧基甲基(MOM)、甲基、苄基、甲氧基苄基或四氢吡喃基时，中间体比64得到更有效的氟化。
以下实施例旨在说明本发明，但不用来限制本发明。
实验：通过文献步骤(Organic Synthesis，年度第72卷，第6页；J.Org.Chem.1991，56，4056-4058)由商购的保护D-甘露醇来制备2，3-O-异亚丙基-D-甘油醛(39)。其它试剂，包括40和AD-混合-β，都来自商品渠道。
实施例
实施例1
反式-2，3-二脱氧-4，5-O-异亚丙基-2-C-甲基-D-甘油基-戊-2-烯酸乙酯(41)
在室温下，向(乙氧甲酰基亚乙基)三苯基正膦(40，25克，69毫摩尔)的干燥CH2Cl2(65毫升)溶液中滴加2，3-O-异亚丙基-D-甘油醛(39，9.41克，72.3毫摩尔)的CH2Cl2(30毫升)溶液。将该混合物在室温下搅拌过夜。然后将反应混合物浓缩至干燥，用轻石油醚(300毫升)进行稀释，在室温下保持2小时。通过过滤除去沉淀的三苯基膦氧化物，在真空下浓缩剩余部分(aliquot)。通过硅胶柱色谱使用0-1.5％的EtOAc(在己烷中)对剩余物进行纯化，得到油状物质41(10.4克，71％)(Carbohydrate Res.，115，250-253(1983))。1H NMR(CDCl3)δ1.30(t，J＝6.8Hz，3H，-OCH2CH3)，1.41(，s，3H，CH3)，1.45(，s，3H，CH3)，1.89(d，J＝1.2Hz，3H，2-CH3)，3.63(t，J＝8.0Hz，1H，H-5)，4.14-4.23(m，3H，H-5′和-OCH2CH3)，4.86(dd，J＝7.6和13.6Hz，1H，H-4)，6.69(dd，J＝1.6和8.0Hz，1H.H-3)。
实施例2
(2S，3R)-3-[(4R)-2，2-二甲基-[1，3]二氧戊环-4-基]-2，3-二羟基-2-甲基-丙酸乙酯(42)
向配置有磁力搅拌器的圆底烧瓶中加入25毫升叔丁醇、25毫升水和7.0克AD-混合-β。在室温下搅拌产生两个澄清相；下层水相显示为浅黄色。此时加入甲磺酰胺(475毫克)。将该混合物冷却到0℃，当一些溶解的盐沉淀时，立即加入1.07克(5毫摩尔)41，将非均相浆料在0℃剧烈搅拌24小时。然后，在0℃搅拌混合物的同时，加入固体亚硫酸钠(7.5克)，将混合物回暖到室温，并搅拌30-60分钟。向反应混合物中加入EtOAc(50毫升)，在分离各层后，用EtOAc进一步萃取水相。用硫酸钠干燥有机层，并浓缩至干燥。通过硅胶柱色谱使用20％的EtOAc(在己烷中)对剩余物进行纯化，得到固体物质42(1.13克，91％)。1H NMR(DMSO-d6)□1.18(t，J＝6.8Hz，3H，-OCH2CH3)，1.24(，s，3H，CH3)，1.25(，s，3H，CH3)，1.28(s，3H，2-CH3)，3.67(t，J＝7.2Hz，1H)，3.85，4.06和4.12(m，4H)，4.96(s，1H，2-OH，D2O可交换)，5.14(d，J＝7.6Hz，2-OH，D2O可交换)。C11H20O6的分析计算值：C，53.22；H，8.12；检测值：C，53.32；H，8.18。
实施例3
(2S，3R)-3-[(4R)-2，2-二甲基-[1，3]二氧戊环-4-基]-3-苯甲酰氧基-2-羟基-2-甲基丙酸乙酯(43)
向化合物42(245毫克，0.99毫摩尔)的干燥吡啶(3毫升)溶液中滴加BzCl(300毫克，2.1毫摩尔)的吡啶(1毫升)溶液。在将混合物在室温下搅拌2小时后，用H2O(1毫升)猝灭反应。将混合物浓缩至干燥，剩余物在CH2Cl2和饱和NaHCO3溶液中分配。有机相进行干燥(无水Na2SO4)、过滤和浓缩。通过硅胶柱色谱使用5％的EtOAc(在己烷中)对剩余物进行纯化，得到固体物质43(247毫克，71％)。C18H24O7的分析计算值：C，61.35；H，6.86；检测值：C，60.95；H，6.73。
实施例4
(2R，3R)-3-[(4R)-2，2-二甲基-[1，3]二氧戊环-4-基]-3-苯甲酰氧基-2-氟代-2-甲基-丙酸乙酯(44)
在0℃和氮气下，向化合物43(36毫克，0.102毫摩尔)的无水THF(1.5毫升)溶液中加入DAST或Deoxofluor(0.08毫升，0.68毫摩尔)。将反应混合物在室温下搅拌3小时，然后冷却至0℃，用冷的饱和NaHCO3溶液(2毫升)小心处理。用硫酸钠干燥有机层，并浓缩至干燥。通过硅胶柱色谱使用1-3％的EtOAc(在己烷中)对剩余物进行纯化，得到浆料44(24.6毫克，68％)。HR-FAB MS；观察值：m/z 361.1621。C18H23O6FLi的计算值：m/z361.1639(M+H)+。
实施例5
3-O-苯甲酰基-2-甲基-2-脱氧-2-氟代-D-核糖-γ-内酯(45)
化合物44(308毫克，0.86毫摩尔)、MeCN(20毫升)、水(1毫升)和CF3CO2H(0.17毫升)的混合物在80-85℃回流3小时。不分离开链中间体，而是使用Dean-Stark水分离器通过共沸蒸馏直接转化为45。除去的MeCN用干燥甲苯替代，共沸蒸馏一直进行，直到浴温达到130℃为止。在130℃继续搅拌过夜。然后将该混合物冷却到室温，在真空下除去溶剂，得到浆料，通过硅胶柱色谱使用10-15％的EtOAc(在己烷中)对该浆料进行纯化，在溶剂蒸发后得到固体45(136毫克，58.3％)。
实施例6
3，5-二-O-苯甲酰基-2-甲基-2-脱氧-2-氟代-D-核糖-γ-内酯(49)
向45(60毫克，0.224毫摩尔)的EtOAc(1毫升)溶液中加入吡啶(100毫克，1.26毫摩尔)和4-二甲基氨基吡啶(2.7毫克)。将该混合物升温到60℃，滴加BzCl(110毫克，0.79毫摩尔)的EtOAc(0.4毫升)溶液。在搅拌3小时后，将该混合物冷却到0℃，过滤除去盐酸吡啶盐。用EtOH稀释滤液，将该混合物蒸发至干燥。通过硅胶柱色谱使用3-6％的EtOAc(在己烷中)对该剩余物进行纯化，在溶剂蒸发后得到固体49(75毫克，91％)。
实施例7
2-甲基-D-阿拉伯-γ-内酯(46)
用0.3毫升浓HCl处理化合物42(248毫克，1毫摩尔)的EtOH(1.5毫升)溶液。将该反应混合物在室温下搅拌2小时。在真空下除去溶剂(浴温＜45℃)。剩余物与甲苯(3×10毫升)共蒸发，得到剩余物，通过硅胶柱色谱使用70％的EtOAc(在己烷中)对该剩余物进行纯化。蒸发溶剂，得到油状物质46(170毫克，105％)。C6H10O5的分析计算值：C，41.24；H，6.22；检测值：C，41.00；H，6.74。
实施例8
3，5-二-O-苯甲酰基-2-甲基-D-阿拉伯-γ-内酯(47)
在室温下，在75分钟内向经过搅拌的化合物46(880毫克，5.4毫摩尔)的干燥吡啶(80毫升)溶液中滴加BzCl(1.73克，12.29毫摩尔)的干燥吡啶(45毫升)溶液。将该混合物再搅拌90分钟，然后用MeOH(5毫升)进行处理，浓缩至干燥。通过硅胶柱色谱使用12-20％的EtOAc(在己烷中)对该剩余物进行纯化，得到油状物质47(1.1克，55％)。
实施例9
3，5-二-O-苯甲酰基-2-脱氧-2-氟代-2-C-甲基-D-核糖内酯(49)
在室温和氩气下，向化合物47(430毫克，1.16毫摩尔)在无水THF(20毫升)和二异丙基乙胺(1毫升，5.74毫摩尔)的溶液中加入DAST或Deoxofluor(0.48毫升，3.66毫摩尔)。将反应混合物在室温下搅拌3小时，然后冷却至0℃，用冷的饱和NaHCO3溶液(5毫升)小心处理。反应混合物在EtOAc(100毫升)和水(20毫升)之间分配。用硫酸钠干燥有机层，并浓缩至干燥。通过硅胶柱色谱使用3-6％的EtOAc(在己烷中)对剩余物进行纯化，得到固体49(220毫克，51％)。
实施例10
3，5-二-O-苯甲酰基-2-甲基-D-核糖-内酯(48)
在0-5℃和氩气下，向47(160毫克，0.432毫摩尔)的无水CH2Cl2(5毫升)溶液中加入DAST或DEOXOFLUOR(0.15毫升，1.14毫摩尔)。将该反应混合物在0-5℃搅拌1小时，然后在室温下搅拌。24小时后，反应仍然没有良好进行，因为在TLC中没有大量极性较弱的产物。将该反应混合物冷却到0℃，用冷的饱和NaHCO3溶液小心处理。用硫酸钠干燥有机层，并浓缩至干燥。用质子NMR检测剩余物。显示主要产物为3，5-二苯甲酰基-2-甲基-D-核糖-γ-内酯(48)，该产物与权威样品相同。在谱图上检测到痕量49。
实施例11
3，5-二-O-甲氧基甲基-2-C-甲基-D-阿拉伯-γ-内酯(50)
向2-甲基阿拉伯内酯(46)(324毫克，2毫摩尔)在CH2(OMe)2(30毫升)和CH2Cl2(30毫升)的溶液中加入CF3SO3H(50微升)，将该溶液在室温和氩气下搅拌14小时。加入28％的NH4OH(0.1毫升)猝灭反应，加入硫酸钠来干燥混合物。在通过蒸发除去溶剂后，通过闪式色谱在硅胶上用CH2Cl2MeOH(95∶5-9∶1)洗脱来对剩余物进行纯化，得到450毫克(90％)浅黄色油状产物。1H-NMR(DMSO-d6)：6.10(s，OH，D2O可交换)，4.70(q，2H，CH2)，4.62(d，2H，CH2)，4.30(m，1H，H-4)，4.20(d，1H，H-3)，3.80-3.65(m，2H，H-5)，3.30，3.28(2s，6H，2CH3)，1.26(s，3H，CH3)。
实施例12
3，5-二-O-甲氧基甲基-2-脱氧-2-氟代-2-C-甲基-D-核糖-γ-内酯(51)
在-78℃向50(100毫克，0.4毫摩尔)在CH2Cl2(3毫升)和吡啶(0.5毫升)的溶液中加入DAST或DEOXOFLUOR(0.21毫升，1.6毫摩尔)，将该溶液在-78℃搅拌15分钟。然后使该溶液升温到室温，在室温搅拌2小时。通过加入饱和NaHCO3水溶液(0.5毫升)和冰水(0.5毫升)，然后加入CH2Cl2(20毫升)和饱和NaHCO3水溶液(10毫升)来猝灭反应。用CH2Cl2萃取水层两次，用NaHCO3洗涤合并的有机层，用Na2SO4进行干燥。蒸发溶剂，得到棕黄色油状物质51(88毫克，87％)。1H-NMR(DMSO-d6)：4.74(q，J＝6.9 & 18.1Hz，2H，CH2)，4.63(d，J＝0.77Hz，2H，CH2)，4.54(m，1H，H-4)，4.18(dd，J＝7.8&20.0Hz，1H，H-3)，3.86-3.71(m，2H，H-5)，3.34，3.28(2s，6H，2CH3)，1.59(d，J＝24.26Hz，3H，CH3)。
实施例13
4，5-O-异亚丙基-3，4，5-三羟基-2-甲基戊酸乙酯(54)
向活性锌(6.5克，0.10毫摩尔)中加入约20毫升含有39(13.0克，0.1毫摩尔)、53(13.0毫升，0.10毫摩尔)、THF(50毫升)和二乙醚(50毫升)的溶液。在上述加料后，加入一种I2晶体，造成放热，导致溶液回流。在约0.75小时内加入剩余溶液，以维持温和的回流。将混合物逐渐加热到回流，在加料完成后再维持1小时。使混合物冷却到室温，倒入冰(200毫升)和1NHCl(200毫升)中，搅拌，直到大部分冰熔化(约0.5小时)。分离有机层，用二乙醚(2×75毫升)萃取水层。用饱和NaHCO3(1×150毫升)、盐水(1×150毫升)洗涤合并的有机相，干燥(Na2SO4)，过滤，在真空下浓缩到干燥。进一步在真空下干燥，提供作为非对映异构体混合物的54(15.1克，65.1％)。在不进一步纯化的情况下使用该化合物。
实施例14
4，5-O-异亚丙基-3-氧代-2-甲基戊酸乙酯(55)
将化合物54(9.85克，0.042摩尔)溶解在干燥THF(50毫升)中。加入无水DMSO(16.0毫升，0.22摩尔)，使所得溶液冷却到-20℃至-15℃。在15分钟滴加三氟乙酸酐(9.8毫升，0.69摩尔)，将该溶液在-20℃至-15℃搅拌2小时，然后在20分钟内加入无水NEt3(24.0毫升，0.17摩尔)。将所得溶液在室温下搅拌1小时，用二乙醚(50毫升)稀释，用H2O(3×100毫升)洗涤，干燥(Na2SO4)，在真空下浓缩至黄色油状的化合物55(8.1克，82.0％)，该化合物可以不进一步纯化而直接使用。1H NMR(CDCl3，400MHz)：δ1.24-1.38(m，26H)，3.81(q，1.3H，J＝7.3Hz)，3.89(q，1.0H，J＝7.3Hz)，3.99-4.04(m，3H)，4.10-4.20(m，7H)，4.21-4.29(m，3H)，4.51(dd，1.0H，J＝8.1，6.2Hz)，4.58(dd，1.3H，J＝7.7，5.0Hz)。
实施例15
4，5-O-异亚丙基-2-氟代-3-酮基-2-甲基戊酸乙酯(56)
将化合物(7.36克，0.042摩尔)溶解在无水DMF(5.0毫升)中，用Selectfluor(55.0克，0.155摩尔)的DMF(45.0毫升)浆料处理。将该混合物放置在45-50℃的油浴中，在氩气气氛下、在该温度搅拌过夜。在真空下将该溶液浓缩至接近干燥，用二乙醚(约25毫升)处理，用水(3×100毫升)洗涤。使有机相干燥(Na2SO4)，在真空下浓缩至黄色油状化合物56(5.56克，71.2％)，该产物是通过19F NMR确定的2R∶2S(大约1∶1)氟化化合物的混合物。1H NMR(CDCl3，400MHz)：δ1.20-1.46(m，16H)，1.70(2d，3H，J＝22.8Hz)，4.05-4.10(m，2H，)，4.12-4.32(m，2H，)，4.90-97(m，1H)。19F NMR(CDCl3，376MHz，C6F6外标)：δ4.30(q)，4.01(q)。
实施例16
3，5-O-二新戊酰基-2-甲基-D-阿拉伯-γ-内酯(47B)
向42(4毫摩尔，897毫克)的EtOH(20毫升)溶液中加入浓HCl(2.0毫升)，将该溶液在室温下搅拌1小时。将该溶液浓缩至干燥，剩余物与THF(10毫升)共蒸发，溶解于吡啶(6毫升)和CH2Cl2(14毫升)。该溶液在冰浴中冷却。向该溶液中加入新戊酰氯(8毫摩尔，0.98毫升)，将该溶液在0℃搅拌30分钟。向该溶液中再加入一些新戊酰氯(4毫摩尔，0.49毫升)，将该溶液在室温下搅拌5小时。向该溶液中加入4-二甲氨氨基吡啶(100毫克)，将该溶液在室温下搅拌20小时。加入H2O(5毫升)，将该混合物在室温下搅拌20分钟，加入EtOAc(50毫升)。用水、盐水洗涤该混合物，干燥(Na2SO4)。除去溶剂，用EtOAc-己烷重结晶剩余物，得到细晶体(625毫克，47％)。H-NMR(CDCl3)：δ5.18(d，J＝6.80Hz，1H，H-3)，4.45，4.22(m，2H，H-5)，4.41(m，1H，H-4)，3.32(br s，1H，OH，D2O可交换)，1.43(s，1H，Me)，1.25，1.22[ss，18H，C(Me)3]。
实施例17
2-脱氧-3，5-O-二新戊酰基-2-氟代-2-C-甲基-D-核糖-γ-内酯(49B)
向47B(100毫克，0.3毫摩尔)的THF(5毫升)溶液中加入EtNPr2(2毫摩尔，0.35毫升)和Deoxo-Fluor(0.18毫升，0.9毫摩尔)，将该溶液在室温下搅拌4小时。向该溶液中再加入一些Deoxo-Fluor(0.18毫升，0.9毫摩尔)，将该溶液在室温下搅拌16小时，回流1小时。加入EtOAc(50毫升)。用NaHCO3水溶液、盐水洗涤该溶液，干燥(Na2SO4)。除去溶剂，通过色谱柱(10％EtOAc，溶剂为己烷)纯化剩余物，得到固体产物(65毫克，65％)。H-NMR(CDCl3)：δ5.12(m，1H，H-3)，4.68(m，1H，H-4)，4.41，4.18(mm，2H，H-5)，1.63(d，J＝23.2Hz，1H，Me)，1.25，1.20[ss，18H，C(Me)3]。
Claims (4)
1.一种制备下式的2′-脱氧-2′-氟代-2′-C-甲基-β-D-呋喃核糖基核苷的方法：
其中所述碱为：
其中R2和R4分别为H、OH、NH2或OR′；
R′是任选取代的C1-C12直链、支链或环状的烷基；
Y是N或CH；
所述方法包括以下步骤：
(a)使如下式所示的核苷中间体与三氟化二乙基氨基硫或三氟化二(2-甲氧基乙基)氨基硫反应：
其中碱如上所定义，保护基团是苯甲酰基；
其中R3和R5各自独立地是四氢吡喃基、甲基、乙基、苄基、苯甲酰基、对甲氧基苄基、苄氧基甲基、苯氧基甲基、甲氧基甲基、乙氧基甲基、甲磺酰基、甲苯磺酰基、三氟乙酰基或三氯乙酰基，
以生成如下式所示的氟化的中间体：
(b)通过用三卤化硼处理来对步骤(a)的产物的R3和R5基团进行脱保护，以生成如下式所述的中间体：
(c)皂化步骤(b)的产物，以生成所需的核苷。
2.如权利要求1所述的方法，其特征在于，步骤(b)的三卤化硼选自三氟化硼、三氯化硼、三溴化硼或三碘化硼。
3.如权利要求1所述的方法，其特征在于，步骤(c)的皂化反应是用溶于醇中的金属醇盐进行的。
4.如权利要求3所述的方法，其特征在于，所述溶于醇中的金属醇盐是溶于甲醇的甲醇钠。
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| CN104327138B (zh) * | 2014-10-21 | 2017-05-10 | 齐鲁制药有限公司 | Psi‑7977中间体化合物的制备方法 |
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| CN109422710B (zh) * | 2017-08-28 | 2022-06-21 | 常州制药厂有限公司 | 一种索非布韦氟内酯中间体的制备方法 |
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| C10 | Entry into substantive examination | ||
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| C53 | Correction of patent of invention or patent application | ||
| CB02 | Change of applicant information |
Address after: California, USA Applicant after: GILEAD PHARMASSET LLC Address before: Georgia, USA Applicant before: Pharmasset Ltd. |
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Free format text: CORRECT: APPLICANT; FROM: PHARMASSET LTD. TO: CGI PHARMACEUTICALS INC |
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| CI01 | Publication of corrected invention patent application |
Correction item: Priority number Correct: 60/608,230 False: 60/608,320 Number: 39 Volume: 27 |
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| CI02 | Correction of invention patent application |
Correction item: Priority number Correct: 60/608,230 False: 60/608,320 Number: 39 Page: The title page Volume: 27 |
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Free format text: CORRECT: NUMBER OF PRIORITY; FROM: 60/608,320 TO: 60/608,230 |
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