CN1035555C - 非对映选择性合成核苷的方法 - Google Patents

非对映选择性合成核苷的方法 Download PDF

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CN1035555C
CN1035555C CN92103924A CN92103924A CN1035555C CN 1035555 C CN1035555 C CN 1035555C CN 92103924 A CN92103924 A CN 92103924A CN 92103924 A CN92103924 A CN 92103924A CN 1035555 C CN1035555 C CN 1035555C
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T·曼素尔
A·H·L·蔡
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Abstract

本发明涉及高度非对映选择性制备高旋光纯度顺式核苷和核苷类似物和衍生物以及可用于该法的中间体。

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非对映选择性合成核苷的方法
本发明涉及非对映选择性制备旋光顺式核苷以及核苷类似物和衍生物的方法，其中可以高旋光纯度并可立构控制合成要求顺式核苷或核苷类似物或衍生物的给定对映体。本发明还涉及可用于本发明方法的新中间体。
核苷及其类似物和衍生物是重要的一类治疗药剂，如大量核苷对逆病毒，如人免疫缺陷病毒(HIV)，肝炎B病毒(HBV)和人T-淋巴病毒(HTLV)具有抗病毒活性(PCT publicationWO 89/04662和European Patent Publication0349242 A2)。核苷中3＇-叠氮基-3＇-脱氧胸苷(AZT)和2＇，3＇-二脱氧胞苷(DDC)。
大多数核苷和核苷类似物和衍生物中含至少2个手性中心(式(A)中示为*)并以两对旋光异构体存在(即顺式构型2个和反式构型2个)。但一般只有顺式异构体具有有效的生物活性。
Figure C9210392400051
不过相同顺式核苷的不同对映体具有不同的抗病毒活性，可见于M.M.Mansuri et al.，“preparation of TheGeometric Isomers of DDC，DDA，D4C and D4T AsPotential Anti-HIV Agents”，Bioorg.Med.Chem.Lett.，1(1)，pp.65-68(1991)，因此用通常的手段比较经济地立构选择性合成生物活性顺式核苷对映体是一项重要的目标。
大多数制备旋光核苷及其类似物和衍生物的已知方法均是改性天然(即旋光)核苷，其中采用还原法，如脱氧或自由基引发还原而变换碱基或变换糖，可见于C.K.Chu et al.，“GeneralSynthesis of 2＇，3＇-Dideoxynucleosides And2＇，3＇-Didehydro-2＇，3＇-Dideoxynucleosides，”J.Org.Chem.，54，pp.2217-2225(1989)。这些转化法需要多步骤，包括引入保护基和脱保护基并且常常是收率低，而且其中以初始核苷的旋光性开始并一直保持，因此这些方法制成的核苷仅限于天然核苷对映体的特定类似物。另外这些方法要求获得天然核苷，这通常又是昂贵的原料。
其它制备旋光核苷的已知方法仅限于向碱基加糖的糖基化法，其中得到的肯定是顺式和反式异构体的异头混合物，这要求进行烦琐的分离并且导致所需生物活性顺式核苷的收率低。而改进的旨在只产出顺式核苷的糖基化法要求将2＇-或3＇-取代基加到糖中，其中因2＇-或3＇-取代基仅用于控制一种构型(2＇-或3＇-取代基对4＇-取代基呈反式构型时)的顺式核苷合成，所以需要多步骤才能将该取代基引入适当构型中，而且糖基化后必须除去2＇-或3＇-取代基，这又要求增加步骤，可见于L.Wilson和D.Liotta，“A General Method For ControllingStereoehemistry In The Synthesis of 2＇-Deoxyribose Nucleosides”，Tetrahedron Lett.，31，pp.1815-1818(1990)。此外，为获得旋光纯核苷产品，初始糖必须是旋光纯的，这又要求一系列耗时的合成和提纯步骤。
本发明即可克服现有技术的这些困难和缺陷，其中提出式(I)旋光顺式核苷以及核苷类似物和衍生物制备方法。其中W为O，S，S＝O，SO2，NZ或CH2；
X为O，S，S＝O，SO2，NZ，CH2，CHF，CH，CHN3或CHOH；
Y为O，S，CH2，CH，CHF或CHOH；
Z为氢，羟基，烷基或酰基；
R1为氢或酰基；和
R2为嘌呤或嘧啶碱或其类似物或衍生物；只是Y为CH2和X为O，S，S＝O或SO2时，W不为O，S，S＝O或SO2。
本发明方法包括用式(II)化合物的单一对映体使所需嘌呤或嘧啶碱或其类似物或衍生物糖基化步骤
Figure C9210392400081
其中R3为取代羰基或羰基衍生物，而L为离去基。糖基化用式(III)路易斯酸完成其中R5，R6，R7和R8定义如下，还原所得中间产物而得式(I)核苷或核苷类似物或衍生物。
本发明方法优点是不用昂贵的原料，烦琐的加保护基和脱保护基或加入并去除2＇-或3＇-取代基的步骤即可制成式(I)核苷(或其类似物或衍生物)，而且收率高，纯度高和旋光特异性高，并且通过选取适当原料还可容易地控制核苷的立体异构构型。
以构型和非对映选择性方式制备旋光化合物的本发明方法中，采用以下定义：
R2为嘌呤或嘧啶碱基或其类似物或衍生物。
嘌呤或嘧啶碱是天然核苷中发现的，其类似物为与该天然碱类似的碱，表现在其结构类似于该天然碱(原子种类及其排序)，但又具有其它性能或缺乏天然碱的某些功能，其中包括氮原子取代CH基所得类似物，如5-氮嘧啶(如5-氮胞嘧啶)或相反(如7-脱氮嘌呤，如7-脱氮腺嘌呤或7-脱氮鸟嘌呤)或两者(如7-脱氮-8-氮嘌呤)，而这些碱或类似物的衍生物指加环取代基，脱环取代基或用本专业已知的常见取代基，如卤素，羟基，氨基，C1-6烷基改性的碱，总之，这些嘌呤或嘧啶碱，其类似物和衍生物是本专业人员众所周知的。
“核苷类似物或衍生物”指以下述方法之一或其组合加以改性的核苷：碱改性，如加取代基(如5-氟胞嘧啶)或用等排基取代一个基(如7-脱氮腺嘌呤)；糖改性，如用任何基团，包括氢取代C-2和C-3羟基(如2＇，3＇-二脱氧核苷)；用杂原子代换任何环CH基或环氧；变换糖基与碱基的位置(如糖中N-1位常连的嘧啶碱基可例如连在N-3或C-6位并且常连在N-9位的嘌呤可例如连在N-7位)；变换碱基与糖基的位置(如碱基可连在糖中C-2位，如异DDA)或变换糖-碱连接方式的构型(如顺式或反式构型)。
R3为用氢，羟基，三烷基甲硅烷基，三烷基甲硅烷氧基，C1-30烷基，C1-30芳烷基，C1-30烷氧基，C1-30胺(伯，仲或叔)，C1-30烃硫基，C6-20芳基，C1-20烯基，C1-20炔基取代的羰基；C1-6烷基或C6-20芳基取代的1，2-二羰基，如 C1-6烷基或C6-20芳基取代的酸酐，如氮上用氢，C1-20烷基或C1-10烷氧基或C1-10二烷基氨基或碳上用氢，C1-20烷基或C1-20烷氧基取代的偶氮甲碱；用羟基，C1-20烷氧基或C1-20烃硫基取代的硫代羰基(C＝S)；羰基的同系物，如
Figure C9210392400101
硫代羰基的同系物，如
Figure C9210392400102
或偶氮甲碱的同系物，如
Figure C9210392400103
优选取代羰基/羰基衍生物为烷氧羰基，如甲氧羰基，乙氧羰基，异丙氧羰基，叔丁氧羰基和氧羰基；羧基，二乙基碳化二亚胺；吡咯烷酰胺；甲基酮和苯基酮，更优选取代羰基/羰基衍生物为酯和羧基，最优选为酯。
R4为手性辅助剂，用以标明外消旋混合物化学解析所用非对称分子，其中可有一个手性中心，如甲基苄基胺，或几个手性中心，如醇。手性辅助剂的目的是，一旦引入原料，就可简单分离所得非对映混合物，可见于例如J.Jacques et al.，Enantiomers，Racemates And Resolutions，pp.251-369，John Wiley & Sons，New York(1981)。
R5，R6和R7分别选自氢，C1-20烷基(如甲基，乙基，叔丁基)，必要时由卤素(F，Cl，Br，I)，C1-6烷氧基(如甲氧基)或C6-20芳氧基(如苯氧基)取代；C7-20芳烷基(如苄基)，必要时由卤素，C1-20烷基或C1-20烷氧基取代(如对甲氧苄基)；C6-20芳基(如苯基)，必要时由卤素，C1-20烷基或C1-20烷氧基取代；三烷基甲硅烷基；卤素(F，Cl，Br，I)。
R8选自卤素(F，Cl，Br，I)；C1-20磺酸酯，必要时由卤素取代(如三氟甲磺酸酯)；C1-20烷基酯，必要时由卤素取代(如三氟乙酸酯)；多价卤化物(如三碘化物)；式(R5)(R6)(R7)Si的三取代甲硅烷基(R5，R6和R7如上)；饱和或不饱和硒酰C6-20芳基；取代或非取代C6-20芳基亚磺酰基；取代或非取代C1-20烷氧烷基和三烷基甲硅烷氧基。
L为“离去基团”，即可在有或无路易斯酸存在下与适当嘌呤或嘧啶碱反应时去除的原子或基团，适宜离去基包括酰氧基，烷氧基，如烷氧羰基，如乙氧羰基；卤素，如碘，溴，氯或氟；酰氨基；叠氮基；异氰酸根合；取代或非取代饱和或不饱和烃硫基，如甲硫基或苯硫基；取代或非取代饱和或非饱和硒基，亚硒基或硒酰基化合物，如苯基硒或烷基硒。
适宜离去基团还可为-OR，其中R为取代或非取代饱和或不饱和烷基，如C1-6烷基或烯基；取代或非取代脂族或芳族酰基，如C1-6脂肪酰基，如乙酰基和取代或非取代芳酰基，如苯甲酰基；取代或非取代饱和或不饱和烷氧或芳氧羰基，如碳酸甲酯和碳酸苯酯；取代或非取代磺酰咪唑；取代或非取代脂族或芳族氨基羰基，如氨基甲酸苯酯；取代或非取代烷基亚氨酸酯，如三氯乙酰氨酸酯；取代或非取代饱和或不饱和膦酸酯，如二乙基膦酸酯；取代或非取代脂族或芳族亚磺酰基或磺酰基，如甲苯磺酸酯；或氢。
本文中“烷基”为取代(用卤素，羟基或C6-20芳基)或非取代直链、支链或环状C1-30，优选C1-6烃基。
“烯基”和“炔基”指取代(用卤素、羟基或C6-20芳基)或非取代直链，支链或环状并含至少一个不饱和键的C1-20，优选C1-5烃基(如烯丙基)。
“烷氧基”指经氧原子与邻近元素共价结合的取代或非取代C1-30，优选C1-6烷基(如甲氧基和乙氧基)。
“胺”指经氮原子与邻近元素共价结合的C1-30，优选C1-12烷基，芳基，烯基，炔基或芳烷基(如吡咯烷)，包括伯，仲，叔胺和季铵盐。
“硫羟”指经硫原子与邻近元素共价结合的C1-30，优选C1-6烷基，芳基，芳烷基，烯基或炔基(如硫甲基)。
“芳基”指可由至少一个杂原子(如N，O或S)并含至少一个苯型环的C6-15碳环基(如苯基和萘基)。
“芳烷基”指经烷基与邻近原子结合的芳基(如苄基)。
“烷氧烷基”指经烷基与邻近基团结合的烷氧基(如甲氧甲基)。
“芳氧基”指经氧原子共价结合的取代(用卤素，三氟甲基或C1-5烷氧基)或非取代芳基(如苯氧基)。
“酰基”指来自羧酸并代替-OH基的取代(用卤素(F，Cl，Br，I)，C6-20芳基或C1-6烷基)或非取代的基，同于其相关酸，酰基可为脂族的，芳族的，可被取代(用卤素，C1-5烷氧烷基，硝基或O2)或未被取代，不管其分子中另一部分结构如何，官能团性能仍基本保持不变(如乙酰基，丙酰基，异丁酰基，新戊酰基，己酰基，三氟乙酰基，氯乙酰基和环己酰基)。
本发明方法的关键特征是用取代羰基或羰基衍生物作为R3，而不是象现有技术中那样用保护的羟甲基。出人意料的是，将式(III)路易斯酸加入甲硅烷基化嘌呤或嘧啶碱和式(II)糖化合物的混合物中时，取代羰基或羰基衍生物并不象本专业人员已期望的那样会在路易斯酸中裂开。相反，在式(VI)中间产物中的取代羰基/羰基衍生物会迫使嘌呤或嘧啶碱基(R2)加入相对于取代羰基/羰基衍生物基呈顺式的构型中。没有与C4＇连接的取代羰基或羰基衍生物(如在用羟甲基时)，第4步所述偶合过程会形成顺式和反式异构体的混合物。
本发明方法的另一关键特征是选择路易斯酸，式(I)化合物制备过程中所用路易斯酸如下式(III)
Figure C9210392400131
其中R5，R6，R7和R8如上。这些路易斯酸可就地生成或用本专业任何已知方法制得(如见于A.H.Schmidt，“Bromotrimethylsilane and Iodotrimethylsilane-Versatile Reagents for Organic Synthesis”，Aldrichimica Acta，14，pp.31-38(1981)。本发明中优选路易斯酸为碘代三甲基硅烷和三氟甲磺酸三甲基甲硅烷基酯。优选R5，R6和R7为甲基或碘，更优选为甲基。优选R8为碘，氯，溴或磺酸酯，更优选为碘和三氟甲磺酸酯。
本发明优选方法中，式(II)糖的顺式和反式异构体可分级结晶分开并选出要求构型异构体。
Figure C9210392400141
所选顺式或反式异构体可按化学法用手性辅助剂解析。纯手性辅助-糖非对映体可在路易斯酸存在下偶合到甲硅烷基化嘌呤或嘧啶碱上而得顺式构型的旋光核苷，再还原成式(I)核苷。
流程1A和1B示出了适用于式(I)任何核苷的优选方法。
                   流程1A
Figure C9210392400151
Figure C9210392400161
流程1A和1B中各步简述如下：
步骤1：式(IV)初始羰基糖可按本专业任何已知方法制得(可见于例如Farina and Benigni，＂A New Synthesis of2，3＇-Dideoxy-nucleosides For Aids Chemotherapy＂，Tetrahedron Letters，29，pp.1239-1242(1988)and M.okabe et al.＂Synthesis of The Dideoxynucleosides ddCand CNT From Glutamic Acid，Ribonolactone andPyrimidine Bases＂，J.org.Chem.，53，pp.4780-4786(1988).该初始化合物中的羰基可用适当还原剂，如二异戊基硼烷(disiamylborane)化学选择还原而得式(V)顺式和反式异构体，其中顺式异构体一般少于反式异构体。
步骤2：式(V)中间体中的羟基易于用本专业已知的任何方法转化成离去基而得式(II)新中间体(可见于例如T.W.GreeneProtective Groups In Organic Synthesis，pp.50-72，John Wiley & Sons，New York(1981))。该异头混合物可分级结晶分成两种构型的异构体，可调节溶剂而选取顺式或反式异构体(可见于例如D.J.Pasto和C.R.Johnson，“Organic Structure Determination，pp.7-10，Prentice-Hall，Inc.，New Jersey(1969)。
步骤3：式(II)的顺式(流程(A)或反式(流程1B)异构体用手性辅助剂(R4)化学解析。适宜手性辅助剂为高旋光纯度可易于得到镜像的物质，如d-或l-醇。所得式(VI)非对映体易于分级结晶分开。另一方面，该顺式或反式异构体又可酶法或用本专业的其它方法解析(可见于例如Jacques et al.，“Enantiomers，Racemates And Resolutions，pp.251-369，John Wiley & Sons，New York(1981)。非对映体(VI，VII或I)的旋光纯度可经手性HPLC法，特殊的旋转测定法和NMR技术确定。若要求相反的对映体，可用初始手性辅助剂镜像获得。例如，若手性辅助剂d-醇制得(+)对映体核苷，则其镜像l-醇可制成(-)对映体。
步骤4：前述甲硅烷基化(或就地甲硅烷基化)嘌呤或嘧啶碱或其类似物或衍生物可在式(III)路易斯酸，如碘三甲基硅烷(TMSI)或三氟甲磺酸三甲基甲硅烷基酯(TMSOTf)存在下用所得纯非对映体糖基化而得式(VII)顺式构型核苷，该核苷为旋光性的并且基本上无相应反式异构体(即含不多于25％，优选不多于10％，更优选不多于5％反式异构体)。该步骤中式(VI)中间体可偶联到嘌呤或嘧啶碱上而达到更高的顺式异构体收率。嘧啶碱的优选甲硅烷基化剂为三氟甲磺酸叔丁基二甲基甲硅烷基酯。高碳叔丁基据信可通过弱化路易斯酸和甲硅烷基化嘧啶碱之间的相互作用而提高收率。步骤4中的优选试剂混合方法是先将式(VI)的手性辅助糖加入甲硅烷基化嘌呤或嘧啶碱中，然后将式(III)的路易斯酸加入该混合物中。
步骤5：步骤4所得顺式核苷可用适当还原剂还原而除去手性辅助剂并得到式(I)特定立体异构体，其绝对构型对应于式(VII)核苷中间体。如流程1所示，步骤2中所得顺式(流程1A)或反式(流程1B)异构体可制成顺式最终产物。
流程2示出了非对映选择性合成式(I)化合物的第2种方法，可在旋光纯原料易于从市场上获得或易于用已知方法制得的情况下用。
旋光原料用化学选择性方法还原并将所得羟基转化成离去基。可按类似于流程1的方法用非对映混合物制成式(I)化合物。必要时，非对映混合物可分级结晶并用每一分出的旋光非对映体制成式(I)化合物。
流程2示出了适用于任何核苷的本发明第2种方法。
                           流程2
Figure C9210392400201
如流程2合成式(I)核苷的各步骤简述如下：
步骤1：式(IV)原料可以旋光纯态从市场上购得或按已知方法制得(例如可参见于Farina和Benigi，“A NewSynthesis of 2，3′-Dideoxy-nucleosides ForAids Chemotherapy”，Tetrahedron Letters，29，pp.1239-1242(1988)和M.Okabe et al.，“Synthesis of The Dideoxynucleosides ddC andCNT From Glutamic Acid，Ribonolactone andpyrimidine Bases”，J.Org.Chem.，53，pp.4780-4786(1988)。式(IV)单一异构体可用适当还原剂，如二异戊基硼烷化学选择性还原而得式(V)两种非对映体混合物。
步骤2：式(V)两种非对映体的羟基可按本专业任何已知方法转化成离去基而得式(II)两种非对映体混合物。
步骤3：将式(II)非对映混合物与预先甲硅烷基化(或就地甲硅烷基化)嘌呤或嘧啶碱或类似物或衍生物反应。然后加式(III)路易斯酸，如碘三甲基硅烷(TMST)或三氟甲磺酸三甲基甲硅烷基酯(TMSOTf)可制成式(VIII)顺式构型核苷。该核苷基本上无相应反式异构体。
步骤4：式(VIII)旋光页式核苷可用还原剂，优选三乙基硼氢化锂或氢化锂铝，更优选硼氢化钠立体选择性还原，这可在适当溶剂，如四氢呋喃或乙醚中进行，得到式(I)化合物。
另一方面，在第2步骤终了时，顺式或反式异构体又可经分级结晶或色谱法从式(II)非对映混合物中分离。可调整溶剂而选择顺式或反式异构体。式(II)单一非对映体可按步骤3和4进一步处理而得式(I)化合物。
流程3，4和5说明了流程2的方法用于合成顺式二脱氧核苷类似物对映体的情况。
尽管上述用具体试剂和原料说明了本发明方法，但本专业人员可以清楚地看出，当然可用适当的类似试剂和原料制成类似化合物。
                           流程3
Figure C9210392400231
流程3所示的各步骤简述如下：
步骤1：从市场购买或由D-谷氨酸(M.Okabe等人，Synthesis of The Dideoxynucleosides ddCand CNT From Glutamic Acid，Ribonolactone andPyrimidine Bases”，J.Org.Chem.，53，pp.4780-4786(1988))所得原料(2R)-5-氧代-2-四氢呋喃羧酸(IX)，在可配合溶剂(如二氯甲烷)中，在酰化剂(如草酰氯)、酯化催化剂(如4-二甲基氨基嘧啶和碱(如吡啶)存在下，用醇(如乙醇)酯化原料。在可配位的有机溶剂(如四氢呋喃)中，用合适的还原剂(如disiamylborane)还原酯化的化合物(A.Pelter et al.，“Borane Reagents”，Academie Press，P.426(1988))，得到式(X)的化合物。
步骤2在吡啶和酰化催化剂(如4-二甲基氨基吡啶)存在下将式(X)的化合物与酰氯或酸酐(如乙酸酐)反应，得到式(XI)的化合物。
步骤3：将式(XI)的顺-和反-乙酰氧基化合物的混合物与5-氟胞嘧啶或其它嘧啶碱或其类似物反应。嘌呤或嘧啶或其它类似物宜在可配合的有机溶剂中，如含受阻碱(优选2，4，6-可力丁)的二氯甲烷中用六甲基乙硅氮烷甲硅烷基化，最好用三氟甲磺酸叔丁基二甲基甲硅烷基酯就地进行甲硅烷基化。
然后采用高度非对映体选择法加入路易斯酸，较好的是由式(III)的化合物衍生的一种，更好的是碘代三甲基硅烷或三氟甲磺酸三甲基甲硅烷基酯，得到式(XII)的顺式化合物。
步骤5：在合适的溶剂(如乙醇)中，用还原剂(优选硼氢化钠)立体选择还原式(XII)的旋光顺-核苷(具有某些反式异构体)，提纯后得到式(XIII)的化合物。
若需要式(XIII)的对映体，本领域普通技术人员可看出，式(IX)的原料是(2S)-5-氧代-2-四氢呋喃羧酸(流程4)，按流程3所述的方法进行。
                            流程4
Figure C9210392400261
                               流程5
Figure C9210392400271
流程5所示的各步骤简述如下：
步骤1：在可配合的溶剂(如二氯甲烷)中，在酰化剂(如草酰氯)、酯化催化剂(如甲基氨基嘧啶)和碱(如吡啶)存在下，用醇(如乙醇)酯化原料(2R)-5-氧代-2-四氢呋喃羧酸(IX)。在可配合的有机溶剂(如四氢呋喃)中用合适的还原剂(例如二异戊基硼烷)还原酯化的化合物。
步骤2：在吡啶和酰化剂(如4-二甲基氨基吡啶)存在下将式(X)的化合物与酰氯或酸酐(如乙酸酐)反应，得到式(XI)的化合物。
步骤3 ：将式(XI)的顺-和反-乙酰氧基化合物与N-乙酰基胞嘧啶或其它嘧啶碱或类似物反应。嘌呤或嘧啶碱或类似物宜在可配合的有机溶剂(如含受阻碱(优选2，4，6-可力丁)的二氯甲烷中用六甲基乙硅氮烷甲硅烷基化，最好用三氟甲磺酸三甲基甲硅烷基酯就地甲硅烷基化。
然后采用高度非对映体选择法加入路易斯酸，较好的是由式(III)的化合物衍生的一种，更好的是碘代三甲基硅烷，得到顺式核苷。用合适的溶剂(如乙酸乙酯和己烷)研制，获得纯顺式核苷。
在可配合的有机溶剂(如异丙醇)中，最好在回流和酸性条件下，最好用三氟乙酸对N-乙酰基进行水解，得到式(XIV)的脱酰化合物。
步骤4：在合适的溶剂(如乙醇)中，用合适的还原剂(优选硼氢化钠)立体选择还原式(XIV)的旋光顺式核苷，得到式(XV)的化合物。
在本发明的非对映体选择方法中，下列中间体特别重要：
Figure C9210392400291
式中R3、R4和L如上定义；
顺-和反-2R-乙氧羰基(carboethoxy，下同)-5-羟基四氢呋喃；
顺-和反-2S-乙氧羰基-5-羟基四氢呋喃；
顺-和反-2R-乙氧羰基-5-乙酰氧基四氢呋喃；
顺-和反-2S-乙氧羰基-5-乙酰氧基四氢呋喃；
1＇S-(N-4-乙酰基胞嘧啶-1-基)-4＇R-乙氧羰基四氢呋喃；
1＇S-(胞嘧啶-1-基)-4＇R-乙氧羰基四氢呋喃；
1＇R-(5-氟胞嘧啶-1-基)-4＇S-乙氧羰基四氢呋喃和1＇S-(5-氟胞嘧啶-1-基)-4＇S-乙氧羰基四氢呋喃和
1＇S-(5-氟胞嘧啶-1-基)-4＇R-乙氧羰基四氢呋喃和1＇R-(5-氟胞嘧啶-1-基)-4＇R-乙氧羰基四氢呋喃。
下列实施例将说明本发明，这些实施例可实际做出，但并不限制本发明方法的任何方面。除非特别注明，所有的〔α〕D测量均在室温下记录。
实施例1
2R-乙氧羰基-5-氧代-四氢呋喃
Figure C9210392400301
在氩气气氛下30分钟内往冷却的(0℃)搅拌着的5-氧代-2R-四氢呋喃羧酸(3g，23mmol)、4-二甲基氨基吡啶(141mg，0.05当量)和吡啶(3.92ml，2.1当量)的二氯甲烷(15ml)溶液中加入草酰氯(2.11ml，1.05当量)。撒去冷却浴，在室温下搅拌反应混合物10分钟。加入乙醇(2.0ml，1.5当量)，继续再搅拌1小时40分钟。用水和二氯甲烷稀释反应混合物，接着搅拌10分钟。将反应得到的混合物倒入分液漏斗中。除去水相，用1M HCl、饱和NaHCO3和盐水洗涤有机层，然后干燥(Na2SO4)。减压蒸发溶剂，用柱色谱法(1∶1，乙醇乙酯-己烷)提纯获得的粗产物，得到3.23g糖浆状所需产物。
                           1H NMR(CDCl3)：δ1.28(t，3H，J＝7.1Hz).2.20-2.40(m，1H)，4.23(d of q 2H，J＝0.9，7.1Hz)，4.86-4.96(m 1H).
实施例2
顺-和反-2R-乙氧羰基-5-羟基四氢呋喃
在0℃混合35ml BH3 THF(1M，在THF中)和35ml2-甲基-2-丁烯(2M，在THF中)，接着在0℃搅拌75分钟，以制备disiamylborane的溶液。往上述溶液中加入溶于THF(6ml)的2R-乙氧羰基-5-氧代四氢呋喃。在2.5小时内慢慢温热得到的混合物至室温，然后再搅拌15分钟。加入饱和的氯化铵水溶液，接着用乙酸乙酯稀释。搅拌上述混合物10分钟，然后倒入分液漏斗中。依次用饱和NH4Cl和盐水洗涤有机相，然后干燥(Na2SO4)。用旋转式蒸发器除去溶剂，用柱色谱法40％乙酸乙酯-己烷)提纯获得的粗产物。分离所得产物，获得2.05g(70％产率)5位碳上差向异构的异构体的2∶3混合物。也可测定到痕量的开式(Open form)异构体(1H NMR)。标题化合物显示出下列光谱特征：1H NMR(CDCl3)：δ1.28(t，2H，J＝7.1Hz)，1.30(t，1H，J＝7.1Hz)，1.85-2.70(m，4H)，2.59(d，0.33H，J＝5.5Hz)，2.88(d，0.67H，J＝3.1Hz)，4.15-4.65(m，2H)，4.57(d of d，0.33H，J＝6.4，8.3Hz)，4.70(d of d，0.67H，J＝4.1，8.7Hz)，5.59(m，0.33H)，5.74(m，0.67H).
实施例3
顺-和反-2 R-乙氧羰基-5-乙酰氧基四氢呋喃
在5分钟内往冷却(-78℃)的搅拌着的顺-和反-2R-乙氧羰基-5-羟基四氢呋喃的2∶3混合物(2.04g，12.75mmol)，吡啶(1.24ml，1.2当量)和二甲基氨基吡啶(16mg，0.01当量)的二氯甲烷(20ml)溶液中加入乙酰氯(1.09ml，1.2当量)。搅拌得到的混合物10分钟。然后用冰-水浴代替-78℃的冷却浴。继续搅拌4.5小时，同时让浴温慢慢温热至室温。用二氯甲烷稀释反应混合物，然后倒入分液漏斗中。依次用水、1M HCl、饱和NaHCO3和盐水洗涤有机层，然后干燥(Na2SO4)。用旋转式蒸发器除去溶剂，用柱色谱法(40％乙酸乙酯-己烷)提纯获得的粗产物，得到1.757g稠油状的标题化合物(5∶4混合物)
                             1H NMR(CDCl3)；δ1.28(t，1.68H，J＝7.1Hz)，1.29(t，1.32H，J＝7.1Hz)，1.90-2.30(m，3H)，2.30-2.50(m，1H)，4.10-4.30(m，2H)，4.59(t，0.44H，J＝8.0Hz)，4.70(d of d，0.56H，J＝3.2，8.9Hz)，6.33(d of d，0.44H，J＝1.1，3.9Hz)，6.46(d，0.56H，J＝4.5Hz).
实施例4
1＇S-(N-4-乙酰基胞嘧啶-1-基)-4＇R-乙氧羰基四氢呋喃
Figure C9210392400331
在氩气气氛下往搅拌着的含有2，6-二甲基吡啶(35μl，0.298mmol)的N-4-乙酰基胞嘧啶(50mg，0.298mmol)的二氯甲烷(0.75ml)悬浮液中加入三氟甲磺酸三甲基甲硅烷基酯(58μl，0.298mmol)。搅拌得到的混合物15分钟，得到浅色悬浮液。依次往上述悬浮液中加入顺-和反-2R-乙氧羰基-5-乙酰氧基四氢呋喃的5∶4混合物(50mg，0.248mmol)的二氯甲烷(1ml)溶液和碘代三甲基硅烷(35μl，0.248mmol)以产生均相溶液。在室温下进行反应1小时40分钟，然后用Na2S2O3的半饱和溶液骤冷，搅拌得到的混合物5分钟，然后借助于较多的二氯甲烷加入到分液漏斗中，除去水相，用饱和Na2S2O3、水和盐水洗涤有机层，然后干燥(Na2SO4)。用二氯甲烷再萃取合并的水相。合并有机萃取液，减压浓缩，获得83mg粗产物。粗产物的1H NMR分析表明，得到的是预期核苷的顺式和反式(4∶1)的混合物。将粗产物溶于少量氯仿中，往其中加入乙酸乙酯-己烷的3∶7混合物，产生白色沉淀，抽滤收集该沉淀。真空干燥上述沉淀，得到25mg(32％)标题化合物。
                             1H NMR(CDCl3)：δ1.33(t，3H，J＝7.1Hz)，1.90-2.08(m，1H)，2.08-2.30(m，1H)，2.23(s，3H)，4.20-4.40(m，2H)，4.64(t，1H，J＝7.2Hz)，6.15(d of d，1H，J＝4.0，5.9Hz)，7.46(d，1H，J＝7.5Hz)，8.34(brs，1H)，8.82(d，1H，J＝7.5Hz).
浓缩洗液，得到58mg标题化合物顺式和反式混合物(5∶2)以及其1＇-异构体。
实施例5
β-L-2＇，3＇-二脱氧胞嘧啶
在氩气气氛下回流含约4％相应的1＇R-异构体的1＇S-(N-4-乙酰基胞嘧啶-1-基)-4＇R-乙氧羰基四氢呋喃(49mg，0.158mmol)和三氟乙酸(24μl，2当量)于乙醇(1ml)中的混合物2小时40分钟。冷却得到的混合物至室温，然后用乙醇稀释。加入硼氢化钠(18mg，3当量)并搅拌反应混合物1.5小时。加入更多的还原剂(6mg)，继续在搅拌1小时20分钟。加入2滴浓氨水以骤冷反应，接着剧烈搅拌15分钟。减压蒸发溶剂，用柱色谱法(30％甲醇-乙酸乙酯)纯化获得的粗产物，得到28mg(84％)标题化合物。上述产物的1H NMR光谱表明，存在约3％相应的1＇R-异构体。将产物溶于少量甲醇中，往其中加入乙醚，得到20mg(60％)无1＇R-异构体的结晶状白色沉淀的标题化合物。标题化合物显示出下列光谱特征：
                    1H NMR(CD2OD)：δ1.60-2.00(m，3H)，2.25-2.43(m，1H)，3.59(d of d，1H，J＝4.1，12.2Hz)，3.78(d of d，1H，J＝3.1，12.2Hz)，4.00-4.12(m，1H)，5.78(d，1H，J＝7.4Hz)，5.92(d of d，1H，J＝3.1，6.7Hz)，8.02(d，1H，J＝7.5Hz).
实施例6
1＇R-(5-氟胞嘧啶-1-基)-4＇S-乙氧羰基四氢呋喃和1＇S-(5-氟胞嘧啶-1-基)-4＇S-乙氧羰基四氢呋喃
Figure C9210392400361
在氩气气氛下往搅拌着的含2，6-二甲基吡啶(346μl，2.98mmol)的5-氟胞嘧啶-(192mg，1.49mmol)的二氯甲烷(2mL)悬浮液中加入三氟甲磺酸叔丁基二甲基甲硅烷酯(678μL，2.98mmol)。搅拌得到的混合物15分钟，产生均相溶液。依次往上述溶液中加入2S-乙氧羰基-5R-乙酰氧基四氢呋喃和2S-乙氧羰基-5S-乙酰氧基四氢呋喃的2∶1混合物(250mg，1.24mmol)于二氯甲烷(2ml)和碘代三甲基硅烷(176μL，1.24mmol)中的溶液。反应在室温下进行1小时30分钟，然后加入Na2S2O3的半饱和溶液骤冷。搅拌得到的混合物5分钟，然后倒入分液漏斗中。除去水相，用饱和Na2S2O3、水和盐水洗涤有机层，然后干燥(Na2SO4)减压除去溶剂，得到相产物，用柱色谱法(15％甲醇-乙酸乙酯)提纯粗产物，得到199mg(59％)混合的标题化合物(1H NMR表明，(1＇R，4＇S)与(1＇S，4＇S)之比为7∶1)。产物显示出下列光谱特征：
                                    1HNMR(CDCl3)：δ1.15-1.40(2重叠t，3H)，1.90-2.15(m，2H)，2.25-2.55(m，2H)，4.15-4.35(m，2H)，4.54(m，0.87Hz)，4.82(d of d，0.13H，J＝4.4，8.0Hz)，5.70-6.80(未解析m，1H)，6.09(m，1H)，7.40(d，0.13H，J＝6.7Hz)，7.90-8.60(未解析m，1H)，8.48(d，0.87H，J＝6.7Hz).
实施例7
1＇S-(5-氟胞嘧啶-1-基)-4＇R-乙氧羰基四氢呋喃和1＇R-(5-氟胞嘧啶-1-基)-4＇R-乙氧羰基四氢呋喃
Figure C9210392400371
在氩气气氛下往搅拌着的含2，6-二甲基吡啶(69μL，0.594mmol)的5-氟胞嘧啶(38mg，0.297mmol)的二氯甲烷(1mL)悬浮液中加入三氟甲磺酸叔丁基二甲基甲硅烷基酯(137μL，0.594mmol)。搅拌获得的混合物15分钟，得到均相溶液。依次往上述溶液中加入2R-乙氧羰基-5S-乙酰氧基四氢呋喃和2R-乙氧羰基-5R-乙酰氧基四氢呋喃的5∶4混合物(50mg，0.248mmol)于二氯甲烷(1mL)和碘代三甲基甲硅烷(35μL，0.248mmol)中的溶液。在室温下反应进行1小时45分钟，然后用Na2S2O3的半饱和溶液骤冷，搅拌得到的混合物5分钟，然后倒入分液漏斗中。除去水相，用饱和Na2S2O3、水和盐水洗涤有机层，然后干燥(Na2SO4)，减压除去溶剂，得到粗产物。用柱色谱(15％甲醇-乙酸乙酯)提纯粗产物，得到52mg(77％)(1＇R，4＇R)与(1＇S，4＇R)之比为11∶2的混合标题化合物(1H NMR)。该产物显示出下列光谱特征：
                                     1HNMR(CDCl3)：δ1.15-1.40(2重叠t，3H)，1.90-2.10(m，2H)，2.25-2.60(m，2H)，4.15-4.35(m，2H)，4.57(m，0.85Hz)，4.84(d of d，0.15H，J＝4.2，7.8Hz)，5.50-6.30(未解析m，1H)，6.09(m，1H)，7.43(d，0.15H，J＝6.7Hz)，7.50-9.00(未解析m，1H)，8.56(d，0.85H，J＝6.7Hz).
实施例8
β-L-(5-氟)-2＇，3＇-二脱氧胞嘧啶
Figure C9210392400381
往冷却的(0℃)搅拌着的1＇R-(5-氟胞嘧啶-1-基)-4＇R-乙氧羰基四氢呋喃和1＇S-(5-氟胞嘧啶-1-基)-4＇R-乙氧羰基四氢呋喃〔307mg，1.133mmol，(1＇R，4＇R)与(1＇S，4＇R)之比为4∶1的异构体的混合物〕的乙醇(4mL)的悬浮液中加入硼氢化钠(86mg，2当量)。搅拌获得的混合物5分钟并撤去冷却浴。在室温下继续搅拌75分钟。加入4滴浓氢氧化铵以骤冷反应。在搅拌混合物15分钟后，减压除去溶剂，用柱色谱法(25％甲醇-乙酸乙酯)提纯粗产物，得到197mg(76％)预期的4＇-羟甲基产物，为4∶1的混合物。在收集的-种馏份中发现含纯度为97％(1H NMR)的标题化合物。浓缩该馏份，得到14mg浅米色的泡沫。
                  UV(λmax)：282.7，236.4，206.7nm(MeOH)；[α]D-81°(c，0.7 MeOH)；1H NMR(CD3OD)：δ1.77-1.90(m，2H)，1.90-2.03(m，1H)，2.25-2.42(m，1H)，3.61(d of d，1H，J＝3.3，12.3Hz)，3.82(d of d，1H，J＝2.8，12.3Hz)，4.06(m，1H)，5.87(m，1H)，8.32(d，1H，J＝7.0Hz).
实施例9
β-D-(5-氟)-2＇，3＇-二脱氧胞嘧啶
Figure C9210392400391
往冷却的(0℃)搅拌着的1＇R-(5-氟胞嘧啶-1-基)-4＇S-乙氧羰基四氢呋喃和1＇S-(5-氟胞嘧啶-1-基)-4＇S-乙氧羰基四氢呋喃〔199mg，0.734mmol，(1＇R，4＇S)与(1＇S，4＇S)之比为7∶1的异构体的混合物〕的乙醇(3mL)悬浮液中加入硼氢化钠(56mg，2当量)。搅拌获得的混合物5分钟并撤去冷却浴。在室温下继续搅拌过夜(约16小时)。加入4滴浓氢氧化铵以骤冷反应，搅拌混合物15分钟后，减压除去溶剂，用柱色谱法(20％甲醇-乙酸乙酯)提纯粗产物，得到112mg(67％)预期的4＇-羟甲基产物，为(1＇R，4＇S)与(1＇S，4＇S)之比为7∶1的混合物(1H NMR)。在收集的一种馏份中发现，仅含标题化合物(1HNMR)。真空浓缩该馏份，得到27mg白色泡沫。UV(λmax)：283.6，238.2，202.4nm(MeOH)；[α]D+96°(c，0.7MeOH)；1H NMR(CD3OD)：δ1.77-1.90(m，2H)，1.90-2.03(m，1H)，2.25-2.42(m，1H)，3.61(d of d，1H，J＝3.3，12.3Hz)，3.82(d of d，1H，J＝2.8，12.3Hz)，4.06(m，1H)，5.87(m，1H)，8.32(d，1H，J＝7.0Hz).
我们已介绍了一些本发明的优选实施方案，就本领域普通技术人员而言，对这些优选实施方案作些替换、改进和修改是很显然的。因此，所给的权利要求书，而不是上述具体实施例，将确定本发明的范围。

Claims (9)

1.非对映选择性制备式(VIIIA)顺式化合物的方法
式中
R2为嘌呤或嘧啶碱或其类似物或衍生物；
R3为取代的羰基或羰基衍生物；
W为S、S＝O、SO2、O、NZ或CH2；
X为S、S＝O、SO2、O、NZ、CH2、CHF、CH、CHN3或CHOH；
Y为O、S、CH2、CH、CHF或CHOH；和
Z为氢、羟基、烷基或酰基；
只是Y为CH2和X为O、S、S＝O或SO2时，W不为O、S、S＝O或SO2；
该方法包括用式(II)化合物的单一对映体将所需嘌呤或嘧啶碱或其类似物或衍生物糖基化步骤其中的L为离去基团，该糖基化反应用式(III)路易斯酸完成式中：
R5、R6和R7分别选自：氢；C1-20烷基，它可由氟、氯、溴、碘、C1-6烷氧基或C6-20芳氧基取代；C7-20芳烷基，它可由卤素、C1-20烷基或C1-20烷氧基取代；C6-20芳基，它可由氟、氯、溴、碘、C1-20烷基或C1-20烷氧基取代；三烷基甲硅烷基；氟；溴；氯和碘；以及
R8选自：氟；溴；氯；碘；C1-20磺酸酯，它可由氟、氯、溴或碘取代；C1-20烷基酯，它可由氟、氯、溴或碘取代；多价卤化物；式(R5)(R6)(R7)Si的三取代甲硅烷基，其中的R5、R6和R7如上所述；饱和或不饱和硒酰C6-20芳基；取代或非取代C6 -20芳基亚磺酰基；取代或非取代C6-20烷氧烷基；和三烷基甲硅烷氧基；
以及非强制性地将式(VIIIA)所示化合物还原，以制备式(I)所示顺式核苷
式中，R1为氢或酰基。
2.权利要求1的方法，其中还包括在将所需嘌呤或嘧啶碱糖基化之前用手性辅助剂将式(II)化合物解析成单一对映体的步骤。
3.权利要求1或2的方法，其中R2为嘧啶碱。
4.权利要求3的方法，其中嘧啶碱为胞嘧啶。
5.权利要求3的方法，其中嘧啶碱为5-氟胞嘧啶。
6.权利要求1或2的方法，其中路易斯酸选自三氟甲磺酸三甲基甲硅烷基酯和碘三甲基硅烷。
7.权利要求3的方法，其中手性辅助剂选自(d)-醇和(l)-醇。
8.权利要求1或2的方法，其中R3选自烷氧羰基、羧基、二乙基碳化二亚胺、吡咯烷酰胺。
9.权利要求8的方法，其中R3选自烷氧羰基和羧基。
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DE69221936D1 (de) 1997-10-09
CA2069063C (en) 1997-07-15
IE921619A1 (en) 1992-12-02
KR100242921B1 (ko) 2000-03-15
CN1067654A (zh) 1993-01-06
IL116176A (en) 1998-02-08
CZ222496A3 (cs) 1999-04-14

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