CN1280293C - 制备奈韦拉平的改良方法 - Google Patents

制备奈韦拉平的改良方法 Download PDF

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CN1280293C
CN1280293C CNB038105896A CN03810589A CN1280293C CN 1280293 C CN1280293 C CN 1280293C CN B038105896 A CNB038105896 A CN B038105896A CN 03810589 A CN03810589 A CN 03810589A CN 1280293 C CN1280293 C CN 1280293C
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小罗伯特·F·博斯韦尔
伯纳德·F·格普顿
永·S·罗
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Abstract

一种制备奈韦拉平的方法，其包括以下步骤：(a)将式(I)的2-卤素-3-吡啶腈与环丙胺反应，产生2-(环丙基氨基)-3-吡啶腈，其中X为氟、氯、溴或碘原子，优选为氯或溴；(b)水解2-(环丙基氨基)-3-吡啶腈，以产生2-(环丙基氨基)-3-吡啶羧酸；(c)由反应介质中分离2-(环丙基氨基)-3-吡啶羧酸；(d)以氯化剂处理2-(环丙基氨基)-3-吡啶羧酸，以产生2-(环丙基氨基)-3-吡啶羰酰氯；(e)将2-(环丙基氨基)-3-吡啶羰酰氯与式(II)的2-卤素-4-甲基-3-吡啶胺反应，制造N-(2-卤素-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶酰胺，其中X为氟、氯、溴或碘原子，优选为氯或溴，及(f)以强碱处理，将N-(2-卤素-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶酰胺进行环化，得到奈韦拉平。

Description

制备奈韦拉平的改良方法
技术领域
本发明为关于制备奈韦拉平(NEVIRAPINE)的改良方法，及关于实施本改良方法过程时所产生的多个新颖的中间体。
现有技术
奈韦拉平为HIV反转录酶的非核苷抑制剂，其用于治疗人类感染HIV。奈韦拉平的化学名为11-环丙基-5，11-二氢-4-甲基-6H-吡啶基[3，2-b：2′，3′-e][1，4]二氮杂革-6-酮。其结构式为：
奈韦拉平最早已知的合成方法由Hargrave等人描述于美国专利5,366,972中。所使用的合成方法描述于以下的反应图1。
Figure C0381058900042
图1
在Hargrave等人的方法中，2-氯烟酸与亚硫酰氯反应，形成2-氯烟酰氯。其次，如图1所示，2-氯烟酰氯与2-氯4-甲基-3-吡啶胺反应，产生2-氯-N-(2-氯-4-甲基-3-吡啶基)-3-吡啶酰胺。将这与环丙胺反应，得到N-(2-氯-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶羰酰胺。最后的步骤是环化，以产生出奈韦拉平，该反应是以氢化钠处理最终的中间体。
由Schneider等人描述于美国专利第5,569,760的上述方法的改良，为目前用于工业生产奈韦拉平。在该合成的改良中，2-氯-N-(2-氯-4-甲基-3-吡啶基)-3-吡啶酰胺与环丙胺反应，是在有中和剂存在下进行的，该中和剂为周期表第二主族或第二付族元素的氧化物或氢氧化物。优选使用的中和剂为碱土族金属或锌的氧化物或氢氧化物，氧化钙尤佳。
虽然由美国专利5,366,972提供的合成方法为目前已知是最佳的，但其具有多个明显的缺点。首先，由于环丙胺与2-氯-N-(2-氯-4-甲基-3-吡啶基)-3-吡啶酰胺的反应，是在提高的温度(在130℃至150℃之间)下进行并且环丙胺是如此高度挥发，因此该反应必须在高压反应槽内进行。其次，高于约145℃，2-氯-N-(2-氯-4-甲基-3-吡啶基)-3-吡啶酰胺成为热不稳定，并使反应混合物的温度高于该温度时会有爆炸的危险。因此，必须谨慎以小心控制反应混合物的温度，使其保持在145℃以下，直到全部物质已基本上因反应而消耗完。而保持如此严密控制该反应混合物的温度是困难的，而且该反应因其本身放热反应而使其控制更为困难。第三，需要通过过滤来除去中和剂。最后，由于副产物的产生，合成的收率仅约25％。
因此，奈韦拉平有需要有更好的合成方法。
发明内容
本发明通过提供奈韦拉平的合成而满足这需求，它较安全、较高的收率及比至今已知的任何方法更经济。
本发明的详述
本发明所提供的奈韦拉平的改良合成方法，描述于以下的反应图2中。
Figure C0381058900061
在第一反应步骤中，式(I)
的2-卤素-3-吡啶腈(1)与环丙胺(2)反应，产生2-(环丙基氨基)-3-吡啶腈(3)，其中，X为氟、氯、溴或碘原子，优选为氯或溴。该反应是在升高温度下在惰性、含或不含水的有机溶剂中进行。适当的有机溶剂为C1至C6的直链或支链的醇、四氢呋喃、二甲基甲酰胺、二甘醇二甲醚、甲苯、及其类似物。优选的溶剂为含或不含水的乙醇及1-丙醇。视需要，可添加有机或无机的碱，如三乙胺、二异丙基乙基胺、磷酸钾、碳酸钠、碳酸钾及其类似物，作为酸的清除剂。该反应可在室温与回流温度间的温度下进行，但优选的温度为介于77℃及100℃之间。
然后，2-(环丙基氨基)-3-吡啶腈进行水解，以产生2-(环丙基氨基)-3-吡啶羧酸(4)，当其依据所公开的步骤进行分离时，主要以两性离子方式存在，因此如图2所示。水解前，腈的分离可任选的。可使用强酸或强碱溶液，按习用的方式将腈水解为羧酸。水解优选使用过氧化氢及强碱，如氢氧化钠或氢氧化钾的水性混合物，或强碱，如氢氧化钠或氢氧化钾，及1至6个碳原子的醇的水性混合物来进行。最佳的水解为使用水性1-丙醇及氢氧化钾进行。加热至回流可加速水解的速率。
然后2-(环丙基氨基)-3-吡啶羧酸由反应介质中分离出。这可由调整pH至等电点而方便地完成，该等电点在约pH6可达到。由此产生两性离子，该离子沉淀，然后以过滤分离及干燥。若水性醇及碱用于进行水解，该醇首先由蒸馏除去。
其次，该2-(环丙基氨基)-3-吡啶羧酸用氯化剂处理，而产生2-(环丙基氨基)-3-吡啶羰基氯(5)。适当的氯化剂为例如，亚硫酰氯、氯氧化磷、三氯化磷、五氯化磷、光气及草酰氯。氯化反应按熟悉有机合成技术人员已知的方式进行。通常，优选是将羧酸(4)与氯化剂回流，该氯化剂或以纯化的方式使用，或以与适当的非质子性溶剂如甲苯、乙腈、四氢呋喃或其类似物所构成的溶液来使用。优选为以纯的亚硫酰氯回流来进行氯化反应，任何多余的亚硫酰氯可在以后以蒸发法方便地除去。由于大部分氯化剂产生盐酸，该反应步骤的产物(5)示于图2中，描述为氢氯化物。
其次，使2-(环丙基氨基)-3-吡啶羰酰氯(5)与式
Figure C0381058900071
的2-卤素-4-甲基-3-吡啶胺(6)反应，其中，X为氟、氯、溴或碘原子，优选为氯或溴。最佳的反应剂为2-氯-4-甲基-3-吡啶胺。这产生N-(2-卤素-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶酰胺(7)，其中，X为氟、氯、溴、或碘原子，优选为氯或溴。因为它与吡啶胺反应，必须先除去任何残留的氯化剂。若使用高度挥发性的氯化剂如纯亚硫酰氯，则可用蒸发法除去以留下固体酰基氯(5)。若氯化反应，是在溶剂中进行，则使用高沸腾的溶剂较佳，以使氯化剂可用蒸发法除去，留下溶于溶剂中的酰基氯。在任何情况下，该酰基氯(5)保持在无水的条件下。该酰基氯(5)与吡啶胺(6)通过溶解于适当的无水溶剂，如乙腈、四氢呋喃、二甘醇二甲醚、二甲基甲酰胺、二烷、二氯甲烷、或甲苯下进行反应。任意的碱，不管有机或无机，如三乙胺、二异丙基乙胺、磷酸钾、磷酸氢钾、碳酸钠、氢氧化钠、氢氧化钾、或其类似物，可添加到反应混合物中作为酸清除剂。反应速率可因加热至溶剂的沸点而增加。
最后，将酰胺(7)环化以产生奈韦拉平。该环化反应可通过在-30℃至130℃之间用强碱例如，氢化钠(NaH)或六甲基二硅氮烷钠(NaHMDS)在惰性无水有机溶剂，如二甘醇二甲醚、甲苯、或四氢呋喃中处理该酰胺(7)而诱发。
通过2-氯-3-吡啶腈与环丙胺的反应，而合成中间体2-(环丙基氨基)-3-吡啶腈，是由GH.Hardtmann等人在J.Med.Chem.1974，17，636中已知。
中间体，2-(环丙基氨基)-3-吡啶羧酸(4)与2-(环丙基氨基)-3-吡啶羰酰氯(5)被认为是新颖的，因此，被视为本发明的一部分。
优选使用2-氯-3-吡啶腈作为起始材料(1)，因为合成该物质为已知，并市面上有售。另外的2-卤素-3-吡啶腈可由相似的方式容易合成。
环丙胺，起始材料(2)也是市面上有售。
优选使用2-氯-4-甲基-3-吡啶胺作为反应物(6)，因为合成该物质由美国专利6,399,781；5,686,618；5,668,287；5,654,429及5,200,522中已知。其它的2-卤素-4-甲基-3-吡啶胺可由相似的方式容易合成。
以下实施例进一步描述用本发明所提供的改良方法，制备奈韦拉平。虽然反应顺序的每一步骤可先分离出前面步骤的产物来进行，部分反应步骤可在单一反应槽中相继进行，不需分离前一步骤所形成的中间体，因此可减少因容器、时间、清除及劳力的相关成本。以下实施例1至6描述每一步骤完成时所形成的中间体是进行分离的方法。实施例7及8描述部分反应步骤可在单一反应容器中，相继进行，而不需分离前步骤所形成的中间体。
实施例1，制备2-(环丙基氨基)-3-吡啶腈
于配置有机械搅拌器、温度控制器、冷凝器及加料漏斗的反应瓶中，加入2-氯-3-吡啶腈(69.25g，0.50mol)、300ml的乙醇及200ml的水。搅拌下，在30分钟的时间内，在＜30℃的温度下滴加环丙胺(114g，2.0mol)。当完成添加时，将该搅拌的反应混合物加热至回流温度20小时。将反应混合物冷却至60℃，然后用水吸气器抽吸真空的真空蒸馏，以除去350ml过剩的环丙胺及乙醇。留下的水溶液冷却至室温，放置过夜。以过滤收集固体产物，以水冲洗滤饼。产量为81.51g(理论产量为79.5g)。
实施例2，制备2-(环丙基氨基)-3-吡啶羧酸(两性离子)
将45％水性KOH溶液(187g，1.5mol)加入由实施例1的产品及300ml的1-丙醇的混合物中。将该混合物以回流温度加热约5小时，直到以TLC分析显示，腈已被完全水解。将反应混合物冷却至室温，以94g的水处理，以便用共沸蒸馏除去1-丙醇。将约330g的水/l-丙醇共沸物在62℃及21.1英寸水银柱高的气压下蒸馏掉。加入水(130g)于该混合反应物，并使之冷却至5-10℃。以温度能维持于30℃以下的速率加入浓盐酸(148g，1.5mol)。约80-90％的酸加入后，两性离子开始沉淀析出，使得该混合物很稠。当全部酸添加完毕，以过滤来收集固体产物，利用90ml冷水冲洗反应容器至滤饼上。将该产物干燥而得到68.12g的两性离子。
实施例3，制备2-(环丙基氨基)-3-吡啶羰酰氯
将亚硫酰氯(25ml，40.8g，0.343mol)以细流加入乙腈中的由实施例2所得的9.00g，0.048mol 2-(环丙基氨基)-3-吡啶羧酸中。该混合物在回流温度下加热30分钟。将混合物冷却，于40℃/23英寸汞柱高的压力下将亚硫酰氯蒸发掉，直到罐内容物变稠。加入甲苯(25ml)，并继续于40℃蒸发亚硫酰氯及甲苯，直到约一半的液体蒸发掉。使所剩溶液冷却，搅拌以促进结晶。将庚烷(25ml)在搅拌下加入于该混合物中，在一大气压的氮下过滤该混合物得到该标题化合物。
实施例4，制备N-(2-氯-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶酰胺
将2-氯-4-甲基-3-吡啶胺(5.70g，0.040mol)在10ml乙腈中的溶液，快速滴加入由实施例3的酰基氯、磨碎的无水磷酸钾(8.49g，0.04mol)及40ml乙腈所构成的混合物中。该反应混合物于50℃加热20小时，反应过程以HPLC分析进行监视。当反应完全时，将反应混合物冷却至室温，并以50ml水处理，得到具有pH约4.5-5的溶液。将该混合物通过添加稀HCl溶液而酸化至pH1，并于室温下搅拌30分钟。将该反应混合物过滤以除去任何不溶物，将滤液以稀的氢氧化钠溶液碱化至pH9-10，并在室温下搅拌30分钟。然后将混合物通过添加稀盐酸而酸化至pH7-8，在溶液顶部形成暗色油状层。加入水，因为这在过去相似特性的实验中已观察到可促进结晶。油层在搅拌过夜中缓慢结晶。收集固体产物，并于50℃真空烘箱中干燥以得到9.37g的标题化合物。
实施例5，利用六甲基二硅氮烷钠制备11-环丙基-5，11-二氢-4-甲基-6H-二吡啶基[3，2-b：2′，3′-e][1，4]二氮杂-6-酮(奈韦拉平)
将配置有磁搅拌器、温度控制热电偶、加料漏斗、及具有油鼓泡以排除环境空气的冷凝器的反应烧瓶，以氮气惰性化，加入3.02g(0.010mol)由实施例4制的N-(2-氯-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶酰胺及30ml无水THF。滴加六甲基二硅氮烷钠(NaHMDS)在THF(12.7ml，0.025mol)中的40％溶液，并使反应混合物的温度维持在不超过30℃。当添加NaHMDS溶液完成时，将反应混合物加热至回流温度(约63-66℃)。当该反应完成(以HPLC分析)，将混合物冷却至室温。以1.55g(0.050mol)的甲醇及0.45g水(0.025mol)处理反应混合物。在25-30英寸汞柱的气压，50-60℃水浴温度下的旋转蒸馏器中，浓缩该混合物。将重4.44g的残渣产物以50ml水研磨，并通过添加10％HCl溶液，将pH10-12的溶液酸化成pH3。以过滤收集固体产物，以每份10ml的水洗涤滤饼3次。将该滤饼在50-60℃的真空烘箱中干燥以制得奈韦拉平。
实施例6，使用氢化钠制备11-环丙基-5，11-二氢-4-甲基-6H-二吡啶基[3，2-b：2′，3′-e][1，4]二氮杂-6-酮(奈韦拉平)
将具有搅拌器、温度控制热电偶、加料漏斗及有油鼓泡以排除空气的冷凝器的500ml 4NRB烧瓶，以氮气惰性化，加入在矿物油浆料中的60％氢化钠15.00g及120ml二甘醇二甲醚。将混合物加热至130℃，用41.7g(0.138mol)由实施例4制的N-(2-氯-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶酰胺，在70ml二甘醇二甲醚中的溶液于80℃滴加处理。将该反应混合物于130℃加热，直到氢气停止发生。混合物冷却至室温，小心滴加入水(6.75g)。当氢的发生停止后，另加100ml水。加入醋酸(20ml)以使混合物的pH从11-13降低到约7。另外再加入100ml水，将反应混合物于室温条件下搅拌30分钟，以使产物结晶。以过滤收集固体产物，滤饼以100ml水洗，接着以50ml环己烷洗涤以除去从矿物油-氢化钠浆料中的任何残余矿物油。将湿滤饼于50℃的真空烘箱中干燥18小时，以制得35.58g的奈韦拉平。
实施例7，由2-氯-3-吡啶腈，于一单槽中合成2-(环丙基氨基)-3-吡啶羧酸
将具有搅拌器、冷凝器、温度控制器热电偶及加料漏斗的一升4NRB烧瓶，加入2-氯-3-吡啶腈(27.70g，0.20mol)，继而加入120ml1-丙醇及80ml水。将三乙胺(20.2g，0.20mol)一次添加，继而在2分钟的时间内添加环丙胺(17.10g，0.30mol)。以回流加热(86-87℃)反应混合物，2.5小时后，薄层色层(TLC)分析(硅胶，MTBE移动相)显示有一些产物形成。回流搅拌16小时后，TLC分析显示残留少量的起始物。HPLC分析显示含22％起始物，75％2-(环丙基氨基)-3-吡啶腈。再另添加0.1mol(10.1g)的三乙胺(共30.3g，0.30mol的三乙胺)及0.03mol的环丙胺(1.70g)，该混合物继续回流加热3小时。HPLC分析显示残留15％的起始物。另再加4.0g的环丙胺(共0.40mol)并使混合物再回流加热18小时。在时间终了时，HPLC分析显示含2.9％的起始物。
将氢氧化钾(33.6g，0.60mol)加入，并使混合物在真空下加热至约40℃约15分钟以除去任何挥发性的胺。然后将该混合物在大气压下回流加热5小时，以便水解该腈成为羧酸。加水(80ml)，并将正丙醇蒸发作为与水的共沸物(共沸沸点为87.7℃，28.3％水，71.7％正丙醇)。当蒸馏最高温度增加至92℃时，停止蒸馏，使反应混合物冷却。
以冰甲醇浴冷却该反应混合物至约10℃，滴加50ml(59.2g)的37％HCl溶液，并维持该反应混合物不超过25℃。加完所有HCl并搅拌约2分钟后，2-(环丙基氨基)-3-吡啶羧酸开始进行更久的结晶，而产物成为饼状。加水(100ml)以破碎固体块，使混合物成为可搅拌的。约30分钟后，以过滤收集该固体。浓缩滤液以取得另一份固体。以空气抽吸干燥约2小时后，该湿饼固体称重为23.02g。HPLC显示含97％的2-(环丙基氨基)-3-吡啶羧酸及浓度为1.8％与1.3％的两个小而不明的杂质峰。该固体于50℃真空烘箱中干燥65小时而得到18.19g。
实施例8，由2-氯-4-甲基-3-吡啶胺及2-(环丙基氨基)-3-吡啶羧酸(两性离子)单槽合成N-(2-氯-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶酰胺
Figure C0381058900121
在配置有机械搅拌器、冷凝器、加料漏斗及温度控制热电偶的250ml 4NRB烧瓶中加入2-(环丙基氨基)-3-吡啶羧酸(18.46g，0.10mol)。将亚硫酰氯(22ml，0.30mol)以细流在搅拌下加入反应烧瓶中，并将该混合物加热至回流32分钟。将反应混合物冷却，冷凝器以真空蒸馏头替换。将亚硫酰氯在40℃，23英寸的汞柱真空下蒸发掉，直到蒸馏锅中的内容变稠。加入甲苯(30ml)，继续蒸馏直到约大部分液体被蒸发掉。再加入另一30ml的甲苯，约一半的溶剂在真空中蒸发掉。将乙腈(60ml)加入到该残留混合物中。滴加2-氯-4-甲基-3-吡啶胺(11.4g，0.080mol)在40ml乙腈中的溶液，将该反应混合物加热至50℃，并搅拌过夜。于加入2-氯-4-甲基-3-吡啶胺后，将细粉碎的磷酸钾加入。16小时后，于50℃，将100ml水加入到搅拌的反应混合物中(pH4-5)。将反应混合物过滤以除去少量不溶物。将滤液(2层)以50％的氢氧化钠水溶液碱化至pH10-11，然后酸化回到pH8。由HPLC分析，发现大部分产物在甲苯层中。以300ml的稀HCl溶液(pH1)萃取该甲苯层。利用10％NaOH水溶液将该水性酸层碱化至pH8，而导致由研磨而缓缓结晶的油层分离。放置超过2天后，收集固体产物，在50℃真空干燥，而得到21.40g黄褐色的标题化合物。

Claims (6)

1.一种制备奈韦拉平的方法，其包括以下步骤：
(a)将式
的2-卤素-3-吡啶腈与环丙胺反应，产生2-(环丙基氨基)-3-吡啶腈，其中X为氟、氯、溴、或碘原子；
(b)水解2-(环丙基氨基)-3-吡啶腈，以产生2-(环丙基氨基)-3-吡啶羧酸；
(c)由反应介质中分离2-(环丙基氨基)-3-吡啶羧酸；
(d)以氯化剂处理2-(环丙基氨基)-3-吡啶羧酸，以产生2-(环丙基氨基)-3-吡啶碳酰氯；
(e)将2-(环丙基氨基)-3-吡啶碳酰氯与式
Figure C038105890002C2
的2-卤素-4-甲基-3-吡啶胺反应，其中X为氟、氯、溴或碘原子，以产生式
Figure C038105890002C3
的N-(2-卤素-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶酰胺，其中X为氟、氯、溴或碘原子，及
(f)以强碱处理，将N-(2-卤素-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶酰胺进行环化，得到奈韦拉平。
2.一种2-(环丙基氨基)-3-吡啶羧酸的化合物。
3.一种2-(环丙基氨基)-3-吡啶碳酰氯的化合物。
4.一种制备2-(环丙基氨基)-3-吡啶羧酸的方法，该方法包括以下步骤：
(a)将式
的2-卤素3-吡啶腈与环丙胺反应，产生2-(环丙基氨基)-3-吡啶腈，其中X为氟、氯、溴、或碘原子；及
(b)水解2-(环丙基氨基)-3-吡啶腈，以产生2-(环丙基氨基)-3-吡啶羧酸。
5.制备N-(2-卤素-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶酰胺的方法，该方法包括使2-(环丙基氨基)-3-吡啶碳酰氯与下式
Figure C038105890003C2
的2-卤素-4-甲基-3-吡啶胺反应，其中，X为氟、氯、溴或碘原子。
6.根据权利要求5所述的制备下式
的N-(2-卤素-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶酰胺的方法，其中X为氟、氯、溴、或碘原子，该方法包括以下步骤：
(a)以氯化剂处理2-(环丙基氨基)-3-吡啶羧酸，以产生2-(环丙基氨基)-3-吡啶碳酰氯；及
(b)将2-(环丙基氨基)-3-吡啶碳酰氯与下式
的2-卤素-4-甲基-3-吡啶胺反应，以产生N-(2-卤素-4-甲基-3-吡啶基)-2-(环丙基氨基)-3-吡啶酰胺，其中X为氟、氯、溴或碘原子。
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