CN1653065A - 制备萘韦拉平的改良方法 - Google Patents
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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;(e)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;(f)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(g)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
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-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。
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。
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
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G.H.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/1-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120ml 1-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
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,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
的2-卤素-4-甲基-3-吡啶胺反应,其中X为氟、氯、溴或碘原子,优选为氯或溴,以产生式
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,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。
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-吡啶羰酰氯的化合物。
6.一种制备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-吡啶羰酰氯与下式
的2-卤素-4-甲基-3-吡啶胺反应,其中,X为氟、氯、溴或碘原子,优选为氯或溴。
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CN102167699A (zh) * | 2011-03-17 | 2011-08-31 | 湖南博奥德生物医药技术开发有限公司 | 一种奈韦拉平制备方法 |
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