CN1344272A - 制备4,4-二甲基-3β-羟基孕-8,14-二烯-21-羧酸酯的方法以及该方法中的中间产物 - Google Patents
制备4,4-二甲基-3β-羟基孕-8,14-二烯-21-羧酸酯的方法以及该方法中的中间产物 Download PDFInfo
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- CN1344272A CN1344272A CN00805163A CN00805163A CN1344272A CN 1344272 A CN1344272 A CN 1344272A CN 00805163 A CN00805163 A CN 00805163A CN 00805163 A CN00805163 A CN 00805163A CN 1344272 A CN1344272 A CN 1344272A
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- 238000003786 synthesis reaction Methods 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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Abstract
本发明涉及制备通式(1)化合物的方法。本发明还涉及中间体形式的通式(5、6和7)的化合物,以及通式(1)的4,4-二甲基-3β-羟基孕-8,14-二烯-21-羧酸酯在制备4,4-二甲基-5α-胆甾-8,14,24-三烯-3β-醇(2)中的应用。
Description
Byskov等人的研究(Nature 1995,374,559)表明,从人滤泡液中分离的式2的4,4-二甲基-5α-胆甾-8,14,24-三烯-3β-醇(以下称为FF-MAS)是调节减数分裂的内源性物质,而一些有利的激素作用就是由于该减数分裂。因此,该物质对于药物应用例如促进生育率是很重要的。
Dolle等人(J.Am.Chem.Soc.1989,111,278)描述了该天然物质的首次合成,其是在由羊毛甾醇生物合成胆固醇中进行的。由麦角甾醇作为起始物,在18步费时费力的合成法中得到FF-MAS。该合成的大部分是专注于部分化学分解麦角甾醇侧链,随后产生FF-MAS侧链以及对于达到目的所必须的保护基化学。
Schroepfer等人(Bioorg.Med.Chem.Lett.1997,8,233)由脱氢胆固醇作为起始物在13步的合成法中第二个合成了FF-MAS。在该合成法中,费时费力地保护二烯体系对于产生侧链仍是必须的。仅有四个步骤(用于保护的环氧化和重排;用于再生二烯体系的还原和消除反应)是针对保护基策略。
Ruan等人(Med.Chem.Letters 1998,233)第三个合成了FF-MAS。在该合成中,FF-MAS是在15步的合成法中由胆固醇作为起始物而合成的。在此,该合成法的大部分是用于在甾体中费时费力地产生双键体系以及产生侧链。
在尚未公开的DE 198 17 520以及198 23 677中描述了其他方法。这些合成法由3-氧代孕-4-烯-21-羧酸酯作为起始物。这些方法的中心中间产物是如通式1所示的4,4-二甲基-3β-羟基孕-8,14-二烯-21-羧酸酯。
本发明的目的是合成这些中心产物的新方法。本发明的目的还在于在本发明的方法中产生的以前未知的新中间产物,它们本身或者经衍生化可用作合成其他目标分子、例如合成FF-MAS类似物(见WO96/00235)的起始物,并可用于制备4,4-二甲基-5α-胆甾-8,14,24-三烯-3β-醇。
上述目的是通过权利要求来实现的。
在本发明的方法中,比现有技术的已知合成法具有更少的中间步骤,而且纯制步骤数也大大减少。根据本发明的方法
根据以下合成路线1,通式1的4,4-二甲基-3β-羟基孕-8,14-二烯-21-羧酸酯是由雄烯二酮(3)作为起始物在5个步骤中制备的。
用作起始物的雄烯二酮可市售得到。
式3化合物反应形成式4化合物是根据本领域技术人员已知的方法进行的(例如,Helv.Chim.Acta 1980,63,1554;J.Am.Chem.Soc.1954,76,2852)。例如,式3的化合物在碱存在下于溶剂或者溶剂混合物中与烷基化剂反应,所述碱例如是低级醇的碱金属盐,但优选是叔丁醇钾,而所述烷基化剂例如是二甲基硫酸酯、二甲基碳酸酯或者碘甲烷。作为溶剂,可使用低级醇,优选为叔醇以及醚,例如甲基叔丁基醚,或者四氢呋喃,以及它们的混合物。优选使用叔丁醇或者由叔丁醇和四氢呋喃组成的混合物。反应在0-65℃的温度范围、优选15-50℃的温度范围下进行。
式4化合物反应形成式5化合物是根据本领域技术人员已知的方法进行的(例如,Synth.Commun.1977,7,215;JOC 1988,3947;J.Prakt.Chem.1990,367)。例如,式4的化合物在碱存在下于溶剂或者溶剂混合物中与三烷基膦酰基乙酸酯反应,所述碱例如是低级醇的碱金属盐,但优选是甲醇钠,而所述三烷基膦酰基乙酸酯例如是三乙基膦酰基乙酸酯或者三甲基膦酰基乙酸酯。作为溶剂,可使用低级醇,优选为伯醇以及醚,例如甲基叔丁基醚,或者四氢呋喃,以及它们的混合物。优选使用乙醇。反应在0-100℃的温度范围、优选20-80℃的温度范围下进行。
由式4的化合物作为起始物,式5的化合物也可如下制备:与Meldrum酸或者丙二酸酯缩合,然后皂化、脱羧并酯化。
对本领域技术人员熟悉的是,根据标准方法式5化合物中的R1是可变化的。这可通过在酯化步骤中使用其他醇,也可通过重新酯化已经存在的酯来实现。R1因此可代表氢、甲基、乙基、丙基、异丙基、丁基、以及相应的丁基异构体、戊基以及相应的戊基异构体、己基和相应的己基异构体、苯基、苄基、邻、间和对—甲基苯基。
式5的酮反应形成式6的相应3-醇可用相当量的还原剂来进行。例如,可以使用BH3复合物(如与叔丁基胺或者三甲基胺的复合物)、Selectride、硼氢化钠和硼氢化锂、受抑制的氢化铝锂(如LiAl(OtBu)3H);也可使用微生物,如发面酵母或酶,例如3β-羟基甾体脱氢酶。
对于本领域技术人员已知的是,根据所用试剂,可使用各种溶剂或者溶剂混合物以及反应温度。但是在此优选在合适溶剂中的硼氢化物、如硼氢化钠,所述溶剂例如是低级醇或者醇与其他溶剂的混合物,如二氯甲烷、四氢呋喃或者水。反应温度范围是-20℃至40℃,优选为-10℃至10℃。
通式6化合物中17-双键的还原可根据本领域已知的方法。在此情况下,可使用两种基本不同的方法。
在这个方面,按照类似于文献中已知的反应(Synthesis 1996,455),合适的还原剂是在低级醇中的碱土金属混合物。例如,通式6的化合物在低级醇、优选甲醇中与碱土金属、优选镁反应。该反应在0-80℃的温度范围、优选20-50℃的温度范围下进行。
作为其它的还原法,在此情况下还可进行催化氢化。例如,通式6的混合物在合适的催化剂如贵金属或其氧化物、优选氧化铂存在下被氢化。作为溶剂,可使用低级醇,优选乙醇,以及醚,例如甲基叔丁基醚,或者四氢呋喃或者它们的混合物。优选使用四氢呋喃。在此情况下,足以令人惊奇的是,5,6-双键没有被氢化。
已证明添加催化量的酸也是有利的,例如硫酸、磷酸或柠檬酸。优选使用磷酸。反应在10-100℃的温度范围下进行,优选在常压和升高的压力下进行。在此方面,反应优选在20-50℃的温度范围、以及常压下进行。
在单锅法(Eintopfverfahren)中,通过溴化/脱溴化氢/异构化(该方法也可使用相应的氯化物并进行脱氯化氢),可引入7,8-双键并将双键异构化为在目标化合物中建立的双键体系。
首先在7-位进行烯丙基溴化,形成5,6-双键,然后热消除溴化氢,得到5,7-双键体系,其再通过酸性异构化转化为所希望的双键体系。添加酸不是必须的;同时形成的溴化氢可令人满意地达到该目的。
溴化反应是根据本领域技术人员已知的方法进行的。例如,在合适的溶剂中使用N-溴代琥珀酰亚胺或者N,N-二溴二甲基海因,所述溶剂例如是苯、低级烷烃或者卤代烷烃,如四氯化碳。除上述提到的溶剂外,还可使用例如甲酸甲酯(如Angew.Chem.1980,92,471)。
优选使用庚烷作为溶剂。反应在30-130℃的温度范围、优选60-100℃的温度范围下进行。
实施例a)4,4-二甲基雄烯二酮(4)
在室温下向500g雄烯二酮在5升叔丁醇中的溶液内添加411g的叔丁醇钾。然后滴加229ml的碘甲烷,并搅拌混合物1小时。处理时,添加400ml的1M硫酸和2升的水。过滤出沉淀物,并用乙醇重结晶。得到413g的4,4-二甲基雄烯二酮。
1H-NMR(CDCl3):δ=0.89和0.90(2s,3H,18-和19-H3),1.06-2.66(m,17H,雄烯二酮),1.25(s,6H,4-(CH3)2),5.58-5.61(m,1H,6-H)
熔点:165-167℃
元素分析:计算:C 80.21,H 9.62
实测:C 79.96,H 9.61b)(20E)-4,4-二甲基-3-氧代孕-5,17-二烯-21-羧酸乙基酯(5)
将837ml的20%乙醇钠溶液和387ml的三乙基膦酰基乙酸酯添加在310g的4,4-二甲基雄烯二酮于818ml乙醇中的溶液内。回流该混合物5小时,然后通过添加1.6升的水使反应结束。过滤出沉淀物,重新洗涤,然后干燥。得到369g的(20E)-4,4-二甲基-3-氧代孕-5,17-二烯-21-羧酸乙基酯。
1H-NMR(CDCl3):δ=0.85和0.88(2s,3H,18-和19-H3),1.02-2.91(m,17H,雄烯二酮),1.26(s,6H,4-(CH3)2),1.29(t,3H,J=7.0,CO2CH2CH3),4.15(q,2H,J=7.1,CO2CH2CH3),5.55-5.58(m,2H,6-H和20-H)
熔点:136-138℃c)(20E)-4,4-二甲基-3β-羟基-孕-5,17-二烯-21-羧酸乙基酯(6)
将200g在步骤b)中描述的化合物添加在2升乙醇中,然后与20g的硼氢化钠在0.4升水中的溶液于0℃下混合。搅拌11小时。在反应混合物中添加328g柠檬酸于2.8升水中的溶液,1小时后,分离固体。残留物用水洗涤几次,然后真空干燥。得到190g的(20E)-4,4-二甲基-3β-羟基-孕-5,17-二烯-21-羧酸乙基酯,其无需纯制就用于下一步反应中。
1H-NMR(CDCl3):δ=0.83,1.08,1.10和1.15(4s,3H,4-(CH3)2,18-和19-H3),0.91-2.90(m,17H,雄烯二酮),1.28(t,3H,J=7.1,CO2CH2CH3),3.24(dd,1H,J=10.2,5.5,3-H),4.15(q,2H,J=7.1,CO2CH2CH3),5.53-5.59(m,2H,6-H和20-H)
熔点:171-173℃
元素分析:计算:C 77.68,H 9.91
实测:C 77.75,Hd)4,4-二甲基-3β-羟基-孕-5-烯-21-羧酸乙基酯(7)(氢化)
将200g的(20E)-4,4-二甲基-3β-羟基-孕-5,17-二烯-21-羧酸乙基酯溶解在1.2升的THF中,然后与0.4ml的85%磷酸和4g的氧化铂混合。反应容器充入氢气(1bar)。氢吸收完全后,过滤出催化剂,并蒸馏出溶剂。得到210g的4,4-二甲基-3β-羟基-孕-5-烯-21-羧酸乙基酯,其未经纯制就进一步使用。4,4-二甲基-3β-羟基-孕-5-烯-21-羧酸乙基酯(7)(镁还原)
在室温下将5.0g的(20E)-4,4-二甲基-3β-羟基-孕-5,17-二烯-21-羧酸乙基酯溶解在100ml甲醇中,然后与0.5ml的乙酸混合。在反应混合物中分批添加镁屑。2.5小时后,用25ml乙酸酸化,然后与200ml水混合。过滤出沉淀物,用水重新洗涤,然后干燥。得到4.7g的4,4-二甲基-3β-羟基-孕-5-烯-21-羧酸乙基酯,其未经纯制就进一步使用。
1H-NMR(CDCl3):δ=0.61,1.08,1.10和1.15(4s,3H,4-(CH3)2,18-和19-H3),0.92-2.42(m,18H,雄烯二酮),1.25(t,3H,J=7.1,CO2CH2CH3),3.22-3.26(m,1H,3-H),4.11(q,2H,J=7.1,CO2CH2CH3),5.55-5.58(m,1H,6-H)
熔点:127-129℃
元素分析:计算:C 77.27,H 10.38
实测:C 77.00,H 10.20e)4,4-二甲基-3β-羟基孕-8,14-二烯-21-羧酸乙基酯(1)
使100g在步骤d)中描述的化合物与48g的1,3-二溴-5,5-二甲基海因在2.5升正庚烷中回流20小时。冷却后,用乙酸乙酯萃取混合物,有机相用水洗涤几次,然后蒸发浓缩,得到50g的4,4-二甲基-3β-羟基孕-8,14-二烯-21-羧酸乙基酯
1H-NMR(CDCl3):δ=0.75,0.83,1.02和1.03(4s,3H,4-(CH3)2,18-和19-H3),0.62-2.59(m,17H,雄烯二酮),1.26(t,3H,J=7.1,CO2CH2CH3),3.25(dd,1H,J=11.4,4.8,3-H),4.13(q,2H,J=7.1,CO2CH2CH3),5.35(br s,1H,15-H)
MS(计算386.58),在387处有M+峰
进一步处理形成4,4-二甲基-5α-胆甾-8,14,24-三烯-3β-醇(2)(FF-MAS):f)由4,4-二甲基-3β-羟基孕-8,14-二烯-21-羧酸甲基酯起始进一步形成g)4,4-二甲基-3β-[[二甲基(1,1-二甲基乙基)-甲硅烷基]氧基]孕-8,14-二烯-21-羧酸甲基酯
在70℃下使92g的4,4-二甲基-3β-羟基孕-8,14-二烯-21-羧酸甲基酯0.75升的N,N-二甲基甲酰胺、51g的叔丁基二甲基甲硅烷基氯和27.8g的咪唑混合18小时。冷却后,将其倾倒在10升用冰冷却的0.5M盐酸中,然后过滤。滤饼用乙酸乙酯处理,用1N氢氧化钠溶液洗涤至中性,在硫酸钠上干燥,过滤,然后蒸发浓缩。得到124.8g的4,4-二甲基-3β-[[二甲基(1,1-二甲基乙基)-甲硅烷基]氧基]孕-8,14-二烯-21-羧酸甲基酯,其未经纯制就进一步使用。h)4,4-二甲基-3β-[[二甲基(1,1-二甲基乙基)-甲硅烷基]氧基]-5β-胆甾-8,14,24-三烯-21-羧酸甲基酯
将123.5g在步骤b)中描述的化合物溶解在2.0升四氢呋喃中,然后在-20℃下滴加在1.04mol二异丙基酰胺锂溶液中,该二异丙基酰胺锂溶液是由652ml的1.6M正丁基锂己烷溶液和174ml二异丙基酰胺在320ml四氢呋喃中的溶液制备的。在0℃下搅拌40分钟后,冷却至-10℃,然后滴加270g的5-碘-2-甲基-2-戊烯。在0℃下搅拌3小时后,将反应混合物分配在乙酸乙酯以及饱和氯化铵溶液之间。有机相用水及饱和盐水溶液洗涤后,在硫酸钠上干燥,然后过滤,蒸发浓缩,并在硅胶上用正己烷和乙酸乙酯组成的混合物进行粗过滤。得到113g(0.2mol)的4,4-二甲基-3β-[[二甲基(1,1-二甲基乙基)-甲硅烷基]氧基]-5α-胆甾-8,14,24-三烯-21-羧酸甲基酯,其未经纯制就进一步使用。i)4,4-二甲基-3β-[[二甲基(1,1-二甲基乙基)-甲硅烷基]氧基]-5α-胆甾-8,14,24-三烯-21-醇
将112.5g在步骤c)中描述的化合物溶解在0.7升四氢呋喃中,然后在0℃下滴加在15.04g氢化铝锂中,该氢化铝锂悬浮在0.7升的四氢呋喃中。在室温下搅拌3小时后,与60ml用冰冷却的饱和氯化铵溶液混合。搅拌20分钟后,与硫酸钠混合,再经过10分钟后,进行抽滤。蒸发残留物在短柱上用二氯甲烷作为溶剂过滤。蒸发浓缩洗脱物后,得到103.2g的4,4-二甲基-3β-[[二甲基(1,1-二甲基乙基)-甲硅烷基]氧基]-5α-胆甾-8,14,24-三烯-21-醇,其未经纯制就进一步使用。j)4,4-二甲基-3β-[[二甲基(1,1-二甲基乙基)-甲硅烷基]氧基]-5α-胆甾-8,14,24-三烯-21-醇-甲烷磺酸酯
在0℃下,将21.8ml甲烷磺酰氯滴加在102.3g在步骤d)中描述的化合物于440ml二氯甲烷和84ml三乙胺组成的混合物中的溶液内。室温下3小时后,将其分配在水和二氯甲烷之间。用碳酸氢钠溶液、饱和盐水溶液洗涤有机相后,在硫酸钠上干燥,过滤,然后蒸发浓缩,并在硅胶上用己烷和乙酸乙酯组成的混合物进行色谱分离。得到78.2g的4,4-二甲基-3β-[[二甲基(1,1-二甲基乙基)-甲硅烷基]氧基]-5α-胆甾-8,14,24-三烯-21-醇-甲烷磺酸酯。k)4,4-二甲基-3β-[[二甲基(1,1-二甲基乙基)-甲硅烷基]氧基]-5α-胆甾-8,14,24-三烯
根据步骤d)中描述的方法使77.2g在步骤e)中描述的化合物进行反应。在硅胶上用正己烷和乙酸乙酯组成的混合物过滤粗产物后,得到63g的4,4-二甲基-3β-[[二甲基(1,1-二甲基乙基)-甲硅烷基]氧基]-5α-胆甾-8,14,24-三烯。l) 4,4-二甲基-5α-胆甾-8,14,24-三烯-3β-醇
使2g在步骤f)中描述的化合物在5ml的6N盐酸、10ml乙醇和30ml四氢呋喃组成的混合物中于室温下搅拌24小时。然后在乙酸乙酯和水之间分配。用1N氢氧化钠溶液、水及饱和盐水溶液洗涤有机相后,在硫酸钠上干燥并过滤,蒸发残留物在硅胶上用正己烷和乙酸乙酯组成的混合物进行色谱分离。得到1.45g的4,4-二甲基-5α-胆甾-8,14,24-三烯-3β-醇。
NMR数据与文献中记载的相同(J.Am.Chem.Soc.111,1989,278)。
Claims (5)
1、制备通式1之4,4-二甲基-3β-羟基孕-8,14-二烯-21—羧酸酯的方法:其中:R1=氢、支链或直链C1-C6烷基、苯基、苄基、邻、间或对—甲基苯基,其是由以下雄烯二酮3为起始物:a)通过二甲基化形成式4的4,4-二甲基雄烯二酮:b)通过烷基化形成通式5的4,4-二甲基-3-氧代孕-5,17-二烯-21-羧酸酯:其中R1=氢、支链或直链C1-C6烷基、苯基、苄基、邻、间或对—甲基苯基,c)通过还原形成通式6的4,4-二甲基-3β-羟基-孕-5,17-二烯-21-羧酸酯:其中R1=氢、支链或直链C1-C6烷基、苯基、苄基、邻、间或对—甲基苯基,d)通过还原17-双键形成通式7的4,4-二甲基-3β-羟基-孕-5-烯-21-羧酸酯:其中R1=氢、支链或直链C1-C6烷基、苯基、苄基、邻、间或对—甲基苯基,随后进行卤化、脱卤化氢以及异构化,转化为通式(1)的4,4-二甲基-3β-羟基孕-8,14-二烯-21-羧酸酯。
2、通式5的4,4-二甲基-3-氧代孕-5,17-二烯-21-羧酸酯:其中R1=氢、支链或直链C1-C6烷基、苯基、苄基、邻、间或对—甲基苯基。
4、通式(1)的化合物在制备FF-MAS中的应用。
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