CN1359382A - 制备西酞普兰的方法 - Google Patents
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Abstract
一种制备西酞普兰的方法,该方法包括式(IV)化合物的还原水解和将得到的5-甲酰基化合物转化成西酞普兰,式(IV)中R为N,N-二取代的酰胺基或任选取代的4,5-二氢-1,3-噁唑-2-基。
Description
本发明涉及制备众所周知的抗抑郁药西酞普兰,1-[3-(二甲基氨基)丙基]-1-(4-氟苯基)-1,3-二氢-5-异苯并呋喃腈的方法。
发明背景
西酞普兰是众所周知的抗抑郁药,该药在市场上已销售多年,其结构为:式I
西酞普兰是选择性的、中枢作用性血清素(5-羟色胺;5-HT)再吸收抑制剂,因此具有抗抑郁活性。该化合物的抗抑郁活性已在几种出版物上有报导,例如J.Hyttel,Prog.Neuro-Psychopharmacol.& Biol.Psychiat.,1982,6,277-295和A.Gravem.Acta Psychiatr.Scand.,1987,75,478-486。EP-A 474580还进一步公开了该化合物表现出在治疗痴呆和脑血管疾病方面的作用。
西酞普兰首先公开于与US 4,136,193相应的DE 2,657,271中。该专利说明书描述了通过一种方法制备西酞普兰并概括可用于制备西酞普兰的另一种方法。
按照描述的方法,相应的1-(4-氟苯基)-1,3-二氢-5-异苯并呋喃腈与3-(N,N-二甲基氨基)丙基氯在甲基亚硫酰基甲基化物作为缩合剂存在下反应。原料由相应的5-溴衍生物与氰化亚铜反应制备。
按照这一仅用通称术语概括的方法,西酞普兰可通过化合物式II在脱水剂存在下闭环,然后用氰化亚铜置换5-溴基团得到。式II的原料由5-溴-2-苯并[c]呋喃酮经两步连续格氏反应,即分别与4-氟苯基氯化镁和N,N-二甲基氨基丙基氯化镁反应得到。
在美国专利4,650,884中描述了一种用于制备西酞普兰的新的、令人惊奇的方法和中间体。据此式式III的中间体与浓硫酸经过脱水发生环合反应以生成西酞普兰。式III的中间体由5-氰基-2-苯并[c]呋喃酮经两步连续格氏反应,即分别与4-氟苯基卤化镁和N,N-二甲基氨基丙基卤化镁反应得到。
其它方法公开于国际专利申请WO 98019511、WO 98019512和WO98019513中。WO 98019512和WO 98019513涉及方法,其中5-氨基-,5-羧基-或5-(仲-氨基羰基)-2-苯并[c]呋喃酮经两步连续格氏反应、环合并将得到的1,3-二氢异苯并呋喃衍生物转化为相应的5-氰基化合物,即西酞普兰。国际专利申请WO 98019511公开了一种制备西酞普兰的方法,其中(4-取代的-2-羟基甲基苯基-(4-氟苯基)甲醇化合物经环合并且将得到的5-取代的1-(4-氟苯基)-1,3-二氢异苯并呋喃转化为相应的5-氰基衍生物,该衍生物用(3-二甲基氨基)丙基卤进行烷基化得到西酞普兰。
最后,制备西酞普兰的单一对映体的方法公开于美国专利4,943,590,其中也显示式III中间体的环合可通过不稳定的酯与碱完成。
现在,令人惊奇的发现西酞普兰可通过一种新的、有利的且安全的方法用方便的原料制备。
发明概述因此,本发明涉及制备西酞普兰的新方法,它包括下列步骤:a)式IV化合物经还原水解式IV其中R为·基团
,其中R1和R2独立选自低级烷基、芳基和杂芳基,或R1和R2相连并共同表示4-或5-元链,该链任选包含一个S、O或N原子,或·在4-和/或5-位被一个或多个低级烷基、芳基或杂芳基任意取代的4,5-二氢-1,3-噁唑-2-基,和b)将得到的式V的5-甲酰基化合物式V转化成相应的5-氰基化合物,即西酞普兰式I该化合物被作为碱或其可药用盐分离出来。
另一方面,本发明提供新的式V中间体。
本发明还涉及用于制备西酞普兰的具有式IV的新中间体。
本发明的再一方面涉及上述方法,其中的式IV化合物是S-对映体。
另一方面,本发明涉及一种抗抑郁药物组合物,其中包含由本发明方法制备的西酞普兰。
贯穿说明书和权利要求,低级烷基是指含有1-6碳原子的支链的或直链的烷基,包括例如甲基,乙基,1-丙基,2丙基,1-丁基,2-丁基,2-甲基-2-丙基,2,2-二甲基-1-乙基和2-甲基-1-丙基。
术语芳基是指单-或双环碳环芳香基,如苯基和萘基,尤其是苯基。
术语杂芳基是指单-或双环杂环芳香基,如吲哚基,噻吩基,嘧啶基,噁唑基,异噁唑基,噻唑基,异噻唑基,咪唑基,苯并呋喃基,苯并噻吩基,吡啶基,和呋喃基,尤其是嘧啶基,吲哚基,和噻吩基。
卤素是指氟,氯,溴或碘。
还原水解是指基团R还原之后用H2O处理,因此形成醛基。
当R1和R2相连且共同表示4-或5-元链时,该链任选包含一个S、O或N原子,R1和R2跟与之相连的N-原子共同形成5-或6-元环,除与R1和R2相连的N-原子外,该环任选包含一个选自O、S和N的杂原子。这些基团的实例是吗啉基、哌啶基等。
在本发明的一个优选的实施方案中,R是吗啉代羰基,二(低级烷基)氨基羰基或4,4-二(低级烷基)-1,3-噁唑烷-2-基,最优选为吗啉代羰基,二甲基氨基羰基或4,4-二甲基-1,3-噁唑烷-2-基。
优选VI化合物是由相应的5-R-取代的2-苯并[c]呋喃酮衍生物经两步连续格氏反应,即分别与4-卤-氟苯基格氏试剂和3-卤-N,N-二甲基-丙胺格氏试剂反应得到。当R是任选取代的4,5-二氢-1,3-噁唑-2-基时,式VI化合物也可由4-二甲基氨基-1-(4-氟苯基)-丁-1-酮与适当保护的2-(羟基甲基)-4-(4,5-二氢-1,3-噁唑-2-基)-苯基卤化镁衍生物发生格氏反应制得。
式IV化合物的还原水解通过用合适的还原剂如含铝或硼的试剂,合适的是Dibal-H、超氢化物(superhydride)、LiAlH4,BH4 -(Li+、Na+或K+)等对式IV化合物进行还原,随后加入H2O。当R为4,5-二氢-1,3-噁唑-2-基时,该反应可通过用适当的烷基化试剂,如MeI、硫酸二烷基酯等烷基化进行,然后如上进行还原和水解。在所有情况下,还原是在严格控制的条件下进行,优选在约0℃。
式V的5-甲酰基化合物到西酞普兰的转化是通过下列进行的:与试剂R3-X-NH2反应,其中R3为氢、低级烷基,芳基或杂芳基且X是O、N或S,将甲酰基转化为肟或类似基团,然后用常规的脱水试剂,例如二甲亚砜、乙酐/吡啶、吡啶/盐酸或五氯化磷进行脱水。优选的试剂R3-X-NH2是羟胺和其中R3是烷基或芳基且X是N或O的化合物。
式VI化合物的环合可通过酸作用或不稳定的酯和碱反应进行。酸性环合是通过无机酸,如硫酸或磷酸,或有机酸,如甲磺酸、对-甲苯磺酸或三氟乙酸进行的。碱性环合是通过向不稳定的酯,如甲烷磺酰基、对-甲苯磺酰基、10-樟脑磺酰基、三氟乙酰基或三氟甲磺酰基酯中加入碱,如三乙胺、二甲基苯胺、吡啶等进行的。该反应在惰性溶剂中进行,优选在冷却下进行,特别是在约0℃进行并且优选通过“一锅煮”进行,即酯化并同时加入碱。在进一步反应之前式VI中间体可被分离为它的对映体,因此得到能够获得S-西酞普兰的对映体。
用于制备式VI化合物的4-卤-氟苯基的格氏试剂是卤化镁格氏试剂,如氯化镁,溴化镁或碘化镁,优选使用溴化镁格氏试剂。可被应用的3-卤-N,N-二甲基丙基胺的格氏试剂是卤化镁,如氯化物,溴化物或碘化物,优选使用氯化镁格氏试剂。优选两个反应连续进行而不分离中间体。
其它的反应条件、溶剂等是该类反应的常规条件并由本领域的技术人员容易地确定。
用于格氏反应的原料5-R-取代的2-苯并[c]呋喃酮可由5-氯羰基-2-苯并[c]呋喃酮与合适的胺化合物反应制得。
5-氯羰基-2-苯并[c]呋喃酮又可由5-羧基-2-苯并[c]呋喃酮(phtalide)与亚硫酰氯反应而制得。5-羧基-2-苯并[c]呋喃酮可以商购并可用众所周知的方法制得(Tirouflet,J.;Bull.Soc.Sci.Bretagne 26,1959,35)。
通式I化合物可被用作游离碱或其可药用酸加成盐。酸加成盐,如与有机或无机酸形成的酸加成盐可被应用。典型的有机盐是那些与马来酸、富马酸、苯甲酸、抗坏血酸、琥珀酸、草酸、双亚甲基水杨酸、甲磺酸、乙二磺酸、乙酸、丙酸、酒石酸、水杨酸、柠檬酸、葡糖酸、乳酸、苹果酸、扁桃酸、肉桂酸、柠康酸、天冬氨酸、硬脂酸、棕榈酸、衣康酸、乙醇酸(glycolic)、对氨基苯甲酸、谷氨酸、苯磺酸和茶碱乙酸,以及8-卤茶碱,例如8-溴茶碱形成的盐。典型的无机盐是那些与盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸形成的盐。
化合物的酸加成盐可用本领域已知的方法制得。碱与计算量的酸在与水混溶的溶剂如丙酮或乙醇中反应,随后通过浓缩或冷却分离盐,或与过量的酸在与水不混溶的溶剂如乙醚、乙酸乙酯或二氯甲烷中反应,同时分离盐。
本发明药物组合物可以任何适当的方式和任何适当的剂型给药,例如口服片剂、胶囊、粉末剂或糖浆,或非肠道注射用普通无菌溶液。
本发明的药物制剂可通过本领域的常规方法制备。例如,片剂可通过活性成分与普通辅料和/或稀释剂混合,然后在常规压片机中压制混合物而成。辅料和或稀释剂的实例包括:玉米淀粉、土豆淀粉、滑石、硬脂酸镁、明胶、乳糖、树胶等。只要与活性成分相容,可应用任何其它辅料或添加色料、香味剂、防腐剂等。
注射液可按如下制备:将活性成分和可能的添加剂溶于部分注射溶剂,优选无菌水中,将溶液调至预定体积、溶液灭菌并装填到合适的安瓿或小瓶中。
可加入任何合适的在本领域中常用的添加剂,例如增强剂(tonicity agents)、防腐剂、抗氧剂等。
实施例用下列实施例进一步说明本发明。实施例15-(4-吗啉基羰基)-2-苯并[c]呋喃酮
在0℃下,将5-氯羰基-2-苯并-[c]呋喃酮(39g,0.2mole)的THF(400ml)溶液加到吗啉(22g,0.25mole)和三乙胺(26g,0.25mole)的THF(200ml)溶液中。搅拌混合物1小时并温至室温。然后将反应混合物倒入冰水(500ml)中,在真空下蒸出THF并将溶液的pH调至pH=2。将溶液冷至5℃,滤出沉淀的结晶并用水(100ml)洗涤。产量:38.0g,78%。DSC起始点(onset):83℃和107℃,纯度:99.6%(hplc,峰面积)。1H NMR(DMSO-d6,250MHz):3.2-3.7(8H,m),5.45(2H,s),7.60(1H,d,J=7.5Hz),7.72(1H,s),7.92(1H,d,J=7.5Hz)。13C NMR(DMSO-d6,62.9MHz):42.1,47.7,66.1,70.0,121.6,125.3,125.7,127.7,141.2,147.7,168.0,170.1。对C13H13O4N1的分析计算值:C:63.15,H:5.30,N:5.66。实测值C:62.94,H:5.52,N:5.53。
实施例25-(N,N-二甲基氨基甲酰基)-2-苯并-[c]呋喃酮
将5-氯羰基-2-苯并-[c]呋喃酮(32g,0.16mole)的THF(300ml)溶液加到二甲胺(40%v/v水溶液,300ml)和冰(100g)中,搅拌混合物1小时。在真空下蒸出THF,在5℃下滤出沉淀的结晶并用水(100ml)洗涤。
产量:30.0g,90%。DSC起始点:154℃,1H NMR(DMSO-d6,250MHz):2.9(3H,s),3.03(3H,s),5.45(2H,s),7.57(1H,d,J=7.5Hz),7.70(1H,s),7.90(1H,d,J=7.5Hz)。13C NMR(DMSO-d6,62.9MHz):34.7,40.0,70.0,121.4,125.1,125.5,127.6,142.1,147.6,169.0,170.1。对C11H11O3N1的分析计算值C:64.38,H:5.40,N:6.83。实测值C:64.17,H:5.44,N:6.61。
实施例35-(1-羟基-2-甲基丙-2-基)氨基甲酰基-2-苯并-[c]呋喃酮
方法A):在0℃下,将5-氯羰基-2-苯并-[c]呋喃酮(39g,0.2mole)的THF(400ml)溶液加到2-氨基-2-甲基丙-1-醇(22.3g,0.25mole)和三乙胺(26g,0.25mole)的THF(200ml)溶液中,搅拌混合物1小时并温至室温,然后将反应混合物倒入冰水(500ml)中,在真空下蒸出THF并将溶液的pH调至pH=2。将溶液冷至5℃并放置过夜。过滤沉淀的结晶并用冷水(100ml)洗涤。
产量:34.0g,68%。DSC起始点:165℃。纯度:99.7%(hplc,峰面积)。1H NMR(DMSO-d6,250MHz):1.33(6H,s),3.54(2H,s),5.47(2H,s),7.84(1H,s),7.90(1H,d,J=7.5Hz),7.97(1H,d,J=7.5Hz),8.03(1H,s)。13C NMR(DMSO-d6,62.9MHz):23.6,55.4,67.2,70.1,122.1,124.8,126.7,128.3,141.2,147.3,165.8,170.2。对C13H15O4N1的分析计算值:C:62.64,H:6.07,N:5.62。实测值C:62.37,H:6.13,N:5.53。
方法B):将5-乙氧基羰基-2-苯并-[c]呋喃酮(82g,0.4mole)加到2-氨基-2甲基丙-1-醇(44.6g,0.5mole)的甲苯(100ml)溶液中,加热混合物回流24小时。冷却后过滤出标题化合物并用热甲苯重结晶。
产量:85.0g,85%。纯度:95.0%(hplc,峰面积)。
实施例45-(4-吗啉基羰基)-1-(3-二甲基氨基丙基)-1-(4-氟苯基)-1,3-二氢异苯并呋喃,草酸盐
将由4-氟溴苯(31g,0.17mole)和镁屑(6g,0.24mole)在无水THF(100ml)中制得的4-氟苯基溴化镁溶液滴加到5-(4-吗啉基羰基)-2-苯并-[c]呋喃酮(36g,0.15mole)的无水THF(150ml)的悬浮液中。温度保持在5℃以下。滴完后在室温下搅拌反应混合物1.5小时。
向该反应混合物中加入由3-二甲基氨基丙基氯(22.3g,0.17mole)和镁屑(6g,0.24mole)在无水THF(150ml)中制得的第二格氏溶液,滴加过程中保持温度在10℃以下。在室温下搅拌反应过夜。
将反应混合物倒入冰水(300ml)和饱和氯化铵溶液(100ml)中,在真空下蒸出THF。加入二氯甲烷(300ml)并分出有机相,用水(2×100ml)和盐水(50ml)洗涤。有机相用2M HCl(2×100ml)萃取。向水相中加入4M NaOH(100ml)达到最终pH为9或更高。水层用DCM(400ml)萃取,有机相用水(100ml),盐水(50ml)洗涤并用MgSO4(20g)干燥。
向有机相中加入三乙胺(20g,0.2mole)并将溶液冷至5℃,滴加甲烷磺酰氯(12g,0.11mole)的DCM(100ml),加完后搅拌反应混合物1小时。用0.1M NaOH(2×100ml)洗涤反应混合物,有机相经干燥(MgSO4,10g)并在真空下蒸发溶剂。将如此得到的物质溶于丙酮(100ml)中并用溶于丙酮(100ml)的无水草酸(13.5g,0.15mole)处理。将混合物在室温下放置过夜并过滤出沉淀的草酸盐得到。
产量:19g,26%。DSC起始点166℃。1H NMR(DMSO-d6,250MHz):1.35-1.63(2H,m),2.20(2H,t,J=10Hz),2.64(6H,s),2.97(2H,t,J=10Hz),3.3-3.7(8H,m),5.13(1H,d,J=12.5Hz),5.23(1H,d,J=12.5Hz),7.15(2H,t,J=8.5Hz),7.32(2H,s+d,J=1.2Hz),7.52-7.65(3H,t+d,J=8.5Hz,J=1.2Hz)。对C24H29N1F1O3·1.1C2H2O4的分析计算值:C:61.52,H:6.15,N:5.48。实测值C:61.53,H:6.22,N:5.40。
实施例55-(N,N-二甲基氨基甲酰基)-1-(3-二甲基氨基丙基)-1-(4-氟苯基)-1,3-二氢异苯并呋喃,草酸盐
将由4-氟溴苯(16.5g,0.09mole)和镁屑(3g,0.12mole)在无水THF(50ml)中制得的4-氟苯基溴化镁溶液滴加到5-N,N-二甲基氨基甲酰基-2-苯并-[c]呋喃酮(16.5g,0.08mole)的无水THF(50ml)的悬浮液中,保持温度在5℃以下。加完后在室温下搅拌反应混合物1.5小时。
将由3-二甲基氨基丙基氯(12g,0.09mole)和镁屑(3g,0.12mole)在无水THF(50ml)中制得的第二格氏溶液加到反应混合物中,并在滴加过程中保持温度在10℃以下。在室温下搅拌反应2小时。
将反应混合物倒入冰水(100ml)和饱和的氯化铵溶液(50ml)中,在真空下蒸出THF。加入二氯甲烷(100ml)并分出有机相,用水(2×50ml)和盐水(50ml)洗涤,有机相用2M HCl(2×100ml)萃取。向水相加入4M NaOH(100ml)达到pH9或更高。水层用二氯甲烷(200ml)萃取,用水(50ml)、盐水(50ml)洗涤有机相并用MgSO4(20g)干燥。在真空下蒸出二氯甲烷。向如此得到的物质中加入DCM(250ml)和三乙胺(20g,0.2mole),将溶液冷至5℃,滴加甲烷磺酰氯(18g,0.16mole),加完后搅拌反应混合物1小时。用0.1M NaOH(2×100ml)洗涤反应混合物,干燥(MgSO4,10g)有机相并在真空下蒸发溶剂。产量:16.5g,69%。1H NMR(DMSO-d6,250MHz):1.35-1.58(2H,m),2.23(2H,t,J=8Hz),2.50(6H,s),2.83(2H,t,J=8Hz),2.89(3H,s),2.97(3H,s),5.13(1H,d,J=12.5Hz),5.21(1H,d,J=12.5Hz),7.17(2H,t,J=8.5Hz),7.30-7.38(2H,s+d,J=7.5Hz),7.54-7.66(3H,dd+d,J=8.5Hz,J=6Hz,J=7.5Hz)。草酸盐从丙酮中沉淀出。
实施例65-甲酰基-1-(3-二甲基氨基丙基)-1-(4-氟苯基)-1,3-二氢异苯并呋喃
将实施例4的酰胺(0.025mole)溶于甲苯(100ml)中,将溶液冷至0℃并保持在0℃下滴加Dibal-H(30ml,1M的甲苯溶液,0.03mole)。撤去冷却装置并再搅拌溶液2小时。小心加入冰水(5g)并搅拌30min。加入K2CO3(20g)并继续搅拌10分钟。过滤悬浮液,用水洗涤(30ml)有机相。在真空下蒸出甲苯,剩下透明油状标题化合物(游离碱状态)。
产量:7g,88%。
从丙酮中得到草酸盐,DSC起始点:128℃。1H NMR(DMSO-d6,250MHz):1.35-1.65(2H,m),2.24(2H,t,J=8Hz),2.66(6H,s),3.02(2H,t,J=8Hz),5.18(1H,d,J=13Hz),5.28(1H,d,J=13Hz),7.17(2H,t,J=8.5Hz),7.60(2H,dd,J=8.5HzJ=6Hz),7.75(1H,d,J=7.5Hz),7.82(1H,s),7.88(1H,d,J=7.5Hz)。对C20H22N1F1O2·1.2C2H2O4的分析计算值:C:61.79,H:5.65,N:3.22。实测值C:61.62,H:5.86,N:3.45。
实施例75-甲酰基-1-(3-二甲基氨基丙基)-1-(4-氟苯基)-1,3-二氢异苯并呋喃肟
将5-甲酰基-1-(3-二甲基氨基丙基)-1-(4-氟苯基)-1,3-二氢异苯并呋喃(33g,0.1mole)溶于EtOH(150ml)中,加入盐酸羟胺(14g,0.2mole)的水(150ml)溶液并用NaOH(28%aq)将pH调至pH=10。搅拌混合物14小时。在真空下除去EtOH并加入EtOAc(200ml)和水(100ml),将两相分开,蒸出有机相中的溶剂得到油状的肟。产量:33g,96%。1H NMR(DMSO-d6,250MHz):1.15-1.43(2H,m),2.02(6H,s),2.15(4H,t+t,J=7Hz),5.10(1H,d,J=12.5Hz),5.18(1H,d,J=12.5Hz),7.10-7.30(4H,m),7.50-7.63(3H,m),8.19(1H,s),11.34(1H,s)。
从丙酮中结晶出标题化合物的草酸盐,DSC:熔融下反应(reaction onset)。1H NMR(DMSO-d6,250MHz):1.36-1.63(2H,m),2.20(2H,t,J=8Hz),2.65(6H,s),3.00(2H,t,J=8Hz),5.11(1H,d,J=12.5Hz),5.21(1H,d,J=12.5Hz),7.16(2H,t,J=8.5Hz),7.45-7.63(5H,m),8.15(1H,s)9.35-10.05(2H,宽峰)。对C20H23N2O2F1·1.05C2H2O4的分析计算值:C:60.75,H:5.79,N:6.41。实测值C:60.55,H:6.06,N:5.93。
实施例81-(3-二甲基氨基丙基)-1-(4-氟苯基)-1,3-二氢异苯并呋喃-5-腈及其草酸盐
方法A):将5-甲酰基-1-(3-二甲基氨基丙基)-1-(4-氟苯基)-1,3-二氢异苯并呋喃肟或草酸盐(12g)溶于乙酐(20ml)和吡啶(80ml)中,加热该溶液回流2小时。在真空下蒸出挥发性物质,剩余物用甲苯(2×100ml)共沸蒸馏。将如此得到的物质溶于丙酮中并加入草酸(5g)。该溶液于0℃下放置14小时,过滤得到标题化合物的草酸氢盐。产量:9.6g,66%。DSC起始点:155℃。
方法B):将5-甲酰基-1-(3-二甲基氨基丙基)-1-(4-氟苯基)-1,3-二氢异苯并呋喃肟,草酸盐(1.0g)悬浮于甲苯(10ml)中,加入SOCl2(2ml)并在回流温度下加热混合物15分钟。在真空下蒸发挥发性溶剂剩下油状物,用甲苯(10ml)处理该油状物并用2N NaOH(5ml,aq)和水(5ml)洗涤。蒸发甲苯相剩下油状标题化合物(游离碱)。产量=0.62g,83%,纯度:>98.0%(hplc,峰面积)。
Claims (19)
2.权利要求1的方法,其中式V的5-甲酰基化合物到西酞普兰的转化是通过与试剂R3-X-NH2反应,其中的R3为氢、低级烷基、芳基或杂芳基并且X为O、N或S,然后通过用脱水剂脱水将甲酰基转化完成的。
4.权利要求3的方法,其中R1和R2是低级烷基或R1和R2相连并共同代表4-或5-元链,该链任选包含S、O或N原子。
5.权利要求4的方法,其中R1和R2都为甲基或R1和R2和与之相连的N原子一起形成吗啉基。
6.权利要求1或2的方法,其中R是任选取代的4,5-二氢-1,3-噁唑-2-基。
7.权利要求6的方法,其中R是4,5-二氢-4,4-二甲基-1,3-噁唑-2-基。
8.权利要求1-7的任一项方法,其特征是式IV的中间体是由相应的式VI化合物环合制备的:式VI
其中R如权利要求1所定义。
9.权利要求8的方法,其特征是式VI化合物是由相应的5-取代的2-苯并[c]呋喃酮衍生物通过两步连续的格氏反应,即分别与4-卤-氟苯基格氏试剂和3-卤-N,N-二甲基-丙胺格氏试剂反应得到的。
10.权利要求6和8的方法,其特征是式VI化合物由4-二甲基氨基-1-(4-氟苯基)-丁-1-酮与适当保护的2-(羟基甲基)-4-(1,3-噁唑-2-基)-苯基卤化镁衍生物通过格氏反应制备的。
11.权利要求8-10的方法,其中式VI化合物的环合是通过由无机酸,例如硫酸或磷酸,或有机酸,例如甲磺酸、对-甲苯磺酸或三氟乙酸的酸性环合实施的。
12.权利要求8-10的方法,其中式VI化合物的环合是经过不稳定的酯优选同时酯化和加入碱通过碱性环合进行的。
13.权利要求12的方法,其中的不稳定酯是甲烷磺酰基酯、对-甲苯磺酰基酯、10-樟脑磺酰基酯、三氟乙酰基酯或三氟甲烷磺酰基酯并且碱是三乙胺、二甲基苯胺或吡啶。
14.权利要求11-13的方法,其中在进一步反应之前将式VI中间体分离成其对映体,因此得到生成S-西酞普兰的对映体。
17.一种抗抑郁药物组合物,它包含按权利要求1-14任一项的方法制备的西酞普兰。
18.权利要求15的中间体用于制备西酞普兰的用途。
19.权利要求16的中间体用于制备西酞普兰的用途。
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Cited By (3)
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CN111533662A (zh) * | 2020-04-07 | 2020-08-14 | 福建海西新药创制有限公司 | 一种西酞普兰中间体的合成方法 |
CN111533662B (zh) * | 2020-04-07 | 2022-08-23 | 福建海西新药创制有限公司 | 一种西酞普兰中间体的合成方法 |
WO2022152078A1 (zh) * | 2021-01-14 | 2022-07-21 | 浙江华海药业股份有限公司 | 一种西酞普兰或s-西酞普兰的纯化方法 |
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