CN1286687A - 制备西酞普兰的方法 - Google Patents
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Abstract
公开了一种制备西酞普兰的方法,包括将式Ⅳ化合物(其中R1是H或C1-6烷基羰基)连续和4-卤代—氟苯基格利雅试剂及3-卤代-N,N-二甲基丙基胺格利雅试剂反应;得到的式Ⅵ化合物进行闭环反应并将所得的1,3-二氢异苯并呋喃化合物转化为相应的5-氰基衍生物,即西酞普兰。
Description
本发明涉及制备已知的抗抑郁药西酞普兰的方法和该方法所用的中间体。
发明背景
西酞普兰是众所周知的已经上市数年的抗抑郁药,具有下面的结构:它是一种选择性的,中枢活性血清素(5-羟基色胺;5-HT)再摄取抑制剂,因此具有抗抑郁活性。该化合物的抗抑郁活性已经报道在一些出版物上,如J.Hyttel,Prog.Neuro-Psychopharmacol.&Biol.Psychiat,1982,6,277-295和AGravem,Acta Psychiatr.Scand,1987,75,478-486,EP-A474580还进一步公开了该化合物在治疗痴呆和脑血管疾病方面显示出作用。
西酞普兰首次公开在和专利US4136193相应的DE2657271上,该专利只用一种方法描述了西酞普兰的制备,并且对可以用来制备西酞普兰的其它方法进行了概括性的描述。
按照所述的方法,在缩合剂二甲亚砜的存在下,将相应的1-(4-氟苯基)-1,3-二氢-5-异苯并呋喃腈与3-(N,N-二甲基)丙基氯反应;起始物是由相应的5-溴衍生物与氰化亚铜反应制备的。
起始物式Ⅱ是由5-溴-2-苯并[c]呋喃酮经过连续两次格利雅(Grignard)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而获得的。
美国专利US4650884公开了一种令人意想不到的制备西酞普兰的新方法和一种中间体。按照该方法,具有下式的中间体:通过与浓硫酸的脱水作用,进行闭环反应以得到西酞普兰。式Ⅲ中间体是由5-氰基-2-苯并[c]呋喃酮经过连续两次格利雅反应,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而获得的。
最后,美国专利US4943590公开了一种制备西酞普兰单一对映体的方法,该方法同样是式Ⅲ中间体闭环,可以经过一种不稳定的酯,使用碱进行。
现已出人意料地发现,可以使用方便易得的起始物,通过效果好而又安全的方法制备西酞普兰。
发明概要
因此,本发明涉及的制备西酞普兰的新方法包括步骤:a)将式Ⅳ化合物与4-卤代-氟苯基格利雅试剂反应;其中R1是H或C1-6烷基羰基;b)将得到的式Ⅴ化合物与3-卤代-N,N-二甲基丙基胺格利雅试剂反应;其中R1如上所定义;c)将得到的式Ⅵ化合物进行闭环反应;其中R1如上所定义;d)将得到的式Ⅶ化合物其中R1如上所定义,转化为相应的5-氰基衍生物,即西酞普兰,以碱或其药物上可接受盐的形式分离出来。
另一方面,本发明提供了新的式Ⅴ中间体。
另一方面,本发明还提供了新的式Ⅵ中间体。
另一方面,本发明还进一步提供了新的式Ⅶ中间体。
此外,本发明还涉及一种抗抑郁药物组合物,其中含有按照本发明方法制备的西酞普兰。
在本申请文件中,C1-6烷基指支链或非支链的具有一到六个碳原子的烷基,包括如甲基、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。
可以在步骤a)使用的4-卤代氟苯基格利雅试剂是其镁的卤化物,如氯化物溴化物和碘化物,优选使用镁的溴化物。司使用的3-卤代-N,N-二甲基丙基格利雅试剂是其镁的卤化物,如氯化物、溴化物和碘化物,优选使用镁的溴化物。优选这两个反应不经过中间产物的分离而连续进行。
式Ⅵ化合物的闭环作用可以通过酸进行,或者当R1是C1-6烷基羰基时,可选择经过不稳定的酯,使用碱进行。进行酸闭环反应使用无机酸(如硫酸或磷酸)或有机酸(如甲磺酸、对甲苯磺酸、或三氟乙酸);进行碱闭环反应是经过不稳定酯(如甲磺酰基、对甲苯磺酰基、10-樟脑磺酰基、三氟乙酰基或三氟甲基磺酰基酯),加入碱(如三乙胺、二甲基苯胺或吡啶)。碱性反应在惰性溶剂中进行,优选在冷却条件下进行,特别优选在大约0℃,并且优选采用一锅反应方法进行,即进行酯化反应和同时加入碱。
当R1为H时,将R1-NH-转化为氰基,优选通过重氮化反应,然后与CN-反应,最优选使用亚硝酸钠(NaNO2)和氰化亚铜(CuCN)和/或氰化钠(NaCN);当R1为C1-6烷基羰基时,首先进行水解,从而得到相应的R1为H的化合物,该化合物按上述方法转化。水解可以在酸性或碱性环境条件下进行。
本发明方法可以在有或没有分离中间体情况不进行。
本发明方法还以用于制备西酞普兰的(S)-对映异构体,在这种情况下,按照美国专利US4943590所述的类似方法,将式Ⅵ化合物分离为光学活性对映异构体,由此得到式Ⅵ化合物的(S)-对映异构体,用于步骤c)的闭环反应,因此,式Ⅵ和Ⅶ的单一对映异构体分别包含在其结构式中。
其它反应条件,溶剂等均为这种反应的常规条件,是本领域技术人员易于确定的。
R1为H的式Ⅳ起始物是市场上买得到的,并可以按照已知方法制备(Tirouflet,J.;Bull.Soc.Sci.Bretagne26,1959,35),R1为乙酰基的化合物可以从氨基化合物(R1为H)经过常规的酰化反应来制备。
在本发明的一个实施方案中,R1为C1-6烷基羰基,特别是甲基-、乙基-、丙基-或丁基羰基。
在本发明的另一个实施方案中,R1为H。
通式Ⅰ化合物可以游离碱或药物上可接受的酸加成盐的形式使用。所用的酸加成盐可以是与无机酸或有机酸形成的盐,成盐有机酸的例子是马来酸、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、乙烷二磺酸、乙酸、丙酸、酒石酸、水杨酸、柠檬酸、葡萄糖酸、乳酸、苹果酸、苦杏仁酸、肉桂酸、柠康酸、天冬氨酸、硬脂酸、棕榈酸、衣康酸、醛糖酸、对-氨基-苯甲酸、谷氨酸、苯磺酸和茶碱乙酸,以及8-卤代茶碱如8-溴茶碱乙酸。成盐无机酸的例子是盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸。
化合物的酸加成盐可按照本领域已知的方法进行制备,在与水互溶的溶剂(如丙酮或乙醇)中,将化合物和计量的酸反应,然后通过浓缩和冷却分离出盐;或者在与水不互溶的溶剂(如乙醚、乙酸乙酯或二氯甲烷)中,与过量的酸反应,自然分离出盐。
本发明的药物组合物可以按任何适当方式和任何适当形式给药,例如以片剂、胶囊、粉剂或糖浆口服给药,以常用的无菌注射液形式进行非肠胃给药。
本发明的药物制剂可以按本领域常规方法制备,例如制备片剂可以将活性成分与常用的佐剂和/或稀释剂混合,然后在常用的制片机上压制混合物。佐剂和稀释剂举例包括:玉米淀粉、土豆淀粉、滑石粉、硬脂酸镁、明胶、乳糖、树胶等,其它佐剂或添加剂着色剂、芳香剂、防腐剂等,只要它们与活性成分是相容的,均可以使用。
制备注射液,可以将活性成分和可用的添加剂溶解于部分注射用溶剂(优选无菌水)中,将溶液调节到所要求的体积,溶液灭菌处理后装入适当的安瓿或小瓶中。本领域常用的适当添加剂均可以加入,如紧张剂、防腐剂、抗氧化剂等。
实施例
通过以下实施例对本发明作进一步的阐述。
实施例14-二甲基氨基-1-(4-氨基-2-羟甲基苯基)-1-(4-氟苯基)丁-1-醇。
由4-氟溴苯(116g,0.66mol)和镁屑(20g,0.8mol)于无水THF(500ml)中制成4-氟苯基溴化镁溶液,将其滴加到5-氨基-2-苯并[c]呋喃酮(30g,0.2mol)于无水THF(500ml)的悬浮液中,温度保持在5℃以下,滴加完毕后,反应混合物在室温下搅拌0.5小时。
由3-二甲基氨基丙基氯(25g,0.2mol)和镁屑(6g,0.25mol)于无水THF(150ml)中制成第二种格利雅溶液,将其加入到反应混合物中,加入期间保持温度在5℃以下,继续搅拌0.5小时,然后停止并在环境温度下放置过夜。
将冰水(1000ml)和乙酸(60g)冲入反应混合物中,真空条件下蒸去THF,水相用乙酸乙酯(2×200ml)洗涤,加入氢氧化铵于水相,得到最终pH9;水相以乙酸乙酯(2×200ml)萃取,过滤有机相并用水(100ml)洗涤,真空蒸去溶剂,得到油状的标题化合物(38.8g,58%)。1HNMR(CDCl3,500MHz):1.45-1.55(1H,m),1.65-1.75(1H,m),2.2(6H,s),2.27(1H,m),2.33(2H,m),2.43(1H,m),3.6-3.7(2H,NH2),3.97(1H,d J=12.5Hz)4.25(1H,J=12.5Hz),6.58(1H,d,J=8Hz),6.62(1H,s),6.95(2H,t,J=8.5Hz),7.25(1H,d,J=8Hz),7.45(2H,dt,J=1.2Hz J=8.5Hz)。5-氨基-1-(3-二甲胺基丙基)-1-(4-氟苯基-1,3-二氢异苯并呋喃。
将粗制的4-二甲基氨基-1-(4-氨基-2-羟甲基苯基)-1-(4-氟苯基)丁-1-醇溶于磷酸(H3PO4)(60%,140g)并加热至80℃保持2小时,将反应混合物浇入冰水(1000ml)中,加入氢氧化铵(NH4OH),得到最终pH9;水相以乙酸乙酯(2×200ml)萃取,将合并的有机相过滤、用水(100ml)洗涤并干燥(硫酸镁(MgSO4),10g),真空蒸去溶剂,得到油状的标题化合物。1HNMR(CDCl3,250MHz):1.3-1.5(2H,m),2.05-2.3(10H,s+m),3.6-3.7(2H,NH2),5.0(1H,s),6.45(1H,d,J=1.8Hz),6.55(1H,dd,J=8Hz J=1.8Hz),6.95(2H,t,J=8.5Hz),7.05(1H,d,J=8Hz),7.45(2H,dt,J=1.2Hz J=8.5Hz).1-(3-二甲胺基丙基)-1-(4-氟苯基)-1,3-二氢异苯并呋喃-5-腈。
5-氨基-1-(3-二甲胺基丙基)-1-(4-氟苯基)-1,3-二氢异苯并呋喃(18g,0.06mol)溶于水(100ml)和硫酸(H2SO4)(8ml),将亚硝酸钠(NaNO2)(4.1g,0.05mol)溶于水(20ml)并在低于5℃下滴加其中,该重氮化溶液于0-5℃搅拌0.5小时,加入饱和碳酸钠(NaCO3)溶液调节pH至6.5,在50-60℃往该溶液中加入水(100ml)和甲苯(120ml)混合物,该混合物含有CuCN(6g,0.067mol)和NaCN(10g,0.2mol),继续搅拌0.5小时,分离两相,水相再用甲苯(100ml)萃取,合并的有机相以NaCN(10%水溶液,2×50ml)洗涤,真空除去溶剂,残留物用硅胶色谱分离(乙酸乙酯∶n-庚烷∶三乙胺;85∶10∶5)得到油状标题化合物(6g,32%)。1HNMR(CDCl3,250MHz):1.35(1H,m),1.45(1H,m),2.1(6H,s),2.15-2.25(4H,m),5.12(1H,d,J=12.5hz),5.18(1H,J=12.5Hz),7.00(2H,t,J=8.5Hz),7.4(2H,t,J=8.5Hz),7.45(1H,d,J=7.5Hz),7.5(1H,s),7.58(1H,d,J=7.5Hz).
实施例24-二甲基氨基-1-(4-乙酰基氨基-2-羟甲基苯基)-1-(4-氟苯基)丁-1-醇
由4-氟溴苯(11.6g,0.067mol)和镁屑(2g,0.08mol)于无水THF(50ml)中制成4-氟苯基溴化镁溶液,将其滴加到5-乙酰基氨基-2-苯并[c]呋喃酮(5g,0.03mol)于无水THF(50ml)的悬浮液中,温度保持在5℃以下,滴加完毕后,反应混合物与室温下搅拌0.5小时。
由3-二甲基氨基丙基氯(3.7g,0.03mol)和镁屑(0.87g,0.036mol)于无水THF(15ml)中制成第二种格利雅溶液,将其加入到反应混合物中,加入期间保持温度在5℃以下,继续搅拌0.5小时,然后停止并在环境温度下放置过夜。
用冰水(100ml)和乙酸(6g)冲中开反应混合物中,真空条件下蒸去THF,水相用乙酸乙酯(2×50ml)洗涤,加入氢氧化铵(NH4OH)于水相,得到最终pH9;水相以乙酸乙酯(2×50ml)萃取,过滤有机相并用水(50ml)洗涤,真空蒸去溶剂,得到油状的标题化合物(6.6g,63%)。1H NMR(DMSO-d6,500MHz):1.15-1.22(1H,m), 1.40-1.50(1H,m),2.02(9H,s+s),2.05(1H,m),2.13(2H,m),2.20(1H,m),3.95(1H,dJ=12.5Hz),4.48(1H,dJ=12.5Hz),7.05(2H,tJ=8.5Hz),7.14(2H,ddJ=8.5HzJ=1.2Hz),7.47(1H,dJ=8Hz),7.58(1H,s),7.64(1H,dJ=8.5Hz).
Claims (17)
2.权利要求1的方法,其中R1是H。
3.权利要求1的方法,其中R1是C1-6烷基羰基。
4.权利要求3的方法,其中C1-6烷基是甲基、乙基、丙基或丁基。
5.权利要求1-4的方法,其中所用的格利雅试剂是镁的卤化物,优选氯化物、溴化物或碘化物。
6.权利要求5的方法,其中步骤a)所用的格利雅试剂是溴化镁。
7.权利要求5的方法,其中步骤b)所用的格利雅剂是氯化镁。
8.权利要求1-7任一项的方法,其中式Ⅵ化合物的闭环是通过酸闭环反应进行,使用无机酸如硫酸或磷酸,或者使用有机酸如甲磺酸、对甲苯磺酸、或三氟乙酸。
9.权利要求3的方法,其中式Ⅵ化合物的闭环是经由不稳定的酯,通过碱闭环反应进行,优选同时进行酯化反应和加入碱。
10.权利要求9的方法,其中的不稳定酯为甲磺酰基、对甲苯磺酰基、10-樟脑磺酰基、三氟乙酰基或三氟甲基磺酰基酯,碱是三乙胺、二甲基苯胺或吡啶。
11.权利要求2的方法,其中R1-NH-基团转化为氰基,是通过重氮化反应,然后与CN-反应来进行的。
12.权利要求3的方法,其中R1-NH-基团转化为氰基,是将C1-6烷基羰基氨基,R1-NH-,水解为相应的R1为H的氨基,然后进行重氮化反应以及与CN-反应。
13.权利要求1-12任一项的方法,其特征在于:在用于步骤c)的闭环反应之前,将式Ⅵ化合物拆分为光学活性的对映异构体,而得到(S)-对映异构体。
17.一种抗抑郁药物组合物,其中含有按照权利要求1-13任一项方法制备的西酞普兰。
Priority Applications (21)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SK682-2000A SK283907B6 (sk) | 1997-11-11 | 1997-11-11 | Spôsob výroby citalopramu a medziprodukty |
DE1042310T DE1042310T1 (de) | 1997-11-11 | 1997-11-11 | Verfahren zur herstellung von citaloprame |
ES97945799T ES2149734T3 (es) | 1997-11-11 | 1997-11-11 | Metodo para la preparacion de citalopram. |
CZ20001736A CZ292911B6 (cs) | 1997-11-11 | 1997-11-11 | Způsob výroby citalopramu |
AT97945799T ATE221522T1 (de) | 1997-11-11 | 1997-11-11 | Verfahren zur herstellung von citalopram |
HU0002953A HUP0002953A3 (en) | 1997-11-11 | 1997-11-11 | Method for preparation of citalopram and intermediates used for them |
CA002291072A CA2291072C (en) | 1997-11-11 | 1997-11-11 | Method for the preparation of citalopram |
EA200000511A EA002770B1 (ru) | 1997-11-11 | 1997-11-11 | Способ получения циталопрама |
CN97182416A CN1286687A (zh) | 1997-11-11 | 1997-11-11 | 制备西酞普兰的方法 |
TR2000/01341T TR200001341T2 (tr) | 1997-11-11 | 1997-11-11 | Sitalopramın hazırlandığı metot |
EP97945799A EP1042310B1 (en) | 1997-11-11 | 1997-11-11 | Method for the preparation of citalopram |
DE69714480T DE69714480T2 (de) | 1997-11-11 | 1997-11-11 | Verfahren zur Herstellung von Citalopram |
AU51168/98A AU738359B2 (en) | 1997-11-11 | 1997-11-11 | Method for the preparation of citalopram |
JP2000583315A JP3813820B2 (ja) | 1997-11-11 | 1997-11-11 | シタロプラムの製造方法 |
UA2000052827A UA62984C2 (en) | 1997-11-11 | 1997-11-11 | A method for the preparation of citalopram |
BR9714925-0A BR9714925A (pt) | 1997-11-11 | 1997-11-11 | Método para preparação de citalopran, composto e composição farmacêutica antidepressiva |
PCT/DK1997/000513 WO1998019512A2 (en) | 1997-11-11 | 1997-11-11 | Method for the preparation of citalopram |
DK97945799T DK1042310T3 (da) | 1997-11-11 | 1997-11-11 | Fremgangsmåde til fremstilling af citalopram |
ZA9810058A ZA9810058B (en) | 1997-11-11 | 1998-11-03 | Method for the preparation of citalopram |
IS5461A IS2009B (is) | 1997-11-11 | 2000-04-18 | Aðferð til framleiðslu á sítalóprami |
US09/564,365 US6258842B1 (en) | 1997-11-11 | 2000-04-28 | Method for the preparation of citalopram |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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CN97182416A CN1286687A (zh) | 1997-11-11 | 1997-11-11 | 制备西酞普兰的方法 |
PCT/DK1997/000513 WO1998019512A2 (en) | 1997-11-11 | 1997-11-11 | Method for the preparation of citalopram |
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CN1286687A true CN1286687A (zh) | 2001-03-07 |
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CN97182416A Pending CN1286687A (zh) | 1997-11-11 | 1997-11-11 | 制备西酞普兰的方法 |
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US (1) | US6258842B1 (zh) |
EP (1) | EP1042310B1 (zh) |
JP (1) | JP3813820B2 (zh) |
CN (1) | CN1286687A (zh) |
AT (1) | ATE221522T1 (zh) |
AU (1) | AU738359B2 (zh) |
BR (1) | BR9714925A (zh) |
CA (1) | CA2291072C (zh) |
CZ (1) | CZ292911B6 (zh) |
DE (2) | DE1042310T1 (zh) |
DK (1) | DK1042310T3 (zh) |
EA (1) | EA002770B1 (zh) |
ES (1) | ES2149734T3 (zh) |
HU (1) | HUP0002953A3 (zh) |
IS (1) | IS2009B (zh) |
SK (1) | SK283907B6 (zh) |
TR (1) | TR200001341T2 (zh) |
UA (1) | UA62984C2 (zh) |
WO (1) | WO1998019512A2 (zh) |
ZA (1) | ZA9810058B (zh) |
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CN100391952C (zh) * | 2005-07-12 | 2008-06-04 | 广东西陇化工有限公司 | 西酞普兰盐的制备方法 |
CN106748627A (zh) * | 2016-11-14 | 2017-05-31 | 苏州市罗森助剂有限公司 | 一种一锅法制备3,5‑二甲基溴苯的方法 |
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- 1997-11-11 ES ES97945799T patent/ES2149734T3/es not_active Expired - Lifetime
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- 1997-11-11 EP EP97945799A patent/EP1042310B1/en not_active Expired - Lifetime
- 1997-11-11 WO PCT/DK1997/000513 patent/WO1998019512A2/en active IP Right Grant
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1311819C (zh) * | 2001-07-31 | 2007-04-25 | H·隆德贝克有限公司 | 含有依他普仑的晶体组合物 |
CN100391952C (zh) * | 2005-07-12 | 2008-06-04 | 广东西陇化工有限公司 | 西酞普兰盐的制备方法 |
CN106748627A (zh) * | 2016-11-14 | 2017-05-31 | 苏州市罗森助剂有限公司 | 一种一锅法制备3,5‑二甲基溴苯的方法 |
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IS5461A (is) | 2000-04-18 |
EA002770B1 (ru) | 2002-08-29 |
AU5116898A (en) | 1998-05-29 |
ATE221522T1 (de) | 2002-08-15 |
ES2149734T3 (es) | 2003-02-16 |
DE1042310T1 (de) | 2001-04-19 |
EP1042310B1 (en) | 2002-07-31 |
DK1042310T3 (da) | 2002-12-02 |
SK283907B6 (sk) | 2004-04-06 |
ES2149734T1 (es) | 2000-11-16 |
WO1998019512A2 (en) | 1998-05-14 |
CA2291072A1 (en) | 1998-05-14 |
WO1998019512A3 (en) | 1998-08-13 |
CZ20001736A3 (cs) | 2000-10-11 |
CZ292911B6 (cs) | 2004-01-14 |
JP3813820B2 (ja) | 2006-08-23 |
ZA9810058B (en) | 1999-05-05 |
UA62984C2 (en) | 2004-01-15 |
TR200001341T2 (tr) | 2000-11-21 |
DE69714480D1 (de) | 2002-09-05 |
EP1042310A2 (en) | 2000-10-11 |
US6258842B1 (en) | 2001-07-10 |
HUP0002953A2 (hu) | 2001-04-28 |
SK6822000A3 (en) | 2000-10-09 |
IS2009B (is) | 2005-05-13 |
EA200000511A1 (ru) | 2000-10-30 |
AU738359B2 (en) | 2001-09-13 |
JP2002530295A (ja) | 2002-09-17 |
DE69714480T2 (de) | 2003-03-06 |
CA2291072C (en) | 2002-08-20 |
BR9714925A (pt) | 2003-07-22 |
HUP0002953A3 (en) | 2002-12-28 |
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