CN1356993A - 西酞普兰的制备方法 - Google Patents

西酞普兰的制备方法 Download PDF

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CN1356993A
CN1356993A CN99816768A CN99816768A CN1356993A CN 1356993 A CN1356993 A CN 1356993A CN 99816768 A CN99816768 A CN 99816768A CN 99816768 A CN99816768 A CN 99816768A CN 1356993 A CN1356993 A CN 1356993A
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H·彼得森
M·H·罗克
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Abstract

一种制备西酞普兰的方法,它包括使其中R为含氰化物来源的Cl或Br的式(IV)化合物在镍催化剂存在下的反应及相应的5－氰基化合物即西酞普兰的分离。

Description

西酞普兰的制备方法
本发明涉及熟知的抗抑郁药西酞普兰，1-[3-(二甲氨基)丙基]-1-(4-氟苯基)-1，3-二氢-5-异苯并呋喃腈(isobenzofurancarbonitrili)的制备方法。
                    本发明的背景
西酞普兰是一种上市多年的熟知的抗抑郁药，其结构如下：
Figure A9981676800041
它是一种选择性的、中枢作用的5-羟色胺(5-羟基色胺；5-HT)再摄取抑制剂，并因而具有抗抑郁活性。该化合物的抗抑郁活性报道于一些出版物中，如，J.Hyttel，Prog的Neuro-Psychopharmacol.&Biol.Psychiat.，1982，6，277-295和A.Gravem的Acta Psychiatr.Scand.，1987，75，478-486。EP-A474580中进一步公开该化合物在治疗痴呆和脑血管疾病所显示的作用。
西酞普兰第一次公开于与US4,136,193同时待审的DE2,657,271中。该专利出版物描述了西酞普兰的一种制备方法，并概述了也可用于西酞普兰制备的另一方法。
根据所述的该方法，相应的1-(4-氟苯基)-1，3-二氢-5-异苯并呋喃腈在作为缩合剂的甲基亚磺酰甲基化物(methylsulfinylmethide)的存在下与3-(N，N-二甲氨基)丙基-氯反应。通过相应的5-溴衍生物与氰化亚铜的反应制备初始原料。
根据只是概括性地描述的该方法，西酞普兰可在脱水剂存在下通过化合物
Figure A9981676800051
的闭环作用，且接着经氰化亚铜用氰基替换5-溴基的情况下获得。用5-溴代2-苯并[c]呋喃酮经两步连续的格利雅反应，即分别与氯化4-氟苯基镁和氯化N，N-二甲氨基丙基镁反应来制备式II的初始原料。
美国专利第4,650,884号描述了一种新的令人惊奇的制备西酞普
Figure A9981676800052
兰的方法和中间体，根据该方法，使下式的中间体
                       式III经历由浓硫酸脱水所致的闭环反应以获得西酞普兰。通过两步连续的格利雅反应，即，由5-氰基2-苯并[c]呋喃酮分别与卤化4-氟苯基镁和卤化N，N-二甲氨基丙基镁反应制备式III中间体。
其它方法公开于国际专利申请号WO 98019511、WO 98019512和WO 98019513中。WO 98019512和WO 98019513涉及到一些方法，其中的5-氨基-、5-羧基-或5-(仲氨基羰基)2-苯并[c]呋喃酮经两步连续的格利雅反应，闭环并将生成的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。国际专利申请号WO98019511公开了一种制备西酞普兰的方法，其中的(4-取代的-2羟甲基苯基-(4-氟苯基)甲醇化合物发生闭环作用，而将生成的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，它经(3-二甲氨基)丙基卤化物烷基化以得到西酞普兰。
最后，制备西酞普兰单一对映体的方法公开于美国专利第4,943,590号，其中也表明可用碱经由不稳定的酯进行式III中间物的闭环反应。
就制备西酞普兰的上述方法而言，包括以氰基替换5-溴基的方法在大规模生产中被证明不是很方便，因为其得率颇低、产物不纯，特别是难于从相应的5-溴代化合物中分离出生成的西酞普兰。
已发现用新的催化方法来获得高得率的、纯度极高的西酞普兰产物，其中的5-氰基替换1-[3-(二甲氨基)丙基]-1-(4-氟苯基)-1，3-二氢-异苯并呋喃中的5-溴基或5-氯基，从而避免的老氰化物替换的老方法中的大量后处理。
                      本发明概述
因此，本发明涉及到一种制备西酞普兰的新方法，它包括使式IV化合物
Figure A9981676800071
，其中R为Cl或Br，与氰化物源如KCN、NaCN或(R’4N)CN在镍催化剂存在下反应，其中R’4指四个可以是相同或不同的且选自氢、直链或支链C1-6烷基的基团，并分离出相应的5-氰基化合物，即为碱的或其药学上可接受的盐的西酞普兰。
Figure A9981676800072
本发明另一方面涉及上述方法，其中式IV化合物为S-对映体。
本发明的又一个方面涉及含通过本发明的方法制备的西酞普兰的抗抑郁药用组合物。
通过本发明的方法可以高得率地获得纯产物的西酞普兰，因此免去了昂贵的提纯步骤。而且，与已知的氰基交换方法相比，本反应可在更适宜的溶剂中，在低温和低过量CN-中进行。本发明因只用少量的重金属(heavy)而具有环境方面的优势。最后，本方法产生易于转化为所需的盐的改良的晶状产物。
所用的氰化物源可以是任何有用的来源。优选的来源为KCN、NaCN或(R’4N)CN，其中的R’4定义如上。以化学计算的量或过量使用该类氰化物源，优选每当量式IV的初始原料用1-2当量。R’4N+适于为(Bu)4N+。氰化物化合物优选NaCN或KCN或Zn(CN)2。
镍催化剂可为任何合适的含可起催化剂作用的络合物的Ni(O)或Ni(II)，如Ni(PPh3)3、(σ-芳基)-Ni(PPh3)2Cl等等。镍催化剂及其制备描述于WO 96/11906、EP-A-613720或EP-A-384392。
在本发明的一个实施方案中，该反应在催化量的Cu+或Zn2+的存在下进行。
在一个特别优选的实施方案中，镍(O)络合物是在氰化反应之前，在过量络合物配体(优选三苯膦)的存在下，通过用金属如锌、镁或锰还原镍(II)前体如NiCl2或NiBr2而原位制备的。
镍-催化剂适用量为0.5-10，优选2-6，最优选约4-5摩尔％。
Cu+和Zn2+的催化量各指低于化学计算量如0.1-5、优选1-3当量％。可用任何方便的Cu+和Zn2+的来源。优选采用CuI形式的Cu+，Zn2+可方便地作为Zn(CN)2盐或通过用锌还原镍(II)化合物而原位形成。
在本发明的优选实施方案中，R为氯。
在本发明特别优选的实施方案中，其中R为Cl的式IV化合物，在如上述优选原位制备的Ni(PPh3)3的存在下与NaCN或KCN反应。
其中R为溴或氯的式IV中间物可如DE2,657,271和相关的US4,136,193中所述，可各自由溴代2-苯并[c]呋喃酮和氯代2-苯并[c]呋喃酮制得。
该反应可在任何合适的溶剂，优选乙腈、丙腈、四氢呋喃和乙酸乙酯中进行。
其它反应条件、溶剂等为这类反应的常规条件而易于为本领域的技术人员所确定。
总式I的化合物可用作游离碱或其药学上可接受的酸加成盐。作为酸加成盐，可使用与有机或无机酸形成的这类盐。这类有机盐的实例有与下列酸所形成的盐：马来酸、富马酸、苯甲酸、抗坏血酸、琥珀酸、草酸、二亚甲基水杨酸、甲磺酸、乙二磺酸、乙酸、丙酸、酒石酸、水杨酸、柠檬酸、萄糖酸、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、邻-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-溴代茶碱。这类无机盐的实例有与氢氯酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸所形成的盐。
可通过本领域所熟知的方法制备该化合物的酸加成盐。所述碱与计算量的酸在水可混溶的溶剂如丙酮或乙醇中反应，接着通过浓缩和冷却分离所述盐；或与过量的酸在水不混溶的溶剂如乙醚、乙酸乙酯或二氯甲烷中反应，而自然分离出盐。
本发明的药用组合物可采用任何合适的方式和任何合适的形式给药，例如，以片剂、胶囊、散剂或糖浆的形式口服；或以常用的无菌注射液经肠胃外给药。
可通过本领域的常规方法制备本发明的药物制剂。比如，可通过将活性成分与普通的辅助剂和/或稀释剂相混合，接着在常规的压片机内压制该混合物来制备片剂。辅助剂或稀释剂的实例包括：玉米淀粉、马铃薯淀粉、滑石粉、硬脂酸镁、明胶、乳糖、树胶等等。其它任何辅助剂或添加的着色剂、芳香剂、防腐剂等都可采用，只要它们与所述的活性成分适配。
将所述的活性成分和可能的添加物溶解于部分注射用溶剂，优选无菌水中，将溶液调节到所需的体积，将溶液灭菌并装入合适的安瓿瓶或管制瓶中，可制备注射液。可加入本领域常用的任何适用添加剂，如张度剂、防腐剂、抗氧化剂等。
                       实施例
通过下列实施例进一步说明本发明。
                      实施例1
                   西酞普兰草酸盐
在氮气氛围中将NiCl2(0.077克，0.006摩尔)和三苯膦(0.63克，0.0024摩尔)在乙腈(50毫升)中的混合物回流加热45分钟。冷却到室温后，在溶于乙腈(25毫升)的1-(4′-氟苯基)-1-(3-二甲氨基丙基)-5-氯酞(5.0克，0.015摩尔)溶液加入之前，加入锌粉(0.39克，0.006摩尔)搅拌15分钟。进一步搅拌10分钟后加入NaCN(0.32克，0.0065摩尔)，并将该反应回流加热过夜、冷却、用乙醚稀释，然后经硅藻土过滤。用盐水洗涤滤液、干燥(MgSO4)并减压浓缩。将残余物溶于丙酮(50毫升)，再边搅拌边加入溶于丙酮(10毫升)中的草酸(1.35克，0.015摩尔)溶液。经过滤分离西酞普兰草酸盐，然后从乙醇中重结晶并真空干燥成纯的西酞普兰草酸盐(3.4克，55％)。

Claims (13)

1.一种制备西酞普兰的方法，它包括式IV化合物其中R为Cl或Br，与氰化物源在镍催化剂存在下的反应及相应的5-氰基化合物，即作为碱或其药学上可接受的盐的西酞普兰的分离
Figure A9981676800022
2.权利要求1的方法，其中R为氯。
3.权利要求1或2的方法，其中氰化物源为KCN、NaCN、Zn(CN)2或(R’4N)CN，其中R’4指四个可以是相同或不同且选自氢、直链或支链C1-6烷基的基团。
4.权利要求1-3中任一项的方法，其中氰化物源为NaCN或KCN。
5.权利要求1-4中任一项的方法，其中镍催化剂为Ni(PPh3)3或(σ-芳基)-Ni(PPh)2Cl。
6.权利要求1-5中任一项的方法，其中镍催化剂为镍(O)络合物，它是在过量络合物配体的存在下，在氰化反应之前通过用金属如锌、镁或锰还原镍(II)前体如NiCl2而原位制备的。
7.权利要求6的方法，其中镍(II)前体为NiCl2，金属为锌，络合物配体为三苯膦。
8.权利要求1的方法，其中R为Cl的式IV化合物与NaCN或KCN在Ni(PPh3)3催化剂存在下反应。
9.权利要求10的方法，其中Ni(PPh3)3是在氰化反应之前，在过量络合物三苯膦配体的存在下，通过用锌还原NiCl2而原位制备的。
10.权利要求1-9中任一项的方法，其中所述反应在催化量的Cu+，优选以CuI的形式存在下进行。
11.权利要求1-9中任一项的方法，其中所述反应在催化量的Zn2+的存在下进行。
12.权利要求1-11中任一项的方法，其中式IV化合物为S-对映体。
13.一种抗抑郁药用组合物，该组合物含有通过权利要求1-12中任一项的方法制备的西酞普兰。
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Families Citing this family (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1140886E (pt) 1998-12-23 2003-08-29 Lundbeck & Co As H Metodo para a preparacao de 5- cianoftalida
AR022329A1 (es) 1999-01-29 2002-09-04 Lundbeck & Co As H Metodo para la preparacion de 5-cianoftalida
ES2195554T5 (es) 1999-04-14 2010-02-02 H. Lundbeck A/S Metodo para la preparacion de citalopram.
ITMI991579A1 (it) 1999-06-25 2001-01-15 Lundbeck & Co As H Metodo per la preparazione di citalopram
ITMI991581A1 (it) * 1999-06-25 2001-01-15 Lundbeck & Co As H Metodo per la preparazione di citalopram
TR200401456T1 (tr) 1999-10-25 2005-04-21 H. Lundbeck A/S Sitalopram hazırlanması için yöntem.
ES2169709A1 (es) 1999-10-25 2002-07-01 Lundbeck & Co As H Metodo para la preparacion de citalopram
AR026063A1 (es) 1999-11-01 2002-12-26 Lundbeck & Co As H Metodo para la preparacion de 5-carboxiftalida.
AU778751B2 (en) 1999-12-28 2004-12-16 H. Lundbeck A/S Method for the preparation of citalopram
ATE253568T1 (de) 1999-12-30 2003-11-15 Lundbeck & Co As H Verfahren zur herstellung von citalopram
WO2001051477A1 (en) 2000-01-14 2001-07-19 H. Lundbeck A/S Method for the preparation of 5-cyanophthalide
FR2805812A1 (fr) 2000-02-24 2001-09-07 Lundbeck & Co As H Procede de preparation du citalopram
NL1017417C1 (nl) 2000-03-03 2001-03-16 Lundbeck & Co As H Werkwijze voor de bereiding van Citalopram.
GB0005477D0 (en) 2000-03-07 2000-04-26 Resolution Chemicals Limited Process for the preparation of citalopram
PL360110A1 (en) 2000-03-13 2004-09-06 H.Lundbeck A/S Method for the preparation of citalopram
GB2357762B (en) * 2000-03-13 2002-01-30 Lundbeck & Co As H Crystalline base of citalopram
NL1017500C1 (nl) 2000-03-13 2001-04-26 Lundbeck & Co As H Werkwijze voor de bereiding van Citalopram.
JP2003527385A (ja) 2000-03-13 2003-09-16 ハー・ルンドベック・アクチエゼルスカベット ５−置換された１−（４−フルオロフェニル）−１，３−ジヒドロイソベンゾフランの段階的アルキル化法
PL360107A1 (en) 2000-03-14 2004-09-06 H.Lundbeck A/S Method for the preparation of citalopram
CZ20023406A3 (cs) * 2000-03-16 2003-01-15 H. Lundbeck A/S Způsob výroby 5-kyano-1-(4-fluorfenyl)-1,3-dihydroisobenzofuranu
AR032455A1 (es) 2000-05-12 2003-11-12 Lundbeck & Co As H Metodo para la preparacion de citalopram, un intermediario empleado en el metodo, un metodo para la preparacion del intermediario empleado en el metodo y composicion farmaceutica antidepresiva
IL148525A0 (en) * 2000-07-06 2002-09-12 Lundbeck & Co As H Method for the preparation of citalopram
IL144817A0 (en) * 2000-08-18 2002-06-30 Lundbeck & Co As H Method for the preparation of citalopram
CA2360303C (en) * 2000-12-22 2003-08-12 Marco Villa Process for the preparation of pure citalopram
EP1181272B1 (en) * 2000-12-28 2002-08-28 H. Lundbeck A/S Process for the preparation of pure citalopram
CA2435925A1 (en) 2001-01-30 2002-08-08 Orion Corporation Fermion Process for the preparation of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile
PL372133A1 (en) * 2001-03-09 2005-07-11 Ranbaxy Laboratories Limited Process for the preparation of citalopram
TR200400189T2 (tr) * 2001-07-31 2004-12-21 H.Lundbeck A/S Esitalopram içeren kristal yapılı bileşim.
WO2003057132A2 (en) 2002-01-07 2003-07-17 Sun Pharmaceutical Industries Limited Process for the preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)- 1,3-dihydro-5-isobenzofuran carbonitrile
PE20040991A1 (es) 2002-08-12 2004-12-27 Lundbeck & Co As H Separacion de intermediarios para la preparacion de escitalopram
AU2003223105A1 (en) * 2003-03-24 2004-10-18 Hetero Drugs Limited Novel crystalline forms of (s)-citalopram oxalate
EP1486492A3 (en) * 2003-06-10 2005-02-23 Sun Pharmaceuticals Industries Ltd. A process for hydrogenolysis of [1-(3-dimethylamino)propyl)]-1-(4-fluorophenyl)-1,3-dihydro-5-halo-isobenzofuran.
TWI339651B (en) 2004-02-12 2011-04-01 Lundbeck & Co As H Method for the separation of intermediates which may be used for the preparation of escitalopram
JP2006008603A (ja) * 2004-06-25 2006-01-12 Sumitomo Chemical Co Ltd 光学活性シタロプラムの製造方法、その中間体およびその製造方法
DE05815687T1 (de) 2004-08-23 2007-10-18 Sun Pharmaceutical Industries Ltd. Verfahren zur herstellung von citalopram und enantiomeren
WO2006103550A1 (en) * 2005-03-31 2006-10-05 Ranbaxy Laboratories Limited Processes for the preparation of citalopram and its intermediate 5-aminophthalide
TWI347942B (en) 2005-06-22 2011-09-01 Lundbeck & Co As H Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base
US7834201B2 (en) 2005-06-22 2010-11-16 H. Lundbeck A/S Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base
EP2017271A1 (en) 2007-07-06 2009-01-21 Aurobindo Pharma Limited Process for the preparation of escitalopram

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1143702A (zh) 1965-03-18
GB1526331A (en) * 1976-01-14 1978-09-27 Kefalas As Phthalanes
GB8419963D0 (en) 1984-08-06 1984-09-12 Lundbeck & Co As H Intermediate compound and method
GB8814057D0 (en) 1988-06-14 1988-07-20 Lundbeck & Co As H New enantiomers & their isolation
CA2010159A1 (en) 1989-02-21 1990-08-21 James J. Maul Cyanation of haloaromatics utilizing catalysts generated in situ starting with nic1 or nic1 6h 0
US5296507A (en) 1990-09-06 1994-03-22 H.Lundbeck A/S Treatment of cerbrovascular disorders
DE19626659A1 (de) 1996-07-03 1998-01-08 Basf Ag Verfahren zur Herstellung von Phthaliden
DE19627697A1 (de) 1996-07-10 1998-01-15 Basf Ag Verfahren zur Herstellung von Phthaliden
DE19706648A1 (de) 1997-02-20 1998-08-27 Bayer Ag Verfahren zur Herstellung von aromatischen Nitrilen
DK1015416T3 (da) 1997-07-08 2001-11-05 Lundbeck & Co As H Fremgangsmåde til fremstilling af citalopram
UA62985C2 (en) 1997-11-10 2004-01-15 Lunnbeck As H A method for the preparation of citalopram
JP3813820B2 (ja) 1997-11-11 2006-08-23 ハー・ルンドベック・アクチエゼルスカベット シタロプラムの製造方法
EA002977B1 (ru) 1998-10-20 2002-12-26 Х.Лундбекк А/С Способ получения циталопрама
PT1140886E (pt) 1998-12-23 2003-08-29 Lundbeck & Co As H Metodo para a preparacao de 5- cianoftalida
AR022329A1 (es) 1999-01-29 2002-09-04 Lundbeck & Co As H Metodo para la preparacion de 5-cianoftalida
DE10015280A1 (de) 1999-03-29 2001-01-04 Nissan Chemical Ind Ltd Verfahren zur Herstellung von Benzonitrilverbindungen
ES2195554T5 (es) 1999-04-14 2010-02-02 H. Lundbeck A/S Metodo para la preparacion de citalopram.
ITMI991581A1 (it) 1999-06-25 2001-01-15 Lundbeck & Co As H Metodo per la preparazione di citalopram
ITMI991579A1 (it) 1999-06-25 2001-01-15 Lundbeck & Co As H Metodo per la preparazione di citalopram
ES2169709A1 (es) 1999-10-25 2002-07-01 Lundbeck & Co As H Metodo para la preparacion de citalopram
US6310222B1 (en) 1999-11-01 2001-10-30 Sumika Fine Chemicals Co., Ltd. Production method of 5-phthalancarbonitrile compound, intermediate therefor and production method of the intermediate
GB0005477D0 (en) 2000-03-07 2000-04-26 Resolution Chemicals Limited Process for the preparation of citalopram
CA2360303C (en) 2000-12-22 2003-08-12 Marco Villa Process for the preparation of pure citalopram
EP1181272B1 (en) 2000-12-28 2002-08-28 H. Lundbeck A/S Process for the preparation of pure citalopram

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ITMI991579A1 (it) 2001-01-15
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IS5862A (is) 2001-02-23
NO20010318L (no) 2001-02-20
EA200101071A1 (ru) 2002-02-28
AT409960B (de) 2002-12-27
US6750358B2 (en) 2004-06-15
FI20010154A (fi) 2001-02-09
KR20020011982A (ko) 2002-02-09
CN1129593C (zh) 2003-12-03
HK1047745A1 (en) 2003-03-07
HUP0103417A3 (en) 2003-01-28
GB2354240B (en) 2001-05-23
MXPA01010986A (es) 2002-06-04
BR9917367A (pt) 2002-03-05
DE19983486T1 (de) 2001-10-18
ATE213237T1 (de) 2002-02-15
JP2002523432A (ja) 2002-07-30
SE0100194D0 (sv) 2001-01-24
GB0101508D0 (en) 2001-03-07
ATA904099A (de) 2002-05-15
FI108538B (fi) 2002-02-15
JP3389571B2 (ja) 2003-03-24
HUP0103417A2 (hu) 2002-01-28
SI1105382T1 (en) 2002-06-30
BG106190A (en) 2002-08-30
AT4366U1 (de) 2001-06-25
NO20010318D0 (no) 2001-01-19
DE19983486C2 (de) 2002-09-05
WO2000011926A3 (en) 2000-06-29
AU2001100433B4 (en) 2002-01-17
SE516689C2 (sv) 2002-02-12
AU2001100433A4 (en) 2001-11-01
CH691304A5 (de) 2001-06-29
EP1105382B1 (en) 2002-02-13
PL345971A1 (en) 2002-01-14
PT1105382E (pt) 2002-07-31
UA62023C2 (en) 2003-12-15
AR020573A1 (es) 2002-05-15
CA2290125C (en) 2004-08-10
CZ292174B6 (cs) 2003-08-13
SE0100194L (sv) 2001-04-25
IL145960A0 (en) 2002-07-25
WO2000011926A2 (en) 2000-03-09
KR100491369B1 (ko) 2005-05-24
SK18412001A3 (sk) 2002-05-09
GB2354240A (en) 2001-03-21
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