CN1398263A - 制备西酞普兰的方法 - Google Patents
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Abstract
本发明涉及一种制备西酞普兰或其任一种对映体和酸加成盐的方法,它包括式(II)化合物与具有式(III)的双烯反应,其中X为O、S、SO2、-N=N-、-CO-O-、-O-CO-,或与具有式(IV)的双烯反应,其中R为烷基或任选取代的芳基或芳基烷基。本发明也涉及在制备西酞普兰的新方法中使用的中间体以及根据新方法制备的西酞普兰。
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
它具有选择性,主要作为血清素(5-羟基色胺;5-HT)再摄取抑制剂,具有抗抑郁活性。此化合物的抗抑郁活性已在多种出版物中报导,如J.Hyttel,Prog.Neuro-Psychopharmacol.& Biol.Psychiat.,1982,6,277-295和A.Gravem,Acta Psychiatr.Scand.,1987,75,478-486。在EP-A 474580中也公开了此化合物在治疗痴呆和脑血管疾病方面的效果。
西酞普兰首次公开在相应于US 4,136,193的DE 2,657,271中。此专利公布描述了通过一种方法制备西酞普兰并概述了可以用来制备西酞普兰的另一种方法。
依据此方法的描述,相应的1-(4-氟苯基)-1,3-二氢-5-异苯并呋喃腈和3-(N,N-二甲基氨基)氯丙烷在作为缩合剂的二甲亚砜(methylsulfinylmethide)存在下反应。原料通过和氰化亚铜反应从相应的5-溴衍生物制备。
根据仅概括描述的第二种方法,西酞普兰可以通过化合物:在脱水剂存在下的闭环作用和随后通过使用氰化亚铜使5-溴基团与氰基交换得到。式II的原料通过两次连续的格利雅反应从5-溴二苯并[c]呋喃酮得到,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中描述了用来制备西酞普兰的一种新颖和令人惊奇的方法和中间体,根据其描述,为了得到西酞普兰,通过用浓硫酸脱水使式的中间体发生闭环反应。式III的中间体通过两次连续的格利雅反应从5-氰基二苯并[c]呋喃酮制备,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制备。
国际专利申请WO 98/019511、WO 98/019512和WO 98/019513号中公开了其他方法。WO 98/019512和WO 98/019513涉及其中5-氨基-、5-羧基-或5-(仲氨基羰基)二苯并[c]呋喃酮经过两次连续的格利雅反应,闭环和将得到的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的方法。国际专利申请WO 98/019511号公开了生产西酞普兰的方法,其中为了得到西酞普兰将4-取代的2-羟基甲基苯基-(4-氟苯基)甲醇化合物进行闭环作用,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-氰基衍生物并用(3-二甲基氨基)丙基卤化物进行烷基化。
最后,在美国专利4,943,590号中公开了西酞普兰的单一对映体的制备方法,其中也发表了式III的中间体的闭环作用可以经不稳定的酯和碱来实现。
现在已经发现西酞普兰可以通过一种新方法得到,其中西酞普兰骨架通过二氢苯并呋喃和双烯的第尔斯-阿尔德反应形成。
本发明概述
因此,本发明涉及一种新的制备西酞普兰、其对映体和酸加成盐的方法,所述方法包括:
与
或者与
式II化合物和式III的双烯的反应通过使用进行第尔斯-阿尔德型反应的常规反应条件来进行。因此,反应适于在溶剂如苯、甲苯、1,3,5-三甲苯中、60℃至180℃之间的温度下,优选在回流条件下进行。
式II化合物和式III的双烯的最初反应导致具有式的中间体的形成,其中X如上定义。
式II′的中间体的氧化导致西酞普兰的形成。
式II′的中间体的氧化在氧和例如Pd/C、S、二脱氧苯醌(dideoxyquinon)和氯醌的试剂的存在下进行。
在某些情况下,即当式III化合物为3-氰基呋喃时,式II′的中间体向西酞普兰的转化是在路易斯酸或无机酸存在下进行的。适当的路易斯酸包括ZnCl2、TiCl4、BF3、Et2O等。适当的无机酸包括盐酸、硫酸等。
当在此过程中使用的式III化合物为3-氰基呋喃时式II′的中间体可以被离析。
式II化合物和式IV化合物的反应通过使用进行第尔斯-阿尔德型反应的常规反应条件来进行。因此,反应适于在惰性溶剂如苯、甲苯、1,3,5-三甲苯中、60℃至180℃之间的温度下,优选在回流条件下进行。在式IV中的芳基和芳基烷基取代基R可以被如卤素、烷基、烷氧基等取代基取代。
式V化合物向式VI化合物的转化适于在酸性介质水溶液或在碱性介质水溶液中进行。
将氰基引入到式VI化合物中适于通过式VI化合物和NaCN、KCN或TMSCN在水溶液中进行反应,然后通过使用常规的脱水剂如亚硫酰氯、POCl3、P2O5或Vilsmeier试剂脱水来实现。当使用TMSCN时,反应适于在路易斯酸如ZnCl2、ZnI2或BF3、Et2O存在下进行。
式VII化合物在氧和例如Pd/C、二脱氧苯醌、氯醌等试剂的存在下被氧化形成西酞普兰。
另一方面,本发明涉及其中以S-对映体的形式使用式II化合物的上述方法。
再一方面,本发明涉及通过本发明的方法生产的西酞普兰和S-西酞普兰以及含通过本发明的方法生产的西酞普兰或S-西酞普兰的抗抑郁药用组合物。
根据本发明,式II的化合物可以通过下述方法由4-氟苯甲酸衍生物来制备,并转化为西酞普兰及其盐,该方法包括:
与M+、+C≡C-CH2-O-Z其中M+为金属离子,Z为保护基团或氢,
反应,之后除去保护基团Z;
和具有式HalMg(CH2)3NMe2,其中Hal为氯或溴的格利雅试剂反应;
iii)得到的式X的化合物
还原形成式XI的化合物
将其用脱水剂处理形成式II的化合物。
式VIII化合物和M+、+C≡C-CH2-OZ的反应适于在四氢呋喃、Et2O或甲苯中进行。适当的保护基团Z包括四氢吡喃、三烷基甲硅烷基等。根据常规的除去保护基团的方法来除去所述保护基团。
式IX化合物和格利雅试剂的反应使用常规的格利雅反应条件来进行。适当的格利雅反应的溶剂包括四氢呋喃、Et2O和甲苯。
式X化合物的还原在水或乙醇中使用阮内镍或Lindlar催化剂作为还原剂来进行。
用脱水剂处理式XI的化合物适于在甲苯、EtOAc或四氢呋喃中进行。适当的脱水剂包括甲苯磺酰氯、甲磺酰氯等。
或者,式II化合物可以通过下述方法由4-氟苯甲醛制备,并转化为西酞普兰及其盐,所述方法包括:
iv)式XII的4-氟苯甲醛
和M+、+C≡C-CH2-O-Z其中M+为金属离子,Z为保护基团或氢,反应,然后通过
v)氧化得到的式XIII化合物
vi)式IX化合物和具有式HalMg(CH2)3NMe2,其中Hal为氯或溴的格利雅试剂反应;之后将式X的化合物转化为上述式II的化合物。
式XII化合物和M+、+C≡C-CH2-OZ的反应适于在四氢呋喃、Et2O或甲苯中进行。保护基团Z可以是四氢吡喃、三烷基甲硅烷基等。
式XIII化合物的氧化在氧的存在下,适当的是在例如Pd/C、DDQ、氯醌等试剂的存在下进行。
根据除去保护基团的常规方法来除去保护基团Z。
根据本发明的第三个实施方案,式II化合物也可以通过下面的方法从二甲基氨基丙基-4-氟苯酮(benzophenon)来制备,并转化为西酞普兰及其盐,所述方法包括:
viii)式XIV的化合物
和具有式HalMgCCCH2OMgHal,其中Hal为氯或溴的格利雅试剂反应;然后通过将得到的式X化合物转化为上述的式II化合物。
式XIV化合物和格利雅试剂的反应使用常规的格利雅反应条件来进行。适当的格利雅反应溶剂包括四氢呋喃、Et2O和甲苯。
根据本发明优选的实施方案,用来制备西酞普兰的式III的双烯选自3-氰基呋喃、3-氰基噻吩1,1-二氧化物、4-氰基-哒嗪和2-氧杂-2H-吡喃-5-腈。
上面概述的西酞普兰的总合成包含使用用来制备西酞普兰的新中间体。上面图示的式(II)、(XI)和(X)的新中间体也构成本发明的一部分。
式III的原料为已知的或可以通过常规的方法来制备。
因此,3-氰基-呋喃为可以使用常规的方法从相应的3-溴-呋喃、3-甲酰基-呋喃或3-羧基-呋喃制备的已知化合物。
3-氰基-噻吩1,1-二氧化物可以使用如过氧化物通过3-氰基-噻吩的氧化来制备。3-氰基-噻吩可以从文献中得知,并能从相应的3-溴-、3-甲酰基-和3-羧基-噻吩来制备。
4-氰基-哒嗪可以通过使用如KMnO4作为氧化剂氧化苯并哒嗪,然后通过将得到的哒嗪-4,5-二羧酸脱羧并使用常规的方法将羧酸转化为腈来制备。
2-氧杂-2H-吡喃-5-腈可以使用将羧基转化为氰基的常规方法从相应的羧酸来制备。2-氧杂-2H-吡喃-5-羧酸可以如Organic Synthesis,IV,201-202页中所述制备。
对映体形式的式II、X、XI、XIII的中间体可以使用常规的分离技术或如在US-A-4.943.590中所述获得。
为了分离非对映异构体盐混合物并将旋光性化合物离析为游离碱或其盐,用旋光性酸如用(-)-或(+)-酒石酸或(-)-或(+)-樟脑-10-磺酸处理所述化合物是有利的。
化合物(II)、(X)和(XI)的盐可以是任意的酸加成盐,包括上面提及的药学上可接受的酸加成盐,如盐酸盐、氢溴酸盐等。
通式I的化合物可以用作游离碱或其药学上可接受的酸加成盐。作为酸加成盐,可以使用那些与有机或无机酸形成的盐。典型的这类有机盐是那些和马来酸、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、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、对氨基苯甲酸、谷氨酸、苯磺酸和茶碱乙酸以及8-卤茶碱如8-溴茶碱形成的盐。典型的这类无机盐是那些和盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸形成的盐。
本发明化合物的酸加成盐可以通过本领域已知的方法来制备。碱和计算量的酸在水可溶混的溶剂如丙酮或乙醇中反应,随后通过浓缩和冷却将盐离析,或和过量的酸在水不溶混的溶剂如乙醚、乙酸乙酯或二氯甲烷中反应,盐自然分离。
本发明的药用组合物可以以任何适当的方式和任何适当的形式给药,如以片剂、胶囊、粉剂或糖浆形式口服给药,或以通常的无菌注射溶液形式非经肠给药。
本发明的药物制剂可以通过本领域的常规方法来制备。例如,片剂可以通过将活性组分和常规辅剂和/或稀释剂混合,然后在常规的压片机上将混合物压片来制备。辅剂或稀释剂的例子包括:玉米淀粉、马铃薯淀粉、滑石粉、硬脂酸镁、明胶、乳糖、树胶等。可以使用任何其它辅助或添加的着色剂、芳香剂、防腐剂等,条件是它们和活性组分相容。
用于注射的溶液可以通过将活性组分和可能的添加剂溶解在部分用于注射的溶剂,优选无菌水中,将溶液调整至所需的体积,对溶液进行灭菌,装在适当的安瓿或管形瓶中来制备。可以添加任何适当的本领域常用添加剂,如张度剂、防腐剂、抗氧化剂等。
Claims (11)
8.权利要求1的方法,其中以S-对映体的形式使用所述化合物II。
9.根据权利要求1的方法制备的西酞普兰。
10.根据权利要求8的方法制备的S-西酞普兰。
11.一种药用组合物,它包含权利要求9或10的化合物以及适当的一种或多种药学上可接受的载体或稀释剂。
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PCT/DK1999/000739 WO2001047909A1 (en) | 1999-12-28 | 1999-12-28 | Method for the preparation of citalopram |
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NO (1) | NO20023126L (zh) |
NZ (1) | NZ519739A (zh) |
PL (1) | PL355532A1 (zh) |
PT (1) | PT1246812E (zh) |
SI (1) | SI1246812T1 (zh) |
SK (1) | SK9282002A3 (zh) |
TR (1) | TR200201678T2 (zh) |
WO (1) | WO2001047909A1 (zh) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TR200102957T2 (tr) | 1999-04-14 | 2004-12-21 | H. Lundbeck A/S | Sitalopram hazırlanması için metod. |
PT1246813E (pt) | 1999-12-30 | 2004-02-27 | Lundbeck & Co As H | Metodo para a preparacao de citalopram |
KR100660802B1 (ko) | 2000-01-14 | 2006-12-26 | 하. 룬트벡 아크티에 셀스카브 | 5-시아노프탈리드의 제조 방법 |
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 |
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 |
IES20010206A2 (en) | 2000-03-13 | 2002-03-06 | Lundbeck & Co As H | Method for the preparation of citalopram |
HUP0300274A2 (hu) | 2000-03-13 | 2003-06-28 | H. Lundbeck A/S | Eljárás citalopram előállítására |
PL360107A1 (en) | 2000-03-14 | 2004-09-06 | H.Lundbeck A/S | Method for the preparation of citalopram |
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 |
TR200504022T1 (tr) * | 2003-03-24 | 2006-08-21 | Hetero Drugs Limited | (S)-sitalopram oksalatın yeni sıvı kristal formları. |
ITMI20040717A1 (it) * | 2004-04-09 | 2004-07-09 | Adorkem Technology Spa | Procedimento chemo-enzimatico per la preparazione dell'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 |
EP1951726A2 (en) * | 2005-11-14 | 2008-08-06 | H.Lundbeck A/S | Method for the preparation of escitalopram |
WO2009147687A2 (en) * | 2008-06-03 | 2009-12-10 | Shodhana Laboratories Limited | An improved process for the separation of enantiomerically pure compounds |
US20110092719A1 (en) * | 2008-06-16 | 2011-04-21 | Shodhana Laboratories Limited | Preparation of Escitalopram, Its Salts and Intermediates |
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GB1143703A (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 |
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 |
CA2291067C (en) | 1997-07-08 | 2002-07-30 | H. Lundbeck A/S | Method for the preparation of citalopram |
UA62985C2 (en) | 1997-11-10 | 2004-01-15 | Lunnbeck As H | A method for the preparation of citalopram |
WO1998019512A2 (en) | 1997-11-11 | 1998-05-14 | H. Lundbeck A/S | Method for the preparation of citalopram |
IL142346A0 (en) | 1998-10-20 | 2002-03-10 | Lundbeck & Co As H | Method for the preparation of citalopram |
CZ300408B6 (cs) | 1998-12-23 | 2009-05-13 | H. Lundbeck A/S | Zpusob výroby 5-kyanoftalidu |
AR022329A1 (es) | 1999-01-29 | 2002-09-04 | Lundbeck & Co As H | Metodo para la preparacion de 5-cianoftalida |
TR200102957T2 (tr) | 1999-04-14 | 2004-12-21 | H. Lundbeck A/S | Sitalopram hazırlanması için metod. |
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 |
AU742554B2 (en) | 1999-10-25 | 2002-01-03 | H. Lundbeck A/S | Method for the preparation of citalopram |
AR026063A1 (es) | 1999-11-01 | 2002-12-26 | Lundbeck & Co As H | Metodo para la preparacion de 5-carboxiftalida. |
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 |
PT1246813E (pt) | 1999-12-30 | 2004-02-27 | Lundbeck & Co As H | Metodo para a preparacao de citalopram |
KR100660802B1 (ko) | 2000-01-14 | 2006-12-26 | 하. 룬트벡 아크티에 셀스카브 | 5-시아노프탈리드의 제조 방법 |
IES20010143A2 (en) | 2000-02-24 | 2001-07-25 | Lundbeck & Co As H | Method for the preparation of citalopram |
NL1017415C1 (nl) | 2000-02-24 | 2001-05-18 | 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 |
IL144817A0 (en) | 2000-08-18 | 2002-06-30 | Lundbeck & Co As H | Method for the preparation of citalopram |
KR100439329B1 (ko) | 2000-12-22 | 2004-07-07 | 하. 룬트벡 아크티에 셀스카브 | 순수한 시탈로프람의 제조방법 |
PL353369A1 (en) | 2000-12-28 | 2003-11-17 | H.Lundbeck A/S | Process for the preparation of pure citalopram |
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1999
- 1999-12-28 IL IL15033599A patent/IL150335A0/xx unknown
- 1999-12-28 AT AT99962132T patent/ATE261953T1/de not_active IP Right Cessation
- 1999-12-28 DE DE69915713T patent/DE69915713T2/de not_active Expired - Fee Related
- 1999-12-28 JP JP2001549379A patent/JP2003519136A/ja not_active Withdrawn
- 1999-12-28 SI SI9930567T patent/SI1246812T1/xx unknown
- 1999-12-28 KR KR1020027008341A patent/KR20020073489A/ko not_active Application Discontinuation
- 1999-12-28 EP EP99962132A patent/EP1246812B1/en not_active Expired - Lifetime
- 1999-12-28 MX MXPA02006503A patent/MXPA02006503A/es not_active Application Discontinuation
- 1999-12-28 NZ NZ519739A patent/NZ519739A/en unknown
- 1999-12-28 CA CA002395404A patent/CA2395404A1/en not_active Abandoned
- 1999-12-28 WO PCT/DK1999/000739 patent/WO2001047909A1/en not_active Application Discontinuation
- 1999-12-28 CZ CZ20022213A patent/CZ20022213A3/cs unknown
- 1999-12-28 EA EA200200719A patent/EA004742B1/ru not_active IP Right Cessation
- 1999-12-28 PL PL99355532A patent/PL355532A1/xx not_active Application Discontinuation
- 1999-12-28 SK SK928-2002A patent/SK9282002A3/sk unknown
- 1999-12-28 CN CN99817098A patent/CN1398263A/zh active Pending
- 1999-12-28 PT PT99962132T patent/PT1246812E/pt unknown
- 1999-12-28 ES ES99962132T patent/ES2219095T3/es not_active Expired - Lifetime
- 1999-12-28 TR TR2002/01678T patent/TR200201678T2/xx unknown
- 1999-12-28 AU AU18583/00A patent/AU778751B2/en not_active Ceased
- 1999-12-28 HU HU0203635A patent/HUP0203635A3/hu unknown
- 1999-12-28 DK DK99962132T patent/DK1246812T3/da active
-
2002
- 2002-06-19 IS IS6435A patent/IS6435A/is unknown
- 2002-06-25 US US10/183,958 patent/US6762307B2/en not_active Expired - Fee Related
- 2002-06-27 NO NO20023126A patent/NO20023126L/no not_active Application Discontinuation
- 2002-07-22 BG BG106939A patent/BG106939A/xx unknown
Also Published As
Publication number | Publication date |
---|---|
EP1246812A1 (en) | 2002-10-09 |
NO20023126D0 (no) | 2002-06-27 |
SK9282002A3 (en) | 2002-11-06 |
HUP0203635A2 (hu) | 2003-02-28 |
KR20020073489A (ko) | 2002-09-26 |
BG106939A (en) | 2003-03-31 |
CZ20022213A3 (cs) | 2002-09-11 |
NZ519739A (en) | 2004-03-26 |
JP2003519136A (ja) | 2003-06-17 |
WO2001047909A1 (en) | 2001-07-05 |
IL150335A0 (en) | 2002-12-01 |
US20030060641A1 (en) | 2003-03-27 |
DE69915713T2 (de) | 2005-03-03 |
MXPA02006503A (es) | 2002-12-09 |
EP1246812B1 (en) | 2004-03-17 |
EA004742B1 (ru) | 2004-08-26 |
ATE261953T1 (de) | 2004-04-15 |
PT1246812E (pt) | 2004-08-31 |
CA2395404A1 (en) | 2001-07-05 |
AU1858300A (en) | 2001-07-09 |
NO20023126L (no) | 2002-06-27 |
SI1246812T1 (en) | 2004-08-31 |
IS6435A (is) | 2002-06-19 |
HUP0203635A3 (en) | 2005-02-28 |
DK1246812T3 (da) | 2004-07-05 |
DE69915713D1 (de) | 2004-04-22 |
AU778751B2 (en) | 2004-12-16 |
US6762307B2 (en) | 2004-07-13 |
PL355532A1 (en) | 2004-05-04 |
ES2219095T3 (es) | 2004-11-16 |
TR200201678T2 (tr) | 2002-10-21 |
EA200200719A1 (ru) | 2002-12-26 |
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