CN1140521C - 西酞普兰的制备方法 - Google Patents
西酞普兰的制备方法 Download PDFInfo
- Publication number
- CN1140521C CN1140521C CNB998167517A CN99816751A CN1140521C CN 1140521 C CN1140521 C CN 1140521C CN B998167517 A CNB998167517 A CN B998167517A CN 99816751 A CN99816751 A CN 99816751A CN 1140521 C CN1140521 C CN 1140521C
- Authority
- CN
- China
- Prior art keywords
- compound
- general formula
- citalopram
- acid
- milliliters
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/44—Palladium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Materials Engineering (AREA)
- Rheumatology (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Steroid Compounds (AREA)
Abstract
一种制备西酞普兰(citalopram)的方法,包含通式(IV)化合物,与氰化物源在钯催化剂和催化剂量的Cu+或Zn2+存在下,或与Zn(CN)2在钯催化剂存在下发生反应。其中该通式中的R是卤素或CF3-(CF2)n-SO2-,n是0~8。
Description
本发明涉及一种制备已知的抗抑郁药物西酞普兰即(Citalopam)1-[3-(二甲基氨基)丙基]-1-(4-氟代苯基)-1,3-二氢化-5-异苯并呋喃腈的方法。
发明背景
它是中枢作用性(5-羟基色胺;5-HT)的一种选择性再摄取抑制剂,因此具有抗抑郁活性。该化合物的抗抑郁活性在多个出版物中有报道,比如J.Hyttel,Prog.Neuro-Psychopharmacol.&Biol.Psychiat.,1982,6,277-295和A.Gravem,Acta Psychiatr.Scand.,1987,75,478-486。该化合物已经进一步公开显示出在治疗痴呆和脑血管失调方面的效果,EP-A 474580。
西酞普兰首先公开在DE 2,657,013中,对应于美国专利4,136,193。该专利出版物描述了通过一种方法制备西酞普兰并且概括描述了另一个可用来制备西酞普兰的方法。
根据所描述的方法,相应的1-(4-氟代苯基)-1,3-二氢化-5-异苯并呋喃腈与3-(N,N-二甲基氨基)丙基氨在甲基亚磺酰甲基化物缩合剂的存在下发生反应。起始物是由相应的5-溴代衍生物通过与氰化亚铜反应制备的。
根据该方法,只作了笼统的概括,西酞普兰可通过以下化合物:通式II在脱水剂存在下进行环合然后采用氰化亚铜将5-溴代基团与氰基交换的方法而获得。通式II的起始物从5-溴代-2-苯并[c]呋喃酮通过两个连续的格利雅反应,即分别与4-氟代苯基氯化镁和N,N-二甲基氨基丙基氯化镁的反应而获得。
一种用于制备西酞普兰的新型和令人惊奇的方法以及中间体见述于美国专利4,650,884,根据该文,以下通式的中间体通式III通过以浓硫酸脱水而进行环合反应以获得西酞普兰。通式III的中间体从5-氰基-2-苯并[c]呋喃酮通过两个连续的格利雅反应,即分别与4-氟代苯基卤化镁和N,N-二甲基氨基丙基卤化镁的反应而制备。
另外的方法被公开在国际专利申请WO 98019511、WO 98019512和WO 98019513中。WO 98019512和WO 98019513涉及以下方法:5-氨基-、5-羧基-或5-(仲氨基羰基)-2-苯并[c]呋喃酮进行两个连续的格利雅反应、环合反应以及将得到的1,3-二氢化异苯并呋喃衍生物转化成相应的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,其中使(4-取代的2-羟基甲基苯基-(4-氟代苯基)甲醇化合物发生环合并将所得到的5-取代的1-(4-氟代苯基)-1,3-二氢化异苯并呋喃转化成相应的5-氰基衍生物,该衍生物与(3-二甲基氨基)丙基卤进行烷基化以获得西酞普兰。
最后,制备西酞普兰单个对映体的方法被公开在美国专利4,943,590中,其中也表明,通式III中间体的环合反应可经由活泼酯与碱来实现。
就上述制备西酞普兰的方法而言,发现包含5-溴代基团与氰基交换的方法按工业规模实施时不太方便,因为产量相当低、产品不纯并且特别是很难将得到的西酞普兰从相应的5-溴代化合物中分离。
目前已发现可通过新型的催化方法得到高产率的非常纯净的产物西酞普兰,其中5-氰基与1-[3-(二甲基氨基)丙基]-1-(4-氟代苯基)-1,3-二氢化-5-异苯并呋喃的5-卤代或5-三氟甲磺酸酯基团交换,因此避免了老的氰化物交换法中大量整理工序。
发明概述
因此,本发明涉及一种制备西酞普兰的新型方法,包含使通式IV化合物通式IV其中R是碘代、溴代、氯代或CF3-(CF2)n-SO2-O-,其中n是0-8的整数,包括端值点0和8,与氰化物源如KCN、NaCN或(R’)4NCN,其中(R’)4表示四个相同或不同并选自氢和直链或支链C1-6烷基的基团,在钯催化剂和催化量的Cu+或Zn2+存在下进行反应,或与Zn(CN)2在钯催化剂存在下进行反应,以及作为碱或其可药用盐的形式分离出相应的5-氰基化合物,即西酞普兰通式I
另一方面,本发明提供了通式IV的新型中间体,其中R是CF3-(CF2)n-SO2-O-,其中n是0-8范围内的整数,或R是碘。
在另一方面,本发明涉及其中通式IV化合物是S-对映体的上述方法。
还有另一方面,本发明涉及一种抗抑郁药物组合物,包含通过本发明方法制造的西酞普兰。
通过本发明方法,可获得高收率纯净产物西酞普兰,因此减少了高成本的纯化步骤。而且,同已知的氰基交换方法相比,反应可在更适宜的溶剂中、在低温下和在低过量CN-的情况下完成。该方法具有环境优势,因为它只采用少量的重金属。最后,该方法给出改善的结晶产品,使得容易转化成所需的盐。已发现通式IV中间体,其中R是CF3-(CF2)n-SO2-O-,其中n是0-8范围内整数或R是碘,显示出药理活性,即对5-HT再摄取的抑制效果,因此可用作抗抑郁药物。
所用的氰化物源可以是任何有用的源。优选的源是KCN、NaCN或(R’)4NCN,其中(R’)4如上定义。可使用化学计量或过量的氰化物源,优选每当量的通式IV起始物采用1-2当量的氰化物源。(R’)4N+可以便利地是(Bu)4N+。氰化物优选NaCN或KCN或Zn(CN)2。
钯催化剂可以是任何适宜的含有Pd(0)或Pd(II)的催化剂如Pd(PPh3)4、Pd2(dba)3或Pd(PPh)2Cl2等。Pd催化剂适宜用量是1-10、优选2-6、最优选约4-5摩尔%。
Cu+和Zn2+的催化量,分别表示亚化学计量的量,比如0.1-5,优选1-3%。适宜的是,每当量的Pd采用约1/2当量。任何适宜的Cu+和Zn2+源均可被采用。Cu+优选采用CuI形式而Zn2+适宜采用Zn(CN)2盐。
在本发明一个优选的实施方案中,R是CF3-(CF2)n-SO2-O-,其中n是0-8范围内的整数或R是溴或碘,最优选CF3-(CF2)8-SO2-O-、CF3-SO2-O-、溴或碘,特别是溴。
在另一个特别优选的实施方案中,通式IV化合物与Zn(CN)2在钯催化剂、优选Pd(PPh3)4(四(三苯基膦)钯)存在下反应。
其中R是溴或氯的通式IV的中间体可以分别从溴代和氯代2-苯并[c]呋喃酮制备,在DE 2,657,013和相应的美国专利4,136,193中有描述。碘代物可以从相应的2-苯并[c]呋喃酮衍生物被类似地制得而其中R是CF3-(CF2)n-SO2-O-的化合物可以通过常规的三氟甲磺酸化(triflation)反应由相应的羟基化合物来制备。
反应可以在任何适宜的溶剂中进行,优选乙腈、丙腈、四氢呋喃(THF)和醋酸乙酯。
其它反应条件、溶剂等是用于这类反应的常规条件并且现有技术人员容易确定之。
通式I的化合物可以作为自由碱或作为其可药用酸加成盐被使用。就酸加成盐而言,与有机或无机酸形成的盐均可被采用。这类有机盐的实例是那些与马来酸、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、乙烷二磺酸、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-卤代茶碱如8-溴代茶碱形成的盐。这类无机盐的实例是那些与盐酸、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以通过现有技术中已知的方法制备。碱与计算量的酸在水可混溶溶剂如丙酮或乙醇中反应,然后通过浓缩和冷却分离出盐,或者与过量的酸在水不混溶溶剂如乙醚、醋酸乙酯或二氯甲烷中反应,盐自动分离。
本发明的可药用组合物可以以任何适宜的方式给药,并且以任何适宜的形式给药,比如以片剂、胶囊、粉剂或糖浆的形式口服,或者以注射用普通无菌溶液的形式肠外给药。
本发明的药物制剂可以通过现有技术中的常规方法制备。比如,可以通过将活性成份与普通佐药和/或稀释剂混合并随后在常规的压片机上压制混合物的方法制备片剂。佐药或稀释剂的实例包含:玉米淀粉、马铃薯淀粉、滑石、硬脂酸镁、明胶、乳糖、树胶等。只要其与活性成份相容,任何其它的佐药或添加剂、着色剂、香味剂、防腐剂等均可被采用。
可以通过将活性成份和可能的添加剂溶解在一部分注射用溶剂中,优选无菌水中,将溶液调整到所需的体积、溶液消毒并填充入适当的安瓿或小药水瓶中的方法制备注射用溶液。可添加现有技术常用的任何适宜添加剂,比如强健剂、防腐剂、抗氧化剂等。
实施例
通过如下的实施例进一步说明本发明。
实施例1西酞普兰草酸盐方法1
Zn(CN)2(1.2克,0.01摩尔)和1-(4′-氟代苯基)-1-(3-二甲基氨基丙基)-5-溴代phtalane(6.0克,0.016摩尔)在DMF(40毫升)中的混合物在室温下在氩气氛围中搅拌30分钟。通过向反应混合物中鼓泡氩10分钟而除掉溶解的氧气,然后添加四(三苯膦)钯(O)(0.8克,0.0007摩尔,4.3摩尔%)。然后将反应混合物在75℃加热3小时,倒入水中(200毫升)并用乙醚萃取(2×100毫升)、干燥(MgSO4)、过滤和减压浓缩。残留物溶解在丙酮中(10毫升)并在搅拌下添加草酸(0.145克,0.016摩尔)在丙酮(10毫升)中的溶液。过滤分离出西酞普兰草酸盐,用冷乙醚洗涤并真空干燥,得到纯化的西酞普兰,草酸盐(6.1克,92%)。方法2
1-(4′-氟代苯基)-1-(3-二甲基氨基丙基)-5-溴代phtalane(2.5克,0.007摩尔)、NaCN(0.68克,0.014摩尔)和Zn(CN)2(0.014克,0.00012摩尔)在THF(40毫升)中的混合物在室温下在氩气氛围中搅拌30分钟。然后在添加四(三苯膦)钯(O)(0.3克,0.0003摩尔,3.7摩尔%)之前,通过向反应混合物中鼓泡氩而除掉溶解的氧气。然后将反应混合物回流加热过夜、冷却、用乙醚稀释,然后通过塞里塑料过滤。滤液用盐水洗涤、干燥(MgSO4)和减压浓缩。残留物溶解在丙酮中(50毫升)并在搅拌下添加草酸(0.63克,0.007摩尔)在丙酮(10毫升)中的溶液。过滤分离出西酞普兰草酸盐、用冷乙醚洗涤并真空干燥,得到纯化的西酞普兰,草酸盐(2.4克,82%)。
实施例21-(4′-氟代苯基)-1-(3-二甲基氨基丙基)-5-碘代phtalane,草酸盐
向5-碘代-2-苯并[c]呋喃酮(phtalide)(26.0克,0.1摩尔)在干燥THF(100毫升)中的悬浮体中滴加从4-氟代溴代苯(19.3克,0.11摩尔)和镁镟坯(2.92克,0.12摩尔)制备的4-氟代苯基溴化镁在干燥THF(100毫升)中的溶液。温度保持低于0℃。添加结束之后,反应混合物在0℃搅拌3小时。
向反应混合物中添加由3-二甲基氨基丙基氯(14.6克,0.12摩尔)和镁镟坯(3.2克,0.13摩尔)在干燥的THF(100毫升)中制备的第二格利雅溶液。添加过程中温度保持低于0℃。添加结束之后,移除冷却并且反应混合物在室温再搅拌2小时。
然后将反应混合物倒入冰水(200毫升)与NH4Cl饱和溶液(100毫升)的混合物中。在真空下蒸发掉THF。添加甲苯(200毫升),分离出有机相并以1M的HCl(1×100毫升)萃取。然后通过添加25%的NH4OH(15毫升)将水相的pH值调整到9,并且添加甲苯(100毫升)。反应在室温放置过夜。
分离出有机相并在室温下添加70%硫酸(10毫升)。反应混合物在室温搅拌2小时以使环合反应完全。添加25%的NH4OH(20毫升)并分离有机相、过滤和真空蒸发,得到自由碱形式的粗标题化合物。粗料样品(5.0克,11.3毫摩尔)溶解在醋酸乙酯中并且通过二氧化硅过滤。洗脱液1:醋酸乙酯,丢弃之。洗脱液2:比例为95∶5的醋酸乙酯:三乙基胺,收集并真空蒸发之,得到自由碱形式的标题化合物(3.5克,8.2毫摩尔)。
从丙酮中沉淀出草酸盐。DSC起始:82℃和195℃.1H NMR(DMSO d-6,250MHz):1.3-1.65(2H,m),2.15(2H,t,J=10Hz),2.63(6H,s),2.87(2H,t,J=10Hz),5.0-5.2(2H,2d,J=12.5Hz),6.5-7.05(2H,s(宽)),7.16(2H,t,J=7.5Hz),7.35(1H,d,J=8.5Hz),7,55(2H,dt,J=1.2Hz,J=7.5Hz),7.64(1H,d,J=8.5Hz),7.69(1H,s).
实施例31-(3-二甲基氨基-1-丙基)-1-(4-氟代苯基)-5-羟基-1,3-二氢化异苯并呋喃,草酸盐
在温度低于8℃下向5-羟基-2-苯并[c]呋喃酮(10.0克,0.07摩尔)在干燥THF(100毫升)中的悬浮体中滴加从4-氟代溴代苯(24.0克,0.14摩尔)和镁镟坯(4.38克,0.17摩尔)在干燥THF(80毫升)中制备的4-氟代苯基溴化镁溶液。添加结束之后,反应混合物在室温搅拌过夜。
在同时温度保持低于10℃下,向该反应混合物中添加从3-二甲基氨基丙基氯(8.50克,0.07摩尔)和镁镟坯(1.93克,0.07摩尔)在干燥THF(40毫升)中制备的第二格利雅溶液。反应搅拌过夜。
将反应混合物倒入冰水(200毫升)中并且以氯化铵水溶液(300毫升)将pH值调整到7,最后分为两相。水相用醋酸乙酯(300毫升)萃取,然后用25%(w/v)氢氧化铵调成碱性,pH值为8-9。水相用甲苯/醋酸乙酯(3∶2,3×100毫升)萃取。甲苯萃取液以无水硫酸钠干燥并与活性炭搅拌。过滤之后,真空蒸发溶剂,获得油状的标题化合物(10.2克,48%)。
5.1克(16毫摩尔)获得的油溶解在丙酮中(25毫升)并用无水草酸(1.46克,0.016摩尔)处理。混合物在冷藏箱中放置过夜并且过滤出沉淀的草酸盐。收率:4.77克。DSC起始168℃.1H NMR(DMSO-d6,500MHz):1,36-1,58(2H,m),2,05-2,18(2H,m),2,63(6H,s),2,96(2H,t,J=6,5Hz),4,95(1H,d,J=12,5Hz),5,08(1H,d,J=12,5Hz),6,65(1H,s),6,70(1H,d,J=8,5Hz),7,14(2H,t,J=7,5Hz),7,24(1H,d,J=8,5Hz)7,52(2H,dt,J=7,5 J=1,2Hz),9-10(2H,宽s).分析计算值C21H24N1F1O6:C,62,20;H,5,98:N,3,46.实测值:C,62,02;H,5,97;N,3,42.
实施例41-(3-二甲基氨基-1-丙基)-1-(4-氟代苯基)-5-[(三氟代甲基)磺酰基-氧]-1,3-二氢化异苯并呋喃,草酸盐
1-(3-二甲基氨基-1-丙基)-1-(4-氟代苯基)-5-羟基-1,3-二氢化异苯并呋喃(1.79克,5.7毫摩尔)溶解在二氯甲烷(35毫升)中并且在冰/水浴中冷却。保持温度低于5℃,在氮气下逐滴加入三氟甲磺酰氯(0.73毫升,6.8毫摩尔)。反应混合物升温到室温过夜。添加水(40毫升)和三乙基胺(1毫升)并且分离各相。水相以二氯甲烷(25毫升)萃取。组合的有机相以硫酸镁干燥并且在真空下蒸发溶剂。残留物(2.09克自由碱形式的标题化合物)溶解在丙酮中(10毫升)并且以无水草酸(0.51克,5.7毫摩尔)处理。在室温过夜搅拌之后,过滤出沉淀物。收率:0.84克,33%。DSC起始144℃.1H NMR(DMSO-d6,500MHz):1,37-1,57(2H,m),2,15-2,25(2H,m),2,61(6H,s),2,95(2H,t,J=9,4Hz),5,12(1H,d,J=12,5Hz),5,22(1H,d,J=12,5Hz),7,17(2H,t,J=6,3Hz),7,42(1H,d,J=7,8Hz),7,48(1H,s),7,59(2H,dt,J=6,3Hz J=1,2Hz),7,70(1H,d,J=7,8Hz).分析计算值C22H23N1F4O8S1:C,49,16;H,4,32:N,2,61.实测值:C,49,43;H,4,36;N,2,57.
实施例5西酞普兰,草酸盐,方法3
将1-(3-二甲基氨基-1-丙基)-1-(4-氟代苯基)-5-[(三氟代甲基)磺酰基-氧]-1,3-二氢化异苯并呋喃(1.02克,2.3毫摩尔)、氰化钠(0.22克,4.6毫摩尔)、碘化铜(0.05克,0.3毫摩尔)和四(三苯膦)钯(O)(0.125克,0.1毫摩尔)悬浮在乙腈(10毫升)中。悬浮液回流加热5小时,然后在强烈搅拌下冷却到室温过夜。添加醋酸乙酯(30毫升)并且通过塞里塑料过滤混合物。滤液用盐水(60毫升)洗涤并且以硫酸镁干燥,然后真空除去溶剂。粗产品在二氧化硅上进行洗脱(洗脱液:75∶25∶4的醋酸乙酯、乙醇、三乙基胺)。收率:0.22克,30%。
从丙酮中沉淀出草酸盐。
Claims (14)
2.权利要求1的方法,其中氰化物源是KCN、NaCN或(R’)4NCN,其中(R’)4表示四个基团,其可以相同或不同并选自氢和直链或支链的C1-6烷基。
3.权利要求1或2的方法,其中R是CF3-(CF2)n-SO2-O-,其中n是0-8的整数。
4.权利要求1或2的方法,其中R是溴或碘。
5.权利要求1的方法,其中通式IV化合物与Zn(CN)2在钯催化剂存在下发生反应。
6.权利要求1的方法,其中所用的氰化物是NaCN、KCN或Zn(CN)2。
7.权利要求1或2的方法,其中钯催化剂是Pd(PPh3)4、Pd2(dba)3、或Pd(PPh)2Cl2。
8.权利要求7的方法,其中钯催化剂是Pd(PPh3)4。
9.权利要求1或2的方法,其中反应在催化量的Cu+存在下进行。
10.权利要求1或2的方法,其中反应在催化量的Zn2+存在下进行。
12.权利要求1或2的方法,其中通式IV化合物是S-对映体。
13.权利要求11的化合物用于制备西酞普兰碱或其可药用盐的用途。
14.权利要求11的化合物用于制备S-西酞普兰或其可药用盐的用途,所述化合物是S-对映体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA199900920 | 1999-06-25 | ||
DKPA199900920 | 1999-06-25 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2003101187801A Division CN1502616A (zh) | 1999-06-25 | 1999-11-22 | 西酞普兰的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1367786A CN1367786A (zh) | 2002-09-04 |
CN1140521C true CN1140521C (zh) | 2004-03-03 |
Family
ID=8099035
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB998167517A Expired - Fee Related CN1140521C (zh) | 1999-06-25 | 1999-11-22 | 西酞普兰的制备方法 |
CNA2003101187801A Pending CN1502616A (zh) | 1999-06-25 | 1999-11-22 | 西酞普兰的制备方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2003101187801A Pending CN1502616A (zh) | 1999-06-25 | 1999-11-22 | 西酞普兰的制备方法 |
Country Status (36)
Country | Link |
---|---|
US (2) | US20020077353A1 (zh) |
EP (1) | EP1159274B1 (zh) |
JP (1) | JP3447267B2 (zh) |
KR (1) | KR100491368B1 (zh) |
CN (2) | CN1140521C (zh) |
AR (1) | AR020863A1 (zh) |
AT (3) | AT409961B (zh) |
AU (2) | AU1374500A (zh) |
BG (1) | BG65574B1 (zh) |
BR (1) | BR9917368B1 (zh) |
CA (2) | CA2475401A1 (zh) |
CH (1) | CH691305A5 (zh) |
CZ (1) | CZ292198B6 (zh) |
DE (2) | DE19983487C1 (zh) |
DK (2) | DK1159274T3 (zh) |
EA (1) | EA002560B1 (zh) |
ES (2) | ES2194545T3 (zh) |
FI (1) | FI108641B (zh) |
GB (2) | GB2354239B (zh) |
HK (1) | HK1049002B (zh) |
HU (1) | HUP0103235A3 (zh) |
IL (2) | IL145959A0 (zh) |
IS (1) | IS2343B (zh) |
IT (1) | ITMI991581A1 (zh) |
MX (1) | MXPA01010989A (zh) |
NO (1) | NO328542B1 (zh) |
NZ (1) | NZ514979A (zh) |
PL (1) | PL205579B1 (zh) |
PT (1) | PT1159274E (zh) |
SE (1) | SE516690C2 (zh) |
SI (1) | SI1159274T1 (zh) |
SK (1) | SK285813B6 (zh) |
TR (1) | TR200103702T2 (zh) |
UA (1) | UA63034C2 (zh) |
WO (1) | WO2000013648A2 (zh) |
ZA (1) | ZA200108854B (zh) |
Families Citing this family (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2356188C (en) | 1998-12-23 | 2006-05-23 | H. Lundbeck A/S | Method for the preparation of 5-cyanophthalide |
AR022329A1 (es) | 1999-01-29 | 2002-09-04 | Lundbeck & Co As H | Metodo para la preparacion de 5-cianoftalida |
NZ514671A (en) | 1999-04-14 | 2003-10-31 | H | Method for the preparation of citalopram |
ITMI991579A1 (it) | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | Metodo per la preparazione di citalopram |
ES2229774T3 (es) | 1999-10-25 | 2005-04-16 | H. Lundbeck A/S | Metodo para la preparacion de citalopram. |
DK1228056T3 (da) | 1999-10-25 | 2005-01-24 | Lundbeck & Co As H | Fremgangsmåde til fremstilling af citalopram |
AR026063A1 (es) | 1999-11-01 | 2002-12-26 | Lundbeck & Co As H | Metodo para la preparacion de 5-carboxiftalida. |
JP2003519136A (ja) | 1999-12-28 | 2003-06-17 | 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 |
DE69912652T2 (de) | 1999-12-30 | 2004-06-09 | H. Lundbeck A/S | Verfahren zur herstellung von citalopram |
SI1254129T1 (en) | 2000-01-14 | 2004-02-29 | 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. |
NZ521201A (en) | 2000-03-13 | 2004-02-27 | H | 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. |
EP1265881A1 (en) | 2000-03-13 | 2002-12-18 | H. Lundbeck A/S | Stepwise alkylation of 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofurans |
MXPA02008653A (es) | 2000-03-14 | 2003-02-24 | Lundbeck & Co As H | Metodo para la preparacion de citalopram. |
JP2003527388A (ja) * | 2000-03-16 | 2003-09-16 | ハー・ルンドベック・アクチエゼルスカベット | 5−シアノ−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製造方法 |
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 |
CA2383963A1 (en) * | 2000-07-06 | 2002-01-17 | Eva Bolzonella | Method for the preparation of citalopram |
CA2354877C (en) * | 2000-08-18 | 2006-05-02 | H. Lundbeck A/S | Method for the preparation of citalopram |
NL1017525C1 (nl) | 2000-12-22 | 2001-04-26 | Lundbeck & Co As H | Werkwijze voor de bereiding van zuiver Citalopram |
IL147162A0 (en) * | 2000-12-28 | 2002-08-14 | Lundbeck & Co As H | Process for the preparation of pure citalopram |
EP1355897A1 (en) | 2001-01-30 | 2003-10-29 | Orion Corporation Fermion | Process for the preparation of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile |
GB0105627D0 (en) * | 2001-03-07 | 2001-04-25 | Cipla Ltd | Preparation of phthalanes |
JP2005500256A (ja) * | 2001-03-09 | 2005-01-06 | ランバクシー ラボラトリーズ リミテッド | シタロプラム製造方法 |
US6967259B2 (en) * | 2001-09-24 | 2005-11-22 | Pharmachem Technologies Limited | Process for the preparation of Citalopram intermediate |
AU2003222435A1 (en) * | 2002-01-07 | 2003-07-24 | Sun Pharmaceutical Industries Limited | Process for the preparation of 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)- 1,3-dihydro-5-isobenzofuran carbonitrile |
AR040970A1 (es) | 2002-08-12 | 2005-04-27 | Lundbeck & Co As H | Metodo para la separacion de intermediarios que pueden ser utilizados para la preparacion de escitalopram |
US20050154052A1 (en) * | 2003-03-24 | 2005-07-14 | Hetero Drugs Limited | Novel crystalline forms of (s)-citalopram oxalate |
US7019153B2 (en) | 2003-06-10 | 2006-03-28 | Sun Pharmaceutical Industries Limited | Process for hydrogenolysis of [1-(3-dimethylamino)propyl)]-1-(4-fluorophenyl)-1,3-dihydro-5-halo-isobenzofuran acetamido-3-substituted-3-cephem-4-carboxylic acid |
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 |
WO2006021971A2 (en) | 2004-08-23 | 2006-03-02 | Sun Pharmaceutical Industries Limited | 'process for preparation of citalopram and enantiomers' |
US7834201B2 (en) | 2005-06-22 | 2010-11-16 | H. Lundbeck A/S | Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base |
TWI358407B (en) | 2005-06-22 | 2012-02-21 | Lundbeck & Co As H | Crystalline base of escitalopram and orodispersibl |
EP2017271A1 (en) | 2007-07-06 | 2009-01-21 | Aurobindo Pharma Limited | Process for the preparation of escitalopram |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
DK213290D0 (da) * | 1990-09-06 | 1990-09-06 | Lundbeck & Co As H | Treatment of cerebrovascular disorders |
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 |
KR100357975B1 (ko) * | 1997-07-08 | 2002-10-25 | 하. 룬트벡 아크티에 셀스카브 | 시탈로프램의 제조방법 |
UA62985C2 (en) * | 1997-11-10 | 2004-01-15 | Lunnbeck As H | A method for the preparation of citalopram |
CN1286687A (zh) * | 1997-11-11 | 2001-03-07 | H·隆德贝克有限公司 | 制备西酞普兰的方法 |
DE69904853T2 (de) * | 1998-10-20 | 2003-09-04 | Lundbeck As Valby H | Verfahren zur herstellung von citalopram |
CA2356188C (en) * | 1998-12-23 | 2006-05-23 | H. Lundbeck A/S | Method for the preparation of 5-cyanophthalide |
AR022329A1 (es) * | 1999-01-29 | 2002-09-04 | Lundbeck & Co As H | Metodo para la preparacion de 5-cianoftalida |
NZ514671A (en) * | 1999-04-14 | 2003-10-31 | H | Method for the preparation of citalopram |
ITMI991579A1 (it) * | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | Metodo per la preparazione di citalopram |
ES2229774T3 (es) * | 1999-10-25 | 2005-04-16 | H. Lundbeck A/S | 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. |
FR2805812A1 (fr) * | 2000-02-24 | 2001-09-07 | Lundbeck & Co As H | Procede de preparation du citalopram |
IES20010143A2 (en) * | 2000-02-24 | 2001-07-25 | Lundbeck & Co As H | Method for the preparation of citalopram |
CA2354877C (en) * | 2000-08-18 | 2006-05-02 | H. Lundbeck A/S | Method for the preparation of citalopram |
NL1017525C1 (nl) * | 2000-12-22 | 2001-04-26 | Lundbeck & Co As H | Werkwijze voor de bereiding van zuiver Citalopram |
IL147162A0 (en) * | 2000-12-28 | 2002-08-14 | Lundbeck & Co As H | Process for the preparation of pure citalopram |
-
1999
- 1999-07-15 IT IT1999MI001581A patent/ITMI991581A1/it unknown
- 1999-11-22 AT AT0904199A patent/AT409961B/de not_active IP Right Cessation
- 1999-11-22 CZ CZ2001320A patent/CZ292198B6/cs not_active IP Right Cessation
- 1999-11-22 DE DE19983487A patent/DE19983487C1/de not_active Expired - Fee Related
- 1999-11-22 CH CH00308/01A patent/CH691305A5/de not_active IP Right Cessation
- 1999-11-22 AU AU13745/00A patent/AU1374500A/en active Pending
- 1999-11-22 KR KR10-2001-7014053A patent/KR100491368B1/ko not_active IP Right Cessation
- 1999-11-22 TR TR2001/03702T patent/TR200103702T2/xx unknown
- 1999-11-22 UA UA2001118041A patent/UA63034C2/uk unknown
- 1999-11-22 ES ES99968622T patent/ES2194545T3/es not_active Expired - Lifetime
- 1999-11-22 JP JP2000568457A patent/JP3447267B2/ja not_active Expired - Fee Related
- 1999-11-22 SI SI9930276T patent/SI1159274T1/xx unknown
- 1999-11-22 ES ES200150011A patent/ES2189699A1/es not_active Withdrawn
- 1999-11-22 GB GB0101504A patent/GB2354239B/en not_active Expired - Fee Related
- 1999-11-22 CA CA002475401A patent/CA2475401A1/en not_active Abandoned
- 1999-11-22 AU AU2001100440A patent/AU2001100440B4/en not_active Expired
- 1999-11-22 HU HU0103235A patent/HUP0103235A3/hu unknown
- 1999-11-22 DK DK99968622T patent/DK1159274T3/da active
- 1999-11-22 PL PL346237A patent/PL205579B1/pl not_active IP Right Cessation
- 1999-11-22 AT AT99968622T patent/ATE235478T1/de not_active IP Right Cessation
- 1999-11-22 IL IL14595999A patent/IL145959A0/xx active IP Right Grant
- 1999-11-22 EA EA200101072A patent/EA002560B1/ru not_active IP Right Cessation
- 1999-11-22 DE DE69906389T patent/DE69906389T2/de not_active Expired - Lifetime
- 1999-11-22 NZ NZ514979A patent/NZ514979A/en not_active IP Right Cessation
- 1999-11-22 CA CA002290127A patent/CA2290127C/en not_active Expired - Fee Related
- 1999-11-22 PT PT99968622T patent/PT1159274E/pt unknown
- 1999-11-22 GB GB0105182A patent/GB2357761B/en not_active Expired - Fee Related
- 1999-11-22 CN CNB998167517A patent/CN1140521C/zh not_active Expired - Fee Related
- 1999-11-22 CN CNA2003101187801A patent/CN1502616A/zh active Pending
- 1999-11-22 SK SK1840-2001A patent/SK285813B6/sk not_active IP Right Cessation
- 1999-11-22 WO PCT/DK1999/000640 patent/WO2000013648A2/en active IP Right Grant
- 1999-11-22 MX MXPA01010989A patent/MXPA01010989A/es not_active IP Right Cessation
- 1999-11-22 EP EP99968622A patent/EP1159274B1/en not_active Expired - Lifetime
- 1999-11-22 BR BRPI9917368-9A patent/BR9917368B1/pt not_active IP Right Cessation
-
2000
- 2000-06-20 AR ARP000103055A patent/AR020863A1/es active IP Right Grant
-
2001
- 2001-01-15 DK DK200100060A patent/DK200100060A/da not_active Application Discontinuation
- 2001-01-19 NO NO20010319A patent/NO328542B1/no not_active IP Right Cessation
- 2001-01-24 SE SE0100193A patent/SE516690C2/sv not_active IP Right Cessation
- 2001-01-25 FI FI20010155A patent/FI108641B/fi not_active IP Right Cessation
- 2001-02-23 IS IS5861A patent/IS2343B/is unknown
- 2001-03-13 AT AT0018401U patent/AT4365U1/de not_active IP Right Cessation
- 2001-10-16 IL IL145959A patent/IL145959A/en not_active IP Right Cessation
- 2001-10-26 ZA ZA200108854A patent/ZA200108854B/xx unknown
- 2001-11-06 US US10/012,054 patent/US20020077353A1/en not_active Abandoned
- 2001-12-07 BG BG106191A patent/BG65574B1/bg unknown
-
2003
- 2003-02-18 HK HK03101234.1A patent/HK1049002B/zh not_active IP Right Cessation
-
2008
- 2008-12-08 US US12/329,750 patent/US20090088469A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1140521C (zh) | 西酞普兰的制备方法 | |
CN1129593C (zh) | 西酞普兰的制备方法 | |
EP1042310B1 (en) | Method for the preparation of citalopram | |
US20020004604A1 (en) | Method for the preparation of citalopram | |
CZ291440B6 (cs) | Způsob výroby citalopramu | |
BG107065A (bg) | Кристална форма на циталопрам | |
US6579993B2 (en) | Process for the preparation of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile | |
EP1700851B1 (en) | Crystalline citalopram diol intermediate alkali | |
CN1138768C (zh) | 氰酞氟苯胺的制备方法 | |
WO2004011450A1 (en) | Process for the preparation of 1-(3-dimethylaminopropyl) -1-(4-fluorophenyl) -1,3-dihydroisobenzofuran -5-carbonitrile |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C06 | Publication | ||
PB01 | Publication | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1049002 Country of ref document: HK |
|
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20040303 Termination date: 20121122 |