CN1149208C - 制备5-氰基2-苯并[c]呋喃酮的方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 48
- XEEGWTLAFIZLSF-UHFFFAOYSA-N 1-oxo-3h-2-benzofuran-5-carbonitrile Chemical compound N#CC1=CC=C2C(=O)OCC2=C1 XEEGWTLAFIZLSF-UHFFFAOYSA-N 0.000 title abstract 3
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- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 abstract description 6
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- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 abstract 1
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- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
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- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
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- ARCGXLSVLAOJQL-UHFFFAOYSA-N trimellitic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(C(O)=O)=C1 ARCGXLSVLAOJQL-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- NOYCNNBKNIAAHS-UHFFFAOYSA-N FC1=CC=C([Mg])C=C1 Chemical compound FC1=CC=C([Mg])C=C1 NOYCNNBKNIAAHS-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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- YTWOHSWDLJUCRK-UHFFFAOYSA-N thiolane 1,1-dioxide Chemical compound O=S1(=O)CCCC1.O=S1(=O)CCCC1 YTWOHSWDLJUCRK-UHFFFAOYSA-N 0.000 description 1
- 230000001519 thymoleptic effect Effects 0.000 description 1
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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
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Furan Compounds (AREA)
Abstract
制备5-氰基2-苯并[c]呋喃酮的方法,该方法是将5-羧基2-苯并[c]呋喃酮转化为式IV相应的酰胺,其中R是H或C1-6烷基,然后和脱水剂反应,由此得到5-氰基2-苯并[c]呋喃酮。5-羧基2-苯并[c]呋喃酮转化为式IV相应的酰胺可以通过相应的C1-6烷基或苯基酯或酰氯完成,再用氨或C1-6烷基胺酰氨化,转化为式IV的酰胺,通过上述方法,制备抗抑郁药西酞普兰使用的重要中间体,5-氰基2-苯并[c]呋喃酮,可以通过方便方法的及合适的价格以高产率得到。
Description
本发明涉及制备5-氰基2-苯并[c]呋喃酮的新方法,5-氰基2-苯并[c]呋喃酮是制备公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,使用的中间体。
发明的背景
西酞普兰是目前市售数年的公知的抗抑郁药,有以下结构式(I):
式I它是选择性的中枢活性血清素(5-羟色胺;5-HT)再摄入抑制剂,因此具有抗抑郁活性。该化合物的抗抑郁活性报道于某些公开出版物,例如J.Hyttel,Prog.Neuro-Psychopharmcol.& Biol.Psychiat.,1982,6,277-295和A.Gravem,Acta Psychiatr.Scand.,1987,75,478-486。
西酞普兰按照USP№4,650,884公开的方法制备,其中5-氰基2-苯并[c]呋喃酮进行两步连续的格氏反应,即分别和4-氟苯基镁卤化物及N,N-二甲基氨基丙基镁卤化物反应,再将得到的下式(II)化合物:
西酞普兰的对映异构体可以通过USP№4,943,590公开的方法制备,即分离式(II)中间体的对映体,然后进行对映体选择性关环,得到所需的对映体。
因此5-氰基2-苯并[c]呋喃酮是制备西酞普兰的重要的中间体,通过方便的及价格合适的方式以足够好的质量生产该物质是重要的。
制备5-氰基2-苯并[c]呋喃酮的方法已经公开在Bull.Soc.Sci.,26,1951,35(Bretagne)和J.Chem.Soc.,1931,867(Levy和Stephen),根据上述方法5-氨基2-苯并[c]呋喃酮通过重氮化,随后和CuCN反应被转化为相应的5-氰基2-苯并[c]呋喃酮,5-氨基2-苯并[c]呋喃酮通过两步还原反应从4-氨基邻苯二甲酰亚胺得到。
从酰氯合成某些烷基或苯基腈记载于TetrahedronLetters,1982,23,14,1505-1508和Tetrahedron,1998,54,9281中。
虽然许多其它方法失败了,但是发现5-氰基2-苯并[c]呋喃酮可以从5-羧基2-苯并[c]呋喃酮通过方便的及价格合适的方法以高产率制备。
发明的公开
因此,本发明提供从5-羧基2-苯并[c]呋喃酮制备5-氰基2-苯并[c]呋喃酮的新方法,包括:
a)将5-羧基2-苯并[c]呋喃酮转化为式IV的酰胺:
其中R是氢或C1-6烷基,和
b)接着使式IV的酰胺和脱水剂反应,得到5-氰基2-苯并[c]呋喃酮(V);
式VI
式VII其中R1是C1-6烷基或苯基,酰氯通常是用POCl3,PCl5,或SOCl2处理5-羧基2-苯并[c]呋喃酮得到,不使用溶剂或在如甲苯或含有催化量的N,N-二甲基甲酰胺的甲苯的合适溶剂中进行;用醇R1OH处理5-羧基2-苯并[c]呋喃酮可以得到酯,其中R1定义同上,反应在酸,尤其是无机酸或路易斯酸如盐酸,硫酸,POCl3,PCl5,或SOCl2存在下进行。另外酯可以通过酰氯和醇反应得到,然后式VI的酯和式VII的酰氯可以通过使用氨或C1-6的烷基胺酰氨化,尤其是用叔丁基胺酰氨化转化为式IV的酰胺。
在说明书和权利要求书中,C1-6的烷基是指有1-6个(包括1和6)碳原子的直链或支链烷基,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。
b)步骤中使用的脱水剂可以是任何合适的脱水剂,优选的试剂很容易被本领域的技术人员确定,合适的脱水剂例如是SOCl2,POCl3和PCl5,优选SOCl2。
b)步骤反应中不使用溶剂或使用合适的溶剂如甲苯,环丁砜(sulfolan)或容易得到的乙腈。当反应在溶剂中进行时,每当量的式V酰胺使用1.0-1.5当量,优选1.0-1.2当量的脱水剂,而且当使用溶剂时,可以加入催化量的N,N-二甲基甲酰胺,特别是脱水剂是SOCl2时。假如必须存在催化量的N,N-二甲基甲酰胺存在下,优选使用甲苯作为溶剂。
b)步骤反应在升高的温度下进行,优选在溶剂回流温度下进行。
反应时间不重要,很容易由本领域技术人员确定。
5-氰基2-苯并[c]呋喃酮以方便的方法被分离,例如加入水,过滤,然后洗涤结晶,如果需要可以进行重结晶进一步提纯。
在本发明方法的优选实施方案中,式IV的R是H或叔丁基。当反应步骤a)是通过酯完成时,R1优选甲基或乙基。
在本发明方法的优选实施方案中,式III的5-羧基2-苯并[c]呋喃酮在POCl3存在下和醇R1OH反应,优选乙醇,得到相应的式VI的酯,再和氨反应由此得到5-氨基甲酰基2-苯并[c]呋喃酮,再于含有催化量的N,N-二甲基甲酰胺的甲苯中和SOCl2反应。
惊奇地发现在内酯环上基本上没有反应发生,因此通过本发明的方法5-氰基2-苯并[c]呋喃酮能够以高产率得到,该方法比公知的方法方便得多,可以使用更方便和便宜的试剂和合适的条件。
作为原料使用的5-羧基2-苯并[c]呋喃酮可以按照USP№3,607,884或德国专利№2630927公开的方法得到,即在液体SO3中使对苯二甲酸的浓溶液和甲醛反应或者通过偏苯三酸的电化学氢化反应制备。
实施例
本发明进一步用以下实施例说明。
实施例15-氰基2-苯并[c]呋喃酮的制备5-氯羰基2-苯并[c]呋喃酮
5-羧基2-苯并[c]呋喃酮(53g,0.3mol)悬浮于甲苯(200ml)中,加入亚硫酰氯(44g,0.6mol)和N,N-二甲基甲酰胺(DMF)(1ml),混合物在回流温度下加热3小时,冷却到室温,加入正庚烷(200ml),收集形成的结晶,用庚烷(100ml)洗涤,产量52g,88%。DSC起始温度131℃;
1HNMR(CDCl3,500MHz):5.47(2H,s),8.06(1H,d,J=7.5Hz),8.28(1H,d,J=7.5Hz),8.3(1H,s).13C NMR(CDCl3,125MHz):69.4,125.1,126.1,131.1,131.6,137.8,146.6,167.4,169.0.5-叔丁基氨基甲酰基2-苯并[c]呋喃酮
方法A)
5-羧基2-苯并[c]呋喃酮(36g,0.2mol)悬浮于亚硫酰氯(100ml)中,加入DMF(1.5ml),混合物回流1小时,加入甲苯(200ml),真空下蒸发溶剂,残留物溶解在四氢呋喃(THF)(200ml)中,于5℃加入到THF(200ml)中的叔丁基胺(31g,0.42mol)溶液中,将混合物温热到室温,搅拌过夜,将反应物倒入冰水(400ml)中,过滤沉淀出的结晶,用水(100ml)洗涤结晶,产量41g,87%,DSC起始温度189.5℃。
方法B)
5-氯羰基2-苯并[c]呋喃酮(39g,0.2mol)在THF(200ml)中的溶液于室温加入到叔丁基胺(19g,0.25mol)和三乙胺(26g,0.25mol)在THF(200ml)中的溶液中,将混合物搅拌1小时,然后反应混合物倒入冰水(500ml)中,收集形成的结晶,用水(100ml)洗涤,产量42.5g,91%,DSC起始温度:192℃;纯度99.5%(HPLC,峰面积);
1H NMR(DMSO-d6,500MHz):1.4(9H,s),5.46(2H,s),7.88(1H,d,J=7.5Hz),7.95(1H,d,J=7.5Hz),8.04(1H,s).13C NMR(DMSO-d6,125MHz):28.5,51.2,70.0,122.0,124.6,126.6,128.2,141.3,147.2,165.5,170.1.5-乙氧羰基2-苯并[c]呋喃酮
方法A)
5-羧基2-苯并[c]呋喃酮(37g,0.2mol)悬浮于乙醇(400ml)中,滴加POCl3(10g,0.07mol),反应混合物加热到回流温度5小时,冷却到室温,标题化合物结晶出来,过滤结晶,用乙醇(50ml)洗涤,产量35g,87%,DSC起始温度:151℃。
1H NMR(DMSO-d6,250MHz):1.36(3H,t,J=7Hz),4.38(2H,q,J=7Hz),5.48(2H,s),7.95(1H,d,J=7.5Hz),8.12(1H,d,J=7.5Hz),.13C NMR(DMSO-d6,62.5MHz):14.5,61.5,70.1,124.0,125.2,128.8,129.6,134.8,147.6,164.9,169.8.
方法B)
5-氯羰基2-苯并[c]呋喃酮(39g,0.2mol)悬浮于乙醇(200ml)中,混合物加热到回流15分钟,冷却后过滤形成的结晶,用乙醇(50ml)洗涤,产量36g,88%,DSC起始温度:151℃;5-氨基甲酰基2-苯并[c]呋喃酮
方法A)
在压力器中将5-乙氧羰基2-苯并[c]呋喃酮(41g,0.2mol)悬浮于氨(10M,甲醇中的溶液,200ml)中,反应混合物在80℃保持20小时,冷却后反应混合物被倒入冰(250g)中,用浓盐酸调节到pH=1,搅拌混合物2小时,过滤形成的结晶,用水(4×100ml)洗涤,真空干燥,产量33g,93%,DSC起始温度:237℃;
1H NMR(DMSO-d6,250MHHz);5.47(2H,s),7.65(1H,s(NH)),7.92(1H,d,J=7.5Hz),8.06(1H,d,J=7.5Hz),8.14(1H,s),8.22(1H,s(NH)),13C NMR(DMSO-d6,62.5MHz):70.0,122.2,124.9,127.2,128.2,139.7,147.4,167.1,170.1.
方法B)
5-氯羰基2-苯并[c]呋喃酮(20g,0.1mol)溶解于THF(100ml)中,加入到于冰水(300ml)中的氢氧化铵(50ml)中,搅拌混合物30分钟,过滤沉淀出的结晶,用水(100ml)洗涤,真空干燥,产量17.1g,97%,DSC起始温度237℃。5-氰基2-苯并[c]呋喃酮
方法A)
干燥的5-氨基甲酰基2-苯并[c]呋喃酮(36g,0.2mol)悬浮于甲苯(600ml)中,加入亚硫酰氯(36g,0.3mol),再加入DMF(2ml),反应混合物加热到75℃6小时,蒸馏除去甲苯(100ml),残留的溶液冷却到室温,过滤形成的结晶,用甲苯(150ml)和水(100ml)洗涤,产品从甲苯中重结晶,产量22g,80%,DSC起始温度203℃。
方法B)
叔丁基氨基甲酰基2-苯并[c]呋喃酮(23.3g,0.1mol)悬浮于亚硫酰氯(100ml)中,混合物加热到回流30分钟,加入甲苯(100ml),真空除去溶剂,标题产品从乙酸或甲苯中重结晶,产量15.5g,93%(从甲苯中重结晶),DSC起始温度203℃,纯度98%(HPLC,峰面积)。
Claims (17)
2.按照权利要求1的方法,其中5-羧基2-苯并[c]呋喃酮转化为式IV的酰胺可以通过式VI的酯完成:
式VI其中R1是C1-6烷基或苯基,该方法是在酸存在下用醇R1OH处理5-羧基2-苯并[c]呋喃酮,随后再用氨或C1-6的烷基胺酰氨化式VI的酯。
3.按照权利要求1的方法,其中5-羧基2-苯并[c]呋喃酮转化为式IV的酰胺可以通过式VII的酰氯完成:
式VII该方法是用POCl3,PCl5,或SOCl2处理5-羧基2-苯并[c]呋喃酮,随后再用氨或C1-6的烷基胺酰氨化式VII的酰氯。
4.按照权利要求1的方法,其中的5-羧基2-苯并[c]呋喃酮转化为式IV的酰胺通过式VII的酰氯和式VI的酯完成:
式VI
式VII其中R1是C1-6烷基或苯基,该方法是用POCl3,PCl5,或SOCl2处理5-羧基2-苯并[c]呋喃酮,用醇R1OH和这样形成的式VI I酰氯反应,随后再用氨或C1-6的烷基胺酰氨化式VI的酯。
5.按照权利要求2的方法,其中的酸是无机酸或路易斯酸。
6.按照权利要求5的方法,其中无机酸或路易斯酸是盐酸,硫酸,POCl3,PCl5或SOCl2。
7.按照权利要求2,4,5或6的方法,其中R1是甲基或乙基。
8.按照权利要求1-6中的任何一项的方法,其中步骤b)使用的脱水剂是SOCl2,POCl3或PCl5。
9.按照权利要求8的方法,其中脱水剂是SOCl2。
10.按照权利要求1-6中的任何一项的方法,其中步骤b)不使用溶剂或在合适的溶剂中进行。
11.按照权利要求10的方法,其中溶剂是甲苯,环丁砜或乙腈。
12.按照权利要求11的方法,其中溶剂是甲苯。
13.按照权利要求10的方法,其中步骤b)使用的脱水剂是SOCl2,反应在含有催化量的N,N-二甲基甲酰胺的甲苯中进行。
14.按照权利要求1-6中的任何一项的方法,其中的R是H或叔丁基。
15.按照权利要求2的方法,其中5-羧基2-苯并[c]呋喃酮式III和醇R1OH在POCl3存在下反应,得到式VI的酯,然后再和氨反应,由此得到5-氨基甲酰基2-苯并[c]呋喃酮,再和SOCl2反应得到5-氰基2-苯并[c]呋喃酮。
16.按照权利要求15的方法,其中R1OH是乙醇或甲醇。
17.按照权利要求15的方法,其中5-羧基2-苯并[c]呋喃酮式III和乙醇在POCl3存在下反应,得到式VI的乙酯,然后再和氨在甲醇中反应,由此得到5-氨基甲酰基2-苯并[c]呋喃酮,再和SOCl2反应得到5-氰基2-苯并[c]呋喃酮。
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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 |
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 |
DK1228056T3 (da) | 1999-10-25 | 2005-01-24 | Lundbeck & Co As H | Fremgangsmåde til fremstilling af 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. |
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. |
EP1265881A1 (en) | 2000-03-13 | 2002-12-18 | H. Lundbeck A/S | Stepwise alkylation of 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofurans |
NZ521201A (en) | 2000-03-13 | 2004-02-27 | H | Method for the preparation of citalopram |
NL1017500C1 (nl) | 2000-03-13 | 2001-04-26 | Lundbeck & Co As H | Werkwijze voor de bereiding van Citalopram. |
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 |
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 |
EP1321464A1 (en) * | 2001-12-21 | 2003-06-25 | ICROM S.p.A. | Process for the preparation of 5-cyanophthalide and intermediates useful therein |
CN101362743A (zh) | 2003-03-21 | 2009-02-11 | H.隆德贝克有限公司 | 用于制备西酞普兰和依他普仑的中间体 |
US20050154052A1 (en) * | 2003-03-24 | 2005-07-14 | Hetero Drugs Limited | Novel crystalline forms of (s)-citalopram oxalate |
EP1777221A1 (en) * | 2005-10-14 | 2007-04-25 | Adorkem Technology SpA | Process for the preparation of 5-cyanophthalide starting from 5-carboxyphthalide |
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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 |
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 |
ES2229774T3 (es) | 1999-10-25 | 2005-04-16 | H. Lundbeck A/S | Metodo para la preparacion de citalopram. |
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