公开(公告)号：EP1412341B1

公开(公告)日：2004-12-08

申请号：EP02742848.1

申请日：2002-06-25

申请人： H. Lundbeck A/S

发明人： HUMBLE, Rikke, Eva ,  CHRISTENSEN, Troels, Volsgaard ,  ROCK, Michael, Harold ,  NIELSEN, Ole ,  PETERSEN, Hans ,  DANCER, Robert

IPC分类号： C07D307/87

CPC分类号： C07D307/87

摘要： The invention relates to a process for the preparation of racemic citalopram free base or an acid addition salt thereof and/or R- or S-citalopram as the free base or an acid addition salt thereof by separation of a mixture of R- and S-citalopram with more than 50% of one of the enantiomers into a fraction consisting of racemic citalopram and/or a fraction of S-citalopram or R-citalopram characterized in that i) citalopram is precipitated from a solvent as the free base or as an acid addition salt thereof; ii) the precipitate formed is separated from the mother liquor; iia) if the precipitate is crystalline it is optionally recrystallised one or more times to form racemic citalopram, and then optionally converted into an acid addition salt thereof; iib) if the precipitate is not crystalline, steps i) and ii) are optionally repeated until a crystalline precipitate is obtained and the crystalline precipitate is recrystallised one or more times to form racemic citalopram, and then optionally converted into an acid addition salt thereof; iii) the mother liquor is optionally subjected to further purification and S-citalopram or R-citalopram is isolated from the mother liquor and optionally converted into an acid addition salt thereof.

摘要翻译： 本发明涉及一种制备外消旋西酞普兰游离碱或其酸加成盐和/或作为游离碱或其酸加成盐的R-或S-西酞普兰的方法，其通过分离R-和S- 西酞普兰与超过50％的一种对映体进入由外消旋西酞普兰和/或一部分S-西酞普兰或R-西酞普兰组成的部分，其特征在于i）西酞普兰以游离碱或酸形式从溶剂中沉淀出来 其加成盐; ii）将形成的沉淀从母液中分离出来; 如果沉淀物是结晶的，则任选重结晶一次或多次以形成外消旋西酞普兰，然后任选转化为其酸加成盐; 如果沉淀物不是结晶的，则任选重复步骤i）和ii）直至获得结晶沉淀物，并将结晶沉淀物重结晶一次或多次以形成外消旋西酞普兰，然后任选转化成其酸加成盐; iii）任选地将母液进一步纯化，从母液中分离出S-西酞普兰或R-西酞普兰，并任选转化为其酸加成盐。

公开(公告)号：EP1581483A1

公开(公告)日：2005-10-05

申请号：EP03767476.9

申请日：2003-12-18

申请人： H. LUNDBECK A/S

发明人： PETERSEN, Hans ,  DANCER, Robert ,  CHRISTIANSEN, Brian ,  HUMBLE, Rikke, Eva

IPC分类号： C07C253/34 ,  C07D307/87

CPC分类号： C07D307/87 ,  C07C253/34

摘要： In the following, citalopram diol means 4-(4-(dimethylamino)-l­-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)-benzonitrile, as free base and/or acid addition salt. The invention relates to a process for the preparation of racemic citalopram diol and/or R- or S-citalopram diol, comprising the separation of a non-racemic mixture of R- and S-citalopram diol with more than 50% of one of the enantiomers into a fraction being enriched with S- or R-citalopram diol and a fraction comprising RS-citalopram diol wherein the ratio of R-citalopram diol:S-citalopram diol is equal to 1:1 or closer to 1:1 than in the initial mixture. The method is characterized in that (i) RS-citalopram diol is precipitated from a solution of the initial non-racemic mixture, or R- or S-citalopram diol is dissolved into a solvent from the initial non-racemic mixture, leaving a residue of RS-citalopram diol, and in that (ii) the residue/precipitate formed is separated from the final solution phase, followed by optional steps of repetition, recrystallisation, purification, isolation and conversion between free base and salts. The invention also relates to a process for the preparation of RS-citalopram, S-citalopram or R-citalopram (all as free base and/or acid addition salt) comprising the method described above followed by ring closure.

公开(公告)号：EP1412341A1

公开(公告)日：2004-04-28

申请号：EP02742848.1

申请日：2002-06-25

申请人： H. Lundbeck A/S

发明人： HUMBLE, Rikke, Eva ,  CHRISTENSEN, Troels, Volsgaard ,  ROCK, Michael, Harold ,  NIELSEN, Ole ,  PETERSEN, Hans ,  DANCER, Robert

IPC分类号： C07D307/87

CPC分类号： C07D307/87

摘要： The invention relates to a process for the preparation of racemic citalopram free base or an acid addition salt thereof and/or R- or S-citalopram as the free base or an acid addition salt thereof by separation of a mixture of R- and S-citalopram with more than 50% of one of the enantiomers into a fraction consisting of racemic citalopram and/or a fraction of S-citalopram or R-citalopram characterized in that i) citalopram is precipitated from a solvent as the free base or as an acid addition salt thereof; ii) the precipitate formed is separated from the mother liquor; iia) if the precipitate is crystalline it is optionally recrystallised one or more times to form racemic citalopram, and then optionally converted into an acid addition salt thereof; iib) if the precipitate is not crystalline, steps i) and ii) are optionally repeated until a crystalline precipitate is obtained and the crystalline precipitate is recrystallised one or more times to form racemic citalopram, and then optionally converted into an acid addition salt thereof; iii) the mother liquor is optionally subjected to further purification and S-citalopram or R-citalopram is isolated from the mother liquor and optionally converted into an acid addition salt thereof.

公开(公告)号：EP1581483B1

公开(公告)日：2012-06-06

申请号：EP03767476.9

申请日：2003-12-18

申请人： H. Lundbeck A/S

发明人： PETERSEN, Hans ,  DANCER, Robert ,  CHRISTIANSEN, Brian ,  HUMBLE, Rikke, Eva

IPC分类号： C07C253/34 ,  C07D307/87

CPC分类号： C07D307/87 ,  C07C253/34

摘要： In the following, citalopram diol means 4-(4-(dimethylamino)-l­-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)-benzonitrile, as free base and/or acid addition salt. The invention relates to a process for the preparation of racemic citalopram diol and/or R- or S-citalopram diol, comprising the separation of a non-racemic mixture of R- and S-citalopram diol with more than 50% of one of the enantiomers into a fraction being enriched with S- or R-citalopram diol and a fraction comprising RS-citalopram diol wherein the ratio of R-citalopram diol:S-citalopram diol is equal to 1:1 or closer to 1:1 than in the initial mixture. The method is characterized in that (i) RS-citalopram diol is precipitated from a solution of the initial non-racemic mixture, or R- or S-citalopram diol is dissolved into a solvent from the initial non-racemic mixture, leaving a residue of RS-citalopram diol, and in that (ii) the residue/precipitate formed is separated from the final solution phase, followed by optional steps of repetition, recrystallisation, purification, isolation and conversion between free base and salts. The invention also relates to a process for the preparation of RS-citalopram, S-citalopram or R-citalopram (all as free base and/or acid addition salt) comprising the method described above followed by ring closure.

公开(公告)号：EP1611118A2

公开(公告)日：2006-01-04

申请号：EP04721125.5

申请日：2004-03-17

申请人： H. LUNDBECK A/S

发明人： PITTELKOW, Thomas ,  CASTELLIN, Andrea ,  SBROGIO, Federico ,  DAHLBERG, Nielsen, Poul ,  ZANON, Jacopo ,  SOGAARD, Steen ,  HUMBLE, Rikke, Eva

IPC分类号： C07D307/88

CPC分类号： C07D307/88

摘要： Methods for manufacture of 5-alkoxycarbonylphthtalides are disclosed. The 5-alkoxycarbonylphthtalides are useful in syntheses of the well-known antidepressants citalopram and escitalopram. A method for preparing an alkoxycarbonylphtalide of formula (III) comprising: (a) reacting a compound of formula (VIIIa) with a formaldehyde and oleum; and (b) addition of an alcohol R3-OH to the reaction of step (a); wherein X and Y of formula (VIIIa) may be selected independently from the group consisting of: OR1, OR2, a halogen (such as C1, Br, I), and NR; wherein R, R1 and R2 are independently h or a C1-6-alkyl or phenyl.