cas 59729-33-8, Citalopram | Articles data

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Palladium-catalyzed heteroallylation of unactivated alkenes-synthesis of citalopram
A palladium-catalyzed difunctionalization of unactivated alkenes with tethered nucleophiles is reported. The versatile reaction occurs with simple allylic halides and can be carried out under air. The methodology provides rapid access to a wide array of desirable heterocyclic targets, as illustrated by a concise synthesis of the widely prescribed antidepressant citalopram.
Hewitt, Joanne F. M.,Williams, Lewis,Aggarwal, Pooja,Smith, Craig D.,France, David J.
p. 3538 - 3543
(2013)
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Method for preparing citalopram and S - citalopram
The invention relates to a method of preparing citalopram and S-citalopram by carrying out cyclization reaction on a diol compound (II) or S-diol compound (II') in a nixed solvent of a C4-C7 ketone solvent and water and aryl sulfonyl chloride or alkyl sulfonyl chloride under an alkaline condition. The solvent used by the invention is great in solubility to reactants and products, so that the use level of the solvent is reduced, the yield is improved and meanwhile the method is good in post-treatment extraction effect and simple and convenient to operate. The compounds (II and II') are as shown in the specification.
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Paragraph 0011; 0024-0025

(2021/07/01)

MANGANESE (III) CATALYZED C--H AMINATIONS
Reactions that directly install nitrogen into C—H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Selective intramolecular C—H amination reactions that achieve high levels of reactivity, while maintaining excellent site-selectivity and functional-group tolerance is a challenging problem. Herein is reported a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C—H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site-selectivity. In the presence of Br?nsted or Lewis acid, the [MnIII(ClPc)]-catalyzed C—H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies indicate that C—H amination proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C—H cleavage is the rate-determining step of the reaction. Collectively these mechanistic features contrast previous base-metal catalyzed C—H aminations.
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Paragraph 0710-0712

(2019/04/25)

Ex situ generation of stoichiometric HCN and its application in the Pd-catalysed cyanation of aryl bromides: Evidence for a transmetallation step between two oxidative addition Pd-complexes
A protocol for the Pd-catalysed cyanation of aryl bromides using near stoichiometric and gaseous hydrogen cyanide is reported for the first time. A two-chamber reactor was adopted for the safe liberation of ex situ generated HCN in a closed environment, which proved highly efficient in the Ni-catalysed hydrocyanation as the test reaction. Subsequently, this setup was exploited for converting a range of aryl and heteroaryl bromides (28 examples) directly into the corresponding benzonitriles in high yields, without the need for cyanide salts. Cyanation was achieved employing the Pd(0) precatalyst, P(tBu)3-Pd-G3 and a weak base, potassium acetate, in a dioxane-water solvent mixture. The methodology was also suitable for the synthesis of 13C-labelled benzonitriles with ex situ generated 13C-hydrogen cyanide. Stoichiometric studies with the metal complexes were undertaken to delineate the mechanism for this catalytic transformation. Treatment of Pd(P(tBu)3)2 with H13CN in THF provided two Pd-hydride complexes, (P(tBu)3)2Pd(H)(13CN), and [(P(tBu)3)Pd(H)]2Pd(13CN)4, both of which were isolated and characterised by NMR spectroscopy and X-ray crystal structure analysis. When the same reaction was performed in a THF : water mixture in the presence of KOAc, only (P(tBu)3)2Pd(H)(13CN) was formed. Subjection of this cyano hydride metal complex with the oxidative addition complex (P(tBu)3)Pd(Ph)(Br) in a 1 : 1 ratio in THF led to a transmetallation step with the formation of (P(tBu)3)2Pd(H)(Br) and 13C-benzonitrile from a reductive elimination step. These experiments suggest the possibility of a catalytic cycle involving initially the formation of two Pd(ii)-species from the oxidative addition of LnPd(0) into HCN and an aryl bromide followed by a transmetallation step to LnPd(Ar)(CN) and LnPd(H)(Br), which both reductively eliminate, the latter in the presence of KOAc, to generate the benzonitrile and LnPd(0).
Kristensen, Steffan K.,Eikeland, Espen Z.,Taarning, Esben,Lindhardt, Anders T.,Skrydstrup, Troels
p. 8094 - 8105
(2017/11/27)

Copper-catalysed cyanoalkylative cycloetherification of alkenes to 1,3-dihydroisobenzofurans: development and application to the synthesis of citalopram
A copper-catalysed cyanoalkylative cycloetherification of alkenes was developed. Heating a solution of substituted (2-vinylphenyl)methanol in MeCN/MeOH (v/v 7/3) in the presence of a catalytic amount of copper(ii) tetrafluoroborate hydrate [Cu(BF4)2·6H2O], bathophenanthroline, K3PO4, BnOH and (tBuO)2 afforded 1,3-dihydroisobenzofurans (phthalanes) via formation of one C(sp3)-C(sp3) and one C(sp3)-O bonds. A concise synthesis of citalopram, a marketed anti-depressant drug, was accomplished by applying this novel synthetic transformation.
Ha, Tu M.,Wang, Qian,Zhu, Jieping
supporting information
p. 11100 - 11103
(2016/09/19)

Alkene Dioxygenation with Malonoyl Peroxides: Synthesis of γ-Lactones, Isobenzofuranones, and Tetrahydrofurans
Treatment of homoallylic alcohols or carboxylic acids with malonoyl peroxide 1 provides a stereoselective method for the preparation of tetrahydrofurans, γ-lactones, and isobenzofuranones in 44-82% yield and up to 27:1 trans selectivity. Application of this simple and effective heterocyclization in the synthesis of the antidepressant citalopram is also described.
Alamillo-Ferrer, Carla,Karabourniotis-Sotti, Marianna,Kennedy, Alan R.,Campbell, Matthew,Tomkinson, Nicholas C. O.
p. 3102 - 3105
(2016/07/13)

Novel and improved process for the preparation of citalopram
A novel process for the preparation of citalopram (1) has been described. The key intermediate 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran- 5-carbonitrile (2) of citalopram is prepared using novel intermediates. The process involves simple acylation, hydrolysis and reduction, which can be easily adapted to commercial scale.
Reddy, M. Pulla,Bhujanga Rao,Usharani,Dubey
p. 1829 - 1832
(2012/01/13)

Preparation of Escitalopram, Its Salts and Intermediates
The present patent application relates to an improved process for the preparation of escitalopram, its salts and intermediates. It also relates to a novel crystalline form S of citalopram diol intermediate, process for preparation and its use in the preparation of citalopram, escitalopram and their salts.
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(2011/05/03)

PREPARATION OF ESCITALOPRAM, ITS SALTS AND INTERMEDIATES
The present patent application relates to an improved process for the preparation of escitalopram, its salts and intermediates. It also relates to a novel crystalline form S of citalopram diol intermediate, process for preparation and its use in the preparation of citalopram, escitalopram and their salts.
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Page/Page column 20

(2010/04/03)

Process for the Preparation of Escitalopram
The present invention provides a novel process for the preparation of a compound of Formula III, and novel processes for preparing escitalopram using the compound of Formula III.
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Page/Page column 7-8

(2010/08/18)

Structure-activity relationships for a novel series of citalopram (1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5- carbonitrile) analogues at monoamine transporters
(±)-Citalopram (1, 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1, 3-dihydroisobenzofuran-5-carbonitrile), and its eutomer, escitalopram (S-(+)-1) are selective serotonin reuptake inhibitors (SSRIs) that are used clinically to treat anxiety and depression. To further explore structure-activity relationships at the serotonin transporter (SERT), a series of (±)-4- and 5-substituted citalopram analogues were designed, synthesized, and evaluated for binding at the SERT, dopamine transporter (DAT) and norepinephrine transporter (NET) in native rodent tissue. Many of these analogues showed high SERT binding affinities (Ki = 1-40 nM) and selectivities over both NET and DAT. Selected enantiomeric pairs of analogues were synthesized and both retained enantioselectivity as with S- and R-1, wherein S > R at the SERT. In addition, the enantiomeric pairs of 1 and 5 were tested for binding at the homologous bacterial leucine transporter (LeuT), wherein low affinities and the absence of enantioselectivity suggested distinctive binding sites for these compounds at SERT as compared to LeuT. These novel ligands will provide molecular tools to elucidate drug-protein interactions at the SERT and to relate those to behavioral actions in vivo.
Zhang, Peng,Cyriac, George,Kopajtic, Theresa,Zhao, Yongfang,Javitch, Jonathan A.,Katz, Jonathan L.,Newman, Amy Hauck
experimental part
p. 6112 - 6121
(2010/11/16)

PROCESSES FOR THE PREPARATION OF CITALOPRAM AND ITS INTERMEDIATE 5-AMINOPHTHALIDE
The invention relates to processes for the preparation of 5-amino-2-benzofuran- l(3H)-one of Formula (I), and to the use of this compound as an intermediate for the preparation of citalopram. The invention also relates to a process for the preparation of citalopram or a salt thereof, and pharmaceutical compositions that include the citalopram or a salt thereof.
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Page/Page column 10

(2010/11/24)

PROCESSES FOR PRODUCING 5-PHTHALANCARBONITRILE AND CITALOPRAM
A process for producing the compound represented by the formula (II) which comprises reacting the compound represented by the formula (I) with oxalyl chloride; and a process for producing the compound represented by the formula (III) which comprises a step in which the compound represented by the formula (I) is reacted with oxalyl chloride to obtain the compound represented by the formula (II) and a step in which the compound represented by the formula (II) is reacted with a 3-dimethylaminopropyl halide.
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Page/Page column 9-10

(2008/06/13)

CRYSTALLINE CITALOPRAM DIOL INTERMEDIATE ALKALI
The present invention relates to the diol intermediate of citalopram useful for treatment of depression, that is to say, the crystal of free alkali of 3-hydroxylmethyl-4-[1-(4-fluorophenyl)-1-hydroxyl-4-(dimethylamino)] butylbenzonitrile and the method of crystallization thereof. The present invention has disclosed the method to prepare pure citalopram and its purified salts through crystallization of the described alkali;the optical resolution method of citalopram diol intermediate, the method to prepare S-citalopram and its purified salts by crystals mentioned above. The present invention has also disclosed the method to prepare citalopram and its purified salts, S-citalopram and its purified salts, as well as pharmaceutical formulation thereof obtained. Using methods of the present invention, the quality and yield of the product can be signally improved, and the production cost of the medicinal material can be decreased.
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Page/Page column 10

(2008/06/13)

PROCESS FOR THE PREPARATION OF CITALOPRAM AND ESCITALOPRAM
A process is described for the preparation of citalopram (I) and of the active enantiomer thereof, escitalopram (II), which process comprises the cyclisation reaction of the corresponding precursor diol of the formula III or, respectively, IV in the presence of an azodicarboxylate, a phosphine and a strong base.
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Page/Page column 7-8

(2008/06/13)

IMPROVED PROCESS FOR THE MANUFACTURE OF CITALOPRAM HYDROBROMIDE
The present invention describes an improved process for the preparation of extremely pure 1-(4'-Fluorophenyl)-1-(3-dimethylaminopropyl)-5-phthalanecarbonitrile and its bromide salt (citalopram hydrobromide), which is a well known antidepressant. Other aspect of the invention are isolation of crystalline (4-Bromo-2-hydroxymethyl)phenyl-(4-fluorophenyl)-3-(dimethylaminopropyl)methanol (Bromodiol) and conversion of desmethylcitalopram which is formed during the cyanide exchange reaction, to Citalopram by heating with a mixture of formaldhyde and formic acid in chloroform. The resulting citalopram is conventionally purified using extraction methodology.
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Page/Page column 11

(2008/06/13)

PRODUCT
A process of purifying citalopram, either in racemic or enantiomeric form, which process comprises (i) providing a crude mixture comprising citalopram, either in racemic or enantiomeric form, dissolved in a water immiscible organic solvent, and which mixture also includes one or more citalopram derivatives which are present as citalopram. impurities; (ii) washing the crude mixture with at least one dilute aqueous solution of a polybasic acid, either in free form or as a partial alkali metal salt, so as to separate citalopram from citalopram impurities present in the crude mixture; and (iii) where required converting citalopram free base, separated from citalopram impurities further to step (ii), to a pharmaceutically acceptable salt.
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Page/Page column 11-12

(2008/06/13)

ONE POT SYNTHESIS OF CITALOPRAM FROM 5-CYANOPHTHALIDE
A process for one pot synthesis of citalopram is disclosed. The process comprises subjecting 5-cyano phthalide to Grignard reduction followed cyclization and followed by C-alkylation reaction to obtain citalopram without isolation and purification of any intermediates. In another embodiment, 5-cyano phthalide is subjected to sequential Grignard reactions followed by cyclization to obtain citalopram without isolation and purification of any intermediate stages.
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Page/Page column 10-11

(2008/06/13)

A METHOD FOR THE PREPARATION OF CITALOPRAM ACID ADDITION SALTS
The present invention discloses a simple in situ method for the purification of citalopram acid addition salts without isolating crystalline citalopram base as a solid, wherein citalopram base is treated with metal hydrides in solvent medium followed by acid addition, to remove structurally similar impurities by filtration to get crude citalopram acid addition salts. The resulting citalopram salts are subjected to simple purification to get pharmaceutically acceptable acid addition salts. The said citalopram base is prepared by subjecting 5-cyanophthalane to an eco-friendly and safe C-alkylation reaction with 3,N,N dimethylaminopropyl chloride in the presence of strong base in a mixture of dimethylsulfoxide and toluene.
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Page/Page column 8-9

(2010/02/13)

PREPARATION OF ESCITALOPRAM
Enantiomerically enriched citalopram is prepared by methylating enantiomerically enriched didesmethylcitalopram, obtained by directly resolving racemic didesmethylcitalopram using a chiral acid.
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Page/Page column 30

(2008/06/13)

A PROCESS FOR THE PREPARATION OF HIGH PURITY ESCITALOPRAM
The present invention discloses an improved process for the preparation of high purity escitalopram base of formula (I) by reacting the acid addition salt of formula (XVIII) with copper (I) cyanide and with or without copper (I) iodide in dimethylformamide medium at 145-150 °C. Cyanation on the acid addition salt of formula (XVIII) is found to be superior in yield and quality over the parent base compound of formula (XVII). The process is compatible to scale up operations thereby making the process commercially viable for escitalopram oxalate. Escitalopram oxalate is an antidepressant available in the market.
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Page/Page column 16-17

(2008/06/13)

Method for the preparation of citalopram
A method for the preparation of citalopram and its pharmaceutically acceptable salts is described; it's obtained starting from 5-cyanophthalide by reaction with a mixture of 4-fluorophenyl magnesium bromide and 3-dimethylaminopropyl magnesium chloride. The intermediate obtained is showed here-below: wherein X is an halogen, preferably chlorine or bromine, which is cyclized without any isolation.
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Page/Page column 5

(2008/06/13)

Method of manufacturing citalopram
The present invention provides, inter alia, a novel process for the preparation of Citalopram, a known antidepressant.
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Page/Page column 27

(2010/02/11)

Preparation of pure citalopram
The present invention relates to an industrially advantageous method for the purification of Citalopram (Formula I) wherein desmethyl citalopram (Formula II), present in crude Citalopram as an impurity, is methylated to produce pure Citalopram. The resulting Citalopram product is isolated as the base or a pharmaceutically acceptable salt thereof
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Page column 3

(2008/06/13)

PROCESS FOR THE MANUFACTURE OF CITALOPRAM HYDROBROMIDE FROM 5-BROMOPHTHALIDE
A process for the preparation of 1-(4′-fluorophenyl)-1-(3-dimethylamino-propyl)-5-phthalanecarbonitrile of formula (I), or a pharmaceutically acceptable salt thereof, comprising performing two successive Grignard reactions on 5-bromophthalide, wherein the 5-bromophthalide is reacted with the first Grignard reagent in the presence of a Lewis acid, so reducing by-product formation and improving yields.
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Page 4

(2010/02/06)

PROCESS FOR THE PREPARATION OF 1-(3-DIMETHYLAMINOPROPYL) -1-(4-FLUOROPHENYL) -1,3-DIHYDROISOBENZOFURAN -5-CARBONITRILE
The present invention is directed to novel processes for the preparation of citalopram comprising halogenation of a phthalide compound of formula II, wherein R is a suitable group to be changed to CN, to afford an acid halogenide compound of formula III wherein R is as defined above and X is halogen, and thereafter obtaining citalopram through two successive reactions with suitable organometallic halides or organoboranes or by a reaction with organometallic 4-fluorophenylhalide or 4-fluorophenylborane followed by reduction and alkylation, and an exchange of R to cyano to afford citalopram. The order of the reactions can be varied depending e.g. on the starting compound used.
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Page 16

(2010/11/30)

A process for hydrogenolysis of [1-(3-dimethylamino)propyl)]-1-(4-fluorophenyl)-1,3-dihydro-5-halo-isobenzofuran.
The present invention provides a process for decreasing the content of [1-(3-dimethylamino)propyl)]-1-(4-fluorophenyl)-1,3-dihydro-5-halo-isobenzofuran, a compound of formula 1, wherein X is halogen, by converting to a compound of formula 3, comprising subjecting [1-(3-dimethylamino)propyl)]-1-(4-fluorophenyl)-1,3-dihydro-5-halo-isobenzofuran present as impurity in crude 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile to hydrogenolysis.
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Page 12

(2008/06/13)

Process for the production of citalopram
The invention relates to a process for the manufacture of salts of citalopram in high purity. By the careful selection of solvents and the careful manipulation of the pH value, citalopram salts may be isolated in the absence of 5-chlorocitalopram, 5-bromocitalo-pram, desmethyl-citalopram and 5-carobxyamide citalopram.
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Page 4

(2008/06/13)

Process for the preparation of citalopram
Preparation of citalopram comprises the steps of: (a) converting the compound of Formula (I) to a compound of Formula (II), wherein R in Formula (I) represents a C2 to C5 alkylene group which may be substituted or unsubstituted, and R1 in the compounds of Formula (II) represents a carboxylic acid group or a salt or an ester thereof; and (b) converting the compound of Formula (II) to form citalopram or a pharmaceutically acceptable salt thereof, or a direct conversion of the compound of Formula (I) to citalopram
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Page 11

(2010/02/05)

Process for the preparation of citalopram hydrobromide
The present invention relates to an industrially advantageous process for the preparation of pure citalopram hydrobromide.
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Page 3

(2008/06/13)

PROCESS FOR THE PREPARATION OF HIGH PURITY CITALOPRAM AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
This invention discloses an improved process for the preparation of high purity citalopram base and its hydrobromide salt of formulae (I) and (Ia): which comprises: i. Isolation of crude citalopram base after water work up of the reaction into a non polar aromatic or dialkyl ether solvent. ii. Extraction of the citalopram base into aqueous organic acid. iii. Neutralization of acid layer with organic base to a controlled pH (7.0-8.0) iv. Extraction of the pure base into a non-polar aromatic or dialkyl ether solvent and crytallization form the same solvent after concentrating to certain volume under reduced pressure. v. Preparation of high purity citalopram hydrobromide in a non-polar aromatic or dialkyl ether solvent using 40-50 % HBr in acetic acid as HBr source and crystallizing out form the same solvent. Alternatively preparation of HBr salt in aqueous medium using aqueous HBr and crystallizing out from the same medium at 0 10 °C. vi. Recrystallization of high purity citalopram hydrobromide salt of pharmaceutically acceptable grade form a mixture of alcoholic solvent.
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Page 15-16

(2010/02/06)

PROCESS FOR THE PRODUCTION OF CITALOPRAM
The invention relates to a process for the manufacture of salts of citalopram in high purity. By the careful selection of solvents and the careful manipulation of the pH value, citalopram salts may be isolated in the absence of 5-chlorocitalopram, 5-bromocitalo-pram, desmethyl-citalopram and 5-carobxyamide citalopram.
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Page/Page column 10; 11

(2008/06/13)

PURIFICATION OF CITALOPRAM
Crude citalopram base is purified by adsorbtion on a solid support, washing the support to selectively remove impurities, and releasing the purified base from the support.
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Page/Page column 4

(2008/06/13)

Process for the preparation of 5-subtituted isobenzofurans
There is described a process for the preparation of citalopram and of its pharmaceutically acceptable salts, which comprises treating a 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbaldoxime, O-substituted preferably with a diphenylmethyl or triphenylmethyl group, with formic-acetic anhydride. Furthermore, the total synthesis of citalopram, as free base or in form of its pharmaceutically acceptable salt, starting from 5-formylphthalide is described.
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(2008/06/13)

Method for the preparation of citalopram
The present invention relates to a method for the preparation of citalopram or any of its enantiomers and acid addition salts thereof comprising reaction of a compound of formula II with a diene having the formula wherein X is O, S, SO2, —N═N—, —CO—O—, —O—CO—, or or with a diene having the formula wherein R is alkyl or optionally substituted aryl or arylalkyl. The invention also relates to intermediates used in the new process for the preparation of citalopram, as well as citalopram prepared according to the new process.
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(2008/06/13)

Method for the preparation of citalopram
The invention relates to a method for the preparation of citalopram comprising reaction of a compound of formula II with a compound having the formula wherein R is halogen or —O—SO2-X, wherein X is alkyl, alkenyl, alkynyl or optionally alkyl substituted aryl or aralkyl, and R1 is dimethylamino, halogen, —O—SO2-X wherein X is as defined above, provided that R is not halogen when R1 is dimethylamino; and if R1 is dimethylamino followed by isolation of citalopram base or a pharmaceutically acceptable acid addition salt thereof, and if R1 is halogen or —O—SO2-X, wherein X is as defined above, followed by conversion of the resulting compound of formula wherein R2 is halogen or a group of formula —O—SO2-X wherein X is as defined above to citalopram, followed by isolation of citalopram base or a pharmaceutically acceptable acid addition salt thereof.
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(2008/06/13)

Pharmaceutical composition containing citalopram
A solid unit dosage form comprising citalopram, which is prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, or by filling of said mixture in a hard gelatine capsule. Large crystals of a pharmaceutical acceptable salt of citalopram and method for the manufacture of said large crystals.
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(2008/06/13)

Improved process for the preparation of citalopram and its hydrobromide
A process is described for the preparation of citalopram (an anti-depressant drug), which process comprises the C-alkylation of 1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (5-cyanophthalane) with 3-dimethylaminopropylchloride in the presence of potassium tertiary butoxide. Suitably, the alkylation is carried out in the presence of dimethylsulphoxide (DMSO). The citalopram thereby produced can be isolated as a crystalline solid in one step from the reaction mixture by adding an equal volume of a water-miscible solvent, such as IPA, to the mixture. A process is also described for preparing citalopram hydrobromide, which process comprises reacting citalopram (base) with aqueous hydrobromic acid, such as at pH 1-3.
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(2008/06/13)

Improved process for the manufacture of citalopram hydrobromide from 5-bromophthalide
A process for the preparation of 1-(4'-fluorophenyl)-1-(3-dimethylamino-propyl)-5-phthalanecarbonitrile of formula (I), or a pharmaceutically acceptable salt thereof, comprising performing two successive Grignard reactions on 5-bromophthalide, wherein the 5-bromophthalide is reacted with the first Grignard reagent in the presence of a Lewis acid, so reducing by-product formation and improving yields.
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(2008/06/13)

Method for the preparation of citalopram
A method for the preparation of citalopram comprising reaction of a compound of formula 5-aminomethyl-1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran with an oxidising agent to prepare citalopram.
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(2008/06/13)

Process for preparing citalopram
Process for preparing purified citalopram or one of its salts that comprises the purification of citalopram by selective extractions of citalopram or of its impurities with organic solvents and water under specific conditions of pH and temperature. The crude citalopram can be prepared by a process that comprises reacting 1-[3-(dimethylamine)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-bromoisobenzofuran with copper cyanide.
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(2008/06/13)

Process for the preparation of citalopram
The present invention provides, inter alia, a novel process for the preparation of Citalopram, a known antidepressant.
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(2008/06/13)

Crystalline base of citalopram and hydrochoride or hydrobromide salt thereof
The present invention relates to the crystalline base of the well known antidepressant drug citalopram, 1-[3 -(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran-carbonitrile, formulations of said base, a process for the preparation of purified salts of citalopram, such as the hydrobromide, using the base, the salts obtained by said process and formulations containing such salts.
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Example 2

(2008/06/13)

PRODUCTION METHOD OF CITALOPRAM, INTERMMEDIATE THEREFOR AND PRODUCTION METHOD OF THE INTERMEDIATE
Citalopram can be industrially and economically produced and at a high yield by reacting a compound of the following formula [VI] with 3-(dimethylamino)propyl chloride in the presence of at least one of N,N,N′,N′-tetramethylethylenediamine and 1,3-dimethyl-2-imidazolidinone and a condensing agent. The compound of the following formula [III], which is a key compound for the production of citalopram, can be easily produced by subjecting the compound of the following formula [II] to reduction and cyclization. 1
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(2008/06/13)

Method for the preparation of citalopram
A method for the manufacture of citalopram characterized in (i) reaction of 1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-5-halophthalane with an activated magnesium to form the Grignard reagent [3-[1-(4-fluorophenyl)-1,3 dihydro-isobenzofuran-1-yl]propyl]dimethylamine 5-magnesium halide followed by (ii) reaction of [3-[1-(4-fluorophenyl)-1,3 dihydro-isobenzofuran-1-yl]propyl)dimethylamine 5-magnesium halide with a compound containing a —CN group bound to a leaving group to form citalopram.
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(2008/06/13)

Method for the preparation of citalopram
A method for the preparation of citalopram comprising reductive hydrolysis of a compound of Formula (IV) wherein R is a N,N-disubstituted amid group or an optionally substituted 4,5-dihydro-1,3-oxazol-2-yl group, and conversion of the resulting 5-formyl compound to citalopram.
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(2008/06/13)

Method for the preparation of citalopram
Method for the preparation of citalopram comprising reaction of a compound of Formula (IV) wherein R is halogen, or CF3—(CF2)n—SO2—, n being 0 to 8, with a cyanide source in the presence of a palladium catalyst and a catalytic amount of C+ or Zn2+, or with Zn(CN)2 in the presence of a palladium catalyst.
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(2008/06/13)

Method for the preparation of pure citalopram
The present invention relates to the process for the preparation and purification of citalopram (I) in which a compound of formula (II) wherein Z is iodo, bromo, chloro or CF3—(CF2)n—SO2—O—, n being 0, 1, 2, 3, 4, 5, 6, 7 or 8, is subjected to a cyanide exchange reaction with a cyanide source; the resultant crude citalopram product is optionally subjected to some initial purification and subsequently treated with an amide or an amide-like group forming agent; the reaction mixture is then subjected to an acid/base wash and/or crystallisation and recrystallisation of citalopram in order to remove the amides formed from the crude citalopram mixture; and the resulting citalopram product is optionally further purified, worked up and isolated as the base or a pharmaceutically acceptable salt thereof.
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(2008/06/13)

Process for the preparation of 1-(3-dimethylaminopropyl)-1-(4-Fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile
Method for the preparation of 1-(3-dimethylaminopropyl)-1-(4-fluoro-phenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram) comprising the reaction of a compound of formula wherein X is a halogen, with organometallic dimethylaminopropyl halide. Other aspects of the invention are new compounds of formula II and formula III and their preparation.
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(2008/06/13)

Process for the preparation of pure citalopram
A process for the preparation of citalopram of formula (I) in which a compound of formula (II) wherein Z is iodo, bromo, chloro or CF3—(CF2)n—SO2—O— n being 0, 1, 2, 3, 4, 5, 6, 7 or 8, is subjected to a cyanide exchange reaction in which the group Z is exchanged with cyanide by reaction with a cyanide source; the resultant crude citalopram product is optionally subjected to some initial purification and the crude citalopram base is subsequently subjected to a film distillation process; the resulting citalopram product is then optionally further purified and worked up and isolated as the base or a pharmaceutically acceptable salt thereof.
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(2008/06/13)