- Synthesis method of citalopram intermediate
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The invention provides a preparation method of a citalopram intermediate 4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl) benzonitrile. The method provided by the invention has the advantages of cheap and easily available raw materials, short reaction steps, high yield, simple post-treatment, easy operation and the like, reduces the cost, has certain technical advantages,and is suitable for large-scale industrial production.
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- Preparation method of high-optical-purity escitalopram oxalate intermediate S-configuration diol
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The invention discloses a preparation method of an escitalopram oxalate intermediate S-configuration diol. The preparation method comprises the following steps: (1) carrying out hydrobromic acid salinization on racemic diol (4-(4-dimethylamino-1-p-fluorophenyl-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrile) to obtain free racemic diol; and (2) carrying out chiral resolution on the free racemic diolby using (+)-di-p-toluoyl-D-tartaric acid in isopropanol by adopting a standing resolution mode, and conducting crystallization to obtain an escitalopram oxalate intermediate S-configuration diol crude product, and carrying out recrystallization refining on the crude product in an organic solvent to obtain the escitalopram oxalate intermediate with high optical purity. The method disclosed by theinvention is high in resolution efficiency and high in product yield, and the prepared diol intermediate is high in optical purity and can meet the requirements of industrial production.
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Page/Page column 5-9
(2019/08/12)
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- PROCESS FOR PRODUCING HYDROBROMIDE OF DIOL COMPOUND
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PROBLEM TO BE SOLVED: To provide a method for producing 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile hydrobromide with a high purity and a high isolation yield. SOLUTION: Provided is a process for producing 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile hydrobromide characterized in bringing 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile and hydrogen bromide into contact in a mixed solvent of an ester-based solvent and water. SELECTED DRAWING: None COPYRIGHT: (C)2019,JPOandINPIT
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Paragraph 0038-0039
(2020/05/14)
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- Synthesis of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethyl benzonitrile
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The invention relates to synthesis of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethyl benzonitrile. The synthesis comprises the following steps: 1) dispersing 5-cyano isobenzofuranone into a solvent for optimizing a Grignard reaction, adding a p-fluorophenyl magnesium bromide solution, and performing a primary Grignard reaction, wherein the solvent is chlorinated hydrocarbon, ethanediol diether, 1,3-propanediol diether, 1,4-butanediol diether or 1,4-dioxane; 2) continuing to add a 1-(3-(N, N-dimethylamino) propyl) magnesium chloride solution, and performing a secondary Grignard reaction to obtain a mixed reaction solution; and 3) performing posttreatment on the mixed reaction solution to obtain 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethyl benzonitrile. By the synthesis method, generation of byproducts is effectively inhibited and the yield and the purity of the target product are improved.
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Paragraph 0059; 0064-0066; 0067; 0089; 0090; 0113-0114
(2017/07/21)
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- Added-metal-free catalytic nucleophilic addition of Grignard reagents to ketones
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On the basis of the investigation of the combinational effect of quaternary ammonium salts and organic bases, an added-metal-free catalytic system for nucleophilic addition reactions of a variety of Grignard reagents to diverse ketones in THF solvent has been developed to produce tertiary alcohols in good to excellent yields. By using tetrabutylammonium chloride (NBu4Cl) as a catalyst and diglyme (DGDE) as an additive, this system strongly enhances the efficiency of addition at the expense of enolization and reduction. NBu 4Cl should help to shift the Schlenk equilibrium of Grignard reagents to the side of dimeric Grignard reagents to favor the additions of Grignard reagents to ketones via a favored six-membered transition state to form the desired tertiary alcohols, and DGDE should increase the nucleophilic reactivities of Grignard reagents by coordination. This catalytic system has been applied in the efficient synthesis of Citalopram, an effective U.S. FDA-approved antidepressant, and a recyclable version of this catalytic synthesis has also been devised.
- Zong, Hua,Huang, Huayin,Liu, Junfeng,Bian, Guangling,Song, Ling
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experimental part
p. 4645 - 4652
(2012/07/03)
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- Preparation of Escitalopram, Its Salts and Intermediates
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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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- PREPARATION OF ESCITALOPRAM
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A substantially pure (S)-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile intermediate for preparing escitalopram is prepared by: a) combining racemic (±)-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile with (?)-di-p-toluoyltartaric acid, in a solvent; b) separating a solid phase comprising a salt of (?)-di-p-toluyltartaric acid with (R)-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile enantiomer, and a liquid phase comprising a salt of (?)-di-p-toluoyltartaric acid with (S)-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxy-butyl]-3-(hydroxymethyl)benzonitrile enantiomer; c) reacting the liquid phase with a base and isolating enantiomerically enriched (S)-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile enantiomer; d) combining enantiomerically enriched (S)-enantiomer obtained in c) with (+)-di-p-toluoyltartaric acid, in a solvent; and e) reacting a precipitate from d) with a base.
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Page/Page column 4
(2010/10/19)
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- 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
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(±)-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
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experimental part
p. 6112 - 6121
(2010/11/16)
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- PREPARATION OF ESCITALOPRAM, ITS SALTS AND INTERMEDIATES
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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 17; 19
(2010/04/03)
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- PROCESS FOR THE PREPARATION OF ESCITALOPRAM OR ITS ACID ADDITION SALTS
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The present invention relates to Formula (I), a process for the preparation of highly pure Escitalopram or its acid addition salts which comprises: a) reacting racemic diol or its ester derivative (III) with an optically active acid and at least one solvent to get enantiomerically pure diastereomer (IIIA); b) separating the enantiomerically pure diastereomer (IIIA) from its optically active acid salt by treating it with base and followed by stereo selective cyclization; c) separating the Escitalopram base.
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Page/Page column 11
(2010/11/24)
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- CRYSTALLINE CITALOPRAM DIOL INTERMEDIATE ALKALI
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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 9
(2008/06/13)
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- ONE POT SYNTHESIS OF CITALOPRAM FROM 5-CYANOPHTHALIDE
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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)
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- METHOD FOR THE SEPARATION OF INTERMEDIATES WHICH MAY BE USED FOR THE PREPARATION OF ESCITALOPRAM
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The present invention relates to a novel method for the preparation of diol intermediates having the formula (II) and/or the opposite enantiomer of an acylated diol having the formula (IV) useful for the preparation of escitalopram involving selective enzymatic acylation or deacylation.
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