103146-25-4

Basic information

• Product Name: 4-[4-(Dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile
• Synonyms: (-)4-[4-(dimethylamino)-1-(4’-fluorophenyl)-1-(hydroxybutyl-3-(hydroxymethyl)] benzonitrile .hydrobromic (Intermediate of Citalopram);4-[4-(Dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile;Citadiol;EscitalopraM interMediate A;4-(4-(DIMETHYLAMINO)-1-(4-FLUOROPHENYL)-1-HYDROXY-1-BUTYL)-3-(HYDROXYMETHYL)BENZONITRILE HYDROBROMIDE;Citalopram Impurity O
• CAS NO: 103146-25-4
• Molecular Formula: C₂₀H₂₃FN₂O₂
• Molecular Weight: 342.41
• EINECS: 430-780-1
• Product Categories: API intermediates;Citalopram, Escitalopram
• Mol File: 103146-25-4.mol

Chemical Properties

• Boiling Point: 537.231 °C at 760 mmHg
• Flash Point: 278.708 °C
• Appearance: White solid
• Density: 1.223 g/cm³
• Storage Temp.: 2-8°C
• PKA: 12.97±0.29(Predicted)
• CAS DataBase Reference: 4-[4-(Dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile(CAS DataBase Reference)
• NIST Chemistry Reference: 4-[4-(Dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile(103146-25-4)
• EPA Substance Registry System: 4-[4-(Dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile(103146-25-4)

Safety Data

• Hazardous Substances Data: 103146-25-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Vonoprazan is used as a potassium-competitive acid blocker for the treatment of acid-related diseases such as gastroesophageal reflux disease (GERD) and peptic ulcers. Its application is based on its ability to reduce gastric acid secretion by inhibiting the H+/K+-ATPase enzyme, thereby alleviating symptoms and promoting healing of the affected areas.
Used in Gastroenterology:
In the field of gastroenterology, Vonoprazan is utilized as a therapeutic agent for managing gastric acid-related disorders. Its fast onset of action and superior efficacy contribute to improved patient outcomes and enhanced treatment options for conditions such as GERD and peptic ulcers.
Used in Drug Development:
Vonoprazan's unique mechanism of action and superior efficacy compared to traditional proton pump inhibitors make it a valuable compound in drug development. Researchers and pharmaceutical companies may explore its potential for the development of new drugs or drug combinations to address acid-related diseases and improve treatment options for patients.

Upstream product

• 717133-25-0 citalopram diol hydrochloride 
• 103146-26-5 4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrile hydrobromide 
• 19070-16-7 3-(N,N-dimethylamino)propylmagnesium chloride 
• 82104-74-3 1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile 
• 352-13-6 4-flourophenylmagnesium bromide 
• 460-00-4 1-Bromo-4-fluorobenzene 
• 5407-04-5 3-(dimethylamino)propyl chloride hydrochloride 
• 557-21-1 zinc(II) cyanide 
• 60666-70-8 2-bromo-5-chlorobenzyl alcohol 
• 3874-54-2 4-(4-fluorophenyl)-4-oxo-n-butyl chloride 
• 21739-93-5 2-bromo-5-chlorobenzoic acid 
• 128173-53-5 (x)C₂₀H₁₈O₈*C₂₀H₂₃FN₂O₂ 
• 260371-16-2 4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile 

Downstream Products

• 488787-59-3 (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile 
• 674806-14-5 (S)-(-)-3-(acetoxymethyl)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]benzonitrile 
• 219861-18-4 (R)-(+)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile 

Relevant articles and documents

Synthesis method of citalopram intermediate

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.

Preparation method of high-optical-purity escitalopram oxalate intermediate S-configuration diol

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.

PROCESS FOR PRODUCING HYDROBROMIDE OF DIOL COMPOUND

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

Synthesis of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethyl benzonitrile

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.

Added-metal-free catalytic nucleophilic addition of Grignard reagents to ketones

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.

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.

PREPARATION OF ESCITALOPRAM

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.

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.

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.

PROCESS FOR THE PREPARATION OF ESCITALOPRAM OR ITS ACID ADDITION SALTS

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.