128173-53-5

Usage

Uses

Used in Pharmaceutical Industry:
(-)-4-(4-Dimethylamino)-1-(4-fluorophenyl)-1-(hydroxybuty)-3-hydroxymethyl)-benzonitrile hemi D-(+)-di-p-toloyltartaric acid salt is used as an impurity in the synthesis of Escitalopram, an antidepressant medication. Its presence in the synthesis process is crucial for the development of this medication, which is an inhibitor of serotonin (5-HT) uptake. Escitalopram is widely used to treat various mental health conditions, including major depressive disorder, generalized anxiety disorder, and panic disorder.
As an impurity in the synthesis of Escitalopram, (-)-4-(4-Dimethylamino)-1-(4-fluorophenyl)-1-(hydroxybuty)-3-hydroxymethyl)-benzonitrile hemi D-(+)-di-p-toloyltartaric acid salt plays a significant role in the production of this essential medication. The complex structure of (-)-4-(4-Dimethylamino)-1-(4-fluorophenyl)-1-(hydroxybuty)-3-hydroxymethyl)-benzonitrile hemi D-(+)-di-p-toloyltartaric acid salt allows it to contribute to the overall effectiveness of Escitalopram, making it a valuable component in the pharmaceutical industry.

InChI:InChI=1/2C20H23FN2O2.C20H18O8/c2*1-23(2)11-3-10-20(25,17-5-7-18(21)8-6-17)19-9-4-15(13-22)12-16(19)14-24;1-11-3-7-13(8-4-11)19(25)27-15(17(21)22)16(18(23)24)28-20(26)14-9-5-12(2)6-10-14/h2*4-9,12,24-25H,3,10-11,14H2,1-2H3;3-10,15-16H,1-2H3,(H,21,22)(H,23,24)/t2*20-;15-,16-/m000/s1

Upstream product

• 32634-68-7 (2S,3S)-di-4-toluoyltartaric acid 
• 103146-25-4 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile 
• 460-00-4 1-Bromo-4-fluorobenzene 
• 352-13-6 4-flourophenylmagnesium bromide 
• 5407-04-5 3-(dimethylamino)propyl chloride hydrochloride 
• 19070-16-7 3-(N,N-dimethylamino)propylmagnesium chloride 
• 32634-66-5 Di-p-toluoyl-L-tartaric acid 
• 128196-01-0 escitalopram 
• 103146-26-5 4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrile hydrobromide 
• 82104-74-3 1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile 
• 717133-32-9 (+/-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile, oxalate 

Downstream Products

• 103146-25-4 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile 
• 219861-08-2 escitalopram oxalate 

Relevant academic research and scientific papers

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

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 (1S)-4-[4-(DIMETHYLAMINO)-1-(4'-FLUOROPHENYL)-1-HYDROXYBUTYL]-3-(HYDROXYMETHYL)-BENZONITRILE HEMI(+)-DI-(p-TOLUOYL) TARTARIC ACID SALT, AND PROCESS FOR PRODUCING (1S)-1-[3-(DIMETHYLAMINO)PROPYL]-1-(4-FLUOROPHENYL)-1,3-DIHYDRO-ISOBENZOFURAN-5-CARBO-NITRILE AND SALT THEREOF USING SAID TARTARIC ACID SALT

PROBLEM TO BE SOLVED: To provide a production process in which (1S)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile hemi(+)-di-(p-toluoyl) tartaric acid salt that has extremely high chemical purity and optical purity is obtained in high yield. SOLUTION: Provided is a production process characterized in producing a tartaric acid salt as a crystallized product by reacting racemate 4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile with (+)-di-(p-toluoyl) tartaric acid to yield (1S)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile hemi(+)-di-(p-toluoyl) tartaric acid salt and followed by carrying out crystallization of the tartaric acid salt with a solvent containing 1-butanol. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPO&INPIT

PRODUCTION METHOD OF (1S)-1-[3-(DIMETHYLAMINO)PROPYL]-1-(4-FLUOROPHENYL)-1,3-DIHYDROISOBENZOFURAN-5-CARBONITRILE OXALATE

PROBLEM TO BE SOLVED: To provide a (1S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (escitalopram) oxalate having extremely high optical purity and extremely little residual solvent. SOLUTION: The following production method is used: (1S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile oxalate, by 1 part by mass, is dissolved and heated in an organic solvent containing 8-15 parts by volume of ethanol, then the solution is cooled at a rate of at least 25°C/h or more to crystallize so as to obtain the oxalate as a crystallized product. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT

PRODUCTION METHOD OF S-4-[4-(DIMETHYLAMINO)-1-(4'-FLUOROPHENYL)-1-HYDROXYBUTYL]-3-(HYDROXYMETHYL)-BENZONITRILE, AND PRODUCTION METHOD OF (1S)-1-[3-(DIMETHYLAMINO)PROPYL]-1-(4-FLUOROPHENYL)-1,3-DIHYDROISOBENZOFURAN-5-CARBONITRILE AND SALT THEREOF USING THE COMPOUND

PROBLEM TO BE SOLVED: To provide a (1S)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile having extremely high chemical purity and optical purity, and escitalopram having extremely high optical purity and its salt obtained from the above compound. SOLUTION: The following production method is used: (1S)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile hemi(+)-di-(p-toluoyl) tartrate is made to react in a solvent comprising at least one sparingly water-soluble organic solvent selected from the group consisting of aromatic hydrocarbons and halogenated hydrocarbons, and water so as to obtain an educt of the tartrate. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT

PRODUCTION METHOD OF (1S)-4-[4-(DIMETHYLAMINO)-1-(4'-FLUOROPHENYL)-1-HYDROXYBUTYL]-3-(HYDROXYMETHYL)-BENZONITRILE HEMI(+)-DI-(p-TOLUOYL) TARTRATE, AND PRODUCTION METHOD OF (1S)-1-[3-(DIMETHYLAMINO)PROPYL]-1-(4-FLUOROPHENYL)-1,3-DIHYDROISOBENZOFURAN-5-CARBONITRILE AND SALT THEREOF USING THE TARTRATE

PROBLEM TO BE SOLVED: To provide a (1S)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile hemi(+)-di-(p-toluoyl) tartrate having extremely high optical purity, and escitalopram having extremely high optical purity and its salt obtained from the above tartrate. SOLUTION: A production method is used, in which a crude (1S)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile hemi(+)-di-(p-toluoyl) tartrate is recrystallized in a mixture solvent of alcohol and water, with the content of the water being 3.0 to 15.0 mass% in the mixture solvent of the alcohol and water, so as to obtain a recrystallized material of the above tartrate having extremely high optical purity. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT

METHOD FOR RESOLUTION OF CITALOPRAM INTERMEDIATE 5-CYANO DIOL

Provided is a method for resolution of formula 4-[4-dimethylamino-1-(4-fluorophenyl)-1-hydroxylbutyl]-3-hydroxy-methyl benzonitrile as an enantiomer thereof, comprising the following steps: a salt of (S)-4-[4-dimethylamino-1-(4-fluorophenyl)-1-hydroxylbutyl]-3-hydroxymethyl benzonitrile with a resolving agent D-(+)di-p-toluoyl tartaric acid was crystallized in a resolving solvent; the method is characterized in that the resolving solvent is an ether solvent. Also provided is a new crystal form of the resolved intermediate.

NOVEL RECOVERY AND RECYCLING PROCESS OF RACEMIC 4-(4-DIMETHYLAMINO)-1-(4'-FLUOROPHENYL)-1-(HYDROXYBUTYL)-3-(HYDROXYMETHYL)-BENZONITRILE

Disclosed herein is a novel recovery and recycling process of racemic 4-(4- dimethylamino)-1-(4'-fluorophenyl)-1-(hydroxybutyl)-3-(hydroxymethyl)- benzonitrile (hereinafter referred as cyanodiol). The racemic cyanodiol is an intermediate useful for preparation of Citalopram, Escitalopram or pharmaceutically acceptable salts thereof.

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.