219861-08-2

Usage

Uses

1. Pharmaceutical Industry:
Escitalopram oxalate is used as a pharmaceutical primary standard for the quantification of the analyte in pharmaceutical formulations using analytical techniques.
2. Antidepressant:
Escitalopram oxalate is used as an inhibitor of serotonin (5-HT) uptake for treating depression and anxiety disorders. It is twice as effective as the racemate and over 100 fold more potent than the R-enantiomer in inhibiting the 5HT reuptake in vivo in rat brain synaptosomes.
3. Labelled Inhibitor:
Escitalopram oxalate is used as a labelled inhibitor of serotonin (5-HT) uptake, serving as an antidepressant in various research and clinical applications.
4. Antineoplastic:
Escitalopram oxalate is used as an antineoplastic agent, potentially aiding in the treatment of cancer by modulating various oncological signaling pathways.
5. Quality Control:
Escitalopram oxalate serves as a pharmaceutical secondary standard for application in quality control, providing a convenient and cost-effective alternative to the preparation of in-house working standards for pharmaceutical laboratories and manufacturers.

Originator

Lundbeck (Denmark)

Biochem/physiol Actions

Escitalopram is a selective serotonin reuptake inhibitor (SSRI), the S-enantiomer and eutomer of citalopram.

Synthesis

The synthesis of escitalopram was carried out in several different routes [30-33]. 5-Cyanophthalide (72) was treated with Grignard reagent 73 at 0°C to provide intermediate 75 which was reacted in situ with another Grignard reagent 76 to afford the diol in a one-pot process. Racemic diol 77 was resolved using (+)-p-toluoyltartaric acid to afford desired S isomer 78 in 55% yield. The ring closure reaction was carried out at 0°C using methanesulfonyl chloride in toluene to furnish escitalopram (7) in 60% yield.

InChI:InChI=1/C20H21FN2O.C2H2O4/c1-23(2)11-3-10-20(17-5-7-18(21)8-6-17)19-9-4-15(13-22)12-16(19)14-24-20;3-1(4)2(5)6/h4-9,12H,3,10-11,14H2,1-2H3;(H,3,4)(H,5,6)/t20-;/m1./s1

Synthetic route

oxalic acid (144-62-7) + (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile (488787-59-3) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Stage #1: (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile With methanesulfonyl chloride; triethylamine In dichloromethane at 5℃; for 2h; Stage #2: oxalic acid	65%
Stage #1: (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile With potassium carbonate; 2,5-dichloronitrobenzene In dimethyl sulfoxide at 20 - 100℃; for 15h; Stage #2: oxalic acid In acetone at 30℃;
Stage #1: (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile With bis(phenyl) carbonate; sodium methylate In acetonitrile at 79 - 80℃; for 4h; Stage #2: oxalic acid In ethyl acetate for 3h; Reagent/catalyst; Reflux;	3.02 g

(1S)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile hemi-(+)-di-(p-toluoyl) tartaric acid salt + oxalic acid (144-62-7) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Stage #1: (1S)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile hemi-(+)-di-(p-toluoyl) tartaric acid salt With sodium hydroxide In diethyl ether; water at 25℃; for 0.5h; Stage #2: With triethylamine In diethyl ether; water; toluene at 5℃; for 0.5h; Stage #3: oxalic acid Further stages;	85%
Stage #1: (1S)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile hemi-(+)-di-(p-toluoyl) tartaric acid salt With ammonia In dichloromethane; water pH=9; Stage #2: With triethylamine; p-toluenesulfonyl chloride In dichloromethane at 5℃; for 1h; Stage #3: oxalic acid In acetone	n/a

(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(4-nitrobenzoyloxymethyl)benzonitrile hydrochloride + oxalic acid (144-62-7) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Stage #1: (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(4-nitrobenzoyloxymethyl)benzonitrile hydrochloride With sodium hydrogencarbonate In water; ethyl acetate Stage #2: With potassium carbonate In dimethyl sulfoxide at 90 - 100℃; for 2h; Stage #3: oxalic acid	82%

oxalic acid (144-62-7) + escitalopram (128196-01-0) → escitalopram oxalate (219861-08-2)

Conditions	Yield
In acetone at 25 - 30℃; Industry scale;	98.57%
In acetonitrile at 50℃; for 0.5h;	89%
In acetone at 25 - 45℃; for 1.5h;	85%

(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxymethyl)benzonitrile hydrochloride (878007-22-8) + oxalic acid (144-62-7) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Stage #1: (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxymethyl)benzonitrile hydrochloride With potassium carbonate at 100℃; for 0.5h; Stage #2: oxalic acid	64%

formaldehyd (50-00-0) + oxalic acid (144-62-7) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Stage #1: 1-(3-aminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile; (-)-di-p-toluoyl tartaric acid salt With sodium hydroxide In water; toluene pH=11 - 13; Stage #2: formaldehyd; formic acid In water at 95 - 100℃; for 3 - 4h; Stage #3: oxalic acid With hydrogenchloride more than 3 stages;

(S)-citalopram (L)-tartrate (1073819-95-0) + oxalic acid (144-62-7) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Stage #1: (S)-citalopram (L)-tartrate With sodium hydroxide In water; ethyl acetate pH=10; Stage #2: oxalic acid In ethyl acetate

escitalopram (128196-01-0) → escitalopram oxalate (219861-08-2)

Conditions	Yield
With oxalic acid In acetone at 10℃; for 1h;
With oxalic acid In ethanol at 5 - 20℃; for 10.5h; Product distribution / selectivity;

oxalic acid (144-62-7) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Stage #1: escitalopram With hydrogen bromide In isopropyl alcohol at 20℃; for 2.16667h; pH=3.5 - 4; Stage #2: With ammonia In water; ethyl acetate for 0.5h; pH=9 - 9.5; Stage #3: oxalic acid In isopropyl alcohol at 20 - 40℃; for 2.16667h; Purification / work up;
Stage #1: oxalic acid With ammonia In water; ethyl acetate pH=9 - 9.5; Stage #2: oxalic acid In isopropyl alcohol at 20 - 40℃; for 2.16667h; Purification / work up;
Stage #1: (+)-(S)-citalopram hydrobromide With ammonia In water; ethyl acetate pH=9 - 9.5; Stage #2: oxalic acid In isopropyl alcohol at 20 - 40℃; for 2.16667h; Purification / work up;

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

Conditions	Yield
Multi-step reaction with 3 steps 1.1: isopropyl alcohol / 3 h / 20 - 45 °C 2.1: ammonia / water / pH ~ 9 2.2: 3 h / -5 °C 3.1: isopropyl alcohol / 0.5 h / 50 - 60 °C View Scheme
Multi-step reaction with 3 steps 1.1: isopropyl alcohol / 25 - 70 °C / Resolution of racemate 2.1: ammonium hydroxide / dichloromethane; water / 1 h / 5 - 15 °C 2.2: -5 - 5 °C 3.1: acetone / 20 - 40 °C View Scheme
Multi-step reaction with 4 steps 1.1: isopropyl alcohol / 25 - 35 °C 2.1: sodium hydroxide / diethyl ether; water / 0.5 h / 25 °C 3.1: triethylamine / toluene / 0.5 h / 5 °C 3.2: 1 h / 5 °C 4.1: acetone / 1.5 h / 25 - 45 °C View Scheme

Citalopram oxalate → (-)-Citalopram oxalate + escitalopram oxalate (219861-08-2)

Conditions	Yield
With stainless steel column (100 mm L x 4.6 mm i.d) packed with iniferter-mediated grafting of molecularly imprinted polymers on porous silica beads In acetonitrile at 40℃; pH=3; Resolution of racemate;

4-flourophenylmagnesium bromide (352-13-6) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: tetrahydrofuran / 0.25 h / -5 °C 1.2: 0.5 h / -5 - 20 °C 1.3: pH 2 2.1: isopropyl alcohol / 3 h / 20 - 45 °C 3.1: ammonia / water / pH ~ 9 3.2: 3 h / -5 °C 4.1: isopropyl alcohol / 0.5 h / 50 - 60 °C View Scheme
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 4 h / 5 - 15 °C / Inert atmosphere 1.2: 4 h / 0 - 15 °C 2.1: hydrogen bromide / 1.5 h / 5 - 30 °C 3.1: sodium hydroxide / water / 0.5 h / 25 °C 3.2: 4 h / 25 - 40 °C 4.1: sodium hydroxide / water; toluene / 0.5 h / 25 °C 4.2: 0.25 h / 25 °C 4.3: 1 h / -15 °C 5.1: acetonitrile / 4.5 h / 25 - 50 °C View Scheme

3-(N,N-dimethylamino)propylmagnesium chloride (19070-16-7) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: tetrahydrofuran / 0.25 h / -5 °C 1.2: 0.5 h / -5 - 20 °C 1.3: pH 2 2.1: isopropyl alcohol / 3 h / 20 - 45 °C 3.1: ammonia / water / pH ~ 9 3.2: 3 h / -5 °C 4.1: isopropyl alcohol / 0.5 h / 50 - 60 °C View Scheme
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 4 h / 5 - 15 °C / Inert atmosphere 1.2: 4 h / 0 - 15 °C 2.1: hydrogen bromide / 1.5 h / 5 - 30 °C 3.1: sodium hydroxide / water / 0.5 h / 25 °C 3.2: 4 h / 25 - 40 °C 4.1: sodium hydroxide / water; toluene / 0.5 h / 25 °C 4.2: 0.25 h / 25 °C 4.3: 1 h / -15 °C 5.1: acetonitrile / 4.5 h / 25 - 50 °C View Scheme

1-Bromo-4-fluorobenzene (460-00-4) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: iodine; magnesium / tetrahydrofuran / 5 h / 80 - 85 °C / Reflux 2.1: tetrahydrofuran / 0.25 h / -5 °C 2.2: 0.5 h / -5 - 20 °C 2.3: pH 2 3.1: isopropyl alcohol / 3 h / 20 - 45 °C 4.1: ammonia / water / pH ~ 9 4.2: 3 h / -5 °C 5.1: isopropyl alcohol / 0.5 h / 50 - 60 °C View Scheme

3-(dimethylamino)propyl chloride hydrochloride (5407-04-5) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium hydroxide / water / 0 - 5 °C 1.2: 4 h / 100 - 110 °C / Reflux 2.1: tetrahydrofuran / 0.25 h / -5 °C 2.2: 0.5 h / -5 - 20 °C 2.3: pH 2 3.1: isopropyl alcohol / 3 h / 20 - 45 °C 4.1: ammonia / water / pH ~ 9 4.2: 3 h / -5 °C 5.1: isopropyl alcohol / 0.5 h / 50 - 60 °C View Scheme

(R)-4-(4-dimethylamino-1-(4'-fluorophenyl)-1-hydroxybutyl)-3-hydroxymethylbenzonitrile, salt with (+)-O,O'-di-p-toluoyltartaric acid (917483-01-3) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: ammonia / water / pH ~ 9 1.2: 3 h / -5 °C 2.1: isopropyl alcohol / 0.5 h / 50 - 60 °C View Scheme

(-)-(S)-4-(4-dimethylamino-1-(4'-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)-benzonitrile (+)-di-p-toluoyl-D-tartaric acid salt → escitalopram oxalate (219861-08-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: ammonium hydroxide / dichloromethane; water / 1 h / 5 - 15 °C 1.2: -5 - 5 °C 2.1: acetone / 20 - 40 °C View Scheme

1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile (82104-74-3) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 4 h / 5 - 15 °C / Inert atmosphere 1.2: 4 h / 0 - 15 °C 2.1: hydrogen bromide / 1.5 h / 5 - 30 °C 3.1: sodium hydroxide / water / 0.5 h / 25 °C 3.2: 4 h / 25 - 40 °C 4.1: sodium hydroxide / water; toluene / 0.5 h / 25 °C 4.2: 0.25 h / 25 °C 4.3: 1 h / -15 °C 5.1: acetonitrile / 4.5 h / 25 - 50 °C View Scheme

4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrile hydrobromide (103146-26-5) → escitalopram oxalate (219861-08-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water / 0.5 h / 25 °C 1.2: 4 h / 25 - 40 °C 2.1: sodium hydroxide / water; toluene / 0.5 h / 25 °C 2.2: 0.25 h / 25 °C 2.3: 1 h / -15 °C 3.1: acetonitrile / 4.5 h / 25 - 50 °C View Scheme

Upstream product

• 144-62-7 oxalic acid 
• 128196-01-0 escitalopram 
• 50-00-0 formaldehyd 
• 1073819-95-0 (S)-citalopram (L)-tartrate 
• 488787-59-3 (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile 
• 128173-53-5 (1S)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile hemi-(+)-di-(p-toluoyl) tartaric acid salt 
• 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 
• 917483-01-3 (R)-4-(4-dimethylamino-1-(4'-fluorophenyl)-1-hydroxybutyl)-3-hydroxymethylbenzonitrile, salt with (+)-O,O'-di-p-toluoyltartaric acid 
• 128173-53-5 (-)-(S)-4-(4-dimethylamino-1-(4'-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)-benzonitrile (+)-di-p-toluoyl-D-tartaric acid salt 
• 878007-22-8 (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxymethyl)benzonitrile hydrochloride 

Downstream Products

• 128196-01-0 escitalopram 
• 1373405-37-8 C₂₀H₁₈O₈*C₂₀H₂₁FN₂O 

Relevant academic research and scientific papers

Iniferter-mediated grafting of molecularly imprinted polymers on porous silica beads for the enantiomeric resolution of drugs

A surface-imprinted chiral stationary phase for the enantiomeric resolution of the antidepressant drug, citalopram, is presented in this work. N, N′-diethylaminodithiocarbamoylpropyl(trimethoxy)silane has been used as silane iniferter for the surface functionalization of the solid silica support. A molecularly imprinted polymer thin film, in the nm scale, was then grafted on the silanized silica using itaconic acid as the functional monomer and ethylene glycol dimethacrylate as the cross-linker in the presence of the template S-citalopram. The total monomer amount was calculated to obtain the desired thickness. Non-imprinted stationary phases were prepared similarly in the absence of S-citalopram. Characterization of the materials was carried out by scanning electron microscopy, thermogravimetric analysis, elemental analysis and Fourier transform infrared spectroscopy. Stationary phases have been applied to the chromatographic separation of the target. Conditions for best chromatographic resolution of the enantiomers were optimized, and it was found that a mobile phase consisting of a mixture of formate buffer (40 mM, pH 3) and acetonitrile (30:70 v/v) at 40 °C provided best results. Binding behaviour of the developed material was finally assessed by batch rebinding experiments. The obtained binding isotherm was fitted to different binding models being the Freundlich-Langmuir model, the one that best fitted the experimental data. The developed material has shown high selectivity for the target enantiomer, and the stationary phase could be undoubtedly exploited for chiral separation of the drug.

A New method for the production of citalopram and escitalopram using carbonates

In production of citalopram and escitalopram, the present invention relates to methods for producing citalopram and escitalopram of high purity and high yield and producing addition salt using the same which do not separately separate and obtain an intermediate compound before a cyclization reaction and conduct a cyclization reaction of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile, represented by chemical formula 3, or (S)-(-)-4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile, represented by chemical formula 3a, with a carbonate compound without a post treatment process such as separation, concentration, etc. of the intermediate compound.COPYRIGHT KIPO 2020

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

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 (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

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

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)-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 chemical purity and 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 dissolved within a temperature range of 40°C or lower and crystallized to obtain a crystallized product of the above tartrate. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT

New process for preparing Citalopram and Escitalopram

The present invention provides a production method comprising the steps of: producing a compound of chemical formula 2 by esterifying a compound of chemical formula 3 with a compound of chemical formula 4; and synthesizing citalopram by cyclizing the compound of chemical formula 2 under the presence of a base. In the formulas, X is a leaving group, and Y is selected from H, NO_2, CF_3, CN, or Cl. According to the present invention, citalopram and escitalopram are produced at high purity and high yield.COPYRIGHT KIPO 2017

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.