128196-01-0

Usage

Uses

Used in Pharmaceutical Industry:
Escitalopram is used as an antidepressant medication for the treatment of major depressive disorder, generalized anxiety disorder, panic disorder, social anxiety disorder, and obsessive-compulsive disorder. It functions as a selective serotonin reuptake inhibitor, which helps to increase the levels of serotonin in the brain, leading to an improvement in mood and a reduction in anxiety.
Used in Antidepressant Applications:
Escitalopram is used as a therapeutic agent for the treatment of depression. It works by inhibiting the reuptake of serotonin, a neurotransmitter that plays a crucial role in regulating mood, sleep, and appetite. By increasing the availability of serotonin in the brain, Escitalopram helps to alleviate the symptoms of depression and improve the overall well-being of the patient.

Biological Activity

escitalopram （lexapro，cipralex）is a selective inihibitor of serotonin(5-ht) reuptake (ssri) with a ki value of 6.6nm for [3h]-5-ht uptake [1].escitalopram is the s-(+)-enantiomer of citalopram and has the inhibition of [3h]-5-ht uptake and [125i]-rti-55 binding in cos-1 cells expressing the human serotonin transporter (5-htt) with ki values of 6.6±1.4nm and 3.9±2.2nm, respectively. in addition, escitalopram has been reported to inhibit the accumulation of 3h-labelled monoamines into rat brain synaptosomes in vitro with ic50 values of 2.1±0.75nm, 2500±202nm and 40000±15500nm for [3h]-5-ht, [3h]-i-na and [3h]-da, respectively. apart from these, escitalopram has shown the in vitro affinity for rat histamine h1 receptors and the rat sigma σ1 site with ki values of 1500±780nm and 100±71nm, respectively [1].

Mechanism of action

Escitalopram is the S-enantiomer of citalopram that binds with high affinity and selectivity to the human SERT equivalent to (±)-citalopram. It has been reported that nearly all the activity resides in the S-enantiomer and that R-citalopram actually counteracts the action of the S-enantiomer. Studies show that escitalopram exhibits twice the activity of citalopram and is at least 27 times more potent than the R-enantiomer. The R-enantiomer inhibits the S-enantiomer at the transporter. Escitalopram's mechanism of action is common to the SSRIs.

Pharmacokinetics

The pharmacokinetics for escitalopram does not exhibit stereoisomer selectivity and, therefore, is similar to that for citalopram. Likewise, it exhibits linear pharmacokinetics so that plasma levels increase proportionately and predictably with increased doses, and its half-life of 27 to 32 hours is consistent with once-daily dosing. It also has been found that R-citalopram is cleared more slowly than the S-enantiomer. Therefore, when the drug is used as a racemic mixture (citalopram), the inactive isomer predominates at steady state. This is an added incentive for use of the enantiomerically pure escitalopram. Escitalopram has negligible effects on CYP isoforms, suggesting a low potential for drug–drug interactions. Escitalopram is indicated for patients with major depressive disorder, generalized anxiety disorder, panic disorder, and social anxiety disorder.

Clinical Use

SSRI antidepressant:Depressive illnessPanic and social anxiety disorder

Drug interactions

Potentially hazardous interactions with other drugsAnalgesics: increased risk of bleeding with aspirin and NSAIDs; risk of CNS toxicity increased with tramadol.Anti-arrhythmics: increased risk of ventricular arrhythmias with amiodarone, disopyramide and dronedarone - avoid.Antibacterials: increased risk of ventricular arrhythmias with IV erythromycin, moxifloxacin, pentamidine and telithromycin.Anticoagulants: effect of coumarins possibly enhanced; possibly increased risk of bleeding with dabigatran.Antidepressants: avoid concomitant use with MAOI, increased risk of toxicity; increased risk of CNS toxicity with moclobemide - avoid concomitant use; avoid concomitant use with St John’s wort; possibly enhanced serotonergic effects with dapoxetine and duloxetine; can increase concentration of tricyclics; increased agitation and nausea with tryptophan; increased risk of CNS toxicity with rasagiline; possible increased risk of convulsions with vortioxetineAntiepileptics: convulsive threshold lowered.Antihistamines: increased risk of ventricular arrhythmias with mizolastine - avoid.Antimalarials: avoid concomitant use with artemether/lumefantrine and piperaquine with artenimol; possible increased risk of ventricular arrhythmias with chloroquine and quinine.Antipsychotics: possibly increased risk of ventricular arrhythmias with haloperidol, phenothiazines and pimozide - avoid.Antivirals: concentration possibly increased by ritonavir.Beta-blockers: increased risk of ventricular arrhythmias with sotalol - avoid.Dopaminergics: avoid with selegiline; increased risk of CNS toxicity with rasagiline.5HT1 agonist: increased risk of CNS toxicity with sumatriptan; possibly increased risk of serotonergic effects with naratriptan.Linezolid: use with care, possibly increased risk of side effects.Lithium: increased risk of CNS effectsMethylthioninium: risk of CNS toxicity - avoid if possible.

Metabolism

Escitalopram is metabolised in the liver to the demethylated and didemethylated metabolites. Both of these are pharmacologically active. Alternatively, the nitrogen may be oxidised to form the N-oxide metabolite. Both parent substance and metabolites are partly excreted as glucuronides. After multiple dosing the mean concentrations of the demethyl and didemethyl metabolites are usually 28-31% and <5%, respectively, of the escitalopram concentration. Biotransformation of escitalopram to the demethylated metabolite is mediated primarily by CYP2C19. Some contribution by the enzymes CYP3A4 and CYP2D6 is possible. The major metabolites have a significantly longer half-life than the parent drug.Escitalopram and major metabolites are assumed to be eliminated by both hepatic and renal routes, with the major part of the dose excreted as metabolites in the urine.

references

[1] sánchez c1, bergqvist pb, brennum lt, gupta s, hogg s, larsen a, wiborg o. escitalopram, the s-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. psychopharmacology (berl). 2003 jun;167(4):353-62. epub 2003 apr 26.

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)

Upstream product

• 852705-13-6 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-5-bromo-1,3-dihydroisobenzofuran methanesulfonate salt 
• 544-92-3 copper(I) cyanide 
• 852705-11-4 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-5-bromo-1,3-dihydroisobenzofuran benzoate salt 
• 852705-14-7 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-5-bromo-1,3-dihydroisobenzofuran trifluoromethanesulfonate salt 
• 852705-15-8 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-5-bromo-1,3-dihydroisobenzofuran perchlorate salt 
• 852705-10-3 C₂H₄O₂*C₁₉H₂₁BrFNO 
• 59729-33-8 1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile 
• 166037-78-1 (+)-Didemethylcitalopram 
• 50-00-0 formaldehyd 
• 64-18-6 formic acid 
• 488148-14-7 (S)-(+)-3-(5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)-N,N-dimethylpropan-1-amine 
• 878655-30-2 (S)-{3-[5-iodo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl}dimethylamine 
• 1073819-95-0 (S)-citalopram (L)-tartrate 
• 219861-18-4 (R)-(+)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile 

Downstream Products

• 817203-55-7 (S)-1-(3-chloropropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile 
• 144025-14-9 (+)-Desmethylcitalopram 
• 917482-45-2 (+)-Citalopram N-oxide 
• 526204-44-4 (S)-1-(4-Fluoro-phenyl)-1-(3-oxo-propyl)-1,3-dihydro-isobenzofuran-5-carbonitrile 
• 766508-94-5 (S)-Citalopram propionic acid 
• 817203-57-9 (S)-1-(4-fluorophenyl)-1-(3-methylamino-[3-d2]-propyl)-1,3-dihydro-isobenzofuran-5-carbonitrile 
• 817203-56-8 (S)-1-(4-fluorophenyl)-1-(3-hydroxy-[3-d2]-propyl)-1,3-dihydro-isobenzofuran-5-carbonitrile 
• 1116112-98-1 S-citalopram hydrochloride 
• 219861-08-2 escitalopram oxalate 
• 128173-53-5 (S)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile (+)-di-p-toluoyltartaric acid salt 
• 1425794-14-4 (S)-(3-(5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)propyl)dimethylselenonium trifluoromethanesulfonate 
• 1425794-09-7 (S)-1-(4-fluorophenyl)-1-(3-(methylthio)propyl)-1,3-dihydroisobenzofuran-5-carbonitrile 
• 1425794-12-2 (S)-1-(4-fluorophenyl)-1-(3-(methyselanyl)propyl)-1,3-dihydroisobenzofuran-5-carbonitrile 
• 1425794-11-1 (S)-(3-(5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)propyl)dimethylsulfonium trifluoromethanesulfonate 

Relevant academic research and scientific papers

A Photoswitchable Inhibitor of the Human Serotonin Transporter

The human serotonin transporter (hSERT) terminates serotonergic signaling through reuptake of neurotransmitter into presynaptic neurons and is a target for many antidepressant drugs. We describe here the development of a photoswitchable hSERT inhibitor, termed azo-escitalopram, that can be reversibly switched between trans and cis configurations using light of different wavelengths. The dark-adapted trans isomer was found to be significantly less active than the cis isomer, formed upon irradiation.

Substrate modification approach to achieve efficient resolution: Didesmethylcitalopram: A key intermediate for escitalopram

Research work presented here describes an approach to achieve the enantiopure escitalopram (1) via didesmethyl escitalopram (4), which is easily resolvable compared to citalopram (1a) through diastereomeric salt crystallization. The resolved intermediate (didesmethylcitalopram) was subsequently used for the preparation of the desired drug. This simple modification of the substrate makes a remarkable difference in the chemical resolution process. The first resolution of didesmethylcitalopram (±)-4 to furnish (+)-4, a novel key intermediate to assemble escitalopram (1) was achieved via diastereomeric salt resolution using (-)-di-p-toluoyltartaric acid (DPTTA). The resolution conditions were optimized; a key feature of this process is the addition of specific quantity of water at a specific temperature to the reaction mixture.

Enzymatic resolution of a quaternary stereogenic centre as the key step in the synthesis of (S)-(+)-citalopram

The enzymatic resolution of 4-[(4-dimethylamino)-1-(4′-fluorophenyl)- 1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile, a useful intermediate in the synthesis of enantiomerically pure citalopram, has been studied. Candida antarctica lipase B (CAL-B) catalyzes the enzymatic acetylation of the primary benzylic alcohol with high enantioselectivity at the quaternary stereogenic centre. The enzymatic enantioselective hydrolysis of the 3-acetyloxymethyl derivative catalyzed by CAL-B is also possible.

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.

NEW SALT AND SOLID STATE FORMS OF ESCITALOPRAM

The present disclosure relates to a new salt of escitalopram and its solid state forms, processes for the preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

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