62498-67-3

Basic information

• Product Name: 1-(4-fluorophenyl)-1,3-dihydro-1-[3-(methylamino)propyl]isobenzofuran-5-carbonitrile
• Synonyms: 1-(4-fluorophenyl)-1,3-dihydro-1-[3-(methylamino)propyl]isobenzofuran-5-carbonitrile;monodesmethylcitalopram;1-(4-Fluorophenyl)-1,3-dihydro-1-[3-(methylamino)propyl]-5-isobenzofurancarbonitrile;1-[3-(Methylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile;Lu-11-109;Desmethylcitalopram maleate;Citalopram Related Compound D (15 mg) (1-(4'-fluorophenyl)-1-(3-(methylamino)propyl)-1,3-dihydroisobenzofuran-5-carbonitrile hydrochloride);Citalopram Impurity 28
• CAS NO: 62498-67-3
• Molecular Formula: C₁₉H₁₉FN₂O
• Molecular Weight: 310.3653632
• EINECS: 263-573-8
• Product Categories: Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals
• Mol File: 62498-67-3.mol
• Article Data: 10

Chemical Properties

• Boiling Point: 429.4°Cat760mmHg
• Flash Point: 213.5°C
• Appearance: /
• Density: 1.2g/cm³
• Vapor Pressure: 1.4E-07mmHg at 25°C
• Refractive Index: 1.592
• CAS DataBase Reference: 1-(4-fluorophenyl)-1,3-dihydro-1-[3-(methylamino)propyl]isobenzofuran-5-carbonitrile(CAS DataBase Reference)
• NIST Chemistry Reference: 1-(4-fluorophenyl)-1,3-dihydro-1-[3-(methylamino)propyl]isobenzofuran-5-carbonitrile(62498-67-3)
• EPA Substance Registry System: 1-(4-fluorophenyl)-1,3-dihydro-1-[3-(methylamino)propyl]isobenzofuran-5-carbonitrile(62498-67-3)

Safety Data

• Hazardous Substances Data: 62498-67-3(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Solid

Uses

A metabolite of Citalopram, an inhibitor of serotonin (5-HT) uptake, 1-(4-fluorophenyl)-1,3-dihydro-1-[3-(methylamino)propyl]isobenzofuran-5-carbonitrile can be used as an antidepressant.

InChI:InChI=1/C19H19FN2O/c1-22-10-2-9-19(16-4-6-17(20)7-5-16)18-8-3-14(12-21)11-15(18)13-23-19/h3-8,11,22H,2,9-10,13H2,1H3

Synthetic route

1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile (59729-33-8) → rac-desmethylcitalopram (62498-67-3)

Conditions	Yield
Stage #1: 1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile With carbonochloridic acid 1-chloro-ethyl ester In dichloromethane; toluene at 10 - 20℃; Industry scale; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane; toluene at 20 - 65℃; Industry scale;	91.5%
Multi-step reaction with 2 steps 1: 6 h / 130 °C 2: 0.31 g / MeOH / 5 h / Heating View Scheme
Multi-step reaction with 2 steps 1.1: 6 h / 130 °C 2.1: MeOH / 5 h / Heating 2.2: 0.31 g / NaOH / tetrahydrofuran; H2O View Scheme
Stage #1: 1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile With carbonochloridic acid, chloromethyl ester In 1,2-dichloro-ethane at 0 - 90℃; Stage #2: With methanol at 60 - 65℃; Stage #3: With ammonia In water at 20 - 35℃; pH=9.5;
Stage #1: 1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile With carbonochloridic acid 1-chloro-ethyl ester; potassium carbonate In 1,2-dichloro-ethane for 4h; Inert atmosphere; Reflux; Stage #2: In methanol for 2h; Reflux;

citalopram hydrobromide (59729-32-7) → rac-desmethylcitalopram (62498-67-3)

Conditions	Yield
Stage #1: citalopram hydrobromide With ammonium hydroxide In water Stage #2: With carbonochloridic acid 1-chloro-ethyl ester In 1,2-dichloro-ethane at 0℃; for 18h; Inert atmosphere; Reflux;	78%

citalopram hydrobromide → rac-desmethylcitalopram (62498-67-3)

Conditions	Yield
Stage #1: citalopram hydrobromide With carbonochloridic acid 1-chloro-ethyl ester In methanol at 65 - 130℃; for 11h; Stage #2: With sodium hydroxide In tetrahydrofuran at 25℃; for 14h;	74%

{3-[5-cyano-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-methyl-carbamic acid 1-chloro-ethyl ester (1025972-63-7) → 1-(4-fluoro-phenyl)-1-(3-methylamino-propyl)-1,3-dihydro-isobenzofuran-5-carboxylic acid methyl ester + rac-desmethylcitalopram (62498-67-3)

Conditions	Yield
With methanol for 5h; Heating; Title compound not separated from byproducts;	A n/a B 0.31 g

{3-[5-cyano-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-methyl-carbamic acid 1-chloro-ethyl ester (1025972-63-7) → sodium; 1-(4-fluoro-phenyl)-1-(3-methylamino-propyl)-1,3-dihydro-isobenzofuran-5-carboxylate + rac-desmethylcitalopram (62498-67-3)

Conditions	Yield
Stage #1: {3-[5-cyano-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-methyl-carbamic acid 1-chloro-ethyl ester With methanol for 5h; Heating; Stage #2: With sodium hydroxide In tetrahydrofuran; water	A n/a B 0.31 g

C19H17FN2O → rac-desmethylcitalopram (62498-67-3)

Conditions	Yield
With sodium tetrahydroborate In methanol at 10 - 20℃; for 0.5h;

3-(5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)-N,N-dimethylpropan-1-amine (64169-39-7) + copper(I) cyanide (544-92-3) → rac-desmethylcitalopram (62498-67-3) + 1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile (59729-33-8)

Conditions	Yield
at 140 - 150℃;
In DMF (N,N-dimethyl-formamide) at 40 - 165℃; for 6.5 - 8.5h;

1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile (59729-33-8) → rac-desmethylcitalopram (62498-67-3) + Citalopram N-Oxide (63284-72-0)

Conditions	Yield
With NADH In methanol at 37℃; for 0.5h; pH=7.4; Kinetics; Reagent/catalyst; Enzymatic reaction;

rac-desmethylcitalopram (62498-67-3) + N-phthalimidyl-2-aminoacetaldehyde (2913-97-5) → 1-(3-((2-(1,3-dioxoisoindolin-2-yl)ethyl)(methyl)amino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507402-14-3)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	96%

1-benzofuran-3-carbaldehyde (4687-25-6) + rac-desmethylcitalopram (62498-67-3) → 1-(3-((benzofuran-3-yl-methyl)(methyl)amino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507401-92-4)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	95%

rac-desmethylcitalopram (62498-67-3) + Cyclopropanecarboxaldehyde (1489-69-6) → 1-(3-((cyclopropylmethyl)(methyl)amino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507401-87-7)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	94%

pyridine-4-carbaldehyde (872-85-5) + rac-desmethylcitalopram (62498-67-3) → 1-(4-fluorophenyl)-1-(3-(methyl(pyridin-4-yl)amino)propyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507401-96-8)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	94%

cyclohexanedione monoethylene ketal (4746-97-8) + rac-desmethylcitalopram (62498-67-3) → 1-(4-fluorophenyl)-1-(3-(methyl(1,4-dioxaspiro[4.5]decan-8-yl)-amino)propyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507402-18-7)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	94%

benzothiophene-3-carboxaldehyde (5381-20-4) + rac-desmethylcitalopram (62498-67-3) → 1-(3-((benzo[b]thiophen-3-yl-methyl)(methyl)amino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507401-93-5)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	94%

1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde + rac-desmethylcitalopram (62498-67-3) → 1-(3-(((1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl)methyl)(methyl)amino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507402-05-2)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	94%

rac-desmethylcitalopram (62498-67-3) + butyraldehyde (123-72-8) → 1-(3-(butyl(methyl)amino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507401-89-9)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	93%

rac-desmethylcitalopram (62498-67-3) + propionaldehyde (123-38-6) → 1-(4-fluorophenyl)-1-(3-(methyl(propyl)amino)propyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507401-88-8)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	92%

rac-desmethylcitalopram (62498-67-3) + β-naphthaldehyde (66-99-9) → 1-(4-fluorophenyl)-1-(3-(methyl(naphthalen-2-ylmethyl)amino)-propyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507402-01-8)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	92%

rac-desmethylcitalopram (62498-67-3) + 9H-fluorene-2-carbaldehyde (30084-90-3) → 1-(3-(((9H-fluoren-2-yl)methyl)(methyl)amino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507402-03-0)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	92%

rac-desmethylcitalopram (62498-67-3) + 3-formyl-5-methoxy-indole-1-carboxylic acid tert-butyl ester → tert-butyl-3-(((3-(5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)propyl)(methyl)amino)methyl)-5-methoxy-1H-indole-1-carboxylate (1507402-11-0)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	91%

rac-desmethylcitalopram (62498-67-3) + 4-dimethylamino-benzaldehyde (100-10-7) → 1-(3-((4-(dimethylamino)benzyl)(methyl)amino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507401-94-6)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	90%

quinoline-4-carboxaldehyde (4363-93-3) + rac-desmethylcitalopram (62498-67-3) → 1-(4-fluorophenyl)-1-(3-(methyl(quinolin-4-ylmethyl)amino)-propyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507401-98-0)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	89%

rac-desmethylcitalopram (62498-67-3) + 1-tert-butoxycarbonyl-3-formylindole (57476-50-3) → tert-butyl-3-(((3-(5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)propyl)(methyl)amino)methyl)-1H-indole-1-carboxylate (1507402-07-4)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	87%

rac-desmethylcitalopram (62498-67-3) + phenylacetaldehyde (122-78-1) → 1-(4-fluorophenyl)-1-(3-(methyl(phenethyl)amino)propyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507401-90-2)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	86%

rac-desmethylcitalopram (62498-67-3) + 3-benzyl propionaldehyde (18328-11-5) → 1-(4-fluorophenyl)-1-(3-(methyl(4-phenylbutyl)amino)propyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1507401-91-3)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere;	72%

rac-desmethylcitalopram (62498-67-3) + Di-p-toluoyl-L-tartaric acid (32634-66-5) → (+)-desmethyl citalopram DPTTA salt (1084839-40-6)

Conditions	Yield
In isopropyl alcohol at 20 - 45℃; Product distribution / selectivity; Industry scale;	44.6%

rac-desmethylcitalopram (62498-67-3) + 2-(4Chlorobutyl)-dioxolan-4-ylmethoxymethyl polystyrene + phenylhydrazine hydrochloride (59-88-1) + sodium hydrogencarbonate (144-55-8) → 1-[3-[[3-(1H-Indol-3-yl)propyl]methylamino]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile

Conditions	Yield
With sodium iodide; ammonia; N-ethyl-N,N-diisopropylamine; Zinc chloride In tetrahydrofuran; methanol; water; acetic acid; N,N-dimethyl-formamide	42%

rac-desmethylcitalopram (62498-67-3) + methyl acetimidate (14777-29-8, 85273-25-2) → N-{3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl}-N-methyl-ethanimidamide

Conditions	Yield
In toluene at 80℃; for 14h; Inert atmosphere;	40%

2,3,4,5-tetrahydro-6-methoxypyridine (5693-62-9) + rac-desmethylcitalopram (62498-67-3) → 1-(4-fluorophenyl)-1-{3-[methyl(3,4,5,6-tetrahydropyridin-2-yl)amino]propyl}-1,3-dihydro-2-benzofuran-5-carbonitrile

Conditions	Yield
at 80℃; for 15h;	24%

rac-desmethylcitalopram (62498-67-3) + methyl benzenecarboximidoate hydrochloride → N-{3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl}-N-methyl-phenylmethanimidamide

Conditions	Yield
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 80℃; for 15h;	19%

rac-desmethylcitalopram (62498-67-3) + L-Tartaric acid (87-69-4) → desmethylcitalopram L-tartrate (526204-73-9)

Conditions	Yield
In methanol; water at 20℃; for 1h;

Upstream product

• 64169-39-7 3-(5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)-N,N-dimethylpropan-1-amine 
• 544-92-3 copper(I) cyanide 
• 59729-33-8 1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile 
• 59729-32-7 citalopram hydrobromide 
• 1025972-63-7 {3-[5-cyano-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-methyl-carbamic acid 1-chloro-ethyl ester 

Downstream Products

• 526204-73-9 desmethylcitalopram L-tartrate 
• 144025-14-9 (+)-Desmethylcitalopram 
• 1585941-23-6 (S)-1-(3-((3-(1,3-dioxoisoindolin-2-yl)propyl)(methyl)amino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile 
• 1585941-24-7 (S)-1-(3-((5-(1,3-dioxoisoindolin-2-yl)pentyl)(methyl)amino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile 
• 1585941-25-8 (S)-1-(3-((3-aminopropyl)(methyl)amino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile 
• 1585941-26-9 (S)-1-(3-((5-aminopentyl)(methyl)amino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile 
• 1084839-40-6 (+)-desmethyl citalopram DPTTA salt 
• 97743-99-2 Desmethylcitalopram hydrochloride 
• 1101848-95-6 (S)-(+)-1-(4-fluorophenyl)-1-(3-methylaminopropyl)-1,3-dihydroisobenzofuran-5-carbonitrile, (-)-di-p-toluoyl-D-tartaric acid salt 
• 59729-33-8 1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile 

Relevant articles and documents

Effect of CYP2D6 genetic polymorphism on the metabolism of citalopram in vitro

Genetic polymorphisms of CYP2D6 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. We aimed at investigating the role of CYP2D6 in the metabolism of citalopram and identifying the effect of 24 CYP2D6 allelic variants we found in Chinese Han population on the metabolism of citalopram in vitro. These CYP2D6 variants expressed by insect cells system were incubated with 10-1000 μM citalopram for 30 min at 37 °C and the reaction was terminated by cooling to -80 °C immediately. Citalopram and its metabolites were analyzed by high-performance liquid chromatography (HPLC). The intrinsic clearance (Vmax/Km) values of the variants toward citalopram metabolites were significantly altered, 38-129% for demethylcitalopram and 13-138% for citalopram N-oxide when compared with CYP2D6?1. Most of the tested rare alleles exhibited significantly decreased values due to increased Km and/or decreased Vmax values. We conclude that recombinant system could be used to investigate the enzymes involved in drug metabolism and these findings suggest that more attention should be paid to subjects carrying these CYP2D6 alleles when administering citalopram in the clinic.

Novel and high affinity fluorescent ligands for the serotonin transporter based on (S)-citalopram

Novel rhodamine-labeled ligands, based on (S)-citalopram, were synthesized and evaluated for uptake inhibition at the human serotonin, dopamine, and norepinephrine transporters (hSERT, hDAT, and hNET, respectively) and for binding at SERT, in transiently

Process for the Preparation of Escitalopram

The present invention provides a novel process for the preparation of a compound of Formula III, and novel processes for preparing escitalopram using the compound of Formula III.