64169-67-1

Basic information

• Product Name: 1-(4-Fluorophenyl)-1,3-dihydro isobenzofuran-5-carbonitile
• Synonyms: 5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran;1-(4-Fluorophenyl)-1,3-dihydro isobenzofuran-5-carbonitile;1-(4-FLUOROPHENYL)-1,3-DIHYDROISOBENZOFURAN-5-CARBONITRILE;1-(4-FLUOROPHENYL)-1,3-DIHYDRO-5-ISOBENZOFURANCARBONITRILE;1-(4-Fluorophenyl)-1,3-dihyrosobenzofuran-5-carbonitrile;1-(4-fluorophenyl)-1,3-dihydro-iso benzofuran-5-carbonibrile;RAC-1-(4-FLUORO-PHENYL)-1,3-DIHYDRO-ISOBEZOFURAN-5-CARBONITRILE;1-(4-Fluorophenyl)-1,3-dihydroisobenzofurane-5-cyano
• CAS NO: 64169-67-1
• Molecular Formula: C₁₅H₁₀FNO
• Molecular Weight: 239.24
• Product Categories: Aromatic Nitriles;Furan&Benzofuran;Heterocyclic Compounds;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 64169-67-1.mol

Chemical Properties

• Melting Point: 95-97°C
• Boiling Point: 375°C
• Flash Point: 180.754 °C
• Appearance: white to light yellow crystal powder
• Density: 1.29
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.62
• Storage Temp.: -20°C Freezer
• Solubility: Chloroform (Slightly), Dichloromethane, Methanol (Slightly, Sonicated)
• CAS DataBase Reference: 1-(4-Fluorophenyl)-1,3-dihydro isobenzofuran-5-carbonitile(CAS DataBase Reference)
• NIST Chemistry Reference: 1-(4-Fluorophenyl)-1,3-dihydro isobenzofuran-5-carbonitile(64169-67-1)
• EPA Substance Registry System: 1-(4-Fluorophenyl)-1,3-dihydro isobenzofuran-5-carbonitile(64169-67-1)

Safety Data

• Hazardous Substances Data: 64169-67-1(Hazardous Substances Data)

Usage

InChI:InChI=1/C15H10FNO/c16-13-4-2-11(3-5-13)15-14-6-1-10(8-17)7-12(14)9-18-15/h1-7,15H,9H2

Upstream product

• 64169-66-0 5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran 
• 544-92-3 copper(I) cyanide 
• 82104-74-3 1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile 
• 445312-08-3 3-chloromethyl-4-(4-fluoro-benzoyl)-benzonitrile 
• 762266-07-9 4-(bis(4-fluorophenyl)hydroxymethyl)-3-(hydroxymethyl)benzonitrile 
• 207680-98-6 4-[(4-fluoro-phenyl)-hydroxy-methyl]-3-hydroxymethyl-benzonitrile 
• 335612-73-2 1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbardehyde oxime 
• 335612-71-0 5-hydroxymethyl-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran 
• 335612-72-1 1-(4-fluorophenyl)-1,3-dihydroisobenzofurane-5-formaldehyde 
• 7439-95-4 magnesium 
• 460-00-4 1-Bromo-4-fluorobenzene 
• 947263-32-3 1-(4-fluorophenyl)-1,3-dihydro-5-chloro-isobenzofuran 
• 64169-34-2 5-bromophthalide 
• 947263-28-7 2-bromo-4-chloro-4'-fluorobenzophenone 

Downstream Products

• 62498-69-5 didesmethylcitalopram 
• 59729-32-7 citalopram hydrobromide 
• 59729-33-8 1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile 
• 345663-47-0 1-[(3-benzyloxy)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile 
• 361343-31-9 5-Aminomethyl-1-(4-Fluoro-phenyl)-1,3-dihydro-isobenzofuran 
• 91283-87-3 citalopram propanoic acid 
• 372941-48-5 1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile 

Relevant articles and documents

Novel and improved process for the preparation of citalopram

A novel process for the preparation of citalopram (1) has been described. The key intermediate 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran- 5-carbonitrile (2) of citalopram is prepared using novel intermediates. The process involves simple acylation, hydrolysis and reduction, which can be easily adapted to commercial scale.

Improved syntheses of N-desmethylcitalopram and N,N-didesmethylcitalopram

An improved and efficient synthesis of N-desmethylcitalopram (2) and N,N-didesmethylcitalopram (3) is presented. The method involved N-demethylation of citalopram (1) using 1-chloroethyl chloroformate to give 2 in 87% yield. Synthesis of 3 was accomplished by alkylation of 8 with 1-(3-bromopropyl)-2,2,5, 5-tetramethyl-1-aza-2,5-disilacyclopentane (9). Copyright Taylor & Francis Group, LLC.

PROCESSES FOR PRODUCING 5-PHTHALANCARBONITRILE AND CITALOPRAM

A process for producing the compound represented by the formula (II) which comprises reacting the compound represented by the formula (I) with oxalyl chloride; and a process for producing the compound represented by the formula (III) which comprises a step in which the compound represented by the formula (I) is reacted with oxalyl chloride to obtain the compound represented by the formula (II) and a step in which the compound represented by the formula (II) is reacted with a 3-dimethylaminopropyl halide.

PROCESS FOR PREPARING 5-SUBSTITUTED -1-(4-FLUOROPHENYL) -1,3-DIHYDROISOBENZOFURANS

The present invention relates to a method for preparation and isolation of hitherto unknown solid boron complex of formula (v), which are obtained when 5-substituted phthalides are reacted with a solution of 4-fluorophenylmagnesiumbromide, followed by in situ reduction and complex formation in the presence of sodiumborohydride. Such boron complexes can be conveniently filtered to remove structurally similar impurities and subsequently subjected to cyclisation reaction in acidic medium to get high pure 5-substituted phthalens, which are key starting materials for manufacturing citalopram and pharmaceutically acceptable acid addition salts.

ONE POT SYNTHESIS OF CITALOPRAM FROM 5-CYANOPHTHALIDE

A process for one pot synthesis of citalopram is disclosed. The process comprises subjecting 5-cyano phthalide to Grignard reduction followed cyclization and followed by C-alkylation reaction to obtain citalopram without isolation and purification of any intermediates. In another embodiment, 5-cyano phthalide is subjected to sequential Grignard reactions followed by cyclization to obtain citalopram without isolation and purification of any intermediate stages.

IMPROVED PROCESS FOR THE PREPARATION OF 5-SUBSTITUTED-1-(4--FLUOROPHENYL)-1,3-DIHYDROISOBENZOFURANS

The present invention provides a process for the preparation of a 5-substituted-l-(4-fluorophenyl)-1,3-dihydro-isobenzofuran of Formula (2), an intermediate for the manufacture of citalopram, which process comprises: (a) carrying out a Grignard reaction on a corresponding 5-substituted phthalide of Formula (3) in a co-solvent system, comprising adding (i) prepared 4-fluorophenyl magnesium halide in an ether solvent to (ii) the 5-substituted phthalide in a suitable organic co-solvent to the ether solvent, to form a corresponding 4-substituted-2-hydroxymethyl-4'-fluorobenzophenone of Formula (4); (b) carrying out a ketone reduction of the 4-substituted-2-hydroxymethyl-4'-fluorobenzophenone of Formula (4) following the Grignard reaction, to form a corresponding 4-substituted-2-hydroxymethylphenyl- 1-(4-fluorophenyl) methanol of Formula (5); and (c) carrying out a cyclisation reaction on the 4-substituted-2 hydroxymethylphenyl- 1-(4-fluorophenyl) methanol of Formula (5) following the reduction reaction, to form said intermediate of Formula (2); wherein R represents Br or CN.

PROCESS FOR THE PREPARATION OF A CYANO-ISOBENZOFURAN

A process for the preparation of citalopram and the pharmaceutically acceptable salts therof is disclosed by reacting 5-cyanophthalide with a 4-fluorophenyl magnesium halide, reducing the 3-hydroxymethyl-4-(4-fluoro-benzoyl)benzonitrile with an agent reducing ketones to alcohols, submitting the thus-obtained 3-hydroxymethyl-4- [(4-fluorophenyl)hydroxymethyl) benzonitrile to a cyclization reaction to give 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile without 1,1-bis(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile and treating 1,1-bis(4 fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile with a 3-(dimetylamino)propyl halide in the presence of a base.

PROCESS FOR THE PREPARATION OF HIGH PURITY CITALOPRAM AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS

This invention discloses an improved process for the preparation of high purity citalopram base and its hydrobromide salt of formulae (I) and (Ia): which comprises: i. Isolation of crude citalopram base after water work up of the reaction into a non polar aromatic or dialkyl ether solvent. ii. Extraction of the citalopram base into aqueous organic acid. iii. Neutralization of acid layer with organic base to a controlled pH (7.0-8.0) iv. Extraction of the pure base into a non-polar aromatic or dialkyl ether solvent and crytallization form the same solvent after concentrating to certain volume under reduced pressure. v. Preparation of high purity citalopram hydrobromide in a non-polar aromatic or dialkyl ether solvent using 40-50 % HBr in acetic acid as HBr source and crystallizing out form the same solvent. Alternatively preparation of HBr salt in aqueous medium using aqueous HBr and crystallizing out from the same medium at 0 10 °C. vi. Recrystallization of high purity citalopram hydrobromide salt of pharmaceutically acceptable grade form a mixture of alcoholic solvent.

PROCESS FOR THE PREPARATION OF 1-(3-DIMETHYLAMINOPROPYL) -1-(4-FLUOROPHENYL) -1,3-DIHYDROISOBENZOFURAN -5-CARBONITRILE

The present invention is directed to novel processes for the preparation of citalopram comprising halogenation of a phthalide compound of formula II, wherein R is a suitable group to be changed to CN, to afford an acid halogenide compound of formula III wherein R is as defined above and X is halogen, and thereafter obtaining citalopram through two successive reactions with suitable organometallic halides or organoboranes or by a reaction with organometallic 4-fluorophenylhalide or 4-fluorophenylborane followed by reduction and alkylation, and an exchange of R to cyano to afford citalopram. The order of the reactions can be varied depending e.g. on the starting compound used.

Method for the preparation of citalopram

A method for the preparation of citalopram wherein the aldehyde of formula is converted to the corresponding 5-cyano compound of formula (I) which is alkylated to form citalopram, which is isolated in the form of the base or an acid addition salt thereof.