260371-16-2

Basic information

• Product Name: 4-(4-fluorobenzoyl)-3-(hydroxyMethyl)benzonitrile
• Synonyms: 4-(4-fluorobenzoyl)-3-(hydroxyMethyl)benzonitrile;Citalopram Impurity 4
• CAS NO: 260371-16-2
• Molecular Formula: C₁₅H₁₀FNO₂
• Molecular Weight: 255.2438032
• Mol File: 260371-16-2.mol
• Article Data: 7

Chemical Properties

• Boiling Point: 486.2±45.0 °C(Predicted)
• Appearance: /
• Density: 1.33±0.1 g/cm3(Predicted)
• Storage Temp.: 2-8°C
• PKA: 13.98±0.10(Predicted)
• CAS DataBase Reference: 4-(4-fluorobenzoyl)-3-(hydroxyMethyl)benzonitrile(CAS DataBase Reference)
• NIST Chemistry Reference: 4-(4-fluorobenzoyl)-3-(hydroxyMethyl)benzonitrile(260371-16-2)
• EPA Substance Registry System: 4-(4-fluorobenzoyl)-3-(hydroxyMethyl)benzonitrile(260371-16-2)

Safety Data

• Hazardous Substances Data: 260371-16-2(Hazardous Substances Data)

Usage

Uses

4-(4-Fluorobenzoyl)-3-hydroxymethylbenzonitrile is an intermediate in the synthesis of Citalopram/Escitalopram, a selective serotonin reuptake inhibitor that relieves the symptoms of diabetes and is used in the treatment of depression.

Synthetic route

1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile (82104-74-3) + 4-flourophenylmagnesium bromide (352-13-6) → 4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2)

Conditions	Yield
Stage #1: 1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile; 4-flourophenylmagnesium bromide In tetrahydrofuran; 1,2-dimethoxyethane at -10℃; for 3.5h; Stage #2: With water; ammonium chloride In tetrahydrofuran; 1,2-dimethoxyethane at 20℃; for 0.0833333h;	86.2%
In tetrahydrofuran at 0 - 5℃; for 5h; Solvent; Temperature;	85%
Stage #1: 1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile; 4-flourophenylmagnesium bromide In tetrahydrofuran; dichloromethane at -6 - -2℃; Stage #2: With water; ammonium chloride In tetrahydrofuran; dichloromethane
In tetrahydrofuran; toluene at -4 - -2℃; Product distribution / selectivity;

1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile (82104-74-3) + 1-Bromo-4-fluorobenzene (460-00-4) → 4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2)

Conditions	Yield
Stage #1: 1-Bromo-4-fluorobenzene With magnesium In tetrahydrofuran Reflux; Inert atmosphere; Stage #2: 1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere;	63%

1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile (82104-74-3) + 4-flourophenylmagnesium bromide (352-13-6) → 4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + 4-(bis(4-fluorophenyl)hydroxymethyl)-3-(hydroxymethyl)benzonitrile (762266-07-9)

Conditions	Yield
In tetrahydrofuran; water at -10 - -5℃; for 3h;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + dihydroxy-methyl-borane (13061-96-6) + (1S,2S)-N-Methylpseudoephedrine (1201-56-5, 14222-20-9, 17605-71-9, 39263-91-7, 42151-56-4, 51018-28-1, 62560-55-8, 87040-40-2, 552-79-4) → C27H28BFN2O3

Conditions	Yield
In toluene at 20 - 70℃; under 45.0045 - 52.5053 Torr; for 1.5h; Product distribution / selectivity;	91%
In toluene at 25 - 65℃; under 7.50075 - 82.5083 Torr; for 1 - 3h; Product distribution / selectivity; Molecular sieve;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + tert-butyldimethylsilyl chloride (18162-48-6) → 4-(4-fluorobenzoyl)-3-(tert-butyldimethylsiloxymethyl)benzonitrile (1370643-21-2)

Conditions	Yield
With 1H-imidazole In dichloromethane at 10 - 15℃; for 0.5h;	84%

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + 4-(bis(4-fluorophenyl)hydroxymethyl)-3-(hydroxymethyl)benzonitrile (762266-07-9) → 4-[(4-fluoro-phenyl)-hydroxy-methyl]-3-hydroxymethyl-benzonitrile (207680-98-6)

Conditions	Yield
Stage #1: 4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile; 4-(bis(4-fluorophenyl)hydroxymethyl)-3-(hydroxymethyl)benzonitrile With sodium hydroxide; sodium tetrahydroborate In tetrahydrofuran; water at 0 - 15℃; for 0.5h; Stage #2: With phosphoric acid In water for 2h; Heating / reflux;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) → 4-[(4-fluoro-phenyl)-hydroxy-methyl]-3-hydroxymethyl-benzonitrile (207680-98-6)

Conditions	Yield
With sodium tetrahydroborate In methanol; toluene at 10 - 15℃; for 2h;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) → boron complex VB

Conditions	Yield
With sodium tetrahydroborate In methanol at 5 - 25℃; for 7 - 9h;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + 3-(N,N-dimethylamino)propylmagnesium chloride (19070-16-7) → 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile (103146-25-4)

Conditions	Yield
In tetrahydrofuran; 1,1-Dibromoethane; dichloromethane; toluene at -5 - 5℃; for 3 - 4h;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + quinindine (56-54-2, 130-95-0, 572-59-8, 572-60-1, 42151-59-7, 47342-58-5, 72402-50-7, 72402-51-8, 72402-52-9, 72402-53-0, 101143-86-6, 101143-87-7, 101143-88-8, 146925-10-2) + diisopropoxymethylborane (86595-27-9) → C36H35BFN3O4

Conditions	Yield
In toluene at 20 - 70℃; for 0.75h; Product distribution / selectivity;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + (1S,2S)-N-Methylpseudoephedrine (1201-56-5, 14222-20-9, 17605-71-9, 39263-91-7, 42151-56-4, 51018-28-1, 62560-55-8, 87040-40-2, 552-79-4) + diisopropoxymethylborane (86595-27-9) → C27H28BFN2O3 + isopropyl alcohol (67-63-0)

Conditions	Yield
In toluene at 20 - 70℃; under 45.0045 - 52.5053 Torr; for 0.866667 - 1.03333h; Product distribution / selectivity;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + (S)-1-dimethylamino-2-propanol (53636-17-2) + diisopropoxymethylborane (86595-27-9) → C21H24BFN2O3

Conditions	Yield
In toluene at 20 - 45℃; for 0.75h; Product distribution / selectivity;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + cinchonidine (118-10-5, 485-70-1, 485-71-2, 550-54-9, 40134-63-2, 72402-55-2, 72402-56-3) + diisopropoxymethylborane (86595-27-9) → C35H33BFN3O3

Conditions	Yield
In toluene at 20 - 70℃; for 0.75h; Product distribution / selectivity;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + (1S,2R)-(+)-N-methylephedrine (42151-56-4) + diisopropoxymethylborane (86595-27-9) → C27H28BFN2O3

Conditions	Yield
In toluene at 20 - 70℃; for 0.75h; Product distribution / selectivity;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + (R)-2-dimethylamino-1-phenyl-ethanol (34469-09-5) + diisopropoxymethylborane (86595-27-9) → C26H26BFN2O3

Conditions	Yield
In toluene at 20 - 70℃; for 0.75h; Product distribution / selectivity;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + dihydroxy-methyl-borane (13061-96-6) + (1S,2R)-(+)-N-methylephedrine (42151-56-4) → C27H28BFN2O3

Conditions	Yield
In toluene at 20 - 70℃; for 0.583333h; Product distribution / selectivity;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + dihydroxy-methyl-borane (13061-96-6) + (S)-2-dimethylamino-1-phenylethanol (2202-68-8, 2202-69-9, 6853-14-1, 34469-09-5) → C26H26BFN2O3

Conditions	Yield
In toluene at 50℃; under 45.0045 - 52.5053 Torr; Product distribution / selectivity;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + Trimethylboroxine (823-96-1) + (1S,2R)-(+)-N-methylephedrine (42151-56-4) → C27H28BFN2O3

Conditions	Yield
In toluene at 20 - 70℃; for 0.583333h; Product distribution / selectivity;

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + 3-(N,N-dimethylamino)propylmagnesium chloride (19070-16-7) → 4-[(4-fluoro-phenyl)-hydroxy-methyl]-3-hydroxymethyl-benzonitrile (207680-98-6) + (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile (488787-59-3) + (+)-(R)-4-(4-dimethylamino-1-(4'-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)-benzonitrile

Conditions	Yield
Stage #1: 4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile With (1S,2R)-(+)-N-methylephedrine In toluene at 20 - 70℃; for 0.75h; Stage #2: 3-(N,N-dimethylamino)propylmagnesium chloride In tetrahydrofuran; toluene at -80℃; for 0.2h; Product distribution / selectivity;	A n/a B n/a C n/a

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + 3-(N,N-dimethylamino)propylmagnesium chloride (19070-16-7) → (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile (488787-59-3)

Conditions	Yield
Stage #1: 4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile With dihydroxy-methyl-borane In toluene at 20 - 70℃; for 0.75h; Stage #2: 3-(N,N-dimethylamino)propylmagnesium chloride In tetrahydrofuran; toluene at -60℃; for 0.2h; Product distribution / selectivity;	n/a

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + 3-(N,N-dimethylamino)propylmagnesium chloride (19070-16-7) → (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile (488787-59-3) + (+)-(R)-4-(4-dimethylamino-1-(4'-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)-benzonitrile

Conditions	Yield
Stage #1: 4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile With (1S,2R)-(+)-N-methylephedrine In toluene at 20 - 70℃; for 0.75h; Stage #2: 3-(N,N-dimethylamino)propylmagnesium chloride In tetrahydrofuran; toluene at -80℃; for 0.2h; Product distribution / selectivity;	A n/a B n/a

4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile (260371-16-2) + tert-butyldimethylsilyl chloride (18162-48-6) → C26H35FN2OSi + C26H35FN2OSi

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1H-imidazole / dichloromethane / 0.5 h / 10 - 15 °C 2.1: sodium hydride / tetrahydrofuran; mineral oil / 3.5 h / 5 - 60 °C / Inert atmosphere 2.2: 60 °C / Inert atmosphere View Scheme

Upstream product

• 82104-74-3 1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile 
• 460-00-4 1-Bromo-4-fluorobenzene 
• 352-13-6 4-flourophenylmagnesium bromide 

Downstream Products

• 1370643-21-2 4-(4-fluorobenzoyl)-3-(tert-butyldimethylsiloxymethyl)benzonitrile 
• 488787-59-3 (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile 
• 219861-18-4 (R)-(+)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile 
• 207680-98-6 4-[(4-fluoro-phenyl)-hydroxy-methyl]-3-hydroxymethyl-benzonitrile 
• 67-63-0 isopropyl alcohol 
• 103146-25-4 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile 

Relevant articles and documents

Preparation method of escitalopram process impurity

The invention relates to a preparation method of an escitalopram process impurity. The escitalopram process impurity is prepared through a reaction of 5-cyanophthalide and 4-fluorophenyl magnesium bromide. The process is simple and the yield is relatively high.

CARBONYL ASYMMETRIC ALKYLATION

This invention relates to processes and intermediates for the stereoselective alkylation of carbonyl groups. The invention in particular allows the stereoselective preparation of the antidepressant drug escitalopram. It has been found that boric or boronic acid derivatives are useful bridging elements for the attachment of a chiral group to a compound containing a carbonyl group to be alkylated. The said borates and boronates are thus useful in a process for the asymmetric alkylation of a carbonyl group in a compound containing a carbonyl group and an anchor group capable of reacting with a boric or boronic acid derivative. The asymmetric alkylation can be carried out by admixing the compound containing a carbonyl group to be alkylated and the anchor group capable of reacting with a boric or boronic acid derivative with a boric or boronic acid derivative, adding a chiral alcohol, and adding an organometallic compound. After the alkylation reaction, the borate and boronate can be easily removed by hydrolysis.

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.