421552-12-7

Basic information

• Product Name: 2-CYANO-5-FLUOROBENZYL BROMIDE
• Synonyms: 2-Cyano-5-flurobenzyl broMide;421552-12-7;2- cyano -5- fluorine benzyl bromide
• CAS NO: 421552-12-7
• Molecular Formula: C₈H₅BrFN
• Molecular Weight: 214.04
• EINECS: 1592732-453-0
• Product Categories: Fluorine series
• Mol File: 421552-12-7.mol
• Article Data: 18

Chemical Properties

• Boiling Point: 264.468 °C at 760 mmHg
• Flash Point: 113.746 °C
• Appearance: /Solid
• Density: 1.591 g/cm³
• Vapor Pressure: 0.01mmHg at 25°C
• Refractive Index: 1.564
• Storage Temp.: 2-8°C
• Solubility: soluble in Methanol
• Sensitive: Lachrymatory
• CAS DataBase Reference: 2-CYANO-5-FLUOROBENZYL BROMIDE(CAS DataBase Reference)
• NIST Chemistry Reference: 2-CYANO-5-FLUOROBENZYL BROMIDE(421552-12-7)
• EPA Substance Registry System: 2-CYANO-5-FLUOROBENZYL BROMIDE(421552-12-7)

Safety Data

• Hazard Codes: C
• RIDADR: 2923
• HazardClass: 8
• PackingGroup: Ⅲ
• Hazardous Substances Data: 421552-12-7(Hazardous Substances Data)

Usage

Uses

2-Cyano-5-fluorobenzyl bromide is a hydrocarbon derivative and can be used as a pharmaceutical intermediate.

InChI:InChI=1/C8H5BrFN/c9-4-7-3-8(10)2-1-6(7)5-11/h1-3H,4H2

Synthetic route

4-fluoro-2-methylbenzonitrile (147754-12-9) → 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7)

Conditions	Yield
With N-Bromosuccinimide; toluene-4-sulfonic acid In tetrachloromethane for 4h; Heating;	86%
With N-Bromosuccinimide; toluene-4-sulfonic acid In tetrachloromethane Reflux;	86%
With N-Bromosuccinimide; dibenzoyl peroxide In chloroform at 85℃; for 24h; Inert atmosphere;	58%

2-Bromo-5-fluorotoluene (452-63-1) → 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / Reflux 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / 2 h / Reflux; Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 24 h / Reflux 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 2 h / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 24 h / Reflux 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 2 h / Reflux; Inert atmosphere View Scheme

3-methyl-6-chlorouracil (4318-56-3) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 2-[(6-chloro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]-4-fluorobenzonitrile (865759-24-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 20 - 55℃; for 4h; Time; Temperature;	98.9%
With N-ethyl-N,N-diisopropylamine In butan-1-ol at 107℃; for 2h; Solvent; Temperature; Reagent/catalyst;	96.6%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 65 - 75℃; for 6h; Temperature; Solvent; Large scale;	96.3%

p-toluidine (106-49-0) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 2-(p-methylphenylamino)methyl-4-fluorobenzonitrile

Conditions	Yield
With sodium ethanolate In tetrahydrofuran at 60℃; for 8h; Reflux;	95%
With potassium carbonate In dimethyl sulfoxide

2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 2-(bromomethyl)-4-fluorobenzaldehyde

Conditions	Yield
Stage #1: 2-(bromomethyl)-4-fluorobenzonitrile With diisobutylaluminium hydride In hexane; dichloromethane at 0 - 20℃; for 3.5h; Inert atmosphere; Stage #2: With hydrogenchloride; water In hexane; dichloromethane at 0℃; for 1h; Inert atmosphere;	94%
With diisobutylaluminium hydride In hexane; dichloromethane at 0 - 20℃; for 3.5h; Inert atmosphere;	94%

4-(piperazin-1-ylmethyl)benzonitrile (89292-70-6) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 2-((4-(4-cyanobenzyl)piperazin-1-yl)methyl)-4-fluorobenzonitrile

Conditions	Yield
With potassium carbonate In acetone at 20℃;	89%

1-(4-trifluoromethylbenzyl)piperazine (107890-32-4) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 2-((4-(4-trifluoromethylbenzyl)piperazin-1-yl)methyl)-4-fluorobenzonitrile

Conditions	Yield
With potassium carbonate In acetone at 20℃;	88%

2-chloro-3H,4H-thieno[3,2-d]pyrimidin-4-one (1245811-20-4) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → C14H7ClFN3OS

Conditions	Yield
Stage #1: 2-chloro-3H,4H-thieno[3,2-d]pyrimidin-4-one With sodium hydride In 1,2-dimethoxyethane; N,N-dimethyl-formamide for 0.333333h; Cooling with ice; Stage #2: With lithium bromide In 1,2-dimethoxyethane; N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #3: 2-(bromomethyl)-4-fluorobenzonitrile In 1,2-dimethoxyethane; N,N-dimethyl-formamide at 65℃; for 14h;	85.3%
Stage #1: 2-chloro-3H,4H-thieno[3,2-d]pyrimidin-4-one With sodium hydride In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h; Stage #2: With lithium bromide In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 20℃; for 0.25h; Stage #3: 2-(bromomethyl)-4-fluorobenzonitrile In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 65℃; for 6h;

1-phenylethyl piperazine (69628-75-7) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 4-fluoro-2-((4-(1-phenylethyl)piperazin-1-yl)methyl)benzonitrile

Conditions	Yield
With potassium carbonate In acetone at 20℃;	85%

1-t-Butoxycarbonylpiperazine (57260-71-6) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → tert-butyl 4-(2-cyano-5-fluorobenzyl)piperazine-1-carboxylate

Conditions	Yield
With potassium carbonate In acetone at 20℃;	85%
With potassium carbonate In acetone at 20℃;	85%
With potassium carbonate at 20℃;

2-methoxy-ethanol (109-86-4) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 4-fluoro-2-((2-methoxyethoxy)methyl)benzonitrile (1569066-21-2)

Conditions	Yield
Stage #1: 2-methoxy-ethanol With sodium hydride In tetrahydrofuran at -60 - 20℃; for 0.5h; Stage #2: 2-(bromomethyl)-4-fluorobenzonitrile In tetrahydrofuran at -60℃; for 1.5h;	84%
Stage #1: 2-methoxy-ethanol With sodium hydride In tetrahydrofuran at -60 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-(bromomethyl)-4-fluorobenzonitrile In tetrahydrofuran at -60 - 20℃; for 3.5h; Inert atmosphere;	84%

1-(1,2,3,4-tetrahydronaphthalen-2-yl)piperazine (1900-04-5) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 4-fluoro-2-((4-(1,2,3,4-tetrahydronaphthalen-2-yl)piperazin-1-yl)methyl)benzonitrile

Conditions	Yield
With potassium carbonate In acetone at 20℃;	84%

1-(2-chloro-benzyl)-piperazine (17532-19-3) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 2-((4-(2-chlorobenzyl)piperazin-1-yl)methyl)-4-fluorobenzonitrile

Conditions	Yield
With potassium carbonate In acetone at 20℃;	83%

2-chloro-7-methylthieno[3,2-d]pyrimidin-4(3H)-one (1265593-71-2) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → C15H9ClFN3OS

Conditions	Yield
Stage #1: 2-chloro-7-methylthieno[3,2-d]pyrimidin-4(3H)-one With sodium hydride In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h; Stage #2: With lithium bromide In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 20℃; for 0.25h; Stage #3: 2-(bromomethyl)-4-fluorobenzonitrile In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 65℃; for 6h;	83%

C4(14)CH5ClN2O2 + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → C12(14)CH9ClFN3O2

Conditions	Yield
With 1-methyl-pyrrolidin-2-one; N-ethyl-N,N-diisopropylamine In ethyl acetate at 65℃; for 2.5h;	82%

1-[(4-chlorophenyl)methyl]piperazine (23145-88-2) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 2-((4-(4-chlorobenzyl)piperazin-1-yl)methyl)-4-fluorobenzonitrile

Conditions	Yield
With potassium carbonate In acetone at 20℃;	80%
With potassium carbonate at 20℃;

1-(4-fluorophenylmethyl)piperazine (70931-28-1) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 4-fluoro-2-((4-(4-fluorobenzyl)piperazin-1-yl)methyl)benzonitrile

Conditions	Yield
With potassium carbonate In acetone at 20℃;	79%

C6H2BrClN2OS + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → C14H6BrClFN3OS

Conditions	Yield
Stage #1: C6H2BrClN2OS With sodium hydride In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h; Stage #2: With lithium bromide In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 20℃; for 0.25h; Stage #3: 2-(bromomethyl)-4-fluorobenzonitrile In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 65℃; for 6h;	78%

1-(3-chlorobenzyl)piperazine (23145-91-7) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 2-((4-(3-chlorobenzyl)piperazin-1-yl)methyl)-4-fluorobenzonitrile

Conditions	Yield
With potassium carbonate In acetone at 20℃;	76%

tert-butyl 2-chloro-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (1377432-80-8) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 2-((2-chloro-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-3-yl)methyl)-4-fluorobenzonitrile

Conditions	Yield
Stage #1: tert-butyl 2-chloro-4-oxo-3H,4H,5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate With sodium hydride In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h; Stage #2: With lithium bromide In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Stage #3: 2-(bromomethyl)-4-fluorobenzonitrile In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 65℃;	75.2%
Stage #1: tert-butyl 2-chloro-4-oxo-3H,4H,5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate With sodium hydride In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil for 0.5h; Cooling with ice; Stage #2: With lithium bromide In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Stage #3: 2-(bromomethyl)-4-fluorobenzonitrile In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 60℃; for 12h;	66.2%

1-(3,4-chlorobenzyl)piperazine (55513-17-2) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → C19H18Cl2FN3

Conditions	Yield
With potassium carbonate In acetone at 20℃; for 3h;	75%

1-(4-methoxyphenyl)piperazine (38212-30-5) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 4-fluoro-2-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)benzonitrile

Conditions	Yield
With potassium carbonate In tetrahydrofuran Reflux;	73%
With potassium carbonate at 20℃;

Trelagliptin + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → C26H24F2N6O2

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4h;	73%

dimethyl amine (124-40-3) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 2-((dimethylamino)methyl)-4-fluorobenzonitrile (1023649-68-4)

Conditions	Yield
at 20℃; for 0.216667h;	68%

ethyl 2-(dimethyl(oxo)- λ6-sulfaneylidene)-2-phenylacetate + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → ethyl 3-(2-cyano-5-fluorophenyl)-2-phenylacrylate

Conditions	Yield
With trifuran-2-yl-phosphane; palladium diacetate; triethylamine; lithium tert-butoxide In toluene at 80℃; for 24h; Schlenk technique; Inert atmosphere; stereoselective reaction;	42%

5-bromo-2-chloro-pyrimidin-4(3H)-one (844843-37-4) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 2-((5-bromo-2-chloro-6-oxopyrimidin-1(6H)-yl)methyl)-4-fluorobenzonitrile

Conditions

Yield

Stage #1: 5-bromo-2-chloro-pyrimidin-4(3H)-one With sodium hydride In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 0℃; Inert atmosphere; Stage #2: With lithium bromide In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 20℃; Inert atmosphere; Stage #3: 2-(bromomethyl)-4-fluorobenzonitrile In 1,2-dimethoxyethane; N,N-dimethyl-formamide; mineral oil at 65℃; Inert atmosphere;

35%

sodium methylate (124-41-4) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 4-fluoro-2-(methoxymethyl)benzonitrile (934012-90-5)

Conditions	Yield
In methanol at 20 - 55℃; for 3h;	28%
In methanol at 20 - 55℃; for 3h;	28%

2-bromo-5-methyl-1,5-dihydro-9H-imidazo[1,2-a]purine-6,9(7H)-dione TFA salt + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 2-(2-bromo-5-methyl-6,9-dioxo-5,6,7,9-tetrahydro-1H-imidazo[1,2-a]purin-1-yl)methyl-4-fluorobenzonitrile (1417715-74-2) + 2-(2-bromo-5-methyl-6,9-dioxo-5,6,7,9-tetrahydro-1H-imidazo[1,2-a]purin-3-yl)methyl-4-fluorobenzonitrile (1417715-75-3)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h;	A 24% B 22%

homophthalic anhydride (703-59-3) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 5,6-dihydro-5-oxo-9-fluoro-indeno[1,2-c]isoquinoline

Conditions	Yield
With triethylamine In acetonitrile for 2h; Heating;	2.180 g

2-amino-5-chloropyridine-3-carboxamide (58483-97-9) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → 5-chloro-1-(2-cyano-5-fluorobenzyl)-2-imino-1,2-dihydropyridine-3-carboxamide hydrochloride (1021873-77-7)

Conditions	Yield
Stage #1: 2-amino-5-chloropyridine-3-carboxamide; 2-(bromomethyl)-4-fluorobenzonitrile In N,N-dimethyl-formamide at 100℃; for 14h; Stage #2: With water; sodium hydrogencarbonate Stage #3: With hydrogenchloride In methanol

C25H39N5O6 (1261999-60-3) + 2-(bromomethyl)-4-fluorobenzonitrile (421552-12-7) → C33H43FN6O6

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 3h;

Upstream product

• 452-63-1 2-Bromo-5-fluorotoluene 
• 147754-12-9 4-fluoro-2-methylbenzonitrile 

Downstream Products

• 865759-24-6 2-[(6-chloro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]-4-fluorobenzonitrile 
• 1261999-69-2 C₃₁H₃₉FN₆O₅ 

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Although the direct-acting antivirals revolutionized the hepatitis C virus (HCV) infection treatment in the last decade, more efforts are needed to reach the elimination of HCV in the absence of a vaccine. 4-(Piperazin-1-yl)-2-((p-tolylamino)methyl)-benzonitrile (1) is a modest HCV inhibitor identified from an in-house screening using a HCV-infected Huh7.5 cell culture. Starting from it, the chemical optimization afforded a new 2-((4-arylpiperazin-1-yl)methyl)benzonitrile scaffold with significantly increased antiviral activity against HCV. A highly effective HCV inhibitor, 35 (L0909, EC50 = 0.022 μM, SI > 600), was identified by the structure-activity relationship study. The biological study revealed that L0909 could block HCV replication by acting on the HCV entry stage. The high sensitivity to clinical resistant HCV mutants and synergistic effect with clinical drugs were observed for this compound. The further pharmaceutical studies demonstrated that L0909 is long-lasting, is orally available, and has low toxicity in vivo. These results show L0909 as a promising HCV entry inhibitor for single or combinational therapeutic potential.

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The invention discloses a synthetic method of trelagliptin, trelagliptin synthesized through the method and a trelagliptin synthesis intermediate. The synthetic method of trelagliptin comprises the following steps: 1, taking 2-hydroxymethyl-4-fluorobenzonitrile as a starting raw material, and conducting a chlorination reaction, so that 2-chloromethyl-4-fluorobenzonitrile is obtained; 2, taking the 2-chloromethyl-4-fluorobenzonitrile as an intermediate, and conducting a condensation reaction, so that 2-[(6-chlorine-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-4-fluorobenzonitrile is obtained; 3, taking the 2-[(6-chlorine-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-4-fluorobenzonitrile as an intermediate, and conducting an ammonolysis reaction, so that trelagliptin alkali is obtained. By means of the method, use of high-toxicity copper cyanide is avoided, safety of the synthesis process is improved, environment friendliness is achieved, the formed chloro intermediate is more stable, and no irritation is caused.