874649-82-8

Basic information

• Product Name: methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate
• Synonyms: methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate;rac-6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic Acid Methyl Ester;methyl 6-fluorochroman-2-carboxylate;Methyl 6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate;TRC-CANADA;Methyl 6-fluorochromane-2-carboxylate;2H-1- benzopyran-2 - carboxylic acid, 6 - fluoro -3,4 - dihydro - methyl
• CAS NO: 874649-82-8
• Molecular Formula: C₁₁H₁₁FO₃
• Molecular Weight: 210.2016432
• Product Categories: Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 874649-82-8.mol
• Article Data: 7

Chemical Properties

• Melting Point: 48 °C
• Boiling Point: 286.8 °C at 760 mmHg
• Flash Point: 123.3 °C
• Appearance: /
• Density: 1.242 g/cm³
• Vapor Pressure: 0.00258mmHg at 25°C
• Refractive Index: 1.514
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Dichloromethane, Methanol
• CAS DataBase Reference: methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate(874649-82-8)
• EPA Substance Registry System: methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate(874649-82-8)

Safety Data

• Hazardous Substances Data: 874649-82-8(Hazardous Substances Data)

Usage

Uses

Intermediate in the preparation of hydroxylated Nebivolol metabolites.

InChI:InChI=1/C11H11FO3/c1-14-11(13)10-4-2-7-6-8(12)3-5-9(7)15-10/h3,5-6,10H,2,4H2,1H3

Synthetic route

6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (99199-59-4) + methanesulfonic acid (75-75-2) → (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8)

Conditions	Yield
With hydrogen; 5%-palladium/activated carbon In tetrahydrofuran at 45 - 55℃; under 3000.3 Torr;	100%

6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (99199-60-7) + methanol (67-56-1) → (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8)

Conditions	Yield
With sulfuric acid at 25 - 30℃;	98%
With sulfuric acid at 30℃; Reflux;	97%
Stage #1: 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid; methanol With sulfuric acid at 20 - 60℃; for 3.5h; Stage #2: With water; sodium hydrogencarbonate In methanol	87.9%
With sulfuric acid at 65 - 70℃; for 8h; Fischer–Speier Esterification;	85%

1-(5-fluoro-2-hydroxyphenyl)ethan-1-one (394-32-1) → (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium methylate; methanol / tetrahydrofuran / 5 - 25 °C 1.2: 5 - 15 °C 1.3: Reflux 2.1: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 45 - 55 °C / 3000.3 Torr View Scheme
Multi-step reaction with 4 steps 1: sodium methylate / methanol / 65 - 70 °C 2: hydrogenchloride / water / 85 - 90 °C 3: hydrogen; palladium on activated charcoal; acetic acid / 75 - 80 °C / Inert atmosphere; Autoclave 4: sulfuric acid / 8 h / 65 - 70 °C View Scheme

C12H13FO5 → (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: aluminum (III) chloride / dichloromethane / 0 - 20 °C 2: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 1 h / 0 °C 3: 5%-palladium/activated carbon; hydrogenchloride; hydrogen / methanol / 5 h / 20 °C / 760.05 Torr View Scheme

methyl 6-fluoro-4-oxo-3,4-dihydro-2H-chroman-2-carboxylate (134102-10-6) → (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8)

Conditions	Yield
With hydrogenchloride; 5%-palladium/activated carbon; hydrogen In methanol at 20℃; under 760.051 Torr; for 5h;

C11H11FO5 → (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 1 h / 0 °C 2: 5%-palladium/activated carbon; hydrogenchloride; hydrogen / methanol / 5 h / 20 °C / 760.05 Torr View Scheme

4-Fluorophenol (371-41-5) → (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8)

Conditions	Yield
Multi-step reaction with 6 steps 1: 45 - 50 °C 2: aluminum (III) chloride; hydrogenchloride / water / 140 - 145 °C 3: sodium methylate / methanol / 65 - 70 °C 4: hydrogenchloride / water / 85 - 90 °C 5: hydrogen; palladium on activated charcoal; acetic acid / 75 - 80 °C / Inert atmosphere; Autoclave 6: sulfuric acid / 8 h / 65 - 70 °C View Scheme

4-fluorophenyl acetate (405-51-6) → (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: aluminum (III) chloride; hydrogenchloride / water / 140 - 145 °C 2: sodium methylate / methanol / 65 - 70 °C 3: hydrogenchloride / water / 85 - 90 °C 4: hydrogen; palladium on activated charcoal; acetic acid / 75 - 80 °C / Inert atmosphere; Autoclave 5: sulfuric acid / 8 h / 65 - 70 °C View Scheme

ethyl 4-(5-fluoro-2-hydroxyphenyl)-2,4-dioxobutanoate → (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / water / 85 - 90 °C 2: hydrogen; palladium on activated charcoal; acetic acid / 75 - 80 °C / Inert atmosphere; Autoclave 3: sulfuric acid / 8 h / 65 - 70 °C View Scheme

6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (99199-59-4) → (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen; palladium on activated charcoal; acetic acid / 75 - 80 °C / Inert atmosphere; Autoclave 2: sulfuric acid / 8 h / 65 - 70 °C View Scheme

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (409346-73-2)

Conditions	Yield
With morpholine; sodium bis(2-methoxyethoxy)aluminium dihydride In toluene at -10℃; for 2h; Reagent/catalyst; Inert atmosphere;	98%

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → 6-fluoro-3,4-dihydro-2H-chromene-2-carbohydrazide

Conditions	Yield
With hydrazine hydrate In ethanol Reflux;	91%

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → dimethylsulfoxonium-2-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-2-oxoethylide (1017878-51-1)

Conditions	Yield
Stage #1: trimethylsulfoxonium iodide With potassium tert-butylate In tetrahydrofuran at 25 - 70℃; for 2 - 2.16667h; Protected from light; Stage #2: (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate In tetrahydrofuran at 20℃; for 3.5 - 19h; Product distribution / selectivity;	48%

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → (+/-)-6-fluoro-3,4-dihydro-8-nitro-2H-1-benzopyran-2-carboxylic acid

Conditions	Yield
With nitric acid

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / -85 - -75 °C 1.2: -80 - 0 °C 2.1: ethanol; sodium tetrahydroborate / 2 h / 0 °C / Inert atmosphere 3.1: sodium hydroxide / isopropyl alcohol; water / 1.5 h / 0 °C / Inert atmosphere View Scheme

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → 2-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2yl)ethanol (1017878-67-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / -85 - -75 °C 1.2: -80 - 0 °C 2.1: ethanol; sodium tetrahydroborate / 2 h / 0 °C / Inert atmosphere View Scheme

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8)

Conditions	Yield
Stage #1: (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate; chlorobromomethane With n-butyllithium In tetrahydrofuran; hexane at -85 - -75℃; Stage #2: With borane In tetrahydrofuran; hexane at -80 - -70℃; Stage #3: With water; sodium hydroxide In tetrahydrofuran; hexane for 2h; Reflux;

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate + chlorobromomethane (74-97-5) → 2-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethan-1-one (943126-72-5)

Conditions	Yield
Stage #1: (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate; chlorobromomethane With n-butyllithium In tetrahydrofuran; hexane at -85 - -75℃; Stage #2: With acetic acid In tetrahydrofuran; hexane; water at -80 - 0℃;

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (409346-73-2) + (6-fluoro-3,4-dihydro-2H-chromene-2-yl)methanol (99199-62-9)

Conditions	Yield
With sodium bis(2-methoxyethoxy)aluminium dihydride In dichloromethane; isopropyl alcohol; toluene at -78 - -73℃; Concentration; Solvent; Inert atmosphere;

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → [1R*(R*)]-6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene + [1S*(R*)]-6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride / dichloromethane; toluene; isopropyl alcohol / -78 - -73 °C / Inert atmosphere 2: potassium tert-butylate / dimethyl sulfoxide / 25 °C View Scheme

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (99199-60-7)

Conditions	Yield
With lithium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 2h;

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → [R*(R*)]-6-fluoro-3,4-dihydro-2-oxiran-2-yl-2H-benzopyran

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride; morpholine / toluene / 2 h / -10 °C / Inert atmosphere 2: trimethylsulfoxonium iodide; sodium methylate / dimethyl sulfoxide; dichloromethane / 2 h / 10 - 15 °C View Scheme

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → (S*,R*)-(+/-)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)methanol

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride; morpholine / toluene / 2 h / -10 °C / Inert atmosphere 2: trimethylsulfoxonium iodide; sodium methylate / dimethyl sulfoxide; dichloromethane / 2 h / 10 - 15 °C 3: water / 6 h / 10 - 30 °C View Scheme

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → [2S*[1R*,5R*(R*)]]α,α'-[[(phenylmethyl)imino]bismethylene] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride; morpholine / toluene / 2 h / -10 °C / Inert atmosphere 2: trimethylsulfoxonium iodide; sodium methylate / dimethyl sulfoxide; dichloromethane / 2 h / 10 - 15 °C 3: methanol / 15 h / 30 °C / Reflux View Scheme
Multi-step reaction with 4 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride; morpholine / toluene / 2 h / -10 °C / Inert atmosphere 2: trimethylsulfoxonium iodide; sodium methylate / dimethyl sulfoxide; dichloromethane / 2 h / 10 - 15 °C 3: water / 6 h / 10 - 30 °C 4: methanol / 15 h / 30 °C / Reflux View Scheme

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → nebivolol hydrochloride

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride; morpholine / toluene / 2 h / -10 °C / Inert atmosphere 2: trimethylsulfoxonium iodide; sodium methylate / dimethyl sulfoxide; dichloromethane / 2 h / 10 - 15 °C 3: methanol / 15 h / 30 °C / Reflux 4: palladium on activated charcoal; hydrogen / acetic acid / 30 - 35 °C View Scheme
Multi-step reaction with 5 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride; morpholine / toluene / 2 h / -10 °C / Inert atmosphere 2: trimethylsulfoxonium iodide; sodium methylate / dimethyl sulfoxide; dichloromethane / 2 h / 10 - 15 °C 3: water / 6 h / 10 - 30 °C 4: methanol / 15 h / 30 °C / Reflux 5: palladium on activated charcoal; hydrogen / acetic acid / 30 - 35 °C View Scheme

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → [R*(S*)]-6-fluoro-3,4-dihydro-2-oxiran-2-yl-2H-benzopyran

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride; morpholine / toluene / 2 h / -10 °C / Inert atmosphere 2: trimethylsulfoxonium iodide; sodium methylate / dimethyl sulfoxide; dichloromethane / 2 h / 10 - 15 °C View Scheme

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → 1-(2,6-difluorobenzyl)-4-(5-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-1,3,4-oxadiazol-2-yl)-1H-1,2,3-triazole

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / ethanol / Reflux 2: trichlorophosphate / Reflux View Scheme

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → 2,5-bis(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-1,3,4-oxadiazole

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / ethanol / Reflux 2: trichlorophosphate / Reflux View Scheme

(-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (874649-82-8) → 6-fluoro-2-(5-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-1,3,4-oxadiazol-2-yl)-4H-chromen-4-one

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / ethanol / Reflux 2: trichlorophosphate / Reflux View Scheme

Upstream product

• 99199-60-7 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 
• 67-56-1 methanol 
• 99199-59-4 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid 
• 405-51-6 4-fluorophenyl acetate 
• 371-41-5 4-Fluorophenol 
• 134102-10-6 methyl 6-fluoro-4-oxo-3,4-dihydro-2H-chroman-2-carboxylate 
• 394-32-1 1-(5-fluoro-2-hydroxyphenyl)ethan-1-one 
• 75-75-2 methanesulfonic acid 

Downstream Products

• 99199-90-3 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran 
• 943126-72-5 2-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethan-1-one 
• 99199-60-7 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 
• 793669-26-8 [R*(S*)]-6-fluoro-3,4-dihydro-2-oxiran-2-yl-2H-benzopyran 
• 409346-73-2 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde 
• 152520-56-4 nebivolol hydrochloride 
• 129050-27-7 (S*,R*)-(+/-)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)methanol 
• 793669-26-8 [R*(R*)]-6-fluoro-3,4-dihydro-2-oxiran-2-yl-2H-benzopyran 
• 793669-26-8 [1R*(R*)]-6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene 
• 793669-26-8 [1S*(R*)]-6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene 
• 99199-62-9 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol 

Relevant articles and documents

Synthesis of novel of 2, 5-disubstituted 1, 3, 4- oxadiazole derivatives and their in vitro anti-inflammatory, anti-oxidant evaluation, and molecular docking study

A series of novel 2, 5-disubstituted 1, 3, 4-Oxadiazole derivatives as a potential anti-inflammatory, and anti-oxidant agent were synthesized via cyclisation. Hydrazide molecule treated with substituted acids in the presence of phosphorus oxychloride (POCl3) as an efficient reagent as well as solvent by conventional method with shorter reaction time and excellent yield. The newly synthesized 1, 3, 4- oxadiazole derivatives exhibited excellent to good anti-inflammatory and anti-oxidant activities compaired to the standard drugs. Molecular docking study on the crucial anti-inflammatory target–cyclooxygenase-2 (COX-2) revealed the ability of the scaffold to correctly recognize the active site and achieve significant bonded and non-bonded interactions with key residues therein. This study could identify potential compounds which can be pertinent starting points for structure-based drug design to obtain newer anti-inflammatory agents.

An efficient and practical enantiospecific synthesis of methyl chromanone- and chroman-2-carboxylates

Chromanone-2-carboxylates and chroman-2-carboxylates are useful building blocks for the synthesis of a variety of bioactive compounds, such as repinotan, fidarestat, and nebivolol. An efficient and practical enantiospecific synthesis of chromanone-2-carboxylates and chroman-2-carboxylates has been accomplished using intramolecular Mitsunobu etherification of methyl (S)-2-hydroxy-4-oxo-4-(2′-hydroxy)phenylbutanoates derived from l-malic acid.

METHOD FOR PREPARING NEBIVOLOL

The present invention relates to a process for the preparation of nebivolol and, more particularly, to an improved process of synthesizing an alpha-haloketone of formula a key intermediate in the preparation of nebivolol.