99199-90-3

Basic information

• Product Name: 6-Fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran
• Synonyms: 6-FLUORO-3,4-DIHYDRO-2H-1-BENZOPYRAN-2-OXARANYL(FOR NEBIVOLOL);6-Fluoro-3,4-Dihydro-2H-1-Benzopyran-2-Oxaranyl;6-FLUORO-3,4-DIHYDRO-2-OXIRANYL-2H-1-BENZOPYRAN;6-FLUORO-2-OXIRANYL-3, 4-DIHYDRO-2H-1-BENZOPYRAN,ENTERPRISE STANDARD;6-Fluoro-3,4-dihydro-2-(2-oxiranyl)-2H-1-benzopyran;6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-oxiranyl;2H-1-Benzopyran,6-fluoro-3,4-dihydro-2-(2-oxiranyl)-;Nebivolol Impurity C (Mixture of Diastereomers)
• CAS NO: 99199-90-3
• Molecular Formula: C₁₁H₁₁FO₂
• Molecular Weight: 194.2
• EINECS: 1312995-182-4
• Mol File: 99199-90-3.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 292 °C
• Flash Point: 138 °C
• Appearance: /
• Density: 1.299
• Vapor Pressure: 0.003mmHg at 25°C
• Refractive Index: 1.568
• CAS DataBase Reference: 6-Fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran(CAS DataBase Reference)
• NIST Chemistry Reference: 6-Fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran(99199-90-3)
• EPA Substance Registry System: 6-Fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran(99199-90-3)

Safety Data

• Hazardous Substances Data: 99199-90-3(Hazardous Substances Data)

Usage

Uses

6-Fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran is used in preparation and application of Smo inhibitors based on nebivolol for preparing Smo inhibitor drugs or antitumor drugs.

InChI:InChI=1/C11H11FO2/c12-8-2-4-9-7(5-8)1-3-10(14-9)11-6-13-11/h2,4-5,10-11H,1,3,6H2

Synthetic route

6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (409346-73-2) + trimethylsulphonium iodide (2181-42-2) → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Stage #1: trimethylsulphonium iodide With sodium hydride In dimethyl sulfoxide cooling; Stage #2: 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde In dimethyl sulfoxide at 20℃; for 1h;	100%

2-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2yl)ethanol (1017878-67-9) → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Stage #1: 2-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2yl)ethanol With sodium hydroxide In water; isopropyl alcohol at 0℃; for 1.5h; Inert atmosphere; Stage #2: With acetic acid In water; isopropyl alcohol; toluene	96%
With sodium hydroxide In dichloromethane; water at -10 - 20℃; for 2.66667h;

6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (409346-73-2) + trimethylsulfoxonium iodide (1774-47-6) → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Stage #1: trimethylsulfoxonium iodide With sodium hydride In dimethyl sulfoxide for 0.5h; Stage #2: 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde In dichloromethane; dimethyl sulfoxide at 20 - 25℃; for 1h;	90%
With sodium hydride In dimethyl sulfoxide at 20 - 25℃; for 1h;	84%
Stage #1: trimethylsulfoxonium iodide With potassium tert-butylate In dimethyl sulfoxide at 20 - 40℃; for 1.5h; Stage #2: 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde In dimethyl sulfoxide at 20 - 40℃; for 1.5h;

1-(6-fluorochroman-2-yl)ethane-1,2-diol (1322623-11-9) → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Stage #1: 1-(6-fluorochroman-2-yl)ethane-1,2-diol With sodium hydride In tert-butyl methyl ether; dimethyl sulfoxide at 50℃; for 1h; Inert atmosphere; Stage #2: With p-toluenesulfonyl chloride In tert-butyl methyl ether for 1h; Reagent/catalyst; Solvent; Inert atmosphere;	90%

2-bromo-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2yl)ethanol → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

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

6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (99199-60-7) → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: Et3N; ClCOOEt / tetrahydrofuran / 10 h / 20 °C 1.2: 90 percent / NaBH4 / tetrahydrofuran; H2O / 5 h / 20 °C 2.1: 78 percent / pyridinium chloroformate/SiO2 / CH2Cl2 / 1.5 h / 20 °C 3.1: NaH / dimethylsulfoxide / cooling 3.2: 100 percent / dimethylsulfoxide / 1 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate; sulfuric acid / diethyl ether; tetrahydrofuran / 0.75 h / 0 - 35 °C 1.2: pH 7 2.1: sodium hydrogencarbonate / iodine; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane / 0.17 h / 20 °C 2.2: 24 h / 20 - 25 °C 3.1: sodium hydride / dimethyl sulfoxide / 0.5 h 3.2: 1 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; sulfuric acid / tetrahydrofuran; diethyl ether / 0.5 h / 0 - 35 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; iodine / dichloromethane; water / 24 h / 20 °C 3: sodium hydride / dimethyl sulfoxide / 1 h / 20 - 25 °C View Scheme

6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (99199-59-4) → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 86 percent / H2 / Pd/C / acetic acid / 70 - 80 °C / 15001.2 Torr 2.1: Et3N; ClCOOEt / tetrahydrofuran / 10 h / 20 °C 2.2: 90 percent / NaBH4 / tetrahydrofuran; H2O / 5 h / 20 °C 3.1: 78 percent / pyridinium chloroformate/SiO2 / CH2Cl2 / 1.5 h / 20 °C 4.1: NaH / dimethylsulfoxide / cooling 4.2: 100 percent / dimethylsulfoxide / 1 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 45 - 55 °C / 3000.3 Torr 2.1: n-butyllithium / hexane; tetrahydrofuran / -85 - -75 °C 2.2: -80 - 0 °C 3.1: ethanol; sodium tetrahydroborate / 2 h / 0 °C / Inert atmosphere 4.1: sodium hydroxide / isopropyl alcohol; water / 1.5 h / 0 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: hydrogen / 5%-palladium/activated carbon / tetrahydrofuran / 45 - 55 °C / 3000.3 Torr 2.1: n-butyllithium / hexane; tetrahydrofuran / -85 - -75 °C 2.2: -80 - -70 °C 2.3: 2 h / Reflux View Scheme

(6-fluoro-3,4-dihydro-2H-chromene-2-yl)methanol (99199-62-9) → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 78 percent / pyridinium chloroformate/SiO2 / CH2Cl2 / 1.5 h / 20 °C 2.1: NaH / dimethylsulfoxide / cooling 2.2: 100 percent / dimethylsulfoxide / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / iodine; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane / 0.17 h / 20 °C 1.2: 24 h / 20 - 25 °C 2.1: sodium hydride / dimethyl sulfoxide / 0.5 h 2.2: 1 h / 20 - 25 °C View Scheme
Multi-step reaction with 2 steps 1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; iodine / dichloromethane; water / 24 h / 20 °C 2: sodium hydride / dimethyl sulfoxide / 1 h / 20 - 25 °C View Scheme

(-)-(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) + chlorobromomethane (74-97-5) → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

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;

1-(5-fluoro-2-hydroxyphenyl)ethan-1-one (394-32-1) → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Multi-step reaction with 5 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 3.1: n-butyllithium / hexane; tetrahydrofuran / -85 - -75 °C 3.2: -80 - 0 °C 4.1: ethanol; sodium tetrahydroborate / 2 h / 0 °C / Inert atmosphere 5.1: sodium hydroxide / isopropyl alcohol; water / 1.5 h / 0 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 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 3.1: n-butyllithium / hexane; tetrahydrofuran / -85 - -75 °C 3.2: -80 - -70 °C 3.3: 2 h / Reflux View Scheme

2-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethan-1-one (943126-72-5) → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol; sodium tetrahydroborate / 2 h / 0 °C / Inert atmosphere 2: sodium hydroxide / isopropyl alcohol; water / 1.5 h / 0 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; water / tetrahydrofuran / 2 h / -5 - 0 °C / Inert atmosphere 2: sodium hydroxide / dichloromethane; water / 2.67 h / -10 - 20 °C View Scheme

6-fluoro-3,4-dihydro-2H-benzopyran-2-carboxylic acid ethyl ester + chlorobromomethane (74-97-5) → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Stage #1: 6-fluoro-3,4-dihydro-2H-benzopyran-2-carboxylic acid ethyl ester; chlorobromomethane With n-butyllithium In tetrahydrofuran; cyclohexane at -60℃; for 2h; Inert atmosphere; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; cyclohexane at -50 - 0℃; for 2h; Inert atmosphere;

6-fluoro-3,4-dihydro-2H-benzopyran-2-carboxylic acid ethyl ester → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium; water / hexane; tetrahydrofuran / 3 h / -60 °C / Inert atmosphere 1.2: 2 h / 0 - 30 °C / Inert atmosphere 2.1: sodium hydroxide / dichloromethane; water / 2.67 h / -10 - 20 °C View Scheme
Multi-step reaction with 3 steps 1: n-butyllithium / hexane; tetrahydrofuran / 3 h / -50 °C / Inert atmosphere 2: sodium tetrahydroborate; water / tetrahydrofuran / 2 h / -5 - 0 °C / Inert atmosphere 3: sodium hydroxide / dichloromethane; water / 2.67 h / -10 - 20 °C View Scheme
Multi-step reaction with 3 steps 1: n-butyllithium / hexane; tetrahydrofuran / 3 h / -60 °C / Inert atmosphere 2: sodium tetrahydroborate; water / tetrahydrofuran / 2 h / -5 - 0 °C / Inert atmosphere 3: sodium hydroxide / dichloromethane; water / 2.67 h / -10 - 20 °C View Scheme

2-amino-1-(-6-fluoro-2-chromanyl) ethanol → 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: sulfuric acid; potassium bromide; sodium nitrite / diethyl ether; water / 20 °C 2: potassium carbonate / acetonitrile / 20 °C View Scheme

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) + benzylamine (100-46-9) → α,α'-[[(phenylmethyl)imino]bismethylene]bis-[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (929706-85-4)

Conditions	Yield
In isopropyl alcohol Reflux;	100%

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) + benzylamine (100-46-9) → 6-fluoro-3,4-dihydro-α-[[(phenylmethyl)amino]methyl]-2H-1-benzopyran-2-methanol (99199-91-4)

Conditions	Yield
In methanol at 20℃;	92%
In isopropyl alcohol for 2h; Heating / reflux;

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) + 6-fluoro-3,4-dihydro-α-[[(phenylmethyl)amino]methyl]-2H-1-benzopyran-2-methanol (99199-91-4) → α,α'-[[(phenylmethyl)imino]bismethylene]bis-[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (929706-85-4)

Conditions	Yield
In ethanol for 4h; Heating;	82%

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) + benzylamine (100-46-9) → (R*,R*)-(±)-α-[(benzylamino)methyl](6-fluoro-2-chromanyl)methanol

Conditions	Yield
In tert-Amyl alcohol at 25℃; for 12h;	58%

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) + C17H16FNO2 → C21H21F2NO4

Conditions	Yield
Stage #1: 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran; C17H16FNO2 In ethanol at 75℃; for 8h; Stage #2: In tert-Amyl alcohol at 25 - 80℃; for 24h;	46%

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) + (R*,R*)-6-fluoro-3,4-dihydro-α-hydroxy-2H-2-[1]benzopyran-ethanamine → [(SRRR)/(RSSS)-α,α'-iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] hydrochloride

Conditions	Yield
In tert-butyl alcohol Reflux;	31%

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) → α,α'-[[(phenylmethyl)imino]bismethylene]bis-[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (929706-85-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 92 percent / methanol / 20 °C 2: 82 percent / ethanol / 4 h / Heating View Scheme

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) → nebivolol (99200-09-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 82 percent / ethanol / 4 h / Heating 2: 65 percent / H2 / Pd/C / 2-methoxy-ethanol / 20 °C / normal pressure View Scheme
Multi-step reaction with 3 steps 1: 92 percent / methanol / 20 °C 2: 82 percent / ethanol / 4 h / Heating 3: 65 percent / H2 / Pd/C / 2-methoxy-ethanol / 20 °C / normal pressure View Scheme
Multi-step reaction with 2 steps 1: isopropyl alcohol / Reflux 2: ammonium formate / palladium 10% on activated carbon / methanol / 3 h / Reflux View Scheme

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) → [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
In hexane; ethyl acetate Purification / work up; Column chromatography; Resolution of diastereomeric mixture;
Product distribution / selectivity; Industry scale; Inert atmosphere; fractional distillation; Resolution of diastereomers; high vacuum conditions;
Purification / work up; Reflux;

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) + 6-fluoro-3,4-dihydro-α-[[(phenylmethyl)amino]methyl]-2H-1-benzopyran-2-methanol (99199-91-4) → N-benzyl-(±)-nebivolol

Conditions	Yield
In methanol at 65 - 70℃; for 15h;

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) + dibenzylamine (103-49-1) → [1R*(R*)]-6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene + C25H26FNO2

Conditions	Yield
In tert-Amyl alcohol at 20℃;

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) + benzylamine (100-46-9) → (S*,R*)-(±)-α-[(benzylamino)methyl](6-fluoro-2-chromanyl)methanol + [1R*(R*)]-6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene

Conditions	Yield
Stage #1: 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran; benzylamine In tert-Amyl alcohol; cyclohexane at 20℃; for 10h; Stage #2: With sodium hydrogen sulfate In tert-Amyl alcohol; cyclohexane Product distribution / selectivity;

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) + tert-butylamine (75-64-9) → C26H33F2NO4 + C26H33F2NO4

Conditions	Yield
Stage #1: 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran; tert-butylamine In tert-Amyl alcohol Stage #2: With sodium hydrogen sulfate In tert-Amyl alcohol; ethanol Reflux;

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) → nebivolol (99200-09-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: cyclohexane; tert-Amyl alcohol / 10 h / 20 °C 2: ethanol / Reflux 3: hydrogen / 10 wt% Pd(OH)2 on carbon / ethyl acetate; ethanol / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / tert-Amyl alcohol 2: ethanol / Reflux 3: hydrogen / 10 wt% Pd(OH)2 on carbon / ethyl acetate; ethanol / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: sodium azide / N,N-dimethyl-formamide / tert-Amyl alcohol / 20 °C 2: ethanol / Reflux 3: hydrogen / 10 wt% Pd(OH)2 on carbon / ethyl acetate; ethanol / Inert atmosphere View Scheme

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) → (S*,R*)-(±)-α-[(benzylamino)methyl](6-fluoro-2-chromanyl)methanol

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium azide / N,N-dimethyl-formamide / tert-Amyl alcohol / 20 °C 2: hydrogen / 5%-palladium/activated carbon / ethanol View Scheme
Multi-step reaction with 2 steps 1: tert-Amyl alcohol / 20 °C 2: hydrogen / 5%-palladium/activated carbon / ethanol View Scheme

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) → [1R*(R*)]-6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene + C11H12FN3O2

Conditions	Yield
With sodium azide; N,N-dimethyl-formamide In tert-Amyl alcohol at 20℃;

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) → N-benzyl-(±)-nebivolol + (+/-)-[2R*[1S*,5R*(R*)]]-α,α'-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]

Conditions	Yield
Multi-step reaction with 2 steps 1: cyclohexane; tert-Amyl alcohol / 10 h / 20 °C 2: ethanol / Reflux View Scheme
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / tert-Amyl alcohol 2: ethanol / Reflux View Scheme
Multi-step reaction with 2 steps 1: sodium azide / N,N-dimethyl-formamide / tert-Amyl alcohol / 20 °C 2: ethanol / Reflux View Scheme
Multi-step reaction with 3 steps 1: sodium azide / N,N-dimethyl-formamide / tert-Amyl alcohol / 20 °C 2: hydrogen / 5%-palladium/activated carbon / ethanol 3: ethanol / Reflux View Scheme
Multi-step reaction with 3 steps 1: tert-Amyl alcohol / 20 °C 2: hydrogen / 5%-palladium/activated carbon / ethanol 3: ethanol / Reflux View Scheme

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) → [(SRRR)/(RSSS)-α,α'-iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] hydrochloride

Conditions	Yield
Multi-step reaction with 4 steps 1: cyclohexane; tert-Amyl alcohol / 10 h / 20 °C 2: ethanol / Reflux 3: hydrogen / 10 wt% Pd(OH)2 on carbon / ethyl acetate; ethanol / Inert atmosphere 4: hydrogenchloride / ethanol View Scheme
Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / tert-Amyl alcohol 2: ethanol / Reflux 3: hydrogen / 10 wt% Pd(OH)2 on carbon / ethyl acetate; ethanol / Inert atmosphere 4: hydrogenchloride / ethanol View Scheme
Multi-step reaction with 4 steps 1: sodium azide / N,N-dimethyl-formamide / tert-Amyl alcohol / 20 °C 2: ethanol / Reflux 3: hydrogen / 10 wt% Pd(OH)2 on carbon / ethyl acetate; ethanol / Inert atmosphere 4: hydrogenchloride / ethanol View Scheme

6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (99199-90-3) + N-benzyloxyamine (622-33-3) → [1R*(R*)]-6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene + C18H20FNO3

Conditions	Yield
N,N-dimethyl-formamide In tert-Amyl alcohol

Upstream product

• 409346-73-2 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde 
• 1774-47-6 trimethylsulfoxonium iodide 
• 874649-82-8 (-)-(R)-methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate 
• 74-97-5 chlorobromomethane 
• 394-32-1 1-(5-fluoro-2-hydroxyphenyl)ethan-1-one 
• 943126-72-5 2-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethan-1-one 
• 1017878-67-9 2-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2yl)ethanol 
• 1322623-11-9 1-(6-fluorochroman-2-yl)ethane-1,2-diol 
• 897661-66-4 2-amino-1-(-6-fluoro-2-chromanyl) ethanol 
• 99199-61-8 6-fluoro-3,4-dihydro-2H-benzopyran-2-carboxylic acid ethyl ester 
• 99199-62-9 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol 
• 99199-59-4 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid 
• 99199-60-7 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 
• 2181-42-2 trimethylsulphonium iodide 

Downstream Products

• 152520-56-4 DL-nebivolol hydrochloride 
• 129050-27-7 (R*,R*)-(±)-α-[(benzylamino)methyl](6-fluoro-2-chromanyl)methanol 
• 1030385-16-0 (S)-2-benzylamino-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol 
• 129050-23-3 (2S)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene 
• 99200-09-6 nebivolol 
• 920299-33-8 (R)-1-((R)-6-Fluoro-chroman-2-yl)-2-[(S)-2-((R)-6-fluoro-chroman-2-yl)-2-hydroxy-ethylamino]-ethanol; hydrochloride 
• 152520-56-4 nebivolol hydrochloride 
• 118457-14-0 R 67142 
• 118457-16-2 nebivolol 
• 9920-09-6 α,α'-iminobis(methylene)bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] hydrochloride 
• 929706-85-4 α,α'-[[(phenylmethyl)imino]bismethylene]bis-[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] 
• 793669-26-8 [1R*(R*)]-6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene 
• 129050-27-7 (S*,R*)-(±)-α-[(benzylamino)methyl](6-fluoro-2-chromanyl)methanol 
• 99200-09-6 nebivolol 

Relevant articles and documents

Preparation method and application of Smo inhibitor based on Nebivolol

The invention discloses a preparation method and an application of a Smo inhibitor based on Nebivolol. The structural formula of the Smo inhibitor is as shown in a formula (I). The invention further discloses a synthetic method and an application of the Smo inhibitor. According to the Smo inhibitor, a beta-receptor retardant Nebivolol with inhibitory activity for Smo proteins serves as a lead compound, and optimization reconstruction is implemented based on the beta-receptor retardant Nebivolol to obtain the Smo inhibitor with good inhibitory activity.

Preparation of 6-fluoro -3,4-dihydro -2H-1-benzopyran-2-oxirane improved method

The invention relates to an improvement method for preparing a nebivolol key intermediate, namely 6-fluorin-3,4-dihydro-2H-1-benzopyranyl-2-epoxy ethane. The method comprises the following steps of: (a) condensing a compound (IV) and dihalogenated methane in the presence of an organic metal lithium compound to obtain a compound (II); (b) reducing the compound (II) to obtain a compound (III); and (c) performing cyclization on the compound (III) under alkaline condition to obtain a compound (I). The scheme of the invention has the advantages of readily available raw materials, easiness in operating, greatly increased reaction yield and purity and high contribution to industrial mass production.

PREPARATION OF NEBIVOLOL

Processes for the synthesis of pharmacologically active 2,2-iminobisethanol derivatives, e.g., 2H-1-benzopyran-2 methanol-α,α′-iminobis(methylene)]bis-[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]], and their pharmaceutically acceptable salts.