3468-01-7

Basic information

• Product Name: 3-Methylflavone-8-carboxylic acid
• Synonyms: LABOTEST-BB LT00454344;8-CARBOXY-3-METHYLFLAVONE;4H-1-BENZOPYRAN-8-CARBOXYLIC ACID, 3-METHYL-4-OXO-2-PHENYL-;3-METHYLFLAVONE-8-CARBOXYLIC ACID;3-Methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid;3-METHYL-4-OXO-2-PHENYL-4H-CHROMENE-8-CARBOXYLIC ACID;TIMTEC-BB SBB001131;3-Methylflavone-8-carboxylic
• CAS NO: 3468-01-7
• Molecular Formula: C₁₇H₁₂O₄
• Molecular Weight: 280.27
• EINECS: 222-425-2
• Product Categories: Pharmaceutical Raw Materials;Pharmaceutical material and intermeidates;Di-substituted Flavones;All Inhibitors;Inhibitors;Heterocycles;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals
• Mol File: 3468-01-7.mol
• Article Data: 4

Chemical Properties

• Melting Point: 234-236°C
• Boiling Point: 485.1 °C at 760 mmHg
• Flash Point: 183.3 °C
• Appearance: White crystalline solid
• Density: 1.336 g/cm³
• Vapor Pressure: 3.2E-10mmHg at 25°C
• Refractive Index: 1.642
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 2.85±0.40(Predicted)
• BRN: 1433509
• CAS DataBase Reference: 3-Methylflavone-8-carboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 3-Methylflavone-8-carboxylic acid(3468-01-7)
• EPA Substance Registry System: 3-Methylflavone-8-carboxylic acid(3468-01-7)

Safety Data

• Statements: 36/37/38
• Safety Statements: 26-36
• Hazardous Substances Data: 3468-01-7(Hazardous Substances Data)

Usage

Chemical Properties

White Crystalline Solid

Uses

The main active metabolite of Flavoxate hydrochloride (FX) in human.

Definition

ChEBI: A member of the class of flavones that is flavone substituted at position 3 by a methyl group and at position 8 by a carboxylic acid group.

InChI:InChI=1/C17H12O4/c1-10-14(18)12-8-5-9-13(17(19)20)16(12)21-15(10)11-6-3-2-4-7-11/h2-9H,1H3,(H,19,20)

Synthetic route

methyl 2-benzoyloxy-3-propionylbenzoate → 3-methylflavone-8-carboxylic acid (3468-01-7)

Conditions	Yield
Stage #1: methyl 2-benzoyloxy-3-propionylbenzoate With aluminum oxide at 165℃; for 4h; Stage #2: With sodium hydroxide In methanol; water at 75 - 80℃; for 1.5h; Temperature;	88%

8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (103085-54-7) → 3-methylflavone-8-carboxylic acid (3468-01-7)

Conditions	Yield
With dihydrogen peroxide In butanone at 90 - 95℃; for 44h;	85%
With nitric acid In benzene Product distribution; Heating; various concentrations of HNO3.;	85%

3-methyl-2-phenyl-8-(1-propenyl)-4H-1-benzopyran-4-one → 3-methylflavone-8-carboxylic acid (3468-01-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 94 percent / NaBr, H2SO4 / acetonitrile; H2O / 2.83 h / 45 °C / electrolysis 2: 1) H2SO4; 2) electrolysis / 1) MeOH, 60 deg C, 40 min; 2) 60 deg C, 48 h. 3: 85 percent / HNO3 / benzene / Heating; various concentrations of HNO3. View Scheme
Multi-step reaction with 4 steps 1: 94 percent / NaBr, H2SO4 / acetonitrile; H2O / 2.83 h / 45 °C / electrolysis 2: 94 percent / 10percent H2SO4 / tetrahydrofuran / 11 h / Ambient temperature 3: 91 percent / H2SO4 / methanol / 6 h / Ambient temperature; electrolysis 4: 85 percent / HNO3 / benzene / Heating; various concentrations of HNO3. View Scheme
Multi-step reaction with 4 steps 1: 94 percent / NaBr, H2SO4 / acetonitrile; H2O / 2.83 h / 45 °C / electrolysis 2: 94 percent / 10percent H2SO4 / tetrahydrofuran / 11 h / Ambient temperature 3: 74 percent / H2SO4, electrolysis / methanol / 50 °C / other temperatures, other reagent, other solvent. 4: 85 percent / HNO3 / benzene / Heating; various concentrations of HNO3. View Scheme

8-(1,2-epoxypropyl)-3-methyl-2-phenyl-4H-1-benzopyran-4-one (103085-50-3) → 3-methylflavone-8-carboxylic acid (3468-01-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) H2SO4; 2) electrolysis / 1) MeOH, 60 deg C, 40 min; 2) 60 deg C, 48 h. 2: 85 percent / HNO3 / benzene / Heating; various concentrations of HNO3. View Scheme
Multi-step reaction with 3 steps 1: 94 percent / 10percent H2SO4 / tetrahydrofuran / 11 h / Ambient temperature 2: 91 percent / H2SO4 / methanol / 6 h / Ambient temperature; electrolysis 3: 85 percent / HNO3 / benzene / Heating; various concentrations of HNO3. View Scheme
Multi-step reaction with 3 steps 1: 94 percent / 10percent H2SO4 / tetrahydrofuran / 11 h / Ambient temperature 2: 74 percent / H2SO4, electrolysis / methanol / 50 °C / other temperatures, other reagent, other solvent. 3: 85 percent / HNO3 / benzene / Heating; various concentrations of HNO3. View Scheme

8-(1,2-dihydroxypropyl)-3-methyl-2-phenyl-4H-1-benzopyran-4-one (103085-53-6) → 3-methylflavone-8-carboxylic acid (3468-01-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 91 percent / H2SO4 / methanol / 6 h / Ambient temperature; electrolysis 2: 85 percent / HNO3 / benzene / Heating; various concentrations of HNO3. View Scheme
Multi-step reaction with 2 steps 1: 74 percent / H2SO4, electrolysis / methanol / 50 °C / other temperatures, other reagent, other solvent. 2: 85 percent / HNO3 / benzene / Heating; various concentrations of HNO3. View Scheme

0.5N-KOH + Methyl 3-methylflavone-8-carboxylate (90101-87-4) → 3-methylflavone-8-carboxylic acid (3468-01-7)

Conditions	Yield
In methanol; water	27.3 g (97.5%)

flavoxate hydrochloride → 3-methylflavone-8-carboxylic acid (3468-01-7)

Conditions	Yield
Stage #1: flavoxate hydrochloride With sodium hydroxide for 3h; Reflux; Stage #2: With hydrogenchloride; water

methyl salicylate (119-36-8) → 3-methylflavone-8-carboxylic acid (3468-01-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: bromine / dichloromethane / 4 h / 0 - 15 °C 1.2: 2.5 h / 60 - 65 °C 1.3: 1.5 h / 20 °C 2.1: sodium hydroxide / dichloromethane / 0 - 25 °C 3.1: aluminum oxide / 4 h / 165 °C 3.2: 1.5 h / 75 - 80 °C View Scheme

3-methylflavone-8-carboxylic acid (3468-01-7) + N,N-Dimethylacrylamide (2680-03-7) → (E)-N,N-dimethyl-3-(3-methyl-4-oxo-2-phenyl-4H-chromen-8-yl)acrylamide

Conditions	Yield
With palladium(II) trifluoroacetate; 2,2-dimethylpropanoic anhydride; bis[2-(diphenylphosphino)phenyl] ether; sodium chloride In 1,4-dioxane at 150℃; for 10h; Heck Reaction; Schlenk technique; Inert atmosphere;	94%

3-methylflavone-8-carboxylic acid (3468-01-7) + phosphonic acid diethyl ester (762-04-9) → diethyl (3-methyl-4-oxo-2-phenyl-4H-chromen-8-yl)phosphonate

Conditions	Yield
With di-tert-butyl dicarbonate; N,N-dimethyl-cyclohexanamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate In 1,4-dioxane at 130℃; for 18h; Schlenk technique; Inert atmosphere; Glovebox;	93%
With di-tert-butyl dicarbonate; N,N-dimethyl-cyclohexanamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate In 1,4-dioxane for 18h; Inert atmosphere; Schlenk technique; Heating;	93%

dibutyl hydrogen phosphite (1809-19-4) + 3-methylflavone-8-carboxylic acid (3468-01-7) → dibutyl (3-methyl-4-oxo-2-phenyl-4H-chromen-8-yl)phosphonate

Conditions	Yield
With di-tert-butyl dicarbonate; N,N-dimethyl-cyclohexanamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate In 1,4-dioxane for 18h; Inert atmosphere; Schlenk technique; Heating;	93%
With di-tert-butyl dicarbonate; N,N-dimethyl-cyclohexanamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate In 1,4-dioxane at 130℃; for 18h; Schlenk technique; Inert atmosphere; Glovebox;	91%

3-methylflavone-8-carboxylic acid (3468-01-7) + dicyclohexylphosphine oxide (14717-29-4) → 8-(dicyclohexylphosphoryl)-3-methyl-2-phenyl-4H-chromen-4-one

Conditions	Yield
With di-tert-butyl dicarbonate; N,N-dimethyl-cyclohexanamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate In 1,4-dioxane at 130℃; for 18h; Schlenk technique; Inert atmosphere; Glovebox;	83%
With di-tert-butyl dicarbonate; N,N-dimethyl-cyclohexanamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate In 1,4-dioxane for 18h; Inert atmosphere; Schlenk technique; Heating;	83%

3-methylflavone-8-carboxylic acid (3468-01-7) + (trifluoromethyl)trimethylsilane (81290-20-2) → 3-methyl-2-phenyl-8-(2,2,2-trifluoroacetyl)-4H-chromen-4-one

Conditions	Yield
With dmap; cesium fluoride; trifluoroacetic anhydride at 120℃; for 15h; Schlenk technique; Inert atmosphere;	80%

3-methylflavone-8-carboxylic acid (3468-01-7) + triethylamine (121-44-8) → N,N-diethyl-3-methyl-4-oxo-2-phenyl-4H-chromene-8-carboxamide (90101-88-5)

Conditions	Yield
With trifuran-2-yl-phosphane; palladium diacetate; 2,2-dimethylpropanoic anhydride In toluene at 120℃; for 15h; Inert atmosphere;	75%

3-methylflavone-8-carboxylic acid (3468-01-7) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → N,N,3-trimethyl-4-oxo-2-phenyl-4H-chromene-8-carboxamide

Conditions	Yield
With trifuran-2-yl-phosphane; palladium diacetate; 2,2-dimethylpropanoic anhydride In toluene at 150℃; for 15h; Inert atmosphere;	75%

8-amino quinoline (578-66-5) + 3-methylflavone-8-carboxylic acid (3468-01-7) → C26H18N2O3

Conditions	Yield
Stage #1: 3-methylflavone-8-carboxylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: 8-amino quinoline With triethylamine In dichloromethane at 0 - 45℃; for 12h;	73%

3-methylflavone-8-carboxylic acid (3468-01-7) + 4-methoxyphenylacetylen (768-60-5) → 8-((4-methoxyphenyl)ethynyl)-3-methyl-2-phenyl-4H-chromen-4-one

Conditions	Yield
With 1,3-bis-(diphenylphosphino)propane; 2,2-dimethylpropanoic anhydride; palladium dichloride In 1,4-dioxane at 150℃; for 16h; Sonogashira Cross-Coupling; Inert atmosphere; Schlenk technique;	70%

3-methylflavone-8-carboxylic acid (3468-01-7) + Diphenylphosphine oxide (4559-70-0) → 8-(diphenylphosphoryl)-3-methyl-2-phenyl-4H-chromen-4-one

Conditions	Yield
With di-tert-butyl dicarbonate; N,N-dimethyl-cyclohexanamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate In 1,4-dioxane at 115℃; for 18h; Schlenk technique; Inert atmosphere; Glovebox;	68%
With di-tert-butyl dicarbonate; N,N-dimethyl-cyclohexanamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate In 1,4-dioxane at 115℃; for 18h; Inert atmosphere; Schlenk technique;	68%

3-methylflavone-8-carboxylic acid (3468-01-7) + ethyl Phenylphosphinate (172487-18-2) → ethyl (3-methyl-4-oxo-2-phenyl-4H-chromen-8-yl)(phenyl)phosphinate

Conditions	Yield
With di-tert-butyl dicarbonate; N,N-dimethyl-cyclohexanamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate In 1,4-dioxane at 130℃; for 18h; Schlenk technique; Inert atmosphere; Glovebox;	67%
With di-tert-butyl dicarbonate; N,N-dimethyl-cyclohexanamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate In 1,4-dioxane for 18h; Inert atmosphere; Schlenk technique; Heating;	67%

2,3,4-tri-O-acetyl-β-D-glucopyranosylamine uronic acid methyl ester (14365-73-2) + 3-methylflavone-8-carboxylic acid (3468-01-7) → (2S,3S,4S,5R,6R)-3,4,5-Triacetoxy-6-[(3-methyl-4-oxo-2-phenyl-4H-chromene-8-carbonyl)-amino]-tetrahydro-pyran-2-carboxylic acid methyl ester

Conditions	Yield
With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 12h;	49%

3-methylflavone-8-carboxylic acid (3468-01-7) + 1-(3-chloropropyl)piperidine hydrochloride (5472-49-1) → 3-(1-piperidinyl)propyl 2-phenyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate

Conditions	Yield
With potassium hydroxide In methanol; isopropyl alcohol for 0.5h; Heating;	32%

3-methylflavone-8-carboxylic acid (3468-01-7) → 1-deoxy-1-{[(3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-yl)carbonyl]amino}-β-D-glucopyranuronic acid

Conditions	Yield
Multi-step reaction with 2 steps 1: 49 percent / HOBT; DMAP; DCC / tetrahydrofuran / 12 h / 20 °C 2: 84 percent / LiOH / methanol; tetrahydrofuran; H2O / 0 °C View Scheme

3-methylflavone-8-carboxylic acid (3468-01-7) + (1α,5α,6α)-3-N-benzyl-6-amino-3-aza-bicyclo[3.1.0]hexane (151860-17-2) → (1α,5α,6α)-6N-[3-benzyl-3-azabicyclo [3.1.0]hexyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxamide

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 4-methyl-morpholine; DMF (N,N-dimethyl-formamide); 1-hydorxy benzotriazole at 0 - 20℃; for 3.5h;

1-aminomethyl-3-benzyl-3-azabicyclo [3.1.0] hexane (134574-95-1) + 3-methylflavone-8-carboxylic acid (3468-01-7) → N-[3-benzyl-3-azabicyclo [3.1.0]hexyl-1-aminomethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxamide

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 4-methyl-morpholine; DMF (N,N-dimethyl-formamide); benzotriazol-1-ol at 0 - 20℃; for 3.5h;

N-(3-chloropropyl)-2-(3,4-dimethoxyphenyl)-N-methyl-ethylamine hydrochloride + 3-methylflavone-8-carboxylic acid (3468-01-7) → 8-{3-[2-(3,4-Dimethoxyphenyl)-N-methylethylamino]propoxycarbonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride (153240-51-8)

Conditions	Yield
With hydrogenchloride; potassium carbonate In N-methyl-acetamide; ethanol; water; isopropyl alcohol

3-methylflavone-8-carboxylic acid (3468-01-7) + 1-(2-methoxyphenyl)-4-(3-chloropropyl)piperazine (21279-77-6) → Rec 15/2667 dihydrochloride

Conditions	Yield
With potassium carbonate In N-methyl-acetamide; ethanol
With potassium carbonate In N-methyl-acetamide; ethanol

Methyl 3-methylflavone-8-carboxylate (90101-87-4) + 3-methylflavone-8-carboxylic acid (3468-01-7) + piperidinoethyl chloride (100859-97-0) → flavoxate hydrochloride

Conditions	Yield
With sodium In N-hydroxyethylpiperidine; benzene

piperidine (110-89-4) + 3-methylflavone-8-carboxylic acid (3468-01-7) + oxiranyl-methanol (556-52-5) + oxiranemethyl 2-phenyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate (86433-56-9) → 2-hydroxy-3-(1-piperidinyl)propyl 2-phenyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate

Conditions	Yield
With triethylamine In water; acetonitrile; benzene

1-(2-aminoisopropyl)-piperidine (54151-70-1) + 3-methylflavone-8-carboxylic acid (3468-01-7) + chloroformic acid ethyl ester (541-41-3) → N-[2-(1-Piperidyl)propyl]-3-methylflavone-8-carboxamide (92606-55-8)

Conditions	Yield
With triethylamine In tetrahydrofuran

quinoline-S + 3-methylflavone-8-carboxylic acid (3468-01-7) + 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride (51950-71-1) + sodium hydrogensulfite → 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (103085-54-7)

Conditions	Yield
With thionyl chloride; palladium In 5,5-dimethyl-1,3-cyclohexadiene; water

1-(2-aminoethyl)pyrrolidine (7154-73-6) + 3-methylflavone-8-carboxylic acid (3468-01-7) + 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride (51950-71-1) → N-[2-(pyrrolidin-1-yl)ethyl]-3-methylflavone-8-carboxamide

Conditions	Yield
With hydrogenchloride; thionyl chloride In benzene

Upstream product

• 90101-87-4 Methyl 3-methylflavone-8-carboxylate 
• 119-36-8 methyl salicylate 
• 3717-88-2 flavoxate hydrochloride 
• 103085-53-6 8-(1,2-dihydroxypropyl)-3-methyl-2-phenyl-4H-1-benzopyran-4-one 
• 103085-54-7 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 
• 103085-50-3 8-(1,2-epoxypropyl)-3-methyl-2-phenyl-4H-1-benzopyran-4-one 
• 3468-00-6 3-methyl-2-phenyl-8-(1-propenyl)-4H-1-benzopyran-4-one 

Downstream Products

• 153240-51-8 8-{3-[2-(3,4-Dimethoxyphenyl)-N-methylethylamino]propoxycarbonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride 
• 90101-88-5 N,N-diethyl-3-methyl-4-oxo-2-phenyl-4H-chromene-8-carboxamide 
• 92606-49-0 N-[(2-Dimethylamino-1-methyl)ethyl]-3-methylflavone-8-carboxamide 
• 103085-54-7 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 

Relevant articles and documents

Spectrofluorimetric determination of 3-methylflavone-8-carboxylic acid, the main active metabolite of flavoxate hydrochloride in human urine

A simple, sensitive and selective spectrofluorimetric method has been developed for the determination of 3-methylflavone-8-carboxylic acid as the main active metabolite of flavoxate hydrochloride in human urine. The proposed method was based on the measurement of the native fluorescence of the metabolite in methanol at an emission wavelength 390 nm, upon excitation at 338 nm. Moreover, the urinary excretion pattern has been calculated using the proposed method. Taking the advantage that 3-methylflavone-8-carboxylic acid is also the alkaline degradate, the proposed method was applied to in vitro determination of flavoxate hydrochloride in tablets dosage form via the measurement of its corresponding degradate. The method was validated in accordance with the ICH requirements and statistically compared to the official method with no significant difference in performance.

Halo-containing 3-methylflavone-8-carboxylic acid derivatives

This invention relates to derivatives of 3-methylflavone-8-carboxylic acid represented by the formula (1) STR1 wherein R represents a hydrogen atom, a lower alkyl group or a group STR2 (wherein R1 and R2 represent a lower alkyl group or R1 and R2, when taken together with the nitrogen atom to which they are attached, may form a heterocyclic ring with or without an intervening hetero atom, and n is an integer of 1 to 4), and X represents a halogen atom, which are useful as intermediates. This invention also relates to processes for preparing the same.