4442-53-9

Basic information

• Product Name: 2,3-Dihydro-1,4-benzodioxine-5-carboxylic acid
• Synonyms: AKOS BBS-00002750;7,10-dioxabicyclo[4.4.0]deca-1,3,5-triene-2-carboxylic acid;5-CARBOXY-1,4-BENZODIOXANE;1,4-BENZODIOXAN-5-CARBOXYLIC ACID;1,4-BENZODIOXANE-5-CARBOXYLIC ACID;2,3-DIHYDRO-BENZO[1,4]DIOXINE-5-CARBOXYLIC ACID;2,3-DIHYDRO-1,4-BENZODIOXINE-5-CARBOXYLIC ACID;2,3-dihydro-1,4-benzodioxin-5-carboxylic acid
• CAS NO: 4442-53-9
• Molecular Formula: C₉H₈O₄
• Molecular Weight: 180.16
• EINECS: 224-670-0
• Product Categories: Acids and Derivatives;Heterocycles;Benzodiozoles, Benzodioxines & Benzodioxepines;Carboxylic Acids;Acids & Esters;Miscellaneous Compounds;Benzodiozoles, Benzodioxines & Benzodioxepines;Carboxylic Acids;BenzodioxanesHeterocyclic Building Blocks;Building Blocks;Heterocyclic Building Blocks;O-Containing;Others
• Mol File: 4442-53-9.mol
• Article Data: 9

Chemical Properties

• Melting Point: 90-94 °C(lit.)
• Boiling Point: 334.1 °C at 760 mmHg
• Flash Point: 139.3 °C
• Appearance: white to light yellow crystal powder
• Density: 1.376 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.587
• Storage Temp.: Sealed in dry,Room Temperature
• PKA: 4.09±0.20(Predicted)
• CAS DataBase Reference: 2,3-Dihydro-1,4-benzodioxine-5-carboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 2,3-Dihydro-1,4-benzodioxine-5-carboxylic acid(4442-53-9)
• EPA Substance Registry System: 2,3-Dihydro-1,4-benzodioxine-5-carboxylic acid(4442-53-9)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36-37/39-36/37/38
• WGK Germany: 3
• Hazardous Substances Data: 4442-53-9(Hazardous Substances Data)

Usage

Chemical Properties

white to light yellow crystal powder

InChI:InChI=1/C9H8O4/c10-9(11)6-2-1-3-7-8(6)13-5-4-12-7/h1-3H,4-5H2,(H,10,11)

Synthetic route

2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester → 2,3-dihydro-1,4-benzodioxine-5-carboxylic acid (4442-53-9)

Conditions	Yield
Stage #1: 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester With sodium hydroxide In water for 3h; Reflux; Stage #2: With hydrogenchloride In water	97%
With sodium hydroxide for 2h; Reflux;	95%
With methanol; sodium hydroxide In tetrahydrofuran; water at 75℃; for 2h;
With lithium hydroxide In water at 20℃;

2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester → 2,3-dihydro-1,4-benzodioxine-5-carboxylic acid (4442-53-9) + methyl 6,7-dibromo-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate

Conditions	Yield
With bromine; acetic acid at 60 - 70℃; for 18h;	A 30% B 32.6%

2,3-Dihydroxybenzoic acid (303-38-8) + ethylene dibromide (106-93-4) → 2,3-dihydro-1,4-benzodioxine-5-carboxylic acid (4442-53-9)

Conditions	Yield
With potassium hydroxide unter Ausschluss von Sauerstoff;
With potassium carbonate In N,N-dimethyl-formamide

methyl-2,3-dihydroxybenzoate (2411-83-8) → 2,3-dihydro-1,4-benzodioxine-5-carboxylic acid (4442-53-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 5 h / Reflux 2: sodium hydroxide / water / 3 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 70 °C / Inert atmosphere 2: methanol; sodium hydroxide / water; tetrahydrofuran / 2 h / 75 °C View Scheme
Multi-step reaction with 2 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: 4 h / 80 °C 2.1: sodium hydroxide / 2 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 12 h / Reflux 2: lithium hydroxide / water / 20 °C View Scheme

2,3-Dihydroxybenzoic acid (303-38-8) → 2,3-dihydro-1,4-benzodioxine-5-carboxylic acid (4442-53-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: sulfuric acid / 10 h / Reflux 2: potassium carbonate / N,N-dimethyl-formamide / 5 h / Reflux 3: sodium hydroxide / water / 3 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: sulfuric acid / 8 h / 90 °C 2: potassium carbonate / acetone / 70 °C / Inert atmosphere 3: methanol; sodium hydroxide / water; tetrahydrofuran / 2 h / 75 °C View Scheme
Multi-step reaction with 3 steps 1.1: sulfuric acid / 8 h / Reflux 2.1: caesium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 4 h / 80 °C 3.1: sodium hydroxide / 2 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: sulfuric acid / 12 h / 5 °C / Reflux 2: potassium carbonate / N,N-dimethyl-formamide / 12 h / Reflux 3: lithium hydroxide / water / 20 °C View Scheme

Upstream product

• 303-38-8 2,3-Dihydroxybenzoic acid 
• 106-93-4 ethylene dibromide 
• 214894-91-4 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester 
• 2411-83-8 methyl-2,3-dihydroxybenzoate 
• 24677-78-9 2,3-dihydroxybenzaldehyde 
• 29668-43-7 2,3-dihydro-benzo[1,4]dioxine-5-carbaldehyde 
• 493-09-4 benzo-1,4-dioxane 
• 124-38-9 carbon dioxide 

Downstream Products

• 532391-79-0 C₂₂H₂₆N₂O₄ 
• 158504-37-1 methyl 8-amino-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate 
• 214894-91-4 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester 
• 1092476-37-3 (R)-N'-[3,5-bis(trifluoromethyl)phenyl]-2-(2,3-dihydro-1,4-benzodioxin-5-yl)-2-(4-methyl-1-piperazinyl)acetohydrazide 
• 1092476-36-2 (S)-N'-[3,5-bis(trifluoromethyl)phenyl]-2-(2,3-dihydro-1,4-benzodioxin-5-yl)-2-(4-methyl-1-piperazinyl)acetohydrazide 
• 274910-20-2 2-(2,3-dihydro-1,4-benzodioxin-5-yl)acetic acid 
• 148703-26-8 8-amino-7-chloro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid 
• 214894-89-0 5-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine 
• 274910-19-9 (2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methanol 

Relevant articles and documents

Synthesis of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide and 3-oxo-3,4-dihydrobenzo[b][1,4]oxazine-8-carboxamide derivatives as PARP1 inhibitors

Poly(ADP-ribose) polymerase 1 (PARP1), a widely explored anticancer drug target, plays an important role in single-strand DNA break repair processes. High-throughput virtual screening (HTVS) of a Maybridge small molecule library using the PARP1-benzimidazole-4-carboxamide co-crystal structure and pharmacophore model led to the identification of eleven compounds. These compounds were evaluated using recombinant PARP1 enzyme assay that resulted in the acquisition of three PARP1 inhibitors: 3 (IC50 = 12 μM), 4 (IC50 = 5.8 μM), and 10 (IC50 = 0.88 μM). Compound 4 (2,3-dihydro-1,4-benzodioxine-5-carboxamide) was selected as a lead and was subjected to further chemical modifications, involving analogue synthesis and scaffold hopping. These efforts led to the identification of (Z)-2-(4-hydroxybenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (49, IC50 = 0.082 μM) as the most potent inhibitor of PARP1 from the series.

Discovery of 2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E2synthase-1

The discovery and SAR of potent, selective dioxane-fused tricyclic benz[d]imidazole derivatives as mPGES-1 inhibitor are herein described. Various amide modifications in this series afforded many potent mPGES-1 inhibitors, of which 17d proved to be suitab

Direct carboxylation of simple arenes with CO2 through a rhodium-catalyzed C-H bond activation

Direct carboxylation of simple arenes under atmospheric pressure of CO2 is achieved through a rhodium-catalyzed C-H bond activation without the assistance of a directing group. Various arenes such as benzene, toluene, xylene, electron-rich or electron-deficient benzene derivatives, and heteroaromatics are directly carboxylated with high TONs. This journal is