500-05-0

Usage

Uses

Used in Chemical Synthesis:
Coumalic acid is used as a chemical intermediate for the synthesis of various compounds due to its ability to undergo thermal decarboxylation to α-pyrone, a Diels-Alder diene. This property allows it to be a valuable building block in the creation of complex organic molecules.
Used in Pharmaceutical Industry:
Coumalic acid is used as a starting material for the development of new pharmaceutical compounds. Its ability to form α-pyrone, a Diels-Alder diene, makes it a promising candidate for the synthesis of novel drugs with potential therapeutic applications.
Used in Polymer Industry:
Coumalic acid can be used as a monomer in the polymer industry to create new polymers with unique properties. The formation of α-pyrone, a Diels-Alder diene, upon thermal decarboxylation can be exploited to design polymers with specific characteristics, such as enhanced stability or reactivity.
Used in Material Science:
Coumalic acid's thermal decarboxylation to α-pyrone, a Diels-Alder diene, can be utilized in the development of new materials with tailored properties. This can be particularly useful in the creation of advanced materials for applications such as electronics, coatings, and adhesives.

Purification Methods

The acid crystallises from MeOH. The methyl ester has m 73-74o (from pet ether) and b 178-180o/60 mm. [Beilstein 18/8 V 120.]

InChI:InChI=1/C6H4O4/c7-5-2-1-4(3-10-5)6(8)9/h1-3H,(H,8,9)/p-1

Synthetic route

methyl coumalate (6018-41-3) → 2H-pyran-2-one-5-carboxylic acid (500-05-0)

Conditions	Yield
With iodine; aluminium In acetonitrile at 80℃; for 18h;	90%

(S)-Malic acid (97-67-6) → 2H-pyran-2-one-5-carboxylic acid (500-05-0)

Conditions	Yield
With trifluorormethanesulfonic acid In 1,2-dichloro-ethane at 100℃; Reagent/catalyst; Temperature; Solvent; regioselective reaction;	86%

malic acid (617-48-1) → 2H-pyran-2-one-5-carboxylic acid (500-05-0)

Conditions	Yield
With sulfuric acid at 80 - 90℃; for 3h;	85%
With sulfuric acid Heating;	67%
Stage #1: malic acid With fuming sulphuric acid In sulfuric acid at 75℃; for 6h; Stage #2: In ice-cold water at 10℃; for 24h;	65%

(S)-Malic acid (97-67-6) → 2H-pyran-2-one-5-carboxylic acid (500-05-0) + (2E)-but-2-enedioic acid (110-17-8)

Conditions	Yield
With methanesulfonic acid In 1,2-dichloro-ethane at 100℃; Reagent/catalyst; Temperature; Solvent;	A 14% B 25%

(S)-Malic acid (97-67-6) + (E)-3-Ureido-but-2-enoic acid ethyl ester (5435-44-9, 22243-66-9) → 2H-pyran-2-one-5-carboxylic acid (500-05-0) + 3-oxopropanoic acid (926-61-4)

sodium formylacetic acid ester → 2H-pyran-2-one-5-carboxylic acid (500-05-0)

Conditions	Yield
With sulfuric acid

(S)-Malic acid (97-67-6) + sulfuric acid (7664-93-9) → 2H-pyran-2-one-5-carboxylic acid (500-05-0)

methyl 4-carbomethoxy-5-methoxy-penta-2(E),4(Z)-dienoate (114106-77-3) + hydrogen bromide (10035-10-6, 12258-64-9) → 2H-pyran-2-one-5-carboxylic acid (500-05-0)

4-formyl-pentenedioic acid dimethyl ester + hydrogen bromide (10035-10-6, 12258-64-9) → 2H-pyran-2-one-5-carboxylic acid (500-05-0)

Conditions	Yield
Kochen;

sulfuric acid (7664-93-9) + sodium 3-ethoxy-3-oxoprop-1-en-1-olate → 2H-pyran-2-one-5-carboxylic acid (500-05-0)

(S)-Malic acid (97-67-6) + sulfuric acid (7664-93-9) → 2H-pyran-2-one-5-carboxylic acid (500-05-0) + 3-oxopropanoic acid (926-61-4)

2H-pyran-2-one-5-carboxylic acid (500-05-0) + ethene (74-85-1) → C8H8O4

Conditions	Yield
In 1,4-dioxane at 110℃; for 16h; Kinetics; Temperature; Diels-Alder Cycloaddition;	98%

2H-pyran-2-one-5-carboxylic acid (500-05-0) → 6-oxo-tetrahydro-pyran-3-carboxylic acid (5807-38-5)

Conditions	Yield
With Raney nickel In methanol; toluene under 760.051 Torr; for 6h;	96.8%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + S-(1-butyn-3-yl)-O-methyl xanthate → methyl coumalate (6018-41-3)

Conditions	Yield
In toluene Heating;	92%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + trimethyl orthoformate (149-73-5) → methyl 4-carbomethoxy-5-methoxy-penta-2(E),4(Z)-dienoate (114106-77-3) + methyl 3,5-dimethoxy-4-carbomethoxypent-4-enoate (114106-78-4)

Conditions	Yield
With sulfuric acid In methanol for 48h; Heating;	A 89% B 6%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + tenofovir disoproxil → tenofovir disoproxil coumalate

Conditions	Yield
In hexane; dichloromethane at 20 - 40℃; Solvent; Temperature;	89%

2H-pyran-2-one-5-carboxylic acid (500-05-0) → 2-oxo-2H-pyran-5-carbonyl chloride (23090-18-8)

Conditions	Yield
With phosphorus pentachloride at 60℃; for 1h;	86%
With thionyl chloride at 100℃; for 8h;	84%
With phosphorus pentachloride at 60℃; for 1h;	80%

maleic anhydride (108-31-6) + 2H-pyran-2-one-5-carboxylic acid (500-05-0) → bicyclo<2.2.2>oct-2-en-2,5-exo,6exo,7exo,8exo-pentacarbonsaeure-5,6:7,8-dianhydrid (77802-48-3)

Conditions	Yield
at 200℃;	86%
at 200℃;	65%
at 200℃; Heating;

2H-pyran-2-one-5-carboxylic acid (500-05-0) + ethanol (64-17-5) → 2-Oxo-2H-pyran-5-carbonseaure-ethylester (5942-96-1)

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane for 18h; Ambient temperature;	86%
With trifluoromethylsulfonic anhydride; triethylamine; Triphenylphosphine oxide In 1,2-dichloro-ethane at 25℃; for 0.25h;	78%

1-Heptene (592-76-7) + 2H-pyran-2-one-5-carboxylic acid (500-05-0) → 4-pentylbenzoic acid (26311-45-5)

Conditions	Yield
With palladium 10% on activated carbon In 1,3,5-trimethyl-benzene at 200℃; Diels-Alder reaction; regioselective reaction;	85%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + 2-(2-chloro-4-(4-chlorobenzoyl)-6-fluorophenoxy)acetohydrazide (1443038-08-1) → [2-4-(4-chloro)benzoyl-2-chloro-6-fluorophenoxy]aceto-N(pyrone-2-one)carbonyl hydrazide

Conditions	Yield
Stage #1: 2-(2-chloro-4-(4-chlorobenzoyl)-6-fluorophenoxy)acetohydrazide With 2,6-dimethylpyridine In dichloromethane at 25 - 30℃; for 0.5h; Stage #2: 2H-pyran-2-one-5-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 0 - 5℃; for 0.5h;	85%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + cyclopropanecarboxylic acid (3-amino-1H-pyrazolo[3,4-d]thiazol-5-yl)-amide, trifluoroacetic acid (937037-30-4) → 1-[5-(cyclopropanecarbonyl-amino)-1H-pyrazolo[3,4-d]thiazol-3-yl]-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid

Conditions	Yield
With pyridine at 20℃; for 8h;	82%

methanol (67-56-1) + 2H-pyran-2-one-5-carboxylic acid (500-05-0) → methyl coumalate (6018-41-3)

Conditions	Yield
for 3h; Reflux;	81.8%
With sulfuric acid for 1h; Heating;	55%
With sulfuric acid

2H-pyran-2-one-5-carboxylic acid (500-05-0) + 2-(4-benzoylphenoxy)acetohydrazide (670221-21-3) → 2-(4-benzoylphenoxy)aceto-N(pyrone-2-one)carbonylhydrazide

Conditions	Yield
Stage #1: 2-(4-benzoylphenoxy)acetohydrazide With 2,6-dimethylpyridine In dichloromethane at 25 - 30℃; for 0.5h; Stage #2: 2H-pyran-2-one-5-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 0 - 5℃; for 0.5h;	81%

2H-pyran-2-one-5-carboxylic acid (500-05-0) → C6H3ClO4

Conditions	Yield
	80%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + tetrakis[bis(trimethylsilyl)methyl]digallane(4) (125370-09-4) → Ga2(CH(SiMe3)2)2(2-oxo-2H-pyran-5-carboxylate)2 (1258211-75-4)

Conditions	Yield
In tetrahydrofuran digallium compd. and acid suspended in THF at room temp.; suspn. stirred at room temp. for 16 h; volatiles removed in vacuo; residue washed with n-pentane;	79%

allylbenzene (300-57-2) + 2H-pyran-2-one-5-carboxylic acid (500-05-0) → 4-Benzylbenzoic acid (620-86-0)

Conditions	Yield
With palladium 10% on activated carbon In 1,3,5-trimethyl-benzene at 200℃; Diels-Alder reaction; regioselective reaction;	79%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + 2-[4-(4-methylbenzoyl)-2-chloro-6-fluorophenoxy]acethydrazide (1443038-11-6) → [2-4(-4-methyl)benzoyl-2-chloro-6-fluorophenoxy]aceto-N-(pyrone-2-one)carbonylhydrazide

Conditions	Yield
Stage #1: 2-[4-(4-methylbenzoyl)-2-chloro-6-fluorophenoxy]acethydrazide With 2,6-dimethylpyridine In dichloromethane at 25 - 30℃; for 0.5h; Stage #2: 2H-pyran-2-one-5-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 0 - 5℃; for 0.5h;	78%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + Dithiocarbonic acid O-[(3S,5S,8R,9S,10S,13R,14S,17R)-17-((R)-1,5-dimethyl-hexyl)-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-3-yl] ester S-prop-2-ynyl ester (165452-00-6) → 6-Oxo-6H-pyran-3-carboxylic acid (3R,5S,8R,9S,10S,13R,14S,17R)-17-((R)-1,5-dimethyl-hexyl)-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-3-yl ester

Conditions	Yield
In toluene Heating;	77%

diazomethane (186581-53-3, 908094-01-9) + 2H-pyran-2-one-5-carboxylic acid (500-05-0) → methyl coumalate (6018-41-3)

Conditions	Yield
In tetrahydrofuran; diethyl ether at 20℃; for 3h;	76.4%

2H-pyran-2-one-5-carboxylic acid (500-05-0) → 5-bromo-2H-pyran-2-one (19978-33-7) + 3,5-dibromo-2H-pyran-2-one (19978-41-7)

Conditions	Yield
With N-Bromosuccinimide; lithium acetate; tetrabutylammomium bromide In tetrachloromethane; acetonitrile at 65℃;	A n/a B 76%
With N-Bromosuccinimide; lithium acetate In water; acetonitrile at 20℃; for 72h; Product distribution; Further Variations:; Reaction partners; reagents ratios; Hundsdiecker reaction;	A 35% B 15%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + 1-Decene (872-05-9) → 4-octylbenzoic acid (3575-31-3)

Conditions	Yield
With palladium 10% on activated carbon In 1,3,5-trimethyl-benzene at 200℃; Diels-Alder reaction; regioselective reaction;	72%
With palladium on activated charcoal In 1,3,5-trimethyl-benzene at 200℃; Diels-Alder Cycloaddition; Sealed tube;	72%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + [2-chloro-6-fluoro-4-(4-fluoro-benzoyl)-phenoxy]acetic acid hydrazide (1443038-07-0) → [2-4-(4-fluoro)benzoyl-2-chloro-6-fluorophenoxy]aceto-N-(pyrone-2-one)carbonylhydrazide

Conditions	Yield
Stage #1: [2-chloro-6-fluoro-4-(4-fluoro-benzoyl)-phenoxy]acetic acid hydrazide With 2,6-dimethylpyridine In dichloromethane at 25 - 30℃; for 0.5h; Stage #2: 2H-pyran-2-one-5-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 0 - 5℃; for 0.5h;	72%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + 1-methoxy-5,6,7,8-tetrafluorobenzobenzobarrelene (14111-43-4) → benzoic acid (65-85-0)

Conditions	Yield
In xylene at 200 - 205℃; for 4h; Product distribution; var. temp. and time;	71%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + propene (187737-37-7) → p-Toluic acid (99-94-5) + m-Toluic acid (99-04-7)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; 5-methyl-dihydro-furan-2-one In toluene at 180℃; under 6723.1 Torr; for 8h; Reagent/catalyst; Solvent; Temperature; Time;	A 70.8% B 15.8%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + benzyl alcohol (100-51-6) → coumalic acid benzyl ester (61752-10-1)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; dichloromethane at 20℃; for 5h;	70%
With 8-aminopyrene-1,3,6-trisulfonic acid, trisodium salt for 15h; Heating;

2H-pyran-2-one-5-carboxylic acid (500-05-0) + 1-undecene (821-95-4) → 4-n-Nonylbenzoic acid (38289-46-2)

Conditions	Yield
With palladium 10% on activated carbon In 1,3,5-trimethyl-benzene at 200℃; Diels-Alder reaction; regioselective reaction;	69%

2H-pyran-2-one-5-carboxylic acid (500-05-0) + 1-(allyloxy)heptane (16519-24-7) → 4-((heptyloxy)methyl)benzoic acid (173265-17-3)

Conditions	Yield
With palladium 10% on activated carbon In 1,3,5-trimethyl-benzene at 200℃; Diels-Alder reaction; regioselective reaction;	66%

Upstream product

• 97-67-6 (S)-Malic acid 
• 5435-44-9 (E)-3-Ureido-but-2-enoic acid ethyl ester 
• 617-48-1 malic acid 
• 7664-93-9 sulfuric acid 
• 114106-77-3 methyl 4-carbomethoxy-5-methoxy-penta-2(E),4(Z)-dienoate 
• 10035-10-6 hydrogen bromide 
• 6018-41-3 methyl coumalate 

Downstream Products

• 6018-41-3 methyl coumalate 
• 220968-29-6 propyl 2-pyrone-5-carboxylate 
• 23090-18-8 2-oxo-2H-pyran-5-carbonyl chloride 
• 5807-38-5 6-oxo-tetrahydro-pyran-3-carboxylic acid 
• 18069-17-5 2-methylglutaric acid 
• 504-31-4 pyran-2-one 
• 1724-02-3 glutaconic acid 
• 123-73-9 crotonaldehyde 
• 5942-96-1 2-Oxo-2H-pyran-5-carbonseaure-ethylester 
• 97507-42-1 ethyl (2E)-4-ethoxycarbonyl-5-ethoxy-2,4-pentadienoate 
• 65-85-0 benzoic acid 
• 4551-62-6 p-deuterobenzoic acid 
• 64-18-6 formic acid 
• 114106-77-3 methyl 4-carbomethoxy-5-methoxy-penta-2(E),4(Z)-dienoate 

Relevant academic research and scientific papers

Cleavage of Carboxylic Esters by Aluminum and Iodine

A one-pot procedure for deprotecting carboxylic esters under nonhydrolytic conditions is described. Typical alkyl carboxylates are readily deblocked to the carboxylic acids by the action of aluminum powder and iodine in anhydrous acetonitrile. Cleavage of lactones affords the corresponding ω-iodoalkylcarboxylic acids. Aryl acetylates undergo deacetylation with the participation of the neighboring group. This method enables the selective cleavage of alkyl carboxylic esters in the presence of aryl esters.

Synthesis method of methyl coumalate

The invention discloses a synthesis method of methyl coumalate. The synthesis method comprises the following steps: adding water-containing sulfuric acid into a kettle, stirring, heating to a temperature of less than 100 DEG C, and adding a pre-prepared saturated malic acid solution in a dropwise manner; carrying out a constant-temperature reaction after the adding, and monitoring the reaction process by using gas chromatography until the malic acid reaction is finished; stopping the stirring, layering, cooling to below 50 DEG C, and separating out a lower layer sulfuric acid aqueous solution;continuously stirring, heating to reflux, and adding a large amount of methanol in a dropwise manner; carrying out a reflux reaction for a certain time, and carrying out gas phase monitoring until coumalic acid disappears; evaporating out most of the solvent to form a slurry in the system, cooling to room temperature, and adding an aqueous solution of an alkaline compound in a dropwise manner toform a large amount of precipitates; and filtering, washing with water, and drying to obtain the methyl coumalate.

A 6 - chloro nicotinic acid preparation method and separation and purification method

The invention discloses a preparation method and a separation and purification method for 6-chloronicotinic acid, belonging to the field of fine chemical engineering. The preparation method comprises the following steps: by taking low-cost DL-malic acid as a raw material, carrying out a cyclization reaction and an ammonification reaction, thereby obtaining 6-hydroxynicotinic acid; by taking 6-hydroxynicotinic acid as a raw material, carrying out a chlorination reaction, thereby obtaining 6-chloronicotinic acid. The reaction conditions are simple, operation is easy, the environmental pollution is slight, and the yield is high. The purification method disclosed by the invention comprises the following step: refining crude 6-chloronicotinic acid by virtue of methanol and activated carbon to finally obtain 6-chloronicotinic acid with the purity of more than 99.5 percent. The requirement of a medical intermediate on the purity is met. The method disclosed by the invention has the advantages of reasonable design, low cost and high economic benefits and has wide application prospects.

Four hydrogen pyrane two fluorine Asia armor propoxycyclohexyl linking group containing a liquid crystal compound, preparation method and application thereof

The invention discloses a liquid crystal compound containing a tetrahydropyrane difluoro methoxy-linking group and a preparation method and application thereof. The liquid crystal compound is represented by a formula I. In a molecular structure of the compound represented by the formula I, the liquid crystal compound containing the tetrahydropyrane difluoro methoxy-linking group (img file='DDA0000475765100000011. TIF' wi='384' he='112'/) has high dielectric anisotropy. What's more important is that the liquid crystal compound further has high response speed and clearing points and low rotational viscosity. Compared with blended liquid crystal compounds, the liquid crystal compound has very important significance. As the formula I, (img file='DDA0000475765100000012. TIF' wi='984' he='256'/).

Stereoselective construction of a key hydroindole precursor of epidithiodiketopiperazine (ETP) natural products

An asymmetric synthetic strategy for constructing the divergent-synthesis monomer of epidithiodiketopiperazine (ETP) natural products has been successfully developed. The functionalized 2,3,3a,4,7,7a-hexahydroindole scaffold was constructed by a diastereoselective inverse electron-demand Diels-Alder (IEDDA) reaction. This journal is the Partner Organisations 2014.

Upgrading malic acid to bio-based benzoates via a Diels-Alder-initiated sequence with the methyl coumalate platform

The conversion of naturally-occurring malic acid to the 2-pyrone methyl coumalate was optimized using a variety of acid catalysts. Coupling methyl coumalate with electron-rich dienophiles in an inverse electron-demand Diels-Alder (IEDDA)/decarboxylation/elimination domino sequence resulted in an investigation of the scope and limitations of the methodology. The thermal, metal-free, and one-pot procedure allows regioselective access to diverse aromatic compounds including tricyclic, biphenyl, and pyridinyl systems for elaboration. A comparison with analogous pyrones demonstrates the striking efficacy of methyl coumalate as a versatile platform for the generation of biorenewable functionalized benzoates. This journal is

Claisen condensation of N-methylpyrrolidinone and α-chloronicotinic esters

Reaction between α-halo-nicotinic esters and a nucleophilic source such as the N-methylpyrrolidin-2-one (NMP) gave unexpected results. The presence of the halide on the pyridine gave a very interesting migration reaction. Extension to 6-methylnicotinic ester derivatives lead to an unexpected carbanion condensation.

A PROCESS FOR THE PREPARATION OF 3-CYANO-1-NAPHTHOIC ACID AND SOME ANALOGUES THEREOF

The present invention is related to a process for the preparation of 3-cyano-1-naphthoic acid and some analogues thereof of formula (1), the intermediate 1-halo-3-cyano naphthalene and some analogues thereof used in this process and a process for the preparation of said intermediate.

A new route for manufacture of 3-cyano-1-naphthalenecarboxylic acid

3-Cyano-1-naphthalenecarboxylic acid is an intermediate required for manufacture of tachykinin receptor antagonists. The 1,3-disubstitution pattern on the naphthalene skeleton complicates the synthesis of this cyano acid. Previous literature-based chemistry is unattractive for large-scale manufacture due to stoichiometric use of mercury salts, low yield, and other operational difficulties. An attractive new route has been developed by establishing the 1,3-substitution on the carbon atoms destined for only one-half of the naphthalene 2-ring system, via 3-bromocoumalate, and then building up the rest of the naphthalene ring system by Diels-Alder addition of 3-bromocoumalate to in situ-generated benzyne. The resulting 4-bromo-2-naphthoate was converted to the required cyanoacid by transformation of ester to nitrile followed by carbonylation of the bromo substituent. The new route has been scaled up successfully and offers significant advantages over previous literature chemistry in terms of improved process environmental implications, improved yield, lower cost, and improved robustness and ease of operation at larger scales of operation.

Allo-, Epiallo- and Pseudoyohimbanes as well as Heteroyohimbanes by Reaction of a Tetracyclic Aldehyde with Acetoacetate in Different Solvents

The reaction of methyl acetoacetate with 4 in CH3OH/ CH3ONa leads to 11 and 12 with yohimbane skeleton but bicyclo ring E.In DMF/ tBuOK, the epialloheteroyohimbane 13 is produced in fairly good yield, whereas in THF/ NaH the allo-19-hydroxyyohimbinone 17 is formed, which undergoes thermal decomposition to the alloyohimb-18-enone 19.Finally, a full description of an early mentioned synthesis of rac-deplancheine (7) is given.