67593-46-8

Basic information

• Product Name: 2-Acetyl-3-(2-chlorophenyl)acrylic acid methyl ester
• Synonyms: METHYL 2-ACETYL-3-(2-CHLOROPHENYL)ACRYLATE;2-ACETYL-3-(2-CHLOROPHENYL)-ACRYLIC ACID METHYL ESTER;2-(2-CHLORO-BENZYLIDENE)-3-OXO-BUTYRIC ACID METHYL ESTER;2-Acetyl-3-(2-Chlorophenyl)-Acryl Acid Methyl Ester;Methyl 2-(2-chlorobenzylidene)acetoaceatate;Butanoic acid, 2-[(2-chlorophenyl)Methylene]-3-oxo-, Methyl ester;Methyl 2-(2-chlorobenzylidene)-3-oxobutanoate;methyl (E)-2-(2-chlorobenzylidene)-3-oxobutanoate
• CAS NO: 67593-46-8
• Molecular Formula: C₁₂H₁₁ClO₃
• Molecular Weight: 238.67
• EINECS: 1592732-453-0
• Mol File: 67593-46-8.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 347.2 °C at 760 mmHg
• Flash Point: 142.6 °C
• Appearance: /
• Density: 1.241 g/cm³
• Vapor Pressure: 5.46E-05mmHg at 25°C
• Refractive Index: 1.564
• CAS DataBase Reference: 2-Acetyl-3-(2-chlorophenyl)acrylic acid methyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: 2-Acetyl-3-(2-chlorophenyl)acrylic acid methyl ester(67593-46-8)
• EPA Substance Registry System: 2-Acetyl-3-(2-chlorophenyl)acrylic acid methyl ester(67593-46-8)

Safety Data

• Hazardous Substances Data: 67593-46-8(Hazardous Substances Data)

Usage

General Description

2-Acetyl-3-(2-chlorophenyl)acrylic acid methyl ester, also known as Clonac, is a chemical compound with the molecular formula C12H11ClO3. It is a synthetic compound used in pharmaceutical research and drug development as a potential anti-inflammatory and analgesic agent. The compound acts as an inhibitor of cyclooxygenase-2 (COX-2), an enzyme involved in the inflammatory response, and has been studied for its potential in treating conditions such as arthritis, inflammatory pain, and cancer. Its structure contains an acetyl group, a chlorophenyl group, and an acrylic acid methyl ester group, making it a versatile and potentially valuable compound for pharmaceutical applications.

InChI:InChI=1/C12H11ClO3/c1-8(14)10(12(15)16-2)7-9-5-3-4-6-11(9)13/h3-7H,1-2H3/b10-7+

Synthetic route

2-chloro-benzaldehyde (89-98-5) + acetoacetic acid methyl ester (105-45-3) → methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8)

Conditions	Yield
With piperidine; acetic acid In benzene for 4h; Ambient temperature;	84%
With piperidine In tetrahydrofuran for 4h; Inert atmosphere; Reflux;

methanolic dimethylamine + 2-chloro-benzaldehyde (89-98-5) + acetoacetic acid methyl ester (105-45-3) → methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8)

Conditions	Yield
With acetic acid In ethyl acetate; isopropyl alcohol

methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8) → methyl 2-(2-chlorobenzyl)-3-oxobutanoate

Conditions	Yield
With triethylsilane; iron(III) chloride hexahydrate In dichloromethane at 20℃; for 36h; chemoselective reaction;	90%

3-amino-4-(2,2-diethoxy-ethoxy)but-2-enoic acid ethyl ester + methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8) → 4-(2-chlorophenyl)-2-(2,2-diethoxy-ethoxymethyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester (225939-13-9)

Conditions	Yield
In toluene for 26h; Heating / reflux;	75.3%

o-chlorobenzylidene malononitrile (2698-41-1) + methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8) → methyl 4,6-bis(2-chlorophenyl)-5,5-dicyano-2-methyl-1,4,5,6-tetrahydropyridine-3-carboxylate

Conditions	Yield
With ammonium hydroxide In methanol at 20℃; for 4h;	73%

methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8) + 3-amino-2-crotonic acid 2,2-ethylenedioxy propyl ester (86780-81-6) → 4-(2-Chloro-phenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-methyl ester 5-(2-methyl-[1,3]dioxolan-2-ylmethyl) ester (103785-54-2)

Conditions	Yield
In ethanol Heating;	47%

methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8) + 3-methylaminobut-2-enoic acid methyl ester (13412-12-9, 21759-68-2, 21759-69-3) → dimethyl 4-(2-chlorophenyl)-1,2,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylate (109329-68-2) + 2-(2-Chloro-phenyl)-4-methyl-6-methylamino-cyclohexa-3,5-diene-1,3-dicarboxylic acid dimethyl ester (109329-69-3)

Conditions	Yield
In benzene for 2h; Heating;	A 36% B 5.2%
In ethanol Heating;	A 5% B n/a

methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8) + acetoacetic acid methyl ester (105-45-3) → 4-(2-chloro-phenyl)-2,6-dimethyl-4H-pyran-3,5-dicarboxylic acid dimethyl ester

Conditions	Yield
With acetic anhydride; zinc(II) chloride Heating;

O-methylisourea hemisulfate (29427-58-5) + methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8) → methyl 6-(2-chlorophenyl)-2-methoxy-4-methyl-1,6-dihydropyrimidine-5-carboxylate + methyl 6-(2-chlorophenyl)-2-methoxy-4-methyl-3,6-dihydropyrimidine-5-carboxylate

Conditions	Yield
With sodium hydrogencarbonate; 1-butyl-3-methylimidazolium Tetrafluoroborate at 55 - 65℃; for 24h; Title compound not separated from byproducts;

O-methylisourea hemisulfate (29427-58-5) + chloroformic acid ethyl ester (541-41-3) + methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8) → methyl 4-(2-chlorophenyl)-3-ethoxycarbonyl-6-methyl-2-oxo-3,4-dihydropyrimidine-1H-5-carboxylate

Conditions	Yield
Stage #1: O-methylisourea hemisulfate; methyl 2-(2-chlorophenylmethylene)acetoacetate With sodium hydrogencarbonate; 1-butyl-3-methylimidazolium Tetrafluoroborate at 55 - 65℃; for 24h; Stage #2: chloroformic acid ethyl ester With pyridine In ethanol at 20℃; for 0.5h; Stage #3: With hydrogenchloride In methanol at 20℃; for 0.666667h;

methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8) → 4-(2-Chloro-phenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-methyl ester 5-(2-oxo-propyl) ester (99880-13-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 47 percent / ethanol / Heating 2: 84 percent / MeSO3H, H2O / ethanol / 6 h / Heating View Scheme

methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8) → 3-Aza-1,5-dicarbomethoxy-9-(2-chlorophenyl)-3-methyl-2,4-dimethylenebicyclo<3.3.1>nonane (109346-07-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 5 percent / ethanol / Heating 2: Diisopropylamine, Butyllithium / 1) THF View Scheme

methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8) → 2-(2-azidoethoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-46-3)

Conditions	Yield
With ammonium acetate In methanol; ethanol

3-Aminocrotononitrile (1118-61-2) + methyl 2-(2-chlorophenylmethylene)acetoacetate (67593-46-8) → methyl 4-(2-chlorophenyl)-5-cyano-1,4-dihydro-2,6-dimethylpyridine-3-carboxylate (67593-29-7)

Conditions	Yield
In ethanol Inert atmosphere; Reflux;

Upstream product

• 89-98-5 2-chloro-benzaldehyde 
• 105-45-3 acetoacetic acid methyl ester 

Downstream Products

• 103785-54-2 4-(2-Chloro-phenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-methyl ester 5-(2-methyl-[1,3]dioxolan-2-ylmethyl) ester 
• 84157-61-9 4-(2-Chloro-phenyl)-2-methyl-6-(2-morpholin-4-yl-ethoxymethyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 5-ethyl ester 3-methyl ester 
• 109329-68-2 dimethyl 4-(2-chlorophenyl)-1,2,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylate 
• 109329-69-3 2-(2-Chloro-phenyl)-4-methyl-6-methylamino-cyclohexa-3,5-diene-1,3-dicarboxylic acid dimethyl ester 
• 99880-13-4 4-(2-Chloro-phenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-methyl ester 5-(2-oxo-propyl) ester 
• 109346-07-8 3-Aza-1,5-dicarbomethoxy-9-(2-chlorophenyl)-3-methyl-2,4-dimethylenebicyclo<3.3.1>nonane 
• 225939-13-9 4-(2-chlorophenyl)-2-(2,2-diethoxy-ethoxymethyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester 
• 88150-62-3 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-phthalimidoethoxymethyl]-1,4-dihydropyridine 
• 88150-46-3 2-(2-azidoethoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine 
• 316828-72-5 4-(2-chloro-phenyl)-2,6-bis-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxymethyl]-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester 
• 67593-29-7 methyl 4-(2-chlorophenyl)-5-cyano-1,4-dihydro-2,6-dimethylpyridine-3-carboxylate 

Relevant articles and documents

Discovery of novel cyanodihydropyridines as potent mineralocorticoid receptor antagonists

A new 1,4-dihydropyridine 5a, containing a cyano group at the C3 position, was recently reported to possess excellent mineralocorticoid receptor (MR) antagonist in vitro potency and no calcium channel-blocker (CCB) activity. In the present study, we report the structure-activity relationships of this novel series of cyano ester dihydropyridines that resulted in R6 substituted analogues with improved metabolic stability while maintaining excellent MR antagonist activity and selectivity against other nuclear receptors. Further structure optimization with the introduction of five-membered ring heterocycles at R6 resulted in compounds with excellent MR antagonist potency and a suitable pharmacokinetic profile. In vivo studies of a promising tool compound in the Dahl salt-sensitive rat model of hypertension showed similar blood pressure (BP) reduction as the steroidal MR antagonist eplerenone, providing proof-of-concept (POC) for a nonsteroidal, orally efficacious MR antagonist.

Process for the preparation of 1,4-dihydropyridinedicarboxylic esters

Benzylidene intermediates, useful in the preparation of dihydropyridines such as nifedipine and amlodipine, are formed by reaction of a ketocarboxylic adid ester with an aldehyde in the presence of a catalytic amount of dimethylamine acetate.