53164-05-9

Basic information

• Product Name: Acemetacin
• Synonyms: ((1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl)acetoxy)aceticacid;(1-(p-chlorbenzoyl)-5-methoxy-2-methylindol-3-acetoxy)essigsaeure;1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1h-indole-3-aceticacicarboxymethyl;1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1h-indole-3-aceticacidcarboxymethyl;2-(2-(1-(p-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl)acetoxy)aceticacid;acemetacinum;acemix;aximeixin
• CAS NO: 53164-05-9
• Molecular Formula: C₂₁H₁₈ClNO₆
• Molecular Weight: 415.82
• EINECS: 258-403-4
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;API;EMFLEX
• Mol File: 53164-05-9.mol
• Article Data: 13

Chemical Properties

• Melting Point: 151.5°C
• Boiling Point: 565.5 °C at 760 mmHg
• Flash Point: 295.8 °C
• Appearance: Light yellow solid
• Density: 1.2387 (rough estimate)
• Vapor Pressure: 1.26E-13mmHg at 25°C
• Refractive Index: 1.6000 (estimate)
• Storage Temp.: -20°C Freezer
• Solubility: Practically insoluble in water, soluble in acetone, slightly soluble in anhydrous ethanol.
• PKA: 2.60±0.10(Predicted)
• Merck: 14,27
• CAS DataBase Reference: Acemetacin(CAS DataBase Reference)
• NIST Chemistry Reference: Acemetacin(53164-05-9)
• EPA Substance Registry System: Acemetacin(53164-05-9)

Safety Data

• Hazard Codes: T+
• Statements: 26/27/28
• Safety Statements: 22-25-36/37/39-45-24/25
• RIDADR: UN 2811
• WGK Germany: 3
• RTECS: NL3521400
• HazardClass: 6.1(a)
• PackingGroup: II
• Hazardous Substances Data: 53164-05-9(Hazardous Substances Data)

Usage

Chemical Properties

Light Yellow Solid

Originator

Rantudil ,Bayer ,W. Germany ,1980

Uses

Different sources of media describe the Uses of 53164-05-9 differently. You can refer to the following data:
1. A potent inhibitor of COX-2 found to have anti-tumor activity in the colon
2. Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory.

Definition

ChEBI: A carboxylic ester that is the carboxymethyl ester of indometacin. A non-steroidal anti-inflammatory drug, it is used in the treatment of rheumatoid arthritis, osteoarthritis, and low back pain, as well as for postoperative pain and inflammation. Its activ ty is due to both acemetacin and its major metabolite, indometacin.

Manufacturing Process

25.4 g (0.050 mol) of [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3- indoleacetoxy]-benzyl acetate were dissolved in 400 ml of glacial acetic acid and hydrogenated on 2.0 g of palladium carbon at room temperature. After the absorption of hydrogen had finished (1 hour), the catalyst was filtered off, the filtrate was concentrated by evaporation under vacuum and the compound was caused to crystallize by adding petroleum ether. The compound melted at 149.5-150.5°C (determined on the micro-Kofler bench); the yield was 19.4 g which corresponds to 93% of the theoretical yield. The starting material for the above step may be prepared as follows: 5 g (0.016 mol) of N1-(p-methoxyphenyl)-p-chlorobenzhydrazide hydrochloride and 4.75 g (0.018 mol) of benzyl levulinoyloxyacetate were heated in 25 ml of glacial acetic acid for 3 hours at 80°C. The solvent was then evaporated off under vacuum. The residue was taken up in chloroform and the solution was washed neutral by shaking with sodium bicarbonate solution and thereafter with water. After drying the chloroform solution, this was subjected to chromatography on aluminium oxide, the eluate was concentrated by evaporation and the viscous oil remaining as residue was crystallized by adding ether. The compound melted at 94-95°C. The yield was 4.1 g which corresponds to 50.7% of the theoretical yield.

Therapeutic Function

Antiinflammatory

Safety Profile

Poison by ingestion, subcutaneous,intraperitoneal, intravenous, and intramuscular routes. Anexperimental teratogen. Other experimental reproductiveeffects. When heated to decomposition it emits toxic fumesof Cl?? and NOx. An anti-inflammatory agent.

InChI:InChI=1/C21H18ClNO6/c1-12-16(10-20(26)29-11-19(24)25)17-9-15(28-2)7-8-18(17)23(12)21(27)13-3-5-14(22)6-4-13/h3-9H,10-11H2,1-2H3,(H,24,25)

Synthetic route

acemetacin tert-butyl ester (75302-98-6) → acemetacin (53164-05-9)

Conditions	Yield
With hydrogenchloride; acetic anhydride In acetic acid at 80℃; for 5h; Large scale;	99.45%
With trifluoroacetic acid In dichloromethane at 20℃; for 48h;	80%

2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid tert-butyl ester (1601-20-3) + acetic acid (64-19-7) → acemetacin (53164-05-9)

Conditions	Yield
With hydrogenchloride; aluminum (III) chloride at 60℃; for 5h; Reagent/catalyst; Temperature; Large scale;	98.8%

<1-(4-Chlorbenzoyl)-5-methoxy-2-methylindol-3-acetoxy>essigsaeurebenzylester (53164-04-8) → acemetacin (53164-05-9)

Conditions	Yield
With aluminum (III) chloride In dichloromethane; N,N-dimethyl-formamide at 80℃; for 24h; Temperature;	97.8%
With palladium 10% on activated carbon; hydrogen In ethyl acetate at 20℃; under 760.051 Torr; for 20h;	95%
With hydrogen; palladium on activated charcoal In ethyl acetate at 40℃; for 1h;	93%

acemetacin tert-butyl ester (75302-98-6) → [1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid (53-86-1) + acemetacin (53164-05-9)

Conditions	Yield
With iodine; aluminium In acetonitrile at 20℃; for 6h; chemoselective reaction;	A 30% B 66%

4-methoxyphenylhydrazine hydrochloride (19501-58-7) → acemetacin (53164-05-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / acetic acid / 1.) 42 h, 28 deg C, 2.) 5 h, 50 deg C 2: 78 percent / various solvent(s) / 3 h / 190 - 195 °C 3: 93 percent / H2 / 5 percent Pd/C / ethyl acetate / 1 h / 40 °C View Scheme

(5-Methoxy-2-methylindol-3-acetoxy)essigsaeurebenzylester (53164-08-2) → acemetacin (53164-05-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 78 percent / various solvent(s) / 3 h / 190 - 195 °C 2: 93 percent / H2 / 5 percent Pd/C / ethyl acetate / 1 h / 40 °C View Scheme

[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid (53-86-1) → acemetacin (53164-05-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) K2CO3 / 1.) DMF, 45 min, 50 deg C, 2.) 3 h, 50 deg C 2: 93 percent / H2 / 5 percent Pd/C / ethyl acetate / 1 h / 40 °C View Scheme

levulinic acid (123-76-2) + phosphorus pentasulfide → acemetacin (53164-05-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) K2CO3 / 1.) DMF, 70 min, 40 deg C, 2.) 4 h, 50 deg C 2: 80 percent / acetic acid / 1.) 42 h, 28 deg C, 2.) 5 h, 50 deg C 3: 78 percent / various solvent(s) / 3 h / 190 - 195 °C 4: 93 percent / H2 / 5 percent Pd/C / ethyl acetate / 1 h / 40 °C View Scheme

Laevulinoyloxyessigsaeurebenzylester (53164-03-7) → acemetacin (53164-05-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / acetic acid / 1.) 42 h, 28 deg C, 2.) 5 h, 50 deg C 2: 78 percent / various solvent(s) / 3 h / 190 - 195 °C 3: 93 percent / H2 / 5 percent Pd/C / ethyl acetate / 1 h / 40 °C View Scheme

4-Methoxyphenylhydrazin-β-sulfonsaeure Natriumsalz → acemetacin (53164-05-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 68 percent / conc. HCl / H2O / 2 h / 20 °C 2: 80 percent / acetic acid / 1.) 42 h, 28 deg C, 2.) 5 h, 50 deg C 3: 78 percent / various solvent(s) / 3 h / 190 - 195 °C 4: 93 percent / H2 / 5 percent Pd/C / ethyl acetate / 1 h / 40 °C View Scheme

N-methyl-N-(2-nitrooxyethyl)ammonium nitrate (145459-16-1) + acemetacin (53164-05-9) → (N-methyl-N-(2-(nitrooxy)ethyl)carbamoyl)methyl 2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate (646511-41-3)

Conditions	Yield
With 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; dmap; triethylamine In dichloromethane at 20℃;	85%

2-nitroxyethylammonium nitrate (4665-58-1) + acemetacin (53164-05-9) → (N-(2-(nitrooxy)ethyl)carbamoyl)methyl 2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate (646511-43-5)

Conditions	Yield
With 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; 2-(Dimethylamino)pyridine	60%

{(1R,2R)-cyclohexane-1,2-diamine}dichloridoplatinum(II) (38780-40-4, 52691-24-4, 61848-70-2, 61848-66-6, 61848-62-2) + acemetacin (53164-05-9) → C27H31Cl2N3O6Pt

Conditions	Yield
With sodium carbonate; silver nitrate In N,N-dimethyl-formamide at 20℃; for 24h; Darkness;	53%

methanol (67-56-1) + acemetacin (53164-05-9) → 2-methoxy-2-oxoethyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate

Conditions	Yield
With tert.-butylnitrite at 40℃; for 48h; Green chemistry;	48%

acemetacin (53164-05-9) + rubitecan (91421-42-0) → acemetacin

Conditions	Yield
With dicyclohexyl-carbodiimide; dmap In DMF (N,N-dimethyl-formamide) at 20℃; for 96h;	32%

acemetacin (53164-05-9) → 2-(4-Chlorphenyl)-6-methoxy-4H-3.1-benzoxazinon-4 + N-(4-Chlor-benzoyl)-5-methoxy-anthranilsaeuremethylester + <2-(4-Chlor-benzoylamino)-5-methoxy>-benzoyl-2-essigsaeuremethylester + <2-(4-Chlor-benzoylamino)-5-methoxy>-benzoyl-2-acetoxy-essigsaeure

Conditions	Yield
With oxygen; methylene blue In methanol for 10h; Irradiation; Further byproducts given;	A 24% B 21% C 11% D 21%

acemetacin (53164-05-9) → 2-Acetyl-N-(4-chlor-benzoyl)-4-methoxy-anilin + N-(4-Chlor-benzoyl)-5-methoxy-anthranilsaeuremethylester + <2-(4-Chlor-benzoylamino)-5-methoxy>-benzoyl-2-essigsaeuremethylester + <2-(4-Chlor-benzoylamino)-5-methoxy>-benzoyl-2-acetoxy-essigsaeure

Conditions	Yield
With oxygen; methylene blue In methanol for 10h; Irradiation; Further byproducts given;	A 10% B 21% C 11% D 21%

acemetacin (53164-05-9) → 5-methoxy-2-methylindol-3-yl acetic acid carboxymethyl ester + para-chlorobenzoic acid (74-11-3)

Conditions	Yield
With sodium hydroxide at 30℃; Kinetics; Equilibrium constant; Further Variations:; Solvents; detergents; micelles; zwitterionic micelles;
With borate buffer at 30℃; pH=9.65; Kinetics; Equilibrium constant; Further Variations:; with/without L-α-phosphatidylcholine vesicles; detergents; micelles;
With perchloric acid In water at 25℃; Kinetics; Product distribution;

acemetacin (53164-05-9) → 5-Methoxy-2-methylindole-3-acetic acid (2882-15-7) + [1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid (53-86-1) + 5-methoxy-2-methylindol-3-yl acetic acid carboxymethyl ester + para-chlorobenzoic acid (74-11-3)

Conditions	Yield
In water at 30℃; Kinetics; Further Variations:; pH-values; Temperatures;

acemetacin (53164-05-9) → 4-chloro-N-hydroxybenzamide (1613-88-3)

Conditions	Yield
Stage #1: acemetacin With sodium hydroxide; hydroxylamine hydrochloride Stage #2: With hydrogenchloride; iron(III) chloride

Cu2(CH3COO)4(H2O)2 + acemetacin (53164-05-9) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → bis(N,N-dimethylformamide)bis-(O,O'-ACM)copper(II) + bis(N,N-dimethylformamide)tetrakis-μ-(O,O'-ACM)dicopper(II)

Conditions	Yield
at 20 - 35℃;

1H-imidazole (288-32-4) + Cu2(CH3COO)4(H2O)2 + acemetacin (53164-05-9) → bis(O,O'-acemetacin)bis(imidazole)copper(II)

Conditions	Yield
In methanol; water for 0.416667h;

zinc diacetate (557-34-6) + water (7732-18-5) + acemetacin (53164-05-9) → bis(O,O'-acemetacin)diaquzinc(II)

Conditions	Yield
In ethanol at 60℃;

Cu2(CH3COO)4(H2O)2 + water (7732-18-5) + acemetacin (53164-05-9) → bis(O,O'-acemetacin)diaquacopper(II)

Conditions	Yield
In ethanol at 20 - 40℃;

[Co(NH3)5(OSO2CF3)](CF3SO3)2 + acemetacin (53164-05-9) → pentaammine(acemetacin)cobalt(III) bis(trifluoromethanesuIfonate)

Conditions	Yield
With triethylamine In dimethyl sulfoxide at 50 - 80℃; for 5h;

1,2,3,4-tetra-O-trimethylsilyl-β-D-glucopyranose (98461-21-3) + acemetacin (53164-05-9) → C39H60ClNO11Si4

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 5h;

Duloxetine (116539-58-3, 116539-59-4, 116539-60-7, 116817-13-1) + acemetacin (53164-05-9) → acemetacin (S)-duloxetine salt (1309349-71-0)

Conditions	Yield
Stage #1: Duloxetine; acemetacin In tetrahydrofuran; methanol Stage #2: In di-isopropyl ether at 12℃; for 12h;
In tetrahydrofuran; methanol Product distribution / selectivity;

Upstream product

• 75302-98-6 acemetacin tert-butyl ester 
• 1601-20-3 2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid tert-butyl ester 
• 64-19-7 acetic acid 
• 53164-08-2 (5-Methoxy-2-methylindol-3-acetoxy)essigsaeurebenzylester 
• 53164-04-8 <1-(4-Chlorbenzoyl)-5-methoxy-2-methylindol-3-acetoxy>essigsaeurebenzylester 
• 53164-03-7 Laevulinoyloxyessigsaeurebenzylester 
• 123-76-2 levulinic acid 
• 53-86-1 [1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid 
• 19501-58-7 4-methoxyphenylhydrazine hydrochloride 

Downstream Products

• 1309349-71-0 acemetacin (S)-duloxetine salt 
• 646511-43-5 (N-(2-(nitrooxy)ethyl)carbamoyl)methyl 2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate 
• 1613-88-3 4-chloro-N-hydroxybenzamide 
• 2882-15-7 5-Methoxy-2-methylindole-3-acetic acid 
• 53-86-1 [1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid 
• 75511-23-8 5-methoxy-2-methylindol-3-yl acetic acid carboxymethyl ester 
• 74-11-3 para-chlorobenzoic acid 

Relevant articles and documents

Preparation method of acemetacin

The invention discloses a preparation method of acemetacin. The preparation method comprises the following steps: (1) introducing hydrogen chloride into glacial acetic acid to prepare an acetic acid solution of hydrogen chloride; (2) adding acetic anhydride into the acetic acid solution of hydrogen chloride prepared in the step (1); (3) adding acemetacin tert-butyl ester into the hydrogen chloride-acetic acid-acetic anhydride mixed acidolysis solution obtained in the step (2), and stirring at a constant temperature; (4) after the reaction is finished, cooling, carrying out standing crystallization, filtering, and carrying out top-washing to obtain a crude product acemetacin; and (5) refining the crude product acemetacin to obtain the finished product acemetacin. The invention provides a preparation method of acemetacin, wherein the influence of moisture in raw materials on an acidolysis reaction of acemetacin tert-butyl ester is eliminated on the premise of adopting the existing equipment, so that the product yield is increased, the production cost is lowered, and the economic benefit is improved.

Preparation method of acemetacin

The invention discloses a synthesis method of acemetacin. The synthesis method includes the steps that A, acemetacin benzyl ester is prepared according to the patent US4600783; B, the acemetacin benzyl ester is dissolved in a solvent, wherein the solvent is one of acetonitrile, methylbenzene and dichloromethane, a benzyl kation scavenging agent is added, the scavenging agent is one of anisole, phenol and N,N-dimethylaniline, and a solution A is obtained; C, aluminum chloride is added into the solvent, the prepared solution A is added at zero temperature, and the materials are stirred at normaltemperature; D, after the reaction is completed, a reaction mixture is poured into ice water, the materials are stirred and then filtered, and crude acemetacin is obtained; E, the obtained crude acemetacin is recrystallized according to the volume ratio of acetone to water being 2:1, vacuum drying is carried out, and the pure acemetacin is obtained. The method is easy to carry out, easy and convenient to operate and suitable for large-scale preparation, the price of aluminum chloride is low, no dechlorinated byproducts are generated, the purity of the acemetacin can reach and be larger than 99.8% only through one step of simple recrystallization, and no heavy metal residues are generated.

Glucose promoiety enables glucose transporter mediated brain uptake of ketoprofen and indomethacin prodrugs in rats

The brain uptake of solutes is efficiently governed by the blood-brain barrier (BBB). The BBB expresses a number of carrier-mediated transport mechanisms, and new knowledge of these BBB transporters can be used in the rational targeted delivery of drug molecules for active transport. One attractive approach is to conjugate an endogenous transporter substrate to the active drug molecule to utilize the prodrug approach. In the present study, ketoprofen and indomethacin were conjugated with glucose and the brain uptake mechanism of the prodrugs was determined with the in situ rat brain perfusion technique. Two of the prodrugs were able to significantly inhibit the uptake of glucose transporter (GluT1)-mediated uptake of glucose, thereby demonstrating affinity to the transporter. Furthermore, the prodrugs were able to cross the BBB in a temperature-dependent manner, suggesting that the brain uptake of the prodrugs is carrier-mediated.