103475-41-8

Basic information

• Product Name: Tepoxalin
• Synonyms: Tepoxalin;1H-Pyrazole-3-propanamide, 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-;3-[1-(4-Methoxyphenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]-N-hydroxy-N-methylpropanamide;RWJ-20485;5-(4-Chlorophenyl)-N-hydroxy-1-(4-Methoxyphenyl)-N-Methyl-1H-pyrazole-3-propanaMide;ORF 20485;3-(5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)-N-hydroxy-N-methylpropanamide
• CAS NO: 103475-41-8
• Molecular Formula: C₂₀H₂₀ClN₃O₃
• Molecular Weight: 385.849
• Product Categories: Amines;Aromatics;Heterocycles;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 103475-41-8.mol

Chemical Properties

• Melting Point: 124-126°
• Boiling Point: 572.991 °C at 760 mmHg
• Flash Point: 300.334 °C
• Appearance: /
• Density: 1.27 g/cm³
• Vapor Pressure: 5.72E-14mmHg at 25°C
• Refractive Index: 1.61
• Storage Temp.: Hygroscopic, Refrigerator, Under Inert Atmosphere
• Solubility: DMSO (Sparingly), Methanol (Slightly)
• Stability: Hygroscopic
• CAS DataBase Reference: Tepoxalin(CAS DataBase Reference)
• NIST Chemistry Reference: Tepoxalin(103475-41-8)
• EPA Substance Registry System: Tepoxalin(103475-41-8)

Safety Data

• Hazardous Substances Data: 103475-41-8(Hazardous Substances Data)

Usage

Veterinary Drugs and Treatments

Tepoxalin is indicated for the treatment of pain and inflammation associated with osteoarthritis in dogs. Because of the drug’s inhibitory effects on leukotrienes, there is interest in seeing if it would be beneficial in the adjunctive treatment of allergic conditions in dogs.

InChI:InChI=1/C20H20ClN3O3/c1-23(26)20(25)12-7-16-13-19(14-3-5-15(21)6-4-14)24(22-16)17-8-10-18(27-2)11-9-17/h3-6,8-11,13,26H,7,12H2,1-2H3

Synthetic route

4-methoxyphenylhydrazine hydrochloride (19501-58-7) + 6-(4-chlorophenyl)-4,6-dioxo-N-hydroxy-N-methylhexanamide (142791-64-8) → tepoxalin (103475-41-8) + 3-<3-(4-chlorophenyl)-1-(4-methoxyphenyl)-5-pyrazolyl>-N-hydroxy-N-methylpropanamide (149065-93-0)

Conditions	Yield
With sodium carbonate In ethanol for 3h; Heating;	A 70% B 10%

oxalyl dichloride (79-37-8) + triethylamine (Et3 N) + N-methylhydroxyamine hydrochloride (4229-44-1) + water (7732-18-5) + 3-[5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl]propionic acid (114150-42-4) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → tepoxalin (103475-41-8)

Conditions	Yield
In tetrahydrofuran	65%

N-methylhydroxyamine hydrochloride (4229-44-1) + 3-[5-(4-Chloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-propionyl chloride (114151-49-4) → tepoxalin (103475-41-8)

Conditions	Yield
With triethylamine In dichloromethane for 1h; Ambient temperature; Yield given;

4,6-dioxo-6-(4-chlorophenyl)hexanoic acid (111881-78-8) → tepoxalin (103475-41-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 81 percent / Ac2O / 0.33 h / Heating 2: 87 percent / Et3N / CH2Cl2 / 16 h / Ambient temperature 3: 70 percent / Na2CO3 / ethanol / 3 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 81 percent / Ac2O / 0.33 h / Heating 2: Et3N / CH2Cl2 / 0.5 h / Ambient temperature 3: 70 percent / Na2CO3 / ethanol / 3 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 81 percent / Ac2O / 0.33 h / Heating 2: 16 percent / Et3N / CH2Cl2 / 0.5 h / Ambient temperature 3: 60 percent Turnov. / CH2Cl2 / 16 h 4: 70 percent / Na2CO3 / ethanol / 3 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 81 percent / Ac2O / 0.33 h / Heating 2: 3 percent / Et3N / CH2Cl2 / 0.5 h / Ambient temperature 3: 74 percent / 10percent HCl / 1 h 4: 70 percent / Na2CO3 / ethanol / 3 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 94 percent / NEt3 / methanol / 6 h / Ambient temperature 2: oxalyl chloride / CH2Cl2 / 3 h / Ambient temperature 3: NEt3 / CH2Cl2 / 1 h / Ambient temperature View Scheme

5-<1-(4-chlorophenyl)-1-oxoethanylidene>-3,4-dihydrofuran-2-one (142791-63-7) → tepoxalin (103475-41-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 87 percent / Et3N / CH2Cl2 / 16 h / Ambient temperature 2: 70 percent / Na2CO3 / ethanol / 3 h / Heating View Scheme
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 0.5 h / Ambient temperature 2: 70 percent / Na2CO3 / ethanol / 3 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 16 percent / Et3N / CH2Cl2 / 0.5 h / Ambient temperature 2: 60 percent Turnov. / CH2Cl2 / 16 h 3: 70 percent / Na2CO3 / ethanol / 3 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 3 percent / Et3N / CH2Cl2 / 0.5 h / Ambient temperature 2: 74 percent / 10percent HCl / 1 h 3: 70 percent / Na2CO3 / ethanol / 3 h / Heating View Scheme

O-(N-methylamino)-6-(4-chlorophenyl)-4,6-dioxohexanoate (144192-63-2) → tepoxalin (103475-41-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 60 percent Turnov. / CH2Cl2 / 16 h 2: 70 percent / Na2CO3 / ethanol / 3 h / Heating View Scheme

6-(4-chlorophenyl)-4-(N-hydroxy-N-methylamino)-6-oxo-N-hydroxy-N-methyl-4-hexenamide (144192-64-3) → tepoxalin (103475-41-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 74 percent / 10percent HCl / 1 h 2: 70 percent / Na2CO3 / ethanol / 3 h / Heating View Scheme

4-methoxyphenylhydrazine hydrochloride (19501-58-7) → tepoxalin (103475-41-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 94 percent / NEt3 / methanol / 6 h / Ambient temperature 2: oxalyl chloride / CH2Cl2 / 3 h / Ambient temperature 3: NEt3 / CH2Cl2 / 1 h / Ambient temperature View Scheme

3-[5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl]propionic acid (114150-42-4) → tepoxalin (103475-41-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: oxalyl chloride / CH2Cl2 / 3 h / Ambient temperature 2: NEt3 / CH2Cl2 / 1 h / Ambient temperature View Scheme

hydroxamic acid + water (7732-18-5) + tepoxalin (103475-41-8) → 3-[5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl]-N-hydroxy-N-methylpropanamide sodium salt monohydrate

Conditions	Yield
	97%

succinic acid anhydride (108-30-5) + hydroxamic acid + tepoxalin (103475-41-8) → 3-[5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl]-N-methyl-N-succinyloxy-propanamide

Conditions	Yield
In pyridine

2-methylmorpholine (27550-90-9) + tepoxalin (103475-41-8) + chloroacetyl chloride (79-04-9) → 3-[5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl] N-Chloroacetyloxy-N-methylpropanamide (114151-03-0)

Conditions	Yield
In tetrahydrofuran

N',N'-dicyclohexylcarbodiimide + dimethylaminoacetic acid (1118-68-9) + tepoxalin (103475-41-8) → 3-[5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl]-N',N'-dimethylglycinyloxy-N-methylpropanamide

Conditions	Yield
In pyridine

Upstream product

• 19501-58-7 4-methoxyphenylhydrazine hydrochloride 
• 142791-64-8 6-(4-chlorophenyl)-4,6-dioxo-N-hydroxy-N-methylhexanamide 
• 111881-78-8 6-(4-chlorophenyl)-4,6-dioxohexanoic acid 
• 142791-63-7 5-<1-(4-chlorophenyl)-1-oxoethanylidene>-3,4-dihydrofuran-2-one 
• 79-37-8 oxalyl dichloride 
• 4229-44-1 N-methylhydroxyamine hydrochloride 
• 7732-18-5 water 
• 114150-42-4 3-[5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl]propionic acid 
• 68-12-2 N,N-dimethyl-formamide 
• 114151-49-4 3-[5-(4-Chloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-propionyl chloride 
• 144192-64-3 6-(4-chlorophenyl)-4-(N-hydroxy-N-methylamino)-6-oxo-N-hydroxy-N-methyl-4-hexenamide 
• 144192-63-2 O-(N-methylamino)-6-(4-chlorophenyl)-4,6-dioxohexanoate 

Downstream Products

• 114151-03-0 3-[5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl] N-Chloroacetyloxy-N-methylpropanamide 

Relevant articles and documents

Process for preparing 1,5-diaryl-3-substituted pyrazoles

A process for making a compound of formula I wherein the substituents are as described in the specification comprising reacting a ketone of formula II with succinic anhydride and an alkoxide base to form a compound of formula III which is reacted with a compound of formula IV to form a compound of V and reacting with an alcohol to form the corresponding ester of formula VI and reacting the ester with N-methylhydroxylamine.

N-hydroxy, N-methyl propanamides

The invention provides a process for preparing 1,5-diaryl pyrazole anti-inflammatory agents. A 6-aryl-4,6-dioxohexanoic acid is treated with acetic anhydride or acetyl chloride to produce an enol lactone, which is added to methylhydroxylamine to generate the dione hydroxamic acid. This dione hydroxamic acid is then treated with 4-methoxyphenylhydrazine hydrochloride to yield the 1,5-diaryl pyrazole. Novel intermediate compounds in the synthetic pathway are also disclosed.

The regioselective synthesis of tepoxalin, 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl]-N-hydroxy-N-me thylpropanamide and related 1,5-diarylpyrazole anti-inflammatory agents

Tepoxalin, a potent anti-inflammatory agent, and its analogs can be synthesized by condensing an appropriate arylhydrazine hydrochloride and a 6-aryl-4,6-dioxohexanoic acid in alcohol with a base catalyst. These diarylpyrazolylpropanoic acids can be converted to their N-methylhydroxamic acids by generating the requisite acid chloride, and allowing it to react with N-methylhydroxylamine.

Regioselective synthesis of a 1,5-disubstituted pyrazole

A highly regioselective synthesis of pyrazoles from a mono-substituted hydrazine and a β-dicarbonyl compound wherein a carboxylic acid moiety is present on the substituent attached to one of the carbonyls. For example, compounds of the formula (I) are formed in marked preference to isomers of formula (IV): STR1

1,5-Diaryl-3-substituted pyrazoles pharmaceutical compositions and use

1,5-Diaryl-3-substituted pyrazoles, a method of their preparation, compositions containing the same and methods of their use are disclosed. The pyrazoles are useful in alleviating inflammatory and cardiovascular disorders in mammals.