59-06-3

Basic information

• Product Name: Ethopabate
• Synonyms: 4-ACETYLAMINO-2-ETHOXY-BENZOIC ACID METHYL ESTER;METHYL 4-ACETAMIDO-2-ETHOXYBENZOATE;ETHOPABATE;Ethopabate, Vetranal;ETHOPABATE (4-ACETYLAMINO-2-ETHOXY-BENZOIC ACID METHYL ESTER);4-Acetamido-2-ethoxybenzoic acid, methyl ester;Ethopatate;Ethytpatate
• CAS NO: 59-06-3
• Molecular Formula: C₁₂H₁₅NO₄
• Molecular Weight: 237.25
• EINECS: 200-414-3
• Product Categories: Aromatic Esters;Amines;Aromatics;Drug Analogues;Intermediates & Fine Chemicals;Pharmaceuticals;NARDIL;animal pharmaceutical
• Mol File: 59-06-3.mol
• Article Data: 6

Chemical Properties

• Melting Point: 148-151 °C
• Boiling Point: 426.1 °C at 760 mmHg
• Flash Point: 211.5 °C
• Appearance: Colorless to yellow liquid
• Density: 1.18 g/cm³
• Vapor Pressure: 1.82E-07mmHg at 25°C
• Refractive Index: 1.545
• Storage Temp.: 0-6°C
• PKA: 14.12±0.70(Predicted)
• Merck: 13,3781
• CAS DataBase Reference: Ethopabate(CAS DataBase Reference)
• NIST Chemistry Reference: Ethopabate(59-06-3)
• EPA Substance Registry System: Ethopabate(59-06-3)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• WGK Germany: 3
• Hazardous Substances Data: 59-06-3(Hazardous Substances Data)

Usage

Chemical Properties

White to Off-White Solid

Uses

Different sources of media describe the Uses of 59-06-3 differently. You can refer to the following data:
1. A supplementary drug that improves the coccidiostatic effect of nicarbazin and amprolium in order to cure coccidiosis in chickens.
2. antidepressant

Clinical Use

Ethopabate is only a narrow anticoccidial spectrum drug against Eimeria acervulina. It has no or only slight activity against E. maxima, E. necatrix, E. tenella or E. brunetti. Today, ethopabate is applied only in combination with amprolium and sulfonamide.

Molecular Interactions

Ethopabate is a 2-substituted PABA derivative (=4-acetamido-2-ethoxybenzoic acid methylester) and functions as a prodrug. Its activity becomes potentiated by pyrimethamine and antagonised by the simultaneous administration of PABA. Thus, the mode of action of ethopabate is similar to that of sulfonamides or sulfones.

InChI:InChI=1/C12H15NO4/c1-4-17-11-7-9(13-8(2)14)5-6-10(11)12(15)16-3/h5-7H,4H2,1-3H3,(H,13,14)

Synthetic route

methyl 4-acetamido-2-hydroxybenzoate (4093-28-1) + ethyl iodide (75-03-6) → methyl 4-acetamido-2-ethoxybenzoate (59-06-3)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20 - 30℃; for 24h;	98.4%
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 6h;	97%

diethyl sulfate (64-67-5) + methyl 4-acetamido-2-hydroxybenzoate (4093-28-1) → methyl 4-acetamido-2-ethoxybenzoate (59-06-3)

Conditions	Yield
With triethylamine In acetone at 40 - 65℃; for 12h;	97%

ethyl bromide (74-96-4) + methyl 4-acetamido-2-hydroxybenzoate (4093-28-1) → methyl 4-acetamido-2-ethoxybenzoate (59-06-3)

Conditions	Yield
With potassium carbonate In acetone for 14h; Heating;	80%
With sodium hydroxide In N,N-dimethyl-formamide

4-Aminosalicylic acid (65-49-6) → methyl 4-acetamido-2-ethoxybenzoate (59-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: sulfuric acid / 2 h / 20 °C 2: acetic acid / 1 h 3: sodium hydroxide / N,N-dimethyl-formamide View Scheme
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / 3 h / 60 - 65 °C 2: acetylase / 2 h / 35 - 40 °C / pH 6.5 - 7.5 / Enzymatic reaction 3: triethylamine / acetone / 12 h / 40 - 65 °C View Scheme

methyl 4-aminosalicylate (4136-97-4) → methyl 4-acetamido-2-ethoxybenzoate (59-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid / 1 h 2: sodium hydroxide / N,N-dimethyl-formamide View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 2-ethoxy-4-aminobenzoic acid (59-07-4)

Conditions	Yield
With sodium hydroxide; water for 16h; Heating / reflux;	100%
Stage #1: methyl 4-acetamido-2-ethoxybenzoate With sodium hydroxide; water for 16h; Heating / reflux; Stage #2: With hydrogenchloride In water at 0℃;	100%
With potassium hydroxide
With potassium hydroxide

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 4-amino-2-ethoxybenzoic acid lithium salt (617245-68-8)

Conditions	Yield
With lithium hydroxide In tetrahydrofuran; water at 70℃; for 18h;	100%

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 4-Acetylamino-5-chloro-2-ethoxy-benzoic acid methyl ester (4235-43-2)

Conditions	Yield
With N-chloro-succinimide In N,N-dimethyl-formamide at 70℃; for 2h;	97%
With N-chloro-succinimide In N,N-dimethyl-formamide at 70℃; for 3h; Yield given;
With N-chloro-succinimide In N,N-dimethyl-formamide

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → C12H12(2)H3NO4

Conditions	Yield
With [(1,5-cyclooctadiene)Ir(1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)(PPh3)]PF6; deuterium In dichloromethane at 20℃; for 2h; Sealed tube;	95%

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → C12H13(2)H2NO4

Conditions	Yield
With [(1,5-cyclooctadiene)Ir(1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)(PPh3)]PF6; deuterium In dichloromethane at 0℃; for 2h; Sealed tube;	95%

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → methyl 4-acetylamino-5-bromo-2-ethoxybenzoate (483304-07-0)

Conditions	Yield
With N-Bromosuccinimide In N,N-dimethyl-formamide at 80℃; for 3.5h;	94%
With N-Bromosuccinimide In N,N-dimethyl-formamide

2-chloro-5-methyl-3-nitro-pyridine (23056-40-8) + methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 4-(2,6-Dimethylimidazo[4,5-b]pyridin-3-yl)-2-ethoxybenzoic acid methyl ester

Conditions	Yield
	84%

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → methyl 4-acetylamino-2-ethoxy-5-iodobenzoate (483304-08-1)

Conditions	Yield
With sodium periodate; iodine In DMF (N,N-dimethyl-formamide) at 70℃; for 24h;	76%
With steareth-10 In N,N-dimethyl-formamide at 20 - 80℃; for 2.5h;	47%

o-nitroiodobenzene (609-73-4) + methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 2-Ethoxy-4-(2-methyl-benzoimidazol-1-yl)-benzoic acid methyl ester

Conditions	Yield
	76%

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → C12H13N3O8 (1028126-84-2)

Conditions	Yield
With nitric acid at 0 - 20℃; for 1.5h;	65%

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → methyl 4-(acetylamino)-2-ethoxy-5-nitrobenzoate (86718-16-3)

Conditions	Yield
With nitric acid

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 4-amino-5-bromo-2-ethoxybenzoic acid (84923-73-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 94 percent / NBS / dimethylformamide / 3.5 h / 80 °C 2: 98 percent / aq. NaOH / methanol / 4 h / Heating View Scheme
Multi-step reaction with 2 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide 2: sodium hydroxide / ethanol View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 4-amino-2-ethoxy-5-iodobenzoic acid (483304-09-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 47 percent / ICI / dimethylformamide / 2.5 h / 20 - 80 °C 2: 91 percent / aq. NaOH / methanol / Heating View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 4-amino-5-bromo-2-ethoxy-N-(1-ethyl-4-methyl-[1,4]diazepan-6-yl)-benzamide

Conditions	Yield
Multi-step reaction with 3 steps 1: 94 percent / NBS / dimethylformamide / 3.5 h / 80 °C 2: 98 percent / aq. NaOH / methanol / 4 h / Heating 3: EDC / CH2Cl2 / 20 °C View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 4-amino-2-ethoxy-N-(1-ethyl-4-methyl-[1,4]diazepan-6-yl)-5-iodo-benzamide

Conditions	Yield
Multi-step reaction with 3 steps 1: 47 percent / ICI / dimethylformamide / 2.5 h / 20 - 80 °C 2: 91 percent / aq. NaOH / methanol / Heating 3: EDC / CH2Cl2 / 20 °C View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 4-Acetylamino-5-amino-2-ethoxy-benzoic acid methyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: HNO3 2: H2 / Pd/C View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 6-Ethoxy-1H-benzotriazole-5-carboxylic acid (213627-49-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: HNO3 2: H2 / Pd/C 3: NaNO2, aq. HCl 4: aq. NaOH View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 1-Acetyl-6-ethoxy-1H-benzotriazole-5-carboxylic acid methyl ester (213627-48-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: HNO3 2: H2 / Pd/C 3: NaNO2, aq. HCl View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 6-Ethoxy-1H-benzotriazole-5-carboxylic acid (1-ethyl-azepan-3-yl)-amide

Conditions	Yield
Multi-step reaction with 5 steps 1: HNO3 2: H2 / Pd/C 3: NaNO2, aq. HCl 4: aq. NaOH 5: N,N'-carbonyldiimidazole View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 4-amino-5-chloro-2-ethoxybenzoic acid (108282-38-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: NCS / dimethylformamide / 3 h / 70 °C 2: 86.9 percent / 4N NaOH / methanol / 2 h / Heating View Scheme
Multi-step reaction with 2 steps 1: 97 percent / N-chlorosuccinimide (NCS) / dimethylformamide / 2 h / 70 °C 2: 99 percent / NaOH, H2O / ethanol / 5 h / Heating View Scheme
Multi-step reaction with 2 steps 1: N-chloro-succinimide / N,N-dimethyl-formamide 2: sodium hydroxide / ethanol View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 4-Amino-5-chloro-2-ethoxy-N-[2-(tetrahydro-pyrrolizin-7a-yl)-ethyl]-benzamide

Conditions	Yield
Multi-step reaction with 3 steps 1: NCS / dimethylformamide / 3 h / 70 °C 2: 86.9 percent / 4N NaOH / methanol / 2 h / Heating 3: 1.) CDI / 1.) THF, 1 h, 2.) THF, reflux, 1 h View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → methyl 4-amino-5-chloro-2-ethoxybenzoate (112914-03-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 97 percent / N-chlorosuccinimide (NCS) / dimethylformamide / 2 h / 70 °C 2: 99 percent / NaOH, H2O / ethanol / 5 h / Heating 3: 91 percent / thionyl chloride / 4 h / 0 - 20 °C View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → methyl 5-chloro-2-ethoxy-4-(formylamino)benzoate (131322-25-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 97 percent / N-chlorosuccinimide (NCS) / dimethylformamide / 2 h / 70 °C 2: 99 percent / NaOH, H2O / ethanol / 5 h / Heating 3: 91 percent / thionyl chloride / 4 h / 0 - 20 °C 4: 94 percent / acetic anhydride / 2.5 h / 50 °C View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 5-chloro-2-ethoxy-4-(fromylamino)benzoic acid (131322-26-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: 97 percent / N-chlorosuccinimide (NCS) / dimethylformamide / 2 h / 70 °C 2: 99 percent / NaOH, H2O / ethanol / 5 h / Heating 3: 91 percent / thionyl chloride / 4 h / 0 - 20 °C 4: 94 percent / acetic anhydride / 2.5 h / 50 °C 5: 82 percent / NaOH, H2O / ethanol / 1 h / 60 °C View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 4-(acetylamino)-5-chloro-2-ethoxybenzoic acid (112914-09-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 97 percent / N-chlorosuccinimide (NCS) / dimethylformamide / 2 h / 70 °C 2: 73 percent / NaOH, H2O / methanol / 1 h / 60 °C View Scheme

methyl 4-acetamido-2-ethoxybenzoate (59-06-3) → 4-Amino-5-chloro-N-[4-(4-chloro-benzyl)-morpholin-2-ylmethyl]-2-ethoxy-benzamide (112886-52-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 97 percent / N-chlorosuccinimide (NCS) / dimethylformamide / 2 h / 70 °C 2: 99 percent / NaOH, H2O / ethanol / 5 h / Heating 3: 1-ethyl-3-<3-(dimethylamino)propyl>carbodiimide hydrochloride / CH2Cl2 / 4 h / Ambient temperature View Scheme

Upstream product

• 64-67-5 diethyl sulfate 
• 4093-28-1 methyl 4-acetamido-2-hydroxybenzoate 
• 4136-97-4 methyl 4-aminosalicylate 
• 65-49-6 4-Aminosalicylic acid 
• 74-96-4 ethyl bromide 
• 75-03-6 ethyl iodide 

Downstream Products

• 1028126-84-2 C₁₂H₁₃N₃O₈ 
• 1388193-82-5 C₁₂H₁₅Br₂NO₃ 
• 1388193-51-8 Br^(1-)*C₃₂H₃₆ClN₂O₇⁽¹⁺⁾ 
• 1388193-60-9 Br^(1-)*C₃₁H₃₄BrN₂O₇⁽¹⁺⁾ 
• 1388193-61-0 Br^(1-)*C₃₂H₃₆BrN₂O₇⁽¹⁺⁾ 
• 86718-16-3 methyl 4-(acetylamino)-2-ethoxy-5-nitrobenzoate 
• 617245-68-8 4-amino-2-ethoxybenzoic acid lithium salt 
• 100800-71-3 2-ethoxy-4-amino-benzoic acid-(2-dimethylamino-ethyl ester) 
• 131322-34-4 5-Chloro-2-ethoxy-N-[4-(4-fluoro-benzyl)-morpholin-2-ylmethyl]-4-formylamino-benzamide 
• 131322-30-0 4-{2-[(4-Amino-5-chloro-2-ethoxy-benzoylamino)-methyl]-morpholin-4-ylmethyl}-benzoic acid methyl ester 
• 112886-55-2 4-amino-5-chloro-N-[[4-(2-chlorobenzyl)-2-morpholinyl]methyl]-2-ethoxybenzamide 
• 112886-58-5 4-Amino-5-chloro-2-ethoxy-N-[4-(2-fluoro-benzyl)-morpholin-2-ylmethyl]-benzamide 
• 112886-45-0 4-Amino-5-chloro-N-[4-(3-cyano-benzyl)-morpholin-2-ylmethyl]-2-ethoxy-benzamide 
• 112885-41-3 mosapride 

Relevant articles and documents

Preparation method of ethopabate

The invention discloses a preparation method of ethopabate. Initially, para-aminosalicylic acid and p-toluene sulfonic acid are dissolved in methanol to form a mixed solution, the mixed solution is put in a reaction bottle, evenly stirred and heated, and a thermal insulation reaction is carried out; sodium acetate is added into a methyl p-aminosalicylate reaction liquid, the pH and temperature ofthe reaction liquid are controlled, acetylase is added, and a reaction is carried out to obtain methyl p-acetaminosalicylate; methyl p-acetaminosalicylate is added into acetone, heating is carried out, diethyl sulfate is added dropwisely, and after adding dropwisely is completed, a reaction is carried out to obtain ethopabate. The method has the advantages that industrial production can be achieved, resource conservation and environmental protection can be achieved, the cost can be better saved, the product quality is stable, the yield is high, and the method is suitable for large-scale industrial stable production.

Design, synthesis, inhibitory activity, and SAR studies of hydrophobic p-aminosalicylic acid derivatives as neuraminidase inhibitors

A series of hydrophobic p-aminosalicylic acid derivatives containing a lipophilic side chain at C-2 and an amino or guanidine at C-5 were synthesized and evaluated for their ability to inhibit neuraminidase (NA) of influenza A virus (H3N2). All compounds were synthesized in good yields starting from commercially available p-aminosalicylic acid (PAS) using a suitable synthetic strategy. These compounds showed potent inhibitory activity against influenza A NA. Within this series, six compounds, 11, 12, 13e, 16e, 17c, and 18e, have the good potency (IC50 = 0.032-0.049 μM), which are compared to Oseltamivir (IC50 = 0.021 μM) and could be used as lead compounds in the future.

Novel benzamides as selective and potent gastrokinetic agents. 2.1 Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl] benzamide citrate (AS-4370) and related compounds

The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl]benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.