71675-87-1

Basic information

• Product Name: 4-Amino-5-ethylsulfonyl-2-methoxybenzoic acid
• Synonyms: 2-METHOXY-4-AMINO-5-ETHYLSULFONYLBENZOIC ACID;4-AMINO-5-ETHANESULFONYL-2-METHOXY-BENZOIC ACID;4-AMINO-5-(ETHYLSULFONYL)-2-METHOXYBENZOIC ACID;4-Amino-5-(ethylsulphonyl)-o-anisic acid;2-methoxyl-4-amine-5-ethylsulfonylbenzoic acid;2-methoxy-4-amino-5-ethysulfonyl benzoic acid;2-METHOXY-4-AMINO-5-ETHYLSULFAMOYL BENZOIC ACID;BENZOICACID,4-AMINO-5-(ETHYLSULFONYL)-2-METHOXY
• CAS NO: 71675-87-1
• Molecular Formula: C₁₀H₁₃NO₅S
• Molecular Weight: 259.28
• EINECS: 275-833-8
• Product Categories: Organic acids;API intermediates;Aromatics Compounds;Amines;Aromatics;Sulfur & Selenium Compounds
• Mol File: 71675-87-1.mol

Chemical Properties

• Melting Point: 82-85°C
• Boiling Point: 529.6 °C at 760 mmHg
• Flash Point: 274.1 °C
• Appearance: Slightly pink solid
• Density: 1.39 g/cm³
• Vapor Pressure: 4.78E-12mmHg at 25°C
• Refractive Index: 1.568
• Storage Temp.: -20°C Freezer
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 4.09±0.10(Predicted)
• Water Solubility: 8.555g/L at 25℃
• CAS DataBase Reference: 4-Amino-5-ethylsulfonyl-2-methoxybenzoic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 4-Amino-5-ethylsulfonyl-2-methoxybenzoic acid(71675-87-1)
• EPA Substance Registry System: 4-Amino-5-ethylsulfonyl-2-methoxybenzoic acid(71675-87-1)

Safety Data

• HazardClass: IRRITANT
• Hazardous Substances Data: 71675-87-1(Hazardous Substances Data)

Usage

Uses

An impurity found in amisulpride (A633250). Amisulpride EP Impurity E

Flammability and Explosibility

Notclassified

InChI:InChI=1/C10H13NO5S/c1-3-17(14,15)9-4-6(10(12)13)8(16-2)5-7(9)11/h4-5H,3,11H2,1-2H3,(H,12,13)

Synthetic route

methyl 4-amino-5-(ethylthio)-2-methoxybenzoate (1119455-01-4) → 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1)

Conditions	Yield
Stage #1: methyl 4-amino-5-(ethylthio)-2-methoxybenzoate With dihydrogen peroxide; sodium tungstate In isopropyl alcohol at 40 - 45℃; Industry scale; Stage #2: With water; sodium hydroxide In isopropyl alcohol at 60 - 65℃; Industry scale; Stage #3: With hydrogenchloride In water; isopropyl alcohol pH=4 - 4.5; Industry scale;	82%
Multi-step reaction with 2 steps 1.1: sodium hydroxide; water / methanol / 65 °C / Industry scale 1.2: 5 - 10 °C / pH 4 - 4.5 / Industry scale 2.1: dihydrogen peroxide / sodium tungstate / water; methanol / 5 h / 20 - 30 °C View Scheme

2-methoxy-4-amino-5-ethylthio benzoic acid → 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1)

Conditions	Yield
With dihydrogen peroxide; sodium tungstate In methanol; water at 20 - 30℃; for 5h; Product distribution / selectivity;	80%

Methyl 4-amino-2-methoxybenzoate (27492-84-8) → 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: bromine / methanol / 5 - 15 °C / Industry scale 2.1: sodium sulfide / water; acetone / 5 - 15 °C / Industry scale 3.1: sodium hydroxide; water / methanol / 65 °C / Industry scale 3.2: 5 - 10 °C / pH 4 - 4.5 / Industry scale 4.1: dihydrogen peroxide / sodium tungstate / water; methanol / 5 h / 20 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: bromine / methanol / 5 - 15 °C / Industry scale 2.1: sodium sulfide / water; acetone / 5 - 15 °C / Industry scale 3.1: dihydrogen peroxide / sodium tungstate / isopropyl alcohol / 40 - 45 °C / Industry scale 3.2: 60 - 65 °C / Industry scale 3.3: pH 4 - 4.5 / Industry scale View Scheme

4-Aminosalicylic acid (65-49-6) → 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium hydroxide; tetrabutylammomium bromide / acetone / 1 h / 25 - 35 °C / Industry scale 2.1: bromine / methanol / 5 - 15 °C / Industry scale 3.1: sodium sulfide / water; acetone / 5 - 15 °C / Industry scale 4.1: sodium hydroxide; water / methanol / 65 °C / Industry scale 4.2: 5 - 10 °C / pH 4 - 4.5 / Industry scale 5.1: dihydrogen peroxide / sodium tungstate / water; methanol / 5 h / 20 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: potassium hydroxide; tetrabutylammomium bromide / acetone / 1 h / 25 - 35 °C / Industry scale 2.1: bromine / methanol / 5 - 15 °C / Industry scale 3.1: sodium sulfide / water; acetone / 5 - 15 °C / Industry scale 4.1: dihydrogen peroxide / sodium tungstate / isopropyl alcohol / 40 - 45 °C / Industry scale 4.2: 60 - 65 °C / Industry scale 4.3: pH 4 - 4.5 / Industry scale View Scheme

methyl 4-amino-2-methoxy-5-thiocyanatobenzoate (59168-56-8) → 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium sulfide / water; acetone / 5 - 15 °C / Industry scale 2.1: sodium hydroxide; water / methanol / 65 °C / Industry scale 2.2: 5 - 10 °C / pH 4 - 4.5 / Industry scale 3.1: dihydrogen peroxide / sodium tungstate / water; methanol / 5 h / 20 - 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium sulfide / water; acetone / 5 - 15 °C / Industry scale 2.1: dihydrogen peroxide / sodium tungstate / isopropyl alcohol / 40 - 45 °C / Industry scale 2.2: 60 - 65 °C / Industry scale 2.3: pH 4 - 4.5 / Industry scale View Scheme

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → 4-amino-5-(ethylsulfonyl)-N-(S)-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]-2-methoxybenzamide (1390617-35-2)

Conditions	Yield
Stage #1: 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid With chloroformic acid ethyl ester; triethylamine In dichloromethane at 0 - 20℃; for 0.5h; Stage #2: (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine In dichloromethane at 0 - 20℃; for 4h;	93%

1-ethyl-2-pyrrolidinemethanamine (26116-12-1) + 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) → amisulpride (71675-85-9)

Conditions	Yield
Stage #1: 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 10 - 20℃; for 1.5h; Stage #2: 1-ethyl-2-pyrrolidinemethanamine With triethylamine In acetonitrile at 80℃; for 2h;	86.8%
With C36H24B4N2O3 In toluene for 14h; Molecular sieve; Reflux; chemoselective reaction;	76%
With chloroformic acid ethyl ester; triethylamine In acetone at 0 - 30℃;	70%

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + (S)-2-(Aminomethyl)-1-ethylpyrrolidine (22795-99-9) + chloroformic acid ethyl ester (541-41-3) → (-)-Amisulpride

Conditions	Yield
In acetone	84%

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) → C20H24N2O9S2

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25 - 40℃; for 12h; Reagent/catalyst; Solvent;	72.52%

1-allyl 2-aminoethylpyrrolidine + 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + chloroformic acid ethyl ester (541-41-3) → N-[1-allyl 2-pyrrolidylmethyl] 2-methoxy 4-amino 5-ethylsulphonyl benzamide (71675-89-3)

Conditions	Yield
With hydrogenchloride; triethylamine In water; acetone	67%

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + chloroformic acid ethyl ester (541-41-3) + (-)-(S)-2-Aminomethyl-1(cyclopropylmethyl)pyrrolidine (71820-57-0) → LUR 2366 (72135-20-7)

Conditions	Yield
With triethylamine In tetrahydrofuran; water	66.5%

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) → 4-amino-5-(ethylsulfonyl)-2-hydroxybenzoic acid (148516-65-8)

Conditions	Yield
With boron tribromide In dichloromethane at -50 - 20℃;	65%

1-ethyl-2-pyrrolidinemethanamine (26116-12-1) + 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + chloroformic acid ethyl ester (541-41-3) → amisulpride (71675-85-9)

Conditions	Yield
With triethylamine In water; acetone	61%

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + 1-ethyl-2-aminomethylpyrrolidine hydrochloride → amisulpride (71675-85-9)

Conditions	Yield
Stage #1: 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.5h; Stage #2: 1-ethyl-2-aminomethylpyrrolidine hydrochloride With triethylamine In dichloromethane at 20℃;	29.7%

1-cyclohexylmethyl-pyrrolidin-3-R-ylamine + 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + isobutyl chloroformate (543-27-1) → benzamide (55-21-0) + N-(1-cyclohexylmethyl-3-pyrrolidinyl)-2-methoxy-4-amino-5-ethyl-sulphonyl-benzamide (72135-95-6)

Conditions	Yield
With triethylamine In water; ethyl acetate; acetone

1-cyclopropylmethyl-3-aminopyrrolidine + 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + isobutyl chloroformate (543-27-1) → N-(1-cyclopropylmethyl-3-pyrrolidinyl)-2-methoxy-4-amino-5-ethyl-sulphonyl-benzamide (72135-94-5)

Conditions	Yield
With triethylamine In water; acetone; Diethyl carbonate

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) → triethylamine hydrochloride (554-68-7)

Conditions	Yield
With triethylamine In acetone

1-methyl-2-aminomethyl-pyrrolidine (26171-06-2) + 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + chloroformic acid ethyl ester (541-41-3) → N-(1-methyl-2-pyrrolidylmethyl)-2-methoxy-4-amino-5-ethylsulphonylbenzamid (71675-88-2, 71675-93-9)

Conditions	Yield
With triethylamine In water; acetone

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + (R)-2-aminomethyl-1-ethylpyrrolidine (22795-97-7) + isopropyl chloroformate (108-23-6) → (R)-(+)-4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide

Conditions	Yield
Stage #1: 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid; isopropyl chloroformate With triethylamine In acetone at 5℃; for 0.5h; Stage #2: (R)-2-aminomethyl-1-ethylpyrrolidine In acetone at 0 - 20℃; for 1.5h;

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) → R-amisulpride maleic acid

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / acetone / 0.5 h / 5 °C 1.2: 1.5 h / 0 - 20 °C 2.1: methanol / 5 h / 45 °C View Scheme

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) → (R)-(+)-4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide L-tartrate

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / acetone / 0.5 h / 5 °C 1.2: 1.5 h / 0 - 20 °C 2.1: methanol / 2 h / 40 - 45 °C View Scheme

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) → R-amisulpride hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / acetone / 0.5 h / 5 °C 1.2: 1.5 h / 0 - 20 °C 2.1: hydrogenchloride / water; methanol; diethyl ether / 2 h / 20 °C View Scheme

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) → (S)-N-(2,4-dimethoxybenzyl)-4-amino-N-((1-ethylpyrrolidin-2-yl)methyl)-5-(ethylsulfonyl)-2-methoxybenzamide

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / acetone / 0.25 h / 0 - 10 °C / Inert atmosphere 1.2: 1.5 h / -5 - 5 °C 2.1: acetone / 4 h / 0 - 20 °C View Scheme

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) → (-)-Amisulpride

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / acetone / 0.25 h / 0 - 10 °C / Inert atmosphere 1.2: 1.5 h / -5 - 5 °C 2.1: acetone / 4 h / 0 - 20 °C 3.1: hydrogenchloride / methanol; water / 2 h / 20 °C View Scheme

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + pivaloyl chloride (3282-30-2) → 4-amino-2-methoxy-5-ethylsulfonyl benzoate pivalic anhydride

Conditions	Yield
Stage #1: 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid With triethylamine In acetone at 0 - 10℃; for 0.25h; Inert atmosphere; Stage #2: pivaloyl chloride In acetone at -5 - 5℃; for 1.5h;

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + (S)-2-(Aminomethyl)-1-ethylpyrrolidine (22795-99-9) → (-)-Amisulpride

Conditions	Yield
Stage #1: 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid With 4-methyl-morpholine; chloroformic acid ethyl ester In acetone at -10℃; for 1h; Inert atmosphere; Stage #2: (S)-2-(Aminomethyl)-1-ethylpyrrolidine In acetone at -10 - 20℃; Temperature; Reagent/catalyst; Inert atmosphere;	49 g
Stage #1: 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid With 4-methyl-morpholine; chloroformic acid ethyl ester In acetone at -8 - 0℃; Stage #2: (S)-2-(Aminomethyl)-1-ethylpyrrolidine In acetone at 0 - 20℃; Temperature;
Stage #1: 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid With 4-methyl-morpholine; chloroformic acid ethyl ester In acetone at -10℃; for 1h; Stage #2: (S)-2-(Aminomethyl)-1-ethylpyrrolidine In tert-butyl methyl ether; ethyl acetate; acetone for 2h;
With 4-methyl-morpholine; chloroformic acid ethyl ester In acetone at -8 - 20℃; Inert atmosphere;

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + (S)-2-(Aminomethyl)-1-ethylpyrrolidine (22795-99-9) → (S)-(-)-4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide D-tartrate

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 4-methyl-morpholine; chloroformic acid ethyl ester / acetone / 1 h / -10 °C / Inert atmosphere 1.2: -10 - 20 °C / Inert atmosphere 2.1: methanol / 0.75 h / 22 °C View Scheme

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + (R)-2-aminomethyl-1-ethylpyrrolidine (22795-97-7) → (R)-(+)-4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide

Conditions	Yield
With 4-methyl-morpholine; chloroformic acid ethyl ester In acetone at -10 - 20℃; Temperature; Reagent/catalyst; Inert atmosphere;	7 g
Stage #1: 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid With 4-methyl-morpholine; chloroformic acid ethyl ester In acetone at -9℃; for 1h; Stage #2: (R)-2-aminomethyl-1-ethylpyrrolidine In acetone for 16h; Temperature;
Stage #1: 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid With 4-methyl-morpholine; chloroformic acid ethyl ester In acetone at -10℃; for 1h; Stage #2: (R)-2-aminomethyl-1-ethylpyrrolidine In tert-butyl methyl ether; ethyl acetate; acetone for 2h;
Stage #1: 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid With 4-methyl-morpholine; chloroformic acid ethyl ester In acetone at -9℃; for 1h; Stage #2: (R)-2-aminomethyl-1-ethylpyrrolidine In acetone for 16h;

Upstream product

• 1119455-01-4 methyl 4-amino-5-(ethylthio)-2-methoxybenzoate 
• 59168-56-8 methyl 4-amino-2-methoxy-5-thiocyanatobenzoate 
• 65-49-6 4-Aminosalicylic acid 
• 27492-84-8 Methyl 4-amino-2-methoxybenzoate 

Downstream Products

• 71675-85-9 amisulpride 
• 1391054-22-0 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-N-[methyl]-5-(ethylsulfonyl)-2-methoxybenzamide 
• 72005-57-3 (R)-(+)-4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide L-tartrate 
• 72005-57-3 (S)-(-)-4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide D-tartrate 
• 1390617-35-2 4-amino-5-(ethylsulfonyl)-N-(S)-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]-2-methoxybenzamide 
• 148516-65-8 4-amino-5-(ethylsulfonyl)-2-hydroxybenzoic acid 
• 554-68-7 triethylamine hydrochloride 
• 72135-94-5 N-(1-cyclopropylmethyl-3-pyrrolidinyl)-2-methoxy-4-amino-5-ethyl-sulphonyl-benzamide 
• 55-21-0 benzamide 
• 72135-95-6 N-(1-cyclohexylmethyl-3-pyrrolidinyl)-2-methoxy-4-amino-5-ethyl-sulphonyl-benzamide 
• 72135-20-7 LUR 2366 
• 71675-89-3 N-[1-allyl 2-pyrrolidylmethyl] 2-methoxy 4-amino 5-ethylsulphonyl benzamide 
• 71675-88-2 N-(1-methyl-2-pyrrolidylmethyl)-2-methoxy-4-amino-5-ethylsulphonylbenzamid 

Relevant articles and documents

AN IMPROVED PROCESS FOR PREPARATION OF AMISULPRIDE

The present invention is related to a novel process for the preparation of amisulpride (I) which involves : methylation of 4-amino-salicylic-acid (VI) with dimethyl sulphate and base, optionally in presence of TBAB to obtain 4-amino-2-methoxy methyl benzoate (VII) and (ii) oxidation of 4-amino-2-methoxy-5-ethyl thio benzoic acid (IX) or 4-amino-2-methoxy-5- ethyl thio methyl benzoate (X) with oxidizing agent in the presence of sodium tungstate or ammonium molybdate to give 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid (IV) or 2- methoxy-4-amino-5-ethyl-sulfonyl methyl benzoate (XI) respectively.

Compositions of (S) (-)-amisulpride

A composition is provided comprising an antipsychotic effective amount of (S)(-)-amisulpride, (S)-(-)-4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethylsulfonyl)-2-methoxybenzamide. A preferred composition comprises the (D)-tartrate salt of (S)(-)-amisulpride. The (S)(-) enantiomer exhibits antipsychotic properties and administration of the specific enantiomer reduces adverse side effects by reducing toxicity.