24683-26-9

Basic information

• Product Name: Ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide
• Synonyms: (4-Hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid ethyl)1,1-dioxide;Ethyl 4-Hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-Dioxide (Piroxicam Impurity K);2-benzothiazine-3-carboxylic acid ethyl ester-1;2-Methyl-4-hydroxy-2H-1;Meloxicam Related Compound A (25 mg) (ethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate- 1,1-dioxide);MeloxicaM IMpurity A(EP) (USP RC A);Ethyl 4-hydroxy-2-methyl-1,1-dioxo-2H-1,2-benzothiazine-3-carboxylate 97%;ETHYL 4-HYDROXY-2-METHYL-1,1-DIOXO-2H-1,2-BENZOTHIAZINE-3-CARBOXYLATE
• CAS NO: 24683-26-9
• Molecular Formula: C₁₂H₁₃NO₅S
• Molecular Weight: 283.3
• EINECS: 246-403-7
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;Organic acids;API intermediates;(intermediate of piroxicam);Aromatics Compounds;Aromatics;Heterocycles;Building Blocks;Heterocyclic Building Blocks;Thiazines
• Mol File: 24683-26-9.mol
• Article Data: 5

Chemical Properties

• Melting Point: 140-144 °C(lit.)
• Boiling Point: 424.1°Cat760mmHg
• Flash Point: 210.3°C
• Appearance: /
• Density: 1.444g/cm³
• Vapor Pressure: 5.97E-08mmHg at 25°C
• Refractive Index: 1.61
• Storage Temp.: -20°C Freezer
• PKA: 4.50±1.00(Predicted)
• CAS DataBase Reference: Ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide(CAS DataBase Reference)
• NIST Chemistry Reference: Ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide(24683-26-9)
• EPA Substance Registry System: Ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide(24683-26-9)

Safety Data

• Hazard Codes: T
• Statements: 23
• Safety Statements: 45
• RIDADR: UN 2811 6.1/PG 2
• WGK Germany: 2
• RTECS: DL0710425
• Hazardous Substances Data: 24683-26-9(Hazardous Substances Data)

Usage

Description

Ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide is a chemical compound with the molecular formula C12H13NO4S. It is a white to off-white solid and is known for its presence as an impurity in the pharmaceuticals Piroxicam and Meloxicam.

Uses

Used in Pharmaceutical Industry:
Ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide is used as an impurity in the manufacturing process of certain pharmaceutical drugs, specifically Piroxicam (impurity K) and Meloxicam (M216100). Its presence, although as an impurity, is significant for the development and formulation of these medications.
Used in Quality Control and Analysis:
In the pharmaceutical industry, Ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide is also used for quality control and analysis purposes. Its identification and quantification in drug products help ensure the safety, efficacy, and purity of the final medication, contributing to the overall quality assurance process.
Used in Research and Development:
This chemical compound may also be utilized in research and development for the pharmaceutical industry. It can serve as a starting material or a reference compound for the synthesis of new drug candidates or for studying the chemical properties and interactions of related compounds.

InChI:InChI=1/C12H13NO5S/c1-3-18-12(15)10-11(14)8-6-4-5-7-9(8)19(16,17)13(10)2/h4-7,15H,3H2,1-2H3/b12-10+

Synthetic route

4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid ethyl ester 1,1-dioxide (24683-21-4) + dimethyl sulfate (77-78-1) → ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9)

Conditions	Yield
With hydrogenchloride In water at 10℃; for 18h; pH=7.5;	78.9%

2-(Ethoxycarbonylmethyl-methyl-sulfamoyl)-benzoic acid ethyl ester (113412-08-1) → ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9)

Conditions	Yield
With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 5.5h;	76%

4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid ethyl ester 1,1-dioxide (24683-21-4) + methyl iodide (74-88-4) → ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9)

Conditions	Yield
With sodium hydroxide In ethanol at 20℃; for 18h;	72%
With sodium methylate In N,N-dimethyl-formamide
With sodium hydroxide In ethanol; water at 20℃; for 24h;

ethyl 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl) acetate (24683-20-3) → ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 68 percent / EtONa / ethanol / 1 h / 55 °C 2: 72 percent / aq. NaOH / ethanol / 18 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 1) NaOEt / 1) room temperature, 7-10 min.; 2) room temperature, 2 h 2: 76 percent / lithium diisopropylamide / tetrahydrofuran / 5.5 h / -78 °C View Scheme
Multi-step reaction with 2 steps 1: NaOEt / ethanol 2: NaOMe / dimethylformamide View Scheme
Multi-step reaction with 2 steps 1: sodium methylate / dimethyl sulfoxide / 1 h / 30 °C 2: sodium hydroxide / water; ethanol / 24 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride; sodium / ethanol / 0.5 h / 70 °C / pH 8 - 9 2: hydrogenchloride / water / 18 h / 10 °C / pH 7.5 View Scheme

saccharin sodium salt (128-44-9) → ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 72 percent / dimethylformamide / 3 h / 100 °C 2: 68 percent / EtONa / ethanol / 1 h / 55 °C 3: 72 percent / aq. NaOH / ethanol / 18 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 3 h / 75 °C 2: hydrogenchloride; sodium / ethanol / 0.5 h / 70 °C / pH 8 - 9 3: hydrogenchloride / water / 18 h / 10 °C / pH 7.5 View Scheme

4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid ethyl ester 1,1-dioxide (24683-21-4) + methyl halide → ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9)

Conditions	Yield
Stage #1: 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid ethyl ester 1,1-dioxide With sodium hydroxide In ethanol; water Stage #2: methyl halide In ethanol; water at 20℃; for 12h;

saccharin (81-07-2) → ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydride / N,N-dimethyl-formamide / 3.5 h / 80 °C / Cooling with ice 2: sodium methylate / dimethyl sulfoxide / 1 h / 30 °C 3: sodium hydroxide / water; ethanol / 24 h / 20 °C View Scheme

5-methyl-2-thiazol-2-amine (7305-71-7) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → meloxicam (71125-38-7)

Conditions	Yield
In o-xylene for 24h; Product distribution / selectivity; Heating / reflux;	95%
In xylene at 139 - 140℃; for 32 - 37h; Product distribution / selectivity; Heating / reflux; Molecular sieve;	92.48%

trifluoromethylsulfonic anhydride (358-23-6) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → C13H12F3NO7S2

Conditions	Yield
With pyridine In dichloromethane at 0℃; for 24.1667h;	92%
With pyridine In dichloromethane

5-methyl-2-thiazol-2-amine (7305-71-7) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) + 1,2-dichloro-benzene (95-50-1) → meloxicam (71125-38-7)

Conditions	Yield
With 1,2-dichloro-ethane	76%

ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide (105743-62-2)

Conditions	Yield
With hydrazine hydrate In ethanol for 2h; Reflux;	68%

4-chloro-aniline (106-47-8) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → N-(4'-chlorophenyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (35511-63-8)

Conditions	Yield
In N,N-dimethyl-formamide at 140 - 150℃; for 12h;	64%

3-trifluoromethylaniline (98-16-8) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 4-hydroxy-2-methyl-N-[3-(trifluoromethyl)phenyl]-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (35511-66-1)

Conditions	Yield
In N,N-dimethyl-formamide at 140 - 150℃; for 12h;	60%

ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) + 2-amino-6-chloropyrazine (33332-28-4) → N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

Conditions	Yield
	60%

ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) + aniline (62-53-3) → 4-hydroxy-2-methyl-N-phenyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (34258-79-2)

Conditions	Yield
In N,N-dimethyl-formamide at 140 - 150℃; for 12h;	57%

4-trifluoromethylphenylamine (455-14-1) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 4-hydroxy-2-methyl-N-[4-(trifluoromethyl)phenyl]-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (35510-91-9)

Conditions	Yield
In N,N-dimethyl-formamide at 140 - 150℃; for 12h;	56%

5-amino-3,4-dimethylisoxazol (19947-75-2) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid (3,4-dimethyl-isoxazol-5-yl)-amide (55620-59-2)

Conditions	Yield
In xylene for 24h; Heating;	55%

5-methylisoxazol-3-ylamine (1072-67-9) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → isoxicam (34552-84-6)

Conditions	Yield
In xylene for 24h; Heating;	49%

5-amino-3-methylisoxazole (14678-02-5) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid (3-methyl-isoxazol-5-yl)-amide (55620-58-1)

Conditions	Yield
In xylene for 24h; Heating;	43%

ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) + 5-aminoisoxazole (14678-05-8) → 4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid isoxazol-5-ylamide (79672-22-3)

Conditions	Yield
In xylene for 24h; Heating;	35%

3-aminoisoxazole (1750-42-1) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid isoxazol-3-ylamide (38938-72-6)

Conditions	Yield
In xylene for 24h; Heating;	32%

2-amino-4,5-dimethyloxazole (45529-92-8) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid 4,5-dimethyl-oxazol-2-ylamide (40713-57-3)

Conditions	Yield
In xylene for 24h; Heating;

3-aminobenzisothiazole (23031-78-9) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid benzo[d]isothiazol-3-ylamide (67345-05-5)

Conditions	Yield
With toluene-4-sulfonic acid In N,N-dimethyl acetamide at 120 - 140℃;

2-amino-4-methyl-thiazole-5-carbonitrile (67322-84-3) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid 5-cyano-4-methyl-thiazol-2-ylamide (67322-76-3)

Conditions	Yield
In xylene Heating;

5-amino-2,3-dimethylindole (16712-58-6) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid 2,3-dimethyl-indol-5-ylamide (40713-58-4)

Conditions	Yield
In xylene for 24h; Heating;

4-phenyl-oxazol-2-ylamine (33119-65-2) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid 4-phenyl-oxazol-2-ylamide (40713-56-2)

Conditions	Yield
In xylene for 24h; Heating;

6-methoxybenzothiazol-2-ylamine (1747-60-0) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid 6-methoxy-benzothiazol-2-ylamide (67322-75-2)

Conditions	Yield
With toluene-4-sulfonic acid In N,N-dimethyl acetamide at 120 - 140℃;

2-(4-aminophenyl)-6-methyl-1,3-benzothiazole (92-36-4) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid 4-(6-methyl-benzothiazol-2-yl)-anilide (40713-51-7)

Conditions	Yield
In xylene for 24h; Heating;

1H-indazol-5-ylamine (19335-11-6) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid 1(2)H-indazol-5-ylamide (40713-55-1)

Conditions	Yield
In xylene for 24h; Heating;

1-amino-5,6,7,8-tetrahydronaphthalene (2217-41-6) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid 5,6,7,8-tetrahydro-naphthalen-4-ylamide (67322-72-9)

Conditions	Yield
With toluene-4-sulfonic acid In N,N-dimethyl acetamide at 120 - 140℃;

chloridazon (1698-60-8) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-ylamide (67322-81-0)

Conditions	Yield
With toluene-4-sulfonic acid In N,N-dimethyl acetamide at 120 - 140℃;

meta-aminobenzoic acid (99-05-8) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 3-(2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[e][1,2]thiazine-3-carbonylamino)-benzoic acid (67322-68-3)

Conditions	Yield
With toluene-4-sulfonic acid In N,N-dimethyl acetamide at 120 - 140℃;

anthranilic acid (118-92-3) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 2-(2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[e][1,2]thiazine-3-carbonylamino)-benzoic acid (67322-67-2)

Conditions	Yield
With toluene-4-sulfonic acid In N,N-dimethyl acetamide at 120 - 140℃;

ethanolamine (141-43-5) + ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (24683-26-9) → 6-methyl-7,7-dioxo-3,4,6,7-tetrahydro-2H-7λ6-benzo[5,6][1,2]thiazino[3,4-f][1,4]oxazepin-5-one (67343-28-6)

Conditions	Yield
With toluene-4-sulfonic acid In xylene Heating;

Upstream product

• 24683-21-4 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid ethyl ester 1,1-dioxide 
• 77-78-1 dimethyl sulfate 
• 81-07-2 saccharin 
• 128-44-9 saccharin sodium salt 
• 24683-20-3 ethyl 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl) acetate 
• 113412-08-1 2-(Ethoxycarbonylmethyl-methyl-sulfamoyl)-benzoic acid ethyl ester 
• 74-88-4 methyl iodide 

Downstream Products

• 67322-68-3 3-(2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ⁶-benzo[e][1,2]thiazine-3-carbonylamino)-benzoic acid 
• 67322-66-1 [4-(2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-benzo[e][1,2]thiazine-3-carbonylamino)-phenyl]-acetic acid 
• 67322-80-9 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ⁶-benzo[e][1,2]thiazine-3-carboxylic acid 3-oxo-2-phenyl-2,3-dihydro-pyridazin-4-ylamide 
• 67322-78-5 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ⁶-benzo[e][1,2]thiazine-3-carboxylic acid 4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-anilide 
• 67322-69-4 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1λ⁶-benzo[e][1,2]thiazine-3-carboxylic acid 2-cyano-anilide 
• 34552-84-6 isoxicam 
• 1421592-17-7 4-hydroxy-2-methyl-N'-[(E)-phenylmethylidene]-2H-1,2-benzothiazine-3-carbohydrazide-1,1-dioxide 
• 1421592-19-9 4-hydroxy-2-methyl-N'-{(E)-[4-(2-propanyl)phenyl]phenylmethylidene}-2H-1,2-benzothiazine-3-carbohydrazide-1,1-dioxide 
• 1421592-20-2 4-hydroxy-2-methyl-N'-{(E)-[4-(dimethylamino) phenyl]phenylmethylidene}-2H-1,2-benzothiazine-3-carbohydrazide-1,1-dioxide 
• 71125-38-7 meloxicam 
• 67-56-1 methanol 
• 892395-41-4 4-hydroxy-2-methyl-N-methyl-(5-methyl-2-thiazolyl)-2H-l,2-benzothiazine-3-carboxamide-1,1-dioxide 

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