35511-15-0

Usage

Uses

Used in Pharmaceutical Industry:
2-METHYL-4-HYDROXY-2H-1,2-BENZOTHIAZINE-3-CARBOXYLIC METHYL ESTER-1,1-DIOXIDE is used as an impurity in the production of Meloxicam (M216100), a nonsteroidal anti-inflammatory drug (NSAID) used for the treatment of various conditions such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. Its presence as an impurity is monitored and controlled to ensure the safety and efficacy of the final pharmaceutical product.

InChI:InChI=1/C11H11NO5S/c1-12-9(11(14)17-2)10(13)7-5-3-4-6-8(7)18(12,15)16/h3-6,13H,1-2H3

Upstream product

• 85727-15-7 Chloro-(3-hydroxy-2-methyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-acetic acid methyl ester 
• 6639-62-9 methyl 3-oxo-2,3-dihydrobenzo[d][1,2]thiazol-2-acetate 1,1-dioxide 
• 77-78-1 dimethyl sulfate 
• 15448-99-4 N-methylsaccharin 
• 96-34-4 methyl chloroacetate 
• 111-84-2 nonane 
• 76508-33-3 methyl 2- benzoate 
• 128-44-9 saccharin sodium salt 
• 81-07-2 saccharin 
• 35511-14-9 methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide 
• 74-88-4 methyl iodide 
• 113412-07-0 methyl 2-(N-methyl-N-(methoxycarbonylmethyl)sulfamoyl)benzoate 
• 124-41-4 sodium methylate 

Downstream Products

• 34042-85-8 sudoxicam 
• 34552-84-6 isoxicam 
• 71125-38-7 meloxicam 
• 914782-21-1 N-(2-carbamoylphenyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide 
• 35511-63-8 N-(4'-chlorophenyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide 
• 35511-70-7 N-(2-chlorophenyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide 
• 1145656-36-5 N-[3,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide 
• 35510-89-5 N-(2,4-dichlorophenyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide 
• 7305-71-7 5-methyl-2-thiazol-2-amine 
• 1310571-05-1 N'-[(1E)-1-(4-aminophenyl)ethylidene]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide 
• 1310571-04-0 4-hydroxy-N'-[(1E)-1-(4-methoxyphenyl)ethylidene]-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide 
• 1310571-03-9 4-hydroxy-N'-[(1E)-1-(3-methoxyphenyl)ethylidene]-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide 
• 1310571-02-8 4-hydroxy-N'-[(1E)-1-(4-hydroxyphenyl)ethylidene]-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide 

Relevant academic research and scientific papers

A facile one-pot synthesis of 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-benzothiazine 1,1-dioxide, a key intermediate in the synthesis of oxicam anti-inflammatory agents

4-Hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-benzothiazine 1,1-dioxide (8) was synthesized by a one-pot procedure, starting from the readily available saccharine. The synthesis involves 4 transformations with an overall yield equivalent to that from the stepwise process.

Synthesis, monoamine oxidase inhibition activity and molecular docking studies of novel 4-hydroxy-N′-[benzylidene or 1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides

Three series of 4-hydroxy-N′-[benzylidene/1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides (9–11)a-l were synthesized and unraveled to be highly potent dual inhibitors of monoamine oxidases (MAO-A and MAO-B). All the examined compounds demonstrated IC50 values in lower micro-molar range for both MAO-A as well as MAO-B. The most active MAO-A inhibitor was 4-hydroxy-N′-(1-phenylethylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxide (9i) with an IC50 value of 0.11 ± 0.005 μM, whereas, methyl 4-hydroxy-2H-benzo[e][1,2]thiazine-3-carboxylate 1,1-dioxide (3) was the most active MAO-B inhibitor with an IC50 value of 0.21 ± 0.01 μM. Enzyme kinetics studies revealed that the most potent compounds inhibited both MAO enzymes (A & B) in a competitive fashion. Molecular docking studies were also performed to obtain an intuitive picture of inhibition potential for potent inhibitors. The high potency of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability.

Stereopure Functionalized Benzosultams via Ruthenium(II)-Catalyzed Dynamic Kinetic Resolution-Asymmetric Transfer Hydrogenation

A highly diastereo- and enantioselective Ru(II)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation (DKR-ATH) of α-(N-sulfonylimino) and α-(N-sulfonylamino) aryl ketones to 4-hydroxy-benzo-δ- and 3-(α-hydroxy-arylmethyl)-benzo-γ-sultams is presented. By employing enantiopure ansa-Ru[PipSO2DPEN(CH2)4Ph] cat. II with S/C = 10 000 in a HCO2H/Et3N binary mix, up to >99.9% ee and dr >99:1 are obtained with 100% conversion under mild conditions. Application to access the stereopure "structurally simplified TsDPEN" N,N-ligand syn-3-(α-aminobenzyl)-benzo-γ-sultam ("syn-ULTAM") and its structural isomer trans-4-amino-3-phenyl-benzo-δ-sultam (trans-4) is demonstrated.

Microwave assisted synthesis and structure-activity relationship of 4-hydroxy-N′-[1-phenylethylidene]-2H/2-methyl-1,2-benzothiazine-3- carbohydrazide 1,1-dioxides as anti-microbial agents

A series of 4-hydroxy-N′-[1-phenylethylidene]-2H/2-methyl, 1,2-benzothiazine-3-carbohydrazide 1,1-dioxides was synthesized from commercially available sodium saccharin. Base catalyzed ring expansion of methyl (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)acetate followed by ultrasound mediated hydrazinolysis and subsequent reaction with 1-phenylethanones under the influence of microwaves yielded the title compounds. Besides, microwave assisted synthesis of 1,4-dihydropyrazolo[4,3-c][1,2]benzothiazin-3-ol 5,5-dioxide and 4-methyl-1,4-dihydropyrazolo[4,3-c][1,2]benzothiazin-3-ol 5,5-dioxide is also discussed. Most of the synthesized compounds were found to possess moderate to significant anti-microbial (anti-bacterial and anti-fungal) activities. It is found that compounds with greater lipophilicity (N-methyl analogues) possessed higher anti-bacterial activities.

Process for the preparation of crystalline form-1 of 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

The present invention is related to an improved process for preparing crystalline Form I of meloxicam, which produces the Form I in high yield.

Synthesis of potential biologically active 1,2-benzothiazin-3-yl- quinazolin-4(3H)-ones

A series of potential biologically active 2-(4-hydroxy-1,1-dioxido-2H-1,2- benzothiazin-3-yl)quinazolin-4(3H)-ones was synthesized in a straight forward manner by condensation of respective 4-hydroxy-1,2-benzothiazine-1,1-dioxides with anthranilamide followed by simple and high throughput cyclization of N-[2-(aminocarbonyl) phenyl]-4-hydroxy-1,2-benzothiazine-3-carboxamide-1,1- dioxides. All the synthesized compounds were subjected to preliminary evaluation for their biological activity against Gram positive and Gram negative bacteria. Some of the assayed compounds showed marked activity against Bacillus subtilis.

New quaternary ammonium oxicam derivatives targeted toward cartilage: Synthesis, pharmacokinetic studies, and antiinflammatory potency

Analogues of nonsteroidal antiinflammatory drugs (NSAIDs) oxicams, in which the active group was linked to a quaternary ammonium function [(4- hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide-3-carboxamido)2- methylpyridinium iodide or piroxicam-N+ and [3-(4-hydroxy-2-methyl-2H-1,2- benzothiazine-1,1-dioxide-3-carboxamido)propyl]trimethylammonium iodide or propoxicam-N+] were synthesized. Compounds were labeled with tritium for piroxicam-N+ and carbon-14 for propoxicam-N+. Pharmacokinetic studies conducted on rats showed that these molecules were able to highly concentrate in joint cartilages but their bioavailability by the oral way was low. Only propoxicam-N+ exhibited a sufficient water solubility to be administered intravenously. This molecule was able to restore proteoglycans biosynthesis in cultured articular chondrocytes treated with Interleukin-1β with an efficiency identical to that of indomethacin. These results suggest that the functionalization of oxicam derivatives by a quaternary ammonium group greatly increases their affinity toward articular cartilage without eliminating their pharmacological activity. New drugs synthesized according to this scheme could be useful to obtain a significant decrease of the efficient administered dose and consequently an attenuation of adverse effects such as digestive toxicity.

Effect of structural modification of enol-carboxamide-type nonsteroidal antiinflammatory drugs on COX-2/COX-1 selectivity

Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6- and 7-positions of the 4-oxo-1,2-benzothiazine-3- carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothiazines, benzothienothiazines, naphthothiazines, and 1,3- and 1,4- dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.

A facile one-pot synthesis of 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-benzothiazine 1,1-dioxide, a key intermediate in the synthesis of oxicam anti-inflammatory agents

4-Hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-benzothiazine 1,1-dioxide (8) was synthesized by a one-pot procedure, starting from the readily available saccharine. The synthesis involves 4 transformations with an overall yield equivalent to that from the stepwise process.

TITANIUM-MEDIATED DIECKMANN CONDENSATION

The Dieckmann condensation of alkyl 2-(N-methyl-N-(alkoxycarbonylmethyl)sulfamoyl)-benzoates Ia and Ib with titanium tetrachloride-tert-amine or butyltitanium ate complex III affords alkyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxides IIa and IIb which are the piroxicam intermediates.