WO2001040208A2 - Process for synthesis of 4-hydroxy-2h-1,2-benzothiazine-3-carboxamides - Google Patents
Process for synthesis of 4-hydroxy-2h-1,2-benzothiazine-3-carboxamides Download PDFInfo
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- WO2001040208A2 WO2001040208A2 PCT/YU2000/000009 YU0000009W WO0140208A2 WO 2001040208 A2 WO2001040208 A2 WO 2001040208A2 YU 0000009 W YU0000009 W YU 0000009W WO 0140208 A2 WO0140208 A2 WO 0140208A2
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- methyl
- benzothiazine
- hydroxy
- pyridyl
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- 0 C*N**N(*(C)(c1ccccc11)O)C1=N Chemical compound C*N**N(*(C)(c1ccccc11)O)C1=N 0.000 description 2
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
Definitions
- R denotes one of the following radicals: alkyl group (C -C 6 ), cycloalkyl, benzyl, phenyl, pyridyl, methyl-pyridyl, pyrimidyl, thiazole, isothiazole.
- the special interest as non-steroidal antirheumatics characterized by anti- inflammatory and analgesic properties, belongs to: piroxkai ⁇ m (4-hydroxy-2-methyl-N-(2- pyridinyl)-2H-l ,2-benzothiazine-3-carboxamid-l , 1 -dioxide), isoxka ⁇ m (4-hydroxy-2- methyl-N-(5-methyl-3-isoxazolyl)-2H-l ,2-benzothiazine-3-carboxamide-l , 1 -dioxide) and s ⁇ n l ⁇ xka ⁇ ___ (4-hydroxy-2-methyl-N-2-thiazolyl-2H-l, 2-benzothiazine-3-carboxamide-l, 1 - dioxide).
- SocJapam, 1956,76, 1058-63) were the first to apply the Gabriel-Colman rearrangement to saccharin derivatives to obtain various 4-hydroxy-2H- 1 ,2-benzothiazine- 1 , 1 -dioxides.
- Subject of the invention of Spanish patent ES 495,727, for the individual characteristics has the use of ethylester and dimethyl formamide with sodium ethoxide for opening of the cycle at very low temperatures. After that, methylation and final condensation in the dark are carried out, using nitrogen atmosphere in the phase of condensation.
- Suggested invention is related to the process for obtaining the compound 4 - hydroxy - 2 - methyl - 2H - 1,2 - benzothiazine -3 -carboxamide- 1,1 -dioxide, of general formula I,
- R is: alkyl group (Cj-C 6 ), cycloalkyl, benzyl, phenyl, pyridyl, methyl-pyridyl, pyrimidyl, thiazole or isothiazole.
- the synthesis of the compound of formula VI is carried out in dimethyl formamide at temperature between 90°C and 150°C for 2 to 7 hours.
- Reaction of rearrangement of the compound of fo ⁇ nula VI for obtaining the compound of formula VII is carried out at low and controlled temperatures in range of 30- 100°C, while optimal duration of the reaction is from 10 minutes to 4 hours.
- N-mettl ⁇ ylatiom of the compound of formula VII is carried out with dimethyl sulphate in acetonic medium in presence of an alkaline base, in contrast to the process given in the invention EP ⁇ 284 514, where the reaction is carried out in alcoholic medium, using isopropanol. The reaction is carried out during 30 minutes to 3 hours, at temperature between 20-65°C, and white compound of formula VIII is obtained in good yield.
- Phase off com emsatioi.. of the compound of formula VIII with an amine is carried out at temperature of reflux in an inert reaction medium during 10 to 55 hours, and final product of formula I is obtained.
- Concernig amines, in the reaction aromatic or heterocyclic amines, of general formula NH 2 -R, wherein R denotes: 2-pyridyl, alkyl substituted 2-pyridyl, 2-thiazole, 2-thiazole substituted with one or two alkyl groups, while each alkyl has from 1 to 4 carbon atoms or 5-methyl-3- isoxazolyl.
- the compound of formula II is obtained.
- solvents can be used: benzene, toluene, xylene, ethylbenzene, tetrahydrofuran, dimethylformamide, dimethylsulphoxide and acetonitrile.
- a characteristic of present invention is that the phase of condensation is carried out with a catalyst, which provides obtaining highly pure final product, without any problem with colouration, achieving good yield; as well as with use of an adsorbent, which enables performing of reaction of synthesis at a solvent boiling point (at total reflux).
- Present invention also simplifies fte ⁇ n iiisitr ⁇ al process for obtaining piroxicam, using the catalyst, and such otimal ratio of reactants, which avoids azeotropic distillation, and synthesis itself is conducted at the boiling point of the solvent o-xylene (140-144°C).
- Conducting synthesis at temperature of reflux provides usage of up to four times less quantity of solvent (o-xylene) which is advantage of this invention in the process of industrial production, in comparison to known processes, patented so far, which use exclusively azeotropic distillation.
- the advantage of our invention is that it also uses absorbent (silica gel, calcium chloride, potassium carbonate) which disables formation of azeotrope (o-xylene-ethanol) during synthesis, which provides requested high and constant temperature of reaction (140-144°), aiming at obtaining final product in good yield, and with appropriate pharmacopoeic quality.
- absorbent sica gel, calcium chloride, potassium carbonate
- reaction of condensation is carried out with a catalyst, and with an adsorbent
- the mixture is heated for 10 hours with an azeotropic distillation. During distillation, fresh o-xylene in quantity of about 170 cm is added. After the synthesis is completed, carry on with the distillation to the volume of the reaction mixture of about 165 cm , and subsequently poure it out and cool it to 0-5 C. Formed crystals are filtered, washed with hexane and dried, 6,7 g of 4-hydroxy-2-methyl- N-(2- pyridinyl)-2H-l ,2-benzothiazine-3-carboxamide-l , 1 -dioxide (II)- a crystalline white solid, melting point 197-201 C, being obtained.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Suggested invention is related to the field of organic chemistry technology, specifically to the process for preparation of the compound 4-hydroxy - 2 - methyl - 2 H - 1 , 2 - benzothiazine - 3 - carboxamide - 1 , 1 -dioxide, of general formula (I), wherein R denotes one of the following radicals: alkyl group (C2-C6), cycloalkyl, benzyl, phenyl, pyridyl, methyl-pyridyl, pyrimidyl, thiazole, isothiazole. Concerning clinical practice, the special interest, as non-steroidal antirheumatics characterized by anti-inflammatory and analgesic properties, belongs to: piroxicam (4-hydroxy-2-methyl-N-(2-pyridinyl-2H-1,2-benzothiazine-3-carboxamid-1,1-dioxide)), isoxicam (4-hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide)) and sudoxicam (4-hydroxy-2-methyl-N-2-thiazolyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide). Individual characteristics of the present invention are: the use of ethylester and dimethyl formamide with sodium ethoxide for opening of the cycle and for work at low temperatures in the mentioned phase; afterwards, methylation and final condensation with an amine of general formula NH2-Retard tablete, wherein R denotes: 2-pyridyl, alkyl substituted 2-pyridyl, 2-thiazole, 2-thiazole substituted with one or two alkyl groups, while each alkyl has from 1 to 4 carbon atoms or 5-methyl-3- isoxazolyl, using specific catalysts and adsorbents in an inert solvent and inert atmosphere.
Description
PROCESS FOil SYNTHESIS 4-HIBMOX¥-2H-lf2- EENZOT ΗMZINE-3-CAEBϋXAMIDES
Suggested patent is related to the field of organic chemistry technology, specifically to the process for preparation of the compound 4-hydroxy - 2 - methyl - 2 H - 1 , 2 - benzothiazine - 3 - carboxamide - 1 , 1 -dioxide, of general formula (I),
Technical oMem
There was a need to find a new, technically improved process for obtaining the compound of general formula 4-hydroxy - 2 - methyl - 2 H - 1 , 2 - benzothiazine - 3 - carboxamide - 1 , 1 -dioxide, primarily piroxicam, isoxicam and sudoxicam, in good yield and high purity, which enables their usage in pharmaceutical industry, where they are used for treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthrosis and other inflammatory rheumatic and non-rheumatic processes, including onsets and traumatologic lesias.
Abe et al, (X PHaarm. SocJapam, 1956,76, 1058-63) were the first to apply the Gabriel-Colman rearrangement to saccharin derivatives to obtain various 4-hydroxy-2H- 1 ,2-benzothiazine- 1 , 1 -dioxides.
Similarly, Zinnes (X Org. Cfoeim; 1965, 30, 2241) extended these studies in order to obtain new derivatives.
Obtaining certain 4-hydroxy-2H-l,2-benzothiazine-3-carboxamides by means of regrouping of specific saccharin derivatives is already known. In such way, Lombardino in JJ. Medh dnenm. 14, 1171-1175 (1975) describes the use oi saccharin methyl-acetic ester for obtaining 3,4-dihydro-4-oxy-l,2-benzothiazine-3-carboxylate-l, 1-dioxydimethylester using dimethyl sulphoxide and sodium methoxide and pointing out that dimethyl formamide gives bad yields. Later on, the obtained product is methylated with methyl iodide and 4- hydroxy-2-methyl-2H-l,2-benzothiazine-3-carboxylate methylester- 1,1 -dioxide. In MedL Onemm. 16, 493-496 (1973), Lombardino points out that he obtained 4-hydroxy-2-methyl-N- (2-pyridyl)-2H-l,2-benzothiazine-3-carboxylate-l,l -dioxide starting from 4-hydroxy-2- methyl-2H-l,2-benzothiazine-3-carboxylate methylester, 1,1 -dioxide, but without any explanation about the method, pointing out the yield of 45%.
In American patent US 3,591,584, analogous process for obtaining similar compounds is given, showing the need for presence of a catalysts in the last phase of synthesis, due to the low yield.
Subject of the invention of Spanish patent ES 495,727, for the individual characteristics has the use of ethylester and dimethyl formamide with sodium ethoxide for opening of the cycle at very low temperatures. After that, methylation and final condensation in the dark are carried out, using nitrogen atmosphere in the phase of condensation.
In JP 57-7<M88, different amino pyridine derivatives are used for obtaining of piroxicam, and conditions of condensation are explained. Ratio between amine and ester quantity is 1,1-1,3, temperature of reaction is in interval 100-145 C, reaction lasts for 5-30 hours.
Lombardino in ILL §. 4,289,879 emphasized difficulties during obtaining piroxicam with acceptable colour, due to the formation of strongly coloured by products, difficult to
be removed by crystallization. This synthesis has the serious industrial disadvantage of raising the cost of the product significantly, due to the use of more esoteric, and less readily available intermediates.
U.S. 4,1(D)(D),347 describes obtaining 4-hydroxy-2-methyl-2H-l,2-benzothiazine-3- carboxilic acid acid chloride and its condensation with 2- amino pyridine.
Description of the solution of technical problem with feasibility examples
Suggested invention is related to the process for obtaining the compound 4 - hydroxy - 2 - methyl - 2H - 1,2 - benzothiazine -3 -carboxamide- 1,1 -dioxide, of general formula I,
Synthesis starts with catalytic esterification of chloroacetic acid (formula III),
Scheme of technological process of piroxicam synthesis is given in supplement 1.
wich further reacts with sodium saccharinate (formula V)
in an inert atmosphere gives 4-hydroxy~2~methyl-N~(2 yridinyl)~2H-l,2-benzothi zine- carboxamide-l,l-dioxMe, 1. e. piroxicam (formula II).
For the synthesis of the c ompound of formula IV, the following optimal reactants ratio in the reaction of esterifi cation is needed: 1 mol of carbonic acid, 5 mol of corresponding absolute alcohol, 0,2 mol of concentrated sulphuric acid, and the reaction is carried out for 2 - 9 hours, at temperature of reflux.
The synthesis of the compound of formula VI is carried out in dimethyl formamide at temperature between 90°C and 150°C for 2 to 7 hours.
Reaction of rearrangement of the compound of foπnula VI for obtaining the compound of formula VII is carried out at low and controlled temperatures in range of 30- 100°C, while optimal duration of the reaction is from 10 minutes to 4 hours.
The advantage of our invention is that N-mettlιylatiom of the compound of formula VII is carried out with dimethyl sulphate in acetonic medium in presence of an alkaline base, in contrast to the process given in the invention EP © 284 514, where the reaction is carried out in alcoholic medium, using isopropanol. The reaction is carried out during 30 minutes to 3 hours, at temperature between 20-65°C, and white compound of formula VIII is obtained in good yield.
Phase off com emsatioi.. of the compound of formula VIII with an amine is carried out at temperature of reflux in an inert reaction medium during 10 to 55 hours, and final product of formula I is obtained. Concernig amines, in the reaction, aromatic or heterocyclic amines, of general formula NH2-R, wherein R denotes: 2-pyridyl, alkyl substituted 2-pyridyl, 2-thiazole, 2-thiazole substituted with one or two alkyl groups, while each alkyl has from 1 to 4 carbon atoms or 5-methyl-3- isoxazolyl.
Primarily using 2-amino pyridine, the compound of formula II is obtained. As an inert reaction medium, following solvents can be used: benzene, toluene, xylene, ethylbenzene, tetrahydrofuran, dimethylformamide, dimethylsulphoxide and acetonitrile.
A characteristic of present invention is that the phase of condensation is carried out with a catalyst, which provides obtaining highly pure final product, without any problem with colouration, achieving good yield; as well as with use of an adsorbent, which enables performing of reaction of synthesis at a solvent boiling point (at total reflux).
For synthesis of piroxicam, absolutely dry conditions for performing of reaction of condensation are provided, which is attained by an inert atmosphere (reaction is carried out under a nitrogen atmosphere) and use of dry reactants. For example, while using 2-amino pyridine of formula IX, which is highly hygroscopic substance, an unwanted hydrolysis
may occure during reaction, which can reduce the yield. Also, if o-xylene is used, it is necessary to be dry, because presence of water or alcohol significantly reduces o-xylene boiling point, and it is necessary for the reaction of condensation to be conducted at temperature between 140 and 144 C.
In order to obtain the product of high pharmacopoeic purity in a good yield and to avoid formation of by products (resinous substances) during reaction of synthesis of piroxicam, following catalysts are used: _5 jC 2Hϊ 2O. BF3, NH4CI.
Present invention also simplifies fte ήπn iiisitrήal process for obtaining piroxicam, using the catalyst, and such otimal ratio of reactants, which avoids azeotropic distillation, and synthesis itself is conducted at the boiling point of the solvent o-xylene (140-144°C). Conducting synthesis at temperature of reflux provides usage of up to four times less quantity of solvent (o-xylene) which is advantage of this invention in the process of industrial production, in comparison to known processes, patented so far, which use exclusively azeotropic distillation. The advantage of our invention is that it also uses absorbent (silica gel, calcium chloride, potassium carbonate) which disables formation of azeotrope (o-xylene-ethanol) during synthesis, which provides requested high and constant temperature of reaction (140-144°), aiming at obtaining final product in good yield, and with appropriate pharmacopoeic quality.
Advantages of suggested process in reaction of N-meftylatiom, in comparison to the processes known so far, are as follows:
* reaction is carried out in acetonic medium,
* significantly reduced duration of the reaction of synthesis
* the product is obtained in good yield.
Advantages of suggested process in punas® off co__ι l®__ιsaltήo_ι, in comparison to the processes known so far, are as follows:
* absolutely dry conditions for the course of reaction,
* reaction is carried out in an inert atmosphere,
* reaction of condensation is conducted with a catalyst,
* disabled formation of by products,
* obtained product has high pharmacopoeic purity,
* the product is obtained in a good yield.
Advantages of suggested industrial process in reaction of condensation, in comparison to the processes known so far, are as follows:
* reaction of condensation is carried out with a catalyst, and with an adsorbent,
* reaction is carried out at temperature of reflux,
* azeotropic distillation is avoided,
* technical simplicity of execution of the process and apparatus,
* maximally reduced quantity of the solvent used,
* outstanding economy of the process,
* the product is obtained in a good yield.
In order to facilitate understanding of the process which is the subject of the present invention, examples of the different phases of this process are given, but they should not be regarded as limiting.
i.
Obtaining chlor acetic acid ethylester (IV)
To 282 cm3 of absolute ethanol, add 17,9 cm3 of concentrated sulphuric acid and 384,6 g of chloracetic acid (III). Reaction mixture is under a reflux for 5 h and subsequently, it is poured into 800 cm of ice water. Organic phase is separated, and aqueous phase is washed with chloroform. Combined phases are washed with solution of sodium bicarbonate, dried over sodium sulphate and solvent is evaporated, 458,8 g (yield 92%) of chloracetic acid ethylester, d4 20=l,1498, nD 20=l,4227, boiling point 144-146°C being obtained.
'e l
Obtaining 3-oxy-l,2-benzothiazole-2-acetate ethylester (VI)
100 g of chloracetic acid ethylester (IV) is added to a solution of 166,5 g of sodium saccharinate (V) in 372 cm of dimethyl formamide. The reaction mixture is under the reflux for 4 hours, and subsequently, it is poured into 470 cm3 of ice water. After 2 hours, the precipitate is filtered, washed with water and dried, 175,6 g (yield 80%) of 3-oxy-l, 2-
benzothiazole-2 -acetate ethylester - a crystalline white solid, melting point 104-106°C, being obtained.
Obtaining ethyl-4-hvdroxy-2H-l ,2-benzothiazine-3-carboxylate-l , 1 -dioxide (VII)
A prepared solution of 58 g of 3-oxy-l ,2-benzothiazole-2-acetate ethylester (VI) in 336 cm3 of dimethyl formamide, heated to 50°C is added to 215 cm3 of 21% sodium ethylate. The mixture is heated for about 30 minutes at 55°C when an orange precipitate gradually forms. The mixture is poured into 960 cm3 of 3M hydrochloric acid with stirring at temperature lower than 5°C. After half an hour of stirring, the precipitate is separated by filtration, washed with cold water and dried, 43,5 g (yield 75%) of ethyl-4-hydroxy-2H-l ,2- benzothiazine-3-carboxylate-l,l -dioxide - a white solid, melting point 136-139°C, being obtained.
Je 4.
Synthesis of ethyl-4-hydroxy-2-methyl-2H-l ,2-benzothiazine-3-carboxylate-l ', 1- dioxide (VIII)
15 g of ethyl-4-hydroxy-2H-l,2-benzothiazine-3-carboxylate-l,l -dioxide (VII) is dissolved in 122,8 cm of acetone, and subsequently 2,24 g of sodium xydroxide dissolved in 115 cm of water is added, and then, 16 cm of dimethyl sulphate, is added as well. The reaction mixture is maintained with stirring for 2 hours, at 50°C. After cooling to 0-5°C, formed crystals are filtered and washed with cold water, 14,04 g (yield 89%) of ethyl-4- hydroxy-2-methyl-2H-l,2-benzothiazine-3-carboxylate- 1,1 -dioxide - a white solid, melting point 140-142°C, being obtained.
r*? 5.
Synthesis of piroxicam (II), i. e. 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H~l,2- benzothiazine-3 -carboxamide- 1 , 1 -dioxide
To a reaction vessel, containing 226 cm3 of dry o-xylene, add 9,3 g of ethyl-4- hydroxy-2-methyl-2H-l,2-benzotkiazine-3-carboxylate-l,l -dioxide (VIII) and 1,8 g of NHUCI, open a nitrogen inlet, and turn on the heating. Add 3,8 g of 2-amino pyridine (IX) and close the nitrogen inlet. The mixture is heated for 10 hours with an azeotropic distillation. During distillation, fresh o-xylene in quantity of about 170 cm is added. After the synthesis is completed, carry on with the distillation to the volume of the reaction mixture of about 165 cm , and subsequently poure it out and cool it to 0-5 C. Formed crystals are filtered, washed with hexane and dried, 6,7 g of 4-hydroxy-2-methyl- N-(2- pyridinyl)-2H-l ,2-benzothiazine-3-carboxamide-l , 1 -dioxide (II)- a crystalline white solid, melting point 197-201 C, being obtained.
Synthesis of piroxicam (II), i. e. 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-l,2- benzothiazine-3 -carboxamide- 1 , 1 -dioxide
To a reaction vessel, containing 210 cm3 of dry o-xylene, add 10 g of ethyl-4- hydroxy-2-methyl-2H-l,2-benzothiazine-3-carboxylate-l,l -dioxide (VIII), 3,55 g of NHjCl and heat it under an atmosphere of nitrogen and in presence of 0,8 g of CaCl2, at the entering of the condenser. Afterwords, add 4,94 g of 2-amino pyridine (IX) and close the nitrogen inlet. After 12 huors of refluxing, the reaction mixture is poured out and cooled to 0-5°C. Formed crystals are filtered and washed with cold methanol, 7,02 g (yield 60%) of 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-l ,2-benzothiazine-3-carboxamide-l , 1 -dioxide)- a crystalline white solid, melting point 197-201°C, being obtained.
Claims
1. A process for obtaining of the compound 4-hydroxy-2-methyl-2H-l,2-benzothiazine-3- carboxamide- 1,1 -dioxide, of general formula I,
while phase of condensation is carried out in an inert atmosphere and in an inert solvent: benzene, toluene, xylene, ethylbenzene, tetrahydrofuran, dimethylformamide, dimethyl sulphoxide and acetonitrile with use of specific catalysts, according to two possible proceedings, according to the first one, the reaction is carried out with azeotropic distillation, or, according to the industrial proceeding, with use of specific absorbent to prevent formation of azeotropes during synthesis, providing required high and constant reaction temperature, at temperature of reflux, giving compound of general formula (I)
2. A process according to the patent claim 1, denoted by the fact that, in the reaction of N- methylation, acetone is used as a reaction medium.
3. A process according to the patent claim 1, denoted by the fact that, the temperature of the reaction of N-methylation is 20-65°C.
4. A process according to the patent claim 1, denoted by the fact that, the reaction of N- methylation is carried out for 30 minutes to 3 hours.
5. A process according to the patent claim 1, denoted by the fact that, the temperature of reaction in the phase of condensation for obtaining of the compound of formula I, when R has the meaning of 2-pyridyl, the boiling point of the solvent is 140-144°C.
6. A process according to the patent claim 1, denoted by the fact that, in the phase of condensation for obtaining of the compound of formula I, when R has the meaning of 2-pyridyl, specific catalysts are used: _5F5fC2H5, O, BF3, NH4CI.
7. A process according to the patent claim 1, denoted by the fact that, in the phase of condensation for obtaining of the compound of formula I, when R has the meaning of 2-pyridyl, specific adsorbents are used: silica gel, calcium chloride, potassium carbonate.
8. A process according to the patent claim 1, denoted by the fact that, in the phase of condensation for obtaining of the compound of formula I, when R has the meaning of 2-pyridyl, a time of reaction fluctuates between 10 and 55 hours.
9. A process for obtaining of the compound 4-hydroxy-2-methyl-2H-l,2-benzothiazine-3- carboxamide- 1,1 -dioxide, of general formula I, obtained according to the process claimed in patent claims from 1 to 8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU36333/00A AU3633300A (en) | 1999-12-06 | 2000-04-06 | Process for synthesis 4-hydroxy-2h-1,2-benzothiazine-3-carboxamides |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YUP-634/99A RS49867B (en) | 1999-12-06 | 1999-12-06 | Process of synthessis 4-hidroxy -1 ,2-benzothiazine-3carboxamides |
| YUP-634/99 | 1999-12-06 |
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| Publication Number | Publication Date |
|---|---|
| WO2001040208A2 true WO2001040208A2 (en) | 2001-06-08 |
| WO2001040208A3 WO2001040208A3 (en) | 2001-11-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/YU2000/000009 WO2001040208A2 (en) | 1999-12-06 | 2000-04-06 | Process for synthesis of 4-hydroxy-2h-1,2-benzothiazine-3-carboxamides |
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| Country | Link |
|---|---|
| AU (1) | AU3633300A (en) |
| RS (1) | RS49867B (en) |
| WO (1) | WO2001040208A2 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3957772A (en) * | 1975-05-21 | 1976-05-18 | Warner-Lambert Company | Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2h-1,2-benzothiazine 1,1-dioxide |
| DE3212485A1 (en) * | 1982-04-03 | 1983-10-13 | Gödecke AG, 1000 Berlin | METHOD FOR PRODUCING 4-HYDROXY-3- (HETEROCYCLOCARBAMOYL) -2H-1,2-BENZOTHIAZINE-1,1-DIOXIDES |
| EP0146102A2 (en) * | 1983-12-16 | 1985-06-26 | SPA SOCIETA' PRODOTTI ANTIBIOTICI S.p.A. | Process for preparing benzothiazine compounds |
| EP0284514A1 (en) * | 1987-03-27 | 1988-09-28 | Esteve Quimica, S.A. | Process for obtaining 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide |
-
1999
- 1999-12-06 RS YUP-634/99A patent/RS49867B/en unknown
-
2000
- 2000-04-06 AU AU36333/00A patent/AU3633300A/en not_active Abandoned
- 2000-04-06 WO PCT/YU2000/000009 patent/WO2001040208A2/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3957772A (en) * | 1975-05-21 | 1976-05-18 | Warner-Lambert Company | Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2h-1,2-benzothiazine 1,1-dioxide |
| DE3212485A1 (en) * | 1982-04-03 | 1983-10-13 | Gödecke AG, 1000 Berlin | METHOD FOR PRODUCING 4-HYDROXY-3- (HETEROCYCLOCARBAMOYL) -2H-1,2-BENZOTHIAZINE-1,1-DIOXIDES |
| EP0146102A2 (en) * | 1983-12-16 | 1985-06-26 | SPA SOCIETA' PRODOTTI ANTIBIOTICI S.p.A. | Process for preparing benzothiazine compounds |
| EP0284514A1 (en) * | 1987-03-27 | 1988-09-28 | Esteve Quimica, S.A. | Process for obtaining 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide |
Non-Patent Citations (4)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 130, no. 13, 29 March 1999 (1999-03-29) Columbus, Ohio, US; abstract no. 162937r, page 46; XP002148246 & Y. MA ET AL.: "Synthesis of cinnoxicamas antiinflammatory and antirheumatic drug" GUANGDONG YAOXUEYUAN XUEBAO, vol. 14, no. 3, 1998, pages 164-5, * |
| H. ZINNES: JOURNAL OF ORGANIC CHEMISTRY, vol. 30, 1965, pages 2241-2246, XP000938873 cited in the application * |
| J. G. LOMBARDINO ET AL.: JOURNAL OF MEDICINAL CHEMISTRY, vol. 14, no. 12, 1971, pages 1171-1175, XP000938874 cited in the application * |
| K. ABE ET AL.: J. PHARM. SOC. JAPAN, vol. 76, 1956, pages 1058-63, XP000925889 cited in the application * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3633300A (en) | 2001-06-12 |
| YU63499A (en) | 2002-06-19 |
| RS49867B (en) | 2008-08-07 |
| WO2001040208A3 (en) | 2001-11-29 |
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