• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    1. METHOD OF OBTAINING 4-OXI2-METHYL-N-2-PIRICYL-2H-1, 2-BENZTHIAZIN-3-CARBOXAMID-1, 1-DIOXIDE of the formula OH o
    公开号:SU1122224A3
    申请号:SU813338298
    申请日:1981-09-28
    公开日:1984-10-30
    发明作者:Ломбардино Джордж
    申请人:Пфайзер Инк.(Фирма)；
    IPC主号:
    专利说明:

    The invention relates to an improved process for the preparation of 4-hydroxy 2-methyl-N-2-pyridyl-2H-1,2-benzthiazine-3-carboxamide-1, 1-dioxide of formula (1) on rf -cL (b 0 which represents It is an anti-inflammatory agent - piroxicam. There is a known method for preparing a compound of formula (1), which consists in the fact that 4-hydroxy-2-methyl-2H-1, 2-benzthiazine-1,1-dioxide-3-carboxylic acid methyl ester formulas are reacted with 2-aminopyridine in an inert aromatic solvent at the boiling point of the reaction mass, after the end of the The solvent is distilled off and the target product is isolated by repeated recrystallization. 1 The disadvantage of the known method of producing piroxicam is the formation of various amounts of intensely colored by-product which is removed only by repeated recrystallization due to loss of the main amount of the desired product. By-product gives an unacceptable intense yellow coloring the bulk of the target product even if it is contained in very small amounts (for example, 0.5 -one%). This by-product corresponds to the formula. This compound is formed as a by-product during the implementation of the known method, and is not a consequence of contamination of the original compound. Since only purified material is used as a drug, this by-product is removed by repeated recrystallization, as a result of which more time, labor and raw materials are required to purify the target product. The purpose of the invention is to increase the purity of the target product. This goal is achieved by the fact that according to the process for the preparation of the compound of formula (1), the 2-methoxyethyl ester of 4-hydroxy-2-methyl-2H-1,2-benz thiazine-3-carboxylic acid -1,1 dioxide of the formula is reacted with 2- aminopyridine in an inert aromatic solvent at the boiling point of the reaction mixture, with simultaneous distillation of the side-produced 2-methoxyethanol with the solvent, and the desired product is isolated. Xylene is usually used as the aromatic solvent. A distinctive feature of the invention is that the 2-methoxyethyl ester is taken as the acid ester of Formula A, and the 2-methoxyethanol formed by-side is removed by simultaneous distillation with a solvent. Example 1. 4-Oxy-2-methyl-2-pIridyl-2H-1, 2-benzothiazine-3-carboxamide-1, 1-dioxide (piroxicam). 9.26 g (0.098 mol) of 2-methoxyethyl-4-OXY-2H-1, 2-benzthiazine-Zcarboxylate-1, 1-dioxide and 9.26 g (0.098 mol) of 2-aminopyridine are added to 500 ml of xylene in A 1-liter flask equipped with a separatory funnel and reflux condenser, as well as a distributive head with adjustable selection. The stirred reaction mixture is heated to boiling point and xylene is distilled off at a rate of 100 ml / h, maintaining the volume of boiling mass by continuously adding fresh portions of xylene. After 6 hours, the temperature of the head, which is relatively constant, rises to 142 ° C, after which the boiling intensity is lowered. The reaction mixture is then cooled in an ice bath and the precipitated precipitate is removed by filtration and used to transfer the suspension and washing the hexane and dried at 45 ° C in vacuum, resulting in 28.5 g (96% yield) of piroxicam with a temperature of mp 167174 ° C. This product is further investigated by high resolution liquid chromatographic processing using a 60:40 ratio of a 0.1 M solution of secondary sodium phosphate and an aqueous solution (the pH of which is adjusted to 7.5 by adding citric acid) and methanol on a Micro-Bond product. pak (a trademark of the Waters Associates formula for packaging material of a standard column for high resolution liquid chromatographic processing consisting of glass microspheres coated with a siloxyl-substituted vuokisi silicon). Under the conditions created, the retention time for piroxicam is approximately 6 minutes, while the retention time for the potential contaminant O-methoxyethylpyroxicam is 16.5 minutes. No potential contaminant was found in the product of this example. In order to recrystallize, 25 g of the indicated piroxicam is extracted with 190 ml of dimethylacetamide at 70-75 ° C, treated with 1.26 g of activated carbon at 75-80 ° C and the solution is filtered through diatomaceous earth with 55 ml of warm dimethylacetamide used for transfer and washing. A mixture of 173 ml and 173 ml of water is cooled to. The activated carbon-treated filtrate is added to the cooled mixture of water and acetone for 10-15 minutes and the crystals formed are granulated at 0-5 ° C for 5 minutes. The recrystallized piroxicam was filtered by filtration with 154 ml of cold methanol used to transfer and wash the precipitate, resulting in the preparation of 8.75 g of product (75% yield). The IR spectrogram (petrolatum) of this product is identical to the IR spectrogram of authentic piroxicam. The advantage of the proposed method is that it allows to increase the purity of the target product. According to this method, an uncolored target product is obtained which is free from impurities, which makes it possible to eliminate the stage of its repeated recrystallization by a known method, leading to a loss of time, labor and raw materials.
    权利要求:
    Claims (2)
    [1]
    1. METHOD FOR PRODUCING 4-OXY-
    [2]
    2-METHYL-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide of the formula by reaction of an acid ester, a lot of formula A with 2-aminopyridine in an inert aromatic solvent at the boiling point of the reaction mixture and isolation of the target product, which is explained by the fact that, in order to increase the purity of the target product, 2-methoxyethyl ether is taken as an ester of the acid of formula A, and the resulting 2-methoxyethanol is removed by simultaneous distillation with a solvent.
    2. The method of pop. 1, characterized in that xylene is used as an inert aromatic solvent
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    同族专利:
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    DE3171404D1|1985-08-22|
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    FI813003L|1982-03-30|
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    YU42428B|1988-08-31|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    RU2523791C2|2009-03-03|2014-07-27|Пьер Фабр Медикамент|Benzothiazine derivatives, production and use thereof as medical drugs|US3501466A|1967-11-30|1970-03-17|Mcneilab Inc|3-carbamoyl and 3-alkoxycarbonyl benzothiazine-1,1-dioxides|
    US3591584A|1968-08-27|1971-07-06|Pfizer|Benzothiazine dioxides|
    US3787324A|1971-03-01|1974-01-22|Warner Lambert Co|4-hydroxy-3--2h-1,2-benzothiazine 1,dioxides and process for their production|
    US3853862A|1973-04-23|1974-12-10|Pfizer|Production of 4-hydroxy-1,2-benzothiazine-3-carboxamides|
    US4074048A|1976-05-10|1978-02-14|Warner-Lambert Company|Process for the preparation of 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides|US4434164A|1981-06-01|1984-02-28|Pfizer Inc.|Crystalline benzothiazine dioxide salts|
    IN158333B|1981-08-03|1986-10-18|Pfizer|
    GT198276334A|1981-08-03|1984-01-10|PROCEDURE AND INTER-MEDIA FOR THE PRODUCTION OF BENZOTIAZINE CARBOXAMIDES.|
    US4376204A|1981-10-05|1983-03-08|Pfizer Inc.|3-Hydroxy 2-methyl benzisothiazolines as intermediates in production of piroxicam|
    IN159273B|1981-10-05|1987-04-25|Pfizer|
    CA1197244A|1982-04-16|1985-11-26|Medichem, S.A.|Process for the preparation of 4-hydroxy-2-methyl-2h-1,2-benzothiazine-3-carboxamide-1,1-dioxides|
    SU1306476A3|1982-06-17|1987-04-23|Пфайзер,Инк |Method for producing 2-methyl-3-n--carbamoyl-3,4-dihydro-2h-1,2-benzthiazine-1,1-dioxide|
    EP0098422B1|1982-07-07|1987-12-09|Siegfried Aktiengesellschaft|Process for preparing 4-hydroxy-2-methyl-n-2-pyridyl-2h-1,2-benzothiazine-3-carboxamide 1,1-dioxide|
    IT1153293B|1982-10-22|1987-01-14|Francia Famaceutici S R L|DERIVATIVES OF 4-HYDROXY-2-METHYL-2H-1, 2-BENZOTHIAZINE-3-CARBOXYAMIDE 1, 1-DIOXIDE AND PROCEDURE FOR THEIR PREPARATION|
    FI72317C|1983-10-06|1987-05-11|Pfizer|PROCEDURE FOR THE FRAMEWORK OF PHARMACEUTICALS 2-METHYL-4-HYDROXY-2H-1,2-BENZOTHIAZINE-1,1-DIOXIDE -3- -CARBOXAMIDE|
    WO1987006933A1|1986-05-16|1987-11-19|Pfizer Inc.|Benzothiazine dioxide derivatives|
    ES2002646A6|1987-03-27|1988-09-01|Induspol Sa|Process for obtaining 4-hydroxy-2-methyl-N--2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide.|
    WO1989003682A1|1987-10-26|1989-05-05|Pfizer Inc.|Benzothiazine dioxide derivatives|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/191,716|US4289879A|1980-09-29|1980-09-29|Synthetic method and intermediate for piroxicam|
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