The way to obtain 1-phenyl-2,3-dimethyl-4-iteration - 5(yodanthipirina) (options)

 

(57) Abstract:

The invention relates to a method for producing 1-phenyl-2,3-dimethyl-4 iteration-5 (yodanthipirina) with antipyretic antineuralgic action, part antiemeticski drugs such as Felsol, Vastylu and also shown high activity against tick-borne encephalitis. The purpose of the invention is to increase the resource base, reduce the number of technological operations, excluding hazardous-low-tech and reagents, decrease the amount of wastewater. To achieve this goal, iodination of antipyrine or its salt with benzosulfimide (BSCA) is carried out in aqueous, aqueous-organic or organic solvents iadarola a mixture of potassium iodide (KJ), hydrogen peroxide (H2O2) and hydrochloric acid (HCl), which is added at a temperature not exceeding 45oWith, and preferably 2 to 10oWith, or moderowaniem in aqueous-alcoholic medium BSCA and potassium iodide (KJ) is added an aqueous solution of hydrogen peroxide at a temperature of from 30oC to the boiling point of the reaction mass. Found ways of getting yodantipirin have a number of advantages, which are expressed in that give a stable high yields of the target p, the sludge.

The invention relates to the field of organic chemistry and the synthesis of medicinal substances - a method for producing 1-phenyl-2,3-dimethyl-4 - iteration-5 (yodanthipirina) with antipyretic antineuralgic action, part antiemeticski drugs such as Felsol, Vastylu and also shown high activity against tick-borne encephalitis.

One of the ways to get yodanthipirina [1] is that carried out the reaction of 1-phenyl-2,3-dimethylpyrazole (antipyrine) and iodine in aqueous or aqueous-alcoholic medium in the presence of sodium acetate.

The lack of salt antipyrine elemental iodine is the fact that iodine is used in the best case, only half because the other half is spent on the education of salt idiscovered acid, from which it is possible to utilize only 30% of iodine.

In another method of obtaining [2] used the oxidative iodination of antipyrine by potassium iodide, as oxidant is applied potassium Iodate (KJO3in the presence of hydrochloric acid.

With good outputs product, this method requires the use as oxidant expensive and hazardous materials requiring special services oxidative iodination of antipyrine iodine in water [3], containing sodium acetate. An aqueous solution of antipyrine and sodium acetate is brought to the boil and while stirring simultaneously added a mixture of iodine and potassium iodide in water and a mixture of hydrochloric acid and hydrogen peroxide. In addition to hydrogen peroxide is used as oxidizing agent sodium hypochlorite (NaCO), ozone or chlorine. After adding these components to bring the pH of the medium to 7-9. The yield of the target product is 98.5%.

One of the disadvantages of this method is the need for preliminary preparation of the three solutions, which complicates the process. In addition, it requires the use of a large number of components of the reaction, including metallic iodine, when working with large quantities of which have serious technological and environmental problems due to its high volatility. Additive sodium acetate contaminate the target product that requires special treatment and leads to high clogging sewage. The use of oxidants such as ozone and chlorine, creates additional technological difficulties.

In addition to the above disadvantages, all the known methods (including the prototype of the present invention) ispolzuya.

The purpose of the invention is to increase the resource base, reduce the number of technological operations, excluding hazardous-low-tech and reagents, reducing the amount of wastewater.

To achieve these goals, we propose a method of obtaining yodanthipirina, which carry out the oxidative iodination of 1-phenyl-2,3 - dimethylpyrazole (antipyrine) or 1-phenyl-2,3-dimethylpyrazol benzosulfimide (benzosulfimide of antipyrine - BSA) in an aqueous, aqueous-organic or organic acid addition thereto iadarola mixture at a temperature not exceeding 45oC, but it is better in the range of 2 to 10oC, and bring the pH of the reaction mass up to 8-9. Iadarola mixture comprises potassium iodide (KJ), hydrogen peroxide (H2O2) and hydrochloric acid (HCl).

Spend the iodination BSA in aqueous-alcoholic medium by the action of potassium iodide and 5-10% aqueous hydrogen peroxide solution at a temperature of from 30oC to the boiling point of the reaction mass, it is best at a temperature of 70oC. By this method using BSA eliminates hydrochloric acid and the operation preparation iadarola mixture. BSCA is an intermediate for the synthesis of antipyrine, which reduces economic, ekologicheskogo conditions achieved complete conversion of antipyrine and BSA in the target product with a quantitative yield. Practical output of a technical product, usually above 95.2% and depends on the number used as the solvent of the water-alcohol mixture.

For iodination of antipyrine or BSA according to the invention, it is necessary to pre-cook oderous mixture, for example, including potassium iodide (KJ), hydrogen peroxide and hydrochloric acid. You can use various options and modifications cooking specified iadarola mixture. One of the possible ways of getting iadarola mixture described in example 1.

As a result, found conditions was expanded resource base synthesis yodanthipirina. In addition, the reduced number of technological operations and reduced the amount of waste water (decreases the amount of HCl), and also excludes sodium acetate and HCl when ionirovanii BSCA.

The invention is illustrated by the following examples. Example 1. In the flask is charged with 80 ml of hydrochloric acid, 100 g of potassium iodide, the mass is stirred for 15 minutes, cool water and at a temperature not exceeding 40oC under stirring load 85 ml of freshly prepared 16% hydrogen peroxide solution. Then load another 40 ml of hydrochloric acid and 35 ml of a 16% aqueous hydrogen peroxide solution without cooling reactionat to a temperature of 532oC and give exposure 1 h at the same temperature and stirring. In the presence of iodine at the bottom of the flask loaded with stirring an additional quantity of freshly prepared 16%-aqueous solution of hydrogen peroxide and hydrochloric acid. Download lead small portions alternately so that the temperature of the reaction mixture did not exceed 55oC. on average, spent 40 ml of a 16% aqueous solution of hydrogen peroxide and 39 ml of concentrated hydrochloric acid. The reaction mass is additionally stirred for 1 h and at a temperature of 532oC. the resulting solution was cooled to 30oC, filtered and receive oderous mixture of dark cherry color with a density of 1.3 g/cm3(1.2 - 1.4 g/cm3), mass fraction of total iodine 18% (14% to 22%). Get 417 g iadarola mixture or 75 g in terms of the total iodine, which corresponds to the output 98,8%, counting on potassium iodide.

The flask 5 g of antipyrine (4,96 g based on 100% of the basic substance) and 200 ml of water. The resulting mass is stirred until complete dissolution of antipyrine, the solution is cooled to a temperature of 2oC. From the dropping funnel introduced directly into the reaction mass, under vigorous stirring add to 14.3 ml iadarola mixture d=1,305 g/cm3maintained the Xia cheesy aftertaste. The reaction mass is maintained at a temperature of 2 to 10oC, stirring for 30 minutes the End of the reaction is determined by thin layer chromatography on plates Silufol UV-254 with an eluting system chloroform-acetone-ethanol 6:1:0,4. Spot yodanthipirina has Rf0,570,03. To the reaction mass add 15-20% solution of sodium hydroxide to achieve a pH of 8-9. The addition of sodium hydroxide is carried out at intensive stirring and at a temperature of 4 to 10oC. the Reaction mass is maintained at a temperature not exceeding 10oC, stirring for 30 minutes a White precipitate is filtered off, washed with cold water with a temperature of 10 - 15oC to neutral pH of the wash water. Dried, get 8,25 g yodanthipirina, representing 99.2% of the antipyrine. After recrystallization from methanol or ethanol melting point of the target product 160-161oC. the structure of the product is proved using IR and NMR spectroscopy, elemental analysis, and by comparison with identical sample 4-yodanthipirina, the structural formula of which is shown in the drawing.

Example 2. The flask 5 g of antipyrine (4,96 g based on 100% of the basic substance) and 500 ml of water. The resulting mass is stirred until complete dissolution antipiracy weight with vigorous stirring add to 14.3 ml iadarola mixture (d=1,305 g/cm3the content of total iodine 18,22%) with such speed that the temperature at the end of the addition was 45oC, forming a curd-like precipitate. The reaction mass is maintained at a temperature of 45oC, stirring for 30 minutes the Processing of the reaction mixture is carried out as indicated in example 1. Dried receive 6.6 g yodanthipirina that is 79,2% antipyrine. After recrystallization from methanol or ethanol melting point of the target product 160-161oC. the structure of the product proved by IR and NMR spectroscopy, elemental analysis, and by comparison with identical sample 4-yodanthipirina.

Example 3. Into the flask was placed 50 g of antipyrine (49,6 g based on 100% of the basic substance), 1250 ml of 10% aqueous solution of ethanol. The resulting mass is stirred until complete dissolution of antipyrine, cooled to a temperature of 2oC. With vigorous stirring of the dropping funnel introduced directly into the reaction mass, are added dropwise to 158.4 ml iadarola mixture (content of total iodine x 16.75%, d=1.27 g/cm3), with such speed that the temperature at the end of the addition was 4oC. this forms a curd-like precipitate. The reaction mass under stirring vyd is antipyrine, what is 95.9% antipyrine.

Example 4. Into the flask was placed 50 g of antipyrine (49,6 g based on 100% of the basic substance), 500 ml of 20% aqueous solution of methanol.

The resulting mass is stirred until complete dissolution of antipyrine, cooled to a temperature of 2oC. With vigorous stirring of the dropping funnel introduced directly into the reaction mass, are added dropwise 144 ml iadarola mixture (content of total iodine 18%, d=1,3015 g/cm3), with such speed that the temperature at the end of the addition was 4oC. this forms a curd-like precipitate. The reaction mass under stirring incubated for 30 min at 2 - 10oC. Processing of the reaction mixture is carried out as indicated in example 1. Get 80 g yodanthipirina that is 95.9% antipyrine.

Example 5. The flask 5 g of antipyrine (4,96 g based on 100% of the basic substance), 50 ml of methanol. The resulting mass is stirred until complete dissolution of antipyrine, cooled to a temperature of 2oC. With vigorous stirring of the dropping funnel introduced directly into the reaction mass, are added dropwise to 14.4 ml iadarola mixture (content of total iodine 18%, d= 1,3015 g/cm3), with such speed that the under stirring incubated for 30 min at 2 - 10oC. Processing of the reaction mixture were carried out as indicated in example 1. Get to 7.67 g yodanthipirina that is 92% antipyrine.

Example 6. The flask 5 g of antipyrine (4,96 g based on 100% of the basic substance), 50 ml of dimethylformamide. The resulting mass is stirred until complete dissolution of antipyrine, cooled to a temperature of 2oC. With vigorous stirring of the dropping funnel introduced directly into the reaction mass, are added dropwise to 14.4 ml iadarola mixture (content of total iodine 18%, d= 1,3015 g/cm3with such a speed that the temperature at the end of the addition was 4oC. this forms a curd-like precipitate. The reaction mass under stirring incubated for 30 min at 2 - 13oC. Processing of the reaction mixture were carried out as indicated in example 1. Get 8,08 g yodanthipirina that is 97% antipyrine.

Example 7. The flask 5 g of antipyrine (4,96 g based on 100% of the basic substance), 50 ml of acetic acid. The resulting mass is stirred until complete dissolution of antipyrine and at room temperature and vigorous stirring of a dropping funnel introduced directly into the reaction mass, are added dropwise to 14.4 ml iadarola smla 25oC. this forms a curd-like precipitate. The reaction mass under stirring incubated for 30 min at 20 - 25oC. Processing of the reaction mixture were carried out as indicated in example 1. Obtain 2.2 g of yodantipirin that is 26% antipyrine.

Example 8. The flask is 10.6 g BSA (5 g in terms of antipyrine), 125 ml of 10% aqueous solution of ethanol. The resulting mass is stirred until complete dissolution of BSCA, cooled to a temperature of 2oC. With vigorous stirring of the dropping funnel introduced directly into the reaction mass, are added dropwise to 15.9 ml iadarola mixture (content of total iodine of 16.7%, d=1.27 g/cm3), with such speed that the temperature at the end of the addition was 4oC. this forms a curd-like precipitate. The reaction mass under stirring incubated for 30 min at 2 - 10oC. Processing of the reaction mixture were carried out as indicated in example 1. Obtain 7.9 g of yodantipirin that is 95.2 percent for antipyrine.

Example 9. The flask is 10.6 g BSA (5 g in terms of antipyrine), 125 ml of 10% aqueous solution of ethanol. The resulting mass is stirred until complete dissolution of BSCA, heated to a temperature of 45oC. With vigorous stirring of the to the (content of total iodine of 16.7%, d= 1.27 g/cm3with such a speed that the temperature at the end of the addition was 45oC. this forms a curd-like precipitate. The reaction mass under stirring incubated for 30 min at 45oC. Processing of the reaction mixture were carried out as indicated in example 1. Get 6.4g yodanthipirina that is 77% antipyrine.

Example 10. In the flask is charged with 50 g BSA (25,35 g in terms of antipyrine), 23 g of potassium iodide (KJ), 150 ml of 10% aqueous ethanol. Heated the reaction mass to dissolve. At a temperature of 70oC and vigorous stirring was added dropwise within 5-7 min 44,3 ml of 10% aqueous hydrogen peroxide solution (4,58 g 100% H2O2). The reaction mass is heated to boiling and incubated for 1 h with stirring, then add 10-15 ml of 10% aqueous hydrogen peroxide solution until the complete disappearance of the spot of antipyrine on the chromatographic plate. Further maintain the mixture at the boil for a further 30 minutes the Reaction mass is treated with 2 ml of 10% aqueous sodium hydroxide solution, cooled to a temperature of 10oC, the precipitation is filtered off, washed with 100 ml of chilled water. Dry and get to 41.6 g iodantipirine that is 98.3% antipyrine.

oC and vigorous stirring was added dropwise within 5-7 min 221,2 ml of 10% aqueous hydrogen peroxide solution (22.9 grams 100% H2O2). The reaction mass is heated to boiling and incubated for 1 h with stirring, then added dropwise to 44.1-to 66.3 ml of 10% aqueous hydrogen peroxide solution until the complete disappearance of the spot of antipyrine on the chromatographic plate. Further kept at the boil for a further 30 minutes the Reaction mass is treated with 20 ml of 10% aqueous sodium hydroxide solution, cooled to a temperature of 10oC, the precipitation is filtered off, washed with 500 ml of chilled water. Dried, yielding 207 g iodantipirine, representing 97.8% of the antipyrine.

1. The way to obtain 1-phenyl-2,3-dimethyl-4 - iteration-5(yodanthipirina) oxidative moderowaniem of antipyrine in acidic medium, characterized in that Jodorowsky mixture was added to a solution of antipyrine at a temperature not exceeding 45oC.

2. The method according to p. 1, characterized in that the iodination is carried out at a temperature of 2 to 10oC.

3. The method according to p. 2, characterized in that iadarola mixture consists of potassium iodide, hydrogen peroxide and sosnoski or organic solvents.

5. The way of getting p. 4, characterized in that after completion of the reaction the iodination bring the pH of the reaction mass up to 8 - 9.

6. The way to obtain 1-phenyl-2,3-dimethyl-4-iteration-5 oxidative moderowaniem in aqueous-acidic medium, characterized in that Jodorowsky mixture is added to aqueous-alcoholic solution of 1-phenyl-2,3-dimethylpyrazol benzosulfimide at a temperature not exceeding 45oC.

7. The method according to p. 6, characterized in that the iodination is carried out at a temperature of 2 to 10oC.

8. The method according to p. 7, characterized in that iadarola mixture consists of potassium iodide, hydrogen peroxide and hydrochloric acid.

9. The way to obtain 1-phenyl-2,3-dimethyl-4 - iteration-5 oxidative moderowaniem in the aquatic environment, wherein the water-alcohol solution of 1-phenyl-2,3-dimethylpyrazol benzosulfimide and iodide of an alkali metal add an aqueous solution of an oxidant at a temperature of from 30oC to the boiling point of the reaction mass.

10. The method according to p. 9, characterized in that the iodination is carried out at a temperature of 70oC.

11. The method according to p. 10, characterized in that as the oxidant used hydrogen peroxide.

12. The method according to p. 1

 

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FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and synthesis of medicinal substances and can be widely used in synthesis of 1-phenyl-2,3-dimethyl-4-iodopyrazolone-5 (iodoantipyrine). The invention is primarily aimed at designing a method which cuts energy consumption, increases technological and environmental safety during production of pharmacopoeial iodoantipyrine with high output of not less than 95%. The method is based on oxidative iodination of antipyrine with an iodination mixture in the absence of an organic solvent and subsequent synthesis of pharmacopoeial iodoantipyrine. The method is characterised by successive steps for oxidative iodination and synthesis of pharmacopoeial iodoantipyrine in an aqueous medium in a single apparatus. The oxidative iodination process takes place at room temperature with concentration of components in the aqueous medium which ensures output of pharmacopoeial iodoantipyrine of not less than 95%.

EFFECT: simple technology of producing iodoantipyrine and apparatus used in the process, as well as high technological and environmental safety of the method.

7 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of compounds, characterised by formulae (I) and (IB), or pharmaceutically acceptable salts thereof, isomers or hydrates to prepare a medicinal agent for treating or preventing diseases or conditions mediated by the sigma-receptor, selected from psychosis, neuropathic pain or inflammatory pain and movement disorder, such as dystonia or tardive dyskinesia, motor defects, including allodynia/or hyperalgesia. Radicals and symbols in compounds of formulae (I) and (IB) are described in claims 1 and 2. The invention also relates to novel compounds of formulae (I') and (IB'), in which radicals and symbols are described in claims 4 and 5, having pharmacological activity on the sigma-receptor, methods of producing such compounds, a pharmaceutical composition containing said compounds and use of said compounds in preparing a medicinal agent for treating and/or preventing diseases or conditions whose development involves the sigma-receptor. (I), (IB) (I') and (IB').

EFFECT: high effectiveness of the inhibitors.

22 cl, 1 tbl, 3 dwg, 64 ex

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