The method of purification of all e - or 13z-retinoic acid
(57) Abstract:The inventive product - all - E - retinoic acid. BF C20H26O2. The basic substance content of 97.8%. Stability in air at 20°C for 7 days. Reagent 1: all = E - or 13Z-retinoic acid. Reagent: aqueous solution of alkali. Reaction conditions: boiling in the presence of alcohol C1-C3normal or ISO-structure at pH 12 - 14 with the subsequent removal of activated carbon by acidification and extraction of methylene chloride and evaporation, dissolution of the residue in hexane or methylene chloride at 18 - 25°C and low temperature kristallizatsiei at 25 and 15°C. table 2. The invention relates to organic chemistry, namely the method of purification of isomeric all-E - 13Z-retinoic acid and can be used in the production of pharmaceuticals.All-E - 13Z-retinoic acid is very effective in the treatment of severe skin diseases, not amenable to treatment with modern dermatological preparations  , and can be used in Oncology and rheumatology for the treatment of leukemia and arthritis .Isomeric all-E - 13Z-retinoic acid is rapidly oxidized under the action of atmospheric oxygen. Most lability Atherstone forms. Studies have shown that traces of contaminants that pollute all-E - 13Z-retinoic acid, are able to greatly accelerate the process of oxidation of these compounds in the air.Known methods for cleaning retinoic acid - recrystallization from ethanol or isopropanol , low-temperature crystallization from chloroform  , however, these methods do not produce stable to the action of oxygen drugs (examples 12, 20, 25 - comparative).The closest in technical essence to the present invention is a cleaning method  , which 13Z-retinoic acid is first boiled with activated carbon in ethyl acetate, after filtration of coal excess ethyl acetate is removed in vacuum at 75-80aboutWith the solution 13Z-retinoic acid in ethyl acetate stored in the refrigerator at a temperature of -10 to -15aboutC. the Precipitated crystals are filtered and dried in vacuum.The disadvantage of this method is that although 13Z-retinoic acid is obtained in high purity, it is not stable during storage in the presence of oxygen (example 13).The proposed method can achieve much more resistant to the action of oxygen drugs all-E - 13Z-pet is tigerbunny coal in aqueous-alcoholic medium, using alcohols WITH1-C3normal or ISO-structure, in the presence of sodium hydroxide at pH 12 to 14 and the boiling temperature of the solvent, followed by separation of the activated carbon by acidification of the resulting solution, extraction with methylene chloride removal of solvent, the products obtained by dissolving in hexane or methylene chloride at 18-25aboutWith and carrying out the crystallization at a temperature of 18-25aboutWith and carrying out the crystallization at a temperature of -25--15aboutC.A significant feature of the proposed method is a combination of processing coal in aqueous alcoholic alkaline medium at pH 12-14 with low-temperature crystallization from methylene chloride or hexane at a temperature of from -25 to -15aboutAfter dissolution of the treated coal product at 18-25aboutC. Only boiling with charcoal in aqueous alcoholic alkaline environment, and not in ethyl acetate, as in the prototype (example 13 comparative), or only low-temperature crystallization (examples 6.19 - comparative) only slightly increases the stability of isomeric retinoic acid and does not result in stable compounds.Boiling with activated charcoal should be carried out in water and the ethyl acetate not result in retinoic acid, stable when stored (example 13 comparative).As a solvent in the processing of coal used lower alcohols containing from 1 to 3 carbon atoms, normal or ISO-structure, such as methanol, ethanol, propanol or isopropanol.Treatment of activated carbon in aqueous alcoholic alkaline environment should be conducted at pH 12-14. At pH below 12 potassium salt of retinoic acid unstable, which leads to the production of retinoic acid less resistant to oxygen (examples 10, 23 - comparative).Processing in aqueous alcoholic alkaline environment with a pH value above 14, on the one hand does not increase the sustainability of retinoic acid (examples 11, 24 - comparative), and, on the other hand, requires a greater consumption of alkali and therefore uneconomical.During crystallization retinoic acids from hexane or methylene chloride, the temperature of the dissolution shall not exceed 25aboutWith, otherwise decreases the stability of retinoic acid (examples 8, 21 - comparative).The temperature of dissolution below the 18aboutInappropriate because it greatly decreases the solubility of retinoic acid increases the consumption of solvent and decreasing curves).Cleaning isomer of retinoic acid by this method leads not only to increase the stability of the target compounds (table. 1), but also to increase the shelf life of ready medicinal forms, such as suppositories with 13Z-retinoic acid (PL. 2).From the data table. 1 one can see that the stability of labile 13Z-retinoic acid increases more than 10 times, the stability of all-E-retinoic acid increased more than 20 times.Table. 2 shows that the suppositories with 13Z-retinoic acid, obtained by the claimed method, 5 times more resistant than suppositories with 13Z-retinoic acid, purified by the method of crystallization from ethyl acetate.The proposed method retinoic acid obtained as follows: retinoic acid is boiled with activated carbon in aqueous alcoholic alkaline medium at pH 12-14 for 30 minutes After cooling the reaction mixture and removal of activated charcoal, the solution acidified with 5% sulfuric acid solution. Retinoic acid is extracted with methylene chloride, the extract is dried with sodium sulfate, the solvent is removed in vacuum, the residue is dissolved in hexane or methylene chloride at 18-25aboutWith and leave when temperature is me at a residual pressure of 1 mm RT. tbsp. at a temperature of 20aboutC.The invention is illustrated by the following examples.P R I m e R 1. 6 g 13Z-retinoic acid dissolved in a mixture of 170 ml of isopropanol and 170 ml of 0.5 n solution of sodium hydroxide to bring the pH of the resulting solution to 12-14 of 0.5 N. a solution of caustic potash. To the resulting solution was added 6 g of activated charcoal and boiled for 0.5 hours After removal of the activated charcoal, the solution acidified with 5% sulfuric acid solution to pH 2-3. 13Z-retinoic acid is extracted with methylene chloride, the extract washed with water, dried with sodium sulfate, the solvent is removed in vacuum. The residue is dissolved in 18 ml of methylene chloride at 20aboutWith and leave for 12 h at -20aboutC. the Precipitated crystals filtered off, washed with hexane, dried in vacuum at 20aboutC. Gain of 4.2 g 13Z-retinoic acid, the yield was 69.7%, the content of 97.8%, stability (the time during which the storage of the drug in air at a temperature of 20aboutWith the remains of at least 95% of the original substance) - 7 days.P R I m e R s 2-13 carried out analogously to example 1. Conditions of experiments and data on the stability of the drugs 13Z-retinoic acid are presented in table. 1.P R I m eara 12-14). The resulting solution was then treated with activated carbon as in example 1. All-E-retinoic acid is extracted with methylene chloride, after washing with water, the extract is dried with sodium sulfate, the methylene chloride removed in vacuo. The residue is dissolved in 480 ml of methylene chloride at 20aboutC and leave at -20aboutC. Obtain 4.5 g of all-E-retinoic acid; yield 70.3% of the content of 97.5%; resistance (the time during which the storage of the drug in air at a temperature of 20aboutWith the remains of at least 95% of the original substance) 12 months.P R I m e R s 15-25 carried out analogously to example 14. Conditions of experiments and data on the stability of the preparations all-E - retinoic acid are presented in table. 1.Thus, cleaning isomer of retinoic acid on the proposed method increases the stability of the target compounds 10-20 times that not only eliminates difficulties in working with substance, but also economically profitable, because of the loss of substances, due to their instability, can be very significant.The economic effect is obtained also by increasing the shelf life of medicines with retinoic acid, ocimene the new coal in a solvent, followed by the separation of coal and low-temperature crystallization, characterized in that the solvent boiling using an aqueous solution of caustic potash, and the process is carried out at pH 12 - 14 in the presence of alcohol C1- C3normal or isotrate and after separation of the coal resulting solution was acidified with acid and extracted with methylene chloride, which is then evaporated, then the residue is dissolved in hexane or methylene chloride at 18 - 25oWith and carry out low-temperature crystallization at -25 15oC.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to geranyl compounds represented by the following formulas (I-1) , (I-2) or (I-3) wherein R1 means compounds of the following formulas: or R2 means a group remaining after removing all carboxyl groups presenting in carboxylic acid chosen from group consisting of malic acid, citric acid, succinic acid, fumaric acid and others; m = 1, 2 or 3; n = 0, 1 or 2, and m + n represent a number of carboxylic groups presenting in indicated carboxylic acid; R3 means p-hydroxyphenyl or mercapto-group. Also, invention relates to derivatives of mevalonic acid represented by the following formula (I-4): wherein R means -CH2OH or CH3. Also, invention to an antitumor agent comprising as an active component geranyl compound of formulas (I-1), (I-2) or (I-3) or derivative of mevalonic acid of the formula (I-4), and optionally a pharmaceutically acceptable carrier or solvent. Also, invention relates to a method for treatment of liver cancer based on using geranyl compound of formulas (I-1), (I-2) or (I-3), or derivative of mevalonic acid of the formula (I-4) and using proposed compounds in manufacturing an antitumor agent. Invention provides using geranyl compounds or derivatives of mevalonic acid as antitumor agents.
EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.
7 cl, 3 tbl, 17 ex
FIELD: organic chemistry, radiolabeled compounds.
SUBSTANCE: invention relates to tritium uniformly labeled [3H]-trans-3,7-dimethyl-9-(2,6,6-trimethyl-3-oxo-1-cyclohexene-1-yl)-2,4,6,8-nonatetraenic acid of the formula: . This compound is analog of physiologically active compound that can be used in organic chemistry, biology and medicine.
EFFECT: valuable properties of compound.
FIELD: organic chemistry.
SUBSTANCE: invention relates to method for purification of monochloroacetic acid from dichloroacetic acid impurities. Claimed method includes hydrogenolysis in presence of hydrogen in film regime at 135-145°C in cascade of sequentially bonded reactors with fixed bed of heterogeneous catalyst namely palladium on activated carbon. Preferably reactor cascade with intermediate cooling with cold flow of monochloroacetic acid as cooling agent is used.
EFFECT: simplified process; product of improved quality.
3 cl, 7 ex, 3 dwg
SUBSTANCE: invention pertains to the perfection of the method of regulating quantities of dissolved iron in liquid streams during the process of obtaining aromatic carboxylic acids or in the process of cleaning technical aromatic carboxylic acids, characterised by that, to at least, part of the liquid stream for regulating the quantity of dissolved iron in it, at least one peroxide with formula R1-O-O-R2 is added. Here R1 and R2 can be the same or different. They represent hydrogen or a hydrocarbon group, in quantities sufficient for precipitation of the dissolved iron from the liquid. The invention also relates to the perfection of the method of obtaining an aromatic carboxylic acid, through the following stages: A) contacting the crude aromatic material which can be oxidised, with molecular oxygen in the presence of an oxidising catalyst, containing at least, one metal with atomic number from 21 to 82, and a solvent in the form of C2-C5 aliphatic carboxylic acid in a liquid phase reaction mixture in a reactor under conditions of oxidation with formation of a solid product. The product contains technical aromatic carboxylic acid, liquid, containing a solvent and water, and an off-gas, containing water vapour and vapour of the solvent; B) separation of the solid product, containing technical aromatic carboxylic acid from the liquid; C) distillation of at least part of the off gas in a distillation column, equipped with reflux, for separating vapour of the solvent from water vapour. A liquid then forms, containing the solvent, and in the upper distillation cut, containing water vapour; D) returning of at least, part of the liquid from stage B into the reactor; E) dissolution of at least, part of the separated solid product, containing technical aromatic carboxylic acid, in a solvent from the cleaning stage with obtaining of a liquid solution of the cleaning stage; F) contacting the solution from the cleaning stage with hydrogen in the presence of a hydrogenation catalyst and under hydrogenation conditions, sufficient for formation of a solution, containing cleaned aromatic carboxylic acid, and liquid, containing a cleaning solvent; G) separation of the cleaned aromatic carboxylic acid from the solution, containing the cleaning solvent, which is obtained from stage E, with obtaining of solid cleaned aromatic carboxylic acid and a stock solution from the cleaning stage; H) retuning of at least, part of the stock solution from the cleaning stage, to at least, one of the stages B and E; I) addition of at least, one peroxide with formula R1-O-O-R2, where R1 and R2 can be the same or different, and represent hydrogen or a hydrocarbon group, in a liquid from at least one of the other stages, or obtained as a result from at least one of these stages, to which the peroxide is added, in a quantity sufficient for precipitation of iron from the liquid.
EFFECT: controlled reduction of the formation of suspension of iron oxide during production of technical aromatic acid.
19 cl, 1 dwg, 6 ex, 4 tbl
SUBSTANCE: invention relates to an improved method, by which the carboxylic acid/diol mixture, that is suitable as the initial substance for the manufacture of polyester, obtained from the decolourised solution of carboxylic acid without actually isolating the solid dry carboxylic acid. More specifically, the invention relates to the method of manufacturing a mixture of carboxylic acid/diol, where the said method includes the addition of diol to the decolourised solution of carboxylic acid, which includes carboxylic acid and water, in the zone of the reactor etherification, where diol is located at a temperature sufficient for evaporating part of the water in order to become the basic suspending liquid with the formation of the specified carboxylic acid/diol mixture; where the said carboxylic acid and diol enter into a reaction in the zone of etherification with the formation of a flow of a complex hydroxyalkyl ether. The invention also relates to the following variants of the method: the method of manufacture of the carboxylic acid/diol mixture, where the said method includes the following stages: (a) mixing of the powder of damp carboxylic acid with water in the zone for mixing with the formation of the solution of damp carboxylic acid; where the said carboxylic acid is selected from the group, which includes terephthalic acid, isophthatic acid, naphthalenedicarboxylic acid and their mixtures; (b) discolourisation of aforesaid solution of damp carboxylic acid in the zone for reaction obtaining the decolourised solution of carboxylic acid; (c) not necessarily, instantaneous evaporation of the said decolourised solution of carboxylic acid in the zone of instantaneous evaporation for the removal of part of the water from the decolourised solution of carboxylic acid; and (d) addition of diol to the decolourised solution of carboxylic acid in the zone of the reactor of the etherification, where the said diol is located at a temperature, sufficient for the evaporation of part of the water in order to become the basic suspending liquid with the formation of the carboxylic acid/diol mixture; where the aforesaid carboxylic acid and diol then enter the zone of etherification with the formation of the flow of complex hydroxyalkyl ether; and relates to the method of manufacture of carboxylic acid/diol, where the said method includes the following stages: (a) the mixing of the powder of damp carboxylic acid with water in the zone for mixing with the formation of the solution of carboxylic acid; (b) discolourisation of the said solution of damp carboxylic acid in the reactor core with the formation of the decolourised solution of carboxylic acid; (c) crystallisation of the said decolourised solution of carboxylic acid in the zone of crystallisation with the formation of an aqueous suspension; and (d) removal of part of the contaminated water in the aforesaid aqueous solution and addition of diol into the zone of the removal of liquid with the obtaining of the said carboxylic acid/diol mixture, where diol is located at a temperature sufficient for evaporating part of the contaminated water from the said aqueous suspension in order to become the basic suspending liquid.
EFFECT: obtaining mixture of carboxylic acid/diol.
29 cl, 4 dwg
SUBSTANCE: method lies in the following: concentrated solution of lithium salt is introduced into mixture of sodium salts of naphthenic acids, mixed and left for separation into layers and formation of viscous mass of lithium salt of naphthenic acid high-molecular fraction with molecular weight more than 200 in sediment, and in upper water layer - of low-molecular fraction of naphthenic acids lithium salt with molecular weight less than 200, with subsecutive separation.
EFFECT: separation of concentrated water solutions of naphthetic acids lithium salts according to their molecular weight.
2 cl, 2 ex
SUBSTANCE: method of obtaining product - purified carboxylic acid, includes: (a) oxidation of aromatic initial materials in primary oxidation zone with formation of raw carboxylic acid suspension; where raw carboxylic acid suspension contains terephthalic acid; where said oxidation is carried out at temperature within the range from 120°C to 200°C; (b) withdrawal of admixtures from raw suspension of carboxylic acid, removed at temperature from 140°C to 170°C from stage of oxidation of paraxylol in primary oxidation zone and containing terephthalic acid, catalyst, acetic acid and admixtures, realised in zone of solid products and liquid separation with formation of mother liquid flow and product in form of suspension; where part of said catalyst in said suspension of raw carboxylic acid is removed in said mother liquid flow; and where into said zone of solid products and liquid separation optionally additional solvent is added; (c) oxidation of said product in form of suspension in zone of further oxidation with formation of product of further oxidation; where said oxidation is carried out at temperature within the range from 190°C to 280°C; and where said oxidation takes place in said zone of further oxidation at temperature higher than in said primary oxidation zone; (d) crystallisation of said product of further oxidation in crystallisation zone with formation of crystallised product in form of suspension; (e) cooling of said crystallised product in form of suspension in cooling zone with formation of cooled suspension of purified carboxylic acid; and (i) filtration and optionally drying of said cooled suspension of purified carboxylic acid in filtration and drying zone in order to remove part of solvent from said cooled suspension of carboxylic acid with obtaining of said product - purified carboxylic acid.
EFFECT: purified carboxylic acid with nice colour and low level of admixtures, without using stages of purification like hydration.
8 cl, 1 tbl, 1 dwg, 1 ex
SUBSTANCE: method of (meth)acrylic acid purification includes the stages as follows: distillations of the liquid containing raw (meth)acrylic acid being acrylic acid or methacrylic acid with one or more polymerisation inhibitors added as chosen from group consisting of phenol derivative, phenothiazine derivative, copper (meth)acrylate and copper dithiourethane, for the purpose to produce condensate of (meth)acrylic acid, containing (meth)acrylic acid of purity at least 90%; adding polymerisation inhibitor containing phenol derivative to condensate; and delivery of oxygen-containing gas that contains oxygen to condensate of (meth)acrylic acid in reflux tank wherein condensate of (meth)acrylic acid is collected, wherein oxygen-containing gas is delivered to condensate in reflux tank with using small-size bubble liquid injector, and pressure connection for oxygen-containing gas delivery to liquid injector whereat ratio (nm/tn) of oxygen delivery in oxygen-containing gas and condensate flow supplied to reflux tank at 0°C, 1 atm complies with ratio shown in equation 0.004≤A/B≤1.0, where A stands for O2 delivery (nm3/hour), B stands for condensate flow (tn/hour) of the condensate supplied to reflux tank, and symbol n in nm3/hour specifies the value under normal conditions (0°C, 1 atm: normal conditions).
EFFECT: effective method of high purity acid production wherein acid polymer formation in made condensate is prevented.
12 cl, 6 dwg, 7 ex
SUBSTANCE: invention relates to improved method of recovering (meth)acrolein or (meth)acrylic acid, including stage of cooling of gaseous reaction mixture containing (meth)acrolein or (meth)acrylic acid obtained by reaction of catalytic oxidation in vapour phase of one or both reagents selected from (A) propane, propylene or isobutylene and (B) (meth)acrolein, with molecular oxygen or gas, containing molecular oxygen, to temperature 140-250°C; contacting of said gaseous reaction mixture with solvent, whose temperature is 20-50°C, in recovery installation for recovering (meth)acrolein or (meth)acrylic acid in solvent, where said recovery installation contains contact zone, where gaseous reaction mixture contacts with solvent, having transversal section of round form and many devices of gaseous reaction mixture supply for supplying gaseous reaction mixture into contact zone, devices of gaseous reaction mixture supply are installed in contact zone at the same height directed towards contact zone centre, gaseous reaction mixture is supplied to contact zone from devices of gaseous reaction mixture supply and is subjected to collision straight in one point of contact zone, and recovery installation does not have device which prevents direct collision of gaseous mixture supplied from devices of gaseous reaction mixture supply. Invention also relates to recovery installation for recovering (meth)acrolein or (meth)acrylic acid.
EFFECT: ensuring efficient recovering (meth)acrolein or (meth)acrylic acid from gas containing (meth)acrolein or (meth)acrylic acid, preventing polymerisation.
7 cl, 5 dwg, 4 ex
SUBSTANCE: invention refers to advanced method of production of (meth)acrylic acid ester including (meth)acrylic acid purification by contacting raw (meth)acrylic acid containing manganese as an impurity manganese, and cation-exchange resin to remove manganese. To ensure contacting raw (meth)acrylic acid and cation-exchange resin, water is pre-added to (meth)acrylic acid. Besides, the method involves reaction of purified (meth)acrylic acid and alcohol with acid catalyst added.
EFFECT: method allows preventing effectively deactivation of the acid catalyst used in etherification reaction, equipment plugging and can ensure stable ester manufacturing.
3 cl, 5 tbl, 5 ex
SUBSTANCE: invention concerns aggregate for (met)acrylic acid obtainment, including: reactor for (met)acrylic acid obtainment by catalytic gas phase oxidation reaction of one, two or more source compounds including propane, propylene, isobutylene and (met)acrolein, in gas mix of source substances including one, two or more source compounds including propane, propylene, isobutylene and (met)acrolein, and oxygen; heat exchanger connected to reactor and intended for cooling of reaction gas mix including obtained (met)acrylic acid; and absorption column connected to heat exchanger and intended for contact absorbing fluid with reaction gas mix for (met)acrylic acid absorption, so that (met)acrylic acid is absorbed from reaction gas mix by absorbing fluid. Additionally the aggregate includes: bypass pipe connecting reactor and absorption column without the use of intermediary heat exchanger; and device for flow rate adjustment in reaction gas flow passing through bypass pipe in order to maintain almost constant flow rate of gas mix feed of source materials to reactor or almost constant pressure of gas mix of source materials at the reactor inlet. Also invention concerns improved method of (met)acrylic acid obtainment by extraction of (met)acrylic acid absorbed by absorbing fluid.
EFFECT: heat power tapping from reaction gas mix, stable and continuous process even in case of heat exchanger intended for heat power extraction is blocked.
2 cl, 3 dwg, 1 ex
SUBSTANCE: proposed method involves the following stages: (a) reaction of carbon monoxide with at least one reagent chosen from a group, consisting of methanol, methyl acetate, methyl formate and dimethyl ether and their mixture in a reaction medium, containing water, methyl iodide and catalyst for obtaining the reaction product, containing acetic acid; (b) gas-liquid separation of the said reaction product to obtain a volatile phase, containing acetic acid, water and methyl iodide and a less volatile phase, containing the said catalyst; (c) distillation of the above mentioned volatile phase to obtain a purified product of acetic acid and a first overhead fraction, containing water, methylacetate and methyl iodide; (d) phase separation of the above mentioned first overhead fraction to obtain the first liquid phase, containing water, and second liquid phase, containing methyl iodide and methyl acetate; and (e) feeding dimethyl ether directly or indirectly into a decantation tank of light fractions for phase separation of the said first overhead fraction in a quantity, sufficient for increasing separation of the first overhead fraction to form the first and second liquid phases.
EFFECT: improvement of the method of producing acetic acid.
8 cl, 1 dwg