The method of obtaining 2-( 4'- isobutylphenyl)propionic acid (ibuprofen) (and its variants)
(57) Abstract:Essence: getting well-known anti-inflammatory agent 2-( 4' - isobutylphenyl)propyl acid carbonyliron 1-(4-isobutylphenyl)ethanol (IBPE) carbon monoxide in an acidic aqueous medium, for example, containing at least 10% of water, calculated on the weight of the original input (IBFA) at a temperature at least 10 ° C and a pressure of carbon monoxide of at least 500 psig (35 MPa), and in the presence of a catalyst consisting essentially of palladium compounds, in which the valence palladium from 0 to 2 and which is in a complex with at least one phosphine ligand, mixing with the organic phase of the reaction medium, the molar ratio of the compounds of palladium and a ligand of at least 2 : 1 in molar ratio of palladium to (IBFA) below about 1 : 10000; dissociated hydrogen ions and acid, which is essentially an ionisable fully in dilute aqueous solution in such a quantity that the molar ratio of hydrogen ions to (IBFA) introduced into the reaction zone, at least 0.15, and the molar ratio of hydrogen ions to the water at least of 0.025 : 1, dissociated ions of the halogen in such a quantity that the molar Rel is Orada and halogen is gelidity hydrogen. Carbonylation recommend to combine with the method get (IBFA) from isobutylbenzene in which isobutylenes subjected to reaction Friedel-with acetoorcein means to obtain 4' - isobutylacetophenone, which is reactivated by hydrogen in the presence of a hydrogenation catalyst or reducing agent containing active hydrogen with obtaining (IBFA). 6 C. p. F.-ly, 17 PL. The invention relates to a new method of obtaining 2-(4l-isobutylphenyl)propionic acid, known under the name of ibuprofen.Ibuprofen is a well-known anti-inflammatory medication, non-steroidal origin, which was transferred from the ethical, i.e., featured in legalized status. There are various ways of getting ibuprofen use as the source of the product 4-isobutylacetophenone.The described invention aryl-substituted carboxylic acids, for example, (4l-isobutylphenyl)propionic acid or ibuprofen interaction arylamide - governmental alcohols, for example, 1-(4I-isobutylphenyl)-ethanol with carbon monoxide and water in the presence as catalyst of hydrogen fluoride (prototype).In the Japan patent (2) Eilena group may be a phenyl group, containing at least one alkoxygroup, alloctype, hydroxy or amino group as electrondonor Deputy. Such derivative is produced by interaction of a derivative of benzyl alcohol, which may be-aryl-substituted ethanol, where Arianna group is the same as in the synthesized derivative of phenylacetic acid, with carbon monoxide and water, alcohol or phenol in the presence of palladium catalyst. As an auxiliary catalyst may be added an acid compound such as hydrogen chloride and can also be used a solvent such as benzene. In the description of the patent included a comparative example according to which the described method are ibuprofen (not included in the scope of the invention) with a very low output (17,1% ).In the Japan patent (3) described education -(6-methoxy-2-neftel)propionic acid interaction -(6-methoxy-2-naphthyl)ethyl alcohol with carbon monoxide and water in the presence of palladium catalyst and acidic compounds, for example, hydrogen chloride. In the cited patent also States that when using besplodnogo acid compounds in the reaction mixture, it is desirable to add insirument-Qualification of isobutylbenzene acetylchloride in the presence of aluminum chloride as a catalyst.In the publication of the Japan patent (5) describes the obtaining of p-isobutylacetophenone the acetylation of isobutylbenzene appli - cation as Alliluyeva tools acetylchloride (produced by interaction of acetic anhydride with hydrogen fluoride) and as a catalyst a mixture of hydrogen fluoride with boron TRIFLUORIDE.In the Japan patent describes a waterless method of obtaining 2-(4I-isobutylphenyl)-propionic acid in the form of ether by treatment of 1-(4-isobutylphenyl)ethanol IBPE carbon monoxide in a solution containing alkanol and a catalyst, such as a complex of bis(triphenylphosphine)dichloropalladium. The solution may also contain up to 10% of mineral acid such as hydrogen chloride.In accordance with the invention, 2-(4I-isobutylphenyl)propionic acid, i.e., ibuprofen, obtained by carbonylation of 1-(4I-isobutylphenyl)ethanol (IBPE) carbon monoxide in an acidic-aqueous medium, in the presence of dissociated hydrogen ions, dissol - new halide ions, and a catalyst at elevated temperature and pressure, the method is characterized by the fact that in order to simplify the process as a catalyst using a complex of palladium chloride and phenylphosphino and this method is carried out at a temperature of from 100 to 150aboutC, at a pressure of carbon monoxide in the range from 42 to 324 ATM. (600-4750 pound (square inch); the molar ratio of palladium to phosphorus and 1-(4l-isobutylphenyl)ethanol is 1: (2-27): (250-30100); moreover, these dissociatively hydrogen ions provided by the acid, which is essentially completely ionized in dilute aqueous solution so that the molar ratio of dissociated hydrogen ions to 1-(4l-isobutylphenyl)ethanol added in the reaction zone was at least. 0.026 and dissociatively halide ions are present in an amount such that the molar ratio of halide ions to 1-(4l-isobutylphenyl)ethanol added in the reaction zone was at least 0,20.The expression "freely miscible with the organic phase of the reaction medium" means that the ligand does not form a complex with the insoluble substrate, such as a polymer, which does not allow free mixing in the organic phase.The carbonylation reaction proceeds according to equation 1:
When carrying out the carbonylation reaction water may be present in amounts of, for example, of about 10-600% , preferably about 15-100% (based on the original p is in the interval 600-4750 pound. per square inch, and the total reaction time can be, for example, in the range of 0.1 to 24 hours, preferably about 1-6 hoursSome examples of palladium catalysts that can be used, in which palladium complexesa with the appropriate ligand, are: bis(triphenylphosphine)dichloramine, bis(tributylphosphine)dichloramine, bis(tricyclohexylphosphine)dichloro-set - CEN, PI-allyl-triphenylphosphine complex, triphenylpyridinium complex, bis(triphenylphosphine)di - carbonyl-complex, bis(triphenylphosphine)diacetate complex, bis(triphenylphosphine)dinitrate treatment is complex, bis(triphenyltin fin)sulfate complex, tetrakis(triphenylphosphine)-complex, as well as complexes with specific ligands is carbon monoxide, such as chlorocarbonyl bis(triphenylphosphine) complex, in all cases we are talking about palladium complexes. Also suitable as the catalyst metal is palladium on an appropriate medium such as carbon, aluminum oxide, silicon dioxide or inert polymer capable of withstanding the reaction conditions, the incoming complex with one or more wisepress specific ligands.Palladium salt and a phosphine ligand forming nasato input ligand, is preferably sufficient for the formation of a complex with the audience palladium so that the molar ratio P: Pd were equal to at least about 1: 1 in molar ratio of Pd: IBPE at least about 1: 5000. However, if the last relation is such that Pd = 1, a IBPE - 10,000 or more (1: 10000 or more than 10,000, in this case it is necessary to use an excess of phosphine ligand, so that the ratio P: Pd was at least about 2: 1.The catalytic complex may be present in an amount such that the molar ratio of palladium to IBPE was in the range of, for example, about 1: (250-1): 30100, preferably about 1: (15050-1): 30100.Dissociatively hydrogen ions and halide ions may conveniently be introduced into the reaction in the form of hydrogen chloride, hydrogen bromide or hydrogen iodide. However, it is also possible to add hydrogen ions and halide ions from various sources. For example, as a source of hydrogen ions can be used by other acids, an ionisable fully in dilute aqueous solution, for example, inorganic acids such as sulfuric acid, phosphoric acid or polyphosphoric acid, or organic acids such as sulfonic acid, thistechnique halide ions can be used and other water-soluble halide of an ionisable compounds, as, for example, haloge - nenye salts, cations which do not interfere with the reaction, for example, halides of alkali metals such as chlorides, bromides and iodides of potassium, sodium and lithium. The molar ratio of hydrogen ions and halide ions to IBPE (H+/IBPE and X-/IVRI) in each case is at least 0,20.Although it is not essential for carrying out the process in some cases, it may be a beneficial use for the reaction of an organic solvent. Organic solvents that can be used include, for example, ketones such as methyl ethyl ketone, acetone, aromatic hydrocarbons such as benzene and cyclic ethers such as tetrahydrofuran and dioxane. In the case of the use of a solvent is preferable to use ethers, and ketones. If you enter in the system catalytic palladium is in the form of metal or has a zero valence (Pdo), then any solvent used should be non. The solvent may be present in a ratio by weight of solvent to IBPE in the range of, for example, about (0-1000): 1, preferably about (0-10): 1.During the reaction it is also possible presence of inorganic salts. Norgani is, OSPAR, aluminum or silicon, including such anions as hydrosulfate, pyrosulfite, orthophosphate, pyrophosphate, aluminate or silicate and cations such as sodium, potassium, calcium or magnesium or other cations, which do not impede the reaction, for example, ammonium ions or alkylamine, such as tetrabutylammonium. Other inorganic salts such as calcium chloride, can also be added. Inorganic salt in the case of its use, as a rule, is present in a concentration of, for example, 0.1 to 50% , preferably 1-20% based on the whole weight of the load.In some cases, in the course of the reaction can produce undesirable high-boiling fraction, probably due to polymerization of unknown nature. Favorable action is to provide an introduction to the reaction mass of a polymerization inhibitor. Inhibitors that can be used for this purpose include, for example, tert-butylcatechol, hydroquinone, m-dinitrobenzene, P-nitrosodiphenylamine, picric acid, sodium sulfite, hangeron, etc. In the case of inhibitor that can be entered in the quantity, for example, 0.01 to 15% , preferably 0.1 to 15 wt. % in terms of mass IBFA.In addition to this you have the fact - none. The last additive, apparently, can be useful in improving the relationship of ibuprofen to the corresponding linear isomer, namely, 3-(4l-isobutylphenyl)- propionic acid (3-IFPC) using the method of the present invention.Used to get ibuprofen in the method of the present invention IBFA can be synthesized by various methods. Recommend, however, the carbonylation reaction with the receipt of ibuprofen combined with getting IBFA from isobutylbenzene, which is subjected to reaction Friedel-with azetiliruet tool with the formation of the 4I-isobutylacetophenone (IBAF), which is then reactivated by hydrogen in the presence of a catalyst or reducing agent, forming hydrogen with the formation of IBPA.Acetylation by Friedel-Crafts of isobutylbenzene with the formation of the 4I-isobutylacetophenone proceeds in accordance with the reaction equation II Rosina resistant reactor and the mixture was kept at a temperature of, for example, 0-120aboutFrom within, for example 0.5 to 5 hours, the Pressure is not critical and the reaction can be conducted at atmospheric or arising during the reaction pressure. When using as a catalyst HF he may Institute the reaction to provide the desired contact with HF liquid may be used an inert gas, such as nitrogen. Usually use an excess of HF, for example, 10-100 moles, preferably 25-75 moles per mole of isobutylbenzene initially present in the reaction zone.Hydrogenation or restore IBAF education IBFA carried out in accordance with reaction equation (III), where "(N)" means reaktsionnosposobnykh hydrogen in gaseous hydrogen, in the presence of catalytic hydrogenation or hydrogen-containing reducing agent such as sodium borohydride or socialwise hydride.Hydrogenation or recovery, as shown by the reaction equation (III) can be carried out, for example, by contacting IBAF in the form of a solution in an appropriate solvent with catalytic hydrogenation in the presence of hydrogen. The solvent can be, for example: methanol, ethanol, tert-butanol, water, alcohol, toluene, diethyl ether, tetrahydrofuran or 1,4-dioxane, and the ratio by weight IBFA: the solvent can be, for example, in the range of 1: 1-1: 100, preferably 1: 2-1: 20. The hydrogenation catalyst can be, for example, transition metal on the media. Recommended transition metals are Nickel, such as Raney Nickel, noble metals such as palladium, paying, the silica and polymer resin. The concentration of metal on the carrier in the ratio by weight of metal: the media may be in the range of, for example 1: 100-1: 2, preferably 1: 50-1: 10 and the ratio by weight of the catalytic system: IBAF may be, for example, in the range 1: 500-1: 2, preferably 1: 30-1: 5. If the reaction pressure of hydrogen may be, for example, in the range of 10-1200 psiq (0,7-84 MPa), preferably 75-300 psiq (5,3-21 MPa), the reaction temperature, for example, in the range of 10-150aboutWith, preferably 20-80aboutC and the reaction time in the range of, for example, from 0.25 to 10 hours, preferably 1-4 hours under certain conditions to prevent hydrogenolysis may be desirable to add a base or passivation of the reactor base.An alternative to the described hydrogenation reactions is the reaction of recovery is also reflected in equation (III), which is carried out, for example, by slow addition to the cooled solution IBAF in alcohol, such as methanol, ethanol or tert-butanol, or in a simple ether, such as tetrahydrofuran or diethyl ether reductant containing can be released hydrogen, for example: sodium borohydride or potassium or lithium-aluminiumhydride. Then the solution can be heated to canzonette, and comparative examples A-L show the results and conditions of experiments in which at least one of the conditions is not covered by the scope of the invention.Example 1 illustrates the receiving IBAF by acetylation by Friedel-Crafts of isobutylbenzene acetic anhydride as acetylides means in accordance with reaction equation (II), where X is acetoxygroup.P R I m e R 1. Isobutylbenzene (254 g of 1.9 mol) and acetic anhydride (385 g, and 3.8 mol) unloaded into the autoclave (Hast elloy C), which is cooled to 5aboutWith and elute (150 mm Hg). Add anhydrous hydrogen fluoride (1877, 94 mol) and the contents of the autoclave are heated 3 h at 80aboutC. hydrogen Fluoride release through leaching flask with alkali using for leaching of nitrogen. The contents of the autoclave are transferred into ice, neutralized with potassium hydroxide to pH 7 and extracted with ethyl acetate. The ethyl acetate solution is dried over anhydrous magnesium sulfate and after concentration under reduced pressure to get crude product. According to gas-liquid chromatography (GLC) the reaction proceeds with 85% conversion of isobutylbenzene and 81% selectivity to IBAF.Example 2 illustrates the receiving IMFA by hydrogenation using ka is the solvent of methanol.P R I m m e R 2. In a stainless steel autoclave of 300 ml 4 download-isobutylacetophenone (IBAF) (35.2 g, 0,2 mol), 100 ml of methanol and 5 g of 5% palladium on coal as a catalyst. The contents of the autoclave are heated 1 h at 30aboutC and a hydrogen pressure of 100 siq (7 MPa). The resulting mixture is filtered and the methanol removed in a rotary evaporator. According to GC, the reaction proceeds with 99.5% conversion IBAF and 96.6% selectivity to IBFA.Example 3 obtaining IBFA the hydrogenation IBAF by the method of example 2, but without solvent.P R I m e R 3. In the autoclave of 500 ml download IBUF (225 g of 1.26 mol), 5% Rabout/C (10 g, 4.7 mmole) and 2n. NaOH (0.2 ml). The autoclave three times washed with N2(100 psiq (7 MPa)/ double-H2/100 psiq (7 MPa)/. Pressure H2set in 125 psiq (9,5 MPa) and the contents of the autoclave was stirred at room temperature until the termination of absorption of H2. The catalyst is filtered off through a small column telicom. GLC analysis of the crude mixture showed the presence of 92% IBFA and 6.2% 1-(4I-isobutylphenyl)ethane. The mixture is purified by distillation under reduced pressure (so Kip. 85-88aboutC at 0.5 mm Hg) to obtain IBFA 96-97% purity.Example 3A illustrates obtaining IBFA Gadirov the financing of Raney Nickel in the absence of solvent.P R I m e R 3A. In a stainless steel autoclave of 500 ml download IBUF (225 g of 1.26 mol) and Raney Nickel (22,5 g of 0.38 mol). The autoclave three times washed with N2/100 psiq (7 MPa)/ double-H2/100 psiq (7 MPa)/. Pressure H2set in 125 psiq (9,5 MPa), so when the 70aboutWith the pressure in the reactor is equal to 220 psiq (15,4 ATI). The reaction mixture was stirred at 70aboutWith up to the date of termination of hydrogen (about 3 hours). The resulting mixture was filtered. GLC analysis showed the conversion IBAF 99% with a selectivity to IBFA and 1-(4I-isobutylphenyl)ethane respectively 98% and 1.5% .Examples 4-98 illustrates the method of the invention for receiving ibuprofen with carbonyliron IBFA, examples A-1 scope of the invention are not covered.P R I m e R s 4 and 5. In the autoclave of 300 ml (Hastelloy C) load 1-(4I-isobutylphenyl)ethanol (10 g, 56 mmol), PdCl2(PPh3)2(260 mg, 0.37 mmole), 10% HCl (25 g, 68 mmol of HCl, H+/H2O = 0,055) and benzene (27 ml), after which the autoclave is pressurized and twice washed with N2and WITH the. In an autoclave set pressure FROM 800 psiq (56 MPa) and the contents heated under stirring 16 h (example 4) or 6 hours (example 5) when 125-129aboutC. Then the autoclave is cooled to room temperature. WITH strauli the organic fractions are combined dried over anhydrous sodium sulfate and after concentration under reduced pressure get greenish oily product.P R I m e R 6-10. Reproduced the methods of examples 4 and 5, but in the autoclave also download 11 mmol fused potassium hydrosulfate (example 6), sulfuric acid (example 7), polyphosphoric acid (example 8), 11 mmol of potassium hydrosulfate and 0.6 mmole of tetrabutylammonium hydrosulfate (example 9) or 8 mmol of calcium chloride (example 10) and instead of benzene download 27 ml of methyl ethyl ketone (example 10). In addition, add 2.8 mmole of acetophenone in examples 7, 8 and 9 and 0.3 mmole of tert-butylate hin in example 9. The reaction time of 19 hours in examples 6, 7 and 8, and 6 h in examples 9 and 10.Obtained in examples 4-10 products analyzed (GC) content of ibuprofen, 3-(4I-isobutylphenyl)propionic acid, which is the linear isomer of ibuprofen (3-IPPC), 4-isobutylthiazole (CHD) and high-boiling components (VC), which are believed to consist of polymers 4-isobutylthiazole and other high-boiling compounds. The results are shown in table. 1 (where "CONV" denotes the percent conversion IBFA.Comparative examples A-F.In these examples illustrates the effect of the absence of neobhodimie a sufficient amount of hydrogen ions (examples C and D), the lack of a sufficient number of hydrogen ions coming from essentially completely an ionisable in a dilute aqueous solution of the acid (example E) and the lack of a sufficient number of ions of halogen (for example F).Reproduced by the method of example 6, but instead of 10% HCl use water (25 g examples a-E) or 29% H2SO4(27 ml, example F). In addition, in example F do not use potassium hydrosulfate, F instead of benzene use 27 ml of acetic acid, as the chlorine ions in the autoclave load 10 mmol of lithium chloride (example), 24 mmole of lithium chloride (example D) and 69 mmol potassium chloride (example E), also load of 0.3 mmole of tert-butylcatechol (examples A-D), 28 mmol of acetophenone (examples b and D) and 3.2 mmole p-mercaptoacetate (example E). The reaction time of 6 h in examples A, E and F, 8 h in the example, 7 h in the example and 48 h in example D. the results are shown in table. 2.Are given in table. 2 the results show that to achieve significant outputs of ibuprofen requires the presence of a minimum number as dissociated hydrogen ions coming from essentially completely ionized in dilute aqueous acid solution, and halogen ions and increase the time of reaction is by the use of sulfuric acid as a source of dissociated hydrogen ions instead of HCl.I used the technique of example 6, but instead of 10% HCl is used 40% sulfuric acid (25 g, 102 mmole, N.+/H2O = 0,123) in example 11, or 28.4% sulfuric acid (25 g, 71 mmol, N.+/H2O = 0,073) in examples 12 and 13 without adding potassium hydrosulfate in example 11. In addition, in example 11 add 70 mmol potassium chloride in example 12 add 69 mmol potassium chloride in example 13 add 69 mmol of potassium bromide as the source of halogen ions. Instead of benzene as the solvent used 25 ml of acetonitrile in example 12 and 25 ml of methyl ethyl ketone in example 13. In example 12 was added 0.3 mmole of tert-butylcatechol and in examples 11 and 13 added 2.8 mmole of acetophenone. The reaction time of 19 hours in example 11 and 6 h in examples 12 and 13. The results obtained are summarized in table. 3.Results table. 3 show that sulfuric acid is a satisfactory source of hydrogen ions that halide salts are effective sources of halogen ions and that acetonitrile is the least desirable solvent compared to other due to its tendency to promote the formation of high-boiling products at the expense of ibuprofen.P R I m e R 14-17. These examples illustrate the use of HBr as the source is 0% HCl as a source of hydrogen ions and halogen ions use of 16.2% HBr (25 g, 50 mmol, N.+/H2O - 0,044) in examples 14, 15 and 16 and 22,7% HBr (25 g, 70 mmol, N.+/H2O = 0,065) in example 17. As a solvent in examples 16 and 17 using methyl ethyl ketone (27 ml). In example 14 was added 3 mmole of tert-butylcatechol in example 15 was added 3.2 mmole of p-mercaptoacetate. The reaction time of 6 h in examples 14, 15 and 17, and 5.3 h in example 16. The results are shown in table. 4.Results table. 4 show that, for the purposes of the invention HBr is a satisfactory source of hydrogen ions and ions of keloid.P R I m e R 18. Reproduced by the method of example 17, but instead of the solution of HBr as a source of dissociated hydrogen ions using 34 g methanesulfonic acid (H+/H2O = 0,059), and as a source of halogen ions used 69 mmol sodium bromide. Conversion IBFA 99% , and the selectivity with respect to the following components: ibuprofen 71% , 3-IPPC 13% , CHD CL and VC 8% .Obtained in this example, the results show that the methane sulfonic acid is a satisfactory source of dissociated hydrogen ions for the purposes of the present invention.P R I m e R s 19-22. These examples illustrate the use of various additives to the systems the mole tert-butylcatechol in examples 19, 20, 21 and 22, 2.8 mmole of acetophenone in examples 20, 21 and 22 and 3.2 mmole of p-mercaptoacetate in example 22. The reaction time of 15 h in example 19, 20 h in examples 20 and 21 and 19 h in example 22. The results are shown in table. 5.P R I m e R s 23-30. These examples illustrate the application of the method of the invention various solvents.Reproduced by the method of example 6 but instead of benzene is used in 27 ml of the following solvents: toluene (example 23), tetrahydrofuran (example 24), dioxane (examples 25 and 26), acetone (example 27), methyl ethyl ketone (example 28) and acetonitrile (examples 29 and 30), in example 25 using 36 g of 10% HCl. In addition, added 0.3 mmole of tert-butylcatechol in examples 23-25, 29 and 30, 2.8 mmole of acetophenone was added in examples 23-25, 30, 3.2 mmole of p-mercaptoacetate added in examples 26 and 27. The reaction time of 6 h in the examples 23-29 and 19 h in example 30. The results obtained are summarized in table. 6.Results table. 6 show that the method of the invention can be used in a variety of solvents. However, the use of ketones and cyclic ethers, apparently, leads to higher outputs of ibuprofen compared to acetonitrile, which tends to promote the formation of higher concentrations VIII example illustrates the influence of the pressure in the reaction recovery at a minimum, less than required by the present invention.Repeated procedure of example 6, but the pressure in the reaction is 400 psiq (28 MPa) at room temperature. In addition, added 3.2 mmole of p-mercaptoacetate, reaction time 6 h Conversion IBFA 97% during the next selectivity education components: ibuprofen 20% , 3-IFPC 3, coronary heart disease 24% and VK 19% . The results show that when using a pressure below 500 psiq (35 MPa) there is a significant reduction of the yield of ibuprofen with increasing education 4-isobutylthiazole.Examples 31 and 32 and comparative examples H-I.These examples illustrate the effect of changes in the composition of the catalyst.Reproduced the methods of example 16 except that the reaction time of 6 h in examples 31, 32, 1 and 7 and 4.5 h in example N. The catalyst contains of 0.44 mmole PdCl2and 1.9 mmole of triphenylphosphine (PPh3) and add them separately in example 31, 0.37 mmole complex of example 4 and 0.7 mmole PPh3add separately in example 32, 1 g of 5% palladium on coal without adding phosphine ligand in the sample J and 8.4 mmole PdCl2without adding phosphine ligand in example I. In example H, the catalyst is not used. Instead of HBr in example J is used 25 g of 10% HCl and as dissolve the Leno 3.2 mmole of p-mercaptoacetate. The results obtained are summarized in table. 7.Results table. 7 show that the phosphine ligand may be added separately from palladium compounds with satisfactory outputs of ibuprofen, however, the palladium catalyst with ligand other than WITH required to obtain ibuprofen with satisfactory outputs. This was illustrated by examples 31 and 32 in comparison with the results of comparative examples H, I and J, and in the example of N does not apply to the catalyst as in examples I and J does not apply phosphine ligand.In examples 33 and 34 shows the effect of higher and lower temperatures compared to the temperatures used in the previous examples.P R I m e R s 33 and 34. Reproduced by the method of example 16, but the reaction time of 6 h and the reaction temperature 150aboutIn example 33 and 100aboutIn example 34. The results are shown in table. 8.Examples 35-38 show the effect of operating pressures FROM higher and lower than the pressure used in the preceding examples.P R I m e R s 35-38. I used the technique of example 16, but the pressure was varied in each example. The applied pressure and the resulting financial p is e after start of the reaction.P R I m e R s 39-41. Reproduced by the method of example 16, but in example 39 as a solvent instead of methyl ethyl ketone used 27 ml of acetone, and after the introduction of the original 56 mmol IBFA after 30 min added 196,8 additional mmole IBFA, the total time of 4.3 hours In example 40 to the original 56 mmol IBFA after 1 h, add another 56 mmol IBFA, the total reaction time of 6.5 hours Example 41 is similar to example 40, but as the solvent used 27 g of acetone and the total reaction time of 7 hours the results are shown in table. 10.Results table. 10 shows that the initial loading IBFA in the reaction mixture can be added an additional amount IBFA without reducing the output of ibuprofen to an undesirable level.P R I m e R s 42-50. These examples illustrate the obtaining of ibuprofen by carbonyliron IBFA with different loadings PdCl2(PPh3)2as a catalyst and different pressures.Examples carried out in an autoclave of 300 ml, which load 112 mmol IBFA, 54 ml of methyl ethyl ketone (MEK) as the organic solvent, 50 g of 10% aqueous HCl (which creates a constant molar ratio of N+/IBFA = 1,22 and N+/H2O = = 0,055) and various chalicer reaction. The contents of the autoclave are heated to a temperature, which for this series of examples is equal to 125aboutWith, and in the autoclave serves for setting the target pressure as the absorption of CO in the reaction. The reaction temperature is maintained throughout the reaction time, providing intensive mixing. The amount of catalyst in milimolar (Cat. ), achieved the molar ratio of palladium to IBFA (Pd: IBFA), the reaction time and pressure, as well as the results of the reaction terms of percent conversion IBFA (CONV. and percent selectivity with respect to ibuprofen (IBU), 3-(4I-isobutylphenyl)impregnated - about acid (3-IPPC), 4-isobutylthiazole (CHD) and high-boiling products (VK) are given in table. 11. These results and the results in the subsequent examples identified by GC with a maximum precision of 5% . This explains why in a separate selectivity and/or selectivity in some examples, more than 100% .P R I m e R s 51-61. These examples illustrate the effect of different relations of hydrogen ions and palladium to IBFA upon receipt of ibuprofen by carbonyliron IBFA.Reproduced the General procedure of examples 42-50 when used as an organic solvent 54 ml of MEK and various amounts of the pressures and different reaction time. Reaction conditions and the results are shown in table. 12.P R I m e R s 62-66. These examples illustrate the obtaining of ibuprofen by carbonyliron IBFA without adding organic solvent.Reproduced methodology examples 54-61 use 336 mmol IBFA and either 25 g of 20% HCl (H+/IBFA = 0,41, N.+/H2O = = 0,124) or 14 g of 36% HCl (H+/IBFA = 0,41, N.+/H2O = 0,278), 0,26 mmol of catalyst (Pd: IBFA = 1: 1292) and without organic solvent. The reaction temperature 125aboutC and a reaction time of 2 hours the Other reaction conditions and the results are shown in table. 13.P R I m e R s 67-70. These additional examples illustrate the acceptability of Hydrobromic acid as a source of hydrogen ions and halogen in the presence and in the absence of added organic solvent upon receipt of ibuprofen by carbonyliron IBFA.Reproduced the General procedure of examples 42-66 using different quantities IBFA and solvent MEK (including none). 16,2% HBr (H+/H2O = = 0,043) or 20% HB (N+/H2O = 0,056) and catalyst. The reaction temperature 125aboutC. the reaction Conditions and results are summarized in table. 14.E. when using at least one specific conditions, which is somehow different from the conditions described in the examples 42-70, including: the reaction temperature at 140about(Examples 71 and 72), the amount of hydrogen near the lower limit of the invention (examples 73, 74 and 75), the use of 11% HCl (H+/H2O = 0,061) and use as a solvent of dioxane (Diox. ) (examples 74 and 75).Reproduced the General procedure of examples 42 to 70 when using specific conditions, including those specified in the preceding paragraph. These conditions and the results are shown in table. 15.P R I m e R s 76-98. These examples illustrate the method of producing ibuprofen with carbonyliron IBFA according to the invention in an autoclave of 4 l when changing the reaction conditions, including higher molar relationship of Pd to phosphine ligand and HCl concentrations up to 5% (N+/H2O = 0,026).Reproduced the General procedure of examples 42-70 in the autoclave of 4 l when using the acid HCl and the solvent MEK or without solvent, but the catalyst enter separate amounts of palladium dichloride (PdCl2) and triphenylphosphine (PPh3), so that the ratio Pd: P changes in the described limits. Specific reaction conditions including a molar relationship Pallavicini conditions of comparative example 11 from Japan patent (kokai) N SHO 59 (1984)-95238 obtaining as a product of ibuprofen.P R I m e R K. Repeated the procedure of examples 42-75 in the autoclave of 300 ml, but the source material are 84,3 mmole IBFA, as acid is used 8% HCl (4 g, 8.8 mmole), at a molar ratio H+/IBFA = 0,1, use 0,471 mmole catalyst, and solvent are 61 g of dioxane, and the pressure FROM 1700 psiq (119 MPa), the reaction temperature 110aboutC, reaction time 5 hours Conversion IBFA 60% and achieved the following selectivity with respect to the products: ibuprofen and 38.6% , 3-IFPC of 1.4% , ischemic heart disease 2.4% and VK 59,3% .P R I m e R L. Replicated the methodology of example, but use 112 mmol, IFBA, 6 g 8% HCl (H+/IBFA = 0,1) and 82 g of dioxane. Conversion IBFA 68% when the following selectively in relationship to the components: ibuprofen 42% , 3-IFPC of 0.1% , ischemic heart disease 2.1% and VK of 43.5% .The results of examples K and L confirm that the conditions of the Japan patent, including the presence of dissociated hydrogen ions and halide in amounts far below the minimum required according to the method of the invention, lead to relatively low outputs of ibuprofen. (56) The Japan Patent 55 /1980/, 27147.The Japan Patent 59 /1984/, 95238.The Japan Patent 59 /1984/, 95239.Journ. chem. Soc. , 1956, 4943-4945.The Japan Patent 60 /1985/, 188643.The Japan Patent 56 /1981/, 35659. The of 1-(4'-isobutylphenyl)ethanol with carbon monoxide in an acidic aqueous medium in the presence of dissociated hydrogen ions and dissociated halide ions and catalyst at elevated temperature and pressure, characterized in that, to simplify the process, 1-(4'-isobutylphenyl)ethanol by the reaction of isobutylbenzene with azetiliruet agent in the presence of a catalyst of the Friedel -, restore the thus obtained 4-isobutylacetophenone in the presence of a hydrogenation catalyst or reducing agent containing active hydrogen, with a catalyst for carbonylation use complex of palladium chloride and phenylphosphino ligand, provided that the phosphine ligand is mixed with the organic phase of the reaction medium, the carbonylation is carried out at 100 - 150oC and at a pressure of carbon monoxide 42 - 324 ATM, at a molar ratio of palladium, phosphorus, and 1-(4'-isobutylphenyl)ethanol 1 : 2 -- 27 : 250 - 30100, respectively, and dissociatively hydrogen ions provided by the acid, which is essentially completely ionized in dilute aqueous solution so that the molar ratio of dissociated hydrogen ions and 1-(4'-isobutylphenyl)ethanol is added to the reaction zone is at least of 0.20 : 1.0, the molar ratio of hydrogen ions and water - at least 0,026 : 1,0, and dissociatively halide ions are present in such quantity the least 0,20 : 1,0.2. The method according to p. 1, characterized in that said phosphine ligand is triphenylphosphine ligand.3. The method according to PP. 1 and 2, characterized in that the catalyst used palladium dichloro-complex of bis(triphenylphosphine).4. The method according to PP. 1 to 3, characterized in that the source of dissociated hydrogen ions and dissociated halide ion is chloride or hydrogen bromide.5. The method according to PP. 1 to 4, characterized in that the method is carried out in an organic solvent selected from the group consisting of benzene, acetone, methyl ethyl ketone, tetrahydrofuran and dioxane.6. The method of obtaining 2-(4'-isobutylphenyl)propionic acid (ibuprofen), including carbonylation of 1-(4'-isobutylphenyl)-ethanol with carbon monoxide in an acidic-aqueous medium in the presence of dissociated hydrogen ions and dissociated halide ions and catalyst at elevated temperature and pressure, characterized in that, to simplify the process, as the catalyst use complex of palladium chloride and phenylphosphino ligand, provided that the phosphine ligand is mixed with an organic base in the reaction medium, when et is the rate of palladium, phosphorus and 1-(4'-isobutylphenyl)ethanol is 1 : 2 - 27 : 250 - 30100, respectively, and these dissociatively hydrogen ions provided by the acid, which is essentially completely ionized in dilute aqueous solution so that the molar ratio of dissociated hydrogen ions and 1-(4'-isobutylphenyl)ethanol is added to the reaction zone is at least of 0.20 : 1.0, the molar ratio of hydrogen ions and water is at least 0,026 : 1,0, and dissociatively halide ions are present in such capacity, that the molar ratio of halide ions and 1-(4'-isobutylphenyl)ethanol added to the reaction zone is at least 0,20 : 1,0.7. The method according to p. 6, characterized in that said phosphine ligand is triphenylphosphine ligand.8. The method according to PP. 6 and 7, characterized in that the catalyst used palladium dichloro-complex of bis(triphenylphosphine).9. The method according to PP. 6 to 8, characterized in that the source of dissociated hydrogen ions and dissociated halide ion is chloride or hydrogen bromide.10. The method according to PP. 6 to 9, characterized in that the method is carried out in organic Oksana.
FIELD: industrial inorganic synthesis.
SUBSTANCE: process is accomplished by continuously feeding methanol and/or reactive derivative thereof and carbon monoxide into carbonylation reactor filled with reaction mixture containing iridium carbonylation catalyst, methyl iodide cocatalyst, water in limited concentration, acetic acid, and methyl acetate, liquid reaction mixture further including at least one promoter selected from ruthenium, osmium, rhenium, and tungsten. Carbonylation of methanol to produce acetic acid involves reaction with carbon monoxide in liquid reaction mixture. When recovering acetic acid from liquid reaction mixture, concentration of water is maintained therein not exceeding 4.5%. During reaction, partial pressure of carbon monoxide in reactor is maintained within a range between 0 and 6 bar.
EFFECT: accelerated carbonylation reaction, diminished by-product formation, and simplified acetic acid recovery operation.
6 dwg, 3 tbl
FIELD: chemical industry; production of synthesis gas, methanol and acetic acid on its base.
SUBSTANCE: the invention is dealt with the methods of production of synthesis gas, production of methanol and acetic acid on its base. The method of upgrading of the existing installation for production of methanol or methanol/ ammonia provides for simultaneous use of the installation also for production of acetic acid or its derivatives. The existing installation contains a reformer, to which a natural gas or other hydrocarbon and a steam (water), from which a synthesis gas is formed. All the volume of the synthesis gas or its part is processed for separation of carbon dioxide, carbon monoxide and hydrogen. The separated carbon dioxide is fed into an existing circuit of synthesis of methanol for production of methanol or is returned to the inlet of the reformer to increase the share of carbon monoxide in the synthesis gas. The whole volume of the remained synthesis gas and carbon, which has not been fed into the separator of dioxide, may be transformed into methanol in the existing circuit of a synthesis of methanol together with carbon dioxide from the separator and-or carbon dioxide delivered from an external source, and hydrogen from the separator. Then the separated carbon monoxide is subjected to reactions with methanol for production of acetic acid or an intermediate compound of acetic acid according to the routine technology. A part of the acetic acid comes into reaction with oxygen and ethylene with formation of monomer of vinyl acetate. With the help of the new installation for air separation nitrogen is produced for production of additional amount of ammonia by the upgraded initial installation for production of ammonia, where the separated hydrogen interacts with nitrogen with the help of the routine technology. As the finished product contains acetic acid then they in addition install the device for production of a monomer of vinyl acetate using reaction of a part of the acetic acid with ethylene and oxygen. With the purpose of production of the oxygen necessary for production of a monomer of vinyl acetate they additionally install a device for separation of air. At that the amount of nitrogen produced by the device of separation of air corresponds to nitrogen demand for production of additional amount of ammonia. The upgraded installation ensures increased production of additional amount of ammonia as compared with the initial installation for production of methanol. The invention also provides for a method of production of hydrogen and a product chosen from a group consisting of acetic acid, acetic anhydride, methyl formate, methyl acetate and their combinations, from hydrocarbon through methanol and carbon monoxide. For this purpose execute catalytic reforming of hydrocarbon with steam in presence of a relatively small amount of carbon dioxide with formation of the synthesis gas containing hydrogen, carbon monoxide and carbon dioxide, in which synthesis gas is characterized by magnitude of the molar ratio R = ((H2-CO2)/(CO+CO2)) from 2.0 up to 2.9. The reaction mixture contains carbon monoxide, water -up to 20 mass %, a dissolvent and a catalytic system containing at least one halogenated promoter and at least one rhodium compound, iridium compound or their combination. The technical result provides, that reconstruction of operating installations increases their productivity and expands assortment of produced industrial products.
EFFECT: the invention ensures, that reconstruction of operating installations increases their productivity and expands assortment of produced industrial products.
44 cl, 3 ex, 6 dwg
FIELD: chemical technology.
SUBSTANCE: invention relates to a method for removing higher organic iodides from organic media. Method for removing organic iodides containing 10-16 carbon atoms from non-aqueous organic media containing organic iodides with 10-16 carbon atoms is carried out by contacting indicated organic media with silver- or mercury-exchange cationic, ion-exchange substrate at temperature from 50°C to 150°C. Invention proposes a method for removing iodides having 10-16 carbon atoms from acetic acid or acetic anhydride by providing flow of acetic acid or acetic anhydride containing organic iodide having 10-16 carbon atoms. Indicated flow is contacted with macroporous strong acid ion-exchange resin wherein at least 1% of active sites acquire form of silver or mercury at temperature in the range 50°C - 150°C. Indicated silver- or mercury-exchange ion-exchange resin removes effectively at least 90 wt.-% of indicated organic iodides from indicated flow of ready acetic acid or acetic anhydride. Also, invention proposes a method for removing organic iodides containing 10-16 carbon atoms from acetic acid or acetic anhydride involving contact of acetic acid or acetic anhydride comprising dodecyl iodide with silver- or mercury-exchange cationic ion-exchange substrate at temperature in the range 50°C - 150°C. Method provides the complete removing higher organic iodides from flow of acetic acid and/or acetic anhydride.
EFFECT: improved method for removing.
29 cl, 5 dwg, 13 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to technology for manufacturing acetic acid by the carbonylation reaction of methanol with carbon monoxide. Method is carried out in the continuous regimen in the carbonylation reactor wherein methanol and carbon monoxide are fed and catalytically active rhodium-comprising catalyst medium is maintained wherein this medium comprises the following components: water, 0.1-14 wt.-%; methyliodide, 1-20%; alkaline metal iodide salt, 2-20%; methyl acetate and acetic acid, 0.5-30%. The total pressure value in reactor is 15-40 atm. Flow of the reaction products is subjected for rapid evaporation and fed to the distillation stage comprising up to two distillation columns wherein purified acetic acid is separated and some flows recirculating into reactor. Removal of iodide impurities from the final product is carried out by contacting the flow with anion-exchange resin at temperature 100°C, not less, followed by purification stage with sulfocation-exchange resin in form of silver or mercury salt comprising 1% of active sites, not less, at temperature 50°C, not less. The level of aldehyde impurities in the flow recirculating into reactor is regulated by the distillation off method. The content of iodides in acetic acid is less 10 parts/billion. Method provides decrease of energy consumption and preparing acetic acid of high purity degree.
EFFECT: improved producing method.
28 cl, 3 tbl, 7 dwg, 12 ex
FIELD: chemical technology.
SUBSTANCE: invention relates to continuous method for production of acetic acid and/or methyl acetate based on known process of methanol or derivatives thereof (such as dimethyl ether, halogenated methyl or methyl acetate) carbonylation. Process is carried out in homogenous liquid phase under carbon monoxide pressure in presence of catalytic system containing rhodium-based homogeneous catalyst and halogenated promoter, in presence of water in reaction medium and in amount of not less than 14 mass %. In continuous process homogeneous catalyst composition is gradually changed by continuous or discontinuous addition of any iridium compound. Catalyst composition is transformed without process shutdown by transition from rhodium-based catalyst to rhodium/iridium-based catalyst or iridium-based catalyst. Iridium addition makes it possible to decrease water content in reaction system.
EFFECT: modified industrial process of methanol carbonylation by transformation of catalytic system.
19 cl, 7 tbl
FIELD: chemical technology.
SUBSTANCE: invention relates to technology for synthesis of acetic acid by the cabonylation reaction of methanol with carbon monoxide. Method involves preparing the productive flow in the reaction section containing acetic acid, acetaldehyde, water and other impurities. In the cleansing treatment the reaction products are subjected for treatment wherein acetaldehyde impurities are oxidized to either acetic acid after its isolation and recovered to the reaction zone or to carbon dioxide and water that removed from the system. As result, method provides excluding the negative effect of acetaldehyde at step for separation of the reaction products. Oxygen, air or their mixtures, ozone, carbon peroxide or peracetic acid are used as oxidant. As possible variants of the method, the productive flow is fed to distillation column wherein flow of light products or heavy products are isolated under condition that each of these flow involves acetic acid, acetaldehyde and water. Then "light" or "heavy" flow is subjected for oxidation as said above to reduce the concentration of acetaldehyde. As a variant of the method the flow of heavy products can be treated by extraction with water followed by oxidation of acetaldehyde-containing aqueous phase. Invention provides improvement of method due to exclusion of the necessity of purification of the end product from acetaldehyde impurity.
EFFECT: improved treatment method.
20 cl, 3 tbl, 35 ex
FIELD: industrial organic synthesis.
SUBSTANCE: invention relates to continuously producing acetic acid and/or methyl acetate via liquid-phase carbonylation of methanol or a suitable derivative thereof with carbon monoxide in presence of water and catalytic system. Reactor temperature and feeding rate of methanol or suitable methanol derivative are governed by carbon monoxide feeding rate and at least one of parameters determining composition of reaction mixture or removed gases. Preferably, government is effected over many-dimensional predicting regulator of preliminarily programmed electronic device. Concentration of water in reaction medium is maintained at level lower, higher or equal to 14 wt % and that of methyl acetate below 5 % based on the weight of reaction medium. Both concentrations are measured by means of analyzer functioning in neat infrared region.
EFFECT: optimized process conditions and increased yield of products.
19 cl, 2 dwg, 4 ex
FIELD: chemical industry; other industries; methods and devices for production of acetic acid.
SUBSTANCE: invention is pertaining to the production process of the acetic acid by carbonylation of methanol by carbon monoxide in the bubble reactor with fluidized heterogeneous catalyst. Carbonylation reaction is conducted at concentration of the solid catalyst of no less than 100 kg/m3 in terms of the volume of the reaction system. Catalyst is formed with the help vinylpyridine resin with the complex of rhodium deposited on it. Partial pressure of the carbon monoxide in the reactor is between 1.0 and 2.5 MPa, at that the degree of exhaustion of carbon monoxide is between 3 and 15 % of the theoretical reaction volume of carbon monoxide and reduced speed of the liquid is in the interval between 0.2 and 1.0 m/s. Promoter is methyl iodide, and acetic acid and methyl acetate are used in the capacity of the dissolvent. Concentration of water in the reactor makes from 2 up to 10 mass %. The bubble cylindrical reactor column used for realization of the method has the ratio its length L to the diameter D of no less than 8 and is equipped with the external line of circulation and the heat exchanger, which is built in the line of circulation. Besides, the bubble column has the holes used for injection of carbon monoxide, which are located at least on two levels, and also has the narrowed section in the lower part of the cylindrical reactor with the inner diameter from 30 up to 70 % from the rest part of the cylindrical reactor. The hole for injection of carbon monoxide is located in the upper part of the narrowed section for fluidization of the solid catalyst, while other hole for injection of carbon monoxide is located near to the coupling of the reactor and the outer line of circulation located on the bottom of the narrow section for separation and fluidization of the solid catalyst in the outer line of circulation. Technical result of the invention is improvement of the technological form of the production process with the increased yield of the end product.
EFFECT: invention ensures improvement of the technological form of the production process with the increased yield of the end product.
22 cl, 4 tbl, 4 dwg
FIELD: chemical technology.
SUBSTANCE: invention relates to technology for synthesis of acetic acid by carbonylation of methanol. Method for synthesis of acetic acid is carried out by the carbonylation reaction of methanol and/or its reactive derivative in one or some reactors in the liquid reactive composition comprising iridium catalyst for the carbonylation reaction, ruthenium promoter, methyl iodide co-catalyst, methyl acetate, acetic acid and water. Liquid reactive composition from one or some reactors is fed for one or some separation steps by a single equilibrium evaporation to yield (I) vapor fraction containing component able to condensing and exhausting gas of low pressure containing carbon monoxide, and (II) liquid fraction containing iridium catalyst for the carbonylation reaction, ruthenium promoter and acetic acid as a solvent. Components able for condensing are isolated from exhausting gas of low pressure. The concentration of carbon monoxide in exhausting gas is maintained according to the formula: Y > mX + C wherein Y means the molar concentration of carbon monoxide in exhausting gas of low pressure; X means the concentration of ruthenium in the liquid reactive composition as ppm; m means about 0.012, and C means about -8.7. The concentration of carbon monoxide in exhausting gas of low pressure is in the range from 55 to 65 mole%, and the concentration of ruthenium in the liquid reactive composition is up to 5500 ppm. Method provides decreasing loss of the catalyst components at step for isolation of acetic acid based on enhancing stability of the catalytic system.
EFFECT: improved method of synthesis.
29 cl, 6 tbl, 2 dwg, 34 ex
SUBSTANCE: invention pertains to perfection of the method of obtaining acetic acid with rate of volume flow of at least 15g-mol/l/h, a catalytic carbonylation reaction, involving reaction of a compound, chosen from a group containing methanol, methyliodide, methylacetate, dimethyl ether, or their combination, in the presence of carbon monoxide and a catalyst system based on rhodium in a reaction mixture, where the reaction mixture consists of not less than 2.0% mass, water, metal, in concentration of at least 1000 h/million, chosen from a group containing rhodium and a combination of rhodium and iridium, iodide ion in concentration from 2 to 20% weight, and a halogen promoter, chosen from a group, containing halogen-hydrogen, alkyliodide, iodine salt or acetate salt of a group IA metal, group II metal, quatanary ammonium salt, phosphoric acid salt, or their combination in concentration from 2.0% mass to 30.0% mass. The method is used for attaining reaction speed of at least 15 g-mol/l/h. The invention also pertains to the method of obtaining acetic acid from a carbonylation reaction in a system, consisting of a reaction zone and a cleaning zone, and involves the following stages: (a) reaction of methanol, methyliodide, metylacetate, dimethyl ether or their combination with carbon monoxide in the presence of a catalyst system based on rhodium in a reaction mixture, with water content from 0.1% mass to 5.0% mass, iodide ion in concentration from 2 to 20% mass, and a halogen promoter, chosen from a group, containing halogen-hydrogen, alkyliodide, iodine salt or an acetate salt of a group IA metal, group IIA metal, quaternary salt of ammonia, phosphoric acid salt or their combination, in concentration from 2.0% mass to 30.0% mass, and (b) putting a compound, chosen from a group, consisting of methylacetate, dimethyl simple ether, acetic anhydride and their mixture in the reaction zone.
EFFECT: perfection of the method of obtaining acetic acid.
26 cl, 1 dwg, 4 ex, 1 tbl