The method of obtainingarylpropionic acids

 

(57) Abstract:

Usage: in the pharmaceutical industry to obtain non-steroidal compounds with antipyretic, anti-inflammatory and non-narcotic analgesic action. The essence of the invention: improved method of obtaining a - arylpropionic acids nesimetricnim catalytic hydrogenation of derivatives of alpha-relacional acid in the presence of a ruthenium-phosphine catalyst at a temperature below 30oC and corresponding pressure of hydrogen. Preferably the process is conducted in the presence of a base using as the catalyst complex of the formula [Ru(BINAP)XY]nwhere BINAP means a tertiary phosphine of the formula:

< / BR>
in which R1is hydrogen, alkyl, aralkyl, alkaryl, X and Y are nejelanie or recoordination anions of the formula Br-, CL-, F-, Y-BF-4, ClO-4PF-6,, BF4n= 1-10, 8 C.p. f-crystals, 7 PL.

The invention relates to an improved method of asymmetric catalytic hydrogenation ailability of acids to produce the corresponding a-arylpropionic acids with high enantiomeric excess forms. More specifically, the invention from the possible, high pressure in the presence of catalysts for asymmetric hydrogenation. Improved method of asymmetric catalytic hydrogenation proposed in the invention, particularly suitable for use in the synthesis of naproxen (naproxen). Thus, the preferred application of this invention is the synthesis of 2-(6'-methoxy-2'-naphthyl)propionic acid (naproxen) and intermediates obtained and used in this synthesis.

Naproxen is a nonsteroidal compound that has anti-inflammatory, non-narcotic analgesic and antipyretic action. He belongs to the group of compounds are usually classified as arylpropionate acid or arylalkylamine acids, which include naproxen, ibuprofen (ibuprofen), Ketoprofen (ketoprofen), fenoprofen (fenoprofen), suprofen (suprofen), flurbiprofen (flurbiprofen), benoxaprofen (benoxaprofen), pirprofen (pirprofen) and carprofen (carprofen). Each of the compounds in this group connects what they are derivatives of propionic acid.

It was suggested many ways of synthesis to obtain arylpropionic acids and, in particular, naproxen. The first attempts to synthesize these compounds has led to smese mixture, to get more active isomer, as, for example, in the case cinchonidine (cinchonidine) or glutamine (glucamine). However, these separation methods require numerous precrystallization, and, consequently, industrial unattractive.

Recently, attempts were made to obtain pharmaceutically used optical isomer in greater numbers than physiologically inactive isomer, which led to the simplification of the methods of separation. For example, in U.S. patent 4,542,237 method for obtaining a-arylpropionic acid and, in particular, the method of producing naproxen, which includes non-catalytic rearrangement of ketala or thioketal 2-hydroxy-1'-(6'-methoxy-2'-naphthyl)-propane-1-she activating oxypregnanes etherification agent with formation of the corresponding alkilarilsulfonov or ticketline essential substrate. Simultaneous or sequential hydrolysis leads to the formation of the corresponding arylpropionic acid, 2-(6'-methoxy-2'-naphthyl)propionic acid [Piccolo et al. J.Org, Chem. 52, 10-14, (1987) and references below] However, in most cases, the production of the desired isomer with excess enantiomeric forms is limited and still requires numerous perakis is responsible to additional increase the enantiomeric excess of the desired isomer. These methods, however, limited by the output of the desired optical isomer in enantiomeric mixture, sufficient to greatly simplify separation methods. For example, Campolmi et al. (U.S. patent 4,239,914) proposed catalytic asymmetric hydrogenation of 2-(6'-methoxy-2'-naphthyl)acrylic acid using a chiral bidentate complex of phosphine. Preferred compounds include 1,2-ethandiyl-bis(ortho-methoxyphenyl)phenylphosphine (DIPAMP), [2,3-O-isopropylidene-2,3-dioxy-1,4-bis (diphenylphosphine)butane] (DIOP) and N,N'-bis[(+)-a-methylbenzyl]-N, N'-bis(diphenylphosphino)Ethylenediamine (PNNP). Catalytic asymmetric hydrogenation is carried out with the DIOP catalyst at a temperature of 25oC and a hydrogen pressure of 1 and 3.5 at (approximately 15 psi and about 52 psi, respectively) and at the 50oC and a pressure of 3.5 at. Such hydrogenation is also carried out in the presence of a catalyst PNNP at 20oC and 1 at. It is reported that the enantiomeric excess (E. I.) of the desired product is about 70% or less.

Although Campolmi et al. discovered that the hydrogenation can be conducted at temperatures from 0 to 70oC and pressures from 1 to 50 at, however, in Asymmetric Catalysis NFTO ASI Series. Series E: Applied Science, p.p. 24 26, B. Bosnish Editor, Martinus Nijhoff Publishers (1986), was the message, the values of hydrogen above 1 at, leads to reduced the enantiomeric excess (see also Asymmetric Synthesis so 5 "Chiral Catalyst", pp. 60-62, J. D. Morrison, Editor, Academic Press, Inc. 1985).

B J. Org. Chem. 52, 3174-76 (1987), Noyori et al. there was a message about the asymmetric hydrogenation of 2-(6'-methoxy-2-naphthyl)acrylic acid in the presence of catalytic amounts of Ru[(S)2,2'-bis-diphenylphosphino-1,1'-binaphthyl] (OCOCH3)2marked as EN[S-BINAP] (OCOCH3)2when the pressure 112 psi for 24 h, apparently, in absolute methanol at a temperature of 15-30oC (although the latter is not obvious) with 100% conversion, leading to the obtaining of naproxen with high yield and high stereoselectivity.

In EP 0272787, published in 1988 described the catalytic obtaining optically active acids, in particular carboxylic acids of General formula:

< / BR>
where R1, R2, R3selected from the group of hydrogen, alkyl, alkenyl, phenyl, naphthyl which may be substituted,

the hydrogenation of , -unsaturated acid of the formula

< / BR>
in an aprotic solvent, mainly in the presence of equimolar amount of the tertiary amine and the optically active Ru-phosphine complex as a catalyst at a pressure of 4-135 kg/cm2by distillation of the solvent.

Preischemia from 1 to 100 hours at a temperature of 0-80oC and a pressure of from 4 to 135 kg/cm2.

However, the given examples show that successful asymmetric hydrogenation alkenylboronic and arlenovich acid conditions are not identical, and that the conditions specified in the patent, do not provide products with stable high enantiomeric excess and high total yield.

The task of the invention to provide-arylpropionic acids with high enantiomeric excess optical isomer and a high total yield in industrial-suitable conditions.

The task is solved by a method of obtaining a-arylpropionic acid by catalytic asymmetric hydrogenation of a-arylpropionic acid in the presence of ruinirovannogo catalyst under hydrogen pressure, suitable for asymmetric catalytic hydrogenation at a temperature below 30oC and corresponding pressure of hydrogen.

Preferably the process is conducted in the presence of a base, such as triethylamine.

Especially, it is desirable to conduct the process at a temperature of approximately 15oC or lower and a pressure of 5 kg/cm2and above, in particular at a temperature of -5oC and a pressure of 36 MPa.

In the most preferred retinirovannyh complex of the General formula:

[Ru(BINAP)XY]n< / BR>
where BINAP means a tertiary phosphine of the formula:

< / BR>
where

R' is hydrogen, substituted or unsubstituted alkyl, C1-C4substituted or unsubstituted aryl, aralkyl or alkaryl;

X and Y nejelanie or recoordination anions, is independently selected from the group consisting of bromide, chloride, fluoride, iodide, BF-4, ClO-4PF-6, BPh-4;;

n 1-10, and to carry out the process at temperatures below 30oC.

Preferably the process is carried out at a temperature of approximately 15oC or below.

The specified catalyst is particularly effective when using a base, such as the lower trialkylamine or hydroxide of an alkali metal. Satisfactory results are obtained without using the base.

The above and ruthenium complexes with chiral phosphine compounds described in Asymmetric Synthesis, I. 5 "Chiral Catalyst" (1985) and Asymmetric Catalysts, NATO ASI Series, Series E (1986), as mentioned above. Other catalysts of the type DIPAMP are the catalysts described in U.S. patent 4,142,992 (W. S. Knowles et al.). Getting bisphosphine compounds proposed in U.S. patent 4,008,281 too Knowles, W. S. et al. Optically active binaphthyl compounds in more detail apicary type DIOP) more specifically provided in U.S. patent 4,142,992.

Thus, a suitable catalyst for the asymmetric hydrogenation is chosen from the group consisting of ruthenium complex containing optically active bisphosphinic the compounds of formula:

< / BR>
where

A and B each independently represents substituted and unsubstituted alkyl, C1-C12substituted and unsubstituted cycloalkyl C4-C7substituted or unsubstituted aryl; provided that such substituents do not create significant steric around the phosphorus atom, and A and B are different from each other; b) optically active bisphosphonate binaphthalene compounds of the formula [Ru(BINAP)] (OCOR)2and RuxHyClz(BINAP)2(S)pwhere BINAP represents a tertiary phosphine of the formula:

< / BR>
where

R1matter R3listed below

S is a tertiary amine and, when y is 0, x 2, z 4, then p is 0 or 1 if y 1, x 1, z 1, then p 0; in) of ruthenium catalysts containing chiral phosphines represented by the formula:

< / BR>
where R2represents substituted and unsubstituted alkyl, C1-C12substituted and unsubstituted cycloalkyl C4-C7substituted and unsubstituted aryl, aralkyl and alkaryl; g) complexes fashinable a phosphine of the formula:

< / BR>
where R3represents substituted and unsubstituted alkyl, C1-C6substituted and unsubstituted halogenated alkyl, C1-C6substituted and unsubstituted aryl and substituted and unsubstituted aralkyl and alkaryl; R4represents hydrogen, substituted and unsubstituted alkyl, C1-C6substituted and unsubstituted alkoxyl C1-C6; R5represents alkyl, C1-C6substituted and unsubstituted aryl; and S is a tertiary amine, and when y is 0, x 2, z 4, then p is 0 or 1, and if y 1, x 1, z 1, then p 0.

In practice, there are many other catalysts for asymmetric hydrogenation and it can be expected that such catalysts can be also successfully used in the present invention. The preferred catalyst is an optically active binaphthalene connection ruthenium, better chloro-derivative, and not acetylpromazine. Exemplary catalysts include [RuCl2(BINAP)]2[NEt3] RuHCl[BINAP]2, Ru[BINAP](BF4)2. Additional examples binaphthalene catalysts are those which are produced by interaction of the chloride complex of ruthenium with binaphthalene ligand. In addition, examples are those cat is UP>4and/or those in which binarily ligand substituted billnum ligand. These types of catalysts is presented in the patent SHA 4,766,255 as being unsatisfactory for obtaining optical isomers. At present, however, it has been discovered that the use of such catalysts for the catalytic hydrogenation-ailability acids gives the corresponding a-arylpropionic acids with high enantiomeric excess.

Catalytic hydrogenation with the use of such catalysts is conducted according to known standard methods in a homogeneous system comprising a catalyst, an organic solvent and possibly a base, preferably an organic base, such as nitrogen-containing base, such as triethylamine, tributylamine and other organic elements, preferably other tertiary amines. Examples of suitable inorganic bases are sodium hydroxide and potassium hydroxide. The use of reason, especially with ruthenium catalyst, favors the increase of the enantiomeric excess a-arylpropionic acid. It was found that when the substrate is applied with a ruthenium catalyst, a satisfactory result is practically in all cases it is preferable to use temperatures below 15oC.

The molar ratio of catalyst/substrate can be varied from 1:20 to 1: 20000, preferably from 1:100 to 1:10000. The preferred molar ratio of catalyst/substrate is about 1:10000. The molar ratio of substrate/nitrogenous base can be varied from 100:1 to 1:5, from 10:1 to 1: 1. The weight ratio of substrate/solvent can be varied from 1: 10000 to 1:1, from 1:100 to 1:3. The catalysts can be used in the form of a complex of the bis-olefin, arena or coordinated compounds.

In accordance with the invention receives, in particular, naproxen with high enantiomeric excess of the desired optical isomer asymmetric hydrogenation of 2-(6'-methoxy-2'-naphthyl)-acrylic acid in the presence of ruthenium coordination complex as a catalyst for asymmetric hydrogenation, such as, for example, bis-phosphine catalyst for hydrogenation. In this way the increase of the enantiomeric excess simplifies phase separation.

The presented invention is also directed to the full method of obtaining 2-arylpropionic acids, especially on the receiving naproxen, and intermediate products obtained and used in this way is Rabotnov acid electrochemically carboxylating of arylketones.

Detailed description of the invention.

As mentioned above, the presented invention is the discovery that a-ailability acid, such as 2-[6'-methoxy-2'-naphthyl]acrylic acid, can be converted into the corresponding a-arylpropionic acid with unexpectedly high excess enantiomeric forms, when conducting the reaction at low temperatures and, possibly, high pressure hydrogen in the presence of a catalyst for asymmetric hydrogenation. Examples a - ailability acids used in the present invention include acid represented by the formula:

< / BR>
where

Ar is chosen from para-isobutylphenyl, 6-chlorambucil-2, 3-phenoxyphenyl, 2-isopropylidene-5, 2-fluoro-4-biphenyl and 6-methoxy-2-naphthyl. Preferred-relacional acid is 2-[6'-methoxy-2'-naphthyl]acrylic acid.

a-Ailability acid used in the invention can be obtained by using well-known techniques. The preferred technique involves dehydration of the acid-treated electrochemically carboxylating arylketones corresponding to the specified a-relacional acid. a-Arylketones produced by methods well known in practice. the Zuya as starting material 2-methoxynaphthalene.

The method of electrochemical carboxylation of a-arylketones, and subsequent treatment with an acid are described in U.S. patent 4, 601, 797, shown above as a reference. The method consists in the electrolysis at the cathode of arylketones in the presence of carbon dioxide, which is carried out in an electrolytic environment for the implementation of the accession of carbon dioxide to arylketones. Electrochemically carboxypropanoyl arylketones then treated with acid and obtain the corresponding 2-aryl-2-oxopropionate acid.

Then 2-aryl-2-oxopropionate acid dehydration, using well-known methods of dehydration, obtaining the appropriate a - relacional acid. The preferred method of dehydration involves the use of a suspension of fused potassium bisulfate in chlorobenzene at 130oC for 15 h can Also be used for other solid catalysts, such as KHSO4(dry, not fused), sulfonic acids associated with the polymer (resin), etc.

In order to increase the reaction rate, chlorobenzene can be replaced by dichlorbenzene, and the reaction is carried out at 150-160oC for 2 or 3 hours it is Also possible to use other solvents, such is the congestion and the substrate relacional acid. In order to achieve a high yield of the desired product,you can use a small number of compounds that bind free radicals, namely from 100 to 10,000 parts per million based on the number of 2-aryl-2-oxopropanoic acid. Examples of compounds that bind free radicals, are 2,6-di-tert.-butyl-4-were, substituted or unsubstituted hydrochinone, delayintolerant, etc., the Preferred connection binding free radicals, is 2,6-di-tert. -butyl-4-METHYLPHENOL. Such compounds that bind free radicals, can be used by themselves and in combination with other compounds.

Then a - ailability acid asymmetrically hydronaut at low temperature, using a catalyst for asymmetric hydrogenation. The hydrogenation reaction is carried out at a temperature below 15oC, better below 10oC, namely at a temperature below or equal to 5oC. the Lower limit temperature at which carry out the reaction is not critical, since the temperature can be up to -15oC and you can get excellent results from a high enantiomeric excess of the desired product.

The hydrogenation reaction can PROPADIENE above 5 MPa, for example, when 73 MPa. The upper limit on the hydrogen pressure is not critical, however, this upper limit will depend on the capabilities of the equipment.

The preferred synthesis of naproxen includes the following sequence of reactions and the catalytic hydrogenation related to this invention will be carried out as the last stage:

< / BR>
In this preferred synthesis of the first stage is a typical synthesis of ether on Williams, which consists in the reaction of 2-oxidation (1) with meteorous agent such as dimethylsulfate, obtaining 2-methoxynaphthalene (2). On the other hand, 2-methoxynaphthalene industrially available and manufactured by a company Sigma-Aldrich.

The second stage of the synthesis involves the reaction of acylation by Friedel-Crafts 2-methoxynaphthalene (2) to obtain the corresponding 2-acetyl-6-methoxynaphthalene (3). The acylation derivatives of naphthalene (reaction Friedel -) is a well-known method, which is described in Jap. SHO 59-51234.

The third stage involves electrochemical carboxylation of acetyl fragment 2-acetyl-6-methoxynaphthalene (3) with subsequent acid treatment to obtain 2-(6'-methoxy-2'-naphthyl)-the th treatment with an acid is described fully in U.S. patent 4,601,797.

Dehydration (4) to obtain 2-(6'-methoxy-2'-naphthyl)acrylic acid (5) is conducted in the fourth stage at 106oC for 3 h, using a suspension of fused potassium bisulfate in 1,2-dichlorobenzene, as described previously. As stated above, you can also use other acidic catalysts.

Thus, on the one hand, the presented invention is directed to a method of obtaining-arylpropionic acids with high enantiomeric excess forms using the catalyst for asymmetric hydrogenation at a temperature below -30oC, preferably below 15oC and, perhaps, when the hydrogen pressure above 5 MPa.

On the other hand, the presented invention is directed to an asymmetric catalytic hydrogenation of the product of dehydration of spent acid elektricheski carboxylating of arylketones.

Another aspect of the presents invention is that it is directed to a method of producing naproxen catalytic asymmetric hydrogenation product of dehydration of the acid-treated electrochemically carboxylating 2-acetyl-6-methoxynaphthalene.

Equivalents of the above catalysts and compounds, as well as etc usual varieties of deputies. In addition, in cases where the Deputy is defined as hydrogen, or can be hydrogen, the exact chemical nature of the substituent in the same position and which is other than hydrogen, is not decisive, because it is not negatively affect the General methods of synthesis.

Experienced specialist without further elaboration, using this description can apply the presented invention with the greatest success. Therefore, preferred specific examples should be considered as merely illustrative and not limiting in any way the invention.

Optical yields were determined according to standard methods for the rotation of the plane of polarization or by chiral gas chromatography of the corresponding ether derivatives of menthol (industrial available (+)-isomer, obtained from Sigma-Aldrich), using the column CHIRASILVAL-L, obtained from Chrompack.

Example 1. This example illustrates the effect of reaction temperature on the enantiomeric excess (E. I. ) of the desired product obtained by catalytic asymmetric hydrogenation according to the invention.

In enameled reactor stainless steel downloaded 0.02 g a-(6'-metoclo according to the method described in U.S. patent 4,142,992, and 4 g of methanol. The solution was well stirred with a magnetic stirrer at different temperatures and pressures of hydrogen for 16 hours. The results are shown in table.1.

It should be noted that in the presence of DIPAMP catalyst reduction temperature leads to a significant increase in the enantiomeric excess of the desired product. For example, comparing the experiences of "a" and "b", the reduction of temperature from 23 to 5oC leads to an increase in E. I. 7% Further decrease in temperature of 10oC, -5oC, as in the experience of "C" leads to an overall increase in the enantiomeric excess (E. I.) 18.8% in Addition, when comparing experiments "a", "d" and "e" shows that the increase in hydrogen pressure from 5.8 to 50.8 MPa leads to an increase in E. I. 19% and an additional increase in pressure of 7.3 MPa, i.e. up to 58.1 MPa leads to an overall increase of E. I. 26%

Example 2. This example illustrates the effect of temperature in the presence of various catalysts for asymmetric hydrogenation. In enameled stainless steel autoclave with a capacity of 50 ml, equipped with a magnetic stirrer, was placed a-(6'-methoxy-2'-naphthyl)acrylic acid (obtained as in example 3) in the amount indicated in the table. 2, one equivalent of triethylamine, 3 g Dogo catalyst). Then the solution was altered at the temperature and pressure of hydrogen (their values are given in table.2) within the time specified here.

When comparing experiments "a" and "c" shows that the combination of low temperature and high pressure leads to an increase in E. I. 18% in the presence of a catalyst DIOP. Similarly, the comparison of experiments "d" and "g" indicates that the combination of low temperature and high pressure leads to an increase in E. I. 35% in the presence of BINAP catalyst. In addition, the decrease in temperature without increasing the pressure results, as shown by comparison of experiments "e" and "g" and experiments with "d" and "h", to the increase of E. I. constituting from 10% at higher pressures, i.e., to 72.6 MPa to 23% at nominal pressures of 14.5 MPa.

Example 3. This example illustrates the preferred receiving naproxen according to the proposed invention.

Synthesis of 2-acetyl-6-methoxynaphthalene

In a three-neck flask with a capacity of 2 l, equipped with a mechanical stirrer, was placed 700 ml of nitrobenzene. The solvent was cooled to approximately 10oC in an ice bath and added to it with stirring to 54.4 g (0,408 mole) aluminum chloride. After the dissolution of AlCl3to the solution was added of 56.5 g of 2-methoxynaphthalene (0,36 mo is kusnoy acid, maintaining the temperature of the mixture about 8oC. Upon completion of the addition stirring is continued at the 8oC for 3 hours and Then the stirring was stopped and the flask was placed in a bath with a high temperature. Redakcionnuyu the mixture was stirred at 402oC for 20 hours and Then the contents of the flask were poured into a large chemical beaker containing 1 l of ice water and 100 ml of concentrated hydrochloric acid. The cooled mixture was stirred with a magnetic stirrer for 30 min, then left to stand for 20 min for separation of the phases. (To facilitate separation of the phases to the mixture is usually added about 100 ml of chloroform).

The organic layer was collected and washed with dilute sodium bicarbonate solution, and then ion exchange water (2-3 times until neutral).

Organic solvents drove in a rotary evaporator, and the residue was distilled on the surf Kugelrohr (0.5 mm Hg, 100-120oC). The crude yellow product (68 g), collected in the receiver was recrystallized from 100 ml of hot methanol, cooling the solution to about 5othroughout the night. The white crystals were filtered off and washed twice with 50 ml of cold methanol. After drying in vacuum for 24 h received the Lee and evaporated to dryness. According to the1H NMR analysis of the residue contained about 4 g of 2-acetyl-6-methoxynaphthalene and about 5 g of 1-acetyl-2-methoxynaphthalene. Then they can be separated by crystallization.

Synthesis of oxynitrogen [a-(6'-methoxy-2'-naphthyl)lactic acid]

The reaction vessel of a capacity of 1 l was equipped with a lead cathode (100 cm2), aluminum anode (100 cm2and a mechanical stirrer. In this reactor were added 10 g of 2-acetyl-6-methoxynaphthalene, 15 g of tetrabutylammonium bromide (electrolyte) and 500 ml of dried DMF. The mixture was stirred to obtain a homogeneous solution, and then was cooled to about 0oC, barbotine through it drained CO2-gas. After 30 min of ozonation CO2(in order to saturate the solution of CO2) was included constant current of 0.6 a, 11 b), which was passed through the solution, continuing the stirring solution and bubbling through it CO2. The electrolysis was continued for 5 hours After turning on the current and cessation CO2dimethylformamidine the solution was collected in a round bottom flask. The solvent drove on rotary vacuum pump, and the residue was good which for 3 h with about 100 ml of water. The solid was filtered, and then was stirred for 3 the mi-water (about 30 ml). The product was dried in vacuum for 3 days. According to the analysis, this dry powder contained 8.8 g a-(6'-methoxy-2'-naphthyl)lactic acid and 1.8 g of 2-acetyl-2-methoxynaphthalene (educt). The original substance is removed from a product by repeated washing with toluene.

Synthesis of 2-(6'-methoxy-2'-naphthyl)acrylic acid

In a round bottom flask with a capacity of 250 ml were placed 7.5 g a-(6'-methoxy-2'-naphthyl)lactic acid, 12.5 g of fused potassium bisulfate, 0,007 g delayintolerant, 0.02 g of 2,6-di-tert. -butyl-4-METHYLPHENOL and 80 ml of 1,2-dichlorobenzene (solvent). The mixture was well stirred for 3 h at 160oC, and then filtered. The solid is washed with 100 ml of hot methylene chloride and filtered. The filtrates were combined and evaporated to dryness on a rotary vacuum pump. Received 2-(6'-methoxy-2'-naphthyl)acrylic acid with a yield of 95%

Hydrogenation of 2-(6'-methoxy-2'-naphthyl)acrylic acid

In a stainless steel autoclave with a capacity of 100 ml were placed in a nitrogen atmosphere 5 g of 2-(6'-methoxy-2'-naphthyl)acrylic acid, 2.2 g of triethylamine, 0.04 g of [Ru2Cl4(S-BINAP)2]NEt3and 80 ml of methanol. The mixture was well stirred at -2oC and the hydrogen pressure to 58.1 MPa for 16 hours According to the analysis, the solution stereorama for completion of the reaction may be less.

Example 4. This example illustrates the extremely high enantiomeric excess obtained with the use of catalytic complexes chloro-Ru-BINAP, and explains the best way of conducting asymmetric hydrogenation of a-ailability acids with the same catalyst. The first two catalyst are given in table.3, obtained by the method specified in EP 0272787 A2, and all the catalysts used in such a molar ratio substrate/catalyst/solvent/amine, which is similar to the ratio shown in example 3. Carried out the reaction between a derivative of ruthenium chloride and cycloocta-1,5-diene (COD) in ethanol solution, and then the reaction of one mole of the resulting complex with 1.2 moles of a suitable BINAP derived by heating in a solvent such as toluene or ethanol, in the presence of 4 moles of a tertiary amine such as triethylamine. All hydrogenation was carried out in the presence of triethylamine (1 mol/mol), unless otherwise noted.

Example 5. This example illustrates the effect of temperature and pressure, I. E. when the hydrogenation of 2-(6'-methoxy-2'-naphthyl)acrylic acid (obtained as described in example 3), in the presence of a catalyst [Ru2Cl4(BINAP)2] (NEt)3(in terms of analogichnye the effect of temperature and pressure on the E. I. for naproxen, when using as the catalyst Ru(BINAP) (OAc)2in the presence of triethylamine (obtained by the method of Noyori et al.) in conditions analogous to example 5. The results are shown in table.5.

Example 7. This example illustrates the effectiveness of the use of reason in asymmetric hydrogenation of a-ailability acids. The results are shown in table.6.

Example 8. This example illustrates the hydrogenation of 2-(para-isobutylphenyl)acrylic acid to obtain 2-(para-isobutylphenyl)propionic acid using conventional methods of hydrogenation described in example 3. As the catalyst used [RuCl2(S-BINAP)]2NEt3and as the Foundation of the triethylamine. In each experiment the yield of 2-(para-isobutylphenyl)propionic acid (in the form of a salt of triethylamine) sotalol 100% the Results are shown in table.7.

It is assumed that the use of other catalysts for asymmetric hydrogenation, such as complexes of other optically active bisphosphine compounds, bearily compounds and binaphthalene compounds will lead to the same results, if you follow the instructions in the invention.

The preceding examples can be repeated with analine.

Listed below are the methods and prmery receiving and data 31P NMR used in the invention catalysts.

The method of obtaining.

Catalysts of the formula [Ru(BINAP)XY]ncan be obtained by the interaction of the ruthenium complex anion, i.e., ruthenium chloride, ruthenium bromide, ruthenium iodide, fluoride, ruthenium, etc., including mixtures thereof, with cycloocta-1,5-diene(COD) in a suitable solvent for the formation of [RuXY(COD)]nwhich is then subjected to interaction with the connection BINAP when heated (primer, when the distillation temperature of the solution) and in a suitable solvent system. Suitable solvents for the complex interaction EN-anion with COD include ethanol, propanol, isopropanol, etc., a Suitable solvent system for interaction [RuXY(COD)]nconnection BINAP include solvents in the form of organic acids, such as acetic acid, propionic acid, butyric acid, etc., including mixtures thereof. Such solvents can also be combined with non-polar organic solvents, such as arene solvents such as benzene, toluene, etc. and mixtures thereof. In that case, if the solvent system is a mixture of organicheskie this mixture may lie in the range from 1:10 to 10:1. The ratio of solvent in the form of organic acids to non-polar organic solvent is preferably 1:1.

Example A. In the bulb-type Fischer-porter, equipped with a magnetic stirrer in the form of a rod, put 0,43 g of [Ru(COD)Cl2]n(from Morton Thiokol), 1 g of S-BINAP (from Aldrich) and 80 ml of degassed acetic acid. The mixture permissively in nitrogen atmosphere at a temperature of 115oC for 18 hours the Solvent is evaporated in vacuum and the residue was converted into a powder, and it was used as a catalytic mixture of the formula [Ru(BINAP)Cl2]n. According to elemental analysis of this crude mixture the molar ratio of Ru/BINAP/Cl is 1/1,2/1,9.

Example B. In the bulb-type Fischer-porter capacity of 100 ml were placed 0,103 g [RuCl2(COD)]n(0,365 mmol), 0,0227 g S-BINAP (0,365 mmol) and 5 ml of degassed acetic acid and 5 ml of degassed toluene. The mixture was thoroughly stirred with a magnetic stirrer in a nitrogen atmosphere at a temperature of 116oC for 17 hours by Evaporation of the solvent in vacuo got to 0.29 g of a red solid product formula [Ru(BINAP)Cl2]n. This red solid product can be used as a chiral catalyst. Preferably this product can be add to the toluene, etc.

1. Way to obtain-arylpropionic acids of the catalytic asymmetric hydrogenation of-arylpropionic acid in the presence of an optically active ruthenium-phosphine catalyst under hydrogen pressure, suitable for catalytic asymmetric hydrogenation, characterized in that the catalytic asymmetric hydrogenation is carried out at a temperature below 30oWith and corresponding pressure of hydrogen.

2. The method according to p. 1, characterized in that the catalytic asymmetric hydrogenation is carried out in the presence of a base, such as triethylamine.

3. The method according to p. 1, characterized in that the catalytic asymmetric hydrogenation is carried out at a temperature of approximately 15oC or lower and a hydrogen pressure of 5 ATM or higher.

4. The method according to p. 3, wherein the process is conducted at -5oC and a hydrogen pressure of about 36 atmospheres.

5. The method according to p. 1, characterized in that as a catalyst for asymmetric hydrogenation take a ruthenium-phosphine complex of the General formula

[Ru(BJNAP)XY]n,

where BYNAP a tertiary phosphine of General formula

< / BR>
where R' is hydrogen, substituted or unsubstituted WITH1-C6-alkyl, substituted or unsubstituted aryl, Ara is lorida, fluoride, iodide, BF4, ClO4PF6, BPh4,

n 1 10,

and the process is conducted at a temperature below 30oC.

6. The method according to p. 1, characterized in that the as - arylpropionic acid take 2-(6'-methoxy-2'-naphthyl)propanolol acid obtained by dehydration of 2-(6'-methoxy-2'-naphthyl)-2-hydroxypropionic acid, obtained by electrochemical carboxylation of 2-acetyl-6-methoxynaphthalene and subsequent processing of the product acid, having obtained 2-acetyl-6-methoxynaphthalene by acylation according to the Friedel-Crafts 2-methoxynaphthalene obtained by esterification of 2-hydroxynaphthalene by Williamson.

7. The method according to p. 1, characterized in that-arylpropionic acid is an acid selected from the group comprising naproxen, ibuprofen, Ketoprofen, pirprofen, suprofen, fenoprofen, flurbiprofen, benoxaprofen and carprofen.

8. The method according to p. 7, characterized in that the above-arylpropionic acid selected from naproxen or ibuprofen.

9. The method according to p. 8, wherein the specified-arylpropionic acid is naproxen.

The priorities of the signs and items:

22.06.89 hydrogenation is conducted at temperatures below 15oAnd pressu

 

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