Method for asymmetrical hydrogenation of acrylic acid derivatives, catalysed by transition metals, and novel catalyst system for asymmetrical catalysis with transition metals

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method for asymmetrical hydrogenation, catalysed by transition metals, acrylic acid derivatives of formula (I), in which R1 denotes H or optionally substituted C1-C20-alkyl, C5-C20-aryl or C5-C20-heteroryl radical, R2 denotes optionally substituted C1-C20-alkyl, C5-C20-aryl or C5-C20-heteroaryl radical, and R3 denotes H or C1-C6-alkyl radical, which involves hydrogenation of compounds of formula (I), optionally in a solvent, in the presence of one or more hydrogen donors, using a catalyst system which contains a transition metal selected from ruthenium, rhodium and iridium and a combination of a chiral phosphoric ligand of formula (II), in which Cn, together with two oxygen atoms and a phosphorus atom, form an optionally substituted ring, having 2-6 carbon atoms, and R4 denotes an optionally substituted alkyl, aryl, alkoxy- or aryloxy-radical or a NR5R6 group in which R5 and R6 can be independently hydrogen or optionally substituted alkyl, aryl, aralkyl or alkaryl radical, or together with a nitrogen atom can form a ring, and an achiral phosphinic ligand of formula (III), in which R is optionally substituted alkyl or aryl radical, to obtain corresponding compounds of formula (IV) in which each R1, R2 and R3 are as described above. Formula (I), Formula (II), Formula P(R)3 (III), Formula (IV).

EFFECT: improved method for asymmetrical hydrogenation.

20 cl, 3 tbl, 29 ex

 

The technical field to which the invention relates.

The present invention relates to a method of asymmetric hydrogenation of derivatives of acrylic acid, which is catalyzed by transition metals, such as derivatives of alpha-substituted cinnamic acid, into the corresponding chiral acid or esters, as well as a new catalytic system, with a specific ligand system consisting of chiral phosphorus ligand and achiral phosphine ligand asymmetric catalysis.

Derivatives of acrylic acid derivatives such as alpha-substituted cinnamic acid, are valuable intermediate compounds for pharmaceutical preparations, such as Delta-amino-gamma-hydroxy-omega-arylalkylamines, which have the renin-any abscopal properties and can be used as protivogipertonicheskoe funds in pharmaceutical preparations.

The level of technology

The catalysts and methods of asymmetric hydrogenation of unsaturated compounds catalyzed by transition metals, already described in literature

For example, in WO 02/02500 noted that the asymmetric hydrogenation of alpha, beta-unsaturated carboxylic acids using homogeneous catalysts, asymmetric hydrogenation is essentially known and what is ASMA effective catalysts for this process are ruthenium and rhodium catalysts. Used ligands are chiral di-tertiary diphosphine. With the help of these systems according to WO 02/02500 can be achieved values of the optical output of up to 80%. In WO 02/02500 to improve these catalysts is proposed to use bidentate ligand with the main structure ferrocenyl.

Log Adv. Synth. Catal. 2003, t, p.160-164, described more diphosphine ligands based on ferrocenyl-aryl core structure, known as a family of ligands "Volvos", which are used in asymmetric hydrogenation of olefins and ketones on rhodium or ruthenium catalysts. The ligands Volvos used in combination with the compound of ruthenium or rhodium, for example, Ru(methylallyl)2COD, [(NBD)2Rh]BF4or [(COD)2Rh]BF4for example, in the process of hydrogenation of derivatives of cinnamic acid, which is achieved by optical purity up to 95% EE.

The disadvantage of this method, in particular, is the high cost of the ligand Volvos, because its synthesis is very complicated.

In WO 02/04466 disclosed additional catalysts, which have a monodentate ligand. However, it was found that monophosphine catalytic system described in this document, they have less activity against derivatives of cinnamic acid, in particular, this requires the I longer hydrogenation, and this leads to the formation of excess enantiomers of low quality.

In WO 2004/035208 described mixture monophosphoric compounds as ligand systems for asymmetric catalysis by transition metals. Example 8 in this application it is known that a mixture of chiral pozvonochnyh or fofanah of achiral ligands and monophosphine ligand leads to significantly worse results concerning the optical purity than in the case of mixtures of chiral monophosphine connections.

Because there is a great need for improved methods with improved catalytic systems in the field of asymmetric hydrogenation of acrylic acid derivatives, the present invention is to develop a method of asymmetric hydrogenation of acrylic acid derivatives catalyzed by transition metals, as well as a new catalytic system that provides a simple, inexpensive method of obtaining the desired compounds having a higher optical purity, compared with the prior art, up to 100%, and with higher outputs, up to 100% of theoretical.

Accordingly, the present invention provides a method of asymmetric hydrogenation catalyzed by transition metals, acrylic acid derivatives of the formula (I)

p> in which R1represents H or optionally substituted C1-C20-alkyl, C5-C20-aryl or C5-C20-heteroaryl radical, R2means optionally substituted C1-C20-alkyl, C5-C20-aryl or C5-C20-heteroaryl radical and R3means N or C1-C6is an alkyl radical, which comprises the hydrogenation of compounds of formula (I), optionally in a solvent, in the presence of one or more hydrogen donors, using a catalytic system, which contains the transition metal from the group of ruthenium, rhodium and iridium, and a combination of chiral phosphorus ligand of the formula (II)

in which Cn, together with two oxygen atoms and the phosphorus atom, form an optionally substituted ring having from 2 to 6 carbon atoms, and R4represents an optionally substituted alkyl, aryl, alkoxy or aryloxyalkyl or a group NR5R6in which each R5and R6independently can be hydrogen or optionally substituted alkyl, aryl, Uralkali or alcuronium radical, or together with the nitrogen atom can form a ring, and achiral phosphine ligand of the formula (III)

in which R is what I optionally substituted alkyl or aryl radical, obtaining the corresponding compounds of the formula (IV)

in which each R1, R2and R3has the above value.

The used substrates are derivatives of acrylic acid of the formula (I)in which R1means H or optionally substituted C1-C20is an alkyl radical, or optionally substituted C5-C20-aryl or C5-C20-heteroaryl radical and R2represents an optionally substituted C1-C20is an alkyl radical, or optionally substituted C5-C20-aryl or C5-C20-heteroaryl radical.

It should be understood that the term alkyl radicals means a linear, branched or cyclic alkyl radicals having from 1 to 20 carbon atoms, an alkyl chain which optionally may contain one or more double or triple bonds or it may be interrupted by one or more heteroatoms from the group N, O and S.

Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, propenyl, n-butyl, tert-butyl, cyclopentyl, butinyl, n-hexyl, cyclohexyl, isooctyl, undecyl, neuleptil, pentadecyl, tetrahydropyrrole, tetrahydrofuranyl, dimethyl sulphide and other

Preference is given to linear, branched and cyclic alkyl radicals, having from 1 to 12 carbon atoms, an alkyl chain which optionally may have a double or triple bond and optionally may contain a heteroatom.

Aryl and heteroaryl radicals are aromatic radicals having 5 to 20 carbon atoms, such as cyclopentadienyl, phenyl, diphenylol, indenyl, naphthyl, pyrrolyl, furanyl, indolyl, pyridinyl and other Preference is given to phenyl or naphthyl.

Radicals can be mono - or polyamideimide suitable substituents.

Suitable substituents are, for example, With1-C20-alkoxygroup, preferably1-C12-alkoxygroup,1-C20is an alkyl group, preferably1-C6-alkyl, C6-C20-aryl group, preferably phenyl, trifter-C1-C6-alkyl, preferably trifluoromethyl, poly-C1-C20-alkoxygroup, halogen atom such as F, Cl, Br or I, hydroxyl, amino, nitro, nitrile, carboxylic acid, esters of carboxylic acids or carboxamide and other

Particularly preferred substituents are1-C6-alkoxygroup,1-C6is an alkyl group, trifluoromethyl, a poly-C1-C6-alkoxygroup, F, Cl or Br.

R3is a or N, or C1-C6is an alkyl radical.

Especially preferred is equipment substrates are those compounds of formula (I), in which R2represents phenyl or1-C6alkyl group, and R1is optionally mono - or polyamidine phenyl radical, and R3means N.

The method according to the invention for asymmetric hydrogenation catalyzed by transition metals acrylic acid derivatives of the formula (I) proceeds in the presence of one or more hydrogen donors. In this regard, it should be understood that the term donor hydrogen means compounds that are capable of transferring hydrogen to the substrate, such as H2, aliphatic or aromatic alcohols With1-C10for example isopropanol or cyclohexanol, unsaturated hydrocarbons having 5 to 10 carbon atoms, for example 1,4-dihydrobenzo or hydroquinone, or a mixture of formic acid and triethylamine, and others (see WO 02/04466).

In some cases, such as in the case of alcohol or hydrocarbon, the hydrogen donor can also serve as a solvent, so there is no need to use an additional solvent.

Preference is given to using N2as a donor of hydrogen. In the method according to the invention, the hydrogen pressure is from 1 to 200 bar, preferably from 10 to 150 bar and more preferably from 15 to 100 bar.

The process temperature is between -20 and +120°C, preferably from 0 to 80°C and b is more preferably from 20 to 65°C.

Preferably asymmetric hydrogenation is carried out in the absence of oxygen.

The method according to the invention is not necessarily carried out in a solvent.

Preferred solvents are organic solvents, for example alcohols, esters, amides, ethers, ketones, aromatic hydrocarbons and halogenated hydrocarbons. Particular preference is given to using protonotaria solvents.

Examples of preferred solvents are ethyl acetate, methanol, isopropanol, acetone, tetrahydrofuran, dichloromethane, toluene or dibromide.

In addition, if desired, you can use a mixture of one or more of the above solvents with water. In this case, the volume ratio of solvent to water is preferably from 2:1 to 8:1, more preferably from 3:1 to 6:1. Preference is given to mixtures of one or more protonotaria solvents with water, resulting from the use of this technique can be achieved by a certain increase of the enantiomeric purity of the product.

The preferred solvent for the method according to the invention is a mixture of isopropanol and water.

The catalyst used according to the invention is a catalytic system which comprises a transition metal from groups who Utena, rhodium and iridium, and a combination of chiral phosphorus ligand of the formula (II) and achiral phosphine ligand of the formula (III).

Preferred transition metal is ruthenium or rhodium, more preferably rhodium.

The chiral ligands of the formula (II) are known and described, for example, in WO 02/04466 or WO 2004/035208.

In the formula (II) alkyl, aryl, alkoxy, aryloxy, kalkilya or alkaline groups preferably have 1 to 20 carbon atoms and may be optionally substituted by one or more substituents from the group of hydroxyl, alkyl, alkoxy, phenyl, nitrile, ether carboxylic acids or halogen.

More preferably, the radical R4in the formula (II) may be optionally substituted linear, branched or cyclic With1-C8-alkyl radical, optionally substituted phenyl radical, optionally substituted C1-C8-alkoxyalkyl, optionally substituted panelaccordion or NR5R6the group, which independently each a radical R5and R6preferably is optional phenylseleno alkyl group having 1-6 carbon atoms, more preferably having 1-3 carbon atoms, or together with the nitrogen atom form a ring which, in addition, optionally may contain a heteroatom such as O, N or S, the example morpholino ring, piperidine ring, pyrolidine ring and other More preferably R5and R6together with the nitrogen atom form a 5-membered or 6-membered ring which may optionally contain a heteroatom.

Preferably Cn represents a chiral substituted C4chain (chain 4 optionally substituted carbon atoms) with a predominantly one configuration, for example, with an enantiomeric excess of greater than 95%, preferably more than 99%.

More preferably the group Cn together with the two oxygen atoms and the phosphorus atom forms a 7-membered ring containing 4 carbon atoms, in this case, every two carbon atoms are part of the optionally substituted aryl group.

More preferably the aryl group is an optionally substituted phenyl or naftalina group. Preferably the substituents are attached in ortho-position.

Examples of preferred chiral ligands of the formula (II) are compounds of the formulas (IIa) and (IIb)

where raftiline groups are not necessarily mono - or polyamideimide halogen, for example chlorine or bromine, alkyl, preferably1-C6-alkyl, or alkoxy, preferably1-C6-alkoxy, aryl, site is preferably a phenyl, aryloxy, preferably phenyloxy, R4represents an optionally substituted C1-C6is an alkyl radical, optionally substituted phenyl radical, optionally phenylselenenyl1-C8-alkoxyalkyl or optional1-C6-alkyl substituted phenyloxirane, and each radical R5and R6independently represents an optional phenylseleno alkyl group having 1-6 carbon atoms, more preferably 1-3 carbon atoms, or together with the nitrogen atom forms a ring.

In addition, the preferred chiral ligands of the formula (II) are compounds of the formulas (IIc) and (IId)

where phenyl group optionally is mono - or polyamideimide halogen, for example chlorine or bromine, alkyl, preferably1-C6-alkyl, or alkoxy, preferably1-C6-alkoxy, aryl, preferably phenyl, aryloxy, preferably phenyloxy, R4is optionally substituted C1-C6-alkyl radical, optionally substituted phenyl radical, optionally phenylselenenyl1-C8-alkoxyalkyl or optional1-C6-alkyl substituted by panelaccordion, and independently each R5and R6 is an optional phenylseleno alkyl group having 1-6 carbon atoms, more preferably having 1-3 carbon atoms, or together with the nitrogen atom they form a ring.

Particularly preferred chiral ligands of the formula (II) are compounds of formula (IIe) and (IIf)

in which R4represents an optionally substituted C1-C6is an alkyl radical, optionally substituted phenyl radical, optionally phenylselenenyl1-C6-alkoxyalkyl or optional1-C6-alkyl substituted phenyloxirane, each radical R5and R6independently represents a C1-C6-alkyl group or together with the nitrogen atom forms a 5-membered or 6-membered ring, which optionally may also contain an oxygen atom or sulfur, and R7is a linear or branched C1-C6-alkyl radical, optionally substituted phenyl radical, optionally phenylselenenyl1-C6-alkoxyalkyl or optional1-C6-alkyl substituted by panelaccordion.

In addition, particularly preferred chiral ligands of the formula (II) are compounds of formula (IIg) and (IIh)

in which R4represents an optionally substituted C1-C6is an alkyl radical, optionally substituted phenyl radical, optionally phenylselenenyl1-C4-alkoxyalkyl or optional1-C6-alkyl substituted phenyloxirane, each R5and R6independently represents a C1-C6is an alkyl group or, together with the nitrogen atom, forms a 5-membered or 6-membered ring, which optionally may also contain an oxygen atom or sulfur, and each R7and R8represents a linear or branched C1-C6is an alkyl radical, optionally substituted phenyl radical, optionally phenylselenenyl1-C6-alkoxyalkyl, or optional With1-C6-alkyl substituted panelaccordion.

Used chiral ligands have an enantiomeric purity of at least 50%, preferably at least 90% and more preferably more than 99%.

As the second ligand catalyst system used according to the invention, contains achiral phosphine ligand of the formula (III) P(R)3in which R does not necessarily represent substituted alkyl or aryl radical.

Preferably R is a linear, branched or cyclic Alky the capacity radical, having from 2 to 10 carbon atoms, more preferably having from 4 to 6 carbon atoms, or a phenyl radical, optionally mono - or politeley halogen or alkyl With1-C2.

Particularly preferred radicals are phenyl, ortho-tolyl, meta-tolyl, para-tolyl, xylyl, meta-chlorophenyl, para-chlorophenyl, ortho-methoxyphenyl, para-methoxyphenyl, meta-methoxyphenyl, mesityl, cyclohexyl, n-butyl and tert-butyl.

The ratio of the chiral ligand of formula (II) and achiral ligand of formula (III) in the method according to the present invention is from 10:1 to 1:5, preferably from 5:1 to 1:2, more preferably from 2.5:1 to 1.2:1.

The catalytic system according to the invention can be obtained in the same manner as in WO 02/04466.

Preference is given to the interaction of the chiral ligand and achiral ligand with a precursor of a catalyst containing a transition metal.

Examples of suitable precursors of the catalyst are (COD = 1, 5cyclooctadiene, NBD = norbornadiene) [Rh(COD)2Cl]2, [Rh(COD)2]BF4, [Rh(NBD)2]BF4, Ru(SLA)3, Ru(methylallyl)2COD, [Ru(cimal)Cl2]2and other

The molar ratio of the transition metal in the catalyst : the chiral ligand is from 1:0.5 to 1:5, preferably from 1:1 to 1:2.

The molar ratio of reagent : transitional IU is all in the catalyst is from 100:1 to 1,000,000:1, preferably from 1000:1 to 10000:1.

In the method according to the invention, for example, the substrate of formula (I), ligands of formulas (II) and (III) the predecessor, which contains the transition metal is dissolved in a solvent, in a suitable reactor, for example in an autoclave. Then the reactor is preferably rinsed with an inert gas such as nitrogen, if it is desirable to exclude oxygen. The mixture is then heated to the desired process temperature. However, preferably first dissolved in a solvent, only the substrate, then the reactor is preferably rinsed with an inert gas. Then, after heating to the appropriate temperature process, a substrate solution load the suspension ligands having formula (II) and (III)in degassed solvent and the precursor, which includes a transition metal.

Subsequently, when a suitable process temperature add the hydrogen donor. Preference is given to hydrogen, which is injected to a specified pressure. After the process is complete, and optional cooling of the reaction mixture of the target end product produce by conventional methods, depending on the state of aggregation of matter.

In addition, it is possible that the catalyst complex is first prepared, for example, by the interaction of ligands (II) and (III) precursor in degassed solvent is ri room temperature, under stirring reactions mixture for a certain period of time. Then distilled volatile compounds in order to obtain a solid complex catalyst, which in the following is added to the substrate solution.

Using the method according to the invention, and particularly with the use of specific catalytic system it is possible to carry out the hydrogenation of acrylic acid derivatives, first, with significantly less cost compared with the prior art and, secondly, with a remarkably high enantioselectivity. The upshot is a final product having a higher optical purity.

In addition, the present invention provides a catalytic system for asymmetric catalysis with transition metals, which includes a transition metal of groups VIII, IX or X of the periodic table and the combination of chiral phosphorus ligand of the formula (IIa), (IIb), (IIe) or (IId) and achiral phosphine ligand of the formula (III), R(R)3in which R represents optionally substituted alkyl or aryl radical.

The catalytic system according to the invention is suitable for asymmetric catalysis with transition metals, especially for asymmetric kadrirovania unsaturated compounds catalyzed by transition metals.

In the case the ratio of the chiral ligand of formula (IIa) - (IId) and achiral ligand of formula (III) may range from 10:1 to 1:5. Preferably this ratio is from 5:1 to 1:2, more preferably from 2.5:1 to 1.2:1.

Suitable transition metals are the elements of groups VIII, IX or X. Preference is given to using ruthenium, rhodium or iridium.

In addition, the present invention provides the use of a catalytic system according to the invention for the asymmetric hydrogenation of unsaturated compounds catalyzed by transition metals.

Example 1. Obtaining (R)-5-methoxy-3-(3-methoxypropane)-α-(1-methylethyl)-phenylpropane acid

In an autoclave with a capacity of 450 ml suspended 50 g (178,35 mmol) of E-2-[[5-methoxy-3-(3-methoxypropane)phenyl]methylene]-3-methylbutanoic acid, 100 mg (0,234 mmol) of the ligand of formula (IIe) (>95%) of (2,6-dimethyl-3,5-dioxa-4-phosphacyclohexane[2,1-a;3,4-a']dinatale-4-yl)piperidine, or 47.6 mg (0,1172 mmol) of Rh(COD)2BF4and 30.8 mg (0,117 mmol) of triphenylphosphine in 160 ml of isopropanol (IPA):N2O=4:1. The autoclave rinsed 5 times with nitrogen and heated to 55°C. Then, the autoclave rinsed 3 times with hydrogen and then create pressure H280 bar without stirring. Then under a pressure of 80 bar at 55°C and the stirring speed of 100 rpm, the mixture is subjected to hydrogenation in the night. After 18 hours, the autoclave is cooled and produce the target product.

In the course of equal 50,35 g (96,6% of theory).

Optical purity 95.3% of it.

Examples 2-8

Carry out the hydrogenation of alpha-methylcatechol acid analogously to example 1. Choose from the following process conditions:

1 mmol of substrate, the reaction temperature 30°C; pressure H225 bar; 4 ml solvent IPA:H2O=4:1, the reaction time is 16 hours; 0.01 mmol catalyst Rh(COD)2BF4, 0.02 mmol of chiral ligand, as in example 1, 0.01 mmol achiral ligand P(R)3; the values of R are listed in table 1.

Table 1
Example No.R%
2phenyl88
3ortho-tolyl97
4meta-tolyl87
5xylyl89
6meta - chlorophenyl89
7para-chlorophenyl90
8 cyclohexyl87

In all examples was achieved the degree of conversion of 100%.

Examples 9-13

Analogously to example 1 carried out the hydrogenation of derivatives of substituted acrylic acid of the formula

Specific values of the radicals R1and R2shown in table 2. Choose from the following process conditions:

1 mmol of substrate, the reaction temperature 30°C; pressure H225 bar; 4 ml solvent IPA:H2O=4:1, the reaction time is 16 hours; 0.01 mmol catalyst Rh(COD)2BF4, 0.02 mmol of chiral ligand, as in example 1, except that the ring in some cases contains an oxygen atom (see table 2), 0.01 mmol achiral ligand P(R)3; the values of R shown in table 2.

td align="left">
Table 2
Example No.R1R2RRing% eea
9methylmethylphenylO87
10phenylisopropylo-tolylCH299b
113,4-methoxyphenylisopropylphenylCH292
124-CF3phenylisopropylm-tolylCH295
13*phenylphenylo-tolylCH295
* Example 13 were conducted at 60°C.
(a) the Degree of transformation in all examples 100% except example 10bwith a conversion of 98%.

Comparative examples

Carry out the hydrogenation of alpha-methylcatechol acid analogously to examples 2-8. For comparison in each case is gidrirovanie carried out once with a ligand system according to the invention, which consists of a combination of chiral ligand and achiral ligand PPh3and one time only using the chiral ligand (without achiral ligand).

Choose from the following process conditions:

1 mmol of substrate, reaction temperature 60°C; pressure H225 bar; 4 ml solvent IPA:H2O=4:1, reaction time 5 hours; 0.01 mmol catalyst Rh(COD)2BF4, 0.02 mmol of chiral ligand of the following formula, 0.01 mmol achiral ligand P(R)3.

The time duration L1A:NR5R6= N(methyl)2L2a:NR5R6= N(methyl)2
L1b:NR5R6= morpholineL2b:NR5R6= morpholine
L1c:NR5R6= piperidineL2c:NR5R6= piperidine
L1d:NR5R6= (R)-α-is ethylbenzylamine L2d:NR5R6= pyrrolidin

Table 3
Comparative experimentThe ligandThe degree of conversion (%)its (%)
1The time duration L1A438
2The time duration L1A+PPh310043
3L1b720
4L1b+PPh310055
5L1c760
6L1c+PPh310063
7L1d910
810037
9L2a9110
10L2a+PPh310080
11L2b823
12L2b+PPh310080
13L2c812
14L2c+PPh310085
15L2d8616
16L2d+PPh310076

1. Way asymmetric hydrogenation catalyzed by transition metals, acrylic acid derivatives of the formula (I)

in which R1represents H or neoba is consequently replaced With 1-C20-alkyl, C5-C20-aryl or C5-C20-heteroaryl radical, R2means optionally substituted C1-C20-alkyl, C5-C20-aryl or C5-C20-heteroaryl radical, and R3means N or C1-C6is an alkyl radical, which comprises the hydrogenation of compounds of formula (I), optionally in a solvent, in the presence of one or more hydrogen donors, using a catalytic system, which contains the transition metal from the group of ruthenium, rhodium and iridium, and a combination of chiral phosphorus ligand of the formula (II)

in which Cn, together with two oxygen atoms and the phosphorus atom, form an optionally substituted ring having from 2 to 6 carbon atoms, and R4represents an optionally substituted alkyl, aryl, alkoxy or aryloxy-radical or the group NR5R6in which each R5and R6independently can be hydrogen or optionally substituted alkyl, aryl, Uralkali or alcuronium radical, or together with the nitrogen atom can form a ring, and achiral phosphine ligand of the formula (III)

in which R is optionally substituted alkyl or aryl radical, with the floor is the treatment of the corresponding compounds of the formula (IV)

in which each R1, R2and R3has the above value.

2. The method according to claim 1, in which solvents are suitable hydrogen donors or alcohols, esters, amides, ethers, ketones, aromatic hydrocarbons and halogenated hydrocarbons, optionally in combination with water.

3. The method according to claim 2, in which solvents are used in combination with water, and the volume ratio of solvent to water is from 2:1 to 8:1.

4. The method according to claim 3 in which the solvent used is a mixture of 2-propanol and water in a volumetric ratio of from 3:1 to 6:1.

5. The method according to claim 1, in which the applicable donor hydrogen is hydrogen.

6. The method according to claim 1, wherein the process temperature is between -20°C and +120°C.

7. The method according to claim 1, in which the used chiral ligands have an enantiomeric purity of at least 90% of it.

8. The method according to claim 1, in which the used transition metal is ruthenium or rhodium.

9. The method according to claim 1, in which the use of chiral ligands of the formula (II), where the radical R4represents an optionally substituted linear, branched or cyclic C1-C8is an alkyl radical, optionally substituted phenyl radical, optionally substituted C1-C8-alkoxyalkyl, optional the nutrient substituted panelaccordion or NR 5R6the group, which independently each a radical R5and R6preferably is optional phenylseleno alkyl group having 1-6 carbon atoms, or together with the nitrogen atom form a ring which optionally may contain a heteroatom.

10. The method according to claim 1, in which the use of chiral ligands of the formulae (IIa), (IIb), (IIC) or (IId)


where raftiline and phenyl groups optionally is mono - or polyamideimide halogen, alkyl, alkoxygroup, aryl or arroceros, R4represents an optionally substituted C1-C6is an alkyl radical, optionally substituted phenyl radical, optionally phenylselenenyl C1-C8-alkoxyalkyl or optional C1-C6-alkyl substituted phenyloxirane, and each radical R5and R6independently represents phenylseleno alkyl group having 1-6 carbon atoms, or together with the nitrogen atom forms a ring.

11. The method according to claim 1, in which the use of chiral ligands of the formula (IIe), (IIf), (IIg) or (IIh)


in which R4is the battle optionally substituted C 1-C6is an alkyl radical, optionally substituted phenyl radical, optionally phenylselenenyl C1-C6-alkoxyalkyl or optional C1-C6-alkyl substituted phenyloxirane, each radical R5and R6independently represents a C1-C6is an alkyl group, or together with the nitrogen atom forms a 5-membered or 6-membered ring, which optionally may also contain an oxygen atom or sulfur, and each R7and R8represents a linear or branched C1-C6is an alkyl radical, optionally substituted phenyl radical, optionally phenylselenenyl C1-C6-alkoxyalkyl, or optional C1-C6-alkyl substituted panelaccordion.

12. The method according to claim 1, in which the use of achiral ligands of the formula (III)in which R represents a linear, branched or cyclic alkyl radical having from 2 to 10 carbon atoms, or a phenyl radical, optionally mono - or politeley halogen or1-C2-alkyl.

13. The method according to claim 1, in which the ratio of the chiral ligand of formula (II) to the achiral ligand of formula (III) is from 10:1 to 1:5.

14. The method according to claim 1, in which the molar ratio of the transition metal in the catalyst to a chiral ligand of formula (II) is about the 1: 0.5 to 1:5.

15. The method according to claim 1, wherein the transition metal used as catalyst precursor selected from the group of [Rh(COD)2Cl]2, [Rh(COD)2]BF4, [Rh(NBD)2}]BF4, Ru(SLA)3, Ru(methylallyl)2COD, [Ru(cimal)Cl2]2where COD means cyclooctadiene and NBD means norbornadiene.

16. The method according to any one of claims 1 to 15, in which the substrate of formula (I), ligands of formulas (II) and (III) the predecessor, which contains the transition metal is first dissolved in a solvent, in a suitable reactor, then the reactor optional purge with an inert gas, and then heated to the desired process temperature; or first dissolved in a solvent, only the substrate of formula (I), then the reactor optional purge with an inert gas, and only after heating to the appropriate temperature process in the substrate solution load the suspension ligands having formula (II) and (III)in degassed solvent and the precursor, which includes a transition metal, and then in both cases, when a suitable process temperature add the hydrogen donor.

17. The use of catalytic systems for asymmetric catalysis with transition metals, which includes a transition metal of groups VIII, IX or X, and the combination of chiral phosphorus ligand of the formula (IIa), (IIb), (IIC) or (IId)


where raftiline and phenyl groups optionally is mono - or polyamideimide halogen, alkyl, alkoxy, aryl or arroceros, R4 is an optionally substituted C1-C6is an alkyl radical, optionally substituted phenyl radical, optionally phenylselenenyl C1-C8-alkoxyalkyl or optional C1-C8-alkyl substituted phenyloxirane, and each radical R5and R6independently represents phenylseleno alkyl group having 1-6 carbon atoms, or together with the nitrogen atom forms a ring, and achiral phosphine ligand of the formula (III)

in which R is optionally substituted alkyl or aryl radical, for simmetricheskogo hydrogenation catalyzed by transition metals, acrylic acid derivatives of the formula (I)

in which R1represents H or optionally substituted C1-C20-alkyl, C5-C20-aryl or C5-C20-heteroaryl radical, R2means optionally substituted C1-C20-alkyl, C5-C20-aryl or C5-C20-heteroaryl radical, and R 3means N or C1-C6is an alkyl radical.

18. The application 17, in which the transition metal is ruthenium, rhodium or iridium.

19. The application 17, in which the chiral ligand is a ligand of the formula (IIe), (IIf), (IIg) or (IIh)


in which R4represents an optionally substituted C1-C6is an alkyl radical, optionally substituted phenyl radical, or optional phenylselenenyl C1-C6-alkoxyalkyl, each radical R5and R6independently represents a C1-C6is an alkyl group, or together with the nitrogen atom, forms a 5-membered or 6-membered ring, which optionally may also contain an oxygen atom or sulfur, and each R7and R8represents a linear or branched C1-C6is an alkyl radical.

20. Use one of PP-19, in which the catalytic system has a molar ratio of chiral ligand to achiral ligand equal from 2.5:1 to 1.2:1.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of carboxylic acid represented by the general formula (I): , their pharmaceutically acceptable salts or esters wherein values Y, L, X, T, Z, M, R1, W and are given in the invention claim. Proposed compounds possess insulin-sensitizing effect and they are double agonists with respect to PPARα and γ, and triple agonists with respect to PPARα, β(δ) and γ. Except for, the invention relates to a medicinal agent and pharmaceutical compositions based on the claimed derivatives of carboxylic acid, to methods for prophylaxis or treatment of diseases, and to using derivatives carboxylic acid for preparing a medicinal agent.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

56 cl, 2 tbl, 609 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel intermediate compounds and inmproved method for synthesis of compound of the formula (C): . Proposed method is based on using inexpensive parent substances and provides synthesis of intermediate compounds with the high yield and high purity degree being without carrying out procedures for chromatographic purification and can be realized in large-scale industry manufacture. Invention relates to improved methods for synthesis of compound of the formula (I): , compound of the formula (II): , compound of the formula (III): , compound of the formula (VIII): , compound of the formula (IX): , and to a reagent consisting of boron tribromide and 2,6-dimethylpyridine. Method is used for a sparing and selective splitting a methyl group in aromatic methyl ethers.

EFFECT: improved method of synthesis.

12 cl, 8 ex

The invention relates to an improved method for producing a p-hydroxymandelic compounds by condensation in the water, in the presence of an alkaline agent, an aromatic compound containing at least one hydroxyl group and having a free parapolitica, with Glyoxylic acid

The invention relates to new bicyclic aromatic compounds of General formula (I) having the ability to bind RXRand pharmaceutical compositions based on them, which can be used in medicine, veterinary medicine and in cosmetics

The invention relates to a new process for the preparation of 2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentanol acid of the formula (I)

OCOOH

(I) This connection is used for regulating the level of blood lipids

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid of formula (I) through a Suzuki reaction between 3-adamantyl-4-methoxyphenylcarboxylic acid of formula (II) and 6-bromo-2-naphthoic acid of formula (III), wherein the reaction between compounds (II) and (III) is carried out at temperature between 60 and 110°C for between 30 minutes and 24 hours in an inert gas atmosphere in the presence of a palladium catalyst and a base in a polar solvent, followed by treatment with an acid. The invention also relates to use of compounds of formulae (II) and (III) to produce a compound of formula (I).

EFFECT: single-step method enables to obtain desired product with high output.

13 cl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid of formula (I) through a Suzuki reaction between 3-adamantyl-4-methoxyphenylcarboxylic acid of formula (II) and 6-bromo-2-naphthoic acid of formula (III), wherein the reaction between compounds (II) and (III) is carried out at temperature between 60 and 110°C for between 30 minutes and 24 hours in an inert gas atmosphere in the presence of a palladium catalyst and a base in a polar solvent, followed by treatment with an acid. The invention also relates to use of compounds of formulae (II) and (III) to produce a compound of formula (I).

EFFECT: single-step method enables to obtain desired product with high output.

13 cl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of anionic surfactants, specifically to methods of producing carboxymethylates of oxyethylated alkylphenols used as components of detergents for domestic and industrial purposes - intensification of oil extraction processes by increasing ratio of extraction of oil from oil deposits. The method of producing oxyethylated alkylphenol-based anionic surfactants is realised through condensation of oxyethylated alkylphenols with sodium monochloroacetate in molar ratio 1.0:(0.8-1.0) in nitrogen medium while heating in the presence of an alkaline agent at 45-50°C. The alkaline agent used is crystalline potassium hydroxide taken in molar ratio to the oxyethylated alkylphenol equal to (0.7-1.0):1.0 or its mixture with crystalline sodium hydroxide in the same molar ratio to the oxyethylated alkylphenol. After condensation, a hydrogen ion concentration (pH) regulator is added to the reaction mixture in molar ratio of pH regulator to the oxyethylated alkylphenol equal to (0.01-0.1):1.0 until attaining pH of the reaction mixture of 8.0-9.0. The anionic surfactant is stored without partial decomposition and resin formation for not less than 100 days.

EFFECT: efficient method of producing anionic surfactants.

4 cl, 1 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of obtaining monochloracetic acid (MCA) and can be used in chemical industry. MCA is an essential product in production of carboxymethyl cellulose, various pesticides and medicinal agents. The method involves a step for chlorinating acetic acid with molecular chlorine in a bubbling reactor in the presence of a homogeneous catalyst, hydrogenolysis of chlorination products in the presence of a fixed-bed catalyst based on palladium and extraction of the end product through rectification under vacuum, where the hydrogenolysis step is carried out in film mode with direct-flow movement of liquid and gas.

EFFECT: lower consumption indices of raw material, higher quality of the obtained MCA and increased amount of recycled material.

4 cl, 1 dwg, 1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to chemistry of organochlorine compounds, and specifically to an improved method of producing chlorine-substituted aryloxycarboxylic acids through chlorination of acids of general formula

where R1 is H, haloid, C1-C4alkyl, n is an integer ranging from 1 to 3, or salts thereof with subsequent extraction of the end product, wherein the chlorinating agent used is solid calcium hyprochlorite in the absence of solvents, and the process is activated by mechanical action in form of impact or impact-shear loading the mixture of solid reagents.

EFFECT: method increases output and purity of the end product, and also simplifies the process technology.

5 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention refers to methods of producing sulphur trioxide and tetrabromphthalic anhydride. Sulphur trioxide is produced by method involving that the first gas flow containing SO2, SO3 and oxygen and/or air, is supplied to vanadium-containing catalyst layer wherein SO2 is oxidised in SO3, and the second gas flow containing sulphur trioxide is isolated. This method is improved with supplying evaporated sulphur to the first gas flow, so produced mixture is supplied through considerable part of catalyst layer then exposed at one or more temperatures within approximately 450 to 700°C. Sulphur is oxidised to SO2. Consequently the second gas flow isolated from lower tail end of catalyst layer is enriched with sulphur trioxide to be used for producing compounds, such as tetrabromphthalic anhydride.

EFFECT: inventions allow for higher process efficiency.

34 cl, 5 dwg, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to the perfection of the method of obtaining monochloracetic acid from chlorine and acetic acid in the presence of a catalyst through reactive distillation. The given method and the device for reactive distillation are much less complex than known reactors.

EFFECT: invention allows to obtain monochloracetic acid with a low content of over-chlorinated products.

11 cl, 1 tbl, 1 dwg, 1 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel intermediate compounds and inmproved method for synthesis of compound of the formula (C): . Proposed method is based on using inexpensive parent substances and provides synthesis of intermediate compounds with the high yield and high purity degree being without carrying out procedures for chromatographic purification and can be realized in large-scale industry manufacture. Invention relates to improved methods for synthesis of compound of the formula (I): , compound of the formula (II): , compound of the formula (III): , compound of the formula (VIII): , compound of the formula (IX): , and to a reagent consisting of boron tribromide and 2,6-dimethylpyridine. Method is used for a sparing and selective splitting a methyl group in aromatic methyl ethers.

EFFECT: improved method of synthesis.

12 cl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel intermediate compounds and inmproved method for synthesis of compound of the formula (C): . Proposed method is based on using inexpensive parent substances and provides synthesis of intermediate compounds with the high yield and high purity degree being without carrying out procedures for chromatographic purification and can be realized in large-scale industry manufacture. Invention relates to improved methods for synthesis of compound of the formula (I): , compound of the formula (II): , compound of the formula (III): , compound of the formula (VIII): , compound of the formula (IX): , and to a reagent consisting of boron tribromide and 2,6-dimethylpyridine. Method is used for a sparing and selective splitting a methyl group in aromatic methyl ethers.

EFFECT: improved method of synthesis.

12 cl, 8 ex

FIELD: industrial organic synthesis.

SUBSTANCE: process is accomplished via catalytic chlorination of acetic acid at elevated temperature involving as catalyst crude acetyl chloride obtained as by-product in oxyethylidenediphosphonic acid synthesis at acetic acid-to-crude acetyl chloride weight ratio 1:(0.1-0.4). Crude acetyl chloride is employed either individually or in the form of acetic acid solution with content of principal solution no less than 90 wt %.

EFFECT: reduced level of dichloroacetic acid in final product and enabled utilization of chemical production waste.

2 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid of formula (I) through a Suzuki reaction between 3-adamantyl-4-methoxyphenylcarboxylic acid of formula (II) and 6-bromo-2-naphthoic acid of formula (III), wherein the reaction between compounds (II) and (III) is carried out at temperature between 60 and 110°C for between 30 minutes and 24 hours in an inert gas atmosphere in the presence of a palladium catalyst and a base in a polar solvent, followed by treatment with an acid. The invention also relates to use of compounds of formulae (II) and (III) to produce a compound of formula (I).

EFFECT: single-step method enables to obtain desired product with high output.

13 cl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method for synthesis of alkyl(meth)acrylates which are used in synthesis of polymers and copolymers with other polymerisable compounds, involving a step for re-esterification of alkyl ester of α-hydroxycarboxylic acid with (meth)acrylic acid, accompanied by formation of alkyl(meth)acrylates and α-hydroxycarboxylic acid, and a step for dehydration of α-hydroxycarboxylic acid, accompanied by formation of (meth)acrylic acid.

EFFECT: method enables to obtain a product with high selectivity.

22 cl, 2 tbl, 2 dwg, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to improved method of salicylates of alkaline earth metals for application as detergents for lubricating materials. Method of obtaining alkylated salicytates of alkaline earth metals includes following stages: A) alkylating salicylic acid with linear α-olefin, containing, at last, 14 carbon atoms, in presence of water-free methane sulfonic acid with formation of oil-soluble alkylated salicylic acid; B) neutralisation of oil-soluble alkylated salicylic acid; C) excessive alkalisation of oil-soluble alkylated salicylic acid by carboxylating lime by means of CO2 in presence of oxygen-containing organic solvent and surface-active substance; D) filtration of stage (C) product; and E) removal of solvent by distillation. Alternatively, alkylsalicylic acid can be subjected to interaction with preliminary processed with alkali highly-alkaline sulfonate of earth alkaline metal, for instance, with calcium sulfonate, in order to obtain salicylate salts of earth alkaline metals with different per cent content of dispersed salts of alkaline earth metals carbonates. In claimed method it is not necessary to filter end product which is preferable doe industry.

EFFECT: obtaining salicylates of alkaline earth metals for application as detergents for lubricating materials.

8 cl, 4 ex

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