Method of obtaining propionic acid derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining (S)-2-methoxy-3-{4[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl}propionic acid of formula (I) or its salts, in which formula (II) compound or its salt is hydrated in the presence of an iridium-including catalyst, in which the catalyst includes iridium and formula (III) compound, in which R1 stands for hydrogen, isopropyl, phenyl or benzyl and in which R2 stands for phenyl, 3,5-dimethylphenyl or 3,5-di-tert-butylphenyl. The invention also relates to the application of a complex of the catalyst, containing iridium and the formula (III) compound for obtaining the formula (I) compound.

EFFECT: obtaining the formula (I) compound with a high degree of conversion and enantiomeric purity.

6 cl, 4 tbl, 21 ex

 

The present invention relates to a new method of producing (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid or its salts.

The present invention in particular relates to a method for producing compounds of formula (I)

or salts thereof, wherein the compound of formula (II)

or its salt hydrate

(a) in the presence of a catalyst comprising iridium; or

(b) in the presence of a catalyst comprising ruthenium and a compound of the formula (IV), (V), (VI) or (VII)

;;

;;

in which

R3denotes alkyl, cycloalkyl or aryl;

R4denotes cycloalkyl, aryl or heteroaryl;

R5denotes cycloalkyl or aryl;

R6denotes cycloalkyl or aryl;

R7denotes cycloalkyl or aryl;

R8denotes cycloalkyl or aryl; and

R9denotes cycloalkyl or aryl.

The compound of formula (I) are known in the art and described for example in international application WO 02/092084. It is preferably applicable for the prevention and/or treatment of diabetes mellitus type I and II.

The method proposed in the present invention, allows to synthesize Conn�tion of formula (I) with high enantiomeric excess. It may be carried out in dichloromethane, and it is possible to eliminate the use of mixtures of solvents. The method using a catalyst comprising iridium, results in particularly high yield and high enantiomeric excess of the compound of formula (I). In addition, the optically pure compound of formula (I) is prepared without the use of a plurality of operations of crystallization diastereoisomeric salts.

The term "catalyst" means a complex of ruthenium or iridium, respectively, with a chiral ligand. In such complexes, ruthenium ruthenium is preferably characterized by the oxidation state II. In such complexes, iridium iridium is preferably characterized by a degree of oxidation I.

The term "alkyl" means having branched or linear chain monovalent alkyl radical containing from 1 to 8 carbon atoms, preferably from 1 to 4 carbon atoms. An example of this term are also radicals such as methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, tert-butyl, etc., and methyl, tert-butyl and isopropyl are preferred.

The term "alkoxygroup" refers to the group alkyl-O-. The preferred alkoxygroup is a methoxy group.

The term "cycloalkyl" means a monovalent carbocyclic radical containing from 3 to 10 carbon atoms, preferably from 3 to 6 carbon atoms, such as CEC�propyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cyclohexyl is preferred cycloalkyl.

The term "aryl" means phenyl or naftalina group, preferably the phenyl group, which can optionally be mono - or polyamidine, preferably mono-, di - or trisubstituted the following substituents: halogen, a hydroxy-group, CN, CF3, NO2NH2, N(H, alkyl), N(alkyl)2carboxypropyl, aminocarbonyl, alkyl, alkoxygroup, phenyl and/or fenoxaprop. Preferred substituents are halogen, alkyl, CF3and alkoxygroup, preferably alkyl, CF3and alkoxygroup.

The term "heteroaryl" means an aromatic 5 - or 6-membered ring which may contain 1, 2 or 3 atoms selected from the group comprising nitrogen, oxygen and/or sulfur, such as furyl, pyridyl, 1,2-, 1,3 - and 1,4-diazines, thienyl, isoxazolyl, oxazolyl, imidazolyl or pyrrolyl. The term "heteroaryl" also means a bicyclic aromatic group containing two 5 - or 6-membered ring in which one or both rings can contain 1, 2 or 3 atoms selected from the group comprising nitrogen, oxygen and/or sulphur, such as, for example, indole or quinoline, or partially hydrogenated bicyclic aromatic groups, such as, for example, indolinyl. Heteroaryl group may contain substituents, describing�nye previously for the term "aryl". Preferred heteroaryl groups are 2-thienyl and 2 fuel. 2 Fuel is especially preferred.

The term "halide" means a halogen atom with a negative charge, such as fluoride, chloride, bromide and iodide.

The term "pharmaceutically acceptable salt" includes salts of compounds of formula (I) with pharmaceutically acceptable bases such as alkali metal salts, e.g. salts of Na and K salts of alkaline earth metals such as CA and Mg salts, and ammonium salts or alkyl-substituted ammonium, such as, for example, salts of trimethylamine. Preferred pharmaceutically acceptable salt of the compound of formula (I) is a sodium salt.

The term η5"this means-5, which is usually used in coordination chemistry. It indicates the number of electrons that are common to the Central metal atom and a ligand in a coordination compound or complex.

The preferred method is a method proposed in the present invention, in which the catalyst comprises iridium and the compound of formula (III), (VIII) or (IX)

;;

or;

in which

R1denotes hydrogen, alkyl, aryl or arylalkyl;

R2denotes aryl; and

R10denotes aryl.

Also preferred is FPIC�b, defined above, in which the catalyst comprises iridium and the compound of formula (III)

in which R1and R2are as defined above.

R1preferably denotes hydrogen, alkyl, phenyl or benzyl, more preferably hydrogen, alkyl or benzyl.

In particular, the method defined above, in which R1denotes hydrogen, isopropyl, phenyl or benzyl is preferred. More preferably, if R1denotes hydrogen, isopropyl or benzyl.

Also preferred is a method as defined above, in which R2denotes phenyl or phenyl substituted by one or two alkilani.

In addition, preferred is a method proposed in the present invention, in which R2denotes phenyl, 3,5-dimethylphenyl or 3,5-di-tert-butylphenyl.

The method proposed in the present invention, in which R10represents a 3,5-dimethylphenyl, is also preferred.

The compound of formula (IX) is an (S,R,R)-1,1'-bis-[((1-N,N-dimethylamino)adilfaranj)(phenylphosphino)]ferrocene.

A preferred compound of formula (VIII) is an (S,S)-[1,3-dimethyl-1,3-propanediyl]bis[di(3,5-dimethylphenyl)phosphine].

Especially preferred is the method proposed in the present invention, � which the compound of formula (III) represents a

(Sa,S)-7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-diphenylphosphino-1,1'-spirobiindane;

(Sa,S)-7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-di(3,5-dimethylphenyl)phosphino-1,1'-spirobiindane;

(Sa,S)-7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane;

(Sa,S)-7-[4,5-dihydro-4-phenyloxazol-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane;

(Sa,S)-7-[4,5-dihydro-4-isopropylamino-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane; or

(Sa)-7-[4,5-dihydrooxazolo-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane.

Also preferred is a method proposed in the present invention, in which the compound of formula (III) represents a

(Sa,S)-7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane;

(Sa,S)-7-[4,5-dihydro-4-isopropylamino-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane; or

(Sa)-7-[4,5-dihydrooxazolo-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane.

In addition, preferred is a method as defined above, in which the catalyst is Ir(L1)(L2)nY,

in which

L1denotes a compound of formula (III), (VIII) or (IX) as defined above;

L2denotes cyclooctene, 1,5-cyclooctadiene, ethylene, 1,5-hexadien or norbornadiene;

Y is chloride, iodide, bromide, fluoride, triptorelin, tet�afterbirth, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetraphenylborate, hexafluoroantimonate, hexaflurophosphate, triflic, mesilate, perchlorate, perromat, periodate, nitrate, hydrogen sulfate or acetylacetonate; and

n is 1 or 2.

Especially preferred is a method in which L stands for a compound of formula (III).

Y preferably denotes chloride, tetrafluoroborate, hexaphosphate or tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, more preferably, tetrafluoroborate or tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.

n preferably is 1.

Especially preferred is the method proposed in the present invention, in which the catalyst is

[Ir((S,S)-7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];

[Ir((S,S)-7-[4,5-dihydro-4-isopropylamino-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate]; or

[Ir((S)-7-[4,5-dihydrooxazolo-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate].

Also preferred is a method as defined above, in which the catalyst comprises ruthenium and the compound of formula (IV), (V), (VI) or (VII)

; ;

;;

in which R3-R9are as defined above.

R3preferably denotes alkyl, cyclohexyl, phenyl, alkylphenyl or dialkylphenol.

Especially preferred is a method as defined above, in which R3denotes tert-butyl, cyclohexyl, phenyl, 2-methylphenyl or 3,5-dimethylphenyl.

In addition, R4preferably denotes alkyl, cyclohexyl, phenyl, naphthyl, furyl or phenyl containing from 1 to 3 substituents independently selected from the group comprising trifluoromethyl, alkyl and alkoxygroup.

The method proposed in the present invention, in which R4denotes tert-butyl, cyclohexyl, phenyl, 3,5-dateformatitem, 4-triptoreline, 3,5-dimethyl-4-methoxyphenyl, 1-naphthyl or 2-furyl, is also preferred.

R5preferably denotes cyclohexyl, phenyl or phenyl containing from 1 to 3 substituents independently selected from the group comprising alkyl and alkoxygroup.

Furthermore, the method proposed in the present invention, in which R5denotes phenyl, cyclohexyl, 3,5-dimethyl-4-methoxyphenyl or 3,5-dimethylphenyl, is also preferred.

R6preferably denotes cyclohexyl, norbornyl, phenyl or phenyl containing 1 to 3 �of amestitelj, independently selected from the group comprising alkyl and trifluoromethyl.

In addition, preferred is a method as defined above, in which R6denotes phenyl, cyclohexyl, 3,5-dimethylphenyl, 3,5-dateformatitem or norbornyl.

R7preferably denotes cyclohexyl, phenyl or phenyl containing from 1 to 3 substituents independently selected from the group comprising alkyl, trifluoromethyl and alkoxygroup.

Also preferred is a method proposed in the present invention, in which R represents cyclohexyl, phenyl, 3,5-dimethylphenyl, 3,5-dateformatitem, 3,5-dimethyl-4-methoxyphenyl or 2-methylphenyl.

Especially preferred is the method proposed in the present invention, in which R is cyclohexyl or phenyl.

The method proposed in the present invention, in which R9represents cyclohexyl or phenyl is preferred.

Furthermore, especially preferred is a method proposed in the present invention, in which the compound of formula (IV), (V), (VI), (VII) or (VIII) is a

(S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]atilde-tert-butylphosphine;

(S)-1-[(R)-2-(dicyclohexylphosphino)ferrocenyl]atilde-tert-butylphosphine;

(S)-1-[(R)-2-(di-(4-triptoreline)phosphino)ferrocenyl]atilde-tert-butylphosphine;

(S)-1-[(R)-2-(di-(3,5-DIMET�l-4-methoxyphenyl)phosphino)ferrocenyl]atilde-tert-butylphosphine;

(S)-1-[(R)-2-(di-2-furylthio)ferrocenyl]atilde-tert-butylphosphine;

(αR,αR)-2,2'-bis(α-N,N-dimethylaminophenyl)-(S,S)-1,1'-bis(diphenylphosphino)ferrocene;

(αR,αR)-2,2'-bis(α-N,N-dimethanonaphthalene)-(S,S)-1,1'-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene;

(R)-1-diphenylphosphino-2-[(S)-α-(N,N-dimethylamino)-o-diphenylphosphinoethyl)methyl]ferrocene;

(S)-1-[(S)-2-(2'-diphenylphosphinyl)ferrocenyl]atilde(bis-3,5-triptoreline)phosphine;

(R)-1-[(R)-2-(2'-dicyclohexylphosphino)ferrocenyl]atilde(bis-3,5-triptoreline)phosphine; or

(R)-1-[(R)-2-(2'-diphenylphosphinyl)ferrocenyl]atilde-(2-norbornyl)phosphine.

In addition, also preferred is a method proposed in the present invention, in which the compound of formula (IV), (V), (VI) or (VII) is a

(S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]atilde-tert-butylphosphine; or

(S)-1-[(R)-2-(di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]atilde-tert-butylphosphine.

Especially preferred is a method as defined above, in which the catalyst is Ru(L3)(L4)(L5)mYpin which

L3denotes a compound of formula (IV), (V), (VI) or (VII) as defined above;

L4denotes η5-2,4-dimethylpentane, cyclopentadienyl or η5-2,3,4-trimethylpentane;

L5denotes a halide, acetonitrile, diethyl�th ether, water, acetone, tetrahydrofuran, dioxane, pyridine, imidazole or thiophene;

Y denotes tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetrafluoroborate, tetraphenylborate, hexafluoroantimonate, hexaflurophosphate, triflic, mesilate, hydrogen sulfate or perchlorate;

m is 0 or 1; and

p is 0 or 1.

L5preferably represents iodine.

m is preferably equal to 1.

R is preferably equal to 1.

Especially preferred is a method as defined above, in which the catalyst is

[Ru(η5-2,4-dimethylpentane)((S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]atilde-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];

[Ru(η5-2,4-dimethylpentane)((S)-1-[(R)-2-(dicyclohexylphosphino)ferrocenyl]atilde-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];

[Ru(η5-2,4-dimethylpentane)((S)-1-[(R)-2-(di-(4-triptoreline)phosphino)ferrocenyl]atilde-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];

[Ru(η5-2,4-dimethylpentane)((S)-1-[(R)-2-(di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]atilde-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];

[Ru(η5-2,4-dimethylpentane)((S)-1-[(R)-2-(di-2-furylthio)ferrocenyl]atilde-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];

[Ru(η5-2,4-dimethylpentane)((αR,αR)-2,2'-bis(α-N,N-dimethylaminophenyl)-(S,S)-1,1'-bis(diphenylphosphino)ferrocene) (acetonitril�)][tetrafluoroborate];

[Ru(η5-2,4-dimethylpentane)((αR,αR)-2,2'-bis(α-N,N-dimethylaminophenyl)-(S,S)-1,1'-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene)(acetonitrile)][tetrafluoroborate];

[Ru(η5-2,4-dimethylpentane)((R)-1-diphenylphosphino-2-[(S)-α-(N,N-dimethylamino)-o-diphenylphosphinoethyl)methyl]ferrocene)];

[Ru(η5-2,4-dimethylpentane)((S)-1-[(S)-2-(2'-diphenylphosphinyl)ferrocenyl]atilde(bis-3,5-triptoreline)phosphine)(acetonitrile)][tetrafluoroborate];

[Ru(η5-2,4-dimethylpentane)((R)-1-[(R)-2-(2'-dicyclohexylphosphino)ferrocenyl]atilde(bis-3,5-triptoreline)phosphine)(acetonitrile)][tetrafluoroborate]; or

[Ru(η5-2,4-dimethylpentane)((R)-1-[(R)-2-(2'-diphenylphosphinyl)ferrocenyl]atilde-(2-norbornyl)phosphine)(acetonitrile)][tetrafluoroborate].

Also especially preferred is the method proposed in the present invention, in which the catalyst is

[Ru(η5-2,4-dimethylpentane)((S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]atilde-tert-butylphosphine)(acetonitrile)][tetrafluoroborate]; or

[Ru(η5-2,4-dimethylpentane)((S)-1-[(R)-2-(di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]atilde-tert-butylphosphine)(acetonitrile)][tetrafluoroborate].

In the context of the present invention, the compound of formula (II) can be hydrogenated with hydrogen gas under pressure.

If you use iridium Cathal�congestion, the method preferably is carried out at a temperature at from 10 to 120°C, more preferably from 40 to 100°C, particularly preferably from 60 to 80°C.

If using a catalyst comprising iridium, the method is preferably carried out in a solvent selected from the group comprising alcohols, fluorinated alcohols, tetrahydrofuran, methyltetrahydrofuran, dichloro methane, dialkylamide ethers, aromatic solvents such as benzene, toluene, CF3-C6N5mono - and polyfluorinated aromatic solvents and mixtures thereof, more preferably in methanol, tetrahydrofuran, dichloro methane and mixtures thereof, most preferably in a mixture of methanol/tetrahydrofuran 3:2.

If using a catalyst comprising iridium, the method is preferably carried out at a hydrogen pressure equal to from 1 to 200 bar, more preferably from 10 to 100 bar, particularly preferably from 40 to 60 bar.

If using a catalyst comprising iridium, the ratio substrate/catalyst (mol/mol) is preferably from 10 to 50000, more preferably from 100 to 10000, particularly preferably from 1000 to 5000.

If using a catalyst comprising ruthenium, the method is preferably carried out at a temperature at from 10 to 120°C, more preferably from 20 to 80°C., particularly preferably from 30 to 50°C.

If used catalysis�Thor, including ruthenium, the method is preferably carried out in a solvent selected from the group comprising alcohols, tetrahydrofuran, dichloro methane, fluorinated alcohols, methyltetrahydrofuran, ethers and mixtures thereof, preferably methanol, tetrahydrofuran, dichloro methane and mixtures thereof, more preferably in a mixture of dichloro methane/tetrahydrofuran 1:1 or in dichloromethane, and particularly preferably in dichloromethane.

If using a catalyst comprising ruthenium, the method is preferably carried out at a hydrogen pressure equal to from 1 to 200 bar, more preferably from 10 to 100 bar, particularly preferably from 40 to 60 bar.

If using a catalyst comprising ruthenium, the ratio substrate/catalyst (mol/mol) is preferably from 10 to 50000, more preferably from 100 to 10000, particularly preferably from 1000 to 5000.

The compound of formula (I) in a preferred configuration (S) received with ligands indicated in the table below in the experimental section. If chiral ligand or catalyst is preferably leads to the compound of formula (I) in the configuration (R), it is clear that for obtaining a compound of formula (I) in the configuration (S) should be used ligand or catalyst in the opposite configuration. Both enantiomer of chiral ligands are available to the same extent.

The present invention also apply� to the compound of formula (I), defined above, or its salt obtained by the method proposed in the present invention.

In addition, the present invention also relates to the use of a catalyst, as defined above, to obtain compounds of formula (I) as defined above.

Catalysts for use in the method proposed in the present invention, can be obtained by the reaction of a compound of formula [Ir(L)Cl]2, [Ir(L)2]BARF or [Ir(L)2]BF4where L denotes a neutral ligand, for example, COD, needed a ligand of formula (III), (IX), (X) or (XI), for example, (S,S)-3,5-Xyl-Skewphos or (S,R,R)-TRIFER, in a suitable solvent, such as, for example, dichloro methane or methanol. The catalyst can be used after isolation or obtain in situ. The ligands of formula (III), (IX), (X) or (XI) can be obtained by well-known techniques, for example, compound [Ir(COD)Cl]2and [Ir+(COD)2]BF4are commercially available, for example, sells firm Strem Chemicals Inc., Newburgport, Mass. USA, or they can be obtained by well-known techniques, for example, J. Herde et al., Inorg. Syn. 1974, 18-20 or M. Green et al., J. Chem. Soc. 1971, 2334-2337.

The term "neutral ligand" when used in the present invention means easy sharing of a ligand such as an olefin, e.g. ethylene, propylene, cyclooctene, 1,5-hexadiene, norbornadiene, 1,5-cyclooctadiene, nitrile, such as acetonitrile or benzonitrile, or also races�foretell, such as, for example, tetrahydrofuran, toluene, etc., If there is more than one such ligand, they can also differ from each other. Preferred neutral ligand is cyclooctadiene.

Examples

Abbreviations

η5-2,4-DMP = η5-2,4-dimethylpentane,

THF = tetrahydrofuran,

NCMe = acetonitrile,

TFA = trifluoroacetic acid,

COD = 1,5-cyclooctadiene,

BARF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate,

CT = room temperature,

S/C = ratio substrate/catalyst (mol/mol),

HPLC = high performance liquid chromatography,

EI = enantiomeric excess = [(S)-(R)]/[(S)+(R)].

All containing ferrocenyl-diphosphine ligands firm sells Solvias AG, CH-4002 Basel. Complexes of ruthenium sells firm Umicore AG, D-63457 Hanau-Wolfgang, or they can be obtained in accordance with O. Briel et al. in "Catalysis of Organic Reactions", 2009, 203, CRC Press, Boca Raton. Containing oxazolin-monophosphine ligands (ligands SIPHOX) and the corresponding complexes of iridium firm sells Nankai University, Tianjin 300071 China or they can be obtained in accordance with Q. L. Zhou et al. J. Am. Chem. Soc. 2008, 130, 8584. Xyl-Skewphos and 3,5-tBu-MeOBIPHEP firm sells Solvias AG, CH-4002 Basel. TRIFER firm sells Phoenix Chemicals, 34 Thursby Rod., Bromborough, Wirral CH62, 3PW, United Kingdom (UK) or they can be obtained in accordance with R. McCormack et al. Angew. Chem. Int. Ed. 2007, 46, 4141-44.

The numbering of the atoms in the ligands SIPHOX presented below:

Chiral phosphorus-containing ligands

DesignationChemical name
Ph-Bn-SIPHOX7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-diphenylphosphino-1,1'-spirobiindane
Xyl-Bn-SIPHOX7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-di(3,5-dimethylphenyl)phosphino-1,1'-spirobiindane
DBT-Bn-SIPHOX7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane
DBT-Ph-SIPHOX7-[4,5-dihydro-4-phenyloxazol-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane
DBT-iPr-SIPHOX7-[4,5-dihydro-4-isopropylamino-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane
DBT-H-SIPHOX7-[4,5-dihydrooxazolo-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane
TRIFER1,1'-bis-[((1-N,N-dimethylamino)adilfaranj)(phenylphosphino)]ferrocene
Xyl-Skewphos[1,3-dimethyl-1,3-propanediyl]bis[di(3,5-dimethylphenyl)phosphine]

DesignationChemical name
PPF-PtBu21-[2-(diphenylphosphino)ferrocenyl]atilde-tert-butylphosphine
Cy2PF-PtBu21-[2-(dicyclohexylphosphino)ferrocenyl]atilde-tert-butylphosphine
(4-CF3Ph)2PF-PtBu21-[2-(di-(4-triptoreline)phosphino)ferrocenyl]atilde-tert-butylphosphine
(3,5-Me2-4-MeOPh)2PF-PtBu21 -[2-(di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]atilde-tert-butylphosphine
2-Fur2PF-PtBu21-[2-(di-2-furylthio)ferrocenyl]atilde-tert-butylphosphine
NMe2-PPh2-Mandyphos2,2'-bis(a-N,N-dimethylaminophenyl)-1,1'-bis(diphenylphosphino) ferrocene
NMe2-P(3,5-Me-4-MeOPh)2-Mandyphos2,2'-bis(a-N,N-dimethylaminophenyl)-1,1'-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene
PPPhCHNMe2-F-PP1-diphenylphosphino-2-[α-(N,N-dimethylamino)-o-diphenylphosphinoethyl)methyl]ferrocene
PPPhPCHCH3-R(3,5-CF3Ph)21-[2-(2'-diphenylphosphinyl) ferrocenyl]-atilde(bis-3,5-triptoreline)phosphine
Cy2PPhFCH1-[2-(2'-dicyclohexylphosphino)ferrocenyl]atilde(bis-3,5-triptoreline)phosphine
CH3R(3,5-CF3Ph)2
PPPhFCHCH3-R(Norbornyl)21-[2-(2'-diphenylphosphinyl)ferrocenyl]atilde-(2-norbornyl)phosphine

Synthesis of metal complexes of iridium: examples 1A-1b

Example 1.a: the Receipt of [Ir((S,S)-Xyl-Skewphos)(COD)]BF4

In the test tube Slinka volume of 25 ml was placed 100 mg (S,S)-Xyl-Skewphos (0.18 mmole), 60 mg of [Ir(COD)Cl]2(0.09 mmole) and 5 ml of dichloromethane. To the resulting dark red solution of the two portions was added 35 mg of tetrafluoroborate silver (0.18 mmole) and the resulting suspension was stirred for 2 h at CT. The reaction mixture was filtered through a material dicalite speedex and the filter cake was washed with 6 ml of dichloromethane. The combined filtrates evaporated to dryness in a rotary evaporator (50°C/5 mbar). The resulting crude product was washed with 8 ml of hexane and dried in a high vacuum and received 563 mg (85%) [Ir((S,S)-Xyl-Skewphos)(COD)]BF4as a red solid. OP-MS: 853,4 m/z of [Ir((S,S)-Xyl-Skewphos)(COD)]+,31/sup> P-NMR (CDCl3): 14,6 part./mn (s).

Example 1.b: Receipt of [Ir((S,R,R)-Trifer)(COD)]BARF

In the test tube Slinka volume of 100 ml were placed 400 mg (S,R,R)-TRIFER (or 0.44 mmole), 584 mg Ir(COD)2]BARF (up to 0.46 mmole) and 40 ml of methanol. The resulting orange solution was stirred for 5 h at CT. Then there was added 12 ml of water and the resulting crystals were filtered. The filter cake was washed with 32 ml of a mixture methanol/water (4:1) and dried in a high vacuum and has obtained 804 mg (88%) of [Ir((S,R,R)-TRIFER)(COD)]BARF in the form of orange crystals. OP-MS (mass spectroscopy, Fourier transform): 1213,2 m/z of [Ir((S,R,R)-TRIFER)(COD)]+.31P-NMR (CDCl3): 6,2 part./mn (s).

Synthesis of 2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid by asymmetric hydrogenation of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid: examples 2 to 19 and comparative example A

Example 2

In the glove camera (the contents Of2≤2 part./million) in a stainless steel autoclave with a volume of 185 ml were placed 2.00 g (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid (4,59 mmole), was 35.9 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0.018 mmole, S/C 250), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml (S)-1-phenylethylamine (0,93 mmole). The autoclave was sealed and the hydrogenation was carried out at 60°C under a hydrogen pressure of 30 bar. After 16 h Aut�Keylock opened and the yellowish solution was evaporated to dryness in a rotary evaporator (50°C/5 mbar) and received the crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity, component 99,6% (the degree of conversion of >99.9 percent), and enantiomeric excess, amounting to 99.5%.

The HPLC method for the determination of chemical purity (expressed in % of the peak area (S)-phenylethylamine not included): YMC-Pack Pro C18, 150×4.6 mm; mobile phase A: mobile phase A: water with addition of 0.1% TFA, B: NCMe with the addition of 0.1% TFA, 22°C, 2 ml/min in isocratic mode a/51/49% for 10 min, gradient mode from 51/49% to 5/95% in 10 min and 5 min at 5/95%, 285 nm. Retention times: 11.2 min (S)- and (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid; and 12.4 min ((E)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]the thiophene-7-yl}-acrylic acid; 14,0 min (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid.

The HPLC method for the determination of EI (area %): column Chiralpak-ADH, 25 cm × 4.6 mm, 85% heptane/10% ethanol with addition of 0.4% trifluoroacetic acid, flow rate 0.7 ml/min, 30°C, 270 nm. Retention times: 22,4 min (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid; 26,3 min (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid.

Examples 3.1-3.4

By the method similar to that used in example 2, the following hydrogenation was carried out at 60°C under a pressure of nitric acid�and, equal to 30 bar (duration of response: 16 h), using the iridium complexes of the General formula [Ir(phosphorus-containing ligand)(COO)]WAKRAH as catalysts and obtained crude 2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as specified in table 1.

Table 1
Example No.Phosphorus-containing ligandThe degree of conversion [%]The purity of the acid (I) [%] EI acid I [%]/configuration
3.1(S. S)-Xyl-Bn-SIPHOX)99,897,688,9/S
3.2(S,S)-DBT-Ph-SIPHOX)the 99.999,498,0/S
3.3(S,S)-DBT-iPr-SIPHOX)>the 99.999,399,3/S
3.4(S)-DBT-H-SIPHOX)>the 99.998,399,3/S

Example 4

In the glove Kama�(the contents Of 2≤2 part./million) in a stainless steel autoclave with a volume of 185 ml were placed 2.00 g (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid (4,59 mmole), 8,96 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0,0046 mmole, S/C 1'000), 24 ml of methanol and 16 ml of tetrahydrofuran and 0.12 ml (S)-1-phenylethylamine (0,93 mmole). The autoclave was sealed and the hydrogenation was carried out at 60°C under a hydrogen pressure of 30 bar. After 16 h, the autoclave was opened and the yellowish solution was evaporated to dryness in a rotary evaporator (50°C/5 mbar) and received the crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity, part of 99.2% (the degree of conversion of 99.8%) and enantiomeric purity, component 99.3% of.

Examples 5.1-5.2

By the method similar to that used in example 4, the following hydrogenation was carried out at 60°C under a hydrogen pressure of 30 bar (duration of response: 16 h), using the iridium complexes of the General formula [Ir(phosphorus-containing ligand)(COO)]WAKRAH as catalysts and obtained crude 2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as specified in table 2.

Table 2
Example No.Phosphorus-containing ligandThe degree of conversion [%]The purity of the acid (I) [%] EI acid I [%]/configuration
5.1(S,S)-DBT-iPr-SIPHOX)the 99.999,598,7/S
5.2(S)-DBT-H-SIPHOX)the 99.998,199,3/S

Example 6

In the glove camera (the contents Of2≤2 part./million) in a stainless steel autoclave with a volume of 185 ml were placed 2.00 g (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid (4,59 mmole), 4,48 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0,0023 mmole, S/C 2'000), 24 ml of methanol and 16 ml of tetrahydrofuran and 0.12 ml (S)-1-phenylethylamine (0,93 mmole). The autoclave was sealed and the hydrogenation was carried out at 60°C for 20 h and then 80°C for 2 h under hydrogen pressure of 30 bar. After opening the autoclave yellowish solution evaporated to dryness in a rotary evaporator (50°C/5 mbar) and received the crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity, part of 99.2% (grade� transformation > 99,9%) and enantiomeric purity, part of 99.4%.

Example 7

In the glove camera (the contents Of2≤2 part./million) in a stainless steel autoclave with a volume of 185 ml were placed 2.00 g (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid (4,59 mmole), 8,96 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0,0046 mmole, S/C 1'000), 24 ml of methanol and 16 ml of tetrahydrofuran and 0.12 ml (S)-1-phenylethylamine (0,93 mmole). The autoclave was sealed and the hydrogenation was carried out at 60°C for 8 h and then 80°C for 2 h under hydrogen pressure of 30 bar. After opening the autoclave yellowish solution evaporated to dryness in a rotary evaporator (50°C/5 mbar) and received 2,24 g of crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity, part of 99.2% (the degree of conversion of >99.9 percent), and enantiomeric purity, component of 99.2%. The crude product was dissolved in 50 ml of ethyl acetate. Added 10 ml of water and 3 ml of 2M aqueous HCl solution and the biphasic mixture was stirred at 55°C for 15 min, the Organic layer was separated, the aqueous layer was extracted with 20 ml of ethyl acetate and the combined organic layers were stirred with 0.5 g of charcoal (Darko KB) by CT within 30 min After filtration through celite the clear solution was dried over 3 g of sulfate Natrii evaporated to dryness (40°C/10 mbar). The crude product was dissolved in 50 ml isopropylacetate when boiling to reflux (temperature of the oil bath to 100°C) and allowed to cool to room temperature and spontaneous crystallization began. The crystals formed were filtered, washed with 10 ml isopropylacetate and dried at 60°C/10 mbar for 2 h and received 1.40 g (70%) of pure (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as white crystals with a chemical purity, part of 99.8% and enantiomeric purity, component >99.9% of EI.

Example 8

In the glove camera (the contents Of2≤2 part./million) in a stainless steel autoclave with a volume of 185 ml were placed 2.00 g (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid (4,59 mmole), 4,48 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0,0023 mmole, S/C 2'000), 24 ml of methanol and 16 ml of tetrahydrofuran and 0.12 ml (S)-1-phenylethylamine (0,93 mmole). The autoclave was sealed and the hydrogenation was carried out at 60°C for 20 h and then 80°C for 2 h under hydrogen pressure equal to 10 bar. After opening the autoclave yellowish solution evaporated to dryness in a rotary evaporator (50°C/5 mbar) and received the crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid�wow substances with a chemical purity, component to 98.9% (the degree of conversion of >99.9 percent), and enantiomeric purity, component 99,6%.

Example 9

By the method similar to that used in example 4, the following hydrogenation was carried out at 40°C under a hydrogen pressure of 30 bar (duration of response: 16 h), using [Ir((S,S)-Xyl-Skewphos)(COD)]BF4(S/C 1'000) as catalysts and received crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity as component of 98.8% (degree of conversion of 99.4%) and enantiomeric purity of 85%.

Example 10

By the method similar to that used in example 2, the following hydrogenation was carried out at 60°C under a hydrogen pressure of 30 bar (duration of response: 16 h), using [Ir((S,R,R)-Trifer)(COD)]BARF (S/C 250) as catalysts and received crude (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity, part of 98.0% (the degree of conversion of >99.9 percent), and enantiomeric purity, component 86%.

Example 11

In the glove camera (the contents Of2≤2 part./million) in a stainless steel autoclave with a volume of 50 ml were placed 1.00 g (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]type�-7-yl}-acrylic acid (2,30 mmole),1,99 mg of [Ru(η 5-2,4-DMP)((R)-(S)-PPF-PtBu2)(NCMe)]BF4(0,0023 mmole, S/C 1'000), 12 ml of methanol, 8 ml of dichloromethane and 0.06 ml (S)-1-phenylethylamine (0.47 mmole). The autoclave was sealed and the hydrogenation was carried out at 40°C under a hydrogen pressure of 30 bar. After 16 h, the autoclave was opened and the yellowish solution was evaporated to dryness in a rotary evaporator (50°C/5 mbar) and received the crude (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity, component 99,6% (the degree of conversion of >99.9 percent), and enantiomeric purity, component of 89%.

The HPLC method for the determination of chemical purity (expressed in % of the peak area (S)-phenylethylamine not included): YMC-Pack Pro C18, 150×4.6 mm; mobile phase A: mobile phase A: water with addition of 0.1% TFA, B: NCMe with the addition of 0.1% TFA, 22°C, 2 ml/min in isocratic mode a/51/49% for 10 min, gradient mode from 51/49% to 5/95% in 10 min and 5 min at 5/95%, 285 nm. Retention times: 11.2 min (S)- and (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid; and 12.4 min ((E)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]the thiophene-7-yl}-acrylic acid; 14,0 min (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid.

The HPLC method for the determination of EI (area %): column Chiralpak-ADH, with 25� × 4.6 mm, 90% heptane/10% ethanol with addition of 0.5% trifluoroacetic acid, flow rate 0.7 ml/min, 30°C, 270 nm. The retention times with 22.1 min (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid; 26,0 min (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid.

Examples 12.1-12.5

By the method similar to that used in example 11, the following hydrogenation was carried out at 40°C under a hydrogen pressure of 30 bar (duration of response: 16 hours) with the use of ruthenium complexes of General formula [Ru(η5-2,4-DMP)(phosphorus-containing ligand)(NCMe)]BF4as catalysts and obtained crude 2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as specified in table 3.

Table 3
Example No.Phosphorus-containing ligandThe degree of conversion [%]The purity of the acid (I) [%] EI acid I [%]/configuration
12.1(R)-(R)-PPPhFCHCH3-R(norbornyl)2>the 99.997,169/S
12.2(R)-(R)-Cy2PPhFCH-CH3R(3,5-CF3Ph)2>the 99.999,479/S
12.3(R)-(S)-NMe2-PPh2-Mandyphos99,699,169/S
12.4(R)-(S)-NMe2-P(3,5-Me-4-MeOPh)2-Mandyphos99,398,870/S
12.5(R)-(R)-PPPhFCHCH3-P(3,5-CF3Ph)2>the 99.999,658/R

Example 13

By the method similar to that used in example 11, the following hydrogenation was carried out at 40°C under a hydrogen pressure of 30 bar (duration of response: 16 h), using the ruthenium complex [Ru(η5-2,4-DMP)((S)-(R)-PPPhCHNMe2F-RR)] as catalysts and received crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity, part of 98.7% (the degree of conversion of 99.2% and enantiomeric purity, constituting 46%.

Example 14

In the glove camera (contains�R O 2≤2 part./million) in a stainless steel autoclave with a volume of 50 ml was placed at 2.26 mg [Ru(η5-2,4-DMP)((S)-(R)-(3,5-Me2-4-MeOPh)2PF-PtBu2)(NCMe)]BF4(0,0023 mmole, S/C 1'000) and 6 ml of dichloromethane. The resulting purple solution was stirred for 2 h at CT. Then was added 1.00 g (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid (2,30 mmole), 4 ml of dichloromethane, 10 ml THF and 0.06 ml (S)-1-phenylethylamine (0.47 mmole). The autoclave was sealed and the hydrogenation was carried out under stirring at 40°C. under hydrogen pressure of 30 bar. After 16 h, the autoclave was opened and the yellowish solution was evaporated to dryness in a rotary evaporator (50°C/5 mbar) and received the crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity, component of 99.5% (the degree of conversion of>99.9 percent), and enantiomeric purity, component of 87%.

Example 15

By the method similar to that used in example 14, the following hydrogenation was carried out at 40°C under a hydrogen pressure of 30 bar (duration of response: 16 h), using the ruthenium complex [Ru(η5-2,4-DMP)((S)-(R)-2-Fur2PP-PtBu2)(NCMe)]BF4as catalysts and received crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-PR�peony acid (acid I) as a white solid with a chemical purity, component to 99.3% (the degree of conversion of >99.9 percent), and enantiomeric purity, constituting 73%.

Example 16

In the glove camera (the content of O2≤2 part./million) in a stainless steel autoclave with a volume of 50 ml was placed 1,99 mg [Ru(η52,4-DMP)((R)-(S)-PPF-PtBu2)(NCMe)]BF4(0,0023 mmole, S/C 1'000) and 5 ml of dichloromethane. The resulting purple solution was stirred for 2 h at CT. Then was added 1.00 g (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid (2,30 mmole), 2.5 ml of dichloromethane, 7.5 ml THF and 0.06 ml (S)-1-phenylethylamine (0.47 mmole). The autoclave was sealed and the hydrogenation was carried out under stirring at 40°C. under hydrogen pressure of 30 bar. After 16 h, the autoclave was opened and the yellowish solution was evaporated to dryness in a rotary evaporator (50°C/5 mbar) and received (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity, part of 99.2% (the degree of conversion of >99.9 percent), and enantiomeric purity, component of 90%.

Examples 17.1-17.2

By the method similar to that used in example 16, the following hydrogenation was carried out at 40°C under a hydrogen pressure of 30 bar (duration of response: 16 hours) with the use of ruthenium complexes of General formula [Ru(η5-2,4-DMP)(phosphorus-containing ligand)(NCMe)]BF as catalysts and obtained crude 2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as specified in table 4.

Table 4
Example No.Phosphorus-containing ligandThe degree of conversion [%]The purity of the acid (I) [%] EI acid I [%]/configuration
17.1(S)-(R)-Cy2PF-PtBu298,798,674/S
17.2(S)-(R)-(4-CF3Ph)2PF-PtBu2the 99.999,684/S

Example 18

In the glove camera (the contents Of2≤2 part./million) in a stainless steel autoclave with a volume of 50 ml was placed 0,66 mg [Ru(η5-2,4-DMP)((R)-(S)-PPF-PtBu2)(NCMe)]BF4(0,0008 mmole, S/C 3'000) and 5 ml of dichloromethane. The resulting purple solution was stirred for 2 h at CT. Then was added 1.00 g (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid (2,30 mmole), 2.5 ml of dichloromethane, 7.5 ml THF and 0.06 ml (S)-1-f�of militiamen (0.47 mmole). The autoclave was sealed and the hydrogenation was carried out under stirring at 40°C. under hydrogen pressure of 30 bar. After 16 h, the autoclave was opened and the yellowish solution was evaporated to dryness in a rotary evaporator (50°C/5 mbar) and received (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity, component of 99.5% (the degree of conversion of 99.9%) and enantiomeric purity as component of 89%.

Example 19

In the glove camera (the contents Of2≤2 part./million) in a stainless steel autoclave with a volume of 50 ml was placed 0,66 mg [Ru(η5-2,4-DMP)((R)-(S)-PPF-PtBu2)(NCMe)]BF4(0,0008 mmole, S/C 3'000) and 5 ml of dichloromethane. The resulting purple solution was stirred for 2 h at CT. Then was added 1.00 g (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid (2,30 mmole), 10 ml of dichloromethane and 0.06 ml (S)-1-phenylethylamine (0.47 mmole). The autoclave was sealed and the hydrogenation was carried out under stirring at 40°C. under hydrogen pressure of 30 bar. After 16 h, the autoclave was opened and the yellowish solution was evaporated to dryness in a rotary evaporator (50°C/5 mbar) and received (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity, with�a component of 99.5% (the degree of conversion of 99.9%), and enantiomeric purity, constituting 90%.

Comparative example A

In the glove camera (the contents Of2≤2 part./million) in a stainless steel autoclave with a volume of 50 ml was placed 0,62 mg [Ru(SLA)2((S)-TMTR)] (0,0008 mmole, S/C 3'000) (obtained in accordance with EP 1670792 B1; TMBTP = 2,2',5,5'-Tetramethyl-4,4'-bis(diphenylphosphino)-3,3'-bithiophene) and 5 ml of methanol. The resulting orange solution was stirred for 2 h at CT. Then 1.00 g (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-acrylic acid (2,30 mmole), 4 ml of methanol, 6 ml of THF and 0.06 ml (S)-1-phenylethylamine (0.47 mmole) was added. The autoclave was sealed and the hydrogenation was carried out under stirring at 40°C. under hydrogen pressure of 30 bar. After 16 h, the autoclave was opened and the yellowish solution was evaporated to dryness in a rotary evaporator (50°C/5 mbar) and received the crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-yl}-propionic acid (acid I) as a white solid with a chemical purity, part of 99.7% (the degree of conversion of 99.9%) and enantiomeric purity, constituting 89%.

1. A method for producing a compound of formula (I)

or salts thereof, wherein the compound of formula (II)

or its salt hydrate
in the presence of a catalyst comprising iridium,
in which cat�lizator includes iridium and the compound of formula (III)

in which R1denotes hydrogen, isopropyl, phenyl or benzyl and
in which R2denotes phenyl, 3,5-dimethylphenyl or 3,5-di-tert-butylphenyl.

2. A method according to claim 1, wherein the compound of formula (III) is a
(Sa,S)-7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-diphenylphosphino-1,1'-spirobiindane;
(Sa,S)-7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-di(3,5-dimethylphenyl)phosphino-1,1'-spirobiindane;
(Sa,S)-7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane;
(Sa,S)-7-[4,5-dihydro-4-phenyloxazol-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane;
(Sa,S)-7-[4,5-dihydro-4-isopropylamino-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane; or
(Sa)-7-[4,5-dihydrooxazolo-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane.

3. A method according to claim 1 or 2, wherein the compound of formula (III) is a
(Sa,S)-7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane;
(Sa,S)-7-[4,5-dihydro-4-isopropylamino-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane; or
(Sa)-7-[4,5-dihydrooxazolo-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane.

4. A method according to any one of claims.1-3, in which the catalyst is
Ir(L1)(L2)nY,
in which
L1denotes a compound of formula (III), as defined in any one of claims.1-;
L2denotes cyclooctene, 1,5-cyclooctadiene, ethylene, 1,5-hexadien or norbornadiene;
Y is chloride, iodide, bromide, fluoride, triptorelin, tetrafluoroborate, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetraphenylborate, hexafluoroantimonate, hexaflurophosphate, triflic, mesilate, perchlorate, perromat, periodate, nitrate, hydrogen sulfate or acetylacetonate; and
n is 1 or 2.

5. A method according to any one of claims.1-4, in which the catalyst is
[Ir((S,S)-7-[4,5-dihydro-4-benzisoxazol-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];
[Ir((S,S)-7-[4,5-dihydro-4-isopropylamino-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate] or
[Ir((S)-7-[4,5-dihydrooxazolo-2-yl]-7'-di(3,5-di-tert-butylphenyl)phosphino-1,1'-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate].

6. The use of the catalyst according to any of claims.1-5 to obtain the compound of formula (I) according to claim 1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: claimed invention relates to method of obtaining organic salts, which contain anions of bis(perfluoroalkyl)phosphinate and can be applied in organic synthesis. Difference of claimed method lies in the fact that it includes carrying out reaction of tris(perfluoroalkyl)phosphinoxide with alcohol and organic base, stronger than alcohol.

EFFECT: elaboration of new method of obtaining organic salts with properties of ionic liquids.

11 cl, 14 ex

FIELD: chemistry of organophosphorus compounds, chemical technology.

SUBSTANCE: invention relates to fluorinated phosphoric acids of the general formula: [RyPF6-y]-H+ [I] wherein y = 1, 2 or 3; ligands R are similar and R represents perfluorinated (C1-C8)-alkyl or aryl group or partially fluorinated (C1-C8)-alkyl or aryl group wherein some atoms F and H can be replaced for chlorine atom. Also, invention relates to a method for synthesis of above described acids by interaction perfluoroalkylphosphorane with fluorohydrogen in the presence of suitable solvent and/or proton acceptor, to salts comprising cation and anion of above described acid, and to a method for synthesis of salts. Acids of the formula [I] can be easily synthesized and show high proton activity and stable at room temperature in highly concentrated solution.

EFFECT: improved method of synthesis, improved and valuable properties of acids.

18 cl, 33 ex

FIELD: organic chemistry, chemical technology, electrolytes.

SUBSTANCE: invention relates to new fluoroalkyl phosphates that can be used as electrolytes in primary current sources, secondary current sources, capacitors, super capacitors and/or galvanic units. Invention describes fluoroalkyl phosphates of the general formula (I): Mn+[PFx(CyF2y+1-zHz)6-x]n wherein 1 ≤ x ≤ 6, 1 ≤ y ≤ 8, 0 ≤ z ≤ 2y + 1, 1 ≤ n ≤ 5 and Mn+ means a monovalent, bivalent or trivalent cation, in particular: NR1R2R3R4, PR1R2R3R4, P(NR1R2)kR3mR44-k-m (wherein k = 1-4; m = 0-3 and k + m ≤ 4), C(NR1R2)(NR3R4)(NR5R6), C(aryl)3, Rb or tropylium wherein R1-R8 mean hydrogen atom (H), alkyl or (C1-C8)-aryl that can be substituted partially for F, Cl or Br atoms and wherein Mn+ means Li+, Na+, Cs+, K+ and Ag+ are excluded. Except for, invention describes a method for preparing fluoroalkyl phosphates and electrolytes for primary current sources based on fluoroalkyl phosphates. Invention provides preparing new compounds possessing useful properties.

EFFECT: improved preparing method, valuable properties of compounds.

11 cl, 1 dwg, 7 ex

The invention relates to novel achiral diphosphine ligands bilaterales type

The invention relates to the field of chemistry of nitrogen-containing heterocyclic compounds and organophosphorus compounds, namely piperazinone salt bis(oxymethyl)phosphinic acid of General formula (I) having anthelminthic activity, not having toxic and local reactive action on the organism of the animal

The invention relates to a new method of obtaining perphosphate lithium General formula (I), where a = 1, 2, 3, 4, or 5, b = 0 or 1, C = 0, 1, 2 or 3, d = 0, 1, 2 or 3; e = 1, 2, 3, or 4, provided that the sum of a+e = 6, the sum of b+c+d = 3, and b and C are not simultaneously denote 0, provided the ligands (CHbFc(CF3)d) can be different, and monochlor - or fluorine-, dichloro - or debtor, chlortetracycline, hormone, HARDI-, Hartry or chlortetracycline, formano, Ferdi-, fortri or fortetracycline or cryptomonadales subjected to electrochemical fluorination in an inert solvent, the resulting mixture of products if necessary, divide by distillation at various fluorinated products and the fluorinated alkylphosphine, put in an aprotic, polar solvent at from -35 to 60oWith interaction with lithium fluoride

The invention relates to a new organoboron compound having catalytic activity, of the formula I

[RjM-Xd-MRj]a-bAc+(I)

in which R are, independently of one another, identical and denote C1-C40alkyl; X is, independently from each other, equal or different and denote C1-C40alkyl; M is, independently of one another, identical or different and denote an element of IIIa, IVa, Va group of the Periodic system of elements, provided that one M is boron, a is a cation of an element Ia, IIa and IIIa groups of the Periodic system of elements, carbene-hydronium - or sulfonyl - cation or compound Quaternary ammonium, and a is an integer from 0 to 10, b is an integer from 0 to 10, C is an integer from 0 to 10 and a = C; d is 1; j is an integer from 1 to 3

FIELD: chemistry.

SUBSTANCE: invention relates to a novel derivative of ferrocene 1-(1,1,1,3,3,3-hexafluoro-2-ferrocenylprop-2-yl)-imidazole of formula

which shows an antitumour activity. Also claimed is a method of its obtaining (versions).

EFFECT: invention makes it possible to obtain the novel derivative of ferrocene, which can be applied in medicine for chemotherapy of oncologic diseases.

4 cl, 1 dwg, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a method of producing heteroannular 1,1'-bis-(dimethylalkoxysilyl)-ferrocenes by reacting anhydrous iron chloride and dimethylalkoxysilyl cyclopentadienes in the medium of an organic solvent, wherein the deprotonation agent of the condensation reaction of iron chloride with silyl derivatives of cyclopentadiene used is sodium derivatives of lower alcohols, such as sodium methylate, ethylate or isopropylate.

EFFECT: high cost-effectiveness and high output of non-defective products.

4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing novel diad compounds (I) having two different chromophoric fragments that are not coupled to each other and contain azo groups and ferrocene residues, and use thereof to extinguish fluorescence of fluorophores (I) where Fc is ferrocenyl; R1-H or Fc;R2 is H or ortho- or para-hydroxy-; R3 is ortho- or meta-, or para-nitro-, or ortho- or meta-, or para-nitrophenylazo-, or para-N,N-dimethylamino-, or para-carboxy-; L is para-carbamoyl vinylidene acetophenone or para-carboxamidovinylidene acetophenone, or para-N-(2-carbamoylethyl)-carboxamidovinylidene acetophenone, or para-(4-[methylamino] butoxy)-vinylidene acetophenone, or N,N-di[4{1-(para-vinylidene acetophenylamino)-methyl-1,2,3-triazolyl}butyl]amino group. The method of producing (I) involves aldol-crotonic condensation of ferrocene aldehyde with para-substituted acetophenone and reacting the obtained ferrocenylidene acetophenone (2) with an azo compound, or adding to (2) reactive groups and azo coupling with a diazo salt. Effectiveness of (I) in extinguishing fluorophores in a solution and in a composition of nucleic acids in a wide spectral range is shown, which enables to use (I) to label biological macromolecules and design oligonucleotide hybridisation probes for molecular diagnosis methods.

EFFECT: diad compounds (I) have high molar extinction coefficients, a wide absorption spectrum and electroactivity; also described is a method of extinguishing fluorescence of fluorophores in double-stranded structures of nucleic acids using (I).

2 cl, 8 dwg, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to methods of producing heteroannular ferrocene derivatives. Disclosed is a method of producing 1,1'-bis(dimethyl alkoxysilyl)ferrocenes by reacting heteroannular 1,1'-dilithium ferrocene with dimethyl alkoxychlorosilanes in the medium of inert solvents.

EFFECT: fewer steps and high selectivity of the method.

2 cl, 1 tbl, 5 ex

FIELD: semi-conductors.

SUBSTANCE: invention refers to polymers on the base of poly(ferrocenyl)sylane used in photon semiconductor matrixes. The invention proposes celled polymer on the base of poly(ferrocenyl)sylane including repeating blocks with three types of structures, way of its manufacturing based on spatial crossing of basic polymer and binding agent and the film including the substrate and connected to it celled polymer on the base of poly(ferrocenyl)sylane.

EFFECT: proposed celled polymers have 3D structures and are produced using technological method that does not require special multistage cleaning of precursors.

12 cl, 1 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of platinum metal salts, particularly palladium salts and specifically palladium propionate. The method of producing palladium propionate involves dissolving palladium metal in concentrated nitric acid, evaporation of the obtained solution, wherein after evaporation and before crystallisation of the palladium (II) nitrate salt at solution temperature (15-80)°C, the palladium nitrate is treated with NO taken in amount of (0.3-0.7) m3 (standard conditions) per 1 kg of the initial palladium metal and propionic acid is added in amount of (2.0-3.0) l per 1 kg of the initial palladium metal or propionic acid anhydride in amount of (2.0-2.5) l per 1 kg of palladium. The formed solution or suspension heated in an inert gas atmosphere in amount of approximately 20 m3 (standard conditions) per 1 m3, at temperature (90-120)°C for (30-60) minutes if propionic acid is added, or at temperature (80-110)°C for not less than 30 minutes if propionic acid anhydride is added, and the obtained solution or suspension is cooled to temperature not higher than 20°C, with crystallisation of the product for not less than 6 hours.

EFFECT: stable method of producing palladium propionate and extraction with high output in monophase state.

2 cl, 41 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae I or I', in which radicals R1 denote a hydrogen atom and R'1 denotes C1-C4-alkyl; X1 and X2 each independently denotes a fluoro-phosphine group, where secondary phosphine groups X1 and X2 contain hydrocarbon radicals containing 1-22 carbon atoms and can be unsubstituted or substituted, and/or contain heteroatoms selected from groups comprising O, S and N(C1-C4-alkyl); R2 denotes hydrogen; T denotes C-bonded C3-C20-heteroarylene in which heteroaryl groups, from which heteroarylene is obtained, are pyrrole, N-methylpyrrole, furan, thiophene, indole, N-methylindole, benzofuran, benzothiophene, pyridine, pyrimidine and quinoline; v equals 0; group X1 in the heteroarylene heterocycle is bonded in the ortho-position relative the T-C* bond; * denotes a mixture of racemic or enantiomerically pure diastereomers or pure racemic or enantiomerically pure diastereomers. The invention also discloses metal complexes, a method producing chiral organic compounds and use of metal complexes for producing chiral organic compounds.

EFFECT: high optical output during hydrogenation of prochiral organic compounds.

17 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula I, , where R1 represents phenyl, R2 represents dimethylamine group, and R represents radical of formula , where R3 represents methyl, R4 represents H, or methoxyl, which are ligands for metal complexes, used as homogenous catalysts of hydration of prochiral organic compounds, containing binary bonds.

EFFECT: very high activity and productivity and enantioselectivity.

6 cl, 7 ex

Catalyst system // 2326123

FIELD: chemistry.

SUBSTANCE: catalyst system is described. It consists of compounds with general formula I or its salt, bonded to a VIIIB metal, where A1 and A2, as well as A3, A4 and A5 (when present), K, D, E, X1-X4, Q1, Q2, M, L1 assume values given in the formula of invention.

EFFECT: system is suitable for carbonylation of ethenoid unsaturated compounds.

45 cl, 32 ex, 9 tbl

FIELD: fuel additives.

SUBSTANCE: ferrocene is alkylated with gasoline pyrolysis products containing up to 30-35% various-structure unsaturated hydrocarbons in presence of ferrous chloride, bicyclopentadienyl, and diethylamine at ambient temperature. Thereafter, 1-5% of AlCCl4 catalytic system activated with 5-25% of diisopropyl ether is added and reaction mixture is stirred at 20 to 90°C for 0.5 to 8 h. Resulting product is adsorbed and then desired product is recovered.

EFFECT: enabled preparation of additive with 96-98% purity and yield up to 74%.

3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula I, or their racemic mixture, or their individual optic isomers, or pharmaceutically acceptable salts possessing the properties of TGR bile acid receptor agonist. The invention also refers to methods for preparing the compounds. In general formula I , X represents amino group R'R"N, wherein the substitutes R' and R" can be optionally identical, or represents hydrogen, C1-C6alkyl, C3-C6cycloalkyl; substituted C1-C6alkyl, wherein the substitute is specified in phenyl or phenoxy, each of which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy, phenyloxy, C3-C6cycloalkyl, 5-6-merous heteroaryl with 1 nitrogen atom; aryl specified in phenyl optionally substituted by fluorine, C1-C3alkyl, C1-C3 alkoxy; 5-6-merous heteroaryl with nitrogen atom as heteroatom; C2-C4alkenyl, acyl specified in C1-C6alkylcarbonyl or C3-C6cycloalkylcarbonyl; or substituted oxygroup, which represents hydroxy group, wherein hydrogen is substituted by C1-C6alkyl optionally substituted by hydroxy, di(C1-C3alkyl)amino, phenyl, which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy; C2-C4alkenyl; and 5-6-merous heterocyclyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom; R1a and R1b represents hydrogen, C1-C3alkyl, or R1a and R1b together form methylene chain -(CH2)n-, wherein n=2-5; R1c and R1d represents hydrogen, C1-C3alkyl; R2 represents acyl group specified in C1-C6alkylcarbonyl, wherein alkyl can be substituted by phenyl or phenoxy, each of which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy; C3-C6cycloalkylcarbonyl; phenylcarbonyl, which can be substituted by halogen, C1-C3alkyl, C1-C3alkoxygroup, oxygroup, C1-C3alkylene dioxygroup; 5-6-merous heteroarylcarbonyl with nitrogen atom, or oxygen atom, or sulphur atom as heteroatom, optionally substituted by carboxy, halogen or C1-C3alkoxycarbonyl, substituted aminocarbonyl group, wherein the substitute can be specified in C1-C6alkyl optionally substituted by C1-C3alkoxycarbonyl, halogen, 5-6-merous heteroaryl together with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom; C3-C6cycloalkyl; phenyl optionally substituted by halogen, C1-C3alkyl, C1-C3alkoxy, C1-C3alkoxycarbonyl, C1-C3alkylenedioxygroup; 5-6-merous heteroarym with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom optionally substituted by carboxy, C1-C3alkoxycarbonyl; aminocarbonyl group substituted by C1-C3alkyl; sulphonyl group specified in alkylsuphonyl optionally substituted by hydroxyl group, cyano group, phenyl, which is optionally substituted by C1-C3alkyl, halogen, C1-C3alkoxy group; henylsulphonyl oprtionally substituted by C1-C3alkyl, halogen, C1-C3alkoxy group, cyano group, C1-C3alkylene dioxygroup, or 5-6-merous heteroarylsulphonyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom optionally substituted by halogen, C1-C3alkyl, C1-C3alkoxy group; R3 represents hydrogen.

EFFECT: compounds can be used for preparing the pharmaceutical composition applicable in treating or preventing metabolic diseases, such as diabetes, obesity, diabetic obesity, metabolic syndrome, hypercholesterolemia, dislipidemia.

14 cl, 17 dwg, 8 tbl, 16 ex

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining di-{ 4-[(tetrahydro -4H-1,4-oxazin-4-yl)-methylsulphanyl]-phenyl} ether oxalate of formula

as water-soluble substance with fungicidal activity. Essence of method consists in interaction of di-{ 4-[(tetrahydro -4H-1,4-oxazin-4-yl)-methylsulphanyl]-phenyl} ether with equimolar quantity of oxalic acid (COOH)2 at room (~20°C) temperature for 15 min.

EFFECT: output constitutes 99%.

2 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

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