Method of enantioselective hydration of aminoalcohols

FIELD: chemistry.

SUBSTANCE: method of enantiomeric obtaining aminoalcohols of formula I in which R1, R2 and n have values given in invention formula, lies in enantioselective hydration of aminoketones in presence of non-racemic catalyst, representing complex of transitive metal, which contains one or more metals and its salts, selected from group, including rhodium, iridium, ruthenium and palladium, in which transitive metal forms complex with chiral diphosphine ligand A.

EFFECT: improvement of synthesis of aminoalcohols, which are acceptable as precursors for obtaining anti-depressants.

11 cl, 6 ex

 

The invention relates to a method of enantioselective get aminoalcohols of the formula I

in which

R1means a saturated, unsaturated or aromatic carbocyclic or heterocyclic radical, which is unsubstituted or mono - or polyamidine R3and/or R4,

R2means alkyl containing 1-20 carbon atoms, or N

R3, R4each independently mean H, alkyl or alkoxy containing 1 to 20 carbon atoms, aryl, aryloxy or COOR2, F, Cl, Br, IT, CN, NO2N(R2)2or NHCOR2and

n is 0, 1, 2 or 3

by enantioselective hydrogenation of aminoketones formula II

in which

R1, R2and n have the meanings mentioned above, in the presence of nerazmokaemogo catalyst, which is characterized in that the catalyst is a complex of a transition metal, while the transition metal complexion with chiral diphosphine ligand A.

in which

R5, R6, R7and R8each independently mean H, alkyl or alkoxy containing 1 to 20 carbon atoms, aryl, aryloxy or F, Cl, Br, N(R2)2or NHCOR2

R9and R10each independently will dugogasyaschy

,

or cyclohexyl

R11means H, alkyl or alkoxy containing 1 to 20 carbon atoms, aryl, aryloxy or SO3Na, COOR12, F, Cl, N(R12or NHCOR12,

R12means alkyl containing 1-20 carbon atoms, or N, and

m is 0, 1, 2 or 3,

where R5and R6, R6and R7and R7and R8together can also have values

-(CH2)4-, -CH=CH-CH=CH-,or

or

where

Y means HE, P(cyclohexyl)2, R(3, 5dimethylphenyl)2or P(C(CH3)3)2,

Z denotes N or P(phenyl)2,

Q means PPh2, P(cyclohexyl)2P[3,5-bis(trifluoromethyl)phenyl]2P(4-methoxy-3, 5dimethylphenyl)2or P(C(CH3)3)2

and

Ph means phenyl, o-, m - or p-or were dimetilfenil.

In the compounds of formula A, R9and R10preferably means or cyclohexyl

Particular preference is given to compounds of the formula A1

where Ph mn has the treatment, above, and X is H, alkyl, O(alkyl ), Cl, or F, a R' represents an alkyl(alkyl) or F. Particular preference is given to compounds of the formula A3, where Ph means phenyl, X is H and R' means och3.

Preferred compounds of formula a are symmetric.

The compounds of formula II are preferably used in the form of salts accession acid, in particular, are acceptable acid additive salts of strong acids, such as, for example, hydrochloric acid, methyl-, p-toluene - or benzolsulfonat acid, perchloric, sulfuric or phosphoric acid, are also acceptable acetic acid, formic acid or prapanova acid. Particular preference is given to salts of sulfuric acid or hydrochloridum compounds of formula II. The use of acid additive salts of compounds of formula II get acid additive salts of compounds of formula I, from which the free base can be released by addition of a strong base such as a carbonate or hydroxide of an alkali metal.

The invention thus relates, in particular, to a method for producing optically active forms of salt, hydrate and solvate, for example, alcoholate, compounds of the formula I, in particular compounds of the formula I, in which n is 1.

The invention preferably improves Shin is ez optically active aryl-substituted 3-monoalkylphenol, which are acceptable as precursors for receiving antidepressants.

In particular, it opens the possibility of obtaining enantiomerically pure or enriched enantiomers (S)-3-methylamino-1-(2-thienyl)-1-propanol in a simple way, using as starting compound 3-methylamino-1-(2-thienyl)-1-propanone. Alternatively, enantiomerically pure or enriched enantiomers (S)-3-methylamino-1-phenyl-1-propanol can be obtained by a simple method using as starting compound 3-methylamino-1-phenyl-1-propanone.

The splitting of racemic alcohol can in fact obtain the desired enantiomer 3-methylamino-1-(2-thienyl)-1-propanol with a maximum yield of 50% (for example, similar Chirality 2000, 12, 26 or EP 650965).

J. Labelled Compd. Radiopharm. 1995, 36(3), 213 and Tetrahedron Lett. 1990, 31(49), 7101 describe asymmetric synthesis of (S)-3-methylamino-1-(2-thienyl)-1-propanol. However, both methods of synthesis require additional transformations or stoichiometric use of chiral reagent. In contrast, the method in accordance with the invention described in this application results in the desired enantiomer of the final product with high selectivity and without the implementation of additional transformations.

In the General case of a homogeneous hydrogenation of 3-aminoketones is problematic because in most cases produced products, to be deleted instead of the desired alcohol (J. were obtained. Chem. 1982, 232, 17 or Synlett, 1997, 1306). In the method in accordance with the invention, such removal has been demonstrated as unimportant (percentage of product that should be deleted is less than 2%).

Comparable processes for the preparation of 3-aminoalcohols described in Synlett 1991, 689, however, such connections are restored to the corresponding alcohols with significantly worse enantioselectivity. Although homogeneous ruthenium catalyst used in the Org. Lett. 2000, 2(12), 1749, provide alcohol in the hydrogenation of 3-dimetilaminokhalkona with such good selectivity, it is necessary to undertake a complex demethylation to obtain the desired (S)-3-methylamino-1-(2-thienyl)-1-propanol or (S)-3-methylamino-1-phenyl-1-propanol, unlike the method in accordance with the invention. The formation of toxic and carcinogenic methyl chloride is a special disadvantage in this case.

The invention, therefore, is finding ways to produce compounds that can be used, in particular, as intermediates in the synthesis of medicines, and which does not have the above disadvantages.

It was found that the compounds of formula I and its salts, which are important premiato the different compounds in pharmaceuticals production, in particular, those that are shown, for example, effects on the Central nervous system, can be obtained by enantioselective hydrogenation of compounds of formula II in the presence of chiral, nerazmokaemogo catalyst transition metal.

Above and below, the radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11and R12,Q, Y and Z and the indices m and n have the meanings stated for formula I, II, a and b, unless specifically stated otherwise. If they are used more than once in the formula, the values of the individual radicals are independent from each other.

In the above formulas, the alkyl contains from 1 to 20 carbon atoms, preferably from 1 to 6, in particular 1, 2, 3 or 4 carbon atoms. Alkyl preferably denotes methyl or ethyl, and propyl, isopropyl, also, butyl, isobutyl, sec-butyl or tert-butyl.

R1preferably represents an aromatic carbocyclic or heterocyclic radical, which is unsubstituted or substituted R3and/or R4. This radical may be mono - or polycyclic and is preferably mono - or bicyclic, but, in particular, monocyclic. R1especially preferably is unsubstituted.

If R1means carbocycle the ical radical, this radical preferably represents, for example, phenyl, o-, m - or p-tolyl, o-, m - or p-hydroxyphenyl, o-, m - or p-methoxyphenyl, o-, m - or p-forfinal.

If R1means a heterocyclic radical, it is a 2 - or 3-furyl, 2 - or 3-thienyl, 1-, 2 - or 3-pyrrolyl, 1-, 2-, 4 - or 5-imidazolyl, 1-, 3-, 4 - or 5-pyrazolyl, 2-, 4 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, and preferably 1,2,3-triazole-1-, -4 - or-5-yl, 1,2,4-triazole-1, -3 - or-5-yl, 1 - or 5-tetrazolyl, 1,2,3-oxadiazol-4 - or-5-yl, 1,2,4-oxadiazol-3 - or-5-yl, 1,3,4-thiadiazole-2 - or-5-yl, 1,2,4-the thiadiazole-C - or-5-yl, 1,2,3-thiadiazole-4 - or-5-yl, 3 - or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 4 - or 5-isoindolyl, 1-, 2-, 4 - or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6 - or 7-benzimidazolyl, 2-, 4-, 5-, 6 - or 7-benzoxazolyl, 3-, 4-, 5-, 6 - or 7-benzisoxazole, 2-, 4-, 5-, 6 - or 7-benzothiazolyl, 2-, 4-, 5-, 6 - or 7-benzisothiazole, 4-, 5-, 6 - or 7-benzo-2,1,3-oxadiazole, 2-, 3-, 4-, 5-, 6-, 7 - or 8-chinolin, 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethanolic, 3-, 4-, 5-, 6-, 7 - or 8-indolinyl, 2-, 4-, 5-, 6-, 7 - or 8-hintline, 5 - or 6-honokalani, 2-, 3-, 5-, 6-, 7 - or 8-2H-benzo[1,4]oxazinyl, and preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazole-4 - or-5-yl or 2,1,3-benzoxadiazole-5-yl, for example, are preferred.

Heterocyclic radical which can also be partially or fully gidrirovanny. Used heterocyclic radical may also, therefore, to represent, for example, 2,3-dihydro-2-, -3-, -4 - or-5-furyl, 2,5-dihydro-2-, -3-, -4 - or 5-furyl, tetrahydro-2 - or-3-furyl, 1,3-dioxolane-4-yl, tetrahydro-2 - or-3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4 - or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4 - or-5-pyrrolyl, 1-, 2 - or 3-pyrrolidinyl, tetrahydro-1-, -2 - or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4 - or-5-pyrazolyl, tetrahydro-1-, -3 - or-4-pyrazolyl, 1,4-dihydro-1-, -2-, -3 - or 4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5 - or-6-pyridyl, 1-, 2-, 3 - or 4-piperidinyl, 2-, 3 - or 4-morpholinyl, tetrahydro-2-, -3 - or-4-pyranyl, 1,4-dioxane, 1,3-dioxane-2-, -4-or-5-yl, hexahydro-1-, -3 - or-4-pyridazinyl, hexahydro-1-, -2-, -4 - or-5-pyrimidinyl, 1-, 2 - or 3-piperazinil, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7 - or-8-chinolin, 1,2,3,4-tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7 - or-8-ethanolic, 2-, 3-, 5-, 6-, 7 - or 8-3,4-dihydro-2H-benzo[1,4]oxazinyl, and preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-atlanticcity, 3,4-atlanticcity, 3,4-(diversitronics)phenyl, 2,3-dihydrobenzofuran-5-or 6-yl, 2,3-(2-oxoethylidene)phenyl or also 3,4-dihydro-2H-1,5-benzodioxepin-6 - or -7-yl, furthermore preferably 2,3 - dihydrobenzofuranyl or 2,3-dihydro-2-oxoferryl.

These heterocyclic radicals can be further substituted, R3and/or R4.

R1in particular, predpochtitelno means phenyl or 2-thienyl.

R2preferably means methyl, ethyl, n-propyl or isopropyl, but, in particular, methyl.

R3and R4independently of one another denote H, methyl, in particular, N.

R5and R6preferably denote H, alkyl, O-alkyl, Cl or F.

Preference is also given to compounds of the formula a in which R5and R6together form a ring system.

R7and R8preferably mean N.

R11preferably represents H or methyl, in particular methyl.

R12preferably represents methyl or ethyl.

n is preferably 0 or 1, in particular, 1.

m preferably equals 1.

Aryloxy preferably means, for example, phenyloxy, o-, m - or p-tolyloxy, o-, m - or p-hydroxyphenoxy, o-, m - or p-methoxyphenoxy, o-, m-or p-torpedolike.

Aryl preferably denotes, for example, phenyl, o-, m - or p-tolyl, o-, m-or p-hydroxyphenyl, o-, m - or p-methoxyphenyl, o-, m - or p-forfinal.

Preference is given to using chiral ligands of the formula A.

Ph means phenyl, 2-, 3 - or 4-were, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5dimethylphenyl.

Ph preferably means phenyl, 4-tolyl or 3, 5dimethylphenyl, especially preferred is 4-tolyl.

Y preferably denotes P(C(CH3)3)2.

Z preferably will appoints N.

Q preferably denotes P(phenyl)2.

Preference is given to chiral ligands of the formula In which Z has the values of N and Y P ((CH3)3)2. Preference also is given to ligands of the formula In which Z has the value P(phenyl)2and Y has a value of IT.

Preference also is given to ligands of the formula with the following combinations of the radicals Q and Y:

Q=PPh2; Y=P(diclohexal)2

Q=PPh2; Y=P(tert-butyl)2

Q=P(cyclohexyl)2; Y=P(cyclohexyl)2

Q=PPh2; Y=P(3, 5dimethylphenyl)2

Q=P[3,5-bis(trifluoromethyl)phenyl]2; Y=P(diclohexal)2

Q=P(4-methoxy-3, 5dimethylphenyl)2; Y=P(3, 5dimethylphenyl)2

Q=P[3,5-bis(trifluoromethyl)phenyl]2; Y=P(3, 5dimethylphenyl)2

Q=P(diclohexal)2; Y=P(tert-butyl)2

Q=P(tert-butyl)2; Y=P(3, 5dimethylphenyl)2

The method in accordance with the invention is particularly suitable, in particular, to obtain the alcohols (S)-3-methylamino-1-phenyl-1-propanol or (S)-3-methylamino-1-(2-thienyl)-1-propanol, which can be mainly developed next to the active ingredient DULOXETINE, fluoxetine, tomoxetin and LY227942.

The compounds of formula I have one or more chiral centers and can thus be obtained in different stereoisomeric forms. Formula I reach the AET all such forms.

The term "enantioselective getting" defines the process by which usually produced as a reaction product mixture containing a compound of formula IA

and the compound of formula IB

where R1, R2and n have the meanings mentioned above,

this mixture is racemic and preferably contains only trace amounts of the undesired enantiomer, depending on the chirality and the selectivity of the used catalyst. In this case, the link given above and below, refers to the process of obtaining enantiomerically pure compounds of the formula IA or formula IB. Methods for obtaining enantiomerically pure compounds of formula IA are preferred.

In particular, it was found that the compounds of formula II can be gidrirovanny when using enantiomerically pure complexes of rhodium-phosphine, which contain phosphines, or to obtain enantiomerically pure or enantiomerically enriched compounds of formula I.

The invention also relates to a method for producing compounds of formula I, which is characterized by the fact that chiral, narozeniny the catalyst is an enantiomerically enriched complex of the transition metal containing one or more metals or their salts selected from the gr is PPI, including rhodium, iridium, ruthenium and palladium. Particular preference is given to using transition metal complexes containing rhodium or rhodium salt.

Particular preference is given to salts of the transition metal containing sulfate, chloride, methanesulfonate, toluensulfonate, hexachloroantimonate, hexafluoroantimonate or triftorbyenzola as anion.

Preference is given to using enantiomerically pure complexes of the transition metal.

The term "enantiomerically pure", cited above and below, means enantiomeric purity >90% (error within acceptable limits), preferably >92% (error within acceptable limits) and, in particular, >99% (error within acceptable limits).

Depending on the choice of (R)- or (S)-enantiomer of the ligand in the catalyst (R)- or (S)-enantiomer receive in excess.

Particular preference is given to ligands:

(S)-BINAP:

(S)-ToIBINAP:

where Tol means 4-were. (S)-ToIBINAP is particularly preferred.

The original connection that is used to obtain chiral complexes, preferably is a compound, such as, for example, [Rh(COD)2]OTf (triflate cyclooctadiene), [Rh(COD)Cl]2, [Rh(COD)2]BF4, [Ir(COD)Cl]2, [Ir(COD)2]BF4, [Rh(NBD)Cl]2(chloride norborne errode), [Rh(ethylene)2Cl]2, RhX3·PNO, where X is Cl, Br or I, or [Rh(COD)Cl2]x. [Rh(COD)Cl]2is preferred.

Particularly preferred complexes of rhodium contain one of the following anions: Cl, Br, I, PF6, [PF3(C2P5)3], SbF6BF4, ClO4, BPh4, Tetra(3,5-bis-triptoreline)borate, OOSN3, OOCCF3OON, OOSN2CH3, triftorbyenzola, p-toluensulfonate, methanesulfonate

and

diethyl ether or one of the following unsaturated compounds: 1, 5cyclooctadiene, cyclooctene, 2,5-norbornadiene, norbornene.

The compounds of formula II, as well as the source materials for their production, in addition, is obtained using methods known in themselves, as described in the literature (for example, well-known works, such as Houben-Weyl, Methods der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), strictly following the reaction conditions which are known and acceptable for these reactions. In this application can also be used in ways that are known in themselves, which are not mentioned in this application in more detail.

If it is desired, the starting materials can also be obtained in the same place without isolation from the reaction mixture, but instead immediately turn later in connection formula.

Acceptable solvents, for example, are water, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or Xilin; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as PEG, onomatology or monotropy ether of ethylene glycol, dimethyl ether of ethylene glycol (diglyme); ketones, such as acetone, methyl ethyl ketone or butanone; amides, such as ndimethylacetamide, dimethylacetamide or dimethylformamide (DMF); NITRILES, such as acetonitrile; sulfoxidov, such as dimethylsulfoxide (DMSO); carbon disulfide; nitro compounds such as carbon disulfide; nitro compounds such as nitromethane or nitrobenzene; esters, such as methyl acetate or ethyl acetate, and, if it is desired, mixtures of these solvents with one another or mixtures with water. Particular preference is given to mixtures of hydrocarbons with alcohols, in particular, mixtures of methanol with toluene.

Particular preference is given to the way in which the hydrogenation is carried out in the presence of one or more alcohols, in particular methanol.

Time held the Oia enantioselective hydrogenation ranges from a few hours up to 14 days depending on conditions, the temperature of the reaction is from 0°to 200°normally from 10°to 150°C, preferably from 20°to 130°and, in particular, from 20°C to 70°C. the Ratio of the catalyst/substrate typically ranges from 1:10,000 to 1:20, preferably from 10 to 1:5000 to 1:50, particularly preferably from 1:2000 to 1:100. The reaction time is, for example, from 0.1 to 30 hours, preferably from 3 to 20 hours. The hydrogenation is preferably carried out under conditions of hydrogen pressure 1-250 bar, preferably at pressures 3-210 bar, in particular from 120 to 200 bar.

The reaction is preferably carried out in conditions in the absence of oxygen.

For purification of the compounds of the formula I is desirable to carry out the hydrogenation with crystallization. In this case, in particular, in the case when R1mean 2-thienyl and R2means methyl, high excess enantiomers achieve without a significant reduction in output, which should be acceptable.

The invention also relates to the use of compounds of the formula I as intermediates for the synthesis of medicines. Medications mentioned, for example, in J. Labelled Compd. Radiopharm. 1995, 36(3), 213.

The invention also relates to the use of compounds of the formula I as intermediates for the synthesis of medicines, which show the shape effect on the Central nervous system.

Above and below, all temperatures are in °and the pressure in bars.

EXAMPLES

All reactions were carried out under inert conditions (i.e. in anhydrous reaction conditions and in the absence of oxygen).

1. Obtaining a solution of the catalyst/substrate

Example 1

51,4 mg [Rh(COD)Cl]2was dissolved in 5 ml of a mixture of toluene as a solvent, was added to the solution, which consisted of 5 ml of toluene and equivalents 1,1 (S)-(-)-2,2 bis(di-p-tolylphosphino)-1,1'-binaphthyl.

2. Sampling and analysis

The excess of the enantiomer product of hydrogenation was determined using chiral phase HPLC.

Example 2:

Added 5.3 mg dichloride bis(1,5-cyclooctadiene)derode(I) and 17.2 mg (S)-(-)-2,2 bis(di-p-tolylphosphino) 1,1'-binaphthyl to 8,23 g 3-methylamino-1-(2-thienyl)-1-propanone in a steel autoclave, to this mixture was added 50 ml of methanol and 50 ml of toluene. After closing the reactor, was released the reactor from oxygen by flushing several times with nitrogen and then with hydrogen. The reactor was filled with hydrogen to a pressure of 55 bar and heated to a temperature of 50°C. passing the reaction was tracked by accounting for the pressure drop in the autoclave. The reaction was completed in 15 hours.

The desired alcohol was obtained with the excess enantiomer of 92.8% (error within acceptable limits).

Example 3:

The oily residue, obtained in accordance with Example 2, re is oily in 300 ml of water, three times were extracted, each time with 250 ml of dichloromethane, the organic phase was discarded. Newly added 250 ml of dichloromethane to the aqueous phase, the pH was brought to 14 when using 41,0 g of 32% sodium hydroxide solution and separated phases. The organic phase was separated from the solvent. The obtained oily substance was dissolved in 320 g of MTV mixture of simple ether/toluene at 55°C, was added 2.5 g of activated charcoal and the mixture was filtered hot. After this actually discolored the solution was slowly cooled to room temperature, the reaction mixture for starters made a few crystals and cooled at -15°C for 16 hours. The resulting crystals were filtered off under suction of the liquid and dried in vacuum, obtaining the desired (S)-N-methyl-3-hydroxy-3-(2-thienyl)propanamine with the release of >99% (error within acceptable limits).

Example 4:

18,93 g (92 mmole) 3-methylamino-1-(2-thienyl)-1-propanone was weighed and placed in a steel autoclave was added 90 ml of methanol, the mixture was transferred into an inert state by a threefold introduction of nitrogen under pressure 7 bar, then spent decompression. Weighed 10,8 mg (0,022 mmole) dichloride bis(1,5-cyclooctadiene)derode(1) and 32.5 mg (0,051 mmole) of (S)-BINAP in a test tube Slinka and was dissolved in 18 ml of toluene in an argon atmosphere. This solution was transferred into the autoclave in use is the so called cannula in a countercurrent of nitrogen. The autoclave is then blew three times with hydrogen under a pressure of 10 bar, and then carried out the decompression.

The autoclave was heated to 50°and the internal pressure of the hydrogen is brought to a value of 120 bar, after she had reached this temperature. After 7 hours the introduction of hydrogen had ceased, the reaction was stopped and analyzed the reaction mixture.

The transformation of product: 98%; enantiomer excess in the product: 94%.

Example 5:

495 g of (2.4 mol) of 3-methylamino-1-(2-thienyl)-1-propanone was weighed into a steel autoclave was added 2.3 l of methanol and 0.4 l of toluene and the mixture was transferred into an inert state by a threefold introduction of nitrogen under a pressure of 7 bar, and then carried out the decompression. Weighed 297 mg (0.60 mmole) dichloride bis(1,5-cyclooctadiene)derode(1) and 900 mg (1,325 mmole) of (S)-ToIBINAP in the flask Slinka and was dissolved in 80 ml of toluene in an argon atmosphere. This solution was transferred into the autoclave using the cannula in a countercurrent of nitrogen. The autoclave three times was purged with hydrogen, each time under a pressure of 10 bar, and then spent decompression. The autoclave was heated to a temperature of 50°and the hydrogen pressure inside the autoclave was brought to 60 bar, after this temperature was reached. After 8 hours of continued introduction of hydrogen, the reaction was stopped and analyzed the reaction mixture.

The transformation of the product: >99%; excess Aisne is timer in the product: 92%.

Example 6:

16,46 g (80 mmole) of 3-methylamino-1-(2-thienyl)-1-propanone was weighed into a steel autoclave was added 75 ml of methanol and the mixture was transferred into an inert state by a threefold introduction of nitrogen under pressure 7 bar, then spent decompression. Was weighed 5.2 mg (to 0.011 mmole) dichloride bis(1,5-cyclooctadiene)derode (I) and 15.2 mg (0,022 mmole) of (S)-ToIBINAP in a test tube Slinka and was dissolved in 15 ml of toluene in an argon atmosphere. This solution was transferred into the autoclave using the cannula in a countercurrent of nitrogen. The autoclave is then blew three times with hydrogen, each time under a pressure of 10 bar, and then spent decompression. The autoclave was heated to 50°and the hydrogen pressure inside drove up to 120 bar, after she had reached this temperature. After 11 hours the introduction of hydrogen had ceased, the reaction was stopped and analyzed the reaction solution.

The transformation of the product: >99%; enantiomer excess in the product: 92%.

1. The way enantiomeric get aminoalcohols of the formula I

in which R1means a saturated, unsaturated or aromatic carbocyclic or heterocyclic radical, which is unsubstituted or mono - or polyamidine R3and/or R4,

R2means alkyl containing 1-20 carbon atoms, or N

R3, R 4each independently mean H, alkyl or alkoxy containing 1 to 20 carbon atoms, aryl, aryloxy or COOR2, F, Cl, Br, IT, CN, NO2N(R2)2or NHCOR2,

and n is 1, 2 or 3

by enantioselective hydrogenation of aminoketones formula II

in which R1, R2and n have the meanings mentioned above,

in the presence of nerazmokaemogo catalyst, wherein the catalyst is a complex of the transition metal containing one or more metals or salts selected from the group comprising rhodium, iridium, ruthenium and palladium, in which the transition metal forms a complex with chiral diphosphine ligand And

in which R5R6R7and R8each independently mean H, alkyl or alkoxy containing 1 to 20 carbon atoms, aryl, aryloxy or F, Cl, Br, N(R2)2or NHCOR2

R9and R10each independently of the other means

or cyclohexyl

R11means H, alkyl or alkoxy containing 1 to 20 carbon atoms, aryl, aryloxy or SO3Na, COOR12, F, Cl, N(R12)2or NHCOR12,

R12means alkyl containing 1-20 carbon atoms, or N, and

m is 0, 1, 2 or 3,

where R5and R6, R6and R7and R7and R8together can also have values -(CH2)4-, -CH=CH-CH-CH=CH-or

2. The method according to claim 1, in which R1means phenyl or 2-thienyl.

3. The method according to claim 1 or 2, in which R2means methyl, ethyl, n-propyl or isopropyl.

4. The method according to claim 1, in which n is 1.

5. The method according to claim 1 to obtain (S)-3-methylamino-1-phenyl-1-propanol or (S)-3-methylamino-1-(2-thienyl)-1-propanol or its salt accession acid.

6. The method according to claim 1, characterized in that the chiral diphosphines ligand is a compound of formula A1-A5:

where Ph means phenyl, o-, m - or p-or were dimetilfenil, X is H, alkyl, O(alkyl), Cl or F, and R' represents an alkyl(alkyl), or F.

7. The method according to claim 6, characterized in that the chiral diphosphines ligand is an (S)-(-)-2,2 bis(di-p-tolylphosphino)-1,1'-binaphthyl or (S)-(-)-2,2 bis(diphenylphosphino)-1,1'-binaphthyl.

8. The way recip is of compounds of the formula I according to claim 1, characterized in that the reaction temperature is 0 to 200°C.

9. Method of producing compounds of the formula I according to claim 1, characterized in that the ratio of the catalyst/substrate is from 1:5000 to 1:50.

10. Method of producing compounds of the formula I according to claim 1, characterized in that the hydrogenation is carried out at a hydrogen pressure of 1-200 bar.

11. Method of producing compounds of the formula I according to claim 1, characterized in that the hydrogenation is carried out in the presence of alcohol.

12. Method of producing compounds of the formula I according to claim 1, characterized in that the chiral narozeniny the catalyst is a complex of the transition metal, which contains sulfate, chloride, bromide, iodide, PF6BF4, methanesulfonate, toluensulfonate, hexachloroantimonate, hexafluoroantimonate or triftorbyenzola as anion.



 

Same patents:

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new compositions of general formula (I): where R1 and R2 mean H; R3 means H; R4 means lower alkyl; n is equal to 1-6; X means O; formula group =N-D (where D means H, lower alkyl); Y means ethylene group, ethynylene group, formula group -E-CH2 - (where E means carbonyl, formula group -CH(OH)-), C6-C10arylen C6-C10arylen group substituted with 1-3 substitutes, selected from Group (a) of substitutes; Z means single bond, C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain; R5 means H, C3-C10cycloalkyl group, C6-C10aryl, C6-C10aryl group substituted with 1-3 substitutes selected from Group (a) of substitutes; R6 and R7 are identical or different and represent each H, lower alkyl; Group (a) of substitutes represents group consisting of halogen, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, lower alkylthio group; provided when R5 represents H, Z represents branched C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain, or it pharmacologically acceptable salt.

EFFECT: high immunosuppressive activity of compounds and their effective application for pharmaceutical compositions and for methods of preventive rheumatoid arthritis treatment.

51 cl, 13 tbl, 91 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 5-amino-1-pentene-3-ol of the general formula (I)

as a free form or as their physiologically compatible salts possessing the analgesic effect. In general formula (I) each R1 and R2 means independently of one another (C1-C6)-alkyl that can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or multi-substituted; or R1 and R2 form in common -(CH2)2-9-mono- or bicyclic ring; each R3 and R4 means independently of one another (C1-C6)-alkyl, or R3 and R4 form in common a ring and mean the group -CH2CH2NR22CH2CH2 wherein R22 represents (C1-C10)-alkyl; R5 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched, mono- or multi-substituted or unsubstituted, (C3-C9)-cycloalkyl that is saturated or means phenyl, heteroaryl that can be condensed with benzene ring and chosen from 5-membered heteroaryl with sulfur or oxygen atom as a heteroatom bound through saturated (C1-C3)-alkyl, phenyl bound through saturated (C1-C3)-alkyl-(C3-C10)-cycloalkyl wherein each among all these alkyl, phenyl, heteroaryl and cycloalkyl residues and independently of others can be unsubstituted or mono- or multi-substituted residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, groups -OR18, (C1-C3)-alkyl) that is saturated or branched or unbranched, mono- or multi-substituted halide, or unsubstituted and wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or unbranched; R6 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched and unsubstituted, phenyl or heteroaryl that is chosen from 5-membered heteroaryl with oxygen atom as a heteroatom wherein each of them is unsubstituted or mono- or multi-substituted as indicated above; R7 means H. Also, invention relates to a medicinal agent based on proposed compounds and to a method for their synthesis.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

10 cl, 493 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 1-aminobutane-3-ol of the general formula (I): and their physiologically acceptable salts possessing analgesic effect and capacity for binding habapentin-site. In the general formula (I) R1 and R2 form in common (CH2)2-9-ring; each R3 and R4 independently of one another means (C1-C6)-alkyl that is branched or direct, saturated or unsubstituted, benzyl or phenethyl that are unsubstituted; R5 means (C1-C10)-alkyl that can be saturated, unsaturated, branched or direct or unsubstituted, (C3-C9)-cycloalkyl that is saturated, phenyl or 5-membered sulfur-containing heteroaryl possibly condensed with benzene ring, (C3-C6)-cycloalkyl bound through saturated or unsaturated (C1-C3)-alkyl, 5-membered possibly condensed with benzene ring sulfur-containing heteroaryl bound through saturated or unsaturated (C1-C3)-alkyl wherein each aryl, heteroaryl and cycloalkyl residue independently of one another can be unsubstituted or mono- or multi-substituted with residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct and can be mono- or multi-substituted with halogen atoms wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or direct or unsubstituted; R6 means H; R7 means (C1-C6)-alkyl that is branched or direct, saturated or unsaturated or unsubstituted, (C3-C9)-cycloalkyl that is saturated or unsubstituted, phenyl that is unsubstituted or mono- or multi-substituted or phenyl bound through saturated (C1-C3)-alkyl that can be unsubstituted or mono- or multi-substituted wherein these substitutes can be chosen independently from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct, in free form as their physiologically acceptable salts. Proposed compounds can be used in treatment of pain and first of all neuropathic, chronic and acute pain. Also, invention relates to a method for synthesis of compounds and preparing a medicinal agent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 89 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new N-(2-arylpropionyl)-sulfonamides of the formula (1): wherein R2 means phenyl, thiophenyl optionally substituted with 1-3 substitutes taken independently among halogen atom, (C1-C4)-alkyl, phenyl, phenoxy-group, benzyl, benzoyl, (C1-C7)-acyloxy-group, 2-thienoyl or 1-oxo-2-isoindolyl; R means linear or branched (C1-C16)-alkyl, trifluoromethyl, cyclohexyl, o-tolyl, 3-pyridyl, p-cyanophenylmethyl, p-aminomethylphenylmethyl, 2-cyano-1-propyl, alkoxyethylene group CH3-(CH2)ni-(OCH2CH2)mi- wherein ni and mi mean a whole number from 1 to 3, or the group P1P2N-CH2-CH2- wherein P1 and P2 represent independently hydrogen atom (H), (C1-C3)-alkyl, benzyloxycarbonyl, α-, β- or γ-pyridocarbonyl, carboxycarbonyl or carbalkoxycarbonyl; or R1 and P2 in common with nitrogen atom to which they are bound form morpholino-group; R' means hydrogen atom (H) or linear or branched (C1-C3)-alkyl, or their salts with strong or mean bases. Compounds of the formula (1) show inhibitory activity with respect to chemotaxis and degranulation of neutrophiles induced with interleukin-8 and can be used in pharmaceutical composition used for prophylaxis and treatment of tissue injures.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 dwg, 2 tbl, 18 ex

The invention relates to new derivatives of N, S-substituted N'-1-[(hetero)aryl] -N'-[(hetero)aryl] methylisothiazoline General formula I or their salts with pharmacologically acceptable acids HX in the form of a racemic mixture or in the form of a mixture of stereoisomers, which can be used for the treatment and prevention of diseases associated with dysfunction glutamatergic nanoperiodic

The invention relates to new nitromethylene formula (I)

< / BR>
in which A represents C6-C10aryl, thienyl, benzothiazyl; X denotes halogen, cyano, C1-C7alkyl, trifluoromethyl, C2-C7alkoxy, or cryptometer; p is chosen from 0, 1, 2, 3, 4, or 5; Z represents a bond, -CO-NH-, SO2-NH-, a sulfur atom, sulfinyl group or a C2-C7alkenylamine radical; R1, R2, R3and E indicated in paragraph 1

The invention relates to a method for producing derivatives of 2-aminothiazoline formula I, in which R1represents C1-5alkyl straight or branched chain, R2is1-3alkyl, by reacting the compounds of formula II in which R3represents phenyl which may be optionally mono-pentamidine independently chlorine, methoxy, ethoxy, phenoxy or nitro, with the compound of the formula III in which Y represents a leaving group, in a solvent and in the presence of a base

FIELD: chemistry.

SUBSTANCE: improved is method of obtaining N-methyl-3-phenyl-3-(4-trifluorinemethylphenoxy) - propylamine hydrocloride, which is known under international non-patented name fluoxetin, used in medicine as highly efficient psychotropic preparation. Fluoxetin is obtained by interaction of 3-N-methylamino-1-phenyl-1-propanol with 4-chlorine benzotrifluoride in presence of sodium hydroxide with molar ratio 3-N-methylamino-1-phenyl-1-propanol: 4-chlorinebenzotrifluoride: sodium hydroxide, equal 1:2.3-2.5:8-10, respectively, in dimethylacetamide medium. Preferably process is carried out at temperature 120-125°C during 6 hours. Target product is extracted by toluol, from which by processing with concentrated hydrochloric acid, fluoxetin hydrochloride is isolated. Melting point 155°C (acetone). Method is suitable for industrial application in conditions of pharmacopical fluoxetin hydrochloride production.

EFFECT: method allows to use available raw material and simplifies isolation of target product.

FIELD: chemistry.

SUBSTANCE: invention pertains to the chemical and pharmaceutical industry, particularly to the method of obtaining 3-N-methylamino-1-phenyl-1-propanol(I, "МФО") - semi-finished product of the production of N-methyl-3-phenyl-3-(4-trifluoromethyl-phenoxy)propylamine hydrochloride, known by its international nonproprietary name as fluoxetine and used in medicine as a highly-effective psychotropic preparation. The method is achieved through recovery of natrium borane in 3-N-methylaminopropiophenone in water alkaline medium. In that case, 3-N-methylaminopropiophenone is taken in form of hydrochloride at molar ratio of the reacting substances 3-N-methylaminopropiophenone hydrochloride : natrium borane : caustic soda, equal to1:0.45÷0.5:1÷1.15. The target product is extracted using toluene and kept in crystal form with cooling. The method uses accessible raw materials, minimum excess of reagents and carried out for 1.5 hours, which makes it suitable for industrial use.

EFFECT: design of a method of obtaining the reagent, suitable for industrial use.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the method of obtaining the compound of the formula (IV) , which includes the epoxidation of the compound of the formula (I) the agent of oxidation in the presence of optically active compound with the formation of the compound of formula (II) , adding the gent to break the reaction, in order to extinguish any surplus oxidising agent present, where the agents for breaking the reaction are tri(C1-C6)alkylphosphite; without the isolation of the compound of the formula (II), the interaction of the reaction mixture, which includes the compound of the formula (III) in the presence of the base and the cleaning of the compound of the formula (IV) by crystallisation. The invention also relates to the method of obtaining the compound of the formula (IX) , which includes the reaction of the compound of formula (IV) with a silylation agent with the formation of a compound of the formula (V) ; the reaction of the compound of formula (V) with the silylation agent of the formula R'SO2X, where R' represents the remainder of sulfonic acid (C1-C6) alkyl and the X represents the detached group, with the obtaining of the compound of formula (VII) ; the substitution of the sulphonyloxy-group with the obtaining of the compound of the formula (VIII) and reaction of the compound of the formula (VIII) with ammonia or a compound of ammonia obtaining a compound of the formula (IX). The invention also relates to the intermediate compounds (V) and (VI) The compound of the formula (IX) can be used for obtaining a biologically active material - (S, S) - reboxetin. . In the given structural formulas pit independently are equal to 0 or a whole number from 1 up to 5; each of the groups R and R1, which can be identical or different, represents C1-C6 alkoxy or C1-C6 alkyl; P represents the protective group; R' represents the remainder of sulfonic acid (C1-C6) alkyl.

EFFECT: obtaining aril ethers.

14 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: method for olefine epoxidation is invented which includes the reaction of the raw material containing olefine, oxygen and organic halogenide, in presence of the catalyst containing silver and rhenium precipitated on the carrier where the catalyst contains rhenium at 1.5 mol/kg of the catalyst mass, at maximum, and 0.0015 mmol/m3 of the carrier surface, at maximum, and where the reaction temperature is increased so as to partially reduce the effect of catalyst loss, and the halogenide is presented in relative Q amount which is maintained constant and where the relative amount of Q is the ratio of the effective molar amount of the active halogen compound in the raw material, to the effective molar amount of hydrocarbon, in the raw material. The invention also implies the method for producing the 1,2-diol, the simple ether of the 1,2-diol and/or alkanolamine and the catalyst to be applied in the said method.

EFFECT: stability of catalyst activity is increased.

22 cl, 8 tbl, 3 ex

FIELD: chemistry; obtaining of new alkanolamines.

SUBSTANCE: general formula of alkanolamines is R2CH(OH)CH2NHR1NHCH2CH(OH)R2 (I), where 1: R1=(CH2)2, R2=C6H5OCH2; 2: R1=(CH2)6, R2=C6H5OCH2; 3: R1=(CH2)2, R2=CH2=CHCH2OCH2; 4: R,=(CH2)6, R2=CH2=CHCH2OCH2; 5 R1=(CH2)2, R2=HOCH2; 6: R1=(CH2)6, R2=HOCH2; 7 R1=(CH2)6, R2= ClCH2. The method lies in the reaction of oxirane containing compounds with aliphatic amines in a medium of an aromatic solvent at 40-60°C.

EFFECT: new compounds can be used as hardeners-modifiers of epoxy and urethane compositions, as well as intermediate compounds in organic synthesis and as base for biologically active preparations.

3 cl, 3 tbl, 7 ex

FIELD: organic chemistry, chemical technology, polymers.

SUBSTANCE: invention relates to a method for synthesis of novel compounds - penta-{[poly-(ethyleneoxy)carbonylmethyl]heterylonium}-derivatives of triphenols of the formula: . Method for synthesis of the claimed compounds involves interaction of monochloroacetic acid with an oxyethylated product of condensation of alkyl-(C8-C10)-phenol with 4,4-dimethyldioxane-1,3 in the presence of acid catalyst in medium of a boiling organic solvent and azeotropic removing formed water and the following treatment of the synthesized reaction product with heterocyclic amino-compounds at heating in the molar ratio - oxyethylated product : monochloroacetic acid : heterocyclic amino-compound = 1:(5.0-5.5):(5.0-5.5), respectively. Synthesized compounds possess properties of hydrophilizing modifying agents of polymers. Invention proposes a simple method for hydrophilization of epoxy polymers in their synthesis by mixing epoxy resin, a hardening agent and a modifying agent chosen from the claimed compounds in the amount 0.7-1.5 weight%. Fettling metallic articles (pipelines) by these covers increases their exploitation period from 6 months to 23-24 months based on decreasing precipitation of asphalt-resinous-paraffin deposits from petroleum.

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

9 cl, 1 tbl, 11 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 3,4'-diamino-4-R-benzophenones of the general formula: wherein R means Cl, Br, F, -CH3, -OCH3,

that are used as intermediate product in synthesis of azo dyes useful for staining protein fibers and possessing the unique indices of thermal stability. Method involves steps for nitration reaction of substituted benzophenones with potassium nitrate in concentrated H2SO4, nucleophilic replacing halogen (wherein R means Cl) in interaction with O- and N-nucleophilic compounds in dimethylsulfoxide (DMSO) medium in the presence of K2CO3 and reduction of 3,4'-dinitro-4-R-benzophenones. The nitration reaction of synthesized benzophenones is carried out at temperature 20oC for 5 h in the mole ratio 4'-nitro-4-R-benzophenone : KNO3 = 1.0:1.15. Nucleophilic replacing halogen is carried out at temperature 40-60oC for 1-5 h in the mole ratio substrate : nucleophilic compound = 1.0:1.05, and reduction of dinitrobenzophenones is carried out with SnCl2 x 2H2O in 18% HCl medium, in the mole ratio 3,4'-dinitro-4-R-benzophenone : SnCl2 x 2H2O = 1:6, at temperature 20oC for 0.15 h. Invention provides decreasing cost of synthesis, reducing time and temperature in carrying out the process, enhancing purity and yield of end products.

EFFECT: improved method of synthesis.

4 tbl, 4 ex

FIELD: industrial organic synthesis.

SUBSTANCE: invention provides improved 2,7-bis[2-(diethylamino)ethoxy]fluorenone dihydrochloride production process comprising stages of sulfurization of fluorenone followed by neutralization of obtained reaction mass, isolation of purified fluorenone-2,7-disulfonic acid disodium salt, "alkaline melting" of this salt in presence of sodium nitrate to form 4.4'-dihydroxydiphenyldicarboxylic acid, cyclization to form 2,7-dihydroxyfluorene and alkylation thereof. More specifically, 2,7-dihydroxyfluorene obtained in cyclization stage is converted into alkali metal salt and toluene solution of 2-diethylaminoethyl chloride is added to preheated aqueous solution of the above salt at molar ratio 1:(3-5), preferably 1:4, to form 2,7-bis[2-(diethylamino)ethoxy]fluorenone, which is then treated with concentrated aqueous hydrochloric acid at molar ratio 1:(3.5-4), preferably 1:3.5.

EFFECT: increased yield and improved quality of product, and simplified process.

3 cl, 3 dwg, 4 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to methods (variants) for synthesis O-desmethylvenlafaxine. One method involves demethylation of venlafaxine with high-molecular alkane thiolate anion, arylalkyl or arene in alcoholic or simple ether solvent or their mixture. Another method involves demethylation of venlafaxine with dodecylthiolate and polyethylene glycol-400 in the presence of sodium methylate in methanol at temperature from about 180°C to about 200°C for from about 2 h to about 5 h followed by neutralization of the reaction product to about pH 9.5 in the presence of isopropanol. The claimed methods are effective with respect to both time and material.

EFFECT: improved methods of synthesis.

21 cl, 1 sch, 4 ex

FIELD: rectification of organic compounds.

SUBSTANCE: all-purpose installation enables purification of high-boiling vacuum rectification solvents, in particular ethylene glycol, monoethanolamine, methyl cellosolve, ethyl cellosolve, butyl cellosolve, N-methylpyrrolidone, and benzyl alcohol.

EFFECT: enhanced purification efficiency.

8 cl, 1 dwg, 7 tbl, 7 ex

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