Method of producing (s)-(-)-2-(n-propylamino)-5-methoxytetraline and (s)-(-)-2-(n-propylamino)-5-hydroxytetraline, salts thereof with n-3,5-(dinitrobenzoyl)-α-phenylglycine, method of producing (6s)-(-)-5,6,7,8-tetrahydro-6-[propyl(2-thienyl)ethyl]amino-1-naphthol(rotigotine) (versions)

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing optically active compounds: (S)-(-)-2-(N-propylamino)-5-methoxytetraline and (S)-(-)-2-(N-propylamino)-5-hydroxytetraline. Said method involves optical separation of a mixture of enantimers of 2-(N-propylamino)-5-methoxytetraline and 2-(N-propylamino)-5-hydroxytetraline in the presence of an optically active form of N-(3,5-dinitrobenzoyl)-α-phenylglycine. The method enables to obtain a product with high optical purity.

EFFECT: invention also relates to use of salts of (S)-(-)-2-(N-propylamino)-5-methoxytetraline and (S)-(-)-2-(N-propylamino)-5-hydroxytetraline as intermediate compounds when producing rotigotine.

7 cl, 6 ex

 

The technical field to which the invention relates.

The invention relates to a method for producing optically active compounds (S)-(-)-2-(N-propylamino)-5-methoxytyramine, in this context, S-(II), and (S)-(-)-2-(N-propylamino)-5-hydroxytyramine, in this context, S-(III), characterized by a high degree of optical purity from a mixture of enantiomers of 2-(N-propylamino)-5-methoxytyramine (II) and 2-(N-propylamino)-5-hydroxytyramine (III), respectively, when the optical separation using diastereomeric salt of the optically active acid.

The intermediate S-(II) and S-(III) is used for (6S)-(-)-5,6,7,8-tetrahydro-6-[propyl(2-thienyl)ethyl]amino-1-naphthol(rotigotine).

The level of technology

In U.S. patent 4564628 described alkyl derivatives of aminotetraline having dopaminergic activity. Among these compounds is the compound (I),

The studies, which are described in U.S. patent 4657925, it was found that dopaminergic activity of the enantiomers of (6S)-(-)-5,6,7,8-tetrahydro-6-[propyl(2-thienyl)ethyl]amino-1-naphthol, in this context, S-(I)in 140 times higher than the dopaminergic activity of the enantiomers of (6R)-(+)-5,6,7,8-tetrahydro-6-[propyl(2-thienyl)ethyl]amino-1-naphthol.

In U.S. patent 4885308 described using S-(I, active ingredient (another name for rotigotine), for the treatment of Parkinson's disease.

Therefore, there is a need for a method of obtaining optically pure S-(I) enantiomer not containing the enantiomer R-(I).

Currently known methods of obtaining S-(I) based on obtaining the intermediate (S)-2-(N-propylamino)-5-methoxytyramine, S-(II).

In U.S. patent 4657925 described obtaining (S)-2-(N-propylamino)-5-methoxytyramine, S-(II), by separation of the corresponding racemic mixture. However, the method of separation is not described in detail.

In article Hoeve and others, J. Org. Chem., t, str-4515 (1985) describes how to obtain S-(II) when the optical separation of the racemic mixture using chiral (R)-(+)-4-(2-chlorophenyl)-5,5-dimethyl-2-hydroxy-1,3,2-dioxaphospholane-2-oxide phosphoric acid as an agent for the separation. The described method is costly and time-consuming, because you have to get the specified agent, which in turn includes a step of optical separation.

In article Seiler and others, J. Med. Chem., t, str-917 (1986) describes how to obtain S-(II) when profilirovanie with subsequent dibenzylammonium (S)-(-)-2-(N-benzylamino)-5-methoxytyramine, the receipt of which is described in the article McDermed, etc., J. Med. Chem., t, No. 4, 547-549, (1976), which is produced during the restoration aminating 5-methoxytyramine benzylamino, crystallization di the stereoisomeric salts of (-)-almond acid, enriched (S)-enantiomer, optical cleaning specified salts, including six successive stages of recrystallization from ether, and finally, upon receipt amine as the base. This method requires time-consuming and is costly on an industrial scale.

In U.S. patent 4968837 described separation of the intermediate compound (II) enantiomers using L-(-)-dibenzoyltartaric acid, but according to the experience of the authors of the present invention, this method does not allow to obtain compounds with high optical purity, even after successive stages of purification diastereoisomeric salt.

As shown above, none of these methods of obtaining S-(II) and hence S(I) does not allow to scale the process up to industrial level. Therefore, there is a need for an alternative method for obtaining rotigotine, S-(I)that can be used on an industrial scale.

Disclosure of inventions

The purpose of the present invention is to develop an alternative applicable on an industrial scale method of obtaining compounds of (6S)-(-)-5,6,7,8-tetrahydro-6-[propyl(2-thienyl)ethyl]amino-1-naphthol, S-(I)with high optical purity, which allows its use as a medicine.

The purpose of the present invention is realized by surprise the first discovery of the fact, some optically active organic acid to form diastereoisomeric salt of compound (II), and salts of enantiomers R-(II) and S-(II) and enantiomers (III), R-(III) and S-(III), characterized by different solubility in the reaction medium that allows you to share them during crystallization. During crystallization of the mixture of these diastereoisomeric salts in the reaction medium or in a suitable solvent due to their different solubility, the resulting crystals are enriched diastereoisomeric salts of the enantiomers of S-(II) and S-(III), which can be used as intermediates to obtain S-(I). After extraction and purification diastereoisomeric salts of them, you can obtain the intermediate compounds characterized by a high degree of optical purity.

The method according to the present invention allows to obtain the intermediate compound S-(II) and S-(III) with an optical purity of 99% or more, preferably more than 99.9%, with the use of successive stages of recrystallization or resuspendable relevant diastereoisomeric salts.

Compounds (II) and (III), in their racemic form can be obtained by any of the methods described in the literature, for example, as described in article Hacksell, etc., J. Med. Chem., t, No. 12, CTR-1475 (1979), during the restoration aminating 5-methoxy-2-tetralone in prisutstvie and 1-Propylamine, thus obtain the compound (II), and subsequent release of phenolic groups in the presence of 48% HBr, thus receive the compound (III).

Scheme for the synthesis of intermediate compounds S-(II) and S-(III) - the object of the present invention is shown in scheme 1:

The way to obtain S-(II) enantiomer of the present invention includes the optical separation during processing of the mixture of enantiomers (II) in the presence of an acid, (+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine, in a suitable solvent. The obtained salt can precrystallization or resuspendable several times before the formation of compounds of the desired optical purity. Then from the resulting salt can be obtained Amin S-(II) in the form of free base.

The way to obtain the enantiomer S-(III) of the present invention includes the optical separation during processing of the mixture of enantiomers (III) in the presence of an acid, (-)-N-(3,5-dinitrobenzoyl)-α-phenylglycine in a suitable solvent. The obtained salt can precrystallization or resuspendable several times before the formation of compounds of the desired optical purity. Then from the resulting salt can be obtained Amin S-(II) in the form of free base.

The deposition of these diastereoisomeric salts and subsequent stages of recrystallization or resuspendable can be carried out in suitable solvents, is aka as water, alcohols, NITRILES or mixtures thereof. In a preferred embodiment of the present invention the specified solvent is a mixture of acetonitrile and water.

The number of added optically active organic acid may be from about 0.5 to about 1.2 EQ., preferably from about 0.6 to 1 EQ., in the calculation of the amount of the original amine.

One object of the present invention it is also proposed to obtain salts of these intermediates S-(II) and S-(III) in the presence of an optically active acid, (-)-N-(3,5-dinitrobenzoyl)-α-phenylglycine and (+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine formula (V) and (VI) respectively.

In another embodiment, the present invention proposes the use of compounds S-(II) and S-(III) as intermediates to obtain rotigotine, S(I), and these connections receive, as indicated in scheme 2:

where X denotes a suitable leaving group selected from halogen, such as chlorine or bromine, sulfonates, such as mesilate, nosrat or tosylate, etc.

In yet another embodiment, the present invention proposes the use of salt (V) and (VI) as intermediates to obtain rotigotine, S(I).

The implementation of the invention

The following examples are provided to illustrate the present invention and do not limit the scope of the present invention.

Example 1. Obtain (S)-(-)-2-(N-propylamino)-5-methoxytyramine, S-(II)of the racemic mixture in an optical separation in the presence of (+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine

10 g of Compound (II) was dissolved in 120 ml of a mixture acetonitrile/water, 60:40, then added 9.4 g (0.6 EQ.) (+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine. The mixture was heated to dissolve the solids. The mixture is then slowly cooled, when it first appeared opalescent solution, then began precipitation. The mixture was stirred at a temperature of 0-5°C for 2 h, the Suspension was filtered and the obtained solid was dried in a drying Cabinet.

When this was received of 9.8 g of salt (yield 38%). Analysis of the obtained salt by the method GHUR indicates the presence of enantiomers S(II)/R(II) in the ratio of 83:17.

The solid is recrystallized successively from 10 volumes of a mixture of acetonitrile/water, 80:20, were heated to the boiling point of the solvent, and then cooled to a temperature of 0-5°C. After three stages of recrystallization was obtained 3.8 g (total yield 15%) salt (V), the analysis of which method of chiral GHUR indicates the presence of enantiomer (S) in an amount of over 99.5%.

Tmelt. (the DSC peak): 220,27°C.

IR (cm-1, KBr): 3423, 295, 2838, 1664, 1621, 1585, 1542, 1345, 731, 705.

1H-NMR (AMCO-d6): δ to 0.88 (t, 3H), 1,54-to 1.63 (m, 3H), and 2.14 (m, 1H), 2,42 (m, 1H), 2,75 (m, 2H), and 2.83 (t, 2H), 3,03 (dd, 1H), 3,18 (m, 1H), 3,35 (user. s, 2H, NH2+), to 3.73 (s, 3H, OCH3in ), 5.25 (d, 1H, CH-COOH), 6,62 (d, 1H, Ar-H), 6,74 (d, 1H, Ar-H), 7,07 (t, 1H, Ar-H), 7,16 (m, 1H, Ar-H), of 7.23 (t, 2H, Ar-H), was 7.45 (d, 2H, Ar-H), 8,91 (s, 1H, Ar-H), 9,03 (s, 2H, Ar-H), 9,42 (d, 1H, amide NH).

Purified dry salt suspended under stirring in a mixture of toluene (20 ml) and 5% solution of K2CO3(60 ml)was heated at 60°C until complete dissolution of the solids. The layers were separated and the organic layer washed with 5% solution of K2CO3(15 ml), then water (8 ml). The organic layer was concentrated to remove the solvent, was obtained 1.44 g of compound S-(II) in the form of an oil (yield 98%).

IR (cm-1NaCl): 2955, 2930, 2834, 1586, 1469, 1438, 1260, 1095, 766.

1H-NMR (CDC3): δ to 0.92 (t, 3H, CH2-CH3), 1,48 is 1.60 (m, 3H, CH2-CH2-CH3and N-CH-CH2-CH2C)1,80 (user. s, 1H, NH), 2,07 (m, 1H, N-CH-CH2-CH2C)2,50-2,61 (t, 2H, C-CH2-CHN N-CH-CH2-CH2C)to 2.66 (t, 2H, CH2-CH2-CH3), 2,84-of 2.93 (m, 2H, C-CH2-CHN N-CH-CH2-CH2C)2,95-3,10 (dd, 1H, C-CH2-CHN), of 3.78 (s, 3H, och3), 6,63 (d, 1H, Ar-H), of 6.68 (d, 1H, Ar-H), 7,07 (t, 1H, Ar-H).

Specific rotation of the obtained product [α]20D: -73,49 (C=1 in methanol). In U.S. patent 4968837 value [α]20Dis -65, article Seiler M.P. the other, J. Med. Chem., t, No. 6, str-917 (1986) [α]20Dis -72,7 (C=1 in methanol).

Example 2. Obtain (S)-(-)-2-(N-propylamino)-5-hydroxytyramine, S-(III)of the racemic mixture of the optical separation in the presence of (-)-N-(3,5-dinitrobenzoyl)-α-phenylglycine

A suspension of 10 g of compound (III) and 11.7 g (0.7 EQ.) compounds (-)-N-(3,5-dinitrobenzoyl)-α-phenylglycine in 160 ml of a mixture acetonitrile/water, 70:30, was heated to dissolve the solids. The resulting solution was slowly cooled, when it first appeared opalescent solution, then began precipitation. The mixture was stirred at a temperature of 0-5°C for 2 h, the Suspension was filtered and the obtained solid substance was dried.

It was obtained 11.2 g of salt (yield 42%). The analysis of the obtained product by the method GHUR indicates the presence of enantiomers S-(III)/R(III) in a ratio of 91:9.

The solid is recrystallized several times from 10 volumes of a mixture of acetonitrile/water, 80:20, were heated to the boiling point of the solvent, and then cooled to a temperature of 0-5°C. After two stages of recrystallization was obtained 6.0 g (total yield 24%) salt (VI), the analysis of which method of chiral GHUR indicates the presence of enantiomer (S) in an amount of more than 99.9%.

IR (cm-1, KBr): 3450, 3032, 2972, 2854, 1652, 1621, 1539, 1467, 1376, 1275, 729.

1H-NMR (DMSO-d6): δ of 0.87 (t, 3H), 1,53-of 1.62 (m, 3H), 2.13 in (m, 1H), 2,39 (m, 1H), 2,72 (m, 2H), 2,83 t, 2N), of 3.00 (dd, 1H), 3,18 (m, 1H), 3,35 (user. s, 2H, NH2+), 5,23 (d, 1H, CH-COOH), 6,46 (d, 1H, Ar-H), to 6.58 (d, 1H, Ar-H), 6.87 in (t, 1H, Ar-H), 7,17 (t, 1H, Ar-H), 7,24 (t, 2H, Ar-H), 7,44 (d, 2H, Ar-H), 8,91 (s, 1H, Ar-H) 9,03 (d, 2H, Ar-H), 9,41 (d, 1H, amide NH), of 9.55 (s, 1H, OH).

Purified dry salt suspended under stirring in a mixture of toluene (20 ml) and 5% solution of K2CO3(60 ml) and heated at 60°C until complete dissolution of the solids. The layers were separated and the organic layer washed with 5% solution of K2CO3(15 ml), then water (8 ml). The organic layer was concentrated to remove the solvent, were obtained 1.8 g of compound S-(III) in the form of a solid substance (yield 98%).

Tmelt. (the DSC peak): 88,3°C.

IR (cm-1, KBr): 3532, 3269, 2923, 2854, 1585, 1464, 1281, 773.

1H-NMR (DMSO-d6): δ 0,86 (t, 3H), of 1.40 (m, 3H), of 1.94 (m, 1H), of 2.38 (m, 2H), 2,53 (t, 2H), 2,69 (m, 2H), 2,84 (dd, 1H), 3,36 (user. s, 1H, NH), 6,46 (d, 1H, Ar-H), is 6.54 (d, 1H, Ar-H), at 6.84 (t, 1H, Ar-H), the remaining 9.08 (s, 1H, OH).

Specific rotation [α]20D: -74,89 (C=1 in methanol). According to Seiler, M.P., and others, J. Med. Chem., t, No. 6, str-917 (1986), [α]20Dis-75.

Example 3. Obtain (S)-(-)-2-(N-propylamino)-5-hydroxytyramine, S-(III), (S)-(-)-2-(N-propylamino)-5-methoxytyramine, S-(II)

10 g of (S)-(-)-2-(N-propylamino)-5-methoxytyramine, S-(II)obtained as described in example 1 was mixed with 40 ml of 48% HBr solution and 20 ml of acetic acid. The resulting mixture was boiled under reflux for 3 hours during this period began settling of solids. The suspension was slowly cooled to a temperature of 0-5°C, then added 30 ml of water. The reaction mixture was filtered, received an 11.7 g (yield 90%) of bromhidrosis S-(-)-2-(N-propylamino)-5-hydroxytyramine.

Specified, the solid is suspended in 110 ml of water and the suspension was heated to 40°C. Then was added 10 M NaOH solution to a pH of 12.5, when it received the solution. The mixture is then acidified to pH 9-9,5 adding 6 M HCl solution and obtained precipitate solids. The mixture was gradually cooled to 0-5°C and filtered, it was obtained 7.5 g of S-(-)-2-(N-propylamino)-5-hydroxytyramine, S-(III), (yield 90%).

Tmelt. (the DSC peak): 88,25°C.

Specific rotation [α]20D: -74,95 (C=1 in methanol).

Example 4. Receipt of (6S)-(-)-5,6,7,8-tetrahydro-6-[propyl(2-thienyl)ethyl]amino-1-naphthol, S-(I)of S-(-)-2-(N-propylamino)-5-hydroxy-tetraline, S-(III)

10 g of (S)-(-)-2-(N-propylamino)-5-hydroxytyramine, S-(III), obtained as described in example 2, was mixed with 9 g of NaHCO3(2.2 EQ.) and 16 g of 2-nitrobenzenesulfonate 2-(2-thienyl)ethanol (of 1.05 equiv.) in 80 ml of acetonitrile.

The mixture was boiled under reflux for 9 h, then cooled and filtered to remove suspended salts. To the filtrate was added 60 ml of water and evaporated to remove acetonitrile. Then added 40 ml of toluene and the layers were separated. The organic layer was twice washed with 10% solution of NaHCO3. Then add 50ml of water and H 3PO4to pH 1-2. The layers were separated, the acidic aqueous layer was neutralized by adding 30% solution of K2CO3to a pH of 7-7,5 and was extracted with 20 ml ethyl acetate. The organic layer was washed with 10 ml water, the solvent was evaporated, the thus received 10 g of (6S)-(-)-5,6,7,8-tetrahydro-6-[propyl(2-thienyl)ethyl]amino-1-naphthol, S-(I)in a solid white color (yield 70%).

Tmelt. (the DSC peak): 78,94°C.

IR (cm-1, KBr): 3500, 3098, 3065, 2969, 2932, 1585, 1465, 1281, 775, 701.

1H NMR (CDCl3): δ of 0.89 (t, 3H, N-CH2-CH2-CH3)and 1.51 (sextet, 2H, N-CH2-CH2-CH3), was 1.58 (ddd, 1H, N-CH-CH2-CH2C)of 2.10 (ddd, 1H, N-CH-CH2-CH2C)to 2.55 (t, 2H, N-CH2-CH2-CH3), 2,47-2,60 (m, 1H, C-CH2-CHN), 2,67-2,87 (m, 4H, N-CH-CH2-CH2-C and N-CH2-CH2-thiophene), 2,90 (m, 1H, C-CH2-CHN), 2,92-a 3.01 (m, 3H, C-CH2-CHN N-CH2-CH2-thiophene), a 4.83 (s, 1H, OH), to 6.57 (d, 1H, Ar-H), to 6.67 (d, 1H, Ar-H), to 6.80 (d, 1H, Ar-H), 6.90 to (dd, 1H, Ar-H), 6,97 (t, 1H, Ar-H), 7,10 (d, 1H, Ar-H).

Example 5. Getting bromhidrosis (S)-2-(N-n-propyl-N-2-titilation)-5-methoxytyramine, S(IV)·HBr (S)-(-)-2-(N-propylamino)-5-methoxytyramine, S-(II)

10 g of (S)-(-)-2-(N-propylamino)-5-methoxytyramine, S-(II)obtained as described in example 1 was mixed with 13.8 g K2CO3(2.2 EQ.) and 15 g of 2-nitrobenzenesulfonate 2-(2-thienyl)ethanol (of 1.05 equiv.) in 60 ml of acetonitrile. The mixture was boiled under reflux for 9 h, then was cooled to the room temperature, added 80 ml of water, acetonitrile was removed in the process of evaporation, was added 40 ml of toluene and the layers were separated. The organic layer was twice washed with 40 ml of 5% solution of NaHCO3when heated two-phase mixture at 60°C and, finally, water. Then the organic layer was added 40 ml of water and H3PO4(to pH 1-2). The layers were separated, the acid aqueous layer was podslushivaet adding 10 M NaOH to pH 11 and extracted with 30 ml toluene. The organic layer was washed with 20 ml water was evaporated and the obtained product in the form of oil. The product was converted into bromohydrin when re-dissolving it in ethyl acetate and adding HBr/Asón. The obtained solid substance was separated by filtration and dried, to receive and 15.3 g of bromhidrosis (S)-2-(N-n-propyl-N-2-titilation)-5-methoxytyramine, S(IV)·HBr, in the form of a solid white color (yield 82%).

Tmelt. (the DSC peak): 142,59°C.

IR (cm-1, KBr): 2933, 2623, 2546, 1587, 1469, 1438, 1258, 1093, 772.

1H NMR (CDCl3): δ of 1.01 (t, 3H), 1,90 (CH, 1H), 2,08 (m, 1H), 2,59 (m, 2H), 3.00 and-3,70 (m, 11N), of 3.78 (s, 1H, och3), to 6.67 (d, 1H, Ar-H), 6,70 (d, 1H, Ar-H), 6,92 (m, 2H, Ar-H), 7,11 (t, 1H, Ar-H), 7,17 (d, 1H, Ar-H), 11,43 (s, 1H, NH).

Example 6. Receipt of (6S)-(-)-5,6,7,8-tetrahydro-6-[propyl(2-thienyl)ethyl]amino-1-naphthol, S-(I)from bromhidrosis (S)-2-(N-n-propyl-N-2-titilation)-5-methoxytyramine, S(IV)·HBr

10 g of bromhidrosis (S)-2-(N-n-propyl-N-2-titilation)-5-methoxytyramine, S(IV)·HBr was dissolved in 50 ml of dichloromethane at room is based temperature. The mixture was cooled at temperatures below 0-5°C. Then was added dropwise 55 ml BBr3in dichloromethane (5 EQ.) and the mixture was stirred at a temperature of 0-5°C with stirring for 6 hours the reaction mixture was added 60 ml of water. The precipitate solid was separated by filtration. The wet solid is suspended at room temperature in 20 ml of water and 40 ml of ethyl acetate. The mixture was podslushivaet to pH 7-7,5 adding 30% solution of K2CO3. The layers were separated and the aqueous layer was extracted with 20 ml ethyl acetate, which was combined with the previously obtained organic layer. The organic layer was washed with 10 ml water and evaporated, thus received to 6.9 g of (6S)-(-)-5,6,7,8-tetrahydro-6-[propyl(2-thienyl)ethyl]amino-1-naphthol, S-(I)in a solid white color (yield 90%).

Tmelt. (the DSC peak): 78,37°C.

1. A method of obtaining optically active (S)-(-)-2-(N-propylamino)-5-methoxytyramine and (S)-(-)-2-(N-propylamino)-5-hydroxytyramine formula S-(II) and S-(III), respectively:

includes optical separation of the corresponding compounds of formulas (II) and (III):

in the presence of an optically active form of N-(3,5-dinitrobenzoyl)-α-phenylglycine.

2. The method according to claim 1, wherein obtaining optically active compounds S-(II) includes the optical separation of the corresponding compounds (II) in Pris the accordance (+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine.

3. The method according to claim 1, wherein obtaining optically active compounds S-(III) includes the optical separation of the corresponding compound (III) in the presence of (-)-N-(3,5-dinitrobenzoyl)-α-phenylglycine.

4. Salt (S)-(-)-2-(N-propylamino)-5-methoxytyramine, S-(II), and (+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine formula (V):

5. Salt (S)-(-)-2-(N-propylamino)-5-hydroxytyramine, S-(III), and (-)-N-(3,5-dinitrobenzoyl)-α-phenylglycine formula (VI):

6. The use of salts of the formula (V) according to claim 4, as an intermediate connection at reception (6S)-(-)-5,6,7,8-tetrahydro-6-[propyl(2-thienyl)ethyl]amino-1-naphthol (rotigotine).

7. The use of salts of formula (VI) according to claim 5 as an intermediate connection at reception (6S)-(-)-5,6,7,8-tetrahydro-6-[propyl(2-thienyl)ethyl]amino-1-naphthol (rotigotine).



 

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SUBSTANCE: invention relates to novel aminoindane derivatives of formula (Ia) or pharmaceutically acceptable salts thereof, which have NMDA receptor antagonist effect, and can be used to prepare a medicinal agent for treating dementia. In formula (Ia):

,

R1 is a lower alkyl, C5-C6 cycloalkyl, phenyl which can be substituted with OH, lower alkyl, halogen atom, O-alkyl, C5-C6 heteroaryl containing a S atom as a heteroatom, or lower alkyl substituted with one or more halogen atoms, R2 and R3 are identical or different, each denoting alkyl or phenyl, R4 and R5 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-lower alkyl, -lower alkylene-OH or -lower alkylene-O-lower alkyl, R6-R9 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-lower alkyl, halogen atom, lower alkyl substituted with one or more halogen atoms, OH, CN, lower alkenyl or nitrogen-containing C5-C6 heterocyclic group, R10 and R11 are identical or different and each denotes a hydrogen atom or lower alkyl. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: improved properties of the derivative.

6 cl, 15 tbl, 130 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-aminocyclohexanol of the general formula (I) being optionally as their physiologically acceptable salts and first of all physiologically compatible acids. In compound of the general formula (I) R1 and R2 mean independently of one another hydrogen atom (H) or (C1-C8)-alkyl that can be saturated or unsaturated but both R1 and R2 can't mean simultaneously H, or residues R1 and R form a ring in common and mean (CH2)3-6; R2 means unsubstituted phenyl or phenyl substituted with halogen atom that is added through saturated or unsaturated, branched or linear (C1-C4)-alkyl group; R4 means heteroaryl chosen from 5-membered heteroaryl wherein heteroatoms are chosen from nitrogen, oxygen or sulfur atoms and each of these atoms is condensed with benzene ring and means unsubstituted or monosubstituted (C1-C8)-alkyl; -CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7 wherein R6 represents H; R7 represents phenyl that can be unsubstituted or mono- either multi-substituted with halogen atoms. Also, invention relates to a method for synthesis of compounds of the formula (I) and a medicinal agent based on thereof. Synthesized compounds can be sued for preparing a medicinal agent designated for treatment of pain being first of all acute, visceral, neuropathic or chronic pain, and to a medicinal agent designated for treatment of diseases mediated by function of ORL1-receptor, for example, such as fear state, epilepsy, cardiovascular diseases.

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

10 cl, 1 tbl, 21 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing α-aminoacetals of formula (I) in racemic form (I), where * denotes that the C atom is an asymmetric carbon, values of radicals R1-R6 are given in the claim, via racemation of optically rich α-aminoacetals of formula (R)-(I) or (S)-(I) The method involves a step for oxidation of an optically rich compound of formula (R)-(I) or (S)-(I), in the presence of a catalyst, to obtain an oxime of formula (II) and a step for reducing the compound of formula (II) to obtain a compound of formula (I) using a reducing agent.

EFFECT: method enables to obtain a product with high output under mild conditions.

15 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 2,7-bis-[2-(diethylamino)ethoxy]-fluorenone-9 dihydrochloride, having immunomodulating properties and a wide range of antiviral action. The method of producing 2,7-bis-[2-(diethylamino)ethoxy]-fluorenone-9 dihydrochloride involves sulphonation of fluorene, oxidative hydroxylation of a disodium salt of 2,7- fluorene disulphonic acid, cyclisation of 4,4'-dihydroxydiphenyl-2-carboxylic acid, alkylation of 2,7-dihydroxyfluorenone with treatment of the obtained alkylated product with concentrated hydrochloric acid. The obtained product undergoes solvent refining through re-extraction of the alkylated product in an aqueous solution treated with hydrochloric acid to obtain a chloride salt of 2,7-bis-[2-(diethylamino)ethoxy]-fluorenone-9, from which nonpolar impurities are washed off using toluene solution and after treatment with alkali, the obtained phases are separated with extraction of 2,7-bis-[2-(diethylamino)ethoxy]-fluorenone-9 into an organic phase. The latter is washed with water in order to remove polar impurities and the product is converted to a chloride salt by treatment with concentrated hydrochloric acid in molar ratio 1:3.5-1:4. Said extraction steps can be carried 1-3 times.

EFFECT: method enables to cut the number of process operations at the purification step, cut solvent consumption and obtain a high-quality product with 99,85-99,90% content of basic substance.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to two novel polymorphic forms of crystalline levosalbutamol sulfate (enantiometriccaly pure (R)-salbutamol, designated as Form (I) and Form (II). Crystalline Form I of levosalbutamol sulfate is characterised by roentgen powder diffractogram with peaks at 10.8, 11.9, 13.0, 18.3, 28.5±0.2 degrees 2-teta. Pharmaceutical composition can additionally contain therapeutically efficient amount of one or more additional glucorticoids, selected from fluticasone propionate, beclomethason dipropionate or budesonide. Preferably pharmaceutical composition can represent aerosol, dry powder composition or solution/suspension for inhalation and contain pharmaceutically acceptable excipients, suitable for said forms.

EFFECT: elaboration of methods of obtaining novel polymorphic forms and pharmaceutical compositions, containing said polymorphic forms.

54 cl, 6 dwg, 3 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3,3-diphenylpropylamino monoesters in form of highly pure bases, particularly to (R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (fesoterodine), to their preparation and use as medicinal agents for transdermal and transmucous administration.

EFFECT: obtaining a product which contains (R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (fesoterodine) as a free base containing less than 3 wt % salt with degree of purity of over 97 wt %.

17 cl, 4 dwg, 4 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: method involves addition of a phosphorus-containing compound in liquid phase to triethanolamine, where the phosphorus-containing compound is phosphane and/or a compound which releases phosphane, selected from phosphonium halide or metallophosphide which contains group IA, IIA, IIIA or IIB metals in an amount of at least 0.001 wt % while heating and subsequent separation of pure triethanolamine from the additive or additives. Phosphane usually refers to PH3, P2H4 or P4H6. Phosphide refers to lithium phosphide, sodium phosphide, potassium phosphide, magnesium phosphide, calcium phosphide, aluminium phosphide, indium phosphide and/or zinc phosphide. Triethanolamine is mixed with phosphane and/or a compound which releases phosphane in amount of 2 wt % (in terms of pure triethanolamine) before and/or during distillation of the triethanolamine. The desirable time for treatment with the additive is at least 5 minutes at temperature ranging from 40 to 250°C. Triethanolamine may contain water in amount of 0.01-20 wt % (in terms of pure triethanolamine). The invention also relates to triethanolamine containing at least 0.001 (in terms of pure triethanol) of the mass of phosphane and/or a compound which releases phosphan selected from phosphonium halide or metallophosphide containing group IA, IIA, IIIA or IIB metals, which is the initial mixture for enhancing chromaticity.

EFFECT: enhanced chromaticity of triethanolamine.

17 cl

FIELD: chemistry.

SUBSTANCE: phosphoric and/or hypophosphorus acid and a basic compound are added to triethanolamine, where the basic compound is selected from a hydroxide of alkali metals, a hydroxide of alkali-earth metals and [R1R2R3(2-hydroxyethyl)ammonium]hydroxide, where R1, R2 and R3 independently denote an alkyl having 1-30 carbon atoms, or hydroxyalkyl having 2-10 carbon atoms. If a hydroxide of alkali metals is used as the basic compound, molar ratio of acid (acids): hydroxide ranges from 1:0.1 to 1:1, and if hydroxide of alkali-earth metals is used as the basic compound, molar ratio of acid (acids): hydroxide ranges from 1:0.05 to 1:0.5. Phosphoric and/or hypophosphorus acid and the basic compound are added before and/or during distillation of triethanolamine. The invention also relates to triethanolamine containing 0.01-2 wt % (in terms of pure triethanolamine) phosphoric and/or hypophosphorus acid and the corresponding hydroxide.

EFFECT: stability of improved chromaticity of triethanolamine during storage and increased output during distillation of the triethanolamine.

15 cl, 2 tbl

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

The invention relates to a thin cleaning business solutions alkanolamines in the process of absorption and purification of natural, oil, refineries and other hydrocarbon gases from acid components

The invention relates to an improved method of purification of ethambutol, which is a highly effective anti-TB drug

The invention relates to an improved method of purification of 2-(3,4-dioksifenil)ethylamine hydrochloride (DOPAMINE) by dissolving, cleaning filtration, separation of the target product from the filtrate upon cooling, washing the precipitate with acetone to pH 3.5-4.5

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , isomer thereof of formula IA , mixture of isomers thereof IA/C , synthesis method thereof, as well as methods of producing compounds of formula IVA from compounds of formula IA, involving reduction and removal of protection from compounds of formula IA via hydrogenolysis using H2 and a catalytic amount of Pd/C, in the presence of trifluoroacetic acid to obtain a compound of formula VA; further reaction of this compound with Cbz-t-leu-OH, EDC and HOBt to obtain a compound of formula VIA; reaction of compound VIA with H2 and a catalytic amount of Pd/C in the presence of citric acid to obtain an amine and reaction of said amine and 4-amino-3-chlorobenzoic acid in the presence of CDMT and NMM to obtain a compound of formula IVA.

EFFECT: fewer synthesis steps and high output while using dynamic crystallisation.

13 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel optically active phenylthanolamine compounds of formula (I) having a (-)-configuration, or pharmaceutically acceptable salts thereof, which have β2-receptor agonist effect and can be used to treat asthma or bronchitis. In formula (I) R1 is H or halogen; R2 is CF3, CN or halogen; R3 is a straight or branched alkyl, having 1-6 carbon atoms or a cycloalkyl having 3-6 carbon atoms.

EFFECT: high efficiency of using the agents.

9 cl, 1 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: method involves 1) dividing a racemate into two pure enantiomers via chromatographic separation on a chiral polysaccharide as a stationary phase with alcohol as the mobile phase and sorption of the eutomer, 2) repeated racemisation of the distomer with a base using a catalyst in a solvent selected from ether or a mixture of solvents containing ether, at temperature between 80°C and 120°C and 3) subjecting the obtained racemate to separation at step 1) in a repeated cycle. The invention also pertains to use of a pure S-enantiomeric form of a formula I compound, particularly (-)-(S)-N-(1-cyano-2-(5-cyano-2-trifluoromethylphenoxy)-1-methylethyl)-4-trifluoromethylsulfanylbenzamide, for control of entozoic parasites of warm-blooded animals, such as helminths.

EFFECT: efficient method of producing a unique enantiomer from a racemate of amidoacetonitrile compound having a formula in which R1, R2 and R3 independently denote cyano, halo-C1-C6alkyl or halo-C1-C6alkylthio.

15 cl, 1 ex

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