Method for preparing(-)-cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine and intermediates compounds

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention elates to the improved method for preparing (-)-cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine. Method involves conversion of 1-methylpiperidine-4-one to hydrobromide followed by interaction with bromide to obtain 3-(R,S)-bromo-1-methyl-4-oxopiperidine hydrobromide and then with 1,3,5-trimethoxybenzene to obtain 3-(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropridine hydrobromide. Then by addition of the reaction solution with organic solvent 3-(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide is isolated firstly as a solid substance and then product is mixed with water and converted by stirring to 3-(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine. Prepared product is hydrogenated catalytically for preparing racemic 3,4-cis-alcohol and by cleavage of racemate by using chiral accessory reagents (-)-cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine is prepared from racemic 3,4-cis-alcohol as a pure enantiomer. Proposed method provides simplifying a process for preparing abovementioned product and to reduce duration of process due to exclusion the hydroborating stage, oxidation by Swern, reduction with sodium boron hydride used in preparing the same product by the known method. Also, invention describes intermediates compounds: 3-(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide and 3-(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine.

EFFECT: improved preparing method.

3 cl, 10 ex

 

(-)-CIS-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine of formula (II) is the Central structural element in the synthesis of flavopiridol formula (I) (HMR 1275 or L 86-8275), the first inhibitor of cyclin-dependent protein kinase (see, for example, Sedlacek, Hans-Harald; Czech Joerg; Ramachandra Naik; Gurmeet Kaur; Peter Worland; Losiewicz Michael; Parker Bernard; Carlson Bradley; Smith Adaline and others, "Flavopiridol (L 86-8275; NSC 649890), a new kinase inhibitor for tumor therapy", Int. J. Oncol., 9 (6), 1143-1168 [1996], Czech Joerg; Dieter Hoffmann; Ramachandra Naik; Sedlacek, Hans-Harald, "Antitumoral activity of flavone L 86-8275", Int. J. Oncol., 6(1), 31-36 [1995]).

Known so far, is described in European patents EP-B-0241003 and ER-IN-0366061 method for obtaining compounds of formula (II) requires a large investment of time and includes reactions (hydroporinae, oxidation in Turn, restore using sodium borohydride), which can be difficult to control on an industrial scale.

Unexpectedly, the authors found a much simpler method of production, which is depicted in figure 1.

Scheme 1:

The method of obtaining (-)-CIS-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-piperidine of formula (II):

characterized in that

a11 methylpiperidin-4-one of formula (III):

known methods transferred to the hydrobromide; or

and21 methylpiperidin-4-one of formula (III), the bar is dstone before subsequent bromirovanii transferred to the hydrobromide by introducing 1 methylpiperidin-4-it is in the solution bromovalerate in glacial acetic acid and

b) 1-methylpiperidin-4-he-hydrogen bromide in a suitable solvent, such as acetic acid, in the temperature interval from 0 to 30°To enter into interaction with bromine, getting the 3(R,S)-bromo-1-methyl-4-oxopiperidine formula (IV):

in this intermediate product of the formula (IV) directly by adding 0.8 to 1 equivalent of 1,3,5-trimethoxybenzene formula (V):

to the reaction solution at a temperature of from 0 to 30°With turn 3(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine-hydrobromide of the formula (VI):

and, if necessary, add more acetanhydride to remove the formed reaction water;

g1) compound of formula (VI) by mixing the reaction solution in a suitable organic solvent, such as tert.-butyl ether, dichloromethane, etc., first isolated in the form of solids, and then the resulting product is mixed with water and by stirring at a temperature of 50-100°C, preferably at 60 S-80°With turn 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII):

or

g2) the reaction mixture containing the compound of the formula (VI)directly, mix the water and by stirring at a temperature of 50-100° C, preferably at 60-80°With turn 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII), and

g3) obtained by p. g1), respectively, g2) the reaction mixture is cooled, if necessary diluted with further water and at a temperature of 0-30°by adding an aqueous solution of alkali, preferably sodium hydroxide, set pH>12 and deposited 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII)obtained crude product is sucked off and, if necessary, to clean again treated with an aqueous solution of hydrochloric acid, filtered and, if necessary, extracted with not miscible with water solvent, as, for example, ethyl acetate, and then the aqueous phase by adding an aqueous solution of alkali, preferably sodium hydroxide, set pH>12 deposited 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydro-pyridine of the formula (VII), usageprice product, if necessary, for further purification mixed with one or more suitable organic solvents, such as acetone, isopropanol, diisopropyl ether, or mixtures of these solvents; and

d1) the resulting product of formula (VII) in a suitable solvent, such as methanol, isop OPANAL, water or mixtures of these solvents, catalytically hydronaut using a suitable catalyst, e.g. palladium-on-charcoal, rhodium-on-coal, etc., receiving racemic 3,4-CIS-alcohol of formula (VIII):

this process may be generated during the recovery of small amounts of 3,4-TRANS-alcohol can be removed by crystallization from suitable solvents, such as acetone; or

d2for hydrogenation using easily obtained from compounds of formula (VII) esters of the formula (IXa) or carbonates of the formula (IXb):

where in the formula (IXa) R mean (C1-C16)-alkyl, (C6-C14)-aryl-(C1-C16)-alkyl, (C6-C14)-aryl or carboxy-(C2-C6)-alkyl, and in formula (IXb) R mean (C1-C16)-alkyl, (C6-C14)-aryl-(C1-C16)-alkyl or (C6-C14)-aryl, you get the compounds of formula (Ha) or formula (Xb), from which it is possible to release the compound of formula (VIII);

e1by splitting of the racemate using a suitable chiral auxiliary reagents of the compounds of formula (VIII) are obtained in the form of pure enantiomers of CIS-alcohol of formula (II); or

e2) the splitting of the racemate is carried out with the compounds of the formula (XA) or (Xb):

where in the Le (Ha) R mean (C 1-C16)-alkyl, (C6-C14)-aryl-(C1-C16)-alkyl, (C6-C14)-aryl or carboxy-(C2-C6)-alkyl, and in formula (Xb) R mean (C1-C16)-alkyl, (C6-C14)-aryl-(C1-C16)-alkyl or (C6-C14)-aryl, and then the products obtained is converted into a compound of formula (II), the reaction sequence of stages d) and e) may also be changed, i.e. the splitting of the racemate can be done already at the stage of obtaining alcohol of formula (VII) or its derived compounds of formula (IXa) or formula (IXb).

Esters of formula (IXa) or carbonates of the formula (IXb) by analogy with those described in literature (Trost and others, JACS, 116, 10320 [1994] suitable for deracemization to obtain esters in the form of pure enantiomers. After hydrogenation and cleavage of ester will receive (-)-CIS-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-piperidine of formula (II).

3(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine-hydrobromide of the formula (VI) and 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydro-pyridine of the formula (VII) are valuable intermediates in obtaining (-)-CIS-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-piperidine of formula (II).

Examples

Example 1

Getting 3(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2, 3,6-tetrahydro-pyridine-hydrobro the IDA formula (VI).

To 200 ml of glacial acetic acid added to 75.7 ml of 0.44 mol) of a 33%aqueous solution of bromovalerate in glacial acetic acid and then with ice cooling and at a temperature of 20-25°continuously added dropwise 50 g (0.44 mol) of 1-methyl-piperidine-4-she of the formula (III). To the resulting suspension hydrobromide for 30 minutes at a temperature of 20-25°With added dropwise 70,4 g (of 0.44 mol) of bromine will get a clear yellowish solution. Stirred further for 15 minutes at a temperature of 25°and then to the reaction solution was added and 67.2 g (x 0.40 mole) of 1,3,5-trimethoxybenzene formula (V). Then additionally stirred for 1 hour at a temperature of 25°C. Then poured 300 ml of methyl-tert.-butyl ether, while the precipitated oily product. Decanted the supernatant liquid is again stirred with 300 ml of methyl-tert.-butyl ether and decanted. The residue is then stirred with 150 ml of dichloromethane, and the product crystallizes. Received 3 (R,S)-bromo-1-methyl-4(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine-hydrobromide of the formula (VI) is sucked off, washed with 50 ml of dichloromethane and dried in vacuum.

Output: 147 g of nearly colorless crystals

Melting point: 190-192°

Mass spectrometry (ionization electron spray): 342,2 (M+H)+

Example 2

Getting 3(R,S)-guide is hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII)

To 100 ml of glacial acetic acid added to 75.7 ml of 0.44 mol) of a 33%aqueous solution of bromovalerate in glacial acetic acid and then with ice cooling and at a temperature of 20-25°continuously added dropwise 50 g (of 0.44 mol) of 1-methylpiperidin-4-she of the formula (III). To the resulting suspension hydrobromide in nitrogen atmosphere for 30 minutes at a temperature of 20-25°With added dropwise 70,4 g (of 0.44 mol) of bromine will get a clear yellowish solution. Stirred for additional 60 minutes at a temperature of 25°and then to the reaction solution was added and 67.2 g (x 0.40 mole) of 1,3,5-trimethoxybenzene formula (V). Then additionally stirred for 1 hour at a temperature of 25°C. Then poured 400 ml of oxen and the mixture is refluxed for three hours. The reaction mixture was kept overnight at room temperature, diluted with 400 ml of water, then cooled to a temperature of 10°and for four hours at this temperature to an intensively stirred mixture was added dropwise in General, 320 ml of concentrated sodium hydroxide solution (pH after adding amounts to 10.7). This precipitates the alcohol of formula (VII) first slightly buttery condition, however, when a longer stirring then becomes solid and well sucked. The precipitate dark yellow sucked off, about the see water and carefully dried. The crude product is then stirred with 80 ml of acetone and dried in vacuum.

Yield: 55 g of light yellow crystals

Melting point: 125-127°

Mass spectrometry (chemical ionization): 280,3 (M+N)+

1H-NMR (hexacyanometallate) δ (ppm): x 6.15 (s, 2H); the 5.65 (DD, 1H); 4,20 (m, 1H); of 3.80 (s, 3H); 3.75 to (C, 6N); and 3.31 (DD, 1H); 2,89 (m, 1H); 2,84 (DD, 1H); 2.71 to (d, 1H); to 2.57 (DD, 1H); 2,24 (s, 3H).

Example 3

Getting 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII)

To 100 ml of glacial acetic acid added to 75.7 ml of 0.44 mol) of a 33%aqueous solution of bromovalerate in glacial acetic acid and then with ice cooling and at a temperature of 20-25°continuously added dropwise 50 g (of 0.44 mol) of 1-methylpiperidin-4-she of the formula (III). To the resulting suspension hydrobromide in nitrogen atmosphere for 30 minutes at a temperature of 20-25°With added dropwise 70,4 g (of 0.44 mol) of bromine will get a clear yellowish solution. Stirred for additional 60 minutes at a temperature of 25°and then to the reaction solution was added and 67.2 g (0.40 mol) of 1,3,5-trimethoxybenzene formula (V). After 15 minutes when cooled add to 40.8 g (0.4 mol) of acetanhydride and additionally stirred for 1 hour at a temperature of 25°C. Then poured 750 ml of water and the mixture is heated at a temperature of 80°C for 9.5 hours. PEFC is this the reaction mixture is cooled to a temperature of 5-10° With and by addition of 200 ml of concentrated sodium hydroxide solution for 30 minutes to establish a pH of 5.5. This precipitated unreacted 1,3,5-trimethoxybenzoyl. The suspension is filtered and using the following 200 ml of concentrated sodium hydroxide solution at a temperature of 5-10°the filtrate establish a pH of 14. This precipitates the alcohol of formula (VII) first slightly buttery condition, however, when a longer stirring then becomes solid and well sucked. The mixture was incubated over night at room temperature. Then the precipitated light yellow solid is sucked off, washed with about 300 ml of water until neutral and dried thoroughly. Crude yield: 87/2 g of light yellow crystals. The crude product is then stirred with 100 ml of acetone, sucked off and dried in vacuum.

Output: 73 g of crystals slightly yellow in color

Melting point: 125-127°

Mass spectrometry (chemical ionization): 280,3 (M+N)+

Example 4

Obtaining racemic 3,4-CIS-alcohol of formula (VIII)

3.5 g (12.5 mmole) of 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII) is dissolved in 100 ml of methanol and mixed with 0.35 g of catalyst (5%palladium-on-charcoal, pre-washed with methanol) and hydronaut in the autoclave Büchi during the 15 hours at a temperature of 50° C and a hydrogen pressure of 50 bar. Then the catalyst is filtered off, the filtrate is evaporated under vacuum in a rotary evaporator and the residue is stirred with 4 ml of acetone. The resulting product is filtered and dried in vacuum.

Yield: 2.7 g of colorless crystals

Melting point: 131-132°

Mass spectrometry (chemical ionization): of 282.3 (M+N)+

Example 5

Obtaining racemic 3,4-CIS-alcohol of formula (VIII)

10.0 g (35.8 mmole) of 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII) is dissolved in 100 ml of methanol and mixed with 1.5 g of catalyst (5%palladium-on-charcoal, pre-washed with methanol) and hydronaut in the autoclave Büchi for 39 hours at a temperature of 50°and a hydrogen pressure of 50 bar. Then the catalyst is filtered off, the filtrate is evaporated under vacuum in a rotary evaporator and the residue is stirred with 20 ml of acetone. The resulting product is filtered and dried in vacuum.

Yield: 9.2 grams of colorless crystals

Melting point: 131-132°

Mass spectrometry (chemical ionization): 282/3 (M+N)+

Example 6

Getting 3(R,S)-acetoxy-1-methyl-4-(2,4,6-trimethoxyphenyl)- 1,2,3,6-tetrahydropyridine of formula (IXa) [R=methyl]

and 2.79 g (10 mmol) of 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII) is dissolved in 15 ml of acetanhydride lane and mesilat for four hours at a temperature of from 100° C. the Solution is then evaporated in vacuo in a rotary evaporator and the residue is dissolved in 10 ml of water, using sodium hydroxide solution set pH>12 and extracted two times with 20 ml ethyl acetate. The combined organic phases are washed with 10 ml saturated sodium chloride solution, then dried over sodium sulfate and evaporated under vacuum in a rotary evaporator.

Yield: 2.55 g butter

Mass spectrometry (ionization electron spray): 322,2 (M+N)+

Example 7

Getting 3(R,S)-methoxycarbonylamino-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (IXb) [R=methyl]

of 8.37 g (30 mmol) of 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII) is dissolved in 83,7 ml of tetrahydrofuran and mixed with 12.4 ml (90 mmol) of triethylamine. Cooled to a temperature of 5°C for 15 minutes was added dropwise to 2.55 ml (33 mmole) of methyl ether of Harborview acid and additionally stirred for three hours at a temperature of 5-10°C. as a control using thin-layer chromatography shows still have the original substance, add next, 1.0 ml (12.9 mmole) of methyl ether of Harborview acid and again additionally stirred for 1 hour. Then add 50 ml of water and extracted twice with 50 ml ethyl acetate. The combined organic phases are washed with the using 30 ml of a saturated solution of sodium chloride, then dried over sodium sulfate and evaporated under vacuum in a rotary evaporator.

Yield: 8.7 g of an oil which solidifies over time

Mass spectrometry (ionization electron spray): 338,2 (M+N)+

Example 8

Obtaining racemic complex CIS-ester of formula (Ha)[R=methyl]

15,33 g of toluenesulfonic acid salt of 3(R,S)-acetoxy-1-methyl-4- (2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (IXa) [R=methyl] dissolved in 153 ml of methanol, filtered through activated charcoal and the filtrate is mixed with 1,53 g of catalyst (5%rhodium-on-coal) and hydronaut in the autoclave Büchi within 24 hours at a temperature of 50°and a hydrogen pressure of 18 bar. Then the catalyst is filtered off and the filtrate is evaporated under vacuum in a rotary evaporator. The residue is dissolved in 50 ml of water and concentrated sodium hydroxide solution set pH >12. After a short time besieged base. The resulting product is filtered, washed with water and dried in vacuum.

Yield: 8.5 g of colorless crystals

Melting point: 115-117°

Mass spectrometry (chemical ionization): 324,2 (M+H)+

Example 9

Obtaining racemic 3,4-CIS-alcohol of formula (VIII) from the compound of formula (Ha) [R=methyl]

of 1.61 g (5 mmole) of racemic complex CIS-ester of formula (Ha) [R-methyl] 20 ml of methanol and the Pris is under 5 ml of concentrated hydrochloric acid is refluxed for 8 hours. Then the methanol is removed in vacuo, the residue is mixed with 10 ml of water and concentrated sodium hydroxide solution set pH >12. In addition, the product precipitates. The resulting product is filtered, washed with water and dried in vacuum.

Yield: 1.1 g of colorless crystals

Melting point: 131-132°

Mass spectrometry (chemical ionization): 282,4 (M+N)+

Example 10

Splitting (±)-CIS-3-hydroxy-1-methyl-4-(2,4,6-tri-methoxyphenyl)-piperidine

Racemic CIS-3-hydroxy-compound (90 g) was dissolved in methanol (300 ml), enter into an interaction with (-)-dibenzoyltartaric acid (126,4 g) in methanol (200 ml) and heated to boiling. Then slowly add a simple diisopropyl ether (approximately 500 ml) and the resulting clear solution is allowed to cool. While slowly crystallizes tartrate salt, which is filtered off and recrystallized five times from methanol/simple diisopropyl ether, [α]20d=+48,3° (Meon). Tartrate salt (43 g) is suspended in 200 ml of water, is injected into the interaction with hydrochloric acid (2n, 100 ml) and stirred. The reaction mixture is extracted with ether acetic acid 5 times, using each time 100 ml of ether. Tartaric acid is extracted from the selected ether extract. The aqueous layer is treated with a carbonate soda which I to alkaline pH and extracted with chloroform. Chloroformyl the extract is dried over anhydrous sodium sulfate, and concentrate, you get to 17.7 g of (+)-3-hydroxycodone with a melting point 109-111°C [α]20d=+53,81° (Meon).

The filtrates before crystallization tartrate salt concentrate, and again receive the free base as described above. Dissolve the free base (20 g) in methanol (110 ml)is injected into the interaction with the (+)-dibenzoyltartaric acid (29 g)and the solution heated to boiling. Then slowly add a simple diisopropyl ether (110 ml). During curing at room temperature, distilled tartrate, which is filtered off and recrystallized three times from methanol, a simple diisopropyl ether. The output is a 20.2 g [a]20d= -49° (Meon). The free base is allocated, as described above, the yield is 8.2 g, melting point 109-111°, [α]20d=-54,13° (Meon).

1. The method of obtaining (-)-CIS-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-piperidine of formula (II)

characterized in that a21 methylpiperidin-4-one of formula (III)

immediately before the subsequent bromirovanii transferred to the hydrobromide by introducing 1 methylpiperidin-4-it is in the solution bromovalerate in Le is Jana acetic acid; and

b) 1-methylpiperidin-4-he-hydrogen bromide in a suitable solvent in the temperature range from 0 to 30°To enter into interaction with bromine to obtain 3(R,S)-bromo-1-methyl-4-oxo-piperidine-hydrobromide of the formula (IV)

b) the intermediate product of formula (IV) is directly subjected to interaction with 0.8 to 1 equivalent of 1,3,5-trimethoxybenzene formula (V)

by adding it to the reaction solution at a temperature of from 0 to 30°with 3(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine-hydrobromide of the formula (VI)

and, if necessary, add acetanhydride to remove the formed reaction water;

g1) compound of formula (VI) by mixing the reaction solution in a suitable organic solvent, first isolated in the form of solids, and then the resulting product is mixed with water and by stirring at a temperature of 50-100°With turn 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII)

or

g2) the reaction mixture containing the compound of the formula (VI), directly mixed with water and by stirring pritemperature 50-100° With turn 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII), and

g3) received on g1or g2) the reaction mixture is cooled, if necessary diluted with further water and at a temperature of 0-30°by adding an aqueous alkaline solution to establish a pH>12 deposited 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII)obtained crude product is sucked off and, if necessary, to clean again treated with an aqueous hydrochloric acid, filtered and, if necessary, extracted with not miscible with water solvent, and then the aqueous phase by adding an aqueous alkaline solution to establish a pH>12 deposited 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII), usageprice product, if necessary, for further purification mixed with one or more suitable organic solvents or with mixtures of these solvents;

d1) the resulting product of formula (VII) in a suitable solvent or mixtures of these solvents catalytically hydronaut using a suitable catalyst to obtain racemic 3,4-CIS-alcohol of formula (VIII)

in this case, maybe formed of a CR is the recovery of small amounts of 3,4-TRANS-alcohol can be removed by crystallization from a suitable solvent; or

d2for hydrogenation using easily obtained from compounds of formula (VII) esters of the formula (IXa) or carbonates of the formula (IXb)

where in the formula (IXa) R mean (C1-C16)-alkyl, (C6-C14)-aryl-(C1-C16)-alkyl, (C6-C14)-aryl or carboxy-(C2-C6)-alkyl, and in formula (IXb) R mean (C1-C16)-alkyl, (C6-C14)-aryl-(C1-C16)-alkyl or (C6-C14)-aryl,

thus obtain the compounds of formula (Ha) or formula (Xb), from which it is possible to release the compound of formula (VIII);

e1by splitting of the racemate using a suitable chiral auxiliary reagents of the compounds of formula (VIII) are obtained in the form of pure enantiomers of CIS-alcohol of formula (II);

or

e2) the splitting of the racemate is carried out with compounds of formula (XA) or (Xb)

moreover, in the formula (Ha) R mean (C1-C16)-alkyl, (C6-C14)-aryl-(C1-C16)-alkyl, (C6-C14)-aryl or carboxy-(C2-C6)-alkyl, and in formula (Xb) R mean (C1-C16)-alkyl, (C6-C14)-aryl-(C1-C16)-alkyl or (C6-C14)-aryl,

and then the obtained products prewash the Ute in the compound of formula (II), the sequence of the reaction stages d) and e) may also be changed, i.e. the splitting of the racemate can be done already at the stage of obtaining alcohol of formula (VII) or its derived compounds of formula (IXa) or formula (IXb).

2. 3(R,S)-Bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3, 6-tetrahydropyridine-hydrobromide of the formula (VI).

3. 3(R,S)-Hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of formula (VII).



 

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< / BR>
where R1represents a phenyl group which may be optionally substituted by at least one Deputy, which represents a halogen atom; R2represents a C1-C8aliphatic acyl group or (C1-C4alkoxy) carbonyl group; and R3represents a saturated cyclic amino group which has from 2 to 8 carbon atoms in one or more cycles, with the highest nitrogen cycle has from 3 to 7 atoms in the cycle, and the specified saturated cyclic amino group substituted by a group having the formula-S-S-R4where R4and X have the meanings as defined below, and the said saturated cyclic amino group attached via its cyclic nitrogen atom adjacent to the carbon atom that is attached to the substituents R2and R1; R4represents a phenyl group which may be optionally substituted by at least one Deputy, selected IGP and nitro groups; WITH1-C6alkyl group which may be optionally substituted by at least one Deputy, selected from the group consisting of amino groups, carboxyl groups, (C1-C4alkoxy)carbonyl groups, substituents having the formula-NH-A1(where a1represents an-amino acid residue), and substituents having the formula-CO-AND2(where a2represents an-amino acid residue); or (C3-C8cycloalkyl group, and X represents a sulfur atom, sulfinol group or sulfonyloxy group, and the above-mentioned cyclic aminecontaining group may be optionally additionally substituted by a group having the formula = CR5R6where R5and R6are the same or different, and each independently represents a hydrogen atom, a carboxyl group, (C1-C4alkoxy)carbonyl group, karbamoilnuyu group, (C1-C4alkyl) karbamoilnuyu group or di-(C1-C4alkyl)karbamoilnuyu group; or their pharmacologically acceptable salts, pharmaceutical composition having inhibitory action in Rel is the prevention of disease, selected from the group consisting of embolism and thrombosis in a warm-blooded animal

The invention relates to new cyclic amine derivatives of General formula I, where R1represents a phenyl group substituted by halogen atom,2represents C1- C8aliphatic acyl group or (C1- C4alkoxy)carbonyl group, R3represents a 3 - to 7-membered saturated cyclic amino group which may form a condensed ring, where the specified cyclic amino group substituted by the Deputy selected from the group comprising: mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, C1- C4alkyl group, substituted mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, and the number of protective groups for the specified mercaptopropyl includes C1- C20alcoholnye group, C3- C20alkenone group and benzoline group, and the said cyclic amino group, furthermore preferably a substituted group of the formula =CR4R5where R4represents a hydrogen atom, and R5represents a hydrogen atom, a C1- C4alkyl group, carboxypropyl, (C1- C4-alkoxy)carbonyl GRU

The invention relates to the derivatives of acanaloniidae formula (I)

or their pharmaceutically acceptable acid additive salts, where R1means a hydrogen atom or hydroxyl; R2means a hydrogen atom or methyl, X is-O - or-CH2-

The invention relates to new piperidine derivative of formula (I), where R1means naphthyl which may be substituted WITH 1-31-C5alkoxygroup; R2means phenyl or benzyl which may be substituted by 1-3 substituents selected from halogen, cyano, C1-C3alkoxy and nitro; R3means N-[CH(OR4)]2-CH2-O-CH2or R3A= (CH2)k-[CH(OR4)]l(-CH2O-, where R3Ameans HE or1-C3alkoxygroup; R4means N or C1-C3alkyl; k = 1 or 2 and l = 1 or 2 or R3Ameans methylaminopropyl; k = 1 and l = 1, provided that1means 4-methoxynaphthalene-2-yl; R2mean 2-methoxybenzyl or R3Ameans methoxyethoxy; k = 1 and l = 1, provided that R1means 4-methoxynaphthalene-2-yl; R2mean 2-methoxybenzyl or phenyl, substituted in position 2 by cyano, or R3Ameans 1,2,4-triazole-1-yl or imidazol-1-yl; k and l = 1, provided that R1means 4-methoxynaphthalene-2-yl; R2means phenyl, substituted in position 2 by a nitro-group, or a hydroxymethyl group, or imidazol-1-ylmethyl, provided that R1means 4-methoxynaphthalene-2-yl; R2on the Sabbath.

The invention relates to new derivatives of piperidine F.-ly (I), where R1- aryl, heterocyclyl, R2is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridine, diazines, triazoles, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl or furyl which may be substituted with halogen, hydroxy, cyano, CF3, alkyl, R3-H, hydroxy, alkoxy, alkenylacyl, R4-H, alkyl, alkenyl, alkoxy, benzyl, oxo, Q is ethylene or absent, X is a bond, oxygen, sulfur, W is oxygen or sulfur, Z - alkylen, albaniles, -Oh, -S; n = 1, m = 0 or 1

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention elates to the improved method for preparing (-)-cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine. Method involves conversion of 1-methylpiperidine-4-one to hydrobromide followed by interaction with bromide to obtain 3-(R,S)-bromo-1-methyl-4-oxopiperidine hydrobromide and then with 1,3,5-trimethoxybenzene to obtain 3-(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropridine hydrobromide. Then by addition of the reaction solution with organic solvent 3-(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide is isolated firstly as a solid substance and then product is mixed with water and converted by stirring to 3-(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine. Prepared product is hydrogenated catalytically for preparing racemic 3,4-cis-alcohol and by cleavage of racemate by using chiral accessory reagents (-)-cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine is prepared from racemic 3,4-cis-alcohol as a pure enantiomer. Proposed method provides simplifying a process for preparing abovementioned product and to reduce duration of process due to exclusion the hydroborating stage, oxidation by Swern, reduction with sodium boron hydride used in preparing the same product by the known method. Also, invention describes intermediates compounds: 3-(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide and 3-(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine.

EFFECT: improved preparing method.

3 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-hydroxypiperidine of the general formula (I): wherein R means (a): -C(O)(CH2)nC(O)OH; (b): wherein R1 means -N(R2)(R3); each R2 and R3 means hydrogen atom, lower alkyl or cyclic tertiary amine; (c): -P(O)(OH)2 or (d): -C(O)(CH2)n and -NHC(O)(CH2)nN(R2)(R3) wherein n means a whole number 1-4. Indicated compounds can be used as prodrugs in preparing medicinal agents used in treatment of diseases associated with blocking agents for receptors of subtype NMDA.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 1 tbl, 20 ex

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