UA78839C2 - Modified pictet-spengler reaction and products prepared therefrom - Google Patents

Abstract

A method of introducing a second stereogenic center into a tetrahydro-?-carboline have two stereogenic centers using a modified Pictet-Spengler reaction is disclosed. The method provides a desired cis- or trans-isomer in high yield and purity, and in short processes times.

Description

Description of the invention

The present invention relates to a modified Pictet-Spengler reaction for introducing a second stereogenic 2 center into a compound. Namely, the invention relates to a modified Pictet-Spengler reaction, as a result of which the desired cis- or trans-diastereomer of a polycyclic compound with two stereogenic centers is obtained in high yield and purity.

Compounds that exhibit biological activity usually contain at least one asymmetric carbon atom, that is, at least one chiral center. A certain stereoisomer of such a compound usually exhibits excellent biological activity, while other stereoisomers have no or very low biological activity.

Accordingly, researchers have attempted to synthesize the biologically active stereoisomer while minimizing or avoiding the synthesis of inactive stereoisomers or stereoisomers with lower activity.

Stereochemical purity is very important in the field of pharmaceuticals, in which many of the most commonly prescribed drugs exhibit chirality. For example, it is known that the I1-enantiomer of the 12B-adrenergic blocker, propanolol, is 100 times more effective than its O-enantiomer. In addition, optical purity is important in the field of pharmaceuticals because some stereoisomers exhibit harmful activity rather than the desired one or are not inert. For example, the 10-enantiomer of thalidomide is believed to be safe and sedating when prescribed to combat morning sickness in pregnancy, while its corresponding

The I-enanthomer is known as a potential teratogen.

In this way, stereoselective synthesis allows obtaining more suitable substances for medicinal products. For example, it is possible to reduce the dose that is prescribed due to the introduction of a single stereoisomer, rather than a mixture that contains a large number of inactive stereoisomers. A reduced dose of the active stereoisomer will also result in fewer negative side effects compared to a dose that would contain a mixture of stereoisomers. In addition, stereoselective synthesis is more economical due to the simplification or elimination of the stage of separation of the desired c stereoisomer from unwanted stereoisomers, also in this case the amount of raw materials is reduced and costs are reduced due to the fact that reagents are not consumed during the synthesis of unwanted stereoisomers.

Many biologically active substances contain two asymmetric carbon atoms, that is, two stereogenic centers, in which each asymmetric carbon atom is a member of a ring system, and each is bonded to a hydrogen atom and a substituent that is not a hydrogen atom. Therefore, non-hydrogen substituents of asymmetric carbon atoms can have o or cis- or trans-configuration. co

A particularly difficult problem encountered in the synthesis of such biologically active compounds is obtaining high yields and formulation purity of a certain stereoisomer, i.e., the desired so diastereomer, in which the non-hydrogen substituents of asymmetric hydrogen atoms have either a cis- or trans-He) configuration, in depending on which diastereomer is more biologically active.

For such compounds, it is necessary to develop a method of synthesis that will ensure the production of a stereogenic center that will have the necessary stereochemistry, which will determine the yield of the desired diastereomer.

The synthesis technique should also provide high yields of the desired stereoisomer in the fewest number of steps possible, with minimal separation and purification of the diastereomer. "

For example, (US Patent 5,859,006), incorporated herein by reference, describes the synthesis of (b6K,12ac)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4 -methylenedioxyphenyl)-pyrazino-(2,1":6,1|pyrido|3,4-in|indole-c 1,4-dione, which has the structure (1): ;" () 415 "Yulia z y ( ee) E b (ee) o 50 p iChe)

Compound (I) has two asymmetric carbon atoms, each marked with an asterisk, in which the non-hydrogen substituents of the asymmetric carbon atoms have a cis configuration. Compound (I) is obtained by two methods of synthesis,

These are described in US patent No. 5,859,006. Compound (I) is a potential and selective inhibitor of the enzyme phosphodiesterase ROE5, and can be used for many therapeutic purposes, for example, for the treatment of erectile dysfunction in men. i.e.) The first method of synthesis (A), from O-tryptophan, involves few steps, but the yield of the desired diastereomer (i.e., Compound II) is low and requires a separation step from the trans-stereoisomer (Compound Pa). Method (A) also involves the use of highly corrosive trifluoroacetic acid (ie TFO or SEzZSO»H). The main stage in technique A is the classical Pictet-Spengler reaction, which uses Y-tryptophan methyl ester and piperonal to obtain substituted tetrahydro-3-carboline Compounds (I) and (Pa). The second technique (B) provides higher yields of the desired Compound I, but requires many stages of synthesis. In each method of synthesis, the main intermediate compound in the synthesis of Compound (I) is Compound (II). Compound (I) is then synthesized 65 from Compound (II) in two stages of synthesis.

Method A

Su, she 9 in No ssi: -4-90 o Tryptophanmethypic strain Piperanali be di and more -y and

Compound DE) Compound (ah yo Ihnaeri (output 4236) (gpraznizomir) (2nd output) (desired) (undesired) si

Methodology B | in o

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Kk shen l (ee)

Pio YN va so z8 "bltriptofanivtty via o acta sesiyakh shchi y K y y Kuk - s t Roy V V ke sokyK), rsagant-Pavessona t zhk chho - oi shchi sofii (ee) syu 20 bo" ; with Nv sk shi shashi- because I- 65

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ShChI - p. 70 Methodology of synthesis of Compound (I) from Compound (II) from Knibluva tu S-SCHE R YAV - Fi rya so y: so d. su 20 5, ry sche. s - y. -Yu, . The total yield of Compound (I) by method (A) or (B) is from about 2595 to about 30965.

Method (B) requires several stages of synthesis and, therefore, is considered inconvenient. The main stage in the synthesis of Compound (I) is the preparation of Compound (II) by a shorter method of synthesis (A). In method (A), Compound (II) is obtained by the Picte-Spengler cyclization reaction between ХО-tryptophan methyl ester and piperonal in dichloromethane (СХСІ») with two equivalents of trifluoroacetic acid at 492С, as a result of which a mixture of two diastereoisomers is obtained After five days, that is, the desired cis-isomer of tetrahydro-p-carboline of Compound (II) (1K,ZK)) and the undesirable trans-isomer of tetrahydro-p-carboline of Compound (Ia) bo ((15,3K)) in a ratio of approximately 60/40. From this mixture, it is possible to obtain the pure cis-isomer (i.e. Compound

(I) by fractional crystallization with a yield of 42905 (ee»9995 (chiral HPLC)).

The Pictet-Spengler reaction is a direct method of obtaining the tetrahydro-B-carboline of the cyclic system present in Compound (I). In general, the Picte-Spengler reaction involves tryptophan ester and aldehyde to obtain a mixture of cis-1,3- and trans-1,3-tetrahydro-B-carbolines, which are presented below. IN? of course is Si dalkil and 2! may be aliphatic or aromatic, for example (see Momo's US Patents 5,859,006 and 5,981,5271, each of which is incorporated herein by reference.) cy 3-tetrahydro-beta carbol pyrene-1,3-tatrapdro-pata carbon

A major achievement in this field will be the preparation of a modified Pictet-Spengler cyclization reaction, which will significantly improve the diastereoselectivity of the reaction. In particular, the achievement in this field will be to optimize the methodology

A, in which the Picte-Spengler reaction is used between the commercially available SO-tryptophan methyl ester and piperonal, or another aliphatic or aromatic aldehyde to directly obtain enantiomerically pure Compound (II), or a similar tetrahydro-B-carboline, which will not have the inherent disadvantages of of the classic Pictet-Spengler reaction, such as the use of TFO, long reaction time and difficult product separation.

The present invention relates to a method of obtaining the desired diastereomer, cis- or trans-configuration, of a polycyclic compound having two asymmetric carbon atoms of the cyclic system. Namely, the present invention relates to a method of obtaining the desired diastereomer of the compound tetrahydro-B-carboline, which has two Ф 3о asymmetric carbon atoms by means of a modified Picte-Spengler reaction. co

Previous researchers have attempted to obtain the desired diastereomer of a polycyclic ring system that has two asymmetric carbon atoms by the Picte-Spengler cyclization reaction. These attempts were generally unsuccessful due to the fact that the reaction was carried out in a corrosive environment, resulting in mixtures of diastereomers, which adversely affected the product yield in the reaction, which took several days. The method according to the present invention ensures the production of a stereoisomer in a short period of time with good yield indicators, and without using TFO.

In particular, the present invention relates to a method of obtaining the desired diastereomer of tetrahydro-B-carboline, which has two asymmetric carbon atoms, by a modified Pictet-Spengler cyclization reaction, in which the reaction is carried out using a solvent in which only one of the diastereomers is soluble. -at

Another aspect of this invention is an increase in the yield of the desired diastereomer as a result of balancing the unwanted diastereomer in the solution, due to which an additional amount of the desired diastereomer is obtained, which "c" falls into the solution from the precipitate, which causes an increase in the yield of the desired diastereomer at the expense of the unwanted diastereomer.

These and other aspects and novel features of the present invention will become apparent from the following detailed description of -1 15 preferred embodiments.

The present invention is aimed at obtaining the desired diastereomer of a polycyclic compound having two (ee) asymmetric carbon atoms that are members of the cyclic system. The method includes an improved Picte-Spengler reaction, by which the desired diastereomer of tetrahydro-B-carboline is obtained with high yield and purity, as well as a short reaction time. In the improved reaction (95) 50 Picte-Spengler also avoids the use of FD. Although the synthesis of Compounds (I) and (II) is described in detail herein, the present invention is not limited to these compounds. The present invention can be used to synthesize the desired diastereomer of other tetrahydro-B-carbolines by judicious selection of the starting tryptophan ester, e.g., in the O- or I- form, the starting aldehyde, and the reaction solvents used in this modified Picte-Spengler cyclization reaction.

Usually, the Pictet-Spengler reaction starts with obtaining an imine under neutral conditions, then it is carried out

HF) cyclization using trifluoroacetic acid (TFO) in dichloromethane (CHCl) at low temperature

He (4"C). In addition to the primary preparation of the imine, M-substitution of the tryptophanamino group (-MNo) is often carried out to obtain the cis-diastereomer. The Pictet-Spengler reaction (described in US patent No. 5,859,006) under these conditions. As was noted above, the standard Pictet-Spengler reaction has disadvantages such as cycle time, low yield of the desired cis diastereomer, and the use of corrosive TFO.

This invention eliminates the disadvantages of the classic Pictet-Spengler reaction, for example, increases the yield and purity of the desired diastereomer, and also provides for the use of an easier synthesis route. In particular, the present invention relates to a simplified Pictet-Spengler reaction for the preparation of a second cyclic stereogenic center, in which the desired cis- or trans-diastereomer can be obtained in high yield and purity by conducting the reaction in a solvent in which the desired diastereomer is insoluble, and the undesired diastereomer is soluble. A modified Pictet-Spengler reaction of the present invention also provides for use

M-unsubstituted starting material, for example tryptophan in the form of a hydrochloride salt, and in which TFO is not used. Eliminating TFO from the reaction has significant advantages, including improved isolation/identification of tryptophanmethyl hydrochloride and avoidance of corrosive effects of TFO.

Selection of an appropriate solvent for use in the modified Pictet-Spengler reaction of the present invention is known to those skilled in the art. For example, when obtaining Compound (II) by cyclization reaction

Picte-Spengler, it was found that isopropyl alcohol solubilizes the undesired trans diastereomer, while the desired cis diastereomer precipitates out of the reaction mixture. Accordingly, 7/0 Compound (I) is formed in solution as a cis-diastereomer and immediately precipitates, its concentration decreases relative to the trans-diastereomer, Compound (Ia), which remains, due to which a concentration differential is obtained, which causes equilibration, as a result which gives an additional cis-diastereomer. This prolonged reaction time increases the yield and improves the purity of the desired cis-diastereomer.

In particular, the present invention uses a modified Pictet-Spengler cyclization reaction to obtain 7/5 tetrahydro-B-carboline cyclic system, which has two stereogenic centers. The reaction is carried out in a solvent in which the desired diastereomer is soluble at the boiling point or below, and the undesired diastereomer is insoluble at the boiling point or below. The difference in solubility provides a quick and easy separation of the desired diastereomer from the undesired diastereomer. In addition, the dynamic equilibration of cis-/trans- in the solution allows obtaining a more complete transformation of the starting materials into the desired diastereomer, as well as a more complete separation of the desired diastereomer from the undesired diastereomer. Accordingly, another advantage of this invention is cost reduction due to more efficient use of reagents.

As noted earlier, the selection of a reaction solvent that will have the required solubility characteristics can be performed by one skilled in the art. The selection requires only the determination of the solubility of each diastereomer in a particular solvent and the selection of a solvent that will have the solubility/insolubility characteristics described above for the two diastereomers. and)

The following are non-limiting examples of this invention that illustrate the synthesis of Compound (II) by a modified Pictet-Spengler reaction (Stage 2), and the subsequent synthesis of Compound (I) from Compound (I) (Stages C and 4). b (ze) (ee) (ee) and - - . and? -i (ee) (ee) (95) iChe) ime) 60 b5

Stage 2. Y

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compound)

In general, the synthesis of compound (I) by the method according to the present invention includes a synthesis method which

F) consists of four stages. The first stage includes esterification in methanol (Meon) using cationic thionyl chloride (ZOSI) at boiling. The product is crystallized and isolated by filtration. The second stage includes a new and simplified modification of the Pictet-Spengler reaction according to the present invention, in which the hydrochloride of P-tryptophan methyl ester is mixed together with piperonal in isopropyl alcohol (I-RHOH) and heated to boiling to obtain a mixture of diastereomeric adducts.

Due to the fact that the desired cis-diastereomer (Compound (II)) is practically insoluble in isopropyl alcohol at the boiling point and below, crystallization of the cis-diastereomer occurs from a solution in which dynamic cis-trans equilibrium continues. After precipitation of the cis diastereomer from isopropyl 65 alcohol, an equilibration occurs that tends toward the cis diastereomer until the concentration of the cis diastereomer is low enough to be left in solution. The desired diastereomer is isolated in a yield greater than

9096 by crystallization and filtration.

The third stage includes acylation with an aqueous solution of tetrahydrofuran (THF) of the amino substituent (MH 5) of Compound (II), followed by crystallization and filtration. Ring closure with methylamine (MemnH 5) completes the sequence that forms the ring. After changing the solvent, the product is crystallized from an aqueous solution of isopropyl alcohol or another suitable solvent, after which Compound (I) is obtained by filtration in a total yield of approximately 7790.

In general, the modified Pictet-Spengler reaction according to the present invention can be used to prepare the desired diastereomer of tetrahydro-B-carboline compounds without limitation. For example, the modified /o Pictet-Spengler reaction of the present invention can be used to synthesize the desired diastereomer of a class of compounds (described in US Pat. 02/10166, MO 02/36593, MO 01/94345, MO 02/00658, MO 02/00657, MO 02/38563, MO 01/94347,

MO 02/94345, OO 02/00656, PCT/О501/49393, PCT/ОБО2/13719, PCT/ОБО2/00017, PCT/ОБО2/10367,

PCTLIBO2/13703, PCT/YUVO2/11791 and PCT/IO5O2/13897I, each of which is incorporated herein by reference, /5 as well as other substituted tetrahydro-B-carbolines.

In addition to the preparation of tetrahydro-B-carbolinediketo-piperazines such as Compound (I), the present invention can be used to prepare tetrahydro-B-carbolinehydantoines (I) of the desired stereochemistry by reacting a compound such as Compound (II) with an isocyanate having the formula K"7MSO, where B" is aliphatic or aromatic.

IDiv. US Patent Mob 001,847), which is incorporated herein by reference. (1)

Kk 4 s no: o t these

The following are illustrative examples of obtaining Compound (I) by the method according to the present invention. Gee!

Stage 1 so

Controlled HPLC co

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And GU Mes under the pressure of M; "a" Mu BO" Boiling) n AI distillation, cooling m) MTBE, filtration (0276 emissions) ki n

O-Tryptophan (50.Okg, 245mol) was suspended in Meon (270Ol), then added to the prepared solution of ZOSI" and (67.O0kg, 5bZmol) in Meon (250L) at ambient temperature under a nitrogen (Me) atmosphere. (ee) The resulting solution was stirred at boiling for 1-2 hours, then MeOH was distilled from the reaction mixture until approximately 5095 of the initial volume was obtained. Methyl i-butyl ether (MTBE) (350 l) was added, the solution was cooled to 09-59 with constant stirring for an hour. The product was filtered, washed (95) with 50 cold MTBE (150 l), and dried in a vacuum at 6b0eSb to obtain 57.bkg (92495) of hydrochloride

Ge; O-tryptophan methyl ester. "H NMR (400MHz DMSO) 5: 11.15 (1H, s), 8.70 (2H, exchanged), 7.50 (1H, d, J-8.2Hz), 7.35 (1IN, d, J-8.2Hz), 7.24 (1H, s), 7.08-7.05 (1H, m), 7.00-6.97 (1H, m), 4.18-4.16 ( IN, m), 3.61 (ZH, s), 3.36-3.25 (2H, m). HPLC parameters: column: ZB-phenyl 4.6x250 mm; eluent: isocratic 8095 (NgOO 196 TFO) 2095 ASM (acetonitrile); temperature: 409C; flow rate -"Tml/min; UV detection at -285nm; injection volume -2Oml; solvent -1:1 ACM/H2"O; and retention time -10 ) 60 b5 of the walls of the INNYAKON under pressure M.

Н Mr song (slander) pir spehludzhneja futetration (9835 output) yes no "YAN 720 (Compound I)

Y-Tryptophan methyl ester hydrochloride (50.0 kg, 196 bmol) was suspended in isopropyl alcohol (5007) and treated with piperonal (32.4 kg, 21 bmol) at ambient temperature under M atmosphere.

The mixture was stirred between 702C and boiling point (822) for 16-18 hours. At this time, the reaction mixture contained less than 396 Compound Pa. The reaction mixture was then cooled to 02C, filtered and washed with cold isopropyl alcohol (150 l). The product was dried in vacuum at a temperature less than 602 to obtain 69.8 kg (o) (9295) of methyl ester cis-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H -pyridoyl3,4-indole-3-carboxylic acid (Compound (I)). "H NMR (400MHz DMSO) δ: 10.81 (IN, s), 10.67 (1H, exchanged), 10.21 (1H, exchanged), 7.52 (1H, d, J-8.0Hz) . 5.85 (1H, m), 4.71 (IN, m), 3.82 (ZH, s), 3.39-3.23 (2H, m). HPLC parameters: column: ZB-phenyl 4, b6x250mm;

ASM/NhOO, 195 TFO) gradient; temperature: 409C; flow rate "ml/min; UV det.-285nm; injection volume -2 Ωcl; solvent -1:1 ACM/H 20; sample concentration: approximately 0.1mg/ml; and retention time (ee) -6.0 min. co

In a preferred method of obtaining Compound (II) according to the method according to the present invention, a small amount of seed of Compound (I), i.e. about 0.0595-195, and preferably about 0.0595-0.2595, depending on the weight of O-tryptophan methyl ester hydrochloride was added to the reaction mixture before heating. This seed led to the crystallization of the cis-carboline compound (II) in the reaction mixture.

If isopropyl alcohol is used as the solvent, it is preferred that the alcohol solution be "anhydrous, for example 0.1wg.9o of water or less, because a significant amount of water can adversely affect the reaction rate. It is especially preferable that the isopropyl alcohol contained almost no acetone, that is, it contained - 0.9% by weight of acetone or less, to avoid the formation of an undesirable by-product. c The use of a solvent with a high boiling point (for example, propanol, toluene, -» dimethylformamide, or acetic acid) leads to the acceleration of the reaction with the corresponding yield of the product with the desired purity.

Other solvents suitable for the preparation of Compound (II) by the Picte-Spengler reaction (Stage 2) according to the present invention include, but are not limited to, aromatic solvents (e.g., toluene, benzene, or xylene), nitrile (e.g., acetonitrile or propionitrile), ester (e.g. ethyl acetate), alcohol (e.g. propanol or butanol), ether (e.g. THF, MTBE, or dioxane), aliphatic hydrocarbon (ee) (e.g. hexane, heptane), organic acid (e.g. acetic acid), their mixtures and aqueous solutions.

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Compound (Y b5

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Substituted tetrahydro-rD-carboline hydrochloride (I) (83.7 kg, 21 bmol) was suspended in THF (335 L) and deionized water (84 L), treated with triethylamine (EBM) (57.0 kg, 5 bOmol) at 020-202 in an atmosphere of M» .

Chloroacetyl chloride (CHCl(O)CI) (34.2 kg, 00 mmol) in dry THF (0.6 vol) was then added at a rate sufficient to maintain the temperature between 220-102 0, followed by stirring the reaction mixture for two hours. The progress of the reaction was monitored by HPLC for the content of 4wg.9o or less of Compound (II). After completion of the addition reaction, the reaction mixture was distilled under vacuum at a temperature of 3020-5023 to reduce the volume to approximately 3095. Then water (84 L) and isopropyl alcohol (335 L) were added, the reaction mixture was distilled a second time under reduced pressure at a temperature of 3020-5023 to reduce the volume to about 2095. The reaction mixture was then cooled to 2020-2522 and stirred for two hours. The product obtained as a result of the reaction was cyclized, filtered and washed with isopropyl alcohol. The product obtained as a result of the reaction was dried in M vacuum at 809C with the receipt of 86.7 kg (9590) of methyl ester of chloroacetylcarboline he) cis-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro- 1H-pyridoyi3,4-bIndole-3-carboxylic acid. "H NMR (400MHz

DMSO) 5: 10.86 (1H, s), 7.54 (IN, D, J-7.4), 7.27 (1H, d, J-8.0), 7.11-6.99 (2H , m), 6.81-6.75 (2H, m), 6.63 (IN, s), 6.45 (IN, d, J-8.2), 5.97 (2H, d, J -5.8), 5.19(1 H, d, J-6,6), 4.83 (IN, d, J-14), 443 F (IN, d, J-14), 3.45 (1H, d, J-16), 3.10-3.03 (4H, m).

Alternative solvents for Stage C are low molecular weight alcohols such as isopropyl alcohol or n-propyl alcohol, acetone, and methylene chloride. co

Stage 4 that MM and I Koutropnvali HPLC with

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Chloroacetylcarboline (86.0 kg, 201 mol) was added to THF (430 L), the resulting mixture was heated to 3020-5590 M in an atmosphere. and stirred. The resulting solution was then filtered at a temperature of 4520-5022 to remove undissolved particles. Then methylamine (78.2 kg, 1000 mol) was added to the solution at a temperature of 5906-2596. 60 The resulting mixture was stirred at a temperature of 302C-552C for 1 hour or until analysis by HPLC indicated completion of the reaction, i.e. less than 195 chloroacetylcarboline remaining. The mixture was cooled to 020-302С, then isopropyl alcohol (344l) and water (175l) were added, then 12M hydrochloric acid (b7l) to neutralize excess methylamine, that is, to bring the pH level to 2-94. After almost complete removal of THF by distillation, the solution was treated with isopropyl alcohol (26 bOl) and water (75 l), cooled to -520-302C, then stirred for two hours to crystallize the product. The product was filtered and washed with a cold (0920-5923 5090) aqueous solution of isopropyl alcohol. The solvent for washing was filtered at -5 202-302, the product was dried in a vacuum at 80C or lower (for example, 7020-8022) to obtain 75 kg (94.6905) of Compounds ( I) To increase the purity of Compound (I), it is optional to carry out recrystallization from acetic acid.

The control standard was obtained in the same way, additionally purified by double recrystallization from cold acetic acid (HOAc). Compound (I) was dissolved in 13 volumes of HOAc at 802C, the solution was concentrated to obtain one third of the initial volume and then cooled to ambient temperature. The product was filtered, washed with MTBE, dried in a vacuum at 802C. "H NMR (400 MHz, DMSO) 5: 11.0 (IN, s), 7.52 (IN, d, J-7.3 Hz), 7.28 (1H, d, 7.9 Hz), 7.28 (IN, D, J-7.9Hz), 7.06-6.98 (2H, m), 6.85 70 (1H, s), 6.76 (2H, s), 6.11 (IN, c), 5.91 (2H, c), 440-435 (IN, dd, J-4.27, 11.6Hz), 4.17 (1H, d,

J-17.1Gsh), 3.93 (IN, d; J -17.1), 3.54-3.47 (1H, dd, J-4.6, 11.93HZ), 3.32 (IN , c), 3.00-2.91 (4H, m).

HPLC parameters: column: 7ogra ZB-phenyl, 4.bmm in diameter x25mm; particles 2.5 μm; mobile phase: acetonitrile, 0.195 TFO in water; flow rate -1.0 ml/min.; The wavelength of the detector is -285nm; injection volume - 20 μl; column temperature - ambient temperature; and retention time -9,Ochv.

It is obvious that many modifications and changes can be made to the described invention without departing from its basic idea and scope, and therefore the present invention is limited only by the appended claims.

Claims (23)

The formula of the invention 1. The method of obtaining the desired diastereomer of tetrahydro-B-carboline, which has the formula sov. ke ro sch with | | о шт МН МН Н (22) зо EE со which includes stages: со (a) obtaining esterified tryptophan using an alcohol having the formula KOH; and (B) reacting the tryptophan ester from step (a) with an aldehyde having the formula Е?HO to give the desired α diastereomer and the undesirable diastereomer, wherein the reaction is carried out in a solvent in which the desired β diastereomer is insoluble and the undesirable diastereomer is soluble. 2. The method according to item 1, in which the desired diastereomer is insoluble in the solvent from step (5) at the boiling temperature or lower, and the undesired diastereomer is soluble in the solvent from stage (b) at the boiling temperature or lower. 3. The method according to item 1, in which the alcohol B OH is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butyl alcohol, sec-butyl alcohol, t-butyl alcohol and their mixtures we 4. The method according to item 1, in which the alcohol E2OH is methanol. 5. The method according to item 1, in which the aldehyde is an aliphatic aldehyde. 6. The method according to item 1, in which the aldehyde is arylaldehyde. Sh- 7. The method according to item 1, in which the aldehyde B'HNO is piperonal. Go) 8. The method according to claim 1, in which the desired diastereomer is a cis diastereomer. 9. The method according to item 1, in which tryptophan is O-tryptophan. co 10. The method of claim 1, wherein the desired diastereomer is a trans diastereomer. Ha 50 11. The method according to item 1, in which the solvent in stage (B) is selected from the group consisting of an alcohol, an aromatic solvent, a nitrile, an ester, an ether, an aliphatic hydrocarbon, an organic acid, their mixtures, and aqueous solutions. 12. The method according to item 71, in which the solvent in stage (B) is selected from the group consisting of isopropyl alcohol, n-propanol, n-butanol, toluene, xylene, benzene, acetonitrile, propionitrile, 295 acetic acid, ethyl acetate, tetrahydrofuran , methyl-i-butyl ether, dioxane, their mixtures and aqueous HF) solutions. 13. The method of claim 1, wherein the desired diastereomer is a cis diastereomer, and the solvent in step (B) is an alcohol. 14. The method according to item 13, in which the alcohol is selected from the group consisting of isopropyl alcohol, 60 n-propyl alcohol, n-butanol and sec-butyl alcohol. 15. The method according to item 13, in which the alcohol is isopropyl alcohol. 16. The method of obtaining a compound having the formula b5 a, S. ot her izh М М Н 70 v" a which includes stages: (a) preparation of the desired diastereomer of tetrahydro-B-carboline by the method according to point 1; (B) reaction of tetrahydro-B-carboline with chloroacetyl chloride to obtain /M-substituted of tetrahydro-B-carboline; and (c) reactions of M-substituted tetrahydro-B-carboline with an amine having the structure КВ ЗМН», where KZ is a C alkyl or hydrogen. 17. The method according to item 16, in which the amine is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, isopropylamine, butylamine and sec-butylamine. 18. The method according to claim 15, in which the amine is methylamine. 19. The method according to item 16, in which the compound has the structure of M N.O: so I oh and so | and - From o « 0-/ shi p 20. The method according to item 19, in which VZ is methyl. "with 21. The method according to claim 19, in which the compound is purified by recrystallization from cold acetic acid. " 22. The method according to item 16, in which step (c) is carried out in tetrahydrofuran, and in which the tetrahydrofuran is removed and replaced with alcohol to separate and purify the compound. 23. The method of obtaining a compound that has the structural formula: M t VZ so t M su 2 so M i M n : ikh o 3 o i o 60 (which includes the stages of: (a) esterification of O-tryptophan in methanol and thionyl chloride with obtaining O-tryptophan methyl ester hydrochloride; 65 (c) reaction of O-tryptophan methyl ester hydrochloride with piperonal in boiling isopropyl alcohol with obtaining cis-1-(1,3-benzodioxol-5-yl)-2,3,4,9 methyl ester -tetrahydro-1H-pyridoyl3,4-indole-3-carboxylic acid; (c) reaction of the product from stage (B) with chloroacetyl chloride and triethylamine to obtain cis-1-(1,3-benzodioxo-5-yl) methyl ester )-2,3,4,9-tetrahydro-1H-pyridoyl3,4-indole-3-carboxylic acid; and (a) reaction of the product from step (c) with methylamine to give the compound. Official Bulletin of Industrial Property. Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 5 25.04.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s o (22) so s s m. shi s ;» -I (ee) (ee) o 50 iChe) F) ime) 60 b5