Methods of producing oxazolidinones and compositions containing same

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing compounds of formula where R1a and R1b are selected from H and F and one of R1a and R1b is F, Het is tetrazolyl, optionally substituted with methyl, R2 is selected from benzyl and C1-C6 alkyl, optionally substituted with a halogen or C1-C4 alkyloxy. The present method includes combining compounds and where X is selected from Cl, Br, I and trifluoromethanesulphonate, Y is selected from BF3 and BR3R4, R3 and R4 are selected from OH, C1-C6monoalcohols and C1-C6diatomic alcohols, or where R3 and R4 together with B, to which they are attached, form a cyclic boronate optionally substituted with methyl.

EFFECT: obtaining oxazolidinones.

22 cl, 10 ex, 1 tbl

 

DESCRIPTION of the prior art

[0001] the Oxazolidinone find wide application as pharmaceutical agents for the treatment and prevention of such diseases as bacterial infections and atherosclerosis. The value of these compounds stimulates the search for effective methods of their synthesis, such as described in US 20070049759 reaction cross-combination of copper containing catalysts.

US 20070155798, which is reproduced here for reference in its entirety, discloses a potent antibacterial oxazolidinone containing substituted pyridyl phenyl fragments. Originally these pieces were introduced synthetically by the reaction of a combination in the presence of tin compounds, however, due to the toxicity of the latter, their use in pharmaceutical synthesis is undesirable. Thus, there is a need for synthetic methods of obtaining substituted (pyridinyl)phenyl oxazolidinone without the use of tin-containing reagents.

The scope of the invention

[0002] the New methods are useful for obtaining oxazolidinone-containing compounds.

A BRIEF SUMMARY of the INVENTION

[0003] a Method of synthesizing compounds of structural formula

where

R represents H,

R1a and R1b independently you�wound from the group consisting of H and F, provided that at least one of R1a and R1b represents F,

Het represents an optionally substituted five - or six-membered heterocycle containing at least one of the atoms N, O or S,

the method comprises treating compounds having the structural formula

where R2selected from the group consisting of optionally substituted benzyl and optionally substituted C1-C6of alkyl, strong base, or a lithium organic salt followed by the addition of glycidyl of butyrate to the resulting anion under conditions to obtain

.

[0004] In some aspects, the processing step is carried out in the presence of compounds that facilitate the reaction, for example, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.

[0005] In some embodiments, the method includes the additional step of interaction

with POCl3, POCl(OBn)2or P(N-iPr2)(O-tBu)2the conditions for receiving

where R' is PO(OH)2.

[0006] the Method may also include processing the compounds of structural formula

where R' is PO(OH)2the grounds in the condition�ies to obtain compounds of structural formula

where R" is a pharmaceutically acceptable salt, PO(OH)2. In some aspects, the base is a sodium containing base. In some aspects, R" represents a PO3Na2.

[0007] a Separate method of obtaining intermediate or secondary stage, carried out to the stages mentioned above, involves the reaction of a combination of the first intermediate of structural formula

where X is a leaving group selected from Cl, Br, I or triftormetilfullerenov, with a second intermediate of structural formula

where Y is selected from the group consisting of ZnCl, BF3and BR3R4where R3and R4independently selected from the group consisting of HE, and optionally substituted C1-C6mono and dihydric alcohols, and wherein R3and R4together can form a ring under conditions to produce compound of structural formula

.

[0008] In some aspects, the combination reaction is carried out in the presence of a palladium complex, such as a phosphine ligand, associated with palladium, for example, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0) or Pd2(dba)3(Tris(dibenzylideneacetone)dipalladium(0.

[0009] a Separate method of obtaining intermediate or additional stage is carried out until the stage of the combinations specified above, includes

a) treatment of arylhalides structural formula 5A

where X1represents a leaving group, with a strong base, such as n-butyl lithium and then the interaction of the obtained anion with ether trialkylborane acid under conditions to obtain

; or

b) treatment of arylhalides structural formula 5a palladium catalyst, such as PdCl2(dppf)2bis((diphenylphosphino)ferrocene-palladium dichloride and definatelty the ether ziborovoy acid under conditions to obtain

.

[0010] In some embodiments, Y is selected from the group consisting of IN(OH)2, BF3and

.

[0011] In some embodiments, Het is selected from the group consisting of optionally substituted pyrrole, furan, piperazine, piperidine, imidazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, pyrazole, pyrrolidine, oxazole, isoxazole, oxadiazole, pyridine, pyrimidine, thiazole or pyrazine, such as optionally substituted tetryzoline group, for example, 2-methyl-tetrazol-5-yl.

[0012] In some embodiments, and�gaining method also includes processing the compounds of structural formula

glycidyl ether, such as glycidyl butyrate.In some aspects glycidyl ether has the R stereochemistry, such as R-(-)-glycidyl butyrate. This stage of processing may be carried out in the presence hexamethyldisilazide.

[0013] the Compounds obtained by the method described here, include the

,

,

and

[0014] In some embodiments, the compound has the structural formula:

where;

R1a and R1b is independently selected from the group consisting of H and F, provided that at least one of R1a and R1b represents F,

R2selected from the group consisting of optionally substituted benzyl and optionally substituted C1-C6alkyl, and

Het represents an optionally substituted five - or six-membered heterocycle containing at least one of the atoms N, O or S.

[0015] In some embodiments, the compound has the following structural formula:

where

R1a and R1b is independently selected from the group consisting of H and F, provided that at least one of R1a and R1b represents F,

R2 selected from the group consisting of optionally substituted benzyl and optionally substituted C1-C6alkyl, and

Y is selected from the group consisting of ZnCl, BF3and BR3R4where R3and R4independently selected from the group consisting of HE, and optionally substituted C1-C6mono and dihydric alcohols, and wherein R3and R4together can form a ring.

[0016] In some aspects, the composition comprises a compound described herein and obtained in accordance with the method described here, and dimer having the following structural formula or a pharmaceutically acceptable salt of the dimer.

where R1a and R1b are independently selected from H and F, provided that at least one of R1a and R1b represents F,

Het represents an optionally substituted five - or six-membered heterocycle containing at least one of the atoms N, O or S.

[0017] In some aspects, R1a represents the F and R1b represents N and Het represents a 2-methyl-tetrazol-5-yl.

[0018] in embodiments, the composition comprises a compound described herein and obtained in accordance with the process presented above, and there are no songs in the tin impurities.

<> DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION.

[0019] the methods of synthesis of substituted (pyridyl)phenyloxazolidine

where Het represents an optionally substituted five - or six-membered heterocycle containing at least one of the atoms N, O or S, for example, optionally replaced fragments tetrazolyl, oxazolyl, triazolyl, oxadiazolyl, thiazolyl and isoxazolyl. In some aspects, Het represents optionally substituted tetrazolyl, for example, 2-methyl-tetrazol-5-yl.

R1a and R1b is independently selected from H and F, provided that at least one of R1a and R1b represents F,

R is selected from H, PO(OH)2and pharmaceutically acceptable salts RHO(OH)2.

[0020] At least, unless otherwise noted, technical terms take their ordinary meaning, in particular presented in the Dictionary of Scientific and technical Terms McGraw-Hill, 6th edition (McGraw-Hill Dictionary of Scientific and Technical Terms, 6thedition).

[0021] In some embodiments, the methods include obtaining substituted N-(pyridinyl)relaxationof as follows:

[0022] Scheme 1

[0023] In Scheme 1, the first intermediate (4) interacts in Rxn 1 with the second intermediate (6) with more inform�m product compound (7), which is then treated in Rxn 2 glycidyl ether to produce a compound (1).

Scheme 2

[0024] In Scheme 2, intermediate 6 can be obtained by treatment of intermediate 5a 2 equivalents of a strong base, for example, C1-C6alkyl lithium, in particular, n-butyl lithium or t-butyl lithium, followed by addition of the corresponding electrophile, such as ZnCl2or(OR)3for example , C1-C6dialkoxybenzene, in particular triisopropyl of boronate. Treatment water obtained reaction mixture, where elektrofil is dialkoxybenzene ether, gives Bronevoy acid 6a. If dianion 5A to handle cyclic boronate ether, a cyclic ether Bronevoy acid 6b can be selected. If elektrofil is a ZnCl2then the zinc reagent 6 can be selected. Alternative boranova acid can be obtained according to the procedure of the boriding Meury (Miyaura Top. Curr. Chem. 2002, 219, range 11 to 59). In this reaction, the diester ziborovoy acid, such as definecolor the ether ziborovoy acid joins arylhalides (5A), using a palladium catalyst. The ester Bronevoy acid 6b can be hydrolysed with an aqueous solution of acid to obtain Bronevoy acid 6A. Also derived tricorporate 6d can be obtained from Bronevoy acid 6A �the processing of KF and/or KHF 2.

[0025] In the above schemes, X represents a leaving group. In some embodiments, X is selected from Cl, Br, I and triptorelin sulfonate.

[0026] X1represents a leaving group. In some embodiments, X is a halogen, such as Cl, Br or I.

[0027] Het is an optionally substituted five - or six-membered heterocycle containing at least one of the atoms N, O or S, including optionally substituted pyrrole, furan, piperazine, piperidine, imidazole, 1,2,4-triazole, tetrazole, pyrazole, pyrrolidine, oxazole, isoxazol, oxadiazole, pyridine, pyrimidine, thiazole or pyrazine. In some aspects, Het represents optionally substituted tetrazolyl or 2-methyl-tetrazol-5-yl. In some embodiments, Het is unsubstituted or has 1 or 2 substituent.

[0028] R1a and R1b is independently selected from H and F, provided that at least one of R1a and R1b represents F;

Y is selected from ZnCl, BF3and BR3R4where R3and R4independently selected from HE, and optionally substituted C1-C6mono and dihydric alcohols, and wherein R3and R4together can form a ring. In some embodiments, Y is a fun� IN(OH) 2or pinacolborane, namely,,

such as IN(OH)2. C1-C6mono and dihydric alcohols may be optionally substituted C1-C4the alkyl. The reaction Negishi (Negishi) can be carried out to obtain the compounds where Y is a ZnCl (Negishi: Chem. Ind. 1988, 33, 381-407).

[0029] In some embodiments, Het can be unsubstituted or optionally substituted by one or more substituents, for example, independently selected from the group consisting of halogen, hydroxy, amino, C1-4alkylamino, di(C1-4alkyl)amino, cyano, nitro, C1-4alkyl, C1-4alkoxy, C1-4of acyl, C1-4thioalkyl, C1-4DIOXOLANYL substituted With halogen1-4of alkyl and substituted With halogen1-4alkoxy.

[0030] in Scheme 1, R2represents an optionally substituted benzyl or optionally substituted C1-C6alkyl. In some embodiments, benzyl and C1-C6the alkyl are unsubstituted or independently from each other optionally substituted by halogen or alkoxy, such as C1-C4alkyloxy. In some embodiments, R2represents benzyl, and R represents N.

[0031] Suitable catalysts for the reaction cross-combined�I Rxn 1 are palladium complexes, for example, palladium phosphine complexes or dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0) and obtained in situ from Pd2(dba)3(dba = benzylideneacetone) in the presence of DCS3(tricyclohexylphosphine). The ratio of Pd complex to the substrate is not critical for the reaction, but about 1 molar % of the complex (or 4, or 6) is acceptable.

[0032] Cyclization with getting oxazolidinone ring is in Rxn 2 by treating 7 with a strong base, for example, hexamethyldisilazide lithium or a lithium organic salt, for example, n-butyl lithium in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), followed by the addition of a glycidyl ether, such as, R-(-)-glycidyl ether, in particular butyrate to produce a compound 1 (R = H). In one embodiment of the invention is used hexamethyldisilazide lithium as base and tetrahydrofuran (THF) as the solvent with DMPU present to facilitate the reaction, at a temperature between about 0°C and 30°C, and stoichiometry 7 to pillowa ether of about 1:1 on a molar basis.

[0033] If desired, the compound 1 (R = H) can be converted to the dihydrogen phosphate, for example, by treatment with POCl3in accordance with well-known method�mi. For example, compound 1 (R = H) may be treated with POCl3followed by quenching with water or a two-stage process that uses a secure form of oxychloride of phosphorus, such as: POCl(OBn)2where in the first stage is obtained phosphate triavir, and in a second step remove the protective group (e.g. H2/Pd-C to remove the benzyl groups of the ether). Alternative, 5-gidroximetil-oxazolidinone can be processed P(N-iPr2)(O-tBu)2followed by oxidation of the oxidizing reagent such as mCPBA (m-chloroperoxybenzoic acid) followed by treatment with base or aqueous acid to remove groups of the tert-butyl ether.

[0034] the resulting dihydrogen phosphate 1 (R = PO(OH)2) can be further converted into a pharmaceutically acceptable salt, such as disodium salt of compound 1 (R = PO(O)22Na) by reaction with NaOMe or other suitable sodium-containing base.

[0035] the experts in the field of medicinal chemistry understands that the term "pharmaceutically acceptable salt" refers to salts formed corresponding biocompatible cations and/or anions. Such cations include metal elements such as sodium, lithium, potassium, magnesium, aluminum, calcium, zinc and Quaternary cations of organic nitrogen bases, for example, N,N'-dibenziletilendiaminom, chloroprocaine, Ho�Jn, diethanolamine, Ethylenediamine, N-methylglucamine and salts of procaine. Such anions include inorganic acids such as hydrochloric, bromatology, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmitic acid, malonic, hydroxymaleimide, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluensulfonic acid, methanesulfonate, naphthalen-2-sulfonic acid, benzolsulfonat, oximately, itestosterone, Apple, Sterol, tannin and the like acid.

[0036] the Oxazolidinone, obtained by the method described here differ from the oxazolidinone synthesized according to the method presented in US 20070155798. The oxazolidinone obtained in accordance with this process, do not contain impurities because the tin-containing reagents are not used. Additionally, in some embodiments, the formation of dimer as a byproduct, an impurity, such as phosphorus oxychloride (POCl3) is used to transform a hydroxyl dihydrogen phosphate. In particular, the molecule of TR-701 interacts with a molecule of phosphate ester containing at least one P-Cl bond to obtain a dimer, having, for example, the following formula.

[0037] the Amount of impurities is determined by a certain detection limit, which is less than 10% by weight of the composition, and in some cases less 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%, for example, less than 0.1% or 0.05%. Thus, in some embodiments, the compositions contain oxazolidinone obtained in accordance with the process presented here, and dimer. In some embodiments, the compositions contain oxazolidinone without any tin - containing impurities.

[0038] the Oxazolidinone obtained in accordance with the methods provided herein are useful as medicaments and in particular to delay the growth of bacteria, as disclosed in detail in US 20070155798, which is presented here for reference in its entirety.

[0039] the Terms "approximately", "about" and "mostly", as used here, represent an amount close to the stated amount, which is still the desired function or achieves a desired result. For example, the terms "approximately", "about" and "generally" may refer to a number that is less than 10%, less than 5%, less than 1%, less than 0.1% and less than 0.01% of the claimed amount.

Examples

[0040] a Practical embodiment of the method according to the invention is illustrated by the following example which does not limit the amount of Picasa�rd.

Experimental and Analytical Data

[0041] the Reagents were purchased from commercial sources and were used as received. Range of proton magnetic resonance was obtained on a Bruker AVANCE 300 at 300 MHz spectrometer or AVANCE 500 at 500 MHz with tetramethylsilane as a source for internal comparison. Range carbon nuclear magnetic resonance was obtained on the spectrometer Broker AVANCE 500 at 125 MHz for comparing the selected peak of the solvent. Range phosphorus nuclear magnetic resonance was obtained on a Bruker AVANCE 500 at 202 MHz with phosphoric acid for comparison. Spectrum of nuclear magnetic resonance of fluorine was obtained on a Bruker AVANCE 300 at 282 MHz. The mass spectrum was obtained on a spectrometer Finnigan AQA with ionization elektrorazpredelenie. Thin layer chromatography (TLC) was performed using Whatman No. 4500-101 (Diamond No. MK.6F silica gel 60 Å) of the plate. The manifestation of TLC plates was carried out using UV light (254 nm) or by staining with potassium permanganate. HPLC analysis was carried out on a Varian Prostar HPLC, equipped with a Waters SunFire C18 column (150×4.60 mm, 3.5 μm) or Waters XBridge C18 column (75 mm × 4.6 mm × 2.5 μm), using the methods presented below, with the detector at the specified wavelength.

[0042] a Method (Waters SunFire C18 Column)

Time (min)Speed (ml/min)%%
0.01.098.02.0
15.01.05.095.0
25.01.05.095.0
27.01.098.02.0
30.01.098.02.0

A = water with 0.05% (by volume) trifluoroacetic acid

B = acetonitrile with 0.05% (by volume) trifluoroacetic acid

Wavelength = 254 nm

[0043] Method (Waters XBridge C18 Column)

Time (min)Speed (ml/min)%%
0.01.098.02.0
15.01.0 95.0
25.01.05.095.0
27.01.098.02.0
30.01.098.02.0

A = 87% 25 mm solution of ammonium bicarbonate in water/13% acetonitrile

B = acetonitrile

Wavelength = 254 nm

[0044] Method (Waters SunFire C18 Column)

Time (min)Speed (ml/min)%%
0.01.098.02.0
15.01.05.095.0
25.01.05.095.0
27.01.098.02.0
30.01.02.0

A = water with 0.05% (by volume) trifluoroacetic acid

B = acetonitrile with 0.05% (by volume) trifluoroacetic acid

Wavelength = 240 nm.

Example 1: Obtain 5-bromo-2-(2H-tetrazol-5-yl)pyridine, 3

[0045] In a 22-liter, three-neck, round bottom flask equipped with a top stirrer, inlet/outlet for nitrogen, thermocouple and heating mantle was loaded with stirring 5-bromo-2-cyanopyridine (799 g, 4.37 mol, 1 equivalent), N,N-dimethylformamide (6.4 l, 8 volumes), ammonium chloride (350.3 g, 6.55 mol, 1.5 equivalent) and sodium azide (425.7 g, 6.55 mol, 1.5 equivalent). The internal temperature in the reactor was set at 85°C (target temperature 90°C). The set temperature was reached 45 minutes later, then the reaction mixture spontaneously heated to 94°C for 40 minutes. After 1 hour the reaction was completed, HPLC analysis showed complete consumption of the starting materials with the content of 76.7% (AUC - area under the curve) tetrazol ammonium salts. The mixture was cooled and filtered at room temperature. The reactor and the wet precipitate was washed with 2-propanol (3.2 l, 4 volumes) and dried under high vacuum at room temperature to obtain tetrazole ammonium salt in the form of a white solid precipitate (847.9 g, 80% yield, 89.9% AUC). Differential scanning calorimetric experi�ment was held at tetrazol ammonium salts to assess its thermal stability. The salt melted at about 228°C, and the energy collapse occurred at approximately 270°C.

Example 2: Obtain 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine, 4 (X = Br)

[0046] In a 22-liter, chetyrehosnuju, round-bottomed flask equipped with a top stirrer, inlet/outlet for nitrogen, and a thermocouple and placed in an ice/salt bath was loaded with stirring tetrazol ammonium salt (835.0 g, 3.44 mol, 1 equiv), tetrahydrofuran (7.5 l, 9 volumes), N,N-dimethylformamide (2.5 l, 3 volume) and powder sodium hydroxide (343.5 g, 8.59 mol, 2.5 equiv). The reactor was left to reach the value of internal temperature is 12°With, then itmean (1.22 kg, 8.59 mol, 2.5 equivalents) was added dropwise over 50 minutes, maintaining the reaction temperature below 20°C. in 20 minutes after the addition, the rapid increase of temperature, the addition was stopped and the reaction continued to spontaneous heating at 15-20°C for ten minutes. Add the rest of the amount was completed at a constant temperature (18°C). After completion of the addition, the ice bath with salt was removed, and the reactor was equipped with a water condenser and a heating mantle. The internal temperature of the reactor was raised to 40°C, however, the reaction mixture continued to spontaneous heating to 48°C. 6 hours later HPLC analysis showing� complete consumption of starting material. The reaction mixture was cooled to room temperature overnight for convenience. THF was removed by distillation and water (8.35 l, 10 volumes) was added to the reactor. The mixture was stirred for 30 minutes and filtered by vacuum filtration, the reactor and the residue on the filter were washed with water (4.2 l, 5 volumes) to give crude compound 4/N1 isomeric mixture in a solid peach color (500.7 g, 61% yield, 3.85:1 4: 1).

[0047] the Solids (500.7 g) were dissolved in CH2Cl2(2.5 l, 5 volumes), then 6N aqueous HCl (7.5 l, 15 volumes) was added. Two-phase mixture was stirred and the layers separated. At this point, the desired product was in the aqueous layer with HCl. Layer CH2Cl2was washed with 6N aqueous HCl (4.5 l, 3×3 volume), as long as the contents of the connection 4 has not reached the value <5% AUC HPLC analysis. The combined extracts 6N HCl were moved into the reactor, and the pH was brought to 10.6 with 50% aqueous NaOH (~3.2 l), while maintaining the internal temperature below 40°C. the Solids were isolated by vacuum filtration, the reactor and the filter cake was washed with water (1 l, 2 volumes) to give crude compound 4 as a yellow/orange solid (322.4 g, extraction 64%, yield 39%, 93.5% AUC 4, 4.1% of the AUC of the N-1 isomer), as confirmed by HPLC and1H NMR analysis.

[0048] the Crude link� 4 was further purified isopropylacetate (IPAc) suspension (1.61 l, 5 volumes) at 50°C for 1 hour. Upon cooling to room temperature, the solids were filtered, and the filter cake was washed with additional IPAc (500 ml, 1.6 volumes) to give purified compound 4 as a white/yellow solid (275.5 g, extraction of 85%, a yield of 33%, 98.2% AUC), which is confirmed by HPLC and1H NMR analysis. Differential scanning calorimetry of compound 4 showed the decay heat at about 245°C.

Example 3: preparation of benzyl (4-bromo-3-fluorophenyl)carbamate, 5

[0049] a 12-liter, three-neck, round bottom flask equipped with a top stirrer, inlet/outlet for nitrogen, addition funnel and thermocouple were loaded with 4-bromo-3-ftoranila (800.0 g, 4.21 mol, Matrix lot # Q13H), THF (6.4 l, 8 volumes) and solid sodium bicarbonate (530.5 g, 6.32 mol, 1.5 EQ). In the dropping funnel was loaded benzyl chloroformiate (861.9 g, 5.05 mol, 1.2 equiv) was dropwise added to the reactor 70 minutes. The reactor temperature was maintained below 20°C using ice bath. The mixture was maintained for 1 hour, HPLC analysis showed the reaction completed. The reaction mixture was transferred to a 22 l flask and the mixture was diluted with water (6.4 l, 8 volumes). Two-phase mixture was heated to 50°C and maintained at this temperature for 16 hours to extinguish the excess of benzyl chloroformate. CME�ü was transferred hot to a separating funnel to remove the lower aqueous layer. Observed the formation on the surface of solid particles are passed into the aqueous layer. THF layer was filtered through Whatman filter paper #1 to remove some of the particles, and the mixture was moved into a 22 l flask fitted for distillation. Heptane was added in portions and distilled to remove THF. (Please note that it is better to ward off a certain amount of THF prior to the addition of heptane). Only 26.5 l of heptane was added, and was collected in 25 l of distillate. At this point the temperature of the flask reached 97.7°C and the distillate obtained is further contained 0.9% THF1H NMR analysis. The mixture was cooled to room temperature and viscous white suspension was filtered. The filter cake was washed with heptane (4 l). The product was dried in a vacuum oven at 40°C with obtaining 1257.0 g of intermediate compound 5 (92% yield). HPLC analysis showed the content of 98.3% (AUC).

Example 4: Obtain 4-(benzyloxycarbonylamino)-2-ftorhinolonovy acid 6 (R1a= F, R1b= N, R2= Bz, Y = B(OH)2)

[0050] 22-liter, three-neck round bottom flask equipped with a top stirrer, a temperature sensor, 2-l addition funnel and an adapter for nitrogen supply. Into the flask was loaded intermediate 5 (1.00 kg, 3.08 mol, AMRI lot # CAR-L-18(3)), THF (10 l, 10 volumes) and triisopropyl Borat (638.2 g, 3.39 mol, 1.1 EQ). The mixture was stirred and cooled�was given to -72°C in a bath of dry ice/acetone. In the dropping funnel were loaded with 2.5 M n-butyllithium (2.59 l, 6.48 mol, 2.1 EQ) was added dropwise to the reaction mixture for approximately 2 hours. The maximum temperature during the addition was -65°C. progress of the reaction was monitored using HPLC analysis. The acetone was removed from the cooling bath and the reaction was tempered 20% aqueous solution of ammonium chloride (5.5 l), which resulted in increasing the reaction temperature to -1°C. the Phases were separated and the THF layer was evaporated to dryness. The crude product was re-suspended in a mixture of 3:2 ethanol/water (10 l, 10 volumes) at room temperature for 1 hour. The mixture was filtered and the filter cake was washed with a mixture of 3:2 ethanol/water (2×2 l). The product was dried in a vacuum oven at room temperature with obtaining 592.8 g of intermediate 6 (66% yield), which was 89.8% (AUC) by HPLC analysis (Method A). After the19F NMR and HPLC analysis at 240 nm was found that the resulting material contains an admixture (Method C).

[0051] Re-suspending the resulting mixture in 2.5 volumes of CH2Cl2instead of the mixture of 3:2 ethanol/water, allowed to get rid of impurities des-bromo by-product, previously identified by19F the NMR SPECTA and HPLC at 240 nm.

Example 5: Obtain benzyl (4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)carbamate. 7 (Het = 2-methyltetrazol-5-yl, R1a = F, R1b = H, 2=Bz) (Ref.: JAS-G-96) (Ref.: CAR-L-93, DUG-AF-202)

[0052] a 5-liter, three-neck round bottom flask was loaded with compound 4 (200.0 g, 0.833 mol), followed by adding 1,4-dioxane (3 l, 15 volumes). The crude product 6 (361.2 g, 1.249 mol, 1.5 equivalents), Pd2(dba)3(11.44 g, 0.0125 g, 0.015 equivalent) and DCS3(tricyclohexylphosphine) (7.0 g, 0.025 mol, 0.03 equivalent) was loaded and degassed with nitrogen for 30 minutes. The solution To2CO3(195.7 g, 1.7 equivalent) in water (800 ml, 4 volumes) was added, the reaction mixture was heated to 70°C. the Reaction was completed 1 h later with 0.5% (area under the curve) the remainder of the compound 4. The reaction mixture was cooled to 50°C and Darco G-60 (40 g, 0.2 by weight) was added, the mixture was stirred for 30 minutes. Celite 545 (40 g, 0.2 by weight) was loaded, and then the reaction mixture was filtered through Celite 545 (100 g, 0.5 by weight), hydrated with water (300 ml). Hot filtration through Celite caused the precipitation of the product. Tetrahydrofuran (1.2 l, 6 volumes) and brine (600 ml, 3 volumes) were added and the product was re-dissolved at room temperature. The distribution of phases was carried out carefully (Vmax = 28 volumes). Dioxane was concentrated and ethanol (1 l, 5 volumes) was added and concentrated. Then the product was re-suspended in a mixture of ethanol: water (4:1, 2 l, 10 volumes) at 70°C, cooled to room temperature for 3 hours�, filtered and washed with ethanol (2×400 ml). Compound 7 was selected from 87% yield (292.6 g) with a purity of 97.7% (AUC) by HPLC analysis.1H NMR and19F NMR showed the presence of a single connection. Pd analysis showed that 135 MD Pd was present in the product.

[0053] Intermediate 7 was recrystallized from ethyl acetate to reduce the level of palladium. Intermediate 7 (130 g) and ethyl acetate (3.9 l, 30 volumes) were loaded with 5-liter, three-neck round bottom flask. The suspension was heated to 75°C, at this temperature, the solids were dissolved. The hot solution was filtered to remove the palladium mobiles (from 0.2 - to 0.45-µ filters are the best), and returned in a clean 5-liter flask. A solution of ethyl acetate was subjected to distillation at atmospheric pressure for Stripping 2.2 l of ethyl acetate (boiling point 77-78°C). The solution was cooled to 22°C, and the resulting suspension was filtered. The flask and the filter cake was washed with ethyl acetate (3×130 ml). The purified intermediate 7 was dried in a vacuum oven at 50°C To produce 110.5 g of intermediate 7 (85% recovery). HPLC analysis of the purified intermediate 7 showed the content of 98.5% (AUC). Palladium levels in purified product was 6 MD. The mother liquor was evaporated to obtain 18 g of the crude product (14% yield, MD 2254 Pd).

Example 6: preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)�of iridin-5-yl)-3-fluorophenyl)-5-gidroximetil of oxazolidin-2-it, 1 (R = H), also referred to as "TR-700"

[0054] a 5-liter, three-neck, round-bottom flask was equipped with a top stirrer, a thermocouple and a 500 ml addition funnel and an adapter for nitrogen supply. The flask was dried with a hot gun in a stream of nitrogen to an internal temperature of 60°C. Into the flask was loaded intermediate 7 (110.0 g, 0.272 mol, AMRI party # DUG-AF-202(1)) and anhydrous THF (2.2 l, 20 volumes). The suspension was stirred, and turned out the light green solution. Drip funnel with 1.0 M lithium hexamethyldisilazide (299 ml, 0.286 mol, 1.05 equivalent). A solution of LiHMDS was added dropwise to a solution of intermediate 7 in about 25 minutes. The solution acquired a red color. The solution was stirred one hour at room temperature and then 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (34.9 g, 0.272 mol, 1 equivalent) was added, the mixture turned into a yellow suspension. Reaction mass was cooled in an ice bath to 5.7°C.-(-)-Glycidyl butyrate (41.25 g, 0.286 mol, 1.05 equivalent) was added in one portion. The mixture was stirred in an ice bath for 0.5 hours, then was heated to room temperature and was stirred overnight. At this point the reaction mixture became a suspension of a bronze color, and 15 hours later HPLC analysis showed that the mixture contains approximately 87% of TR-700, 1.6% intermediate 7, and about 7% of the butyrate ester connect�of TR-700. A small amount of sodium methoxide in methanol (11 ml, 0.1 volume) was added, and the mixture was stirred for a further 1 hour to remove residual ether. HPLC analysis at this point of the reaction showed that the mixture contains approximately 90.7% of TR-700 and 0.2% butyrate ester. The mixture was quenched by adding 10% by weight solution of ammonium chloride (1.1 l, 10 volumes). Moderate exothermic effect from 22°C to 25°C was observed after the addition of aqueous ammonium chloride. Two-phase mixture was subjected to distillation at a temperature of the reactor at 70°C (atmospheric pressure) to remove approximately 2.2 l of THF. Viscous suspension was obtained, which was diluted with water (550 ml, 5 volumes). The suspension was cooled to room temperature (23.6°C) and filtered. The filter cake was washed with water (1.1 l, 10 volumes) and methanol (550 ml, 5 volumes), to obtain TR-700 in the form of a white solid. The wet precipitate was dried overnight in a vacuum oven at 50°C to obtain 89.7 g of TR-700 (89% yield), which accounted for 97.8% (AUC) by HPLC analysis. The connection of TR-700 was further purified by repeated suspendirovanie 2.7 l (30 volumes) mixture of 4:1 methanol/water at 70°C, cooling to 23°C, filtration and washing with methanol (180 ml). This procedure allowed us to remove the impurity excessively alkilirovanny product. Purified TR-700 was isolated in 96% yield (85% of�schy output), and cleanliness has improved to 98.4% (AUC) by HPLC analysis. The palladium content was 10 ppm.

Example 7: preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-gidroximetil of oxazolidin-2-one dihydro phosphate 1 (R = PO(OH)2also referred to as "TR-701FA"

[0055] a 5-liter, round-bottomed flask, equipped with a jacket cooling circuit was equipped with overhead mechanical stirrer, addition funnel, thermocouple, and inlet for nitrogen. Into the flask was loaded connection of TR-700 (70.0 g, 0.189 mol), THF (1.4 l, 20 volumes) and triethylamine (58.2 g, 0.575 mol, 3 equiv). The suspension was stirred and the temperature of the jacket was set at 0°C. the dropping funnel was loaded with phosphorus oxychloride (87.0 g, 0.567 mol, 3 equivalents) in THF (70 ml, 1 volume). Once the internal temperature reached 1°C, a solution of POCl3was added dropwise over 44 minutes. The maximum internal temperature was 2.2°C. the Mixture was stirred for 3 hours at 1-2°C, at this point HPLC analysis showed that remained 0.5% of compound TR-700. A 5-liter, three-neck round bottom flask equipped with a diaphragm pump Teflon, was filled with water (1.4 l, 20 volumes), it was cooled to 3.8°C in an ice bath with salt. The reaction mixture was pumped for damping under cold water for 1 hour. The maximum temperature in the process of clearing reached 11.9°C. the Reactor � pumping line were washed with water (~210 ml) in a vessel for damping. The resulting yellow suspension was stirred overnight. The suspension was filtered through Whatman paper, and the filter cake was washed with water (700 ml, 10 volumes) and methanol (700 ml, 10 volumes). The product was dried at room temperature in a vacuum oven until constant weight. The crude yield TR-701FA amounted to 81.6 g (96%), purity by HPLC analysis (Method B) - 95.3% (AUC).

Example 8: preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-gidroximetil of oxazolidin-2-phosphate, disodium salt 1 (R = RHO32Na), also referred to as "TR-701"

[0056] the Crude compound 1 (R=PO(OH)2) (60.0 g, 0.133 mol) was loaded into a 2-liter reactor. Methanol (720 ml, 12 volumes) was added, and the suspension was mixed at room temperature. 25% sodium methoxide in methanol (86.1 g, 0.398 mol, 3 equivalents) was added dropwise over 13 minutes. Reaction temperature increased from 20.4°C to 26.8°C With addition of sodium methoxide. The suspension was stirred one hour at room temperature and then was filtered. The reactor and the filter cake was washed with methanol (300 ml, 5 volumes) and acetone (300 ml, 5 volumes). The product was dried in a vacuum oven at 50-60°C To produce 65.3 g of untreated TR-701 (99% yield). The crude product was dissolved in water (653 ml, 10 volumes) to obtain a solution of a straw color. The solution was mixed with coal Drco G-60 (3.3 g, 0.05 by weight) at room temperature for 30 minutes. the pH of the slurry was 7.2, so 5-10 ml of 2 N NaOH was added to increase the pH to 11. The suspension was filtered through Celite 545 (65 g moistened with water). A small amount of coal has passed through the filter. The filtrate was re-filtered through 0.45-µ filter, but some coal has passed again. The filtrate was added dropwise to acetone (2.6 l, 40 volumes) and the resulting suspension was stirred overnight for convenience. The suspension was filtered, diluted with acetone (650 ml), and dried in a vacuum oven at 50°C To produce 46.9 g of compound 1 (R = PO2Na) (71% yield) of gray. HPLC purity of this material amounted to 99.0% (AUC), but because it was grey, it was re-dissolved in water (470 ml). the pH of the aqueous solution was equal to 9.6, so the sodium hydroxide solution was added to increase the pH to 10. The solution was filtered through 0.45-µ filter for discoloration. The filtrate was added dropwise to acetone (1.88 l). The white suspension was filtered and washed with acetone (470 ml). After drying, the product weight TR-701 amounted to 43.2 g (66% yield). HPLC purity (Method B) amounted to 99.6% (AUC). Other types of analyses carried out with this party of compound 1 (R = PO2Na), shown in Table 1.

Example 9: Obtaining purified R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-and�)-3-fluorophenyl)-5-gidroximetil of oxazolidin-2-dihydrogen phosphate, 1 (R = PO(OH)2)

[0057] a 3-liter round bottom flask was loaded crude compound 1 (R = PO(OH)2) (99.8 g, 0.222 mol, AMRI party # AKS) and water (1 l, 10 volumes). the pH of this suspension was 2.05. Fresh 1 M sodium hydroxide solution was obtained by dilution 50.9% solution of sodium hydroxide (39.3 g, 0.50 mol) in a total volume of 0.5 l of water. 1 M sodium hydroxide solution (444 ml, 0.444 mol, 2 equivalents) was added dropwise to a fresh suspension of the free acid. At pH 5.7, the solids dissolved, despite the fact that less than half of the sodium hydroxide solution was added. At the end of the addition the pH amounted to 8.57. Charcoal Darco G-60 (5.1 g, 0.05 by weight) was added to the solution, and the mixture was stirred for 1 hour at room temperature. The suspension was filtered through Whatman filter paper #1 to remove the bulk of the coal, and then through a 0.45-µ filter to remove small particles. The straw-colored filtrate was dropwise added to a 12 liter round bottom flask containing acetone (4 l, 40 volumes). The resulting suspension was stirred for one hour at room temperature, filtered and washed with acetone (500 ml, 5 volumes). Wet sediment was transferred to a 3 liter round bottom flask and left to dry in a nitrogen atmosphere overnight.

[0058] the Disodium salt of compound 1 (R = PO22Na) was re-dissolved� in water (1 l, 10 volumes) and then filtered through filter paper Whatman #1, while in the solution was observed black specks. The filtrate was diluted with THF (1 l, 10 volumes). the pH of the aqueous solution of THF amounted to 9.57. Freshly prepared 2 M hydrochloric acid solution (222 ml, 0.444 mol, 2 equivalents) was added dropwise to bring the pH to a value of 1.34. The product is not precipitated until until approximately 170 ml of 2 M HCl solution was added. The yellow suspension was filtered, washed with water (500 ml, 5 volumes) and methanol (500 ml, 5 volumes). The precipitate on the filter is cracked due to drying out, so it was aligned before adding solvent. The product was dried in a vacuum oven at 60°C for 19.5 hours, 79.3 grams of compound 1 (R = P(OH)2) (80% yield). HPLC analysis (Method B): 99.5% (AUC) tR=5.6 min.1H and31P NMR spectra were consistent with the claimed structure. The level of residual THF by NMR analysis was 1600 MD, and the palladium level was 11 MD. Because intensive drying is not possible to remove all THF, subsequent batches were obtained using ethanol as antibacterial (the solvent in which the product is not soluble).

Example 10: isolation of bis{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl}dihydrogenphosphate (dimer compounds 1)

[0059] the Crude �the connection 1 from example 8 was dissolved in phosphate buffer and subjected to chromatographic analysis on a Gilson preparative HPLC system. The mobile phase was a linear gradient of water and acetonitrile, at t=0 was 100% H2O, and T=20 was 100% acetonitrile. Fractions were analyzed using analytical HPLC. Fractions enriched in the Dimer, were collected to obtain a solution containing more than 60% Dimer. Further purification of the Dimer-enriched fractions was performed by the method of semi preparative HPLC. Was obtained pure dimer: exact mass (m/z 883; calculated for C34H31F2N12O11P2=883.1679 received 883.1658, Δ=2.4 MD m/z 905 calculated for C34H30F2N1O11P2Na=905.1498; received 905.1484, Δ=1.6 MD), the data confirm the formula for this connection.

Table 1
Analysis of TR-701 (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-gidroximetil of oxazolidin-2-one, 1 (R = H)
TestThe result
AppearanceFrom white to yellowish
1N NMRCorresponds to
31P NMRCorresponds to
Retention time5.18 min
The mass spectrum
HPLC purity99.6*
HPLC impurityDimer, 0.09%*
The copper content<1 MD
The palladium content1 MD
The sodium content8.34%
The water content5.5%
Specific rotation-34.9°
Powder x-ray refractionamorphous
Particle size1-300 MK

1. Method of synthesis of compounds of structural formula

in which
R1a and R1b independently from each other selected from H and F, provided that at least one of R1a and R1b represents F,
Het represents tetrazolyl, optionally substituted bromide, and
R2selected from the group consisting of benzyl and C1-C6alkyl, where benzyl and C1-C6alkyl, independently from each other are unsubstituted or substituted by halogen or C1-C4alkyloxy;
moreover, this method �concludes:
the combination of the first intermediate structure

where X is selected from the group consisting of Cl, Br, I, and triftormetilfullerenov, with the second interconnect structure

where Y is selected from the group consisting of BF3and BR3R4and R3and R4independently from each other, selected from the group consisting of HE, C1-C6of monoalcohols and C1-C6dihydric alcohols, or where R3and R4together with In to which they are attached, form an optionally substituted bromide cyclic boronate.

2. Method of synthesis of compounds of structural formula

in which
R1a and R1b independently from each other selected from H and F, provided that at least one of R1a and R1b represents F,
Y is selected from the group consisting of BF3and BR3R4and R3and R4independently from each other, selected from the group consisting of HE, C1-C6of monoalcohols and C1-C6dihydric alcohols, or where R3and R4together with In to which they are attached, form an optionally substituted bromide cyclic boronate, and
R2selected from the group consisting of benzyl and C1-C6alkyl, where benzyl and C1-C6al�Il, independently of one another, are unsubstituted or substituted by halogen or C1-C4alkyloxy;
moreover, the method includes:
a) treatment of arylhalides patterns 5A C1-C6alkyl lithium and then the reaction of the obtained anion with ether trialkylborane acid or a cyclic ester of boric acid; and the structure 5A is a:

where X' represents a halogen; or
(b) processing arylhalides patterns 5A palladium catalyst and definatelty the ether ziborovoy acid; or
c) treatment with boric acid the structure of compounds 6A KF or KHF2; and the structure 6A is a:

3. A method according to claim 2, wherein said C1-C6the alkyl lithium is n-butyllithium; or
where mentioned palladium catalyst is a PdCl2(dppf)2.

4. Method of synthesis of compounds of structural formula

where:
R2represents benzyl,
R1a represents F, a R1b represents N, and Het represents a 2-methyl-tetrazol-5-yl, including:
the combination of the first intermediate structure

wherein X is selected from the group consisting of Cl, Br, I, and triftormetilfullerenov,with the second interconnect structure

wherein Y is selected from the group consisting of IN(OH)2and pinacolborane.

5. Method of synthesis of compounds of structural formula

where
R represents H,
R1a and R1b independently from each other selected from H and F, provided that at least one of R1a and R1b represents F, and
Het represents tetrazolyl, optionally substituted bromide;
moreover, the method includes:
(a) feeding the first intermediate structure

where X is selected from the group consisting of Cl, Br, I and triftormetilfullerenov;
(b) obtaining a second intermediate structure

by processing arylhalides patterns 5A

palladium catalyst and definatelty the ether ziborovoy acid,
where
X' represents a halogen,
R2selected from the group consisting of benzyl and C1-C6alkyl, and benzyl and C1-C6alkyl, independently from each other are unsubstituted or substituted by halogen or C1-C4alkyloxy, and
Y is selected from the group consisting of BF3and BR3R4and R3and R4independently from each other, selected from the group consisting of HE, 1-C6of monoalcohols and C1-C6dihydric alcohols, or where R3and R4together with In to which they are attached, form an optionally substituted bromide cyclic boronate;
(C) a combination of the first intermediate with a second intermediate compound to obtain a mixture, which contains dissolved palladium and the connection patterns

(d) filtering the mixture to reduce the level of palladium; and
(e) treating the compound of structure

glycidyl ether in the presence hexamethyldisilazide lithium or organolithium salt.

6. A method according to claim 5, wherein the palladium catalyst is a PdCl2(dppf)2.

7. The method of claim 5, wherein the processing stage is carried out in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.

8. A method according to claim 4 or 5, wherein the combination is carried out in the presence of a palladium complex.

9. A method according to claim 8, wherein the palladium complex is a phosphine ligand bound to palladium.

10. A method according to claim 9, wherein the palladium complex is selected from the group consisting of dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) and Pd2(dba)3

11. A method according to claim 10, wherein the palladium complex is a Pd2(dba)3.

12. Method �about p. 2, and Y is selected from the group consisting of IN(OH)2, BF3and

13. A method according to claim 12, wherein Y represents B(OH)2.

14. A method according to claim 5, wherein Het represents a 2-methyl-tetrazol-5-yl.

15. A method according to claim 14, wherein X represents Br.

16. Method of synthesis of compounds of structural formula:

wherein R represents H, R1a represents F, and R1b represents N, and Het represents a 2-methyl-tetrazol-5-yl, including:
the combination of the first intermediate structure

where X is selected from the group consisting of Cl, Br, I and triftormetilfullerenov, with the second interconnect structure

where Y is selected from the group consisting of IN(OH)2and pinacolborane, with the formation of compounds of the structure:

where R2represents benzyl; and processing the connection patterns

glycidyl ether.

17. A method according to claim 16, in which the glycidyl ether is glycidyl butyrate.

18. A method according to claim 16, wherein the glycidyl ester has R-stereochemistry.

19. A method according to claim 16, wherein the glycidyl ether is a R-(-)-glycidyl butyrate.

20. A method according to claim 16, wherein R�ku connection patterns

glycidyl ether is carried out in the presence hexamethyldisilazide lithium.

21. The compound of structural formula:

in which
R1a and R1b independently from each other selected from H and F, provided that at least one of R1a and R1b represents F,
R2selected from the group consisting of benzyl and C1-C6alkyl, where benzyl and C1-C6alkyl, independently from each other are unsubstituted or substituted by halogen or C1-C4alkyloxy, and
Het represents tetrazolyl, optionally substituted bromide.

22. The compound of structural formula:

where
R1a and R1b independently from each other selected from H and F, provided that at least one of R1a and R1b represents F,
R2selected from the group consisting of benzyl and C1-C6alkyl, where benzyl and C1-C6alkyl, independently from each other are unsubstituted or substituted by halogen or C1-C4alkyloxy, and
Y is selected from the group consisting of BF3and BR3R4and R3and R4independently from each other, selected from the group consisting of HE, C1-C6of monoalcohols and C1-C6dihydric alcohols, or DG� R 3and R4together with In to which they are attached, form an optionally substituted bromide cyclic boronate.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel (2R,3R,5R)-3-hydroxy-(5-pyrimidin-1-yl)tetrahydrofuran-2-ylmethyl aryl phosphoramidate of general formula I or a stereoisomer or a pharmaceutically acceptable salt thereof, having properties of nucleoside inihibitors of RNA polymerase NS5B of the hepatitis C virus. The invention also relates to a method of producing compounds, pharmaceutical compositions and a medicinal agent based on said compounds. In general formula 1 , R1 is hydrogen, (CH3)2[(CH3)3C]Si, C2-C6acyl, optionally substituted with a benzyloxy group, NR5R6 group, wherein R5 and R6 are independently hydrogen or C1-C4alkyl; 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl or piperidin-4-ylcarbonyl; R2 and R3 are F or R2 is F or OH and R3 is CH3; R4 is hydrogen or methyl; Ar is phenyl, pyridyl or naphthyl, where the phenyl, pyridyl or naphthyl is optionally substituted with at least one of C1-3alkyl, C2-4alkenyl, C2-4alkynyl, C1-3alkoxy, F, Cl, Br, I, nitro, cyano, -N(C1-3alkyl)2; Pm is 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 4-(4-amino-2-oxo-2H-pyrimidin-1-yl), wherein the amino group is optionally substituted with 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl or a C(O)R8 radical, where R8 is C1-C4alkyl, optionally substituted with a NR6R7 group, where R6 and R7 are independently hydrogen or C1-C4alkyl; C1-3alkoxy, optionally substituted with a phenyl; X is O or N-R9, where R9 is C1-C4alkyl, optionally substituted with OH or OCH3; n=1, 2 or 3.

EFFECT: compounds can be used to prevent and treat viral infections, including hepatitis C.

12 cl, 1 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinolines substituted by phosphorus-containing group of formula and applicable in medicine, wherein Z represents V1 and V2 are independently specified in hydrogen or halogen; one of R and R` represent phosphorus-containing substitute Q; the other one is specified in hydrogen or methoxyl; wherein the phosphorus-containing substitute Q represents A represents O; L represents C1-6alkyl; J represents NH or C3-6heterocycloalkyl and J is optionally substituted by G3; X is absent or represents -C(=O)-; X is absent or represents C1-6alkyl; each of R1 and R2 are independently specified in C1-6alkyl or C1-6alkoxy; G3 represents C1-6alkyl, R3S(=O)m-, R5C(=O)- or R3R4NC(=O)-; R3, R4 and R5 are independently specified in 3 or C1-6alkyl; m is equal to 0-2.

EFFECT: there are presented new protein kinase inhibitors effective for treating the diseases associated with abnormal protein kinase activity.

20 cl, 42 ex, 8 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1 or their stereoisomers or pharmaceutically acceptable salts possessing the properties of inhibitors of RNA polymerase HCV NS5B, and to methods for producing them. In general formula 1 R1 represents C1-C4alkyl; R2 and R3 represents fluorine, or R2 represents fluorine, while R3 represents methyl; one of R4 and R5 represents hydrogen, and the other of R4 and R5 represents C1-C6acyl optionally substituted by α-aminoacyl specified in a group containing (dimethylamino)acetyl, 1-tert-butoxycarbonylamino-2-methyl-propylcarbonyl, 1-methylpyrrolidine-2-carbonyl, 1-methylpiperidine-3-carbonyl and 1-methylpiperidine-4-carbonyl, R6 represents hydrogen, methyl, methoxy and halogen.

EFFECT: compounds can be used for treating and preventing viral infections, including hepatitis C, optionally with additional agents specified in an inhibitor of inosin-5-monophosphate dehydrogenase, eg Ribamidine, an inhibitor of hepatitis C protease C NS3, eg Asunaprevir (BMS-650032), an inhibitor of hepatitis C protease C NS3/4A, eg Sofosbuvir (TMC435), an inhibitor of RNA-polymerase NS5A, eg Daclatasvir (BMS-790052) or Ledipasvir (GS-5885).

18 cl, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 2-amino-1-((phosphonoxy)methyl)-3-(3-((4-((2-pyridinyloxy)methyl)phenyl)methyl)-5-isoxazolyl)pyridinium of formula: and salts thereof effective as an antimycotic agent, and to pharmaceutical compositions and therapeutic agents based on it and the use thereof in treating mycotic diseases.

EFFECT: what is presented is the new effective antimycotic agent with improved water solubility and safety.

6 cl, 16 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to derivatives of Ice formula and the use thereof in treating the diseases associated with thrombocyte aggregation ICE', wherein P(O)R5R8 is specified in R1 is specified in phenyl; W is specified in a bond, -O-, -NR3-; R2 is specified in alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, phenyl, heterocyclyl, or heteroaryl, alkoxycarbonyl alkyl, carboxyalkyl or phenyl alkyl; R3 is specified in hydrogen or alkyl; or R2 and R3 form a ring together with a nitrogen atom; Ra is specified in hydrogen or methyl; R4 is specified in alkoxy; n is from 0 to 3; m is from 0 to 1; V is specified in a bond and phenyl; R5 and R8 are specified in hydroxyl, phenyloxy, benzyloxy, -O-(CHR6)-O-C(=O)-R7, -O-(CHR6)-O-C(=O)-O-R7, -O-(CHR6)-C(=O)-O-R9, -NH-(CHR10)-C(=O)-O-R9, -NH-C(CH3)2-C(=O)-O-R9; q is equal to 2; R6 is specified in hydrogen and alkyl; R7 is specified in alkyl or cycloalkyl; R9 is specified in alkyl; R10 is specified in hydrogen, alkyl, phenyl or benzyl; and R11 is specified in hydrogen, alkyl or alkoxy.

EFFECT: new P2Y12 receptor antagonists are produced.

25 cl, 126 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: compounds under the present invention are characterised by properties of aurora-kinase-A and/or aurora-kinase-B inhibitor. In general formula (I) : A represents 5-merous heteroaryl containing two nitrogen atoms; X represents NR14; m represents 0, 1, 2 or 3; Z represents the group chosen from -NR1R2, and 4-7-merous saturated ring connected by carbon atom containing nitrogen atom and substituted at nitrogen atom with C1-C4alkyl substituted by phosphonoxy; R1 represents C1-C6-alkyl substituted by phosphonoxy; R2 represents the group chosen from hydrogen, C1-C6-alkyl where C1-C6-alkyl is optionally substituted with 1, 2 or 3 halogen or C1-C4-alkoxy groups, or R2 represents the group chosen from C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4alkyl; or R1 and R2 together with nitrogen atom whereto attached form 4-7-merous saturated ring substituted at carbon or nitrogen atom by the group chosen from phosphonoxy and C1-C4-alkyl where C1-C4alkyl is substituted by phosphonoxy; R3 represents the group chosen from hydrogen, halogen, C1-C6-alkoxy; R4 represents phenyl substituted with 1-2 halogens; R5, R6, R7 and R14 represent hydrogen. In addition, the invention concerns the pharmaceutical composition containing therapeutically active amount of the compound under the invention, to application of the compound for preparation of a medical product applied in therapy of disease wherefore inhibition of one or more aurora-kinases is efficient, to method treatment, as well as production of the compounds under the invention.

EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: medicine; pharmacology.

SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.

EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.

46 cl, 1 tbl, 233 ex

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing carbonyl derivatives of 5,10,15,20-tetraphenylporphyrin of formula I where R is o-carborane or m-carborane, which are obtained by reacting mercaptocarborane with 5,10,15,20-tetra(n-trifluoromethanesulphonylmethyloxyphenyl)porphyrin in palladium catalysis conditions while boiling in anhydrous toluene while stirring in an atmosphere of an inert gas at room temperature. The method includes successively adding diisopropylethylamine (DIPEA), the corresponding mercaptocarborane, 1,1'-bis(diphenyl-phosphino)ferrocene (dppf) and tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), followed by boiling the reaction mixture in an Ar atmosphere for a few hours, separating the finished products using know techniques; 5,10,15,20-tetra(n-trifluoromethanesulphonylmethyloxyphenyl)porphyrin is obtained by reacting 5,10,15,20-tetrahydroxyporphyrin with a trifluoromethanesulphonic acid anhydride in a medium of methylene chloride in an atmosphere of an inert gas.

EFFECT: obtaining novel carbonyl derivatives of 5,10,15,20-tetraphenylporphyrin, which can be used as anti-tumour agents in boron neutron capture therapy and photodynamic therapy of cancerous diseases.

1 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula: or its pharmaceutically acceptable salts. Values of radicals are as follows: Ra represents member, selected from CN, C(O)NR1R2, C(O)OR3; R1 and R2 represent H, R3 represents H or unsaturated C1-C10 alkyl; X represents member, selected from N, CH and CRb, Rb represents member, selected from halogen, substituted or non-substituted C1-C10 alkyl, C(O)OR4, OR4, NR4R5, where R4 and R5represent members, independently selected from H, substituted or non-substituted C1-C10 alkyl, substituted or non-substituted C1-C10 heteroalkyl, containing at least 1 heteroatom, where heteroatom represents O or N, and heteroatom can take any internal position in heteroalkyl group or take the position, through which alkyl group is bound to the remaining part of molecule, non-substituted C3-C10 cycloalkyl, pyridyl, substituted with CN group, or independently represents ; and , where alkyl and heteroalkyl substituents are independently selected from the group, including: -R', =O, -CO2R', -OR', -OC(O)R', -NR"C(O)R', -NR'R", -CONR'R", pyridyl, halogen, , 4-methylpiperazinyl, 4-methylpiperidinyl, in quantity from 0 to 3; and where R' and R" are independently selected from the group, including hydrogen, non-substituted phenyl, non-substituted C1-C10 alkyl, C1-C10 alkoxy, on condition that R4 and R5, together with atoms to which they are bound, are optionally combined with formation of 4-8-membered non-substituted heterocycloalkyl ring, containing 1-2 heteroatoms, selected from N and O. Also claimed are pharmaceutical compositions, method of treating state, mediated by phosphodiesterase (FDE), a method of FDE inhibition.

EFFECT: invention makes it possible to obtain compounds, capable of inhibiting phosphodiesterase.

134 cl, 141 dwg, 2 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: claimed is a method of obtaining oligoborosilazanes by the interaction of oligosilazanes, which do not contain alkyl radicals at a nitrogen atom, with an aminoborane complex, which does not contain alkyl radicals at a nitrogen atom, with the ratio of silazane to a boron-containing modifier from 3 to 18, with carrying out the process at a temperature of 40-140°C in a mixture of toluene with diglyme or benzene with diethyl ether with the molar ratio from 1:1 to 1:33.

EFFECT: method makes it possible to obtain oligoborosilazanes with the given molecular weight with high output, which is reached due to the step-by-step thermal processing of the reaction mixture at an increased temperature.

2 cl, 4 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to porous crystalline materials. A porous crystalline material having a tetrahedral framework comprising the general structure M1-IM-M2, wherein M1 comprises a metal having the first valency, M2 comprises a metal having the second valency different from the first valency, and IM is imidazolate or a substituted imidazolate linking moiety. One or more of the following conditions is met: M1 comprises a monovalent metal, and M2 comprises a trivalent metal; M1 is Li+; and M2 is B3+. Also claimed is a gas adsorption method, a method of separating gas from a fluid stream containing the gas.

EFFECT: adsorbents with an improved gas uptake on a gravimetric basis.

28 cl, 3 dwg, 8 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining hydrochloride of tertbutyl ester of (4-fluoro-3-pyperidin-4-yl-benzyl)-carbamic acid (I). Method includes reduction of tertbutyl ester of (4-fluoro-3-pyridin-4-yl-benzyl) carbamic acid under conditions of reducing hedrogenisation and then HCl processing with output of hydrochloride of tertbutyl esther of (4-fluoro-3-pyperidin-4-yl-benzyl)-carbamic acid. Also claimed are methods of obtaining intermediate products, namely 5-((tert-butoxycarbonyl)aminomethyl)-2-fluorobenzeneboronic acid and tertbutyl ester of (4-fluoro-3-pyridin-4-yl)benzyl-carbamic acid.

EFFECT: invention makes it possible to considerably simplify obtaining hydrochloride of tertbutyl esther of (4-fluoro-3-pyperidin-4-yl-benzyl)-carbamic acid.

30 cl, 1 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to a method of obtaining of unsubstituted alkyl ammonium and alkyl guanidine 7,8(7,9)-dodeca hydro dicarbo nido undecaborates. The method comprises interaction of unsubstituted o(m)-carboranes with alkylamines and alkyl guanidines in the medium of the lower aliphatic alcohols. Meanwhile the process is performed at combined effect of catalyser and ultrasonic activisation at the temperature 60-80°C in the medium of the lowest aliphatic alcohols or respective water and alcohol mixes. The catalysers are fluorides of alkali metals, ammonium fluorides of or ammonium tetraalkyl fluorides.

EFFECT: invention allows to simplify the named compounds and to increase their yield.

6 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining monohalogenderivatives of 1,2-, 1,7-, 1,12-dicarba-closo-dodecarboranes(12). Method includes interaction of o(m,p)-carboranes with halogenating agents. As the latter used are N-halogenimides (amides): N-halogen-succinimides, 1,3-dihalogen-5,5-dimethylhydantoins, trihalogen-isocyanuric acids, N-halogen-arylsulfonamides and their sodium salts, N-halogenphthalimides, where halogen = Cl, Br, I; aryl = phenyl, p-tolyl, in the medium of acidic organic solvent. As solvent applied are monobasic liquid organic acids of aliphatic series R-COOH, where R=H, CnH2n+1, CnF2n+1, n=1-3. The process is carried out with application of ultrasound activation at temperature 60-80°C for 3-5 hours.

EFFECT: invention makes it possible to reduce energy consumption.

15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining of monohalogen-derivatives of 1,2-,1,7-,1,12-dicarba-closo-dodecaboranes(12). Method includes interaction of o(m,p)carboranes with halogenating agents; as halogenating agents used are N-halogenimides (amides): N-halogen-succinimides, 1,3-dihalogen-5,5-dimethylhydantoins, trihalo-isocyanuric acids, N-halogenaryl-sulfonamides and their sodium salts, N-halogenphthalimides, where halogen= Cl, Br, I; aryl = phenyl, p-tolyl, in medium of acidic organic solvent. As solvent applied are liquid organic monobasic acids of aliphatic series R-COOH, where R=H, CnH2n+1, CnF2n+1, n=1-3. the process is carried out with application of ultrasound activation in presence of catalyst, as catalyst used are strong acids: sulfuric (H2SO4), methanesulfonic (CH3SO2OH) and trifluoromethanesulfonic (CF3SO2OH) in amount 0.1-1.0 mol %. The process is carried out at temperature 20-50°C for 2-4 hours.

EFFECT: invention makes it possible to reduce energy consumption.

15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining pyridinates of 1-fluoro(chloro)-3-alkyl(aryl)borolanes of general formula (1), where R=Bu, X=F (a); R=Hex, X=F (b); R=Hex, X=Cl (c); R=Bn, X=Cl (d). The method includes the interaction of unsaturated compounds, selected from the group of hex-1-ene, oct-1-ene or allylbenzene, with triethylaluminium (AlEt3) in the presence of a catalyst (Cp2ZrCl2) in a ratio of 10:12:0.5 in hexane in an atmosphere of inert gas with mixing for 7 h, addition of boron trifluoride etherate (BF3·Et2O) or boron chloride (BCl3) and pyridine in a double with respect to AlEt3 amount, following mixing at room temperature for 30-60 min.

EFFECT: obtained compounds can be applied as components of catalytic systems in processes of oligo- and polymerisation of olefin, diene and acetylene hydrocarbons, as well as in fine organic and organometallic synthesis.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the technology of producing organoboron compounds, particularly a method for regioselective synthesis of monohalogen derivatives of 1,2-, 1,7-, 1,12-dicarba-closo-dodecaboranes(12). The method involves reacting o(m,p)-carboranes with halogenating agents in a medium of an acidic organic solvent, followed by extraction of the end product. The process is carried out in the presence of a catalyst in the form of a strong acid: sulphuric acid (H2SO4), methanesulphonic acid (CH3SO2OH) and trifluoro-methanesulphonic acid (CF3SO2OH) in amount of 0.1-1.0 mol%. The process is carried out at boiling point of the acidic organic solvent for 2-5 hours, wherein the acidic organic solvent used is monobasic liquid organic acids of the aliphatic series R-COOH, where R=H, CnH2n+1, CnF2n+1, n=1-3, with a linear and branched structure. The halogenating agents used are N-haloimides(amides): N-halosuccinimides, 1,3-dihalo-5,5-dimethyl hydantoins, trihaloisocyanuric acids, N-haloarylsulphonamides and sodium salts thereof, N-halophthalimides, where the halogen is Cl, Br, I; aryl is phenyl, p-tolyl.

EFFECT: invention simplifies synthesis of said compounds, increases efficiency of the process and reduces power consumption.

16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula (I), which possess the properties of HCV polymerase inhibitors. In formula , is specified in a group consisting of a single carbon-carbon bond and a double carbon-carbon bond; R1 and R3 are specified in hydrogen and methyl; R2 represents hydrogen; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C2-C6alkenyloxy, C3-C6alkynyloxy and halo; L represents a bond, and R6 represents a condensed 2-ring carbocyclyl, wherein each substitute is optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI, RJ and RK; or L is specified in a group consisting of a bond, C≡C, C(O)N(RC), N(RD)C(O), C1-C2-alkylene, C(H)2O, OC(H)2, cyclopropyl-1,2-ene, C(H)2N(RL), N(RM)C(H)2, C(O)CH2 and CH2C(O), and R6 is specified in a group consisting of C5-C6-carbocyclyk and 5-6-merous heterocyclyl, wherein each substitute is optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI, RJ, RK, RL and RM; the R4, RE, RF, RG, RH, RI, RJ, RK, RL and RM values are presented in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a drug preparation for HCV RNA polymerase inhibition and hepatitis C treatment, and to a method for preparing the above compounds.

21 cl, 46 dwg, 42 tbl, 140 ex

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