Method of producing ribofuranosyl-pyrimidine nucleosides

FIELD: chemistry.

SUBSTANCE: method enables to obtain 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one of formula (IV), which is a strong inhibitor of NS5B polymerase of hepatitis C virus (HCV).

EFFECT: high yield.

2 cl, 4 ex

 

The present invention relates to a method for preparing 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydrofuran-2-yl)-1H-pyrimidine-2-it formula

which is a strong inhibitor of the NS5B polymerase of hepatitis C virus (HCV).

International PCT publication WO 2006/012440 discloses a method in accordance with the following scheme. The method requires time-consuming separation of the anomers 14 and 16.

The purpose of this invention is the provision of an improved and scalable method for preparing 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2-it formula

in which there are no disadvantages inherent in the known engineering methods.

The method according to the present invention includes

a) the conversion of ester (aryl)alanovoy acid (2R,3R,4R)-2-(aryl)alkanoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydro-furan-3-yl of the formula II

in which R is aryl or alkyl;

in ester (aryl)alanovoy acid (2R,3R,4R)-2-(aryl)alkanoyloxy-5-chloro-4-fluoro-4-methyl-tetrahydro-furan-3-yl of the formula III

in which R is aryl or alkyl;

b) the transition of ester (aryl)Lanovoy acid (2R,3R,4R)-2-(aryl)alkanoyloxy-5-chloro-4-fluoro-4-methyl-tetrahydro-furan-3-yl of the formula III in ester (aryl)alanovoy acid (2R,3R,4R,5R)-3-(aryl)alkanoyloxy-5-(4-benzoylamine-2-oxo-spiramycin-1-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-ylmethyl formula I

in which R is aryl or alkyl, and Bz is benzoyl; and

(C) hydrolization of ester (acrylic)alanovoy acid (2R,3R,4R,5R)-3-(aryl)alkanoyloxy-5-(4-benzoylamine-2-oxo-2H-pyrimidine-1-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-ylmethyl formula I to obtain 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2-it formula IV.

Used herein, the term " (aryl)albanova acid belongs to the group RCO2H, in which R is any alkyl, any aryl, according to the terms specified here. Accordingly, the term ester (aryl)alanovoy acid belongs to the group RCO2R'in which R is either alkyl or aryl. Especially it is characteristic that R' represents a 3' and/or 5' position(I) of the ribose ring. The term "(aryl)alkanoyl and(aryl)alkanoyloxy" refers to the group RCO - and RCOO -, respectively, in which R is as described previously. The term "(aryl)alkanoyloxy" group refers to a group RCOOCH2in which R is as described previously.

Used here, the term "alkyl" denotes a linear or branched saturated monovalent hydrocarbon residue containing from 1 to 10 carbon atoms.

Used here, the term "aryl" refers to a phenolic group.

In preferred in which the approaches of the present invention R is phenyl.

Generally used in this application, the nomenclature is based on AUTONOM™ v.4.0, a computer system Beilstein Institute for the generation of IUPAC systematic nomenclature. In case of discrepancies between the depicted structure and name of this structure shows the structure should be considered as predominant. Moreover, if the stereochemistry of a structure or part of a structure is not indicated, for example, bold or dashed lines, the structure or part of a structure shall be construed as including all stereoisomers.

The transformation stage (a) includes the restoration in the presence of a reducing agent and subsequent chlorination in the presence of glorieuses agent.

Suitable regenerating agent is sodium bis-(2-methoxyethoxy)(2,2,2-triptoreline) alumoweld, which is available under the trademark RedAl® in the form of a solution in toluene.

Recovery usually occurs in an organic solvent, for example in Alojamientos hydrocarbon, such as dichloromethane, at the reaction temperature below 0°C, preferably below -5°C.

After completion of the reduction reaction of the reaction mixture is subjected to a chlorination reaction.

Gloriouse reagent, typically selected from sulfurylchloride, thionyl chloride or acid chloride phosphoric acid.

Predpochtitel is but the use of sulfurylchloride in the presence of additives catalyst bromide tetrabutyl ammonium.

Chlorination, respectively, is performed at the reaction temperature between 0°C and 40°C.

Ester (aryl)alanovoy acid (2R,3R,4R)-2-(aryl)alkanoyloxy-5-chloro-4-fluoro-4-methyl-tetrahydro-furan-3-yl of the formula III can be isolated from the reaction mixture using technologies known to those skilled in this field.

The transition to stage b) comprises the reaction of ester (aryl)alanovoy acid (2R,3R,4R)-2-(aryl)alkanoyloxy-5-chloro-4-fluoro-4-methyl-tetrahydro-furan-3-yl of the formula III with O-(trimethylsilyl)-N4-benzoylation in the presence of Lewis acid.

O-(trimethylsilyl)-N4-benzoylacetone can be prepared directly in the reaction zone N-benzoylacetone with hexamethyldisilazane in the presence of ammonium sulfate in chlorobenzene at reflux.

Commonly used Lewis acid known in the art, are suitable for transition to stage b). Good results were achieved with chloride of tin.

The reaction is usually performed at elevated temperature, for example at 70°C, until then, until the end of the interaction.

Thus obtained ester (aryl)alanovoy acid (2R,3R,4R,5R)-3-(aryl)alkanoyloxy-5-(4-benzoylamine-2-oxo-2H-pyrimidine-1-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-ylmethyl formula I can be isolated from the reaction mixture using the technology known to those skilled in this field.

Hydrolysis in stage c) is carried out in the presence of a base.

Suitable bases are organic bases, such as alkali metal alcoholate. Preferably, the solvent used sodium methoxide in methanol.

The reaction is performed at elevated temperature, for example at 50°C, until, until you complete the hydrolysis.

4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetra hydro-furan-2-yl)-1H-pyrimidine-2-it formula IV may be isolated by methods known to experts in this field of technology.

In another embodiment, the present invention has been developed a method of preparation of the original product, complex ether (aryl)alanovoy acid (2R,3R,4R)-2-(aryl)alkanoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydro-furan-3-yl of the formula II

in which R is phenyl.

The method includes the following stages:

a) transforming a complex ethyl ester (E)-3-((S)-2,2-dimethyl-[1,3]dioxolane-4-yl)-2-methyl-acrylic acid of the formula V

in complex ethyl ester (2S,3R)-3-((R)-2,2-dimethyl-[1,3]dioxolane-4-yl)-2,3-dihydroxy-2-methyl propionic acid of the formula VI

b1) transition complex ethyl ester (2S,3R)-3-((R)-2,2-dimethyl-[1,3]dioxolane-4-yl)-2,-dihydroxy-2-methyl-propionic acid of formula VI in the sulfite of the formula VII

c1) further reaction of the sulfite of the formula VII with a sulfate of the formula VIII

d1) the conversion of the sulfate of the formula VIII in sulfate forgiarini formula IX

e1) decomposition of sulfate forgiarini formula IX to the lactone of the formula X

and in conclusion

f1) the acylation of the lactone of formula X to obtain the final product of formula II in which R is phenyl.

This method can be described by the following SCHEMA:

(a1) acetone-NaMnO4(aq.), ethylene glycol, NaHCO3from -10 to 0°C; aq. NaHSO3(sharply cooled); (b1) i-PrOAc, MeCN, TEA, SOCl2; (c1) i-PrOAc, MeCN, NaOCl; (d1) TEA-3HF, TEA; (el) HCl (aq.)-BaCl2-aq.; (fl) (PhCO)2O, DMAP, MeCN.

It was found that the asymmetric hydroxylation at the stage a1) runs better with sodium permanganate in the presence of ethylene glycol, sodium bicarbonate in acetone at a temperature of -20 to 0°C, which provides access 60-64% diol at a pilot plant. The source component (V) can be obtained from (1S,2S)-l,2-bis-((R)-2,2-dimethyl-[1,3]dioxolane-4-yl)-ethane-1,2-diol (C.R.Schmid and J.D.Bryant, Jerry D., Org. Syn., 1995, 72:6-13) by oxidative cleavage of the diol and processing of the obtained aldehyde complex ethyl ester, 2-(triphenyl-λ5-Postanjian)-propionic acid is.

Cyclic sulfate (VIII) can be prepared by cyclization of vicinal diol, such as thionyl chloride in stage b1) and oxidation of the obtained cyclic sulfite (VII) in stage c1) in the corresponding sulfate (VIII) with NaOCl in the presence of MeCN. It was found that cyclic sulfates can be stabilized during the process by adding trialkylamine, such as TEA or DIPEA in an amount of 2-10 mol.% in relation to the cyclic sulfate. Differential scanning calorimeter (DSC) showed a deviation in the beginning of the decomposition from about 110 to 180°C when added to the component (VIII) 3.5 mol.% DIPEA. The interaction component (VIII) with triethylamine-trihydrochloride/TEA on stage d1) provides sulfate forgery (IX), which in the presence of water leads to the formation of forgiarini (X). Improved output of a component (X) can be achieved at the stage d1) with the introduction of BaCl2in the reaction mixture to remove the released sulfate. In the acidic environment of the concomitant hydrolysis of the acetonide releases triol, which spontaneously tsiklitiria to γ-lactone (X). The interaction of the component (X) with benzoic anhydride and DMAP at a stage f1) provides education dibenzoate of lactone (IIb), which is used at the stage of glycosylation.

While benzoline protective group (R=phenyl) is preferred, may use is to use other strong protective group, selected from methoxymethyl, methoxyethyl, benzoyloxymethyl, ethoxymethyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acyl, including acetyl, pivaloyl, benzoyl, toluyl, 4-phenylbenzyl, 2-, 3 - or 4-nitrobenzoyl, 2-, 3 - or 4-chlorobenzoyl, other substituted benzoyl. The base, which is used to stage f1), includes, but is not limited to the following list: imidazole, pyridine, DMAP, TEA, DIPEA, 1,4-diazabicyclo[2,2,2]octane. The solvent that is used to stage f1), includes, but is not limited to acetonitrile, pyridine, DCM, chloroform, DCE, THF.

Examples

Used abbreviations include: 1,2-dichloroethane (DCE), dichloromethane (DCM), di-ISO-propylethylene (DIPEA), N,N-dimethylacetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), ethanol (EtOH), ethyl acetate (EtOAc), methanol (MeOH), methyl (Me), ethyl (Et), isopropanol (IPA), acetonitrile 5 (MeCN), phenyl (Ph), room temperature (rt or RT), triethylamine (TEA or Et3N), tetrahydrofuran (THF).

Example 1

Ester (14) benzoic acid 3-benzoyloxy-5-(4-benzoylamine-2-oxo-2H-pyrimidine-1-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-ylmethyl

Trifluoroethanol (4.08 kg) is slowly added to a cooled solution (-15°C) RED-AL® solution (12.53 kg) and toluene (21.3 kg) while maintaining the reaction temperature at -10°C or below. After heating to room temperature (about 20°) modified RED-AL reaction mixture (30.1 kg of cooked 37.6 kg) is slowly added to pre-cooled solution (-15°C) fluoroalkene of dibenzoate 10 (10 kg) in DCM (94.7 kg) while maintaining the reaction temperature at -10°C or below. After the restoration of the lactone (controlled during HPLC), the reaction mixture additives are introduced catalyst tetrabutylammonium bromide (90 g). Then added sulfurylchloride (11.86 kg) while maintaining the reaction temperature at 0°C or below. The reaction mixture was then heated to 40°C until until you have completed the education chloride (about 4 hours), or heated to room temperature (20-25°C) and stirred overnight (about 16 hours). The reaction mixture is cooled to about 0°C and carefully added water (100 l) while maintaining the reaction temperature at 15°C or below. The reaction mixture was then stirred at room temperature for about 1 hour to ensure hydrolytic cleavage residue sulfurylchloride and separation of phases. The organic layer is washed with a weak solution of citric acid (prepared by dissolving 15.5 kg of citric acid in 85 litres of water) and then with a weak solution of KOH (prepared by dissolving 15 kg of 50% KOH in 100 litres of water). The organic phase is then concentrated, and the solvents are replaced with chlorobenzene (2×150 kg) by evaporation at atmospheric conditions. The resulting solution containing the component 30, is dehydrated by azeotropic distillation.

Suspension consisting of N-benzoylthiophene (8.85 kg), ammonium sulfate (0.07 kg) and hexamethyldisilane the Ana (6.6 kg) in chlorobenzene (52.4 kg), heated under reflux (about 135°C) and mixed (about 1 hour) until then, until the mixture becomes transparent solution. The reaction mixture is then concentrated under vacuum to obtain O-(trimethylsilyl)-N4-benzoylthiophene, having a consistency similar to syrup. To this concentrate is added to the anhydrous solution of the component 30 in chlorobenzene (as prepared) and tin chloride (28.2 kg). The reaction mixture is maintained at about 70°C until until the required response interaction (about 10 h), as determined in the analysis by high performance liquid chromatography (HPLC). Upon completion, the reaction mixture is cooled to room temperature and diluted with DCM (121 kg). This solution is added to the suspension of solid NaHCO3(47 kg) and CELITE® (9.4 kg) in DCM (100.6 kg). The resulting slurry is cooled to 10-15°C and slowly added water (8.4 kg) for the abrupt cooling of the reaction mixture. The suspension obtained very slowly (caution: gas evolution) is heated under reflux (about 45°C) and held for about 30 minutes. The slurry is then cooled to about 15°C and filtered. The filter cake is re-resuspended in DCM (4×100 l) and filtered. Mixed filtrate is concentrated under atmospheric pressure (collected in this process, the distillate is used for resuspend the Finance filter cake) as long while the temperature of the contents will not rise to about 90°C and then slowly cooled to about -5°C. the resulting slurry is aged at least 2 h at -5°C. the Precipitated product is filtered and washed with IPA (30 kg+20 kg), and dried under vacuum at about 70°C to ensure 8.8 kg (57.3%) of 1-(2-deoxy-2-fluoro-2-methyl-3-5-Dibenzoyl-β-D-ribofuranosyl)-N-4-benzoylthiophene (14, CAS Reg. No. 817204-32-3) with a purity of 99.3%.

Example 2

4-Amino-1-(3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2-she (18)

The slurry 14 (14.7 kg) in MeOH (92.6 kg) treated catalyst in methanol with sodium methoxide (0.275 kg). The reaction mixture is heated to approximately 50°C and aged (about 1 hour) until, until hydrolysis. The reaction mixture is abruptly cooled by adding somaclonal acid (0.115 kg). The resulting solution was concentrated under moderate vacuum, and then the remaining solvent is replaced IPA (80 kg). The contents distilled to a volume of about 50 liters of the resulting slurry is heated to about 80°C and then slowly cooled to about 5°C, and aged (about 2 hours). The precipitate is separated by filtration, washed with IPA (16.8 kg) and dried in an oven at 70°C under vacuum to provide 6.26 kg (88.9%) of the component 18, which has a purity of 99.43%.

Example 3

Complex ethyl ester (24) (2S,3R)-3-[(4R)-2,2-dime the Il-[l,3] dioxolane-4-yl]-2,3-dihydroxy-2-methyl-propionic acid

Suspension, consisting of 22 (10 kg, AS Reg. No 81997-76-4), ethylene glycol (11.6 kg), solid NaHCO3(11.8 kg) and acetone (150 l) is cooled to about -15°C. a Solution consisting of 36% aqueous NaMnO4(19.5 kg) slow boot (over 4 h) in the suspension, and the reaction temperature is maintained at -10°C or below. After stirring for 0.5 h at -10°C, an aliquot of the reaction mixture (about 5 ml) is sharply cooled to 25% water hydrosulfite sodium (about 15 ml). Part of the resulting slurry is filtered and subjected to GC analysis for verification response. After completion of the reaction, the reaction mixture is abruptly cooled slow (over 40 min) by adding cooled (about 0°C) 25% aqueous NaHSO3(60 l). During rapid cooling, the temperature of the reaction mixture reaches 4°C. CELITE® (about 2.5 kg) is then stirred in acetone (8 kg) and added to the dark brown reaction mixture. The resulting slurry is aged at room temperature to obtain a clear brown solution. The mixture is filtered and the filter cake washed with acetone (3×39 kg). Mixed filtrate is concentrated by distillation under vacuum (vacuum of about 24 inches Hg (about 810 mbar); the maximum reactor temperature is 32°C) to remove acetone. The aqueous concentrate is extracted EtOAc (3×27 kg), and mixed the diversified organic extracts washed with water (25 l). The organic phase is then concentrated by atmospheric distillation and EtOAc replaced by toluene. The amount of content has about 20 HP Added heptane (62 kg) and the contents cooled to about 27°C to initiate crystallization. The contents of the apparatus is further cooled to -10°C. After aging overnight at -10°C, the product is filtered, washed with 10% toluene in heptane and dried at 50°C under vacuum to provide 6.91 kg (59.5%) of the component 24 (CA RN 81997-76-4) as a white crystalline phase.

Example 4

(3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-dihydro-furan-2-it (10)

Stage 1 & 2 - In a dry, clean container loads 24 (6.0 kg), isopropyl ether acetic acid (28.0 kg), MeCN (3.8 kg) and TEA (5.4 kg). The mixture is cooled to 5-10°C during cooling slowly added a solution of thionyl chloride 10 (3.2 kg), while the temperature is maintained below 20°C. the Mixture was stirred until complete consumption of starting material (GC analysis). Usually the reaction is completed within 30 min after adding the reagent. To the mixture is added water (9 kg) and after stirring occurs the precipitation mixture. The aqueous phase is removed, and the organic phase washed with a mixture of water (8 kg) and a saturated solution of NaHCO3(4 kg). To the remaining organic phase containing the component 36 is added MeCN(2.5 kg) and solid NaHCO 3(3.1 kg). The resulting slurry is cooled to about 10°C.

Slowly add the bleach (NaOCl solution, 6.89 wt.% aqueous solution, 52.4 kg, 2 equiv.) when this temperature is maintained below 25°C. the Mixture is maintained under stirring over 90-120 min at 20-25°C until until the end of the reaction (GC analysis). After completion of the reaction the mixture is cooled to about 10°C and then quickly cooled in an aqueous solution of Na2SO3(15.1% weight ratio, 21 kg), while the temperature is maintained below 20°C. the Cooled reaction mixture is filtered through a filter with replaceable filter element to remove inorganic solids. The filtrate is asserted, there is a separation of the phases, and the aqueous phase is removed. The organic layer is washed first with a mixture of water (11 kg) and a saturated solution of NaHCO3(4.7 kg), then a saturated solution of NaHCO3(5.1 kg). The organic phase is added DIPEA (220 ml)and the resulting solution was filtered through CELITE® (filter bag) into a clean drum. The reactor is rinsed with isopropyl ether acetic acid (7 kg) and the wash solution is transferred to the drum. The organic phase is then concentrated in vacuum at about 850-950 mbar, the temperature of the jacket of the reactor is maintained at 45-50°C for receiving component 26 in the form of oil (~10 l). Is added DIPEA (280 ml) and negotiating the spacecraft in the vacuum continues (temperature shirt 50-55°C) before the end of the collection of the distillate (the volume content of about 7 l).

Stage 3 - concentrated oil stage 2 containing the component 26 is added 5 TEA (2.34 kg) and TEA-trihydrochloride (1.63 kg). The mixture is heated to 85°C for 2 hours was Carried out sampling of content for process control of the reaction by GC. After completion of the reaction the mixture is added conc. HCl (2.35 kg), and the resulting mixture is heated to about 90°C (a small amount of the collected distillate). The reaction mixture is stirred at about 90°C for 30 min, and then added a saturated aqueous solution of BaCl2(18.8 kg). The suspension obtained is stirred at about 90°C for 4 h the resulting mixture was then dehydrated by azeotropic distillation under vacuum (9-10 inches Hg) by slowly adding n-propanol (119 kg) during distillation, azeotropic mixtures (internal temperature of the contents of about 85-90°C). To the remaining slurry is added toluene (33 kg), and vacuum distillation is continued for distillation residual n-propanol (and traces of water) to the minimum volume for receiving the component 28.

Stage 4 - To the residue formed at stage 3, containing the component 28 is added MeCN (35 kg) and about 15 l of distilled under atmospheric pressure. The reaction mixture is cooled to approximately 10°C, and then added benzoyl chloride (8.27 kg) and DMAP (0.14 kg). TEA (5.84 kg) is slowly added to the reaction mixture, while the La-cooling temperature is maintained below 40°C. Content is maintained at about 20°C and the flow process of benzoylation monitored by HPLC. After completion of the reaction the mixture was added EtOAc (30 kg), and the resulting suspension stirred for about 30 minutes, the Reaction mixture is filtered through CELITE® layer (using Netfilter) to remove inorganic salts. The filter cake washed EtOAc (38 kg). Combined filtrate and wash liquid is washed successively with water (38 kg), a saturated solution of NaHCO3(40 kg) and saturated brine (44 kg). The organic phase is clarified by filtration through a filter with replaceable filter element) and concentrated under moderate vacuum to minimum volume. To the concentrate is added IPA (77 kg) and under moderate vacuum going about 25 l of distilled water, while the internal temperature of the contents reaches about 75°C at the end of the distillation. The remaining solution is then cooled to approximately 5°C for more than 5 h, and in addition sustained during the night. The precipitate is filtered and washed with cold (about 5°C) IPA (24 kg). The product is dried in vacuum at 60-70°C to ensure 6.63 kg (70.7% of theoretical yield of the product 10), the purity of which is 98.2% by HPLC.

1. The way to obtain 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2-it formula

including
a) the conversion of ester (aryl)alanovoy acid (2R,3R,4R)-2-(aryl)alkanoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydro-furan-3-yl of the formula II

in which R is aryl or alkyl,
in ester (aryl)alanovoy acid (2R,3R,4R)-2-(aryl)alkanoyloxy-5-chloro-4-fluoro-4-methyl-tetrahydro-furan-3-yl of the formula III by reduction in the presence of a reducing agent and subsequent chlorination in the presence of glorieuses agent

in which R is aryl or alkyl;
b) the transition of ester (aryl)alanovoy acid (2R,3R,4R)-2-(aryl)alkanoyloxy-5-chloro-4-fluoro-4-methyl-tetrahydro-furan-3-yl of the formula III in ester (aryl)alanovoy acid (2R,3R,4R)-3-(aryl)alkanoyloxy-5-(4-benzoylamine-2-oxo-2H-pyrimidine-1-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-ylmethyl formula I with O-(trimethylsilyl)-N4-benzoylation in the presence of Lewis acid

in which R is aryl or alkyl, and Bz is benzoyl, and
(C) hydrolysate of ester (aryl)alanovoy acid (2R,3R,4R,5R)-3-(aryl)alkanoyloxy-5-(4-benzoylamine-2-oxo-2H-pyrimidine-1-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-ylmethyl formula I to obtain 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydrofuran-2-yl)-1H-pyrimidine-2-it formula IV in the presence of the basis of the Oia.

2. The method according to claim 1, including the production of ester (aryl)alanovoy acid (2R,3R,4R)-2-(aryl)alkanoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydro-furan-3-yl of the formula II

in which R is phenyl,
includes the following stages:
a1) the transformation of complex ethyl ester (E)-3-((S)-2,2-dimethyl-[1,3]dioxolane-4-yl)-2-methyl-acrylic acid of the formula V

in complex ethyl ester (2S,3R)-3-((R)-2,2-dimethyl-[1,3]dioxolane-4-yl)-2,3-dihydroxy-2-methylpropionic acid of formula VI with sodium permanganate in the presence of ethylene glycol and sodium bicarbonate

b1) transition complex ethyl ester (2S,3R)-3-((R)-2,2-dimethyl-[1,3]dioxolane-4-yl)-2,3-dihydroxy-2-methylpropionic acid of formula VI in the sulfite of the formula VII with thionyl chloride

c1) further translation of the sulfite of the formula VII in sulfate of the formula VIII with sodium hypochlorite

d1) transformation of sulfate of formula VIII in the sulfate forgiarini formula IX with trialkylamines and triethylamine-trifoliata

e1) decomposition of sulfate forgiarini formula IX to the lactone of formula X with barium chloride in water

and
f1) the acylation of the lactone of formula X to obtain the final product of formula II with benzamidine in which R is phenyl.



 

Same patents:

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relates to a method of producing one of the said compounds

(formula 45), involving the following steps: (a) reaction of compound

with alkyl-2-bromopropionate in the presence of activated zinc in a suitable solvent to obtain a compound of formula

; (b) adding an oxidising agent to obtain a ketone of formula

; (c) fluorination of the product from step (b) to obtain a fluorinated ketone of formula

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FIELD: chemistry.

SUBSTANCE: invention claims derivatives of 1-α-halogen-2,2-difluoro-2-deoxy-D-ribofuranose of the general formula (I) in solid state, where R1 is benzoyl or ; R2 is hydrogen; and X is CI, Br or I; which can be applied as intermediates in stereoselective method of gemcitabine obtainment. In addition, invention claims stereoselective method of obtaining compounds of the general formula (I), including stages of: (i) recovery of 1-oxoribose of formula to obtain lactol of formula ; (ii) interaction of compound of formula (III) with halogen phosphate compound of formula in the presence of a base to obtain 1-phosphatefuranose derivative of formula ; and (iii) interaction of compound of formula (V) (also included in the claim) with halogen source, with further recrystallisation of obtained product; where R1, R2 and X are the same as indicated above while R3 is phenyl.

EFFECT: efficient method of obtaining derivatives of the abovementioned agent.

11 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: in method of obtaining compound aminoalkyl glucosaminide 4-phosphate of formula , X represents , Y represents -O- or NH-; R1, R2 and R3, each is independently selected from hydrogen and saturated and unsaturated (C2-C24) aliphatic acyl groups; R8 represents -H or -PO3R11R11a, where R11a and R11a, each is independently -H or (C1-C4) aliphatic groups; R9 represents -H, -CH3 or -PO3R13aR14, where R13a and R14, each is independently selected from -H and (C1-C4) aliphatic groups, and where indices n, m, p, q each independently is a integer from 0 to 6 and r is independently integer from 2 to 10; R4 and R5 are independently selected from H and methyl; R6 and R7 are independently selected from H, OH, (C1-C4) oxyaliphatic groups -PO3H2, -OPO3H2, -SO3H, -OSO3H, -NR15R16, -SR15, -CN, -NO2, -CHO, -CO2R15, -CONR15R16, -PO3R15R16, -OPO3R15R16, -SO3R15 and -OSO3R15, where R15 and R16, each is independently selected from H and (C1-C4) aliphatic groups, where aliphatic groups are optionally substituted with aryl; and Z represents -O- or -S-; on condition that one of R8 and R9 represents phosphorus-containing group, but R8 and R9 cannot be simultaneously phosphorus-containing group, including: (a) selective 6-O- silylation of derivative of 2-amino-2-desoxy-β-D-glucopyranose of formula , where X represents O or S; and PG independently represent protecting group, which forms ester, ether or carbonate with oxygen atom of hydroxy group or which forms amide or carbamate with amino group nitrogen atom, respectively; by means of tri-substituted chlorosilane RaRbRcSi-Cl, where Ra, Rb and Rc are independently selected from group, consisting of C1-C6alkyl C3-C6cycloalkyl and optionally substituted phenyl, in presence of tertiary amin, which gives 6-silylated derivative; (b) selective acylation of 4-OH position of obtained 6-O-silylated derivative with 6-3-alkanoyloxyalcanoic acid or hydroxyl-protected (R)-3-hydroxyalkanoic acid presence of a carbodiimide reagent and catalytic 4-dimethylaminopyridine or 4-pyrrolidinopyridine to give a 4-O-acylated derivative; (c) selectively deprotecting the nitrogen protecting groups, sequentially or simultaneously and N,N-diacylating the resulting diamine with (R)-3-alkanoyloxyalkanoic acid or a hydroxy-protected (R)-3-hydroxyalkanoic acid in presence of peptide condensation reagent; (d) introducing a protecting phosphate group at 3-position with a chlorophosphate or phosphoramidite reagent to give a phosphotriester; and (e) simultaneous or sequential deprotecting phosphate, silyl, and remaining protecting groups.

EFFECT: method improvement.

11 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a variant of admixture extraction from composition containing extraneous matter and sucralose, which is used as a sweetener. One of the variants includes following stages: (a) first solvent extraction of the said composition containing sucralose and admixtures in the first solvent with the help of another solvent, at least partially immiscible, in order to remove admixtures to the said second solvent; (b) second solvent extraction of the said composition containing sucralose and admixtures in the first solvent with the help of the third solvent, at least partially immiscible, in order to transfer sucralose to the said third solvent; where stage (a) removes at least a part of admixtures to the second solvent; and stage (b) transports most of sucralose to the third solvent and detains most of admixtures in the first solvent.

EFFECT: efficient removal of admixtures from compositions.

34 cl, 4 tbl, 2 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: developed method of sucralose production using acyl-sucralose implies (a) adjustment of pH factor of specified supplied mixture to value ranged from 8.0 to 12.0 by alkali metal hydroxide addition; (b) buffer addition to specified base mixture in amount enough for specified pH factor stabilization within stated range over holding stage (c); (c) holding of specified base mixture at appropriate temperature over time period enough for effective transformation of specified acyl-sucralose compound into free sucralose; (d) reduction of specified pH factor of specified base mixture up to value from 4 to 8; (e) sucralose release from product of step (d) resulted thereby in released sucralose.

EFFECT: improved method of water deacylation procedure stabilization.

22 cl, 1 tbl, 1 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved solid-phase method for synthesis of radioisotope indicators, in particular, for synthesis of compounds labeled with 18F that can be used as radioactive indicators for positron- emission tomography (PET). In particular, invention relates to a method for synthesis of indicator labeled with 18F that involves treatment of a precursor fixed on resin if the formula (I): SOLID CARRIER-LINKER-X-INDICATOR wherein X means a group promoting to nucleophilic substitution by a definite center of a fixed INDICATOR with 18F- ion for preparing a labeled indicator of the formula (II): 18F-INDICATOR; to compound of the formula (Ib):

and compound of the formula (Ih): ;

to radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in PET; to a cartridge for radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in positron-emission tomography.

EFFECT: improved method of synthesis.

13 cl, 1 sch, 3 ex

FIELD: pharmaceutical technology.

SUBSTANCE: invention relates to the improved sucralose formulation and a method for its crystallization. Method involves controlling pH value of solution in the range from about 5.5 to about 8.5 in the process of formation of sucralose crystals. Invention provides the development of the improved composition comprising crystalline sucralose and possessing the enhanced stability.

EFFECT: improved preparing method, improved properties of composition.

24 cl, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to phosphoramidite derivatives of general formula where Bx denotes adenine, guanine, cytosine, thymine or uracil, where the amine group of adenine, guanine and cytosine can be optionally protected by a protective group selected from acetyl and phenoxyacetyl; R1 is a substitute of general formula in which R11, R12 and R13 are identical or different, and each denotes hydrogen or alkoxy; R2a and R2b are identical or different, and each denotes alkyl; and WG1, WG2 denote a cyano group. The invention also pertains to a multistep method of producing the said compounds. The invention also relates to intermediate compounds of the said method, namely: an intermediate ether compound of general formula where L is a halogen or a C1-C5alkylthio group; WG1 is a cyano group; an intermediate compound of general formula where Bx denotes adenine, guanine, cytosine, thymine or uracil, where the amine group of adesine, guanine and cytosine can be optionally protected by a protective group selected from an acetyl group and a phenoxyacetyl group; and WG1 denotes a cyano group; an intermediate compound of general formula where Bx is as described above; R1 is a substitute of general formula (2); an intermediate compound of general formula where Bx is as described above; A is a silicon-containing substitute of general formula or where R6 denotes alkyl and WG1 denotes a cyano group. The invention also relates to a method of producing an oligonucleotide of general formula where each B independently denotes adenine, guanine, cytosine, uracil or thymine; each R independently denotes H or hydroxyl and at least one of R denotes hydroxyl; Z denotes H or a phosphate group; and n is an integer between 1 and 100, involving steps A-G, characterised by use of said phosphoramidite derivatives as a monomer compound of nucleic acid at step B.

EFFECT: high yield.

7 cl, 1 dwg, 21 ex

FIELD: chemistry.

SUBSTANCE: disclosed are α- and β-crystalline forms of 5'-desoxy-N4-carbopentyloxy-5-fluorocytidine of formula (III) , their preparation method through crystallisation of the raw product from a suitable solvent and pharmaceutical compositions based on the said compounds, having anti-cancer activity. The solvent used when preparing the α-modification is an ester or a mixture of ester-containing solvents. The solvent used when preparing the β-modification is a mixture of water and alkanol or a mixture of tetrahydrofuran and diethyl ether or carbon tetrachloride.

EFFECT: obtaining compounds and pharmaceutical compositions based on the said compounds, having anticancer activity.

10 cl, 2 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula (IX) or to their pharmaceutically acceptable salts having inhibitory activity to hepatitis C, to the related pharmaceutical composition and to their application for making a medical product. In compound of formula (IX) , R1 and R2 independently represent H, phosphate or acyl; X represents O; base* represents pyrimidine base; R12 represents C(Y3)3; Y3 represents H and R13 represents fluorine.

EFFECT: higher efficiency of the composition and treatment method.

31 cl, 14 dwg, 26 ex

FIELD: medicine.

SUBSTANCE: invention relates to method of obtaining gemcitabine hydrochloride, characterised by the following: 2,2-dimethyl-[1,3]-dioxolane-4-carbaldehyde is subjected to interaction with ethyl bromodifluoracetate in presence of zinc in organic solvent medium processing reaction mixture with ultrasound for 5-60 minutes, obtained ethyl 3-hydroxy-2,2-difluoro-3-[2,2-dimethyl-[1,3]dioxolane-4-yl]propionate is subjected to hydrolysis and cyclisation by means of ion-exchange resin in water-alcohol medium obtaining (4R,5R)-4-hydroxy-5-hydroxymethyl-3,3-difluorodihydrofuran-2(3H)-on, which is processed with solution of trimethylchlorosilane in dichloromethane obtaining (4R,5R)-4-trimethylsilyloxy-5-((trimethylsilyloxy)methyl)-3,3-difluorodihydrofuran-2(3H)-on, which is subjected to reduction by means of lithium diisopropylalumohydride in organic solvent medium at cooling to -70°C obtaining (4R,5R)-2-hydroxy-4-(trimethylsilyloxy)-5-((thrimethylsilyloxy)methyl)-3,3-difluorotetrahydrofurane, which is converted into (4R,5R)-2-methylsulphonyloxy-4-(trimethylsilyloxy)-5-((trimethylsilyloxy)methyl)-3,3-difluorotetrahydrofurane by processing with methane sulphonylchloride in solvent medium at cold, obtained (4R,5R)-2-methylsulphonyloxy-4-(trimethylsilyloxy)-5-((trimethylsilyloxy)methyl)-3,3- difluorotetrahydrofurane after optic isomer separation is processed with bis-trimethylsilylacetylcytozine in water-free dichlorethane and boil with trifluoromethane sulphonyloxymethylsilane with further cooling and separation of obtained gemcitabine in form of base or hydrochloride, as well as method of gemcitabine hydrochloride purification by its re-crystallisation from water solution with processing with ultrasound.

EFFECT: invention results in increase of ratio 3-(R)-hydroxy-isomer to 3(S)-hydroxy-isomer.

6 cl, 2 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to anhydrous polymorphic salt representing hemisulphate 1-[4(S)-azido-2(S),3(R)-dihydroxy-4-(hydroxymethyl)-1-(R)-cycloamyl]- cytosine of formula (Ia) possessing extra stability and improved physical properties that facilitates production, transportation of compound and preparation of compositions on the basis of compounds of formula I . Invention also refers to various crystal forms of compounds of formula (Ia), characterised by certain values of lattice constant D (interplanar spacing), to methods of their production from compounds of formula (I), to pharmaceutical compositions on the basis of compounds of formula (Ia) and to method of disease treatment caused by C hepatitis virus, including injection if such treatment is required, of therapeutically effective amount of compound of formula (Ia).

EFFECT: production of compound possessing extra stability and improved physical properties that facilitates production, transportation of compound and preparation of compositions on its basis.

14 cl, 5 dwg, 1 tbl, 9 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention pertains to nucleoside derivatives with general formula (I) , where R1 represents hydrogen; COR5, where R5 is chosen from C1-18 alkyl, phenyl, CH2OPh and CH2Ph; C(=O)OR5, where R5 represents C1-18 alkyl; or COCH(R6)NHR7, where R6 represents C1-5 alkyl, and R7 represents R5OCO, where R5 is C1-18 alkyl, R2 represents hydrogen; COR5 , where R5 is chosen from C1-18 alkyl, C1-18 alkenyl, phenyl or CH2OPh; C(=O)OR5, where R5 is chosen from C1-18 alkyl, C1-18 alkenyl, substituted with low alkyl; C(=O)NHR5, where R5 represents C1-18 alkenyl; or COCH(R6)NHR7, where R6 is chosen from side-chains of natural amino acid and C1-5alkyl, and R7 is chosen from hydrogen and R5OCO, where R5 is C1-18 alkyl; R3 and R4 are the same and are chosen from hydrogen; COR5, where R5 is chosen from C1-18 alkyl, or phenyl; C(=O)OR5, where R5 is C1-18 alkyl, or R3 and R4 together represent C(CH3)2; or their pharmaceutical acidic additive salts; under the condition that, at least one of R1, R2, R3 or R4 is not hydrogen. The invention also relates to pharmaceutical compositions, which have antiviral activity to HCV.

EFFECT: obtaining of a range of new biologically active substances.

15 cl, 2 tbl, 9 ex

FIELD: organic chemistry, antiviral agents.

SUBSTANCE: invention relates to a method for synthesis of β-L-5-fluoro-2',3'-dideoxy-2',3'-didehydrocytidine (β-L-FD4C) that is used as an antiviral agent. This method can be used in the large-scale manufacture of β-L-FD4C and it displays the effectiveness, high economy and ecology acceptable.

EFFECT: improved method of synthesis.

23 cl, 1 tbl, 1 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to oligomer comprising at least one nucleoside analogue of L-ribo-CNA of the general formula (Ia) wherein X represents -O-; B represents nitrogen base; P means radical position in an internucleoside linkage followed by monomer or 5'-terminal hydroxy-group; P* means an internucleoside linkage with precede monomer or 3'-terminal hydroxy-group; R2* and R4* mean in common biradical -(CH2)0-1-O-(CH2)1-3-(CH2)0-1-S-(CH2)1-3- or -(CH2)0-1-NR-(CH2)1-3- wherein R means hydrogen atom, alkyl or acyl; R1*, R2, R3*, R5 and R5* mean hydrogen atom. Also, invention proposes nucleoside analogues used in preparing oligomers. Proposed oligomers elicit the enhanced affinity to complementary nucleic acids and can be used as a tool in molecular-biological investigations and as antisense, antigen agents of agents activating genes.

EFFECT: valuable properties of analogues.

15 cl, 3 tbl, 4 dwg, 17 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new stable crystalline forms of derivative of pyrimidine nucleoside of the formula (I) eliciting the excellent anti-tumor activity. Also, invention relates to pharmaceutical composition eliciting an anti-tumor effect, applying crystalline form for preparing medicinal agent and to a method for prophylaxis or treatment of tumor diseases.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of derivative.

10 cl, 2 tbl, 4 dwg, 9 ex

The invention relates to derivatives of 5’-deoxycitidine General formula

where R1denotes a hydrogen atom or a group which is easily hydrolyzed under physiological environments; R2denotes a hydrogen atom or a group-CO-OR4where R4denotes a saturated hydrocarbon group with a straight or branched chain, containing from one to fifteen carbon atoms, or a group of the formula -(CH2)n-Y, where Y denotes a cyclohexyl or phenyl, and n is an integer from 0 to 4; R3denotes a hydrogen atom, bromine, iodine, cyano, C1-C4alkyl group which may be substituted atom (s) halogen, vinyl or etinilnoy group which may be substituted atom (s) halogen, C1-C4by alkyl; provided that R2and R3may not simultaneously denote a hydrogen atom

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new stable crystalline forms of derivative of pyrimidine nucleoside of the formula (I) eliciting the excellent anti-tumor activity. Also, invention relates to pharmaceutical composition eliciting an anti-tumor effect, applying crystalline form for preparing medicinal agent and to a method for prophylaxis or treatment of tumor diseases.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of derivative.

10 cl, 2 tbl, 4 dwg, 9 ex

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