The method of obtaining 5'-benzoyl-2,3'-angerassertive
(57) Abstract:The invention relates to the field of organic chemistry, and in particular to methods of obtaining derivatives of nucleosides, in particular to obtain 5'-0-benzoyl-2,3'-anhidrosis-thymidine. The method includes processing thymidine organic reagent solution, blocking the 5'-hydroxyl, activating the 3'-hydroxyl by methylchloride and cyclization of salts of alkali metals when heated in an organic solution, thus blocking the 5'-hydroxyl carried out by treatment with benzoyl chloride at a temperature of 5-7 - 0oWith over 70-80 hours after which the product is administered methylsulfonate and sucrose in number, respectively (mol/mol) 0.5 to 0.8:1 and 0.6:0,7:1 in relation to the original thymidine, and the cyclization is conducted water-dioxane solution of sodium carbonate at a temperature of 80-84oC for 1.5 to 3 hours at pH 6.0 and 7.5, and at the stage cyclization ratio of dioxane:water is 3-5,1. 1 C.p. f-crystals, 3 tables. The invention relates to the field of organic chemistry, and in particular to methods of obtaining derivatives of nucleosides, in particular obtaining 5'-o-benzoyl-2,3'-anhidrosis-thymidine (BAT).Derivatives of thymidine at the present time are of considerable interest as the surveillance of AIDS (U.S. patent N 5064946, The Lancet I (8481), Mar. 15, 1986, p.575-580).Derivatives of 2,3-angerassertive derived from D-xylose with its subsequent transformation into a 1-(-D-xylofuranosyl)thiamine and further deoxygenating. The disadvantage of this method is complicated separation and purification (12-15 stages), as well as getting this method a product close to, but not identical to the target.A method of obtaining BAHT from thymidine (J. Organic Chemistry, v.38, No. 25, 1973, p.4299-4305) by treating its solution in dimethylformamide 2-chloro-1-1,2-triptoreline to block 5-hydroxyl, then activate 3-hydroxy-methylchloride, after which the obtained product is isolated and heated to a temperature of 90oWith California in a mixture of water and dimethylformamide, yielding 5'-0-trityl-2,3 anhydration with a total yield of about 30%
The disadvantage of this method is the low yield of the target product associated with large losses in the allocation of intermediates, a significant number of stages of purification (approximately 10-12), the failure to obtain by this method BAHT.The invention was the creation of a more effective method of obtaining the BAT.It was found that the above objective is achieved by implementing locks 5 hidroxil benzoyloxy in a molar with respect to the original thymidine ratio of 0.5 to 0.8; of 0.6-0.7:1, and at the next stage, the cyclization of lead sodium carbonate in water-dioxane solution for 1.5-3 hours at a temperature of 80-84oC and at pH 6.0 and 7.5, the optimal ratio of dioxane: water 3-5:1. In the result of the process in these conditions, succeeded in increasing the yield of the target product to simplify the process, reducing it to six stages. Finding such conditions benzoylation and mesotrione thymidine allows the process without isolating the intermediate product. In particular, among the factors which have a significant effect, is the use of sucrose at the stage of activation, the introduction which allows the formation of a complex with an excess of the Ministry of agriculture to form a protective layer, excluding the negative impact of stress in the next stage, and to ensure the optimization. In the available literature the specified combination of conditions not described. Typically, these reactions proceed in a different temperature range, ratios, and other reagents, etc.Obtaining positive results, including in the transition to industrial conditions in the new set of parameters, demonstrates compliance invention, the criterion of "technical uroven "URAL".Example 1. In the dry unit load 30,0 l (24,460 kg) absolutized pyridine, while stirring load 3.0 kg thymidine, heated the reaction mass to a temperature above 80oWith and dissolve thymidine at this temperature and with stirring for approximately 30 minutes After the complete dissolution of thymidine reaction mass is then cooled approximately the first 40oWith, and then to 0 -10oWith and start benzoylation of thymidine. To this end, the measuring device was added dropwise benzoyl chloride. Just benzoylation spend 1,85 l (2,242 kg) benzoyl chloride, the addition of which spend not less than 48 hours benzoylation Reaction monitored by thin layer chromatography on plates type "Silufol". At the end of the benzoylation reaction without cooling the reaction mass, hold the shutter for approximately two hours and start metilirovanie. From the measuring device with the speed of 60-110 drops per minute load without cooling, 1.3 l (1,924 kg) methanesulfonamide, hold the shutter speed not less than four hours at a temperature not higher than the 9oC. After cooling off and the reaction mass by vacuum via send in the Druk-filter. The resulting napravlennom cloth from filter paper and calico. The precipitate in the amount of approximately 3.2 kg taken from the plant. The filtrate in the amount of approximately 30,0 l return to the office, where the mixture is heated to 20-22oWith there load 2.5 kg of sucrose and lead exposure to sucrose in the mixture and the temperature of 20-22oC for at least four hours. After the reaction mass is directed to a rotary evaporator and distilled pyridine at a temperature in a water bath not exceeding 50oC and a vacuum of 15-20 mm RT.article VAT residue obtained after the distillation of chloroform, cooled to 22-25o(The temperature of the water bath). Get dense, sedentary mass amber color, which is dissolved in 12 l of dioxane. Received dioxane solution is directed into the apparatus and heated to a temperature 82-84oC. at the same time preparing an aqueous solution of sodium carbonate (4.0 l of distilled water and 0.5 kg of 100% sodium carbonate). The amount of water in the preparation of a solution of sodium carbonate depends on the moisture content in the returned remote sites and dioxane. Received soda solution for 15 min add in dioxane solution at a temperature 82-84oWith stirring. Then hold the shutter speed at a temperature of 80-84oC for 1 h 20 min the Noah chromatography on plates type "Silufol" (almost no stain, contains the original substance). After aging the reaction mass is then cooled to a temperature of 60-65oC. the resulting cyclization mixture of salts (anhydration and sodium salt of methansulfonate) filter on Druk-filter. Sediment from the remnants of dioxane press the air. Get around 3.2-3.4 kg of salts containing anhydration, which are unloaded in production capacity, fill with distilled water (1:3) and at a temperature of approximately 80oTo carry out the dissolution of the sodium salt of methansulfonate. Then, the resulting suspension anhydration in aqueous salt solution is cooled to a temperature of 30-40oWith and filtered on Druk-filter. The result is approximately 2.8 kg wet anhydration, which is dried in a vacuum drying Cabinet at a temperature of 35-40oWith a vacuum of 30-40 mm RT.article within 2-3 hours Receive approximately 2.5 kg of anhydration with a mass fraction of moisture not more than 0.3% by mass of the basic substance is not less than 97% in terms of dry substance 1,934 kgExample 2. In the conditions of example 1 was studied the influence of parameters of benzoylation at the output of the target product. The results are shown in table.1.Example 3. the Example 4. In the conditions of example 1 were performed to study the conditions for the cyclization stage. The data are given in table. 3.The invention implemented in a production setting company "URAL industrial-scale.The results obtained for the production of BAP showed that it is possible to obtain a more simple technology product with a yield of about 70% of the high quality of the drug has enabled the manufacture of high-quality azidothymidine with a melting point not lower than 122oS, i.e. exceeding the similar characteristics of drugs firm "Wellcome Foundation, as well as drugs Zidovudine" and "Retrovir". 1. The method of obtaining 5'-benzoyl-2,3'-angerassertive, wherein the thymidine treated with benzoyl chloride at -7 0oWith over 70 to 80 hours, then enter methylsulfonate and sucrose at a molar ratio with the thymidine of 0.5 to 0.8:1 and 0.6 to 0.7:1, respectively, followed by the cyclization of water-dioxane solution of sodium carbonate at 80 - 84oC for 1.5 to 3.0 hours at pH 6.0 to 7.5.2. The method according to p. 1, characterized in that the cyclization stage the ratio of dioxane:water 3 5:1.
FIELD: organic chemistry, biochemistry, medicine, virology.
SUBSTANCE: invention relates to derivatives of 2'=amino-2'-deoxynucleosides of the formula:
wherein R means hydrogen atom (H), alkyl, aminoalkyl; R1 means -(R2NR3) wherein R2 and/or R3 means H, -OH, -NH2, alkyl, benzyl under condition that R doesn't represent H or methyl when R2 and R3 mean H. Compounds elicit an antiviral activity with respect to measles and Marburg viruses exceeding that of ribavirin.
EFFECT: valuable properties of compounds.
4 tbl, 2 dwg, 18 ex
FIELD: medicine, pharmacology, bioorganic chemistry, pharmacy.
SUBSTANCE: invention relates to the effective using amount of β-L-2'-deoxynucleoside of the formula (I) or (II) used in manufacturing a medicinal agent used in treatment of hepatitis B, pharmaceutical compositions containing thereof, and methods for treatment of hepatitis B. Proposed agent shows the enhanced effectiveness in treatment of hepatitis B.
EFFECT: enhanced and valuable medicinal properties of agent.
83 cl, 6 tbl, 11 ex
SUBSTANCE: claimed invention relates to method of gemcitabine hydrochloride purification, which includes enriching gemcitabine hydrochloride with its p-anomer, according to which solution of gemcitabine hydrochloride in water is taken with ratio of water to gemcitabine hydrochloride from 3:1 to 12:1 (wt/vol); solution is processed with activated coal, activated coal being taken in amount from 0.1 to 10 wt % of gemcitabine hydrochloride amount in solution; activated coal is removed from solution with formation of filtered solution; concentration of gemcitabine hydrochloride in filtered solution is increased until ratio of filtered solution to gemcitabine hydrochloride equals from 1:1 to 1:5 (wt/vol), efficient for gemcitabine hydrochloride sedimentation; deposited gemcitabine hydrochloride is isolated; and in case admixture content in deposited gemcitabine hydrochloride is not reduced to required level, stages (a)-(e) are repeated. Claimed invention also relates to method of obtaining gemcitabine hydrochloride using claimed purification method.
EFFECT: creation of efficient method of gemcitabine hydrochloride purification.
5 cl, 1 tbl, 5 dwg, 8 ex
SUBSTANCE: present invention relates to (2'R)-2'-dezoxy-2'-fluoro-2'-C-methylnucleoside (β-D or (β-L) , where X represents O; R1 and R7 independently represent H; R3 represents hydrogen and R4 represents NH2; or its pharmaceutically acceptable salt. The invention also pertains to the method of producing the said compounds, which involves glycosylation of N4-benzoylcytosine with a compound of formula 1-4, where R represents methyl, Pg is chosen from C(O)Ph, CH2Ph or both Pg groups can be included in 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene); with further removal of protection of 3'-OPg and 5'-OPg and N-benzoyl of the obtained product.
EFFECT: invented compounds or their pharmaceutically acceptable salts are used as active ingredients against Flaviviridae family viruses in pharmaceutical compositions and liposomal pharmaceutical compositions.
4 cl, 9 tbl, 5 ex, 4 dwg
SUBSTANCE: invention relates to method of obtaining enriched with β-anomer 2'-desoxy-2',2'-difluorocytidine of formula (I)
, which includes stages: (i) interaction of enriched with α-anomer compound of 1-halogenribofuranose of formula (III) with nucleic base of formula (IV) in solvent obtaining enriched with β-anomer nucleoside of formula (II) , with constant removal of formed in reaction process silylhalogenide of formula R3SiX (V) by distillation using carrier or running inert gas through reaction mixture; and (ii) removal of protective group from enriched with β-anomer nucleoside of formula (II). Invention also relates to method of obtaining hydrate of enriched with β-anomer 2'-desoxy-2',2'-difluorocytidine of formula (I), which at stage (ii) after removal of protective group additionally includes stages of dissolving formula (I) nucleoside in water; heating of obtained solution to temperature from 40 to 60°C; cooling of solution to temperature ranging from 10 to 25°C with or without mixing and without changing pH; and filtering of deposited solid substances.
EFFECT: method improvement.
17 cl, 2 tbl, 7 ex
SUBSTANCE: invention relates to the method of producing 2'-desoxy-β-L-thymidine, which involves reacting 5'-O-trityl- or 5'-O-dimethoxytrityl- substituted 2,2' -anhydro-1 -β-L- arabinofuranosylthymine with a reducing agent RedAl and a complexing agent 15-crown-5-ether in a polar solvent 1,2-dimethoxyethane (DME) or tetrahydrofuran, obtaining 5'-O-trityl- or 5'-O-dimethoxytrityl- substituted 2,2'-desoxy-β-L-thymidine, subjected to protection removal if necessary. The invention also relates to the method of producing 2'-desoxy-β-L-thymidine, which involves reacting L-arabinose with cyanamide with subsequent reaction of the intermediate product - L-arabinofuranosylaminooxazoline - with a cycling or condensing agent, forming 2,2' -anhydro-1-β-L-arabinofuranosylthymine; reaction of the latter with a reducing agent RedAl and a complexing agent 15-crown-5-ether in a polar solvent 1,2-dimethoxyethane (DME) or tetrahydrofuran, obtaining 2'-desoxy-β-L-thymidine, where L-arabinofuranosylaminooxazoline can be protected by trityl or dimethoxytrityl in position 5' before or after reaction with the cycling or condensing agent; and protection removal of optionally protected 2'-desoxy-β-L-thymidine, if this is necessary or desired. Use in the given methods of such a reducing agent as Red-Al, and such a complexing agent as 15-crown -5-ether, causes a reaction of intramolecular protection and production of the required nucleoside product with good output.
EFFECT: compound is of great importance as an antiviral or antineoplastic preparation.
13 cl, 29 dwg, 28 ex
SUBSTANCE: invention relates to a pyrimidine nucleoside compound of general formula (1) , in which one of X and Y is a cyano group and the other is hydrogen; R1 is hydrogen, (R3)(R4)(R5)Si- or a carbonyl group which includes an alkyl monosubstituted with an amino group; R2 is hydrogen or (R6)(R7)(R8)Si-, provided that at least one of R1 and R2 is not hydrogen; or R1 and R2 together form a 6-member cyclic group -Si(R9)(R10)-, where each of R9 and R10 is a straight or branched alkyl; R3, R4 and R5 denote a straight or branched alkyl optionally substituted alkoxy, or cycloalkyl; R6, R7 and R8 denote a straight or branched alkyl optionally substituted alkoxy, cycloalkyl or phenyl, or to pharmacologically acceptable salts thereof. The invention also relates to a range of specific compounds of formula (1) or to their pharmacologically acceptable salts: 5'-O-triisopropylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-diethylisopropylsilyl-2'-cyano-2,-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-dimethylthexylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-(dimethyl-n-octylsilyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-dimethylthexylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-diethylisopropylsilyl -2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-(tert-butyldimethylsily)-2'-cyano-2'-desoxy-1-β-O-arabinofuranosylcytosine; 3'-O-triisopropylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-dimethylthexylsilyl-5'-O-(L-valyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-(L-valyl)-3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; and 3'-O-cyclopropyl-diisopropylsilyl-2'-cyano-2'-desoxy-1-β-D- arabinofuranosylcytosine.
EFFECT: obtaining formula (1) compounds or their pharmacologically acceptable salts for preparing a medicinal agent for treating tumours.
9 cl, 20 tbl, 1 dwg, 73 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to compounds of formula (I) where R1 is chosen from ethyl, n-propyl, isopropyl or isobutyl, and to its pharmaceutically acceptable salts. Besides, the invention refers to a pharmaceutical composition on the basis of said compounds used for treating a hepatitis C virus (HCV) mediated disease, and also to a method of treating the hepatitis C virus (HCV) mediated disease, and to the method of selective O-acylation nucleoside II for producing O-acyl nucleoside I in an alkaline reaction medium including the stages: (i) dissolution of II and DMAP in a heterogeneous mixture of water and a solvent and addition of a water base for pH control between approximately 7.5 to approximately 12; (ii) optional addition of a sufficient amount of saturated aqueous NaCl for preparing a diphase reaction mixture; (iii) addition of an acidating agent and an accessory base sufficient for pH preservation between approximately 7.5 to approximately 12; (iv) reaction monitoring and interruption of adding said acidating agent and said base after sufficient conversion provided; (v) optional contact of O-acylnucleoside with the pharmaceutically acceptable acid to produce a pharmaceutically acceptable salt.
EFFECT: production of the pharmaceutical composition for treating the hepatitis C virus (HCV) mediated disease.
9 cl, 2 tbl, 8 ex
SUBSTANCE: invention relates to 5'-urethane AZT derivatives of general formula
where X = -NH2, -NHMe, -NHEt, .
EFFECT: compounds have low toxicity, can efficiently inhibit reproduction of the immunodeficiency virus type 1 virus in a CEM SS cell culture.
1 cl, 2 tbl, 7 ex
SUBSTANCE: nucleic base (e.g. uracil, cytosine, adenine, guanine, hypoxanthine, xanthine or similar) reacts with perfluoroalkyl halide in the presence of sulphoxide, peroxide and an iron compound to obtain a perfluoroalkyl-substituted nucleic base.
EFFECT: high cost effectiveness as an intermediate compound for producing medicinal agents.
15 cl, 6 tbl