Method for the preparation of 3'-azido-2',3'-dideoxythymidine
(57) Abstract:Usage: chemistry of nucleosides. The inventive process is carried out by sideropenia derivatives of thymidine in an aprotic dipolar solvent with alkylammonium. The invention relates to the chemistry of nucleosides, in particular, to obtain 3'-azido-2', 3'-dideoxythymidine (azidothymidine, AZT), used in medicine as an antiviral drug for the treatment of acquired immunodeficiency syndrome (AIDS).AZT only used in practical therapy antiviral drug effective in the treatment of human immunodeficiency virus /HIV/. The threat of the spread of AIDS makes necessary the creation of a rational technology of production of AZT, based on intrinsically safe chemical processes. Known methods for producing AZT vary or methods of protection of the hydroxyl group in position 5 thymidine at the initial stages of the process, or specificity for ameridial, or, finally, conditions and reagents used in sideropenia derived thymidine subsequent removal of the protective functional groups and purification of the drug AZT.A known way of getting AZT, which consists in odnomernymi derivatives of benzoic acid and triphenylphosphine in the presence of alkylsalicylate with subsequent treatment with an excess of lithium azide in dimethylformamide and enable the intermediate product with sodium methylate.The main disadvantage of this method is the use of being sideropenia as aidarous agent lithium azide. Lithium azide is explosive, sensitive to different initial momenta: mechanical impact (impact, friction), the electric discharge beam of fire. In this regard, the industrial production of AZT using lithium azide is explosive.A known way of getting AZT, which combines the processes of metilirovaniya and ameridial, extremely shortened path synthesis anhydration. Under sideropenia used sodium azide.The disadvantage of this method is the low output AZT: in example 2 of the patent specified output equal to 30.7% in Addition, sodium azide poorly soluble in organic solvents, used under sideropenia, which leads to a considerable increase in the effective volume of the reactor sideropenia, additional consumption of solvent and other shortcomings of the process in heterogeneous environments.A method of obtaining AZT treatment of 5'-O-trityl-2,3'-angebotenen sodium azide in dimethylformamide-water when heated with a subsequent removal trailvoy protection in acid directly from the 5'-trailmaster thymidine.2 the Disadvantage of this method is the low output AZT: 33% (based on 5'-O-trityl-2,3'-angebotenen, as well as the availability of technical difficulties arising from the conditions of the process sideropenia in heterogeneous conditions.The prototype of the present invention, the selected method of getting AZT, described in  the Method includes sideropenia 2,3'-angebotenen lithium azide in an environment of dimethylformamide in the presence of ammonium chloride when heated for 17 hours, the selection of the target product and the crystallization of AZT from organic solvents.2,3'-angebotenen obtained directly from thymidine using as ciclismo reagent 2-chloro-I,1,2-triptorelin. Output AZT 2,3'-angebotenen 55% MP.121 - 122oC.The main disadvantages of the method are the danger of the process of sideropenia caused by the use of as aidarous agent lithium, and low output AZT.The essence of the invention lies in the fact that 3-azido-2', 3'-dideoxythymidine obtained by sideropenia derivatives of thymidine salts of amines, attestations acid, followed by separation of the target product in a known manner.As aidarous agent may use diamniadio.In industrial production of azidothymidine the main problem is the security of the process, because regardless of the method of receiving AZT most dangerous stage is the stage of sideropenia.Use as aidarous agent salts of amines, attestations acid helps to ensure the explosion process of receiving AZT in industrial production.Salt attestations acids and amines are not explosives. They are not susceptible to mechanical stress (shock P 10 kg, H 25 cm, Koper K-44-II, friction P 5000 kg/cm2Koper K-44-III), can withstand rapid heating up to 300-350oC, not they are sublimated from solutions of aprotic solvents. Control of the gas phase reaction volume under sideropenia such as 5'-O-benzoyl-2,3'-angebotenen indicates the security process. It is experimentally shown that when used as aidarous agent dimethylammonium, diethylammonium, triethylammonium pH above the mirror solution >9 and the sample for the presence of attestations acid with FeCl3negative.The new aidarous agent allowed to increase the output of AZT on 23-25% and decreased deryusheva agent when receiving AZT was not obvious. There was no information about their reactivity, in solutions, and most importantly, no data about possible separation in the gas phase explosive attestations acid.Examples of the implementation of the proposed method.Example 1. A mixture of 27 g (0,3 mol) dimethylammonium and 20 g (0,06 mol) of 5'-O-benzoyl-2,3'-angebotenen in 175 ml of dimethylacetamide is heated under 140NC for 40 minutes. After heating the reaction mixture, the solvent is evaporated under vacuum and the residue is dissolved in 100 ml of methylene chloride and washed with water. Then remove the resinous impurities and the solution evaporated to a thick syrupy mass. The residue was diluted with 150 ml of ethanol and poured a solution of 2.5 g (0,063 mol) sodium hydroxide in 50 ml of ethanol, the mixture is stirred at room temperature for 1.5 hours. The presence of the target product is detected by TLC. The solvent is then distilled off under vacuum and the residue diluted with 150 ml of acetone, the precipitate is filtered off, the filter is diluted with 100 ml of acetone, the precipitate is again filtered off and the filtrate is again evaporated. The residue is crystallized from water. Obtain 12.8 g of AZT (yield 80%). MP. 120-122oC. Structure and individuality obtained azidothymidine confirmed by the methods of element is the analysis found, C 44,92; H 4,29; to 26.02 N; calculated for C10H13N5O4C 44,94; H 4.09 to; n 26,21. IR spectrum , cm-1% 2100 (N3).UV spectrummax,min, nm(): 266(11620), 235(2600).An NMR spectrum1H , M. D.(DMSO-d6, GMDS): 11,35 (s, 1H, NH); to 7.67 (s, 1H, H-6); between 6.08 (t, 1H, H-1'); to 5.21 (t, 1H, OH); 4,39 (m, 1H, H-4); a 3.83 (m, 1H, H-3'); 3,63 (m, 2H, H-5'); or 1.77 (s, 3H, CH3).An NMR spectrum13C , M. D.(DMSO-d6): 163,90 (C4); 150,59 (C2); 136,22 (C6); 109,70 (C5); 84,18 (C1'); 83,60 (C4'); 60,97 (C5'); 60,32 (C3'); 36,41 (C2'), KZT 12.39 (C-CH3).According to HPLC the sample AZT, obtained by the proposed method, there is no admixture of toxic substances present in the samples synthesized by known methods.Example 2. Stage sideropenia carried out analogously to example 1, using as solvent dimethylformamide, at a temperature of heating the 120oC and time sideropenia 3 hours. Then the reaction mass is treated as in example 1. 13 g (yield 81%) AZT. MP. 121 -122oC.Example 3. Stage sideropenia carried out under the conditions and quantities of the substances described in example 2, and the hydrolysis is conducted with a solution of ethylate of sodium in 70 ml of ethanol, made from 0,19 g (8.3 mmol) metal nut is si, as described in examples 1 and 2. Gain of 12.6 g (yield 78%) AZT. MP. 120-121,5oC.Example 4. The process is conducted in the conditions and quantities of the substances described in example 3, but the hydrolysis is carried out with a solution of potassium methylate prepared from 0.25 g (6 mmol) of potassium. Gain of 12.9 g (yield 80%) AZT. MP. 121-122,5oC.Example 5. The process is conducted in the conditions and quantities of the substances described in example 2, but as aidarous agent use diethylammonium. Obtain 12.4 g (yield 74%) AZT. MP.121-122oC.Example 6. The process is conducted in the conditions and quantities of the substances described in example 2, but as aidarous agent use triethylammonium. Gain of 12.6 g (yield 78%) AZT. MP. 120 122oC.Example 7. A mixture of 13.5 g (0,06 mol) of 2,3'-angebotenen and 27 g (0,3 mol) dimethylammonium in 150 ml of DMF is Heated at 100oC for 6 hours. After heating, the solvent is evaporated, the residue dissolved in 200 ml of water, then extracted with ethyl acetate 6150 ml, remove the resinous impurities and the product is crystallized from water.Obtain 12.2 g (yield 74%) AZT. MP. 121-122,5oC. Method for the preparation of 3'-azido-2',3'-dideoxythymidine sideropenia derivatives of thymidine in aprotic found the agent used alkylammonium.
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