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 [1] 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.

 

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