Method for the preparation of 3'-azido-2', 3'-dideoxythymidine

 

(57) Abstract:

The invention relates to the synthesis of nucleosides and relates to an improved method for the preparation of 3'-azido-2',3'-dideoxythymidine with the ability to suppress the reproduction of human immunodeficiency virus and finds application in medical practice for the treatment of AIDS. 3'-Azido-2', 3'-dideoxythymidine get sideropenia 5'-O-aroyl-2,3'-angebotenen sodium azide in an aprotic dipolar solvent in the presence of compounds of trivalent boron, followed by removing the protective group and the selection of the target product. It is advisable to carry out sideropenia at a molar ratio of sodium azide compounds of trivalent boron (1,4 - 3,0) and 100 - 110oC. as compounds of trivalent boron is preferable to use boric acid. The yield of the target product 70 - 80% purity (according to HPLC) - a 99.0 - 99.5% pure. 3 C.p. f-crystals.

The invention relates to the synthesis of nucleosides and relates to an improved method for the preparation of 3'-azido-2,2',3'-dideoxythymidine with the ability to suppress the reproduction of human immunodeficiency virus and finds application in medical practice for the treatment of AIDS.

A known method of obtaining azidothymidine sideropenia 5'-O-aroyl-2,3'-angebotenen excess of lithium azide in dimethylformamide. (Mitsunoby O.//The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products.// Synthesis. - 1981. - N 1 - p. 1 - 28) with the subsequent release and allocation of the target product. However, lithium azide is explosive, making the use of this method on an industrial scale is problematic.

A known method of obtaining azidothymidine 5'-O-aroyl-2,3'-angebotenen, which includes his sideropenia sodium azide in dimethylformamide in the presence of lithium chloride and ammonium chloride at 100 106oC for 4.5 h, then heated the reaction mass to 109 - 110oC and holding at this temperature for 3 h followed by maintaining the reaction mass at 111 - 114oC, removing the protective groups and the selection of the target product (RF patent N 2034848, C 07 H 19/073, 1992).

However, prolonged heating of the reaction mixture leads to the partial degradation product sideropenia and the formation of resinous impurities, which leads to significant technological difficulties in the stages of separation and purification of the target product and allows you to get azidothymidine high the decomposing directly under the reaction conditions in the interaction of sodium azide and lithium chloride, what makes sideropenia explosive.

A known method of obtaining azidothymidine sideropenia unprotected 2,3'-angebotenen sodium azide in a mixture of dimethylformamide-water for 5 hours, followed by separation of the target product (European patent N 0306597, C 07 H 19/073, published. 1996). However, poor solubility unprotected 2,3'-angebotenen in the used solvent, the destruction of nucleosides and dimethylformamide under the influence formed in the reaction of sodium hydroxide and prolonged heating of the reaction mixture lead to a significant resinification of the reaction products and the receipt of azidothymidine low purity (I. pl. 116 - 118oC). Obtaining this scheme of azidothymidine high purity associated with additional operations in the stages of extraction and purification of the intermediate and target products and leads to the complication of the process technology.

The closest to being described is a method of obtaining azidothymidine by sideropenia 5'-O-aroyl-2,3'-angebotenen alkylammonium (azides dimethyl-, diethyl-, triethylamine) at 120 - 140oC in an aprotic dipolar solvent (dimethylformamide or dimethylacetamide) VG.).

However, under high temperatures and formed in the reaction of sideropenia alkylamines followed, there is a partial destruction of nucleosides and solvent and resinification of the reaction mass, which complicates treatment and selection as product sideropenia, and the target product and complicates the technological scheme of the process. Lowering the temperature to 100oC and below leads to an increase in the process time up to 6 hours or more, which also leads to thermal degradation of nucleosides.

The proposed method for the preparation of 3'-azido-2',3'-dideoxythymidine allows to reduce the duration of the process sideropenia and implement it at lower temperatures, which contributes to simplification of the process and to obtain the desired product of high purity.

The essence of the present invention is that the 3'azido-2',3'-dideoxythymidine get sideropenia 5'-O-aroyl-2,3'-angebotenen sodium azide in an aprotic dipolar solvent in the presence of compounds of trivalent boron, followed by removing the protective group and the selection of the target product.

The inventive method differs from the known fact that as aidarous agent use sodium azide and pozirovanie when the molar ratio of sodium azide compounds of trivalent boron (1,4 - 3,0) : 1 and 100 - 110oC. as compounds of trivalent boron is preferable to use boric acid.

The process of sideropenia in the presence of compounds of trivalent boron can significantly increase the reaction rate and thus reduce the duration of the process up to 1.5 - 2 h and realize its at a lower temperature of 100 - 110oC, which significantly reduces thermal decomposition of nucleosides and helps to obtain the desired product of high purity. Even on prolonged heating for 5-6 h and higher temperatures of 120 - 140oC in the presence of compounds of trivalent boron resinification of the reaction mixture does not occur.

As compounds of trivalent boron can be used metaboric acid, apirat boron TRIFLUORIDE, etc.

The use of compounds of trivalent boron as a catalyst for the reaction of sideropenia to date was not known.

The method according to the invention is as follows:

To a suspension of 5'-O-aroyl-2,3'-angebotenen in dimethylformamide under intensive stirring, sodium azide and connection travelingthroughout in the system organochlorine solvent water, the organic layer is separated, washed with water and dried. The resulting 5'-O-aroyl-3'-azido-2', 3'-dideoxythymidine will unlock, which dissolve it then dissolve it in methanol, add or ammonium hydroxide, or diethylamine, or dimethylamine and stirred at 80oC for 6-8 hours Then the solvents evaporated to dryness and crystallized target product from a mixture of benzene and acetone. The purity of the target product data confirm UV - and NMR-spectroscopy and HPLC.

For a better understanding of the invention, the following are specific examples of its implementation.

Example 1. To a suspension of 3.28 g (10 mmol) of 5'-O-benzoyl-2,3'-angebotenen in 40 ml of dimethylformamide under intensive stirring of 1.95 g (30 mmol) of sodium azide and 0.61 g (10 mmol) of boric acid. The resulting reaction mass was stirred at 110oC for 1.5 h in the instrument, equipped with an efficient reflux condenser. Then the resulting clear yellow solution with precipitate evaporated on a rotary evaporator at 45oC to dryness. To the residue are added 50 ml of chloroform and 50 ml of water, stirred for 30 min, the organic layer separated, washed with water (3 x 50 ml), dried with Na2SO4, and evaporated to dryness. The remainder rsitem the solvents evaporated to dryness, the residue is crystallized from 50 ml of a mixture of benzene-acetyl-1 : 4,4. Precipitated crystalline precipitate was separated by a glass filter, washed with 10 ml of chilled to 4oC the above mixture and dried under vacuum. Yield 2.2 g (75%). ACCORDING to the HPLC purity of the target product is 99,05%.

UV-spectrum (in water): 1max266 nm (e 9600).

1H-NMR-spectrum (D2O, d), M. D.: 1,93 D. (3H, CH3I , JCH3-H60.5 Hz); 2.55 (2H, H2'); 4,60 - 3,95 m (4H, H3' + H4' + 2H5'); 6,15 t (1H, H1', JH1'H2'6 Hz); 7,66 d (1H, H6, JH6,CH31 Hz).

Example 2. To a suspension of 5 g (15,24 mmol) of 5'-O-benzoyl-2,3'-angebotenen in 62.5 ml of dimethylformamide under intensive stirring, 5 g (76,92 mmol) of sodium azide and 1.6 g (26,22 mmol) of boric acid. The resulting reaction mass was stirred at 100oC for 2 h in the instrument, equipped with an efficient reflux condenser. Then the resulting clear yellow solution with precipitate evaporated on a rotary evaporator at 40oC to dryness. To the residue are added 50 ml of chloroform and 50 ml of water, stirred for 30 min, the organic layer separated, washed with water (3 x 50 ml), dried with Na2SO4, and evaporated to dryness. The residue is dissolved in 18 ml of methanol, add 18 ml of diethylamine and stirred at 80oC t is s white crystalline precipitate was separated by a glass filter, washed with 10 ml of chilled to 4oC the above mixture and dried under vacuum. Output 2,98 g (72%). According to the HPLC purity of the target product is 99,27%.

Example 3. To a suspension of 5 g (15,24 mmol) of 5'-O-benzoyl-2,3'-angebotenen in 62.5 ml of dimethylformamide under intensive stirring, 5 g (76,92 mmol) of sodium azide and 3.3 g (54,09 mmol) of boric acid. The resulting reaction mass was stirred at 100oC for 2 h and then at 120oC for 5 h in the instrument, equipped with an efficient reflux condenser. After treatment of the reaction mixture by the procedure described in example 2, to obtain the target compound in the amount of 3.03 g (74%). According to the HPLC purity of the target product is 99,31%.

Example 4. To a suspension of 5 g (76,92 mmol) of sodium azide and 3.3 g (54,09 mmol) of boric acid in 62.5 ml of dimethylformamide, stirred at 80oC, add 5 g (15,24 mmol) of 5'-O-benzoyl-2,3'-angebotenen. The resulting reaction mass was stirred at 100oC for 2 h in the instrument, equipped with an efficient reflux condenser. Then the resulting clear yellow solution with precipitate evaporated on a rotary evaporator at 45oC to dryness. To the residue are added 50 ml of chloroform and 50 ml of water displaced is. The residue is dissolved in 20.5 ml of methanol, add 17 ml of a 33% aqueous solution of dimethylamine and stirred at 80oC for 6 hours a Further selection of the target product are carried out analogously to example 2. The yield of 3.3 g (80%). According to the HPLC purity of the target product is 99,25%.

1. Method for the preparation of 3'-azido-2',3'-dideoxythymidine sideropenia 5'-0-aroyl-2', 3'-angebotenen in an aprotic dipolar solvent, followed by removal of the protective group and the selection of the target product, characterized in that as aidarous agent use sodium azide and the process is carried out in the presence of compounds of trivalent boron.

2. The method according to p. 1, characterized in that the sodium azide and the connection trivalent boron is used in their molar ratio (1,4 - 3,0) : 1.

3. The method according to p. 1, wherein the process is carried out in the presence of boric acid.

4. The method according to p. 1, wherein the process is carried out at 100 - 110oC.

 

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