The way to obtain 2',3'-dideoxynucleosides

 

(57) Abstract:

Usage: as a drug active against the AIDS virus. The essence of the invention: 21,31-dideoxynucleoside. The output of 20-22%. Reagent 1: 51-O-protected ribonucleoside. Reagent 2: thiophosgene. Reagent 3: phenylsilane in boiling aprotic solvent in the presence of the initiator. The resulting mixture 51-O - protected 21and 31-monoethoxylate treated with thiophosgene in dichloromethane in the presence of 4-dimethylaminopyridine.

The alleged invention relates to a new method of obtaining 21, 31-dideoxynucleosides. A number of 21, 31-dideoxynucleosides and analogues obtained on their basis, have antiviral activity, including in respect of the AIDS virus, which makes possible their use in medicine and immunology [1,2] currently permitted for use as antiretroviral drugs 31-azido-31-deoxythymidine (AET) and 21, 31-dideoxyinosine, some other 21,31-dideoxynucleoside and their counterparts are in various stages of clinical trials.

Most of the ways gender is the position of the 21, 31-didehydro-21,31- dideoxynucleoside, which is then subjected to catalytic hydrogenation and release. To protect the use of tert-butyldimethylsilyloxy (TBDMS) or dimethoxytrityl group.

A method of obtaining 21,31-dideoxynucleosides, according to which the 51-0-protected ribonucleoside is treated with an excess of carbon disulphide in the presence of alkali in dimethyl sulfoxide, the alkylate methyliodide or - bromopropionitrile and received a 21,31-Bissett restore tributyltinhydride by boiling in toluene in the presence of initiator azobisisobutyronitrile (AIBN). The resulting 51-0-protected-21,31- didehydro-21, 31-dideoxynucleoside will unlock using tributylammonium in tetrahydrofuran (THF) and hydronaut over Pd/C. the output of the 21,31-- dideoxynucleosides is about 20% [3]

Another known method consists in the following: 51-O-protected ribonucleoside treated with excess thiocarbonyldiimidazole in dimethylformamide (BODICE), and the 51-O-zasidannya1,31-O-thiocarbonyldi heated in triethylphosphite or podolny-21,31- didehydro-21, 31-dideoxynucleoside will unlock using tributylammonium in THF and hydronaut over Pd/C. the output of the 21,31- dideoxynucleosides is 10 to 30% [3]

The closest in technical essence to the claimed is a method of obtaining a 21,31-dideoxynucleosides by processing the 51-O-protected ribonucleoside excess thiophosgene in an aprotic organic solvent in the presence of an organic base 4-dimethylaminopyridine (4 DMAP) with subsequent deoksigenirovanii formed 21,31-O-thiocarbonate 51-O-protected ribonucleoside by heating in trimethylphosphite. Received 51-0-protected-21, 31-didehydro-21,31- dideoxynucleoside hydronaut over Pd/C and will unlock with tributylammonium in THF. Output 21, 31-dideoxynucleosides is about 25 [4]

The proposed method of obtaining 21,31- dideoxynucleosides lies a fundamentally different scheme of synthesis allowing to avoid a stage catalytic hydrogenation.

The proposed method is that the solution 51-O-protected ribonucleo is UP>-O-thiocarbonate 51-O-protected ribonucleoside toxigenic by its interaction with phenylsilane in boiling aprotic solvent in the presence of initiator, the mixture 51-O-protected 21and 31-monoethoxylate re-treated with thiophosgene at a molar ratio mixture of 51-O-protected 21and 31- monoethoxylate and thiophosgene equal to 1: (0.5 to 1.0), and then phenylsilane and formed 51-O-protected 21,31- dideoxynucleoside will unlock.

The preferred embodiment of the method is to process a mixture of 51-O-protected 21and 31- monoethoxylate thiophosgene in dichloromethane in the presence of 4-dimethylaminopyridine.

The inventive method differs from the known fact that deoksigenirovanii 21, 31-O-thiocarbonate 51-O-protected ribonucleoside carried out by its interaction with phenylsilane in boiling aprotic solvent in the presence of initiator, and the resulting mixture 51-O-protected 21and 31-monoethoxylate re-treated with thiophosgene at a molar ratio mixture of 51-0-protected 211-O-protected 21and 31- monoethoxylate thiophosgene when a molar ratio of 1:(0.5 to 1.0) is formed isomeric mixture of dinuklyeozidofosfatov, when restoring which phenylsilane formed 51-O-protected 21,31-dideoxynucleoside. Recovery phenylsilane goes by free radical mechanism, as in the case of recovery tributyltinhydride, and is carried out in the presence of an initiator of free radicals. It is known that the recovery of the cyclic 21,31-O-thiocarbonate tributyltinhydride leads to a mixture of 21and 31-monomethoxypolyethylene [5] one might expect that the recovery of denuclearisation (acyclic analogue) will lead to equimolecular mixture of 21,31-dideoxynucleotide and monodigitoxoside [6] However, in our case, when restoring denuclearization phenylsilane mainly formed 21,31-dideoxynucleoside. 21,31-Dideoxynucleoside (1) receives in accordance with the following scheme:

< / BR>
where R is a protective group

In the remainder of the heterocyclic bases

The method according to the invention provide the corresponding ribonucleoside. To protect the use of tert-butyldimethylsilyloxy (TBDMS) or dimethoxytrityl group. 51-O-protected ribonucleoside dissolved in acetonitrile, dichloromethane or other suitable organic solvent and treated with an excess of thiophosgene in the presence of an organic base such as triethylamine or 4-dimethylaminopyridine at room temperature. The resulting 21, 31-O-thiocarbonate 51-O-protected ribonucleoside (Ill) toxigenic (restore) phenylsilane in boiling aprotic solvent in the presence of the initiator. As an initiator can be used benzoyl peroxide or azobisisobutyronitrile, and the solvent dioxane, tolyl, their mixture, etc.

The resulting oil containing an isomeric mixture of 51-O-protected 21and 31-monoethoxylate (IV), dissolved in a suitable organic solvent, for example dichloromethane, and re-treated with thiophosgene at room temperature in the presence of organic bases, mostly 4-dimethylaminopyridine. Used in excess is not thiophosgene, as in the first case, and a mixture of 51-O-protected 21and 31- monoethoxylate is icarbonate (V) toxigenic phenylsilane in the same conditions, as in the first case. 51-O-protected 21,31- dideoxynucleoside (VI) is isolated and will unlock using n-tributylammonium in THF. After cleaning, get the 21,31-dideoxynucleoside (l) with a total yield of 20-30

The following examples illustrate the invention.

Example I. Getting 21,31-dideoxyinosine. 830 mg (2.2 mmol) of 51-0-(tert-butyldimethylsilyl)inosine suspended in 20 ml of dichloromethane, added 610 mg (5 mol) of 4 - dimethylaminopyridine (4-DMAR) and at room temperature and the stirring pin solution 190 μl (2.4 mmol) of thiophosgene in 10 ml of acetonitrile. After 0.5 h after the addition the mixture is diluted with chloroform, washed with a 0.01 N model HC1, water, dried (Na2SO4), and evaporated. The residue is triturated with ether, filtered, the precipitate washed with ether. Received 51-0-(tert-butyldimethylsilyl)- 21,31-O-thiocarbonyldi (200 mg, 0.5 mmol, 90% of the basic substance according to HPLC) was dissolved in 10 ml of dry dioxane, add 200 μl (1.6 mmol) of phenylsilane and boil in a stream of nitrogen, adding a solution of benzoyl peroxide in dioxane (50 mg in 5 ml). After 2 h, add 100 ál of phenylsilane. After 4 h (TLC control in the system chloroform-methanol 9: >The resulting oil containing a mixture of 51-0-(tert-butyldimethylsilyl)-21-deoxyinosine and 51-0-(tert-butyldimethylsilyl)- 31-deoxyinosine (1 g, 2.7 mmol) dissolved in 30 ml of dichloromethane, add 0.5 g (4 mmol) 4-DMAR and pin for 2 h, a solution of 120 μl (1.6 mmol) of thiophosgene in 10 ml of dichloromethane. The mixture is left overnight at room temperature. The resulting solution was diluted with chloroform, washed with a 0.01 N model HC1, water, dried (Na2SO4), and evaporated. The residue (1.07 g) is suspended in 30 ml of a mixture of toluene-dioxane 1:1, add 700 μl (5.6 mmol) phenylsilane, 30 mg of benzoyl peroxide and heated in a stream of nitrogen for 20 h by adding after 6 and 12 h another 250 ál of phenylsilane and 50 mg of benzoyl peroxide. Upon completion of the reaction solution is filtered, the filtrate evaporated. The residue is extracted with hot hexane. The oil obtained is dissolved in tetrahydrofuran (THF), was added 1 g (3 mmol) of tetrabutylammonium and stirred at room temperature for 18 hours the Mixture is diluted with water and applied on the column with resin Dw 18 (HE-, 200-400 mesh). Elute with a linear gradient of methanol in water (0-40%). 21,31-Dideoxyinosine emit with a total output of 20 Tons pl. 180-182oC ( Lit.[3] 184 - 186oC). Rfto 0.25 (chloroform-IU is>; 6,4 (dd,IH, J1,2'a3, J1,2'b6, H-l1); to 8.2 (s, IH, H-8); and 8.4 (s,1H,H-2).

Example 2. Getting 21,31-dideoxyinosine. 830 mg (2.2 mmol) of 51-0-(tert-butyldimethylsilyl)inosine was dissolved in 20 ml of acetonitrile, added 610 mg (5 mmol) 4-DMAR and at room temperature and the stirring pin solution 190 μl (2.4 mmol) of thiophosgene in 10 ml of dichloromethane. After 0.5 h after the addition the mixture is diluted with chloroform, washed with a 0.01 N model HC1, water, dried (Na2SO4), evaporated, the residue triturated with ether, filtered, the precipitate washed with ether. Received 51-0-(tert.-butyldimethylsilyl)-21,31-0 - thiocarbonyldi (200 mg, 0.5 mmol, 90 basic substance according to HPLC) was dissolved in 10 ml of dry dioxane, add 200 μl (1.6 mmol) of phenylsilane and boil in a stream of nitrogen, adding a solution of benzoyl peroxide in dioxane (50 mg in 5 ml). After 2 h, add 100 ál of phenylsilane. After 4 h ( TLC control in the system chloroform-methanol 9:1) solution is cooled, filtered, the filtrate evaporated. The residue is shaken out three times with hot hexane.

The resulting oil containing a mixture of 51-0-(tert-butyldimethylsilyl)-21-deoxyinosine and 51-0-(tert-butyldimethylsilyl)- 31-detox solution 150 μl (2 mmol) of thiophosgene in 10 ml of dichloromethane. The mixture is left overnight at room temperature. The resulting solution was diluted with chloroform, washed with a 0.01 N model HC1, water, dried ( Na2SO4), and evaporated. The residue (1 g) is suspended in 50 ml of toluene, add 700 μl (5.6 mmol) of phenylsilane and boil in a stream of nitrogen for 20 h by adding a solution of benzoyl peroxide (150 mg) in toluene. Upon completion of the reaction solution is filtered, the filtrate evaporated. The residue is extracted with hot hexane. The oil obtained is dissolved in THF, was added 1 g (3 mmol) of tetrabutylammonium and stirred at room temperature for 18 hours the Mixture is diluted with water and applied on the column with resin Dowex 18 (HE-, 200-400 mesh). Elute with a linear gradient of methanol in water (0-40%). 21,31-Dideoxyinosine emit with a total yield 22 So pl. 180-182oC.

Thus, based on the proposed method to obtain 21, 31-dideoxynucleosides lies a fundamentally different scheme of synthesis allowing to avoid a stage catalytic hydrogenation.

1. The way to obtain 2', 3'-dideoxynucleosides, including the processing solution of 5'-0-protected ribonucleoside excess thiophosgene in the presence of organic bases with subsequent deoksigenirovanii 2',3'-0-thiocarbonate 5'-0-desoxiguanosine 2',3'-0-thiocarbonate 5'-0-protected ribonucleoside carry out the action of phenylsilane in boiling aprotic solvent in the presence of initiator, obtained after desoxyribose a mixture of 5'-0-protected 2'- and 3'-monoethoxylate re-treated with thiophosgene in the amount of 0.5 to 1.0 mole per mole of this mixture, and then phenylsilane and the resulting 5'-0-protected-2',3'-dideoxynucleoside will unlock.

2. The method according to p. 1, characterized in that the mixture of 5'-0-protected 2'- and 3'-monoethoxylate treated with thiophosgene in dichloromethane in the presence of 4-dimethylaminopyridine.

 

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