The way to obtain 2',3'-dideoxynucleosides

 

(57) Abstract:

Usage: as drugs with antiviral activity including against the AIDS virus. The inventive product 2',3'-dideoxynucleoside f-ly I, where In-timidi, adenosyl, yield 90%. Getting the lead processing solution of 5'-O-protected-2'-deoxynucleoside thiophosgene in the ratio of 1:(0.5 to 1) equivalents in the presence of organic bases with subsequent deoksigenirovanii obtained product phenylsilane in boiling aprotic solvent in the presence of initiator and release actigraphy. Connection structure of f-crystals I:

The alleged invention relates to a new method of obtaining 2',3'-dideoxynucleosides. A number of 2',3'-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 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine, some other 2',3'-dideoxynucleoside and their counterparts are in various stages of clinical trials.

Most of A 2',3'-didehydro-2', 3'-dideoxynucleoside, which is then subjected to catalytic hydrogenation and release.

A method of obtaining 2',3'-dideoxynucleosides, according to which 5'-O-protected ribonucleoside is treated with an excess of carbon disulphide in the presence of alkali in dimethyl sulfoxide, the alkylate methyliodide go --bromopropionitrile and obtained 2',3'-Bissett restore tributyltinhydride by boiling in toluene in the presence of 2,2-azo-bis-isobutyronitrile (AIBN). The resulting 5'-0-protected-2',3'-didehydro-2',3'-dideoxynucleoside will unlock using tributylammonium in tetrahydrofuran (THF) and hydronaut over Pd/C. the Yield of 2',3'-dideoxynucleoside is about 20% [3]

Another well-known way to obtain 2',3'-dideoxynucleoside is in the processing of 5'-O-protected ribonucleoside excess thiophosgene in an aprotic organic solvent in the presence of an organic base 4-dimethylaminopyridine (4 DMAP) with subsequent deoksigenirovanii the resulting 2', 3'-0-thiocarbonate 5'-0-protected ribonucleoside by heating in trimethylphosphite. The obtained 5'-0-protected-2',3'-didehydro-2 3'-dideoxynucleoside hydronaut over Pd/C this will release about helping tributyl the IAOD thiocarbonyldiimidazole [3]

Known methods for producing 2',3'-dideoxynucleosides of 2'-deoxynucleosides based on deoksigenirovanii their derivatives protected at the 5'-position (tert-butyldimethylsilyloxy or dimethoxytrityl protective groups) and acylated at the 3'-position of various thiocarbonyl compounds.

The closest to the technical nature of the claimed is a method of obtaining 2',3'-dideoxynucleosides by treatment of 5'-0-protected 2'-deoxynucleoside excess phenoxythiocarbonyl in acetonitrile in the presence of organic bases with subsequent deoksigenirovanii the resulting 5'-O-protected-3'-0-phenoxythiocarbonyl-2'-deoxynucleoside using tributyltinhydride when heated in an inert solvent. Deoksigenirovanii (recovery of) proceeds by a free radical mechanism and is carried out in the presence of an initiator of free radicals of 2,2-azo-bis-isobutyronitrile (AIBN). The obtained 5'-0-protected-2',3'-dideoxynucleoside will unlock and receive the corresponding 2',3'-dideoxynucleoside with a total yield 3O% [5]

The basis of the proposed method to obtain 2',3'-dideoxynucleosides lies scheme of synthesis allowing to exclude use the tick products make it unsuitable for use in industrial technology.

The proposed method of producing 2',3'-dideoxynucleoside is that the solution of 5'-0-protected 2'-deoxynucleoside treated with thiophosgene in the presence of an organic base at a molar ratio of 5'-0-protected 2'-deoxynucleoside and thiophosgene equal to 1 (0,5 1,0), formed (5'-0-protected-2'-deoxynucleoside-3'-ID) thiocarbonate toxigenic by its interaction with phenylsilane in boiling aprotic solvent in the presence of initiator, and the resulting 5'-0-protected 2',3'- dideoxynucleoside will unlock.

The inventive method differs from the known fact that they use different thiocarbanilide reactant thiophosgene, the original 5'-0-protected 2'-deoxynucleoside treated with thiophosgene when their molar ratio equal to 1 (0,5 1,0), and deoksigenirovanii formed di-(5'-0-protected-2'-deoxynucleoside-3'-yl) thiocarbonate carried out by its interaction with phenylsilane in boiling aprotic solvent.

In the processing of 5'-0-protected-2'-deoxynucleoside thiophosgene when a molar ratio of 1 (0,5 1,0) is formed other than in the known method, 3'-O-thiocarbonyl derivative of 5'-0-protected-2'-deoxynucleoside - dioleoylglycerol, restore the m proceeds by a 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 cyclic 2',3'-0-thiocarbonate tributyltinhydride leads to a mixture of 2'- and 3'-monomethoxypolyethylene [6] one might expect that the recovery of denuclearisation (acyclic analogue) will lead to equimolecular mixture of 2',3'-dideoxynucleoside and monododecanoate [7] However, in our case, when restoring denuclearization phenylsilane mainly formed 2',3'-dideoxynucleoside.

2', 3'-Dideoxynucleoside (I) receive, 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 is as follows.

5'-O-protected 2'-deoxynucleoside (II) are obtained by known methods [3, 5] from the corresponding 2'-deoxynucleoside. To protect the use of tert-butyldimethylsilyloxy (TBDMS) or dimethoxytrityl (TMD) group. 5'-0-protected-2-deoxynucleoside (II) is dissolved in a suitable organic solvent and treated with 0.5 to 1.0 equivalent of thiophosgene in the presence of organic orotan, acetonitrile, etc. of the Formed di-(5'-0-protected-2'-deoxynucleoside-3'-yl) thiocarbonate (III) allocate and toxigenic (restore) phenylsilane in boiling aprotic solvent in the presence of the initiator. As an initiator can be used benzoyl peroxide or 2,2-azo-bis-isobutyronitrile, and the solvent dioxane, tolyl, their mixture and other 5'-O-protected 2', 3'-dideoxynucleoside (IV) is isolated and will unlock using n-tributylammonium in THF. After cleaning, get 2',3'-dideoxynucleoside (I) with a total yield of 35-40 Following examples illustrate the invention.

Example 1. Obtain 3'-deoxythymidine.

a) Di-(5'-0-DS-timid-3'-yl)thiocarbonate.

To a solution of 380 mg (1 mmol) of 5'-O-D-thymidine and 156 mg of 4-DA ( 1,2 mode) in dry dichloromethane was added dropwise at 45oWith in one hour a solution of 57 μl (0.75 mmol) of thiophosgene in dichloromethane. The progress of the reaction is controlled TLC. Upon completion of the reaction (5 h) the solution was diluted with chloroform, washed with 2% model HC1, water, dried with Na2SO4and evaporated. Di-(5'-0-DS-timid-3'-yl)thiocarbonate obtained by crystallization from methanol. So pl. 226-228oC. Rf of 0.54 (chloroform-methanol 95:5). RT 26 minutes

Range PMR: M. D. CDCl3:

OH B>2'b,36, J2'b1'5, J2b,2'a14, H-2'b); of 3.96 (dd, IH, J5'b,4'1,5, J5'b,5'a11,5, H-5'b); Android 4.04 (dd, 1H, J5'a,4'1,5, J5'a,5'b11,5, H5'a); 4,27 (m, 1H,H-4'), 5,67 (m, 1H, J3',2'a= J3',2'b6, H-3'), 6,48 (dd, 1H, J1',2'b5, J1',2'aa 9.5, H-1'), at 7.55 (s, 1H, H-6), 10,15 (s, 1H, NH).

213C-NMR, M. D. CHCl3: -5,4(Si-CH3), 12,6(); 18,3 (), 25,9 (), 37,9(); 64,2(C-5'), 84,1; 84,7, 85,04 (C-1',3',4'), 111,48, 134,89; 150,76, 164,3 (C-2,4,5,6); 193,7(C=S)

b) 3'-Deoxythymidin.

To a solution of 115 mg (0.15 mmol) of di-(5'-0-DS-timid-3'-yl)- thiocarbonate in abs, the dioxane was added 90 μl (0.73 mmol) of phenylsilane and boil in a stream of dry nitrogen with the addition in portions of benzoyl peroxide (0.2 mmol) in the same solvent during the reaction. Upon completion of the reaction (monitoring HPLC), the solution evaporated, the residue chromatographic on silica gel, elwira stepwise gradient of methanol in chloroform (0-10%) and get 5'-0-DS-3'-deoxythymidin about 75% yield a Solution of 100 mg (0.3 mmol) of 5'-0-DS-3'-deoxythymidine and 130 mg (0.4 mmol) of tetrabutylammonium in 10 ml of THF incubated for 12 h at room temperature, evaporated, the residue chromatographic on silica gel, elwira a mixture of chloroform-methanol 9:1, you will receive 3'-deoxythymidin with the release of 90% of T. pl. 153-154oC. Rf of 0.57 (chloroform-methanol 4: 1).

Example 2. Obtain 2',3'-degezondepatient in 10 ml of dry (distilled over San2) acetonitrile at 60oWith added dropwise over 2 h a solution of 77 μl (1 mmol) thiophosgene in 5 ml of acetonitrile. The mixture was incubated for another 5 hours at this temperature. The resulting solution was diluted with chloroform, washed with 2% model HC1, water, dried and evaporated. Di-(5'-0-DS-adenos-3'-yl)thiocarbonate obtained by chromatography of the residue on silica gel with elution step gradient of methanol in chloroform (0-10%). Yield 70% So pl. 167-170oC. Rf of 0.3 (chloroform-methanol 95:5) RT 12 minutes

Range of PMR, M. D. CDCl3:

of 0.16 (s, 6H,Si(CH3)2), and 0.9(s,9H,t-Bu), of 2,75 2,85 (m,2H,H-2'a,2' b) to 4.0 (m, 2H, H-5'a,5 H); was 4.42 (m, 1H,H-4'), to 5.85 (m, 1H, J3',2'aJ3',2b5, H-3') and 6.1 (s, 2H, NH2), to 6.57 (dd, 1H, J1',2'b8,5, J1',2a6,H-1'), and 8.2 (s, 1H, H-8); and 8.4 (s, 1H, H-2)

213C-NMR, M. D. CDCl3:

-5,37, -5,51 (Si(CH3)2); 18,38 (), 25,93 (), 38,97 (C-2'), 63,82 (C-5'), 84,07, 84,27, 85,14 (), 119,73, 138,52; 149,68; 152,91, 155,4 (); 193,36 (C=S)

b) 2',3'-dideoxyadenosine.

To a solution of 100 mg (0.13 mmol) of di-(5'-0-DS-adenyl-3' - yl)-dicarbonate in 10 ml of abs. toluene was added 120 μl (0.96 mmol) of phenylsilane and boil in a stream of nitrogen for 25 h, adding portions of a solution of benzoyl peroxide (0.2 mmol) in toluene. Upon completion of the reaction (monitoring HPLC) the solution is filtered, the filtrate evaporated, the residue chromatographic on silicagel 120 mg (0.34 mmol) of 5'-0-TBDMS-2', 3'-dideoxyadenosine and 130 mg (0.4 mmol) of tetrabutylammonium in 10 ml of THF incubated for 12 h at room temperature, evaporated, the residue chromatographic on silica gel, elwira a mixture of chloroform-methanol 8:1 and get 2', 3'-dideoxyadenosine with the release of 90% of T. pl. 185-186oC (Lit.[4] 186-188oC). Rf of 0.48 (chloroform-methanol 4:1).max(H2O) 260 nm.

The homogeneity of the compounds obtained and the course of the reaction was controlled by TLC on plates Kieselgel 60 F-254 (Merck). Mass spectra FAB obtained on the instrument Bruker WM-500 (500 MHz). HPLC was conducted on a Waters chromatograph 501 using column 25 x 0.4 cm with sorbent Ultrasphere ODS 5 um when elution with 80% acetonitrile in water at a rate of 1 ml/min

Thus, in the present method are different from all known ways to obtain 2',3'-dideoxynucleosides substrate desoxyribose denuclearization and regenerating reagent phenylsilane.

The way to obtain 2', 3' -dideoxynucleosides by processing solution 5'-0-protected-2-deoxynucleoside thiocarbanilide reagent in the presence of organic bases with subsequent deoksigenirovanii formed 3'-0-thiocarbonyl derivative of 5'-0-protected-2'-detect thiocarbanilide reagent use thiophosgene in the amount of 0.5 to 1 equivalent relative to the original connection, and deoksigenirovanii formed di-(5'-0-protected -2'-deoxynucleoside-3'-yl)-thiocarbonate carry out the action of phenylsilane in boiling aprotic solvent in the presence of the initiator.

 

Same patents:

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

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a monohydrate of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide through contact of a compound of formula

with aqueous methylamine at temperature equal to approximately 2.5-7.5°C. The invention also relates to a method of producing an intermediate compound of formula (4): involving reaction of a compound of formula (1) with 14.3-16.7-fold molar excess hydrazine hydrate at temperature equal to approximately 60-65°C to obtain the corresponding hydrazine of formula (2), followed by contact between the compound of formula (2) and excess ethyl-2-formyl-3-oxopropionate, optionally in the presence of an acid.

EFFECT: method enables to obtain, in a single step, a crystalline compound in form of a monohydrate and also exclude undesirable impurities of the compound of formula 2 in the end product owing to use of intermediate product 4.

15 cl, 7 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to anti-tumour purine derivatives of formula (A) and salts thereof, as well as pharmaceutical compositions based thereon, a method for production thereof where W is an alkyl-substituted amine, a pyrrolidine, piperidine, morpholine or piperazine residue, optionally substituted with C1-C6 alkyl or hydroxy; Y is H or a saccharide residue, Z is H; Q is an optionally substituted quinoline residue. The disclosed method involves reacting a corresponding purine protected at the 9th position with corresponding precursors of groups W and Q.

EFFECT: novel compounds with low toxicity, a wide anticancer range, high anticancer activity, high stability, suitable for producing anti-tumour drugs.

12 cl, 3 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: proposed method of producing N2-methyldeoxyguanosine by the method of reductive amination of formaldehyde with deoxyguanosine is carried out with stirring for 36 hours and at a temperature of 25°C in acetate buffer, while simultaneously introducing into the reaction mixture of formaldehyde, deoxyguanosine and sodium cyanoborohydride, the reaction pH is maintained at 5.74 with the following ratio of components, wt %: deoxyguanosine 0.24, sodium cyanoborohydride 0.05, 37% of formaldehyde solution 1.36, 0.2 mM of acetate buffer solution 98.35.

EFFECT: new efficient method for the production of N2-methyldeoxyguanosine with improved yield and selectivity.

1 ex, 5 dwg

Up!