Method of 2',3',5',-tri-o-acetyl-2-phtoradenozine production

FIELD: chemistry.

SUBSTANCE: method implies that suspension 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranozile)purine in 60% anhydrous hydrogen fluoride solution of pyridine is diazotizied with tert-butylnitrite during 1 hour at (-18) - (-22)°C. Reaction mixture is decomposed with cut ice. Reaction product is purified by, flash-chromatography on aluminum oxide. Then produced 2-fluorine-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranozile)purine is hydrogenated at air pressure in 10% acetic acid solution of absolute ethyl acetate with 10% palladium on carbon solution occurrence during 18 hours. Reaction product is purified in acetonitrile solution by flash-chromatography on aluminum oxide at 50-55°C and crystallized from alcohol.

EFFECT: production of compound of high purity with high output.

2 ex

 

The invention relates to organic chemistry, specifically to a method for producing a synthetic precursor of 2-peradenia used in the production of the substance drug fludarabine [2-fluoro-9-(arabinofuranosyl)adenine-5-monophosphate], used for the treatment of neoplastic diseases of the blood.

A method of obtaining 2',3,5'-tri-O-acetyl-2-peradenia involving diazotization of 1.2 mmol of 2-amino-6-fluoro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine 1.7 mmol tert.-butyl nitrite in 5.2 ml of a 60%aqueous solution of hydrogen fluoride in pyridine at -30°C, the reaction product is obtained by decomposing the reaction mixture with crushed ice, and then the ammonolysis of the resulting 2,6-di-fluoro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl) purine 15%solution of anhydrous dimethoxyethane effect of dried ammonia for 15 min at 20°C. the Yield of the target product, isolated by precipitation with chloroform from one stripped off the reaction mixture, is 56% [M.J.Robins, Uznanski. Nonqueous diazotization with tert butyl nitrite. Introduction of fluorine, chlorine and bromine at C-2 of purine nucleosides. Can. J. Chem., 59 (17): 2608-2611 (1981).

A known modification of this method consists in the fact that 57.8 mmol of 90%tert.-butyl nitrite is added over 45 min to a cooled to 0-(-)5°With a solution of 41.3 mmol 2-amino-6-fluoro-substituted purine in 125 ml of 56%aqueous solution of hydrogen fluoride in pyridine. P the following ammonolysis and identification of target Poduct conduct known way and get supercriticality 2',3',5'-tri-O-acetyl-2-Tardenois with the release of 61.4% [J.G.Bauman, R.C.Wirsching. Process for the preparating of fludarabine or fludarabine phosphate from guanosine. US Patent 5668270 Sept., 1997, CL 536/26 .71].

The disadvantage of this method is the limited availability of source 2-amino-6-fluoro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine, obtained with the yield of 93% action 69 mmol spray-dried potassium fluoride 4.7 mmol 2-amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine in 45 ml of anhydrous dimethylformamide in the presence of 2.1 mmol of trimethylamine at 20°in for 14 h, followed by separation of the target product by evaporation of the reaction mixture and purification in chloroform solution by filtration through a membrane filter [M.J.Robins, B.Uznanski. Conversions of adenosine and guanosine to 2,6-di-chloro, 2-amine-6-chloro and derived purine nucleosides. Can. J. Chem., 59 (17); 2601-2607 (1981)].

Known closest to the claimed method of obtaining 2',3',5'-tri-O-acetyl-2-peradenia, including hydrogenation under hydrogen pressure 23.3 mmol 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine in 150 ml of 2-methoxyethanol for 12 h in the presence of 3 g of 10%palladium on coal and subsequent diazotization reaction product 3.4 mmol of 90%tert.-butylnitrite in 10 ml of 56%aqueous solution of hydrogen fluoride in pyridine at-10-(-)15°C. the yield of the crude target compound was 53%

[US Patent 5668270, CL 536/26 .71, 1997]

The disadvantage of this method is the low yield and purity of the target product is the one as well as the application of a 20-fold excess of catalyst under hydrogenation carried out in a special apparatus.

The invention solves the problem of simplifying the method of producing 2',3',5'-tri-O-acetyl-2-fluoro-adenosine purity not less than 99% with increased output.

This object is achieved due to the fact that in a method of producing 2',3',5'-tri-O-acetyl-2-fluoro-adenosine pre-suspension of 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine 60%solution of hydrogen fluoride in pyridine diasterous tert.-butylnitrite within 1 hour (-18)-(-22)°C, the reaction mixture is decomposed crushed ice, the reaction product is cleaned in a solution of chloroform flash chromatography on aluminium oxide, and then the resulting 2-fluoro-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine hydronaut at atmospheric pressure in a 10%solution of acetic acid in the abs. the ethyl acetate in the presence of 10%palladium on coal for 18 h, the reaction product is cleaned in a solution of acetonitrile flash chromatography on aluminium oxide at 50-55°and crystallized from alcohol.

The essence of the method consists in carrying out the diazotization tert.-butylnitrite added at a rate of 10 ml/hour to a suspension of 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (-18)-(-22)°With 60%solution of hydrogen fluoride in pyridine, the cleaning of the reaction product in a solution of chloroform flash chromatography on aluminium oxide and in carrying out the hydrogenation of the resulting 2-fluoro-6-azido-9-(2,3,5-tri-O-acetyl-β -D-ribofuranosyl)purine in 10%solution of acetic acid in the abs. the ethyl acetate at atmospheric pressure in the presence of catalytic amounts of 10%palladium on coal, purification of the target product in a solution of acetonitrile flash chromatography on aluminium oxide at 50-55°C.

This method allows to synthesize 2',3',5'-tri-O-acetyl-2-Tardenois purity not less than 99% with the release of 66.4%.

The invention is illustrated by the examples.

Example 1.

2-Fluoro-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine

To 32 ml of a 60%aqueous solution of hydrogen fluoride in pyridine, cooled to -20°C, under stirring was added 16 g (36.86 mmol) dried 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine, and then for 1 h added dropwise 9 ml (75.5 mmol) of tert.-butyl nitrite. The reaction mixture was stirred for 15 min and poured into a mixture of 150 g of crushed ice and 150 ml of chloroform. The resulting aqueous solution is separated and the chloroform extract washed with 2×100 ml of water, 3×100 ml of 5%sodium bicarbonate solution, 2×100 ml of water, dried with magnesium sulfate, and then filtered through a column of 70 g of aluminum oxide. The column was washed with 100 ml of chloroform, combine the filtrates, evaporated and obtain 12.1 g (75.1%) of chromatographically homogeneous target connection.

When 7-fold reproduction of this method of 0.34 mol 2-amino-6-azido proizvodnjo purine receive 0.25 mol of the target product, the average output of which is 73%. Mass spectrum: m/z 410(M+H-N2)+, 368.5 (M+H-N2, COCH2)+, 326.4 (M+H-N2, 2COCH2)+, 260.4 (Sug+H)+, 151.4 (B+H-N2)+.

Example 2.

2-Fluoro-6-amino-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine

It was saturated with hydrogen a mixture of 600 ml of 10%solution of glacial acetic acid in abs. the ethyl acetate with 0.3 g of 10% palladium on coal added 50 mmol 2-fluoro-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine in 300 ml of the above solution of acetic acid in ethyl acetate. The reaction mixture was stirred in an atmosphere of hydrogen for 18 h, and when the slow absorption of hydrogen, the mixture periodically purge. After completion of the hydrogenation, the reaction mixture is filtered, the filtrate is successively washed with 3×300 ml of water, 2×200 ml of 5%sodium bicarbonate solution, 2×200 ml of water, dried over magnesium sulfate and evaporated. The residue is dissolved in 1 l of abs. acetonitrile at 55-60°and the solution is filtered through a column of 25 g of aluminum oxide and 1 g of activated charcoal at 50-55°C. the Column with sorbent is washed with 250 ml of acetonitrile at the same temperature, the filtrates are combined and concentrated to a total volume of 600 ml of the resulting suspension crystallization allocate 17.5 g (85.1%) 2',3',5'-tri-O-acetyl-2-peradenia, TPL 209-210°C. Recrystallization of this product is that of 700 ml of ethanol 16.3 g (79.1%) of target compound, TPL 210-212°C. HPLC 5.40 (99.7%). Mass spectrum: m/z 432.9 (M-H+Na)+, 412 (M+H)+, 386.6 (M+H-CN)+, 366.9 (M-H, CH3WITH), 352.8 (M-AcOH)+, 259.3 (Sug)+, 217.2 (Sug-CH2CO)+. Range1H NMR (DMSO-d6): δ 8.33 (s, 1H, 8-H), 7.90 (s, 2H, NH2), 6.11 (d, 1H, J=5.86 Hz, 1'-H), 5.90 (t, 1H, J1=J2=5.71 Hz, 2'-H), 5.57 (t, 1H, J1=J2=5.71 Hz, 3'-H), 4.35-4.40 (m, 2H, 5'-H2), 4.23 (dt, 1H, J1=5.6, J2=11.5 Hz, 4'-H), 2.10 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H, PINES3).

Of the total uterine solutions described above emit 3.55 g of crystalline product, TPL 207-211°With additional cleaning which gives 2.8 g (13.6%) of target compound. The total yield of tri-O-acetyl-2-peradenia is 19.07 g (92.7%).

When 7-fold reproduction of this technique from 0.267 mol 2-fluoro-6-acidproducing purine receive 0.243 mol of the target product, which corresponds to its 91%increase average output.

The way to obtain 2',3',5'-tri-O-acetyl-2-peradenia, consisting in the fact that pre-suspension of 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine 60%solution of hydrogen fluoride in pyridine diasterous tert.-butylnitrite for 1 h at (-18)-(-22)°C, the reaction mixture is decomposed crushed ice, the reaction product is cleaned in a solution of chloroform flash chromatography on aluminium oxide, and then the resulting 2-fluoro-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranose who yl)purine hydronaut at atmospheric pressure in 10%acetic acid solution in absolute ethyl acetate in the presence of 10%palladium on coal for 18 hours, the reaction product is cleaned in a solution of acetonitrile flash chromatography on aluminium oxide at 50-55°and crystallized from alcohol.



 

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FIELD: chemistry.

SUBSTANCE: invention applied for relates to process of obtaining 2,6- dichlor-9-(2,3,5-tru-O-acetyl-β-D-ribofuranozyl) purine and may be used in organic chemistry and pharmaceutical industry. The process involves conduction of 2,6- dichlor-9-(2,3,5-tru-O-acetyl-β-D-ribofuranozyl) purine with tret-butyl nitrite in the methylene chloride medium at (-18)-(-22)°C during 2 hours in presence of pyridine hydrochloride and phosphorus oxychloride followed by decomposing the reaction mixture with chipped ice, and cleansing of the target product in methylene chloride with flash-chromatography on silica gel.

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1 ex

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SUBSTANCE: this invention covers method of production of 2-chloroadenosine and may be used in organic chemistry and pharmaceutical industry. The method includes ammonolysis of 2.6-di-chloro-9-(2,3,5-tri-O-acetyl-(β-O-ribofuranozyl)purine in absolute ethyl acetate saturated with ammonia at 0°C during 3 days with further hydrolysis of obtained 5'-0-acetyl-2-chloro-adenosine with 20% ammonia solution in methanol at 20°C during 6 hours, isolation of desired product from the reaction mixture by boiling in mixture of chloroform and methanol, their volumetric ratio 3:1, and purification by crystallization from water.

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FIELD: organic chemistry, medicine.

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15 cl, 6 ex, 5 dwg

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