Process of obtaining 2,6- dichlor-9-(2,3,5-tri-o-acetyl-β-d-ribofuranozyl) purine

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.

EFFECT: obtaining of substance with high grade of purity and high output by simplified technology.

1 ex

 

The invention relates to organic chemistry, specifically to a method for producing 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine, representing the precursor 2-chlorobenzene used in the production of pharmaceutical drug Cladribine (2-chloromethoxypropyl).

A method of obtaining 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine, including action 72.5 mmol of sodium nitrite at 23.4 mmol 2-amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine in 75 ml of 37%hydrochloric acid at 0°C, followed by decomposition of the reaction mixture with ammonium hydroxide. Yield of the crude target compound is 44% [J.F.Gerster, R.K.Robins. "The synthesis of 2-fluoro - and 2-chloroinosine and certain derived purine nucleosides." J.Org.Chem., 31(10):3258-3267 (1966).

The disadvantage of this method is the low yield of the target product.

A method of obtaining 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine, including action 838 mmol nmental nitrite at 819 mmol 2-amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine in 3 l of methylene chloride in the presence of 1.79 mol triphenylmethane and 65 g of potassium carbonate at 40°With subsequent isolation of the target product of the gradient chromatography on silica gel. The yield of the target compound is 74% [R.H.K.Chen et al. "A process for preparing 2-chloro-2'-deoxyadenosine". EP 0547910 B1, 05.03.1997, Int. CL C07H 19/167].

The disadvantage of this method SOS is the RTO in the application of the chromatographic method of separation of target compounds.

Known closest to the claimed method of obtaining 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine, including action 26 mmol of tert.-butyl nitrite in 5 mmol of 2-amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine in 80 ml of dichloroethane in the presence of 7 mmol antimony trichloride at -10°C followed by decomposition of the reaction mixture with crushed ice. The yield of the target product is 84% [M.J.Robins, B.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).

The disadvantage of this method lies in the use of antimony trichloride with toxic and strong corrosion properties.

The invention solves the problem of obtaining 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine more technological way.

This goal is achieved due to the fact that in a method of producing 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine, including the diazotization of 2-amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine tert.-butyl nitrite and decomposition of the reaction mixture with crushed ice, the diazotization is carried out in the environment methylene chloride at (-18)-(-22)°C for 2 h in the presence of pyridine hydrochloride and phosphorus oxychloride, and after decomposition of the reaction mixture additionally carry out purification of the target product in methylene chloride flash chromatogra what s on silica gel.

The essence of the method consists in carrying out the reaction of diazotization 382.8 mmol of tert.-butyl nitrite 234.2 mmol 2-amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine in 2 l of methylene chloride at (-18)-(-22)°in the presence 273.5 mmol of phosphorus oxychloride and 472 mmol of pyridine hydrochloride for 2 h with subsequent flash chromatography of the selected reaction product in chlorinated solvents.

This method allows to simplify the technology and obtain the target product are 100%purity with a yield of 74%.

The invention illustrates the example.

Example

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

To a cooled to 0°stir the solution 234.2 mmol 2-amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine and 477 mmol of dried pyridine hydrochloride in 2 l of anhydrous methylene chloride are added 273.5 mmol of phosphorus oxychloride, the mixture is cooled to -20°and within 2 hours add 382.8 mmol of tert.-butyl nitrite. The mixture continues to be stirred for another 6 h at a temperature not exceeding 0°C, poured over 300 g of crushed ice, the reaction product is extracted with chloroform, the extract was successively washed with 3×300 ml of water, 2×300 ml of 5%sodium bicarbonate solution and again 2×300 ml of water, and then dried over magnesium sulfate and filtered through a column of 200 g of silica gel. Column PR is myauth 450 ml of chloroform, the filtrate is evaporated in vacuo, the residue is crystallized from isopropanol and get 77.8 (74.5%) of target compound, TPL 167-169°C. Mass spectrum: m/z 445.5(M-H)+, 420.4(M-CN)+, 404.2(M-CH2CO)+.

The method of obtaining 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine, including the diazotization of 2-amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine tert.-butyl nitrite and decomposition of the reaction mixture with crushed ice, characterized in that the diazotization is carried out in the environment methylene chloride at (-18)-(-22)°C for 2 h in the presence of pyridine hydrochloride and phosphorus oxychloride, and after decomposition of the reaction mixture additionally carry out purification of the target product in methylene chloride flash chromatography on silica gel.



 

Same patents:

FIELD: chemistry.

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.

EFFECT: production of substance with high purity.

1 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I) wherein each among R represents independently hydrogen atom, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, phenyl or phenyl-(C1-C3)-alkyl; X and X' represent -CH2OH, -CO2R2, -OC(O)R2, -CH2OC(O)R2 or C(O)NR3R4 wherein R2, R3 and R4 represent independently hydrogen atom (H), (C1-C6)-alkyl substituted optionally with one-three (C1-C6)-alkoxy-groups, (C1-C6)-alkylthio-groups, halogen atoms, hydroxy-, amino-, mono-(C1-C6)-alkyl)-amino-, di-(C1-C6)-alkyl)-amino-group; Z and Z' represent independently (C1-C6)-alkyl broken optionally with one-three sulfur atoms (S) or non-peroxide oxygen atom (O), or they absent; n = 1-3; or to its pharmaceutically acceptable salt. Compounds are agonists of adenosine A2A-receptors and can be used for inhibition of inflammatory response or inflammation treatment.

EFFECT: valuable medicinal properties of compounds.

56 cl, 1 tbl, 21 dwg, 37 ex

The invention relates to nucleoside analogs of formula (1) in which R1represents H or a group protecting the hydroxyl, R2represents H, a group protecting the hydroxyl group of phosphoric acid, a protected group, phosphoric acid or a group of the formula P(R3R4in which R3and R4are the same or different and represent a hydroxyl group, a protected hydroxyl group, alkoxygroup, allylthiourea, cyanoacetylurea, amino group, substituted alkyl group; And represents alkylenes group containing from 1 to 4 carbon atoms, and a represents a substituted purine-9-ilen group or substituted 2-oxopyrimidine-1-ilen group containing at least one Deputy, selected from hydroxyl groups, protected hydroxyl groups, amino groups, protected amino groups, alkyl groups

The invention relates to medicine and provides substances that are effective against tumors and viruses, for which conventional anti-tumor agents and antiviral agents exhibit only insufficient effects, and have cancerostatic action and antiviral effects on different tumor immune

The invention relates to certain oxipurinol the nucleosides, compounds related data oxipurinol the nucleosides, acyl derivatives and compositions that contain at least one of these compounds

The invention relates to purine derivative of L-nucleoside of the formula (I), where R1, R2', R3' and R4- N; R2, R3and R5- HE; Z1- N; Z2selected from N and CH; Z3- NR-, -C(R)2, -S-, where R, same or different, selected from H, Br, NH2, alkyl and alkenyl; Z4selected from C=O, -NR-, -C(R)2- where R, same or different, selected from H and Br; Z5Is N; X is selected from H, HE, SH, -SNH2, -S(O)NH2, -S(O)2NH2Y from H and NH2; W is O, and Y represents NH2then Z3is not a-S-

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The invention relates to O6substituted derivatives of guanine, method of their production and to their use for the treatment of tumor cells

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I) wherein each among R represents independently hydrogen atom, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, phenyl or phenyl-(C1-C3)-alkyl; X and X' represent -CH2OH, -CO2R2, -OC(O)R2, -CH2OC(O)R2 or C(O)NR3R4 wherein R2, R3 and R4 represent independently hydrogen atom (H), (C1-C6)-alkyl substituted optionally with one-three (C1-C6)-alkoxy-groups, (C1-C6)-alkylthio-groups, halogen atoms, hydroxy-, amino-, mono-(C1-C6)-alkyl)-amino-, di-(C1-C6)-alkyl)-amino-group; Z and Z' represent independently (C1-C6)-alkyl broken optionally with one-three sulfur atoms (S) or non-peroxide oxygen atom (O), or they absent; n = 1-3; or to its pharmaceutically acceptable salt. Compounds are agonists of adenosine A2A-receptors and can be used for inhibition of inflammatory response or inflammation treatment.

EFFECT: valuable medicinal properties of compounds.

56 cl, 1 tbl, 21 dwg, 37 ex

FIELD: chemistry.

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.

EFFECT: production of substance with high purity.

1 ex

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.

EFFECT: obtaining of substance with high grade of purity and high output by simplified technology.

1 ex

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

FIELD: chemistry.

SUBSTANCE: invention pertains to the method of obtaining 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine and can be used in organic chemistry and pharmaceutical industry. The method lies in that, 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine and sodium azide interact in the presence of the above mentioned tetrametylammonium chloride boiled for 4 hours in absolute acetonitrile. The obtained compound is cleaned by elution of benzol. The residue is dissolved in chloroform and the desired product is separated during precipitation using hexane.

EFFECT: high degree of purity with high output.

1 ex

FIELD: chemistry.

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EFFECT: antilipolytic effect of compounds.

30 cl, 7 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to phosphoramidite derivatives of general formula where Bx denotes adenine, guanine, cytosine, thymine or uracil, where the amine group of adenine, guanine and cytosine can be optionally protected by a protective group selected from acetyl and phenoxyacetyl; R1 is a substitute of general formula in which R11, R12 and R13 are identical or different, and each denotes hydrogen or alkoxy; R2a and R2b are identical or different, and each denotes alkyl; and WG1, WG2 denote a cyano group. The invention also pertains to a multistep method of producing the said compounds. The invention also relates to intermediate compounds of the said method, namely: an intermediate ether compound of general formula where L is a halogen or a C1-C5alkylthio group; WG1 is a cyano group; an intermediate compound of general formula where Bx denotes adenine, guanine, cytosine, thymine or uracil, where the amine group of adesine, guanine and cytosine can be optionally protected by a protective group selected from an acetyl group and a phenoxyacetyl group; and WG1 denotes a cyano group; an intermediate compound of general formula where Bx is as described above; R1 is a substitute of general formula (2); an intermediate compound of general formula where Bx is as described above; A is a silicon-containing substitute of general formula or where R6 denotes alkyl and WG1 denotes a cyano group. The invention also relates to a method of producing an oligonucleotide of general formula where each B independently denotes adenine, guanine, cytosine, uracil or thymine; each R independently denotes H or hydroxyl and at least one of R denotes hydroxyl; Z denotes H or a phosphate group; and n is an integer between 1 and 100, involving steps A-G, characterised by use of said phosphoramidite derivatives as a monomer compound of nucleic acid at step B.

EFFECT: high yield.

7 cl, 1 dwg, 21 ex

FIELD: chemistry.

SUBSTANCE: nucleic base (e.g. uracil, cytosine, adenine, guanine, hypoxanthine, xanthine or similar) reacts with perfluoroalkyl halide in the presence of sulphoxide, peroxide and an iron compound to obtain a perfluoroalkyl-substituted nucleic base.

EFFECT: high cost effectiveness as an intermediate compound for producing medicinal agents.

15 cl, 6 tbl

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.

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15 cl, 7 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for large-scale production of a A2A_adenosine receptor agonist, particularly 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: . The invention also discloses methods of producing intermediate products used to produce said monohydrate, and directly the 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.

EFFECT: novel methods of producing 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide, which enable to obtain large amounts of the end product with good output and high degree of purity.

15 cl, 6 ex, 5 dwg

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