Method of production of 2-chloroadenosine

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

 

The invention relates to organic chemistry, specifically to a method for producing 2-chlorobenzene used for the production of pharmaceutical drug Cladribine, intended for the treatment of neoplastic diseases of the blood.

A method of obtaining 2-chlorobenzene action within 7 days of a saturated solution of ammonia in methanol at 5°With pressure on 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine. The yield of the target product is 57%.

The disadvantage of this method is the low yield of the target product in combination with the use of special equipment.

Known two-stage method of obtaining 2-chlorobenzene, including the state of ammonolysis, leading to the O-acetylamino 2-chlorobenzene, and the stage of hydrolysis of the acetate groups with the formation of the target product. Stage of ammonolysis is performed by the action of dry ammonia in 20 ml of anhydrous dimethoxyethane 2.2 mmol of 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine at 20°C for 8 h, the reaction product highlight gradient chromatography and get 2',3',5'-tri-O-acetyl-2-chloramination with the release of 91%. Stage hydrolysis by this method is carried out by the action of saturated ammonia in methanol solution at 5°C for 7 days [M.J.Robins, B.Uznanski. Conver versions of adenosine to 2,6-dichloro, 2-amino-6-chloro and derived purine nucleosides. Can. J. Chem., 59(17): 2601-207 (1981)].

The disadvantage of this method lies in the difficulty selection 2',3',5'-tri-O-acetyl-2-chlorobenzene.

Known closest to the claimed method of hydrolysis of 10 mmol of 2',3',5'-tri-O-acetyl-6-chloroguanine action 50 ml of 20%ammonia solution in methanol at 20°C for 6 h and the selection of the target product from one stripped off the reaction mixture by treatment with diethyl ether. Output 6-chloroguanine is 90% [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 lies in the complexity of the selection of the target product.

The invention solves the problem of simplifying the process of obtaining 2-chlorobenzene purity not less than 99%.

The problem is solved due to the fact that the method of obtaining 2-chlorobenzene includes the ammonolysis of 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine in absolute ethyl acetate, saturated with ammonia at 0°C for 3 days, hydrolysis of the resulting 5'-O-acetyl-2-chloro-adenosine treatment 20%solution of ammonia in methanol at 20°C for 6 hours, the selection of the target product from the reaction mixture by boiling in a mixture of chloroform and methanol at their volumetric ratio of 3:1 and the purification of the target product by crystallization from water.

The essence of the method consists in carrying out the ammonolysis in absolute ethyl acetate, saturated with ammonia, the ri 0° C for 3 days, hydrolysis of the resulting 5'-O-acetyl-2-chlorobenzene a 20%solution of ammonia in methanol at 20°C for 6 h and the selection of the desired product boiling of the reaction product in a mixture of chloroform and methanol at their volumetric ratio of 3:1.

This method allows to synthesize 2-chloramination 100%purity with a yield of 97%.

The invention illustrates the example.

Example

The mixture 111.8 mmol of 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine in 900 ml of abs. ethyl acetate is saturated with dry ammonia at 0°C and maintained at this temperature in an atmosphere of ammonia for 3 days, the reaction mixture was evaporated, to the residue was added 900 ml of methanol and the resulting suspension with stirring again saturated with ammonia at 20°C for 6 h, cooled to 0°With solution discolor activated charcoal, filtered and the filtrate evaporated. The residue is boiled for 30 min in a mixture of chloroform and methanol at their volumetric ratio of 3:1, the precipitate is filtered off and crystallized from 450 ml of water. Get 95.25 mmol (85%) of 2-chlorobenzene 100%clean, TPL 188-189°C. the mother liquor is evaporated, the residue is dissolved in 120 ml of 20% solution of ammonia in methanol at 20°C, the mixture is stirred for 4 h and the above-described method are 13.4 mmol target product, the total yield is 97%. Mass spectrum: m/z 301.05 (M) +, 323.40 (M-H+Na)+, 169.38 (B+H)+, 134.42 (Sug+H)+. Range1H NMR (DMSO-d6): δ8.4 (s, 1H, 8-H), 7.85 (s, 2H, NH2), 5.84 (d, 1H, 1'-H), 4.51 (dd, 1H, 2'-H), 4.16 (m, 1H, 3'-H), 3.95 (m, 1H, 4'-H), 3.65, 3.55 (m, 2H, 5'-H2).

The method of obtaining 2-chlorobenzene, including the ammonolysis of 2,6-di-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine in absolute ethyl acetate, saturated with ammonia at 0°C for 3 days, and hydrolysis of the resulting 5'-O-acetyl-2-chloro-adenosine treatment 20%solution of ammonia in methanol at 20°C for 6 h, the selection of the target product from the reaction mixture by boiling in a mixture of chloroform and methanol at their volumetric ratio of 3:1 and purification by crystallization from water.



 

Same patents:

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-

The invention relates to novel acyl derivatives of guanosine formula I, inosine formula II, xanthosine formula III, deoxyinosine formula IV, deoxyguanosine formula V, inosine - 2',3'-(acyclic)dialcohol formula VI or pharmaceutically acceptable salts

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

The invention relates to derivatives of adenosine General formula I, where R1is a hydrogen atom, halogen atom, lower alkyl, lower-alkyl, lower S-alkyl or phenyl, and may be in the 2 - or 5-position of the indole; n = 0, 1, and 2, R2- lower alkyl, lower alkenyl, lower quinil,3-C7-cycloalkyl or lower-alkyl, phenyl, possibly substituted by 1-4 substituents selected from a halogen atom, nitro, lower alkyl or O-alkyl groups or a group-NR6R7where R6and R7a hydrogen atom, lower alkyl; pyridyl; thienyl, naphthyl, and in the case when n = 2, R2group-NR8R9where R8and R9at the same time are lower alkyl or form together with the nitrogen atom to which they are attached, a heterocycle selected from the research, piperidine; R3and R4the same or different, is a hydrogen atom or lower alkyl, exhibiting analgesic and antihypertensive activity

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.

SUBSTANCE: in compound of formula (I): , R1 represents C1-4-alkoxy C3-6cycloalkyl optionally substituted with atom of halogen, hydroxyl, trifluoromethyl, optionally substituted with halogen atom 5-6-member heterocyclyl, in which heteroatoms are selected from oxygen, optionally substituted with halogen atoms phenyl or optionally substituted with halogen atoms 5-6-member heteroaryl, in which heteroatoms are selected from nitrogen and/or sulfur; R2 represents hydrogen or trifluoromethyl; R3 represents hydrogen, optionally substituted with atom of halogen, C3-6cycloalkyl, optionally substituted with atom of halogen, trifluoromethyl, C1-4-alkyl phenyl, optionally substituted with atom of halogen, trifluoromethyl, C1-4-alkoxy heterocyclyl, which has in ring 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, or optionally substituted with C1-4-alkyl 5-6-member heterocyclyl, which has in ring 1-2 heteroatoms, selected from nitrogen or oxygen, R4 and R5 independently represent hydrogen; X represents covalent bond or lower alkylene; X1 represents covalent bond or lower alkylene, Y represents covalent bond or lower alkylene, optionally substituted with hydroxy or cycloalkyl; and Z represents -C=C-, -R6C=CR7- or -CHR6CHR7-, where R6 and R7 in each position represent hydrogen or lower alkyl.

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.

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: 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

Up!