Method of producing alkyl-substituted 2-desoxy-2-fluoro-d-ribofuranosyl-pyrimidines and purines and derivatives thereof

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 and R5 independently denote H, benzoyl, pivaloyl or methoxymethyl. The invention also

relates to a method of producing one of the said compounds

(formula 45), involving the following steps: (a) reaction of compound

with alkyl-2-bromopropionate in the presence of activated zinc in a suitable solvent to obtain a compound of formula

; (b) adding an oxidising agent to obtain a ketone of formula

; (c) fluorination of the product from step (b) to obtain a fluorinated ketone of formula

; (d) reduction of the fluorinated ketone from step (c) to obtain a compound of formula

; (e) benzylation of the product from step (d) to obtain a compound of formula

, where Bz denotes benzoyl; (f) cyclisation of the product from step (e) to obtain lactone of formula 45 as the end product.

EFFECT: lactones can be used in synthesis of nucleosides with high anti-HIV activity.

8 cl, 17 ex

 

The scope to which the invention relates.

The invention provides (i) a method of obtaining a derivative of 2-deoxy-2-fluoro-2-methyl-D-ribonolactone, (ii) the conversion of the lactone in nucleosides with potent anti-HIV activity and their analogues, and (iii) the method of obtaining anti-HIV nucleosides containing 2'-deoxy-2'-fluoro-2'-C-methyl-β-D-ribofuranosylpurine of prior nucleoside, preferably of natural origin.

Background of invention

HIV infection has reached epidemic levels worldwide, and has tragic consequences for infected patients. Currently, there is no universally effective treatment for this infection, and the only drugs available for the treatment of chronic hepatitis C are different forms of interferon-alpha (IFN-α), or one, or in combination with ribavirin. However, therapeutic value of these treatments has been compromised largely because of the harmful effects that necessitated the creation of additional treatment methods.

HIV is an enveloped virus of the small size of the collection flaviviruses with positive-strand RNA genome with a length of ~9,6 Tino in the nucleocapsid. The genome contains a single open reading frame (ORF)encoding polyblock from more than 300 amino acids, who split with the formation of the Mature structural and non-structural viral proteins. ORF planiruetsja 5'- and 3'-noncoding sites (NTR's) of several hundred nucleotides, which are important for translation and replication of the RNA. Broadcast polyblock contains the structural core (C) and envelope proteins (E1, E2, P7) at the N-end and then non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, NA5B). Mature structural proteins are formed by splitting the host signal peptidases. The junction between NS2 and NS3 autocatalytically split NS2/NS3 protease, while the other four compounds are decomposed domain NS3 N-terminal serine protease, formed a complex with NS4A. Protein NS3 also has an NTP-dependent activity of helicase, which spins Dunaeva RNA during replication. Protein NS5B has the activity of RNA-dependent RNA polymerase (RDRP), which is essential for viral replication. It should be emphasized that in contrast to HBV or HIV, HCV replication DNA is not involved.

In the application U.S. No. 10/828753 indicated that 1-(2-deoxy-2-fluoro-2-C-methyl-β-D-ribofuranosyl)pitosin (14) is active and selective anti-HIV agent. Methods of synthesis (Schemes 1-3) are not effective, the product yield is 4% or less, and these methods are not applicable on an industrial scale.

Scheme 1

Scheme 2

Scheme 3.

Reagents: (a) SOCl2/CH3CL, arr. cold.; b) NaOEt/EtOH/reverse, cold.;

C) TIPSDSCl2/pyridine /room temperature; (d) CDF3/AU2O/pyridine/room temperature; (e) MeLi/Et2O, -78°C; (f) MeMgBr/Et2O, -50°C; (g) TBAF/THF; (h) Ac2O/PIR; i) DAST/toluene; (j) NH3/MeOH; (k) 1N NaOH/THF/60°C.

You must create a new and economical method for the synthesis of 2-alkyl-2-substituted D-ribofuranosylpurine that have activity against HCV (hepatitis C virus).

The invention

The invention described in this application relates to compositions and methods of synthesis of compounds of General formulas [I] and [II]:

where

X denotes a halogen (F, Cl, Br);

Y denotes N or CH;

Z denotes halogen, HE, OR', SH, SR', NH2That other' or R';

R2' represents C1-C3alkyl, vinyl or ethinyl;

R3'and R5'may be the same or different and denote H, alkyl, aralkyl, acyl, cyclic acetal, such as 2',3'-O-isopropylidene or 2',3-O-benzyliden or 2',3'-cyclic carbonate;

R2, R4, R5and R6independently denote H, halogen, including F, Cl, Br, I, HE, OR', SH, SR', N3, NH2That other', NR'2, NHC(O)OHR', lower C1-C6alkyl, halogenated (F,Cl, Br, I) lower C1-C6alkyl, such as CF3and CH2CH2F, lower1-C6alkenyl, such as CH=CH2, halogenated (F, Cl, Br, I) lower2-C6alkenyl, such as CH=SNS, SN=ADHD and SN=l, lower2-C6quinil, such ashalogenated (F, Cl, Br, I) lower2-C6quinil, hydroxy-lower C1-C6alkyl such as CH2HE and CH2CH2HE, halogenated (F, Cl, Br, I) lower C1-C6alkyl, lower C1-C6alkoxy, such as methoxy, ethoxy, CO2N, CO2R', CONH2, CONHR', CONR'2CH=CHCO2H, CH=CHCO2R'; and

R' denotes a possibly substituted C1-C12alkyl (particularly when the alkyl is an amino acid residue), cycloalkyl, possibly substituted C2-C6quinil, possibly substituted With lower2-C6alkenyl or possibly substituted acyl.

According to other aspects, the invention provides methods for producing nucleosides containing fragment 2-deoxy-2-fluoro-2-C-methyl-D-ribofuranosyl, the General formula III or IV:

by (i) synthesis of 3,5-protected intermediate 2-deoxy-2-fluoro-2-C-methyl-D-ribono-γ-lactone, the General formula V, (ii) transformation of V in purine and pyrimidine nucleosides of observerall III and IV, and (iii) receiving nucleoside of the General formulas III and IV of the prior, preferably, the natural nucleosides:

With regard to formulas III, IV and V above, R4and R5indicated above, and R3and R5can independently denote H, Me, acyl (such as Ac, Bz, substituted Bz), benzyl, substituted benzyl, trityl, trialkylsilyl, treborlegreos, trebovaniyam, TIPDS, TNR, MOM, MEM, or R3and R5associated through-SiR2-O-SiR2or SiR2-, where R denotes lower alkyl, such as Me, Et, n-WG or ISO-RG.

According to another aspect of the present invention proposed new intermediate lactones of the formula V and the methods of obtaining the intermediate of lactones as described in detail below, including intermediate precursor esters, as also described in detail below.

Detailed description of the invention

At the present time, the means to combat flaviviruses, including hepatitis C virus (HCV), Dengue virus (DENV), West Nile virus (WNV) or yellow fever virus (YFV), is unavailable. The only approved method of treatment is the treatment of HCV infection with interferon alpha or a combination of alpha-interferon with nucleoside ribavirin, but therapeutic value of these methods is low because of the harmful consequences. Recently it was found that the group of nucleosides, including 2'-deoxy-2'-fluoro-2'-C-methylcytidine (14), has a strong and selective activity the capacity for replication of HCV in the system of replicons. However, the difficulties of the chemical synthesis of this and similar nucleoside prevent further biophysical, biochemical, pharmacological studies needed to develop drugs used in clinical settings for the treatment of infections caused by flaviviruses.

This invention provides efficient production of nucleosides containing 2-deoxy-2-fluoro-2-C-methyl-D-ribofuranosyl fragment III and IV, by (i) synthesis of intermediate 3,5-substituted 2-deoxy-2-fluoro-2-C-methyl-D-ribono-γ-lactone of General formula V, (ii) the conversion of compound V in purine and pyrimidine nucleosides of General formulas III and IV, and (iii) receipt of nucleosides of formulas III and IV of the obtained pre -, preferably natural nucleosides.

Definition

The term "independently"as used in this application indicates that the variable used independently varies independently from application to application. So, in the connection, such as RaXYRawhere Ra"independently represents carbon or nitrogen, both Ramay be carbon atoms, both Racan be nitrogen atoms, or one of Ramay be a carbon atom, and the other is a nitrogen atom.

Used the terms "enantiomerically pure" or "enantiomerically enriched" refers to a nucleoside composition that includes at least prima is but 95% and preferably, about 97%, 98%, 99% or 100% of a single enantiomer of that nucleoside.

The terms "practically free" or "almost no" refers to a nucleoside composition that includes at least 85 or 90% wt., preferably, 95-98 wt%, and even more preferably 99-100% weight. the specified enantiomer of that nucleoside. Under the preferred alternative in the implementation of the methods and compounds according to the invention, these compounds contain practically no enantiomers.

The term "alkyl", unless otherwise specified, refers to a saturated linear or branched hydrocarbon chain, typically containing 1-10 carbon atoms, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, trebuil, pentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclo-hexylester, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl etc. This term includes both substituted and unsubstituted alkyl groups. Alkyl groups can be substituted by one or more substituents selected from the group consisting of hydroxyl, amine, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic, sulfate, phosphonic acid, phosphate or phosphonate. One or more hydrogen atoms attached to the carbon atom alkyl groups may be substituted by one or more halo atoms is s, for example fluorine or chlorine, or both, for example, it can be trifluoromethyl, deformity, perchloromethyl etc. Hydrocarbon chain may also be interrupted by heteroatoms such as N, O or S.

The term "lower alkyl", unless otherwise specified, refers to C1-C4 saturated linear or branched alkyl group, including both substituted and unsubstituted groups specified above. If not otherwise stated, in the case of alkyl, preferred is lower alkyl. Similarly, when contains alkyl or lower alkyl, are preferred unsubstituted alkyl or lower alkyl.

The term "cycloalkyl", unless otherwise specified, refers to a saturated hydrocarbon ring containing 3-8 carbon atoms, preferably 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl group can also be substituted in the ring in the alkyl group, for example, it can be cyclopropylmethyl etc.

The terms "alkylamino" or "arylamino" refer to the amino group, which contains one or two alkyl or aryl substituent, respectively.

Used herein, the term "protected", if not otherwise stated, refers to a group that is added to atoms of oxygen, nitrogen or phosphorus to prevent reactions or for other purposes. Megachile the major protective group for the atoms of oxygen and nitrogen is known to experts in the field of organic synthesis. Non-limiting examples include C(O)-alkyl, C(O)Ph, C(O)-aryl, CH3CH2-alkyl, CH2alkenyl, CH2Ph, CH2-aryl, CH2O-alkyl, CH2O-aryl, SO2-alkyl, SO2-aryl, trebuchetgreenhill, Trebujeni-silyl, 1,3-(1,1,3,3-tetraisopropyl-disiloxane).

Used the term "aryl", unless otherwise specified, refers to phenyl, diphenyl or naphthyl, preferably, phenyl. This term includes both substituted and unsubstituted groups. The aryl group may be substituted by one or more substituents, including, but without limitation, the substituents selected from the group consisting of hydroxyl, amine, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic, sulfate, phosphonic acid, phosphate or phosphonate, or unsecured, or, if necessary, protected, as it is known in the art, for example as described in T. W. Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis", 3rded., John Wiley & Suns, 1999.

The terms "alkaryl" or "alkylaryl" refers to an alkyl group, aryl Deputy. The terms "aralkyl" or "arylalkyl" refers to aryl group with an alkyl substitute, such as a benzyl group.

The term "halo" includes chlorine, bromine, iodine and fluorine.

The term "allair" or "O-linked ester" refers to an ester of carboxylic acid of the formula C(O)R', which is not arborina group, ester group, R'denotes a linear or branched alkyl or cycloalkyl, or lower alkyl, alkoxyalkyl, including methoxymethyl, aralkyl, including benzyl, aryloxy-alkyl, such as phenoxymethyl, aryl, including phenyl, possibly substituted with halogen (F, Cl, Br, I), C1-C4alkyl or C1-C4alkoxy, sulfonic ethers, such as alkyl - or aralkylamines, including methanesulfonyl, mono-, di - or trifosfatnogo ether, trityl or monomethoxy-trityl, substituted benzyl, trialkylsilyl (for example, dimethyltrimethylene) or diphenylmethylsilane. Aryl groups in the esters preferably include a phenyl group.

The term "acyl" refers to a group of the formula R"C(O), where R" denotes a linear or branched alkyl or cycloalkyl, the remainder of the amino acid, aryl including phenyl, alkylaryl, aralkyl, including benzyl, alkoxyalkyl, including methoxymethyl, aryloxyalkyl, such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including phenyl, substituted by chlorine, bromine, fluorine, iodine, C1-C4alkyl or C1-C4alkoxy, sulfate group, such as alkyl - or aralkylamines, including methanesulfonyl, mono-, di - or trifosfatnogo ester group, trityl or monomethacrylate, substituted benzyl, alkaryl, aralkyl, including benzyl, alkoxyalkyl, including methoxymethyl, aryloxyalkyl, such as the Hairdryer is kemetyl. Aryl groups in esters optimally represent a phenyl group. In particular, the acyl groups include acetyl, TRIFLUOROACETYL, methylacyl, cyclopropylacetic, cyclopropylmethoxy, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo - heptanol, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, α-methoxy-α-cryptomaterial, bromoacetyl, 2-nitrobenzoate, 4-chlorobenzene-acetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetic, perforated, peracetyl, bromodifluoromethyl, methoxy - acetyl, 2-thiopheneacetyl, chlorosulfonated, 3-methoxyphenylacetyl, phenoxy-acetyl, trebuchetms, trichloroacetyl, monochloracetic, dichloracetyl, 7H-dodecafluoroheptyl, perforation, 7H-dodecafluoroheptyl, 7-chloro-dodecafluoroheptyl, Nona-fluoro-3,6-dioxa-heptanol, nonfor-3,6-dioxa-heptanol, perforation, methoxybenzoyl, methyl-3-amino-5-phenylthiophene-2-carboxyl, 3,6-dichloro-2-methoxybenzoyl, 4-(1,1,2,2-tetrafluoroethoxy)benzoyl, 2-bromopropionyl, omega-aminocaproyl, decanoyl, n-pentadecanol, stearyl, 3-cyclopentylpropionyl, 1-benzopyrrole, acetylindole, pivaloate, 1-adamantanecarbonyl, cyclohexanecarbonyl, 2,6-pyridinecarboxylic, cyclo-propanecarboxylate, CYCLOBUTANE-carboxyl, perforceconfiguration, 4-methylbenzoyl, chloromethylthiazole-carbonyl perforceconfiguration, crotonyl, 1-methyl-1H-indazol-3-carbonyl, 2-propenyl, isovaleryl, 1-pyrrolidinecarbonyl, 4-vinylbenzoic. When you use the term "acyl"means a specific and independent indication of acetyl, TRIFLUOROACETYL, methylacetyle, cyclopropylethyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanol, phenylacetyl, diphenylacetyl of cryptomaterial, bromoacetyl, 4-chlorobenzonitrile, 2-chloro-2-phenyl-acetyl, 2-chloro-2,2-di-phenylacetyl, trimethylacetyl, chlortetracycline, perforate, peracetyl, bromodifluoromethyl, 2-thiopheneacetyl, trebuiutsya, trichloroacetyl, monochloracetic, dichloracetyl, methoxybenzoyl, 2-bromopropionyl, decanoyl, n-pentadecanol, sterile, 3-cyclopentylpropionyl, 1-benzene-carboxyla, pivaloate, 1-adamantanecarboxylic, cyclohexanecarboxylic, 2,6-pyridinedicarboxylic, cyclopropanecarboxylic, paclobutrazol, 4-methylbenzoyl, crotonyl, 1-methyl-1H-indazol-3-carbonyl, 2-propenyl, isovaleryl, 4-phenylbenzyl.

The term "lower acyl" refers to acyl group, in which R"is defined above, refers to lower alkyl.

The term "purine" or "pyrimidine" basis includes, but is not limited to, adenine, N6-alkylphenyl, N6-acylpyrin (where "acyl" refers to C(O) (alkyl, aryl, alkylaryl, arylalkyl)), N6-benzylurea, N6-allopurin, N6-vinluan, N6-aceteminphen, N6-acylpyrin, N6-hydroxyalkylated, N6-allylamine, N6-tollesbury, N2-alkylphenyl, N2-alkyl-6-thiopurine, thymine, cytosine, 5-fertilizin, 5-methylcytosine, 6-etherimide, including 6-Aza-cytosine, 2 - and/or 4-mercaptopyrimidine, 5-halouracils, including 5-fluorouracil, With5-alkylpyridine, With5-benzylpyrimidines, With5-galerimizin, C5-vinylpyridin, C5-acetylspiramycin, With5-arylpyrimidine, With5-hydroxyalkyl-purine, C5-aminopyrimidine, With5-cyanopyrimidine, With5-iterkeys, With5-iterkeys, With6-VG-vinylpyridin, With6-VG-vinylpyridin, With5-nitropyrimidin, With5-aminopyrimidine, N2-alkylphenyl, N2-alkyl-6-thiopurine, 5-Aza-cytidine, 5-azauracil, triazolopyridines, imidazopyridines, pyrrolo-pyrimidinyl and pyrazolopyrimidines. Purine bases include, but are not limited to, guanine, adenine, gipoksantin, 2,6-diaminopurine and 6-chloro-purine. Functional oxygen - and nitrogen-containing groups can be protected, if necessary or desirable. Suitable protective groups are well known in the art, and include trimethylsilyl, dimethylhexylamine, trebuchetgreenhill and trebovaniyam, trityl, alkyl groups and acyl is the group such as acetyl and propionyl, methanesulfonyl and p-toluensulfonyl.

The term "amino acid" includes natural and synthetic α, β, γ or δ-amino acids and includes, without limitation, amino acids contained in proteins, namely, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, Proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. According to a preferred variant of the amino acid has the L-configuration. Or amino acid may be derived Alanya, valenica, lacinia, isoleucine, Proline, phenylalanine, tryptophane, methionine, glycine, cerisola, threonine, cysteine, tyrosine, asparagine, glutamine, aspartame, glutaryl, liinil, arginine, histidine, β-alanyl, β-valenica, β-lacinia, β-isoleucine, β-Proline, β-phenyl-alanine, β-tryptophanyl, β-methionine, β-glycine, β-serinya, β-threonine, β-cysteine, β-tyrosine, β-asparagine, β-glutamine, β-aspartyl, β-glutaryl, β-liinil, β-arginine or β-histidine.

When using the term "amino acid", it is considered that specifically and independently each of the esters of α, β, γ or δ-glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, Proline, serine, threonine, cysteine, tyrosine, asparagine glutamine, aspartate, glutamate, lysine, arginine, and histidine in D - and L-configurations.

The term "pharmaceutically acceptable salt or prodrug", as used in this application, is used to specify any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) of a compound that after the introduction of the patient leads to the formation of the active compounds. Pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include the salts on the basis of alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, along with many other salts of other acids known in the pharmaceutical industry. Pharmaceutically acceptable salts can be acid salts accession formed in the presence of the nitrogen atom. Such salts are derived from pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, sulphuric, phosphoric, acetic, citric, tartaric acid and other Pharmaceutically acceptable prodrugs indicate a compound that is converted in the course of metabolism, for example hydrolyzed or oxidized, in the molecule-the host with the formation of compounds according to this invention. Typical examples of prodrugs including the Ute connection which contain biologically unstable protective group in the functional group of the active compounds. Prodrugs include compounds that can be oxidized, restored, laminirowany, diaminononane, gidroksilirovanii, dehydrosilybin, hydrolyzed, digitalizovane, alkylated, dialkylamide, etilirovany, diallylamine, phosphorylated, the dephosphorylated with the formation of active connections.

Getting connections

(i) Synthesis of 3,5-di-O-protected D-ribono-γ-lactone

The Wittig reaction of 2,3-O-isopropylidene-D-glyceraldehyde 39 (Scheme 4) with commercially available compound 40 allows to obtain (E)-product 41 as the primary connection. Dihydroxypropane (J. Org. Chem., 1992, 57, 2768-2771) using AD-mix-β as a reagent dihydroxypropane leads to the formation of only the desired connection 42 c high yield. Lactonization 42 obtaining 2-C-methyl-D-arabino-γ-lactone (46) with a high output is achieved by treatment with HCl/MeOH. Selective O-benzoylation of the primary and secondary Oh-groups leads to the formation of a derivative of 3,5-di-O-benzene 47 high yield. The process of joining 47 DAST or Deoxofluor, [bis-(2-methoxyethyl)amino]sulfur TRIFLUORIDE, under different conditions ensures traces of the desired 2'-fluoro-ribono-γ-lactone 49, but mostly a mixture is formed, from which we distinguish the E. fluorinated ribonolactone (48). However, the process of joining 47 excess, preferably, three (3) equivalents of tertiary amine, preferably aminobutiramida - ethylamine, and the excess, preferably five (5) equivalents of DAST or Deoxofluor, provides the connection 49 with a yield of about 50%. It was also found that the application of 3,5-O-m instead bentilee protection output connection 48 is approaching 90%. Thus, treatment of compound 46 dimethoxymethane in the presence of a strong acid, such as trifluoromethyl-acid provides the connection 50, which after reaction with DAST or Deoxofluor in the presence of a base leads to the formation of compound 49 with the output of the selected product, equal to 87%.

It was also found that even the fluorination can be accomplished by treatment of open-chain monobenzoate 43, which is easily obtained by selective benzoylation of compound 42 using DAST or Deoxofluor, it is desirable ethyl-2-deoxy-2-fluoro-2-C-methyl-3-O-benzoyl-4,5-O-isopropylidene-D-ribnet 44. Lactonization connection 44 leads to the production of γ-lactone 45. Subsequent benzoylation of compound 45 provides education dibenzoate 49.

Scheme 4

According to one variant of the present invention provides a method for the synthesis of intermediate compounds 49 by condensats AI (Reformatskogo) connection 39 with alkyl-2-bromopropionate, such as the connection 53, (Scheme 5) in the presence of activated zinc in ethereal solvent such as diethyl ether or tetrahydrofuran or a mixture of these two solvents), with connection 54, which transform by oxidation in the connection 55. Possible oxidizing agents are activated dimethyl-sulfoxide, such as a mixture of dimethylsulfoxide, triperoxonane anhydride or acetic anhydride (oxidation Swarna-Moffat); chromium trioxide or other chromate; periodinane dess-Martin or perruthenate of tetrapropylammonium (TRAR) with molecular sieves or without them. This oxidation of obtaining p-3 cells, preferably, takes place without affecting the stereochemistry at C-4.

Fluoridation connection 55 is in position 2 with the use of electrophilic fluorination ("F+") in a suitable solvent, such as dimethyl-formamide, tetrahydrofuran, ethanol, trebujena or diethyl ether, or any combination of these solvents known in the art (Rozen, et al., J. Org. Chem., 2001, 66, 7646-7468; Jun-An Ma and Dominique Cahard, Journal of Fluorine Chemistry, 2004, and references listed in these sources) to obtain the connection 56. Some non-limiting examples of electrophilic fluorinating agents include Selectfluor®, N-fluoro-sulfonamide (NFST) and AcOF. Stereoselective ftory which of you can spend in the application of the catalyst, such as asymmetric complex of the transition metal as described Sodeoka et al. (JP 2004010555), or other catalysts. Source β-ketoester 55 may be first converted into caterillar before fluoridation (Rozen, et al., J. Org. Chem., 2001, 66, 7646-7468).

Selective reduction of the C-3 ketone 56 using triphenylsilane in the presence of a Lewis acid such as ll3or in the presence of organic acids, such as triperoxonane acid (Kitazume et al., J. Org. Chem., 1987, 52, 3218-3223) leads to the production of 2,3-antiproductive 57 and 58. However, by applying the stereoselective fluorination in combination with selective restore, you can get a connection 58 with a good yield (with a large diastereomeric excess). Benzylidene connection 58 provides education product 44, which in turn lactone 45, as described above.

Scheme 5

(ii) Receiving nucleosides containing 2-deoxy-2-fluoro-3-methyl-D-ribofuranosyl fragment by condensation.

Lactone, for example, the connection 49, can be recovered to obtain the corresponding sugar using DIBALH. After acetylation anomeric hydroxyl group of the obtained compound 59 (Scheme 12) with great output.

The condensation of 59 with similarbank base (for example, similarbank N4-benzoylation under the reaction conditions Vorbruggen'a) recip who have a mixture of protected anomeric nucleosides 60 and 60. After separation of the anomers get the desired β-nucleoside 14 by removing the protection of the metal alcoholate in alcoholic medium, preferably NaOMe/MeOH, or methanolic ammonia.

Scheme 6

Connection 59 can be turned into a commercially available brominated sugar 61 (Scheme 7), which is condensed with the sodium salt of a purine, for example, sodium salt of N-6-benzyladenine, to obtain the corresponding protected purine nucleoside 62. Desirable free nucleoside 63 can easily be obtained by saponification.

Scheme 7

(iii) Synthesis of prior nucleoside

Using previously obtained nucleosides as starting materials to obtain the desired 2'-C-alkyl-2'-deoxy-2'-fluoro-β-D-ribonucleosides has certain advantages, since the formation of anomers and their subsequent separation can be avoided, resulting in high yields of the target nucleosides.

There were described two methods of obtaining the desired nucleoside 14 of the nucleoside of the original product (Schemes 2 and 3). As indicated above, these methods, however, also lead to two undesirable products 22 and 23, the latter being formed with the participation of neighboring groups, as shown in Scheme 8. The selection of the desired nucleoside 14 of the mixture is quite difficult So this invention prevents the formation of compound 23 with the use of not participating in the reaction of the protective group, such as TPR, methyl, ethyl, benzyl, p-methoxybenzyl, benzoyloxymethyl, phenoxymethyl, methoxymethyl, ethoxymethyl, mesyl, tosyl, TRIFLUOROACETYL, three-chloroacetyl, 3'-Oh group.

Scheme 8

An example is shown in Scheme 17. When N4, 5'-Dibenzoyl-3'-O-mesyl-2'-deoxy-2'-C-methyl-β-D-arabinofuranosylcytosine (64) is treated with DAST or Deoxofluor, produces the desired fluorinated product 65 exit 54% together with the olefin 66 with the release of 39%. As expected, non-fluorinated cytidine derived 67 is not formed in appreciable quantities. There are several ways to remove the protection at the connection 65 with the product 14. An example is shown in Scheme 9, where the double inversion of the 3'-configuration.

Scheme 9

When 3'-O-Deputy does not participate in the reaction and is not removed, such as methoxymethyl (MOM), methyl, benzyl, methoxybenzyl or tetrahydropyranyl, intermediate product perereca more effectively than the connection 64.

The following examples are provided to illustrate the present invention but do not restrict it.

Experimental part:

2,3-O-isopropylidene-D-glyceraldehyde (compound 39) was obtained according to the published methods is e (Organic Synthesis, Annual Volume 72, page 6; J. Org. Chem. 1991, 56, 4056-4058), on the basis of available industrial protected D-mannitol. Other reagents, including the connection 40 and AD-mix-β, also commercially available.

Examples

Example 1

Ethyl-TRANS-2,3-dideoxy-4,5-O-isopropylidene-2-C-methyl-D-glycerin-2-ENOAT (compound 41).

To a solution of (carletonville)triphenylphosphorane (compound 40, 25 g, 69 mmol) in dry CH2CL2(65 ml) at room temperature was added dropwise a solution of 2,3-O-isopropylidene-D-glyceraldehyde (compound 39, 9,41 g of 72.3 mmol) in CH2Cl2(30 ml). The mixture in the day was stirred at room temperature. The reaction mixture was then concentrated to dryness, diluted with petroleum ether (300 ml) and kept for 2 hours at room temperature. Phase precipitate the triphenylphosphine oxide was filtered and an aliquot was concentrated under vacuum. The residue was purified using silikagelevye chromatographic column at 0-1,5% EtOAc in hexano getting connection 41 (10.4 g, 71%) as oil (Carbohydrate Res., 115, 250-253 (1983)).1H NMR (CDCl3): δ of 1.30 (t, J=6.8 Hz, 3H, och2CH3), of 1.41 (s, 3H, CH3), 1,45 (s, 3H, CH3), 1,89 (d, J=1.2 Hz, 3H, 2-CH3), 3,63 (t, J=8.0 Hz, 1H, H-5), 4,14-to 4.23 (m, 3H, H-5' andCH2CH3), a 4.86 (dd, J=7,6 and 13.6 Hz, 1H, H-4), 6,69 (dd, J=1.6 and 8.0 Hz, 1H, H-3).

Example 2

(2S,3R)-3-[(4R)-2,2-dimethyl-[1,3]dioxolane-4-yl]-2,3-dihydroxy-2-meth is propionovoi acid ethyl ester (compound 42).

Into the flask with a round bottom, equipped with a magnetic stirrer, was loaded with 25 ml of tert-VION, 25 ml of water and 7 g of AD-mix-β. Stirring at room temperature, received two transparent phases. The lower aqueous phase was bright yellow. At this moment added methanesulfonamide (475 mg). The mixture was cooled to 0°C, after which the portion of dissolved salts deposited immediately added compound 41 (1.07 g, 5 mmol) and the heterogeneous suspension was intensively stirred for 24 h at 0°C. after this time while stirring the mixture at 0°C was added solid sodium sulfite (7.5 g) and the mixture was left to warm to room temperature and was stirred for 30-60 min To the reaction mixture were added EtOAc (50 mg) and after separation of the layers the aqueous phase was extracted with EtOAc. The organic layer was dried over Na2SO4and concentrated to dryness. The residue was purified using silikagelevye chromatographic column with 20% EtOAc in hexano order to obtain compound 42 (1.13 g, 91%) as a solid.1H NMR (DMSO-d6): δ of 1.18 (t, J=6.8 Hz, 3H, och2CH3), 1,24 (s, 3H, CH3), 1,25 (s, 3H, CH3), of 1.28 (s, 3H, 2-CH3), to 3.67 (t, J=7.2 Hz, 1H), 3,85, 4.06 and of 4.12 (m, 4H), 4,96 (s, 1H, 2-OH, D2O currency.), 5,14 (d, J=7,6 Hz, 2-OH, D2O currency.). The analysis. the calculation for C11H20About6: C, 53.22; H, 8.12; Found: C, 53.32; H, 8.18.

Example 3

(2S,3R)-3-[(4R)-2,2-dimethyl-[1,3]dioxolane-4-yl]-3-benzoyloxy-2-hydroxy-2-methylpropionic acid ethyl ester (compound 43).

To a solution of compound 42 (245 mg, 0,99 mmol) in dry pyridine (3 ml) was added dropwise a solution of BzCl (300 mg, 2.1 mmol) in pyridine (1 ml). Then, at room temperature and the mixture was stirred for 2 h and the reaction mass was rapidly cooled with water (1 ml). The mixture was concentrated to dryness, and the residue was divided between CH2Cl2and a saturated solution of NaHCO3. The organic phase was dried (anhydrous Na2SO4), filtered and concentrated. The residue was purified using silikagelevye chromatographic column with 5% EtOAc in hexano order to obtain compound 43 (247 mg, 71%) as a solid. Analytically calculated for C18H24O7: C, 61.35; H, 6.86; Found: C, 60.95; H, 6.73.

Example 4

(2S,3R)-3-[(4R)-2,2-dimethyl-[1,3]dioxolane-4-yl]-3-benzoyloxy-2-fluoro-2-methylpropionic acid ethyl ester (compound 44).

To a solution of compound 43 (36 mg, is 0.102 mmol) in anhydrous THF (1.5 ml) was added DAST or Deoxofluor (0,08 ml of 0.68 mmol) at 0°C in an atmosphere of argon. The reaction mixture for 3 h and stirred at room temperature, then was cooled to 0°C. and carefully treated with a cold saturated solution of NaHCO3(2 ml). The organic layer was dried over Na2SO4and centered DOS is and. The residue was purified on silikagelevye chromatographic column with 1-3% EtOAc in hexano order to obtain compound 44 (24.6 mg, 68%) as syrup HR-FAB MS. The viewers. m/z 361, 1621. Calculated for C18H23O6FLi: m/z 361,1639 (M+N)+.

Example 5

3-O-benzoyl-2-methyl-2-deoxy-2-fluoro-D-ribono-γ-lactone (compound 45).

A mixture of compound 44 (308 mg, 0.86 mmol), MeCN (20 ml), water (1 ml) and CF3CO2N (0.17 ml) was heated for 3 h in a vessel under reflux at a temperature of 80-85°C. the Intermediate product with an open circuit is not isolated, but directly turned into the compound 45 using azeotropic distillation using a water trap Dean-Stark (Dean-stark). Remote MeCN was replaced with dry toluene and azeotropic distillation was continued until the oil bath temperature reached 130°C. Stirring at a temperature of 130°C was continued for days. Then the mixture was cooled to room temperature, the solvent was removed under vacuum to obtain a syrup, which was purified on silikagelevye chromatographic column with 10-15% EtOAc in hexano order to obtain, after evaporation of the solvents connection 45 (136 mg, 58,3%) as a solid.

Example 6

3,5-di-O-benzoyl-2-methyl-2-deoxy-2-fluoro-D-ribono-γ-lactone (compound 49).

To a solution of compound 45 (60 mg, 0,224 mmol) in EtOAc (1 ml) was added pyridine (100 mg, of 1.26 mmol) and dimethylaminopyridine (2.7 mg). The mixture was heated to 60°C. and was added dropwise a solution of BzCl (110 mg, 0.79, which mmol) in EtOAc (0.4 ml). After stirring for 3 h the mixture was cooled to 0°C and was filtered hydrochloric acid salt of pyridine. The filtrate was diluted tO and the mixture evaporated to dryness. The residue was purified on silikagelevye chromatographic column at 3-6% EtOAc in hexano order to obtain after evaporation of the solvent compound 49 (75 mg, 91%) as a solid substance

Example 7

2-methyl-D-arabino-γ-lactone (compound 46).

A solution of compound 42 (248 mg, 1 mmol) in 1.5 ml tO was treated with concentrated hydrochloric acid (0.3 ml). The reaction mixture was stirred for 2 h at room temperature. The solvent was removed under vacuum (bath temperature less than 45°). The residue evaporated together with toluene (3×10 ml) to obtain a residue, which was purified on silikagelevye chromatographic column with 70% EtOAc in hexano. Evaporation of the solvents results in oily compound 46 (170 mg, 105%). The analysis. calculated for C6H10O5: C, 41.24; H, 6.22; Found: C, 41.00; N, 6.74.

Example 8

3,5-di-O-benzoyl-D-arabino-γ-lactone (compound 47).

To a stirred solution of compound 46 (880 mg, 5.4 mmol) in dry pyridine (80 ml) was added dropwise over 75 min a solution of BzCl (1.73 g, 12,29 mmol) in dry pyridine (45 ml) at room temperature. The mixture was stirred those who tell another 90 min, then processed Meon (5 ml) and concentrated to dryness. The residue was purified on silikagelevye chromatographic column with 12-20% EtOAc in hexano to obtain compound 47 (1.1 mg, 55%) as oil.

Example 9

3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribonolactone (compound 49).

To a solution of compound 47 (430 mg, of 1.16 mmol) in anhydrous THF (20 ml) and diisopropylethylamine (1 ml, 5,74 mmol) was added DAST or DEOXOFLUOR (of 0.48 ml, 3,66 mmol) at room temperature in argon atmosphere. The reaction mixture was stirred at room temperature for 3 h, then was cooled to 0°C. and carefully treated with a cold saturated solution of NaHCO3(5 ml). The reaction mixture was separated between EtOAc (100 ml) and water (20 ml). The organic layer was dried over Na2SO4and concentrated to dryness. The residue was purified on silikagelevye chromatographic column at 3-6% EtOAc in hexano order to obtain compounds 49 (220 mg, 51%) as a solid.

Example 10

3,5-di-O-benzoyl-2-methyl-D-ribonolactone (compound 48).

To a solution of compound 47 (160 mg, 0,432 mmol) in anhydrous CH2CL2(5 ml) was added DAST or DEOXOFLUOR (0.15 ml, to 1.14 mmol) at a temperature of from 0 to 5°C in argon. The reaction mixture was stirred at a temperature of from 0 to 5°C for 1 h, then at room temperature. After 24 h the reaction proceeds well enough yet, because no way is connected a sufficient number of the less polar product according to TLC. The reaction mixture was cooled to 0°C. and carefully treated with a cold saturated solution Panso3. The organic layer was dried over Na2SO4and concentrated to dryness. The precipitate was determined by the method of proton NMR. He showed that the main product is 3,5-Dibenzoyl-2-methyl-D-ribono-γ-lactone (compound 48), which is identical to the authentic sample. Traces connections 49 were detected in the spectrum.

Example 11

3,5-di-O-methoxymethyl-2-C-methyl-D-arabino-γ-lactone (compound 50).

To a solution of 2-methylaminoethanol (compound 46) (324 mg, 2 mmol) in CH2(OMe)2(30 ml) and CH2CL2(30 ml) was added CF3SO3N (50 μl), the solution was stirred for 14 h at room temperature in argon. The reaction mass was cooled by addition of 28% NH4HE (0.1 ml) and the mixture was dried by addition of Na2SO4. After removal of the solvent by evaporation the residue was purified using evaporative chromatography on silica gel, elwira CH2Cl2/MeOH (95:5 to 9:1) to obtain 450 mg (90%) of compound as a pale yellow oil.1H NMR (DMSO-d6): 6,10 (s, IT, D2O currency.), 4,70 (q, 2H, CH2), to 4.62 (d, 2H, CH2), 4,30 (m, 1H, H-4), 4,20 (d, 1H, H-3), 3,80-the 3.65 (m, 2H, H-5), 3,30, 3,28 (2s, 6H, 2 CH3), of 1.26 (s, 3H, CH3).

Example 12

3,5-di-O-methoxymethyl-2-deoxy-2-fluoro-2-C-methyl-D-ribono-γ-lactone (compound 51).

To rest the ru compound 50 (100 mg, 0.4 mmol) in CH3CL2(3 ml) and pyridine (0.5 ml) at -78°C was added DAST or DEOXOFLUOR (of 0.21 ml, 1.6 mmol), the solution was stirred at -78°C for 15 minutes the Solution was allowed to warm to room temperature and at room temperature was stirred for 2 hours, the Reaction mass was rapidly cooled by the addition of saturated aqueous Panso3and ice water (0.5 ml), and then CH2CL2(20 ml) and saturated aqueous Panso3(10 ml). The aqueous layer was extracted twice, CH2Cl2combined organic layers washed with NaHCO3and dried over Na2SO4. Evaporation of the solvent resulted in the receipt of compounds 51 (88 mg, 87%) as a brownish-yellow oil.1H NMR (DMSO-d6): 4,74 (q, J=6,9 and 18.1 Hz, 2H, CH2), 4,63 (d, J=0,77 Hz, 2H, CH2), of 4.54 (m, 1H, H-4), 4,18 (dd, J=7.8 and 20.0 Hz, 1H, H-3), 3,86-3,71 (m, 2H, H-5), 3,34, 3,28 (2s, 6H, 2CH3), to 1.59 (d, J=24,26 Hz, 3H, CH3).

Example 13

Ethyl-4,5-O-isopropylidene-3,4,5-trihydroxy-2-methylvalerate (compound 54)

To an activated zinc (6.5 g, 0.10 mmol) was added about 20 ml of a solution containing the compound 39 (13,0 g, 0.1 mmol), compound 53 (13,0 ml, 0.10 mmol), THF (50 ml) and diethyl ether (50 ml). After additions were introduced one crystal I2, and there were heat that caused the boiling solution under reflux. The remaining solution was added to the tip is of about 0.75 h to maintain weak phlegmy. The mixture is slightly heated under reflux for an additional 1 h after the last addition. The mixture was cooled to room temperature, pouring onto ice (200 ml) and 1N HCl (200 ml)and then stirred until then, until most of the ice has melted (about 0.5 h).

The organic layer was separated, and the aqueous layer was extracted with diethyl ether (2×75 ml). The combined organic layers were washed with saturated NaHCO3(1×150 ml), brine (1×150 ml), dried (Na2SO4), filtered and concentrated to dryness under vacuum. Subsequent drying under vacuum resulted in the receipt of connection 54 in the form of a mixture of diastereoisomers (15,1 g, 65,1%). This compound was used without further purification.

Example 14

Ethyl-4,5-O-isopropylidene-3-oxo-2-methylvalerate (compound 55)

Compound 54 (9,85 g at 0.42 mol) was dissolved in dry THF (50 ml). Added anhydrous DMSO (16.0 ml and 0.22 mol) and the resulting solution was cooled to a temperature of between -20°C and -15°C. Triperoxonane anhydride (9.8 ml, to 0.69 mol) was added dropwise over 15 min and the solution was stirred for 2 hours at a temperature between -20°C and -15°C, after which was added anhydrous NEt3(24,0 ml of 0.17 mol) over 20 minutes the resulting solution was stirred at room temperature for 1 h, diluted with diethyl ether (50 ml), washed with water (3×100 ml), dried (Na2SO4and concentri is ovali under vacuum to obtain compound 55 as a yellow oil (8.1 g, 82,0%)which was used without further purification.1H NMR (CDCl3, 400 MHz): δ 1,24-to 1.38 (m, 26H), 3.81 (q, 1,3 H, J=7,3 Hz)to 3.89 (q, 1,0 H, J=7,3 Hz), 3,99-Android 4.04 (m, 3H), 4,10-4,20 (m, 7H), 4,21-the 4.29 (m, 3H), 4,51 (dd, 1,0 H, J=8,1, 6.2 Hz), 4,58 (dd, 1,3 H, J=7,7, 5.0 Hz).

Example 15

Ethyl-4,5-O-isopropylidene-2-fluoro-3-keto-2-methylvalerate (compound 56)

Compound 55 (of 7.36 g, 0,042 mol) was dissolved in anhydrous DMF (5.0 ml) and was treated with a suspension of Selectfluor (55,0 g, 0,155 mol) in DMF (45,0 ml). The mixture was placed in an oil bath with a temperature of 45-50°C and the suspension was maintained by stirring overnight in an argon atmosphere. The solution was concentrated almost to dryness under vacuum, was treated with diethyl ether (25 ml) and washed with water (3×100 ml). The organic phase was dried (Na2SO4) and concentrated under vacuum to obtain compound 56 as a yellow oil (5,65 g, 71.2 percent), which was approximately a mixture of 1:1 2R:2S fluorinated compounds, as determined19F NMR.1H NMR (CDCl3, 400 MHz): δ 1,20-of 1.46 (m, 16H), 1,70 (2d, 3H, J=22,8 Hz), 4,05-4,10 (m, 2H), 4,12-4,32 (m, 2H), 4,90 is equal to 4.97 (m, 1H),19F NMR (CDCl3, 376 MHz, With6F6external standard): δ4,30 (q)4,01 (q).

Example 16

3,5-O-dipivoxil-2-methyl-D-arabino-γ-lactone (compound 47)

To a solution of compound 42 (4 mmol, 897 mg) in tO (20 ml) was added concentrated hydrochloric acid (2.0 ml) and the solution was stirred for 1 h at room temperature. A solution of Koh which was interaval to dryness and the residue evaporated together with THF (10 ml) and was dissolved in pyridine (6 ml) and CH 2Cl2(14 ml). The solution was cooled in an ice bath. To the solution was added pivaloate (8 mmol, and 0.98 ml) and the solution was stirred at 0°C for 30 min To the solution was added pivaloate (4 mmol, 0,49 ml) and the solution was stirred at room temperature for 5 hours To the solution was added 4-dimethylaminopyridine (100 mg) and the solution was stirred at room temperature for 20 hours was Added N2O (5 ml) and the mixture was stirred at room temperature for 20 minutes was Added tO (50 ml). The mixture was washed with water, brine, dried (Na2SO4). The solvent was removed and the residue was subjected to recrystallization from a mixture of tO-hexane order to obtain small crystals (625 mg, 47%).1H NMR (Dl3): δ by 5.18 (d, J=6,80 Hz, 1H, H-3), 4,45, 4,22 (m, 2H, H-5), to 4.41 (m, 1H, H-4), of 3.32 (br s, 1H, HE, D20 exchange), 1,43 (s, 1H, Me), 1,25,1,22 [ss, 18H, C(Me)3].

Example 17

2-deoxy-3,5-O-dipivoxil-2-fluoro-2-C-methyl-D-ribono-γ-lactone (compound 49B).

To a solution of compound 47B (100 mg, 0.3 mmol) in THF (5 ml) was added EtNPr2(2 mmol, 0.35 ml) and DEOXOFLUOR (of 0.18 ml, 0.9 mmol) and the solution was stirred at room temperature for 4 h the solution was added an additional amount of DEOXOFLUOR (of 0.18 ml, 0.9 mmol) and the solution was stirred at room temperature for 16 h and was heated under reflux for 1 h was Added tO. The washing solution is whether aqueous NaHCO 3, brine, dried (Na2SO4). The solvent was removed and the residue was purified on column (10% tO in hexano) to obtain the product as a solid (65 mg, 65%).1H NMR (CDCl3): δ 5,12 (m, 1H, H-3), and 4.68 (m, 1H, H-4), to 4.41, 4,18 (mm, 2H, H-5), and 1.63 (d, J=23,2 Hz, 1H, Me), 1.25 and 1.20 of [ss, 18H, C(Me)3].

1. The compound of the formula

where R3and R5can independently denote H, benzoyl, pivaloyl or methoxymethyl.

2. The compound according to claim 1, wherein R3and R5denote N.

3. The compound according to claim 1, wherein R3and R5denote benzoyl.

4. The compound according to claim 1, wherein R3and R5denote methoxymethyl.

5. The compound according to claim 1, wherein R3and R5denote pivaloyl.

6. A method of obtaining a compound according to claim 1, where R5denotes N and R3represents benzoyl, which includes stages:
(a) interactions of the compounds of formula 39

with alkyl-2-bromopropionate in the presence of activated zinc in a suitable solvent to obtain compounds of formula 54
;
(b) adding an oxidizing agent to obtain a ketone of formula 55
;
(C) fluorination of the product from step (b) to obtain the fluorinated ketone of formula 56
;
(d) recovering fluorinated ketone from step (C) obtaining the compounds of formula 58

(e) benzilidene of the product from step (d) to obtain the compounds of formula 44

where Bz represents benzoyl;
(f) cyclization of the product from step (e) to obtain the desired lactone of formula 45

7. The method according to claim 6, characterized in that the solvent in stage (a) is selected from the group consisting of diethyl ether and tetrahydrofuran.

8. The method according to claim 6, characterized in that the oxidizing agent at the stage (b) is selected from the group consisting of activated dimethyl sulfoxide, chromate, periodin dessa-Martin and perruthenate of tetrapropylammonium.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a protected fluorinated glucose derivative, involving reaction of a tetraacetylmannose derivative with a fluoride, distinguished by that the reaction is carried out in a solvent which contains water in amount of more than 1000 parts per million and less than 50000 parts per million. Preferably, the protected fluorinated glucose derivative is 2-fluoro-1,3,4,6-tetra-O-acetyl-D-glucose (tetraacetylfluroglucose or pFDG), the tetraacetylmannose derivative is 1,3,4,6-tetra-0-acetyl-2-0-trifluoromethanesulphonyl-β-D- mannopyranose (tetraacetylmannose triflate), the solvent is acetonitrile, the fluoride is a fluoride ion with a potassium counter-ion, and a phase-transfer catalyst, such as 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[8,8,8]-hexacosa, is added to the fluoride.

EFFECT: improved method.

14 cl, 2 tbl, 3 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of [18F]fluororganic compounds ensured by reaction of [18F]fluoride and relevant halogenide or sulphonate with alcoholic vehicle of formula 1 where R1, R2 and R3 represent hydrogen atom or C1-C18 alkyl.

EFFECT: possibility for mild process with low reaction time and high yield.

21 cl, 2 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of 1-α-halogen-2,2-difluoro-2-deoxy-D-ribofuranose of the general formula (I) in solid state, where R1 is benzoyl or ; R2 is hydrogen; and X is CI, Br or I; which can be applied as intermediates in stereoselective method of gemcitabine obtainment. In addition, invention claims stereoselective method of obtaining compounds of the general formula (I), including stages of: (i) recovery of 1-oxoribose of formula to obtain lactol of formula ; (ii) interaction of compound of formula (III) with halogen phosphate compound of formula in the presence of a base to obtain 1-phosphatefuranose derivative of formula ; and (iii) interaction of compound of formula (V) (also included in the claim) with halogen source, with further recrystallisation of obtained product; where R1, R2 and X are the same as indicated above while R3 is phenyl.

EFFECT: efficient method of obtaining derivatives of the abovementioned agent.

11 cl, 6 ex

FIELD: chemistry.

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11 cl, 3 ex

FIELD: chemistry.

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EFFECT: efficient removal of admixtures from compositions.

34 cl, 4 tbl, 2 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: developed method of sucralose production using acyl-sucralose implies (a) adjustment of pH factor of specified supplied mixture to value ranged from 8.0 to 12.0 by alkali metal hydroxide addition; (b) buffer addition to specified base mixture in amount enough for specified pH factor stabilization within stated range over holding stage (c); (c) holding of specified base mixture at appropriate temperature over time period enough for effective transformation of specified acyl-sucralose compound into free sucralose; (d) reduction of specified pH factor of specified base mixture up to value from 4 to 8; (e) sucralose release from product of step (d) resulted thereby in released sucralose.

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22 cl, 1 tbl, 1 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved solid-phase method for synthesis of radioisotope indicators, in particular, for synthesis of compounds labeled with 18F that can be used as radioactive indicators for positron- emission tomography (PET). In particular, invention relates to a method for synthesis of indicator labeled with 18F that involves treatment of a precursor fixed on resin if the formula (I): SOLID CARRIER-LINKER-X-INDICATOR wherein X means a group promoting to nucleophilic substitution by a definite center of a fixed INDICATOR with 18F- ion for preparing a labeled indicator of the formula (II): 18F-INDICATOR; to compound of the formula (Ib):

and compound of the formula (Ih): ;

to radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in PET; to a cartridge for radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in positron-emission tomography.

EFFECT: improved method of synthesis.

13 cl, 1 sch, 3 ex

FIELD: pharmaceutical technology.

SUBSTANCE: invention relates to the improved sucralose formulation and a method for its crystallization. Method involves controlling pH value of solution in the range from about 5.5 to about 8.5 in the process of formation of sucralose crystals. Invention provides the development of the improved composition comprising crystalline sucralose and possessing the enhanced stability.

EFFECT: improved preparing method, improved properties of composition.

24 cl, 4 tbl, 4 ex

The invention relates to medicine, more specifically to radiopharmaceuticals for diagnostic purposes, and may find application in positron emission tomography

FIELD: medicine.

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EFFECT: higher yield, improved purification.

1 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to anthracycline derivatives of general structural formula given below

where R1, R2 and R3 are H or OH; R4 denotes H, OH, C1-C5alkyl, or O-(C1-C5)alkyl; R5 is O or NH; and R6 is selected from a group comprising H, OH and a sugar residue which is The invention also relates to a method of producing said derivatives by reacting 13-ketoanthracycline or acid salt thereof with benzenidesulphonylhydrazide in an alcohol solvent at temperature of approximately 35-50°C for approximately 10-24 hours. The invention also pertains to a method of producing 13-deoxyanthracyclines, involving preparation of an alcoholic solution of the said 13-benzenidesulphonylhydrazine anthracycline; addition of a reducing agent and acid to the said solution; heating said solution without stirring, agitation or dephlegmation in order to reduce said 13-benzenidesulphonylhydrazine anthracycline; neutralisation of said solution with an aqueous solution of a base to obtain said 13-deoxyanthracycline derivative and precipitation; and, additionally, filtration of said precipitate, extraction of said 13-deoxyanthracycline from said precipitate, as well as extraction of said 13-deoxyanthracycline from the filtrate. The invention also relates to a method of producing 5-imino-13-deoxyanthracyclines involving synthesis of 13-deoxyanthracyclines as described above; dissolution of said 13-deoxyanthracyclines in an alcohol and conversion of said 13-deoxyanthracyclines to the corresponding 5-imino-13-deoxyanthracyclines under the effect of ammonia at temperature lower than approximately 20°C. The invention also relates to a method of producing 13-deoxyanthracyclines involving preparation of an alcoholic solution of 13-benzenidesulphonylhydrazine anthracycline having structural formula given below; addition of a reducing agent and a pyridinium acid salt to the said solution and heating said solution to reduce said 13-benzenidesulphonylhydrazine anthracycline. The invention also relates to a method of producing 5-imino-13-deoxyanthracyclines involving preparation of said 13-deoxyanthracycline and its conversion to the corresponding 5-imino-13-deoxyanthracycline under the effect of ammonia at temperature lower than approximately 20°C.

EFFECT: new compounds have useful biological properties.

21 cl, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to anthracycline derivatives of general structural formula given below

where R1, R2 and R3 are H or OH; R4 denotes H, OH, C1-C5alkyl, or O-(C1-C5)alkyl; R5 is O or NH; and R6 is selected from a group comprising H, OH and a sugar residue which is The invention also relates to a method of producing said derivatives by reacting 13-ketoanthracycline or acid salt thereof with benzenidesulphonylhydrazide in an alcohol solvent at temperature of approximately 35-50°C for approximately 10-24 hours. The invention also pertains to a method of producing 13-deoxyanthracyclines, involving preparation of an alcoholic solution of the said 13-benzenidesulphonylhydrazine anthracycline; addition of a reducing agent and acid to the said solution; heating said solution without stirring, agitation or dephlegmation in order to reduce said 13-benzenidesulphonylhydrazine anthracycline; neutralisation of said solution with an aqueous solution of a base to obtain said 13-deoxyanthracycline derivative and precipitation; and, additionally, filtration of said precipitate, extraction of said 13-deoxyanthracycline from said precipitate, as well as extraction of said 13-deoxyanthracycline from the filtrate. The invention also relates to a method of producing 5-imino-13-deoxyanthracyclines involving synthesis of 13-deoxyanthracyclines as described above; dissolution of said 13-deoxyanthracyclines in an alcohol and conversion of said 13-deoxyanthracyclines to the corresponding 5-imino-13-deoxyanthracyclines under the effect of ammonia at temperature lower than approximately 20°C. The invention also relates to a method of producing 13-deoxyanthracyclines involving preparation of an alcoholic solution of 13-benzenidesulphonylhydrazine anthracycline having structural formula given below; addition of a reducing agent and a pyridinium acid salt to the said solution and heating said solution to reduce said 13-benzenidesulphonylhydrazine anthracycline. The invention also relates to a method of producing 5-imino-13-deoxyanthracyclines involving preparation of said 13-deoxyanthracycline and its conversion to the corresponding 5-imino-13-deoxyanthracycline under the effect of ammonia at temperature lower than approximately 20°C.

EFFECT: new compounds have useful biological properties.

21 cl, 4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to antithrombotic compound of formula (I) (oligisaccaride-spacer-A(I)), where oligosaccharide is negatively charged pentasaccharide residue of formula given lower, where R5 - OCH3 or OSO3-, charge is compensated by positively charged counterions, and where pentasaccharide residue is obtained from pentasaccharide which has AT-III mediated anti-Xa activity per se; spacer is, in fact, pharmacologically inactive movably bound residue, which has from 10 to 50 atoms long chain; A is residue of -CH[NH-SO2-R1] [CO-NR2-CH(4-benzamidin)-CO-NR3R4], where R1 - 4-methoxy-2,3,6-trimethyphenyl; R2 - H; NR3R4 is piperidinyl group or its pharmaceutically acceptable salt or derivative, where amino group of amidin residue is protected by hydroxyl or (1-6C) alcoxycarbonyl group; where spacer of formula I compound contains one covalent bond with biotin residue of formula -(CH2)4-NR-BT, where R - H or (1-4C)alkyl and BT is residue . Invention also relates to pharmaceutical composition based on formula I compounds for treatment or prevention of thrombosis or other connected with thrombin diseases.

EFFECT: elaboration of antithrombotic compound for treatment or prevention of thrombosis or other, connected with thrombin diseases.

6 cl, 3 tbl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to antibacterial compounds of general formula I ,

where R1 is hydrogen; R2 is alkyl; R3 is alkyl, alkenyl, cycloalkyl or COR11, where R11 is alkyl, provided that R2 and R3 do not simultaneously denote methyl; W denotes alkenyl; -G(CH2)qJ-, where q varies from 2 to 6; G is absent; J is absent or denotes -N(R12)(CH2)m, where m = 0; R12 is alkyl; R is a heterocycle; R4 is ethyl; R' is methyl; Y is fluorine; and Z is oxygen. The invention also relates to a range of specific compounds listed in the formula of invention. The invention also relates to several different methods for synthesis of compounds of general formula XIII

, where R3 is alkyl, alkenyl, cycloalkyl, or COR11, where R11 is C1 - C6 alkyl, provided that R3 is not methyl; W is G(CH2)qJ-, where q varies from 2 to 6; G is absent, J is absent or denotes N(R12)(CH2)m, where m = 0; R12 is alkyl; and R is a heterocycle.

EFFECT: obtaining novel antibacterial compounds.

7 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to antibacterial compounds of general formula I ,

where R1 is hydrogen; R2 is alkyl; R3 is alkyl, alkenyl, cycloalkyl or COR11, where R11 is alkyl, provided that R2 and R3 do not simultaneously denote methyl; W denotes alkenyl; -G(CH2)qJ-, where q varies from 2 to 6; G is absent; J is absent or denotes -N(R12)(CH2)m, where m = 0; R12 is alkyl; R is a heterocycle; R4 is ethyl; R' is methyl; Y is fluorine; and Z is oxygen. The invention also relates to a range of specific compounds listed in the formula of invention. The invention also relates to several different methods for synthesis of compounds of general formula XIII

, where R3 is alkyl, alkenyl, cycloalkyl, or COR11, where R11 is C1 - C6 alkyl, provided that R3 is not methyl; W is G(CH2)qJ-, where q varies from 2 to 6; G is absent, J is absent or denotes N(R12)(CH2)m, where m = 0; R12 is alkyl; and R is a heterocycle.

EFFECT: obtaining novel antibacterial compounds.

7 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a pyrimidine nucleoside compound of general formula (1) , in which one of X and Y is a cyano group and the other is hydrogen; R1 is hydrogen, (R3)(R4)(R5)Si- or a carbonyl group which includes an alkyl monosubstituted with an amino group; R2 is hydrogen or (R6)(R7)(R8)Si-, provided that at least one of R1 and R2 is not hydrogen; or R1 and R2 together form a 6-member cyclic group -Si(R9)(R10)-, where each of R9 and R10 is a straight or branched alkyl; R3, R4 and R5 denote a straight or branched alkyl optionally substituted alkoxy, or cycloalkyl; R6, R7 and R8 denote a straight or branched alkyl optionally substituted alkoxy, cycloalkyl or phenyl, or to pharmacologically acceptable salts thereof. The invention also relates to a range of specific compounds of formula (1) or to their pharmacologically acceptable salts: 5'-O-triisopropylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-diethylisopropylsilyl-2'-cyano-2,-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-dimethylthexylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-(dimethyl-n-octylsilyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-dimethylthexylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-diethylisopropylsilyl -2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-(tert-butyldimethylsily)-2'-cyano-2'-desoxy-1-β-O-arabinofuranosylcytosine; 3'-O-triisopropylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-dimethylthexylsilyl-5'-O-(L-valyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-(L-valyl)-3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; and 3'-O-cyclopropyl-diisopropylsilyl-2'-cyano-2'-desoxy-1-β-D- arabinofuranosylcytosine.

EFFECT: obtaining formula (1) compounds or their pharmacologically acceptable salts for preparing a medicinal agent for treating tumours.

9 cl, 20 tbl, 1 dwg, 73 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing ivy saponins through extraction from plant material in sealed conditions in an aqueous medium or medium of an aqueous 0.5-5% solution of ammonia at 110-200°C.

EFFECT: extraction at high pressure and high temperature without using additional components in order to obtain efficient results.

3 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing ivy saponins through extraction from plant material in sealed conditions in an aqueous medium or medium of an aqueous 0.5-5% solution of ammonia at 110-200°C.

EFFECT: extraction at high pressure and high temperature without using additional components in order to obtain efficient results.

3 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing aralia aralosides through extraction from plant material in sealed conditions in an aqueous medium or medium of an aqueous 0.5-5% solution of ammonia at 110-200°C.

EFFECT: extraction at high pressure and high temperature without using additional components in order to obtain efficient results.

3 cl, 8 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to phosphoramidates of nucleoside analogs comprising 2',3'-dideoxy-2',3'-didehydrothymidine 5'-phosphodimorpholidate of the formula (I) and phosphoramidates of 3'-azido-3'-deoxythymidine of the formula (II) and the formula (III) that inhibit activity in reproduction of human immunodeficiency virus (HIV). Compounds are resistant to effect of dephosphorylating enzymes and able to penetrate into cells and elicit the selective activity in inhibition of DNA biosynthesis catalyzed by HIV-reverse transcriptase.

EFFECT: valuable medicinal and biochemical properties of nucleoside analogs.

4 dwg, 1 tbl, 5 ex

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