HK1130670B - Preparation of 2'fluoro-2'-alkyl-substituted or other optionally substitued ribofuranosyl pyrimidines and purines and their derivatives - Google Patents

Description

Preparation of 2 '-fluoro-2' -alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives

This application was filed as PCT international patent application at 13.9.2005, filed by american national company Pharmasset, inc., Byoung-Kwon Chun (korean citizen), Peiyuan Wang (chinese citizen), claiming priority from U.S. provisional patent application No. 60/609,783 filed at 14.9.2004, U.S. provisional patent application No. 60/610,035 filed at 15.9.2004, U.S. provisional patent application No. 60/666,230 filed at 29.3.2005, which are incorporated herein by reference in their entirety.

Technical Field

The present invention provides (i) a process for the preparation of 2-deoxy-2-fluoro-2-methyl-D-ribonolactone (ribonolactone) derivatives, (ii) the conversion of intermediate lactones into nucleosides and analogs thereof having potential anti-HCV activity, and (iii) a process for the preparation of anti-HCV nucleosides containing 2 ' -deoxy-2 ' -fluoro-2 ' -C-methyl- β -D-ribofuranosyl nucleosides from preformed, preferably naturally occurring, nucleosides.

Background

HCV infection has become prevalent worldwide, and infected patients suffer significant distress. Currently, there is no universally effective treatment for this infection, and the only drugs used to treat chronic hepatitis c are the various forms of interferon-alpha (IFN- α), used alone or in combination with ribavirin. However, the therapeutic value of these therapeutic measures is greatly diminished due to side effects, and there is an urgent need to develop alternative regimens for treatment.

HCV is a small, enveloped virus of the Flaviviridae family (Flaviviridae) that has a positive single-stranded RNA genome of about 9.6kb in the nucleocapsid. The genome contains an Open Reading Frame (ORF) encoding a polyprotein of just over 3,000 amino acids, which is cleaved to yield mature structural and nonstructural viral proteins. The ORF is flanked by 5 'and 3' untranslated regions (NTRs) of several hundred nucleotides in length that are important for RNA translation and replication. The translated polyprotein contains the structural core (C) and envelope proteins (E1, E2, p7) at the N-terminus, followed by the nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS 5B). Cleavage with host signal peptidase gave the mature structural protein. The NS2/NS3 protease autocatalytically cleaves the junction between NS2 and NS3, while the N-terminal serine protease domain of NS3, which forms a complex with NS4A, cleaves the remaining four junctions. The NS3 protein also has NTP-dependent helicase activity that unwinds duplex RNA during replication. The NS5B protein has RNA-dependent RNA polymerase (RDRP) activity that is critical for viral replication. Unlike HBV or HIV, it is emphasized herein that DNA is not involved in HCV replication.

U.S. patent publication (US 2005/0009737a1) discloses that 1- (2-deoxy-2-fluoro-2-C-methyl- β -D-ribofuranosyl) cytosine (14) is a potent and selective anti-HCV agent. The initial synthetic steps (schemes 1-3) of this compound are very inefficient, have a low overall yield, and are not amenable to large scale production.

Scheme 1

Scheme 2

Scheme 3

The prior known methods for preparing (2 'R) -2' -deoxy-2 '-fluoro-2' -C-methyl nucleosides and analogs thereof from D-xylose, cytidine or uridine are using DAST orFor critical fluorination reactions. However, DAST andare both expensive and dangerous to synthesize industrially, often providing unreliable results. Therefore, these alkylaminosulfurides (alkylamidosulfur trifluorides) are not suitable for industrial production.

As part of the efforts to find better fluorination conditions, it has been found that ring opening of cyclic sulfates with fluorinating agents other than alkylaminosulfur trifluoride is a better method for the synthesis of anti-HCV nucleosides, i.e., (2 'R) -2' -deoxy-2 '-fluoro-2' -C-methylcytidine. In addition, this novel synthetic route has been found to be suitable for other nucleosides as well, including anti-HCV nucleosides, D-2-deoxy-2-fluoro-cytidine (Devos et al, U.S. Pat. No. 6,660,721), anti-HBV nucleosides, D and L-2 ', 3' -didehydro-2 ', 3' -dideoxy-2 '-fluoro-nucleosides (Schinazi et al, U.S. Pat. No. 6,348,587) (I and II of FIG. 3), and other 2' -substituted nucleosides, such as D-and L-FMAU (Su et al, J Med. chem, 1986, 29, 151-154; Chu, et al, U.S. Pat. No. 6,512,107).

There is a need for a novel and inexpensive method for synthesizing 2 ' -C-alkyl-2 ' -deoxy-2 ' -substituted-D-ribopyranosyl nucleosides having anti-HCV activity.

Summary of The Invention

The invention disclosed herein relates to various intermediates and synthetic methods for preparing compounds represented by the following general formulae [ I ] and [ II ],

in the formula

X is halogen (F, Cl, Br),

y is N or CH, and Y is N or CH,

z is halogen, OH, OR ', SH, SR', NH₂NHR 'or R',

R²is' a C₁-C₃Alkyl, vinyl or ethynyl;

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

R²、R⁴And R⁵Independently H, halogen (including F, Cl, Br, I), OH, OR ', SH, SR', N₃、NH₂、NHR’、NR’₂、NHC(O)O R′、C₁-C₆Lower alkyl, halogenated (F, Cl, Br, I) C₁-C₆Lower alkyl (e.g. CF)₃And CH₂CH₂F)、C₂-C₆Lower alkenyl (e.g. CH ═ CH)₂) C of halogenated (F, Cl, Br, I)₂-C₆Lower alkenyl (e.g. CH ═ CHCl, CH ═ CHBr and CH ═ CHI), C₂-C₆Lower alkynyl (e.g. C.ident.CH), halogenated (F, Cl, Br, I) C₂-C₆Lower alkynyl, C₁-C₆Lower alkoxy (e.g. CH)₂OH and CH₂CH₂OH), halogenated (F, Cl, Br, I) C₁-C₆Lower alkoxy, CO₂H、CO₂R’、CONH₂、CONHR’、CONR’₂、CH＝CHCO₂H、CH＝CHCO₂R’；

R' is optionally substituted C₁-C₁₂Alkyl or acyl (especially when alkyl is the residue of an amino acid), cycloalkyl, optionally substituted C₂-C₆Alkynyl, optionally substituted C₂-C₆Lower alkenyl or optionally substituted acyl.

Detailed Description

There is currently no method of combating flavivirus infection, including Hepatitis C Virus (HCV), dengue virus (DENV), West Nile Virus (WNV) or Yellow Fever Virus (YFV). The only approved treatment is the treatment of HCV infection with interferon-alpha alone or in combination with nucleoside ribavirin, but the therapeutic value of these treatments is greatly reduced due to side effects. It has recently been discovered that a class of nucleosides, including 2 ' -deoxy-2 ' -fluoro-2 ' -C-methylcytidine, exhibit potent and selective activity against replication of HCV in a replicon system. However, the difficulty of synthesis of such nucleosides and similar nucleoside compounds has hindered the biophysical, biochemical, pharmacological evaluations that must be performed to develop clinical drugs to treat flavivirus infections.

The present invention provides a process for efficiently preparing nucleosides and intermediates containing 2-deoxy-2-fluoro-2-C-methyl-D-ribofuranosyl moieties.

Definition of

The term "independently" as used herein means that the variables that are independently applied can vary independently from application to application. Thus, in the presence of a catalyst such as R^aXYR^aIn a compound of the formula (II) in which R is^a"independently is carbon or nitrogen", then two R^aAll may be carbon, two R^aAll may be nitrogen, or one R^aMay be carbon and the other R^aIs nitrogen.

As used herein, the term "enantiomerically pure" or "enantiomerically enriched" refers to a nucleoside composition having an enantiomeric content of at least about 95%, preferably about 97%, 98%, 99% or 100% of the nucleoside.

As used herein, the term "substantially free of or" substantially absent "refers to a nucleoside composition having a designated enantiomer of the nucleoside present in an amount of at least 85% or 90% by weight, preferably 95% to 98% by weight, and even more preferably 99% to 100% by weight. In a preferred embodiment, in the methods and compounds of the present invention, the compounds are substantially free of multiple enantiomers.

The term "alkyl" as used herein, unless otherwise indicated, means generally C₁-C₁₀The saturated linear or branched hydrocarbon chain of (1) specifically includes: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2-dimethylbutyl, and 2, 3-dimethylbutyl, and the like. The term includes both substituted and unsubstituted alkyl groups. Alkyl groups may be optionally substituted with one or more moieties selected from: hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate. One or more hydrogen atoms attached to the alkyl carbon atoms may be replaced by one or more halogen atoms (e.g., fluorine or chlorine, or both fluorine and chlorine), such as trifluoromethyl, difluoromethyl, fluorochloromethyl, and the like. The hydrocarbon chain may also be interrupted by heteroatoms such as N, O or S.

As used herein, unless otherwise indicated, the term "lower alkyl" means C₁-C₄Saturated straight or branched chain alkyl groups, including substituted and unsubstituted forms as defined above. Unless otherwise specifically stated in the present application, lower alkyl is preferred when alkyl is a suitable moiety. Also, when alkyl or lower alkyl is a suitable moiety, unsubstituted alkyl or lower alkyl is preferred.

The term "cycloalkyl" as used herein, unless otherwise indicated, refers to a saturated hydrocarbon ring having 3 to 8, preferably 3 to 6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The ring atoms of the cycloalkyl groups may also be substituted with alkyl groups such as cyclopropylmethyl and the like.

The term "alkylamino" or "arylamino" refers to an amino group having one or two alkyl or aryl substituents, respectively.

The term "protected" as used herein, unless otherwise indicated, refers to a group that is added to an oxygen, nitrogen or phosphorus atom to prevent further reaction of the atom or for other purposes. Many oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. Non-limiting examples include: c (O) -alkyl, C (O) Ph, C (O) aryl, CH₃、CH₂-alkyl, CH₂-alkenyl, CH₂Ph、CH₂-aryl, CH₂O-alkyl, CH₂O-aryl, SO₂Alkyl, SO₂Aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and 1, 3- (1, 1, 3, 3-tetraisopropylidenedisilyl ether (dilinoxylidene)).

The term "aryl" as used herein, unless otherwise indicated, refers to phenyl, biphenyl or naphthyl, preferably phenyl. The term includes both substituted and unsubstituted moieties. Aryl groups may be substituted with one or more substituents including, but not limited to: hydroxy, halo, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, these substituents may be unprotected or, if desired, protected by methods known to those skilled in the art, see, for example, t.w. greene and p.g. m.wuts, in "Protective Groups in Organic Synthesis," third edition, John Wiley & Sons, 1999.

The term "alkaryl" or "alkylaryl" refers to an alkyl group with an aryl substituent. The term "aralkyl" or "arylalkyl" refers to an aryl group having an alkyl substituent, e.g., benzyl.

The term "halo" as used herein includes chloro, bromo, iodo and fluoro.

The term "acyl ester" or "O-linked ester" refers to a carboxylic acid ester of the general formula C (O) R ', wherein the non-carbonyl portion of the ester group R' is a straight or branched alkyl or cycloalkyl or lower alkyl; alkoxyalkyl includes methoxymethyl; aralkyl groups include benzyl; aryloxyalkyl such as phenoxymethyl; aryl includes phenyl, optionally substituted by halogen (F, Cl, Br, I), C₁-C₄Alkyl or C₁-C₄Alkoxy substitution; sulfonates such as alkyl or aralkylsulfonyl including methanesulfonyl; monophosphate, diphosphate or triphosphate; trityl or monomethoxytrityl; a substituted benzyl group; trialkylsilyl (e.g. dimethyl-tert-butylsilyl) or diphenylmethylsilyl. The aryl group in the ester group preferably includes a phenyl group.

The term "acyl" refers to a group of the formula R "C (O) -wherein R" is a straight or branched chain alkyl or cycloalkyl group; an amino acid; aryl, including phenyl; an alkylaryl group; aralkyl groups including benzyl; alkoxyalkyl groups including methoxymethyl; aryloxyalkyl such as phenoxymethyl; or optionally substituted by chlorine, bromine, fluorine, iodine, C₁-C₄Alkyl or C₁-C₄Alkoxy-substituted alkyl (including lower alkyl), aryl (including phenyl); sulfonates such as alkyl or aralkylsulfonyl including methanesulfonyl; monophosphate, diphosphate or triphosphate; trityl or monomethoxytrityl; a substituted benzyl group; an alkaryl group; aralkyl groups including benzyl; alkoxyalkyl groups including methoxymethyl; aryloxyalkyl, such as phenoxymethyl. The aryl group in the ester preferably includes a phenyl group. Specifically, the acyl group includes acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, cyclopropylcarboxyl, propionyl, butyryl, isobutyryl, hexanoyl, heptanoyl, octanoyl, neoheptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, α -methoxy- α -trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-phenylacetyl, 4-chloro-phenylacetyl, 2-chloro-2, 2-diphenylacetyl, 2-chloro-2-phenylacetyl, pivaloyl, chlorodifluoroacetoacetylA group, a perfluoroacetyl group, a fluoroacetyl group, a bromodifluoroacetyl group, a methoxyacetyl group, a 2-thienylacetyl group, a chlorosulfonylacetyl group, a 3-methoxyphenylacetyl group, a phenoxyacetyl group, a t-butylacetyl group, a trichloroacetyl group, a monochloroacetyl group, a dichloroacetyl group, a 7H-dodecafluoroheptanoyl group, a perfluoroheptanoyl group, a 7H-dodecafluoroheptanoyl group, a 7-chloro-dodecafluoroheptanoyl group, a 7H-dodecafluoroheptanoyl group, a nonafluoro-3, 6-dioxaheptanoyl group, a perfluoroheptanoyl group, a methoxybenzoyl group, a methyl 3-amino-5-phenylthiophene-2-carboxyl group, a 3, 6-dichloro-2-methoxy-benzoyl group, a, 4- (1, 1, 2, 2-tetrafluoro-ethoxy) -benzoyl, 2-bromo-propionyl, ω -aminocapryl (capryl), decanoyl, n-pentadecanoyl, stearoyl, 3-cyclopentyl-propionyl, 1-phenyl-carboxyl, O-acetyl-mandelyl (mandelyl), pivaloylacetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl, 2, 6-pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl, perfluorocyclohexylcarboxyl, 4-methylbenzoyl, chloromethylisobutylethylOxazolylcarbonyl, perfluorocyclohexylcarboxy, crotonyl, 1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl, 1-pyrrolidinocarbonyl, 4-phenylbenzoyl. When the term acyl is used, it is intended to designate in particular acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl, butyryl, isobutyryl, hexanoyl, heptanoyl, octanoyl, neoheptanoyl, phenylacetyl, diphenylacetyl, ct-trifluoromethyl-phenylacetyl, bromoacetyl, 4-chloro-phenylacetyl, 2-chloro-2, 2-diphenylacetyl, 2-chloro-2-phenylacetyl, pivaloyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, 2-thiopheneacetyl, tert-butylacetyl, trichloroacetyl, monochloroacetyl, dichloroacetyl, methoxybenzoyl, 2-bromo-propionyl, decanoyl, n-pentadecanoyl, stearoyl, hexanoyl, heptanoyl, octanoyl, neoheptanoyl, pivaloyl, fluoroacetyl, 2-thiopheneacetyl, tert, 3-cyclopentyl-propionyl group, 1-phenyl-carboxyl group, pivaloylacetyl group, 1-adamantane-carboxyl group, cyclohexane-carboxyl groupA group, a 2, 6-pyridinedicarboxyl group, a cyclopropane-carboxyl group, a cyclobutane-carboxyl group, a 4-methylbenzoyl group, a crotonyl group, a 1-methyl-1H-indazole-3-carbonyl group, a 2-propenyl group, an isovaleryl group, a 4-phenylbenzoyl group.

The term "lower acyl" refers to acyl groups wherein R "as defined above is lower alkyl.

The terms "natural nucleobase (nucleobase)" and "modified nucleobase" refer to "purine" or "pyrimidine" bases as defined below.

The term "purine" or "pyrimidine" base includes, but is not limited to: adenine and N⁶-alkylpurine, N^bAcylpurines (in which the acyl group is C (O) (alkyl, aryl, alkylaryl or arylalkyl), N⁶-benzylpurine, N⁶-halopurine, N⁶-vinyl purine, N⁶-acetylenic purine, N⁶-acylpurine, N⁶-hydroxyalkylpurine, N⁶Allyl aminopurine, N⁶Thio-allylpurine, N²-alkylpurine, N²-alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine (including 6-azacytosine), 2-and/or 4-mercaptopyrimidine, uracil, 5-halouracil (including 5-fluorouracil), C⁵Alkyl pyrimidines, C⁵-benzylpyrimidine, C⁵-halogenopyrimidine, C⁵-vinyl pyrimidine, C⁵-acetylenic pyrimidines, C⁵Acyl pyrimidine N⁴-acetyl cytosine, N⁴-benzoylcytosine, N⁴Alkyl pyrimidines, C⁵-hydroxyalkylpurine, C⁵Acylaminopyrimidine, C⁵-cyanopyrimidine, C⁵Iodine pyrimidine, C⁶Iodine-pyrimidine, C⁵-Br-vinyl pyrimidine C⁶-Br-vinyl pyrimidine C⁵-nitropyrimidine, C⁵-amino-pyrimidine, N²-alkylpurine, N²-alkyl-6-thiopurine, 5-azacytidine (azacytidinyl), 5-azauracil (azathiopyrimidinyl), triazolopyridinyl (triazolopyridinyl), imidazopyridinyl, pyrrolopyrimidinyl (pyrazolopyrim)idinyl) and pyrazolopyrimidinyl. Purine bases include, but are not limited to: guanine, adenine, hypoxanthine, 2, 6-diaminopurine and 6-chloropurine. The functional oxygen and nitrogen groups on such bases may be protected as needed or desired. Suitable protecting groups are well known to those skilled in the art and include: trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, trityl, alkyl and acyl groups such as acetyl and propionyl, methanesulfonyl and p-toluenesulfonyl.

The term "amino acid" includes naturally occurring and synthetic alpha, beta, gamma or delta amino acids, including but not limited to: the amino acids found in proteins, namely glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine, and histidine. In a preferred embodiment, the amino acid is in the L-configuration. Alternatively, the amino acid may be a derivative of: alanyl, valyl, leucyl, isoleucyl, prolyl, phenylalanyl, tryptophyl, methionyl, glycyl, seryl, threonyl, cysteinyl, tyrosyl, asparaginyl, glutaminyl, asparaginyl, glutaric acid monoacyl (glutamoyl), lysyl, arginyl, histidyl, beta-alanyl, beta-valyl, beta-leucyl, beta-isoleucyl, beta-prolyl, beta-phenylalanyl, beta-tryptophyl, beta-methionyl, beta-glycyl, beta-seryl, beta-threonyl, beta-cysteinyl, beta-tyrosyl, beta-asparaginyl, beta-glutaminyl, beta-asparaginyl, beta-glutaryl, beta-lysyl, beta-arginyl or beta-histidyl. When the term amino acid is used, it is to be understood that the term refers specifically and independently to esters of alpha, beta, gamma or delta glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine in the D and L-configuration.

The term "pharmaceutically acceptable salt or prodrug" is used throughout the specification to describe any pharmaceutically acceptable form of the compound (e.g., ester, phosphate, salt of an ester or related group) that provides the active compound after administration to a patient. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals (such as potassium and sodium), alkaline earth metals (such as calcium and magnesium), and many other acids well known in the pharmaceutical art. Pharmaceutically acceptable salts may also be acid addition salts when formed to contain a nitrogen atom. Such salts may also be derived from pharmaceutically acceptable inorganic or organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, and the like. Pharmaceutically acceptable prodrugs refer to compounds that are capable of undergoing a metabolic change (e.g., hydrolysis or oxidation) in the host to form the compounds of the present invention. Typical examples of prodrugs include compounds having biologically labile protecting groups on functional moieties of the active compound. Prodrugs include compounds capable of oxidation, reduction, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydration, alkylation, dealkylation, acylation, deacylation, phosphorylation, dephosphorylation, thereby producing the active compound.

Applicants have developed a novel and effectively practiced process for the synthesis of 2-C-alkyl-2-deoxy-2-substituted-D-ribofuranose derivatives, which are key intermediates for the preparation of 14 (scheme 1) and its derivatives and analogues, with or without the use of chiral catalysts. The key step in the synthesis of 14 is the asymmetric conversion of 41 to 42 using a chiral catalyst (scheme 4). The previously disclosed method of synthesizing 42 requires a Sharpless AD catalyst, such as dihydroquinidine (DHQD) and its derivatives. The invention disclosed herein relates to stereoselective preparation 42 from 41 using osmium, osmate or permanganate without chiral catalysts. The applicants of the present invention have also developed an effectively implementable method for the synthesis of 49 from 42 using nucleophilic ring opening of the cyclic sulfate 50 in a highly stereoregular and regioselective manner (scheme 6). The methods shown in schemes 4, 5 and 6 are the methods of choice currently used for the preparative synthesis of 14 and related derivatives.

Scheme 4

Scheme 5

Scheme 6

(i) The silylation base/vorburggen conditions should be used.

I. Preparation of the Compounds

(i) Synthesis of cyclic sulfite (IIIa) and cyclic sulfate (IIIb)

The invention relates to the use of cyclic sulfites IIIa (X ═ SO) and cyclic sulfates IIIb (X ═ SO) of the formula III by lactones of the formula IV in a highly stereospecific and regioselective manner₂) Nucleophilic ring opening to prepare 2 '-F-nucleosides represented by general formulas IB and IB-L-and other 2' -substituted nucleosides.

In which the structural formulae IB, IB-L, III, IV have the following meanings:

R¹independently is (C)₁-C₆) Lower alkyl groups, including but not limited to: methyl, ethyl, optionally substituted phenyl, optionally substituted benzyl; or R¹Is part of a cycloalkylene group, including an ethylene (-CH) group forming a cyclopentyl or cyclohexyl group₂CH₂-) or trimethylene (-CH)₂CH₂CH₂-)；

R²、R³Independently is hydrogen, (C)₁-C₆) Lower alkyl including, but not limited to, methyl, hydroxymethyl, methoxymethyl, halomethyl (including, but not limited to, fluoromethyl), ethyl, propyl, optionally substituted vinyl including, but not limited to, vinyl, halovinyl (F-CH ≡ C), optionally substituted ethynyl including, but not limited to, haloethynyl (F-C ≡ C), optionally substituted allyl including, but not limited to, haloallyl (FHC ═ CH-CH)₂-)；

R⁴Independently hydrogen, aryl (including but not limited to phenyl), arylalkyl (including but not limited to benzyl), lower alkyl (including but not limited to methyl, ethyl, propyl). Nu is halogen (F, Cl, Br), N₃，CN，NO₃，CF₃OR NR, where R is acyl including but not limited to acetyl, benzoyl, arylalkyl (including but not limited to benzyl), lower alkyl including but not limited to methyl, ethyl, propyl, CH₂R, wherein R is hydrogen, lower alkyl (including but not limited to methyl, ethyl, propyl);

x is SO₂SO or CO;

b is a natural or modified nucleobase.

In one embodiment, structural formula IB is as follows:

in the formula (I), the compound is shown in the specification,

R²，R³independently is hydrogen, (C)₁-C₆) Lower alkyl including, but not limited to, methyl, hydroxymethyl, methoxymethyl, halomethyl (including, but not limited to, fluoromethyl), ethyl, propyl, optionally substituted vinyl including, but not limited to, vinyl, halovinyl (F-CH ≡ C), optionally substituted ethynyl including, but not limited to, haloethynyl (F-C ≡ C), optionally substituted allyl including, but not limited to, haloallyl (FHC ═ CH-CH)₂-)；

B is a natural or modified nucleobase.

The invention disclosed herein relates to a method for synthesizing a compound of 2-alkyl-4, 5-di-O-protected-2, 3-dihydroxy-pentanoate represented by the following general formula 42B, which is an important intermediate for synthesizing anti-HCV nucleosides of the general formulae [ I ] and [ II ] (below).

Wherein R', R "═ isopropylidene, benzylidene, cyclohexylidene or the like, or part of a cyclic group including ethylene (-CH) groups forming cyclopentyl or cyclohexyl (cyclohexenyl) groups, respectively₂CH₂-) or trimethylene (-CH)₂CH₂CH₂-) according to the formula (I); r 'and R' may independently be C₁-C₆Lower alkyl or C₆-C₂₀Aryl, benzyl and other optionally substituted benzyl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, TIPDS, THP, MOM, MEM and other optional ether protecting groups; or H, acetyl, benzoyl and other optionally substituted acyl groups (R 'and R' are-C (O) -R, wherein R may be C₁-C₆Lower alkyl or C₆-C₂₀Aryl, benzyl or other optionally substituted benzyl);

R₁、R₂independently is hydrogen, (C)₆-C₂₀) Aryl radicalsAnd (C)₁-C₆) Lower alkyl including methyl, hydroxymethyl, methoxymethyl, halomethyl (including fluoromethyl), ethyl, propyl, optionally substituted vinyl including vinyl, halovinyl (F-CH ═ C), optionally substituted ethynyl including haloethynyl (F-C ≡ C), optionally substituted allyl including haloallyl (FHC ═ CH-CH ≡ C)₂-) according to the formula (I); and

R₃independently hydrogen, aryl (including phenyl), arylalkyl (including but not limited to benzyl), (C)_1-6) Lower alkyl, including methyl, ethyl or propyl.

The invention disclosed herein also relates to a method for preparing a compound represented by the following formula 49B, which is prepared from a 2-alkyl-4, 5-di-O-protected-2, 3-dihydroxy-pentanoate derivative represented by the formula [42B ].

In the formula, R³And R⁵May independently be H, CH₃Ac, Bz, pivaloyl or 4-nitrobenzoyl, 3-nitrobenzoyl, 2-nitrobenzoyl, 4-chlorobenzoyl, 3-chlorobenzoyl, 2-chlorobenzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 2-methylbenzoyl, p-phenylbenzoyl and other optionally substituted acyl radicals (R³And R⁵is-C (O) -R, R may independently be C₁-C₆Lower alkyl or C₆-C₂₀Aryl, benzyl, 4-methoxybenzyl and other optionally substituted benzyl (R)³And R⁵May independently be C₆-C₂₀Aryl), trityl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, TIPDS, THP, MOM, MEM, and other optional ether protecting groups (R)³And R⁵May independently be C₁-C₁₀Alkyl, or, R³And R⁵by-SiR₂-O-SiR₂-or-SiR₂-linked, wherein R is lower alkyl, such as Me, Et, n-Pr or i-Pr.

In the formula (I), the compound is shown in the specification,

x is halogen (F, Cl, Br),

y is N or CH, and Y is N or CH,

z is halogen, OH, OR ', SH, SR', NH₂NHR 'or R',

R²is' a C₁-C₃An alkyl group, a vinyl group or an ethynyl group,

R³' and R⁵'may be the same or different and is H, alkyl, aralkyl, acyl, a cyclic acetal, such as 2', 3 '-O-isopropylidene or 2', 3-O-benzylidene, or a 2 ', 3' -cyclic carbonate.

R²、R⁴、R⁵And R⁶Independently H, halogen, including F, Cl, Br, I, OH, OR ', SH, SR', N₃，NH₂，NHR′，NR”，NHC(O)OR′，C₁-C₆Lower alkyl, halo (F, Cl, Br, I) C₁-C₆Lower alkyl, e.g. CF₃And CH₂CH₂F，C₂-C₆Lower alkenyl, e.g. CH ═ CH₂Halogenation of (F, Cl, Br, I) C₂-C₆Lower alkenyl, e.g. CH ═ CHCl, CH ═ CHBr and CH ═ CHI, C₂-C₆Lower alkynyl, e.g. C.ident.CH, halogenated (F, Cl, Br, I) C₂-C₆Lower alkynyl, C₁-C₆Lower alkoxy, e.g. CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) C₁-C₆Lower alkoxy, CO₂H，CO₂R′，CONH₂，CONHR′，CONR′₂，CH＝CHCO₂H，CH＝CHCO₂R'; and

r 'and R' are the same or different and are optionally substituted C₁-C₁₂Alkyl (especially when the alkyl is the residue of an amino acid), cycloalkyl, optionally substituted C₂-C₆Alkynyl, optionally substituted C₂-C₆Lower alkenyl or optionally substituted acyl.

The cyclic sulfate 50 (scheme 6) reacts with tetraethylammonium fluoride or tetramethylammonium fluoride 51 (scheme 6) in a highly stereospecific and regioselective manner to quantitatively produce fluorinated sulfates. After the acid catalyzed cyclization, 2-fluoro-2-C-methyl- γ -ribonolactone 53 is formed in high yield.

The present invention is based on this discovery and provides methods for preparing 2 '-deoxy-2' -substituted nucleosides I and II using the reactions described herein.

(2S, 3R, 4R) -4, 5-O-alkylene-2-dimethyl-2, 3, 4, 5-tetrahydroxy-2-methyl-pentanoic acid ethyl ester (42B) can be prepared by Asymmetric Dihydroxylation (AD) or stereospecific dihydroxylation of Wittig product 41 with or without the use of a chiral catalyst. Whereas Wittig product 41 can be readily prepared from protected (R) glyceraldehyde (schemes 7, 8), wherein R is¹Independently is (C)₁-C₆) Lower alkyl, including but not limited to methyl, ethyl, optionally substituted phenyl, optionally substituted benzyl. Or R¹Is part of a cyclic group comprising an ethylene (-CH) group forming a cyclopentyl or cyclohexyl group, respectively₂CH₂-) or trimethylene (-CH)₂CH₂CH₂-)。R²、R³Independently is hydrogen, (C)₁-C₆) Lower alkyl including, but not limited to, methyl, hydroxymethyl, methoxymethyl, halomethyl (including, but not limited to, fluoromethyl), ethyl, propyl, optionally substituted vinyl including, but not limited to, vinyl, halovinyl (F-CH ═ C), optionally substituted ethynyl including, but not limited to, haloethynyl (F-C ≡ C), optionally substituted allyl including, but not limited to, haloSubstituted allyl (FHC ═ CH-CH)₂-)；R⁴Is acyl including but not limited to acetyl, benzoyl, arylalkyl including but not limited to benzyl, (C)_1-10) Lower alkyl, including but not limited to methyl, ethyl, propyl, CH₂R, wherein R is hydrogen, (C)_1-10) Lower alkyl, including but not limited to methyl, ethyl, propyl.

Scheme 7

The diol (42B) can be converted into the cyclic sulfite (IIIa) by reacting with thionyl chloride (SOCl) in the presence of an alkylamine such as triethylamine, diisopropylethylamine or pyridine₂) Treating and then oxidizing with an oxidizing agent selected from RuCl₃、KMnO₄And TEMPO or a combination of said first group and NaIO₄、KIO₄、HIO₄A combination of one of the second group consisting of mCPBA, NaOCl, and oxone. The solvent of this step is selected from one or more of the following: chloroform, dichloromethane, 1, 2-dichloroethane, diethyl ether, tetrahydrofuran, benzene and toluene, which may be used alone or in combination with water. (GaoY et al, J.Am.chem.Soc.1988, 110, 7538-7539, Berridge et al J.org.chem.1990, 55, 1211-1217). The diols can also be converted directly into the cyclic sulfates (Vb) by treatment with sulfuryl chloride or sulfuryl diimidazole. Alternatively, the diol 42B may be converted to the cyclic carbonate (IIIc) by treatment with carbonyldiimidazole (carbonyl diimidazole) or carbonyldimethoxide (scheme 8) (Chang et al Tetrahedron Lett.1996, 37, 3219-3222).

Scheme 8

(ii) Synthesis of substituted 2-deoxy-D-ribono-gamma-lactones, 53B

Cyclic sulfates (IIIb, scheme 8) are converted to the sulfates of formula 51B in high yield and regioselectivity and stereospecifically (scheme 9) by treatment with tetraalkylammonium fluorides including but not limited to tetramethylammonium fluoride (TMAF), tetraethylammonium fluoride (TEAF) or tetrabutylammonium fluoride (TBAF) or (trimethylsilyl) tris (dimethylamino) sulfide (TAS-F) (Fuentes J et al, Tetrahedron lett.1998, 39, 7149-7152) in protic polar solvents such as acetone, tetrahydrofuran, N-dimethylformamide or acetonitrile (scheme 9). Metal fluorides such as silver fluoride (AgF), potassium fluoride (KF), caesium fluoride (CsF) or rubidium fluoride (RbF), which solvents may be used alone or together with catalytic amounts of tetraalkylammonium fluoride, crown ethers, diglyme or polyethylene glycols or other phase transfer catalysts.

The cyclic sulfate (IIIb) can be prepared by reacting NaBH₄Tetraalkylammonium chloride, tetraalkylammonium bromide, NaN₃Or LiN₃、NH₄OR、NH₄SCN、CF₃I-tetrakis (dimethylamino) -ethylene (TDAE) and tetraalkylammonium nitrate (Gao et al, J.Am.chem.Soc.1988, 110, 7538-7539), KCN, LiCu (R)₂And processed to convert to other 2-substituted sulfates represented by structural formula 51B, wherein R is methyl, ethyl, vinyl, or ethynyl. Similarly, cyclic sulfites (IIIa) can be converted to substituted esters 52B (Chang et al Tetrahedron Lett.1996, 37, 3219-. Compounds of formula 51B and 52B are prepared by reacting H with an acid₂O can be converted to the substituted lactone of formula 53B by treatment in an organic solvent such as methanol, ethanol or acetonitrile.

In the formula 53B, R²、R³Independently is hydrogen, (C)₁-C₆) Lower alkyl including but not limited to methyl, hydroxymethyl, methoxymethyl, halomethyl (including but not limited to fluoromethyl), ethyl, propyl, optionally substituted vinyl including but not limited toWithout limitation, vinyl, halovinyl (F-CH ═ C), optionally substituted ethynyl, including but not limited to haloethynyl (F-C ≡ C), optionally substituted allyl, including but not limited to haloallyl (FHC ═ CH-CH)₂-). Nu is halogen (F, Cl, Br), N₃，CN，NO₃，CF₃SCN, OR OR NR₂Wherein R is acyl including but not limited to acetyl, benzoyl, arylalkyl including but not limited to benzyl, (C)_1-10) Lower alkyl, including but not limited to methyl, ethyl, propyl, CH₂R, wherein R is hydrogen, (C)_1-10) Lower alkyl, including but not limited to methyl, ethyl, propyl.

Scheme 9

(iii) Protection of D-ribono-gamma-lactone (53B)

53B can be selectively protected with a suitable base in a suitable solvent with a suitable protecting agent to give the 5-protected lactone of formula 53C. These protecting groups include, but are not limited to, the following: trityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzyloxymethyl, benzoyl, toluoyl, 4-phenylbenzoyl, 2-, 3-or 4-nitrobenzoyl, 2-, 3-or 4-chlorobenzoyl, other substituted benzoyl. The base includes, but is not limited to, the following bases: imidazole, pyridine, 4- (dimethylamino) pyridine, triethylamine, diisopropylethylamine, 1, 4-diazabicyclo [2, 2, 2] -octane. Solvents include, but are not limited to, the following: pyridine, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran.

Scheme 10

Alternatively, the lactone 53B can be fully protected with a suitable protecting agent in a suitable solvent with a suitable base. Protecting group (R)⁵，R⁶) Including but not limited to the following groups: methoxymethyl, methoxyethyl, benzyloxymethyl, ethoxymethyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acyl including acetyl, pivaloyl, benzoyl, toluoyl, 4-phenylbenzoyl, 2-, 3-or 4-nitrobenzoyl, 2-, 3-or 4-chlorobenzoyl, or other substituted benzoyl. The base includes, but is not limited to, the following bases: imidazole, pyridine, 4- (dimethylamino) pyridine, triethylamine, diisopropylethylamine, 1, 4-diazabicyclo [2, 2]Octane. Solvents include, but are not limited to: pyridine, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran (scheme 10).

(iv) Complex directed beta-glycosylation

Scheme 10a

2-deoxy-2-fluoro-2-C-methyl-ribofuranoside (54: Nu ═ F, R)³＝Me，R⁵＝R⁶Pivaloyl) with silylated N⁴-benzoylcytosine in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) in CHCl₃To obtain a mixture of alpha/beta-anomers in the 2/1 ratio in which the alpha-isomer predominates. However, under similar conditions, under SnCl₄In the same reaction catalyzed, the β -anomer is the major product (α/β ═ 1/4.9). A possible mechanism is presented in scheme 10A (R)⁵And R⁶Is an O-protecting group which may be C_1-20Acyl or silyl or alkyl or aralkyl). 54 in the presence of TMSOTf in CHCl₃In which N is silylated⁴-benzoyl cellThe pyrimidine is treated to form the oxonium intermediate 54-i. The silylating base can attack 54-1 from the top side to yield the β -anomer 55B, or attack from the bottom side to provide the α -anomer 55B- α. Due to steric hindrance (sterohonistrance) caused by the 2-methyl group on the upper side, the silylating base attacks intermediate 54-i primarily from the bottom side (less sterically hindered side) to form a mixture of α/β -anomers with a predominant ratio of the α -anomer of 2/1. And 54 in SnCl₄By silylation of N in the presence of⁴Benzoylcytosine treatment to form the complex 54-ii instead of the oxonium 54-i. Silylated N⁴The benzoylcytosine attacks 54-ii from the less sterically hindered upper side, forming an α/β -anomer mixture with a β -anomer predominating ratio of 1/5.

Compound 54 can be formed from the protected lactone represented by formula 49B, 49B can be reduced to the lactol with DIBAL-H or lithium tri-tert-butoxyaluminum hydride and other hydride reducing agents, and the lactol is then converted to the acylate (the acid) by acylation with an acid halide or an acid anhydride (acyl anhydride) in a suitable solvent in the presence of a suitable base. Acyl halides or anhydrides include, but are not limited to, the following: acetyl chloride (acetic chloride), optionally substituted benzoyl chloride, acetic anhydride, optionally substituted benzoyl anhydride. These bases include, but are not limited to, the following: imidazole, pyridine, 4- (dimethylamino) pyridine, triethylamine, diisopropylethylamine, 1, 4-diazabicyclo [2, 2, 2] octane. Such solvents include, but are not limited to, the following: pyridine, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran.

(v) Synthesis of L-nucleosides, IB-L

The methods for the D-series of structures I and II can be used to prepare L-nucleosides of structures IB-L from (S) -glyceraldehyde (scheme 11).

Scheme 11

(vi) Synthesis of 2-alkyl-4, 5-di-O-protected-2, 3-dihydroxy-pentanoic acid

Currently, the most preferred method of synthesizing nucleosides of formula I and II is to prepare derivatives of the 2-deoxy-2-fluoro-2-C-methyl-D-ribofuranosyl moiety in I and II as shown in scheme 4, scheme 5 and scheme 6 by (I) synthesis of intermediates, derivatives of the 2-alkyl-4, 5-di-O-protected-2, 3-dihydroxy-pentanoate of formula I, (II) conversion of 42B to 3, 5-protected 2-deoxy-2-fluoro-2-C-methyl-D-ribono- γ -lactone of formula 49B, and (iii) conversion of 49B to purine and pyrimidine nucleosides of formula I and II. The key step in scheme 4 is the stereospecific osmium catalyzed dihydroxylation of olefin intermediate 41 to 42 in the presence of the expensive Sharpless AD catalyst. The reaction can also be run smoothly if other chiral compounds such as L-quinidine are used instead of the Sharpless catalyst to give the desired 42. Kishi et al have proposed OsO on allyl alcohol derivatives (esters, ethers, acetals, or ketals)₄In dihydroxylation, the main process of reaction occurs at the olefinic bond face opposite the pre-existing hydroxyl or alkoxy group (Tetrahedron Lett, 1983, 24, 3943). Some examples are shown in scheme 12(Tetrahedron Lett, 1983, 24, 3947). In each case, the main product is formed by addition of OsO from the opposite side of the oxygen adjacent to the secondary carbon₄And is produced. However, the stereoselectivity is not high enough to carry out the preparative synthesis.

Scheme 12

Kishi's Law proposed that stereochemical elucidation is caused by preferential proximity of osmium tetroxide at the olefinic bond face opposite the pre-existing hydroxyl or alkoxy base face, encouraged by Kishi's Law to carry out the di-oxidation of 41 under original conditions but without any chiral catalysts including Sharpless AD catalystAnd (4) hydroxylating. Using Ke₃Fe(CN)₆/K₂OsO₂(OH)₄/K₂CO₃System but without chiral catalyst dihydroxylation of 41 gave 77% yield of the product, a 5: 1 mixture of isomers, the major isomer being the desired compound 42. Contacting an olefin 41 with OsO in the absence of a chiral catalyst using N-methylmorpholine N-oxide (NMO) as an oxidant₄The reaction gave 42 and its isomer as a 5: 1 mixture in 79% yield. Most surprisingly, when t-butyl hydroperoxide (TBHP) is used as the oxidizing agent, the OsO is used in a catalytic amount₄The isolated crystalline product was virtually pure desired 42 in the presence of acetone and ammonium acetate as buffers (this reagent combination was used by Masamune and Sharpless for the synthesis of alditols (j. org. chem, 1982, 47, 1373)). The method is far superior to OsO₄[ NMO and Fe (CN) ]₆ ^3-The method is carried out. On the order of 10 millimoles (mmolar), the desired diol 42 is formed exclusively in an isolated yield of 87%. By violent action¹H NMR analysis, no contamination of the product with other isomers was detected.

It is well known that in OsO₄In the oxidation, the intermediate is cyclic osmate salt V (below) (crisegee, liebig ann. chem., 1936, 522, 75). Cis-dihydroxylation of olefins in alkaline medium with potassium permanganate has been known for a considerable time (Robinson and Robinson, j.chem.soc., 1925, 127, 1628), and the reaction appears to proceed via the cyclic ester VI. Therefore, attempts have been made to dihydroxylate permanganates.

Previous reports have shown that the dihydroxylation of olefins by permanganate under acidic or neutral conditions causes the initial glycol product to be peroxidized with the concomitant formation of ketones and carboxylic esters. Further oxidation of the diol product is slowed only under alkaline conditions. Since compound 41 is a carboxylic acid ester, the reaction cannot be carried out in an aqueous base. Hazra et al (J.chem.Soc.Perkin Trans.I, 1994, 1667) describe the successful dihydroxylation of highly substituted olefins to the corresponding diols using tetradecyltrimethylammonium permanganate (TDTAP) in a mixture of t-BuOH, dichloromethane and water in the presence of 0.1 equivalents KOH. Applying this method to the dihydroxylation of compound 41 resulted in the rapid formation (within 10 minutes at room temperature) of a mixture of compound 42 and its diastereomer (ratio 8: 1) in 71% isolated yield. In a similar reaction, oxidation occurs more rapidly without KOH, but the yield of compound 42 is not improved.

Mukaiyama et al (chem.Lett., 1983, 173) disclose the use of KMnO for olefins₄And 18-crown-6-ether was dihydroxylated in methylene chloride at-40 ℃. Dihydroxylation of compound 41 was attempted under Mukaiyama conditions but at a different temperature to form a 6: 1 mixture of compound 42 and its diastereomers at-40 ℃ in 50% yield and the same mixture at-10 ℃ but in 94% yield.

Surprisingly, the prior art discloses that the double bond is covered by KMnO₄The oxidation is carried out via a diol, wherein the resulting diol is further rapidly oxidized in the absence of a base. Unlike the prior art, it was found that KMnO was used when 41 was used₄The glycol 42 may be sequestered upon treatment without the addition of a base and crown ether. In pure t-butyl alcohol, the oxidation reaction did not proceed even after standing at room temperature for 2 days. Water is added to the mixture to promote the reaction. It was found that the more water in the reaction medium, the faster the reaction proceeded and the poorer the selectivity for 42 formation; the less water in the reaction medium, the slower the reaction proceeds, but the selectivity of formation 42 increases. In any case, the yield is rather poor due to further oxidation.

Most surprisingly, in contradiction to the prior art, it was found that compound 41 was treated with KMnO₄Treatment in acetone gives a 10: 1 mixture in a yield, with 42 being the major component required. It has been found that conducting the reaction in a mixture of acetone and pyridine can improveThe vertical structure is selective.

The following examples are set forth to aid in the understanding of the invention. This section is not intended to, and should not be construed as, limiting in any way the invention set forth in the following claims.

Examples

Example 1

(2S, 3R, 4R) -4, 5-O-isopropylidene-2, 3-O-sulfonyl-2, 3, 4, 5-tetrahydroxy-2-methyl-pentanoic acid ethyl ester (IIIb, R)¹＝CH₃，R²＝H，R³＝CH₃)

To (2S, 3R, 4R) -4, 5-O-isopropylidene-2, 3, 4, 5-tetrahydroxy-2-methyl-pentanoic acid ethyl ester (R) at 0 deg.C¹＝CH₃，R²＝H，R³＝CH₃) (2.0g, 8.06mmol) to a solution of anhydrous dichloromethane (40mL) and triethylamine (3.4mL) was added thionyl chloride (0.88mL, 12.08mmol) dropwise over 10 minutes. The resulting reaction mixture was stirred at 0 ℃ for 10 min, diluted with cold ether (100mL), washed with water (50 mL. times.2) and brine (50 mL. times.2), dried over sodium sulfate, and concentrated to give a residue (IIIa, R)¹＝CH₃，R²＝H，R³＝CH₃) The residue was dissolved in acetonitrile-tetrachloromethane (10: 10 mL). To the resulting solution was then added sodium periodate (2.58g, 12.06mmol), ruthenium trichloride (16mg, 0.077mmol) and water (14mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 10 minutes, diluted with ether (100mL), washed with water (50 mL. times.2), saturated sodium bicarbonate solution (50 mL. times.2) and brine (50 mL. times.2), dried over sodium sulfate, concentrated, and co-evaporated with toluene (30 mL. times.3) to a syrupy residue, and the sulfate IIIb (2.23g, 89%) was used in the next reaction without further purification.¹H NMR(CDCl₃)δ(ppm)5.04(d，1H，J＝9.6Hz，H-3)4.37(m，1H，H-4)，4.29(q，2H，J＝7.6Hz，CH ₂CH₃)，4.17(dd，1H，J＝5.6，9.6Hz，H-5)，4.05(dd，1H，J＝3.2，9.6Hz，H-5’)，1.8(s，3H，CH₃-2)，1.38(s，3H，(CH ₃)₂C)，1.32(t，3H，J＝6.8Hz，CH₂CH ₃)，1.31(s，3H，(CH ₃)₂C)。

Example 2

Tetrabutylammonium salt of ethyl (2R, 3S, 4R) -2-fluoro-4, 5-O-isopropylidene-2-methyl-3-sulfooxy (sulfoxy) -3, 4, 5-trihydroxypentanoate (51B, R)¹＝CH₃，R²＝H，R³＝CH₃，Nu＝F，M⁺Tetrabutyl ammonium)

The method comprises the following steps: tetrabutylammonium fluoride (1M in tetrahydrofuran) solution was added dropwise at 0 ℃ to a solution of the sulfate IIIb from example 1 (628mg, 2.02mmo1) in anhydrous tetrahydrofuranMolecular sieve dry) for 5 minutes. The resulting reaction mixture was stirred at 0 ℃ for 20 minutes, and 2mL of tetrabutylammonium fluoride (1M in tetrahydrofuran) was addedMolecular sieves dry, 3mL), then the reaction mixture was stirred at 0 ℃ for 2h, then concentrated and purified by silica gel column chromatography (EtOAc) to give the fluorinated sulfate, syrup (350mg, 38%).¹H NMR(CDCl₃)δ(ppm)4.66(dd，1H，J＝9.6，25.6Hz，H-3)，4.48(dd，1H，J＝5.2，8.8Hz，H-4)，4.20，4.07(2m，4H，H-5，OCH ₂CH₃)，3.21(m，8H，N(CH ₂CH₂CH₂CH₃)₄)，1.69(d，3H，J＝22.4Hz，CH₃-2)，1.59(m，8H，N(CH₂CH ₂CH₂CH₃)₄)，1.39(m，8H，CH₂CH₂CH ₂CH₃)₄)，1.27-1.25(m，9H，OCH₂CH ₃，(CH ₃)₂C)，0.96(t，12H，J＝6.8Hz，CH₂CH₂CH₂CH ₃)₄.

The method 2 comprises the following steps: tetrabutylammonium fluoride (1M tetrahydrofuran, neutralized with HF-pyridine, 3.1mL) was added dropwise to a solution of cyclic sulfate IIIb (480mg, 1.55mmol) in anhydrous tetrahydrofuran at 0 ℃ for 5 minutes. The resulting reaction mixture was stirred for 39 hours, concentrated and purified by silica gel column Chromatography (CH)₂Cl₂MeOH 10: 1) to give the fluorinated sulfate as a syrup (280mg, 39%).

Example 3

2-deoxy-2-fluoro-2-C-methyl-D-ribono-gamma-lactone (53B, R)²＝H，R³＝CH₃，Nu＝F)

A mixture of the product of example 2 (170mg, 0.370mmol), trifluoroacetic acid (0.8mL) and water (2mL) in acetonitrile (10mL) was heated at 80 ℃ for 1.5 h, diluted with ethyl acetate (15mL), washed with water (10mL) and saturated sodium bicarbonate solution (10 mL). The aqueous layer was saturated with NaCl and extracted with ethyl acetate (10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography on silica gel (hexane: ethyl acetate 1: 1 to CH)₂Cl₂MeOH: 20: 1) to afford the desired compound as a white solid, (60mg, 100%).¹H NMR(CDCl₃)δ(ppm)6.06(d，1H，J＝6.8Hz，HO-3)，5.16(t，1H，J＝4.8Hz，HO-5)，4.26(m，1H，H-4)，3.98(ddd，1H，J＝7.2，8.0，23.2Hz，H-3)，3.78(ddd，1H，J＝2.0，5.2，12.8Hz，H-5)，3.55(ddd，1H，J＝4.4，5.6，12.4Hz，H-5’)，1.48(d，3H，J＝24Hz，CH₃-2)；¹³C NMR(CDCl₃)δ(ppm)171.2(d，J＝21.2Hz，C-1)，92.5(d，J＝177.5Hz，C-2)，83.37(C-4)，70.2(d，J＝15.9Hz，C-3)，59.0(C-5)，17.1(d，J＝25.0Hz，CH₃-C-2).

Example 4

3, 5-di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-riboseAcid-gamma-lactone (49B, R)²＝H，R³＝CH₃，R⁵＝Bz，R⁶＝Bz，Nu＝F)

The compound (60mg, 0.16mmol) of example 3 was dissolved in anhydrous pyridine (1mL), and benzoyl chloride (0.3mL) was added. The resulting reaction mixture was stirred at room temperature for 20 minutes, water (1mL) was added, stirred for 20 minutes, diluted with ethyl acetate (5mL), washed with water (2mL) and 1M HCl (2 mL. times.3), and dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (hexane: ethyl acetate 10: 1) to give 3, 5-di-O-benzoyl-2-deoxy-2-fluoro-D-ribono-gamma-lactone as a white solid (118mg, 87%).¹H NMR(CDCl₃) δ (ppm)8.08(m, 2H, aromatic), 7.99(m, 2H, aromatic), 7.63(m, 1H, aromatic), 7.58(m, 1H, aromatic), 7.49(m, 2H, aromatic), 7.43(m, 2H, aromatic), 5.51(dd, 1H, J ═ 7.2, 17.6Hz, H-3), 5.00(m, 1H, H-4), 4.78(dd, 1H, J ═ 3.6, 12.8Hz, H-5), 4.59(dd, 1H, J ═ 5.2, 12.8Hz, H-5 '), 1.75(d, 3H, J ═ 23.6Hz, CH-5'), and so on₃-2)

Example 5

Tetraethylammonium salt of ethyl (2R, 3S, 4R) -4, 5-dihydroxy-2-fluoro-4, 5-O-isopropylidene-2-methyl-3-sulfoxy (sulfoxoxy) -pentanoate (51B, R)¹＝CH₃，R²＝H，R³＝CH₃，Nu＝F，M⁺Tetraethyl ammonium)

The method comprises the following steps: to a solution of the sulfate ester IIIb (scheme 9) (1.96g, 6.32mmol) in dry N, N-dimethylformamide (20mL) was added tetraethylammonium fluoride hydrate (1.39g, 9.13mmol) in one portion at 0 ℃. The resulting reaction mixture was stirred for 30 minutes, concentrated, and co-evaporated with toluene to give a semi-solid (51b) (3.35g, crude, proton NMR showed actually a product).¹H NMR(CDCl₃)δ(ppm)4.61(dd，1H，J＝9.2，25.6Hz，H-3)，4.51(dd，1H，J＝5.2，9.2Hz，H-4)，4.23-4.05(m，4H，H-5，OCH ₂CH₃)，3.32(q，8H，J＝7.2Hz，N(CH ₂CH₃)₄)，1.69(d，3H，J＝23.2Hz，CH₃-2)，1.31-1.24(m，21H，OCH₂CH ₃，(CH ₃)₂C，N(CH₂CH ₃)₄。

The method 2 comprises the following steps: tetraethylammonium fluoride hydrate (107mg, 0.717mmol) was added in one portion to a solution of sulfate IIIb (148mg, 0.477mmol) in anhydrous acetonitrile (2mL) at 0 ℃. The resulting reaction mixture was stirred for 24 h, concentrated and co-evaporated with toluene to give a semi-solid (257mg, crude, proton NMR showed actually a product).

Example 6

Preparation of 1- (2-deoxy-2-fluoro-2-methyl-3, 5-O-3, 5-dipivaloyl-ribofuranosyl) -N⁴-benzoylcytosine (11b, R)⁵＝R⁶Pivaloyl, R²＝H，R³＝Me)

To 49B (scheme 6) (Nu ═ F, R) at-20 ℃ to-10 ℃²＝H，R³＝Me，R⁵＝R⁶Pivaloyl, 3.44g, 10.36mmol) in THF (70mL) was added LiAl (t-BuO)₃H (13.47mmol, 1M in THF, 13.47mL), -stirring the resulting solution at 10 ℃ to-15 ℃ for 2 hours. To this solution was added further LiAl (t-BuO)₃H (1.35mL, 1.35mmol), the solution was stirred at-10 ℃ for 1H. Ice water (50mL) was added. The mixture was extracted with EtOAc (200mL), and the organic layer was washed with water, brine, and then washed with (Na)₂SO₄) And (5) drying. The solvent is removed to give a crude lactol, which is dissolved in CH₂Cl₂(50 mL). Et was added to the solution₃N (31.08mmol, 4.24mL), 4-dimethylaminopyridine (1mmol, 122mg) and trimethylacetyl chloride (20.7mmol, 2.55mL), the mixture was stirred at room temperature for 16 h. Water (20mL) was added and the resulting mixture was stirred at room temperature for 10 minutes. EtOAc (200mL) was added and the organic solution was washed with water, brine and then washed with (Na)₂SO₄) And (5) drying. After removal of the solvent, the residue was co-evaporated with toluene (2X 20mL) to give crude intermediate (5, 6.74g) which was used without purificationA coupling reaction was used.

N⁴-benzoylcytosine (6.06mmol, 1.30g) and (NH)₄)₂SO₄A suspension (30mmg) in HMDS (16.7mL) was refluxed for 5 hours and the clear solution was concentrated to dryness under reduced pressure. The residue was dissolved in 1, 2-dichloroethane (50 mL). To this solution was added crude 54(1.96g, scheme 6) and SnCl at room temperature₄(1.42mL, 12.12 mmol). The solution was refluxed for 24 hours and then cooled to 0 ℃. To this solution NaHCO was added₃(6.11g, 72.72mmol) and EtOAc (50 mL). Slowly adding H to the mixture₂O (2mL), the resulting mixture was stirred at room temperature for 20 minutes. The solid was removed by filtration. The organic solution was washed with water, brine and then with (Na)₂SO₄) And (5) drying. After removal of the solvent, a syrupy mass was obtained which was a crude mixture of the 4/1 ratio β/α -anomer, with the β -isomer predominating. The crude product was dissolved in MeOH (1mL) at 50 ℃. To the solution was added hexane (10 mL). The mixture was allowed to stand at room temperature for 1 hour and then at 0 ℃ for 2 hours. The crystals were collected by filtration and washed with hexanes to give product 55, scheme 6(323mg, 20.3% from 49). The mother liquor was concentrated to dryness and purified by column chromatography (20-50% EtOAc in hexanes) to afford a second crop of product 55. H-NMR (CDCl)₃)：δ8.82(br s，1H，NH)，8.10，7.89，7.62，7.52(m，7H，H-5，H-6，5Ph-H)，6.41(d，J＝18.4Hz，1H，H-1’)，5.10(m，1H，H-3’)，4.45(d，J＝9.6Hz，1H，H-4’)，4.36(t，J＝2.8Hz，2H，H-5’)，1.35(d，J＝22.0Hz，3H，Me)，1.29，1.23[ss，18H，C(Me)₃]。

Example 7

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-yl ] -2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42)

4-methylmorpholine N-oxide as an oxidizing agent with an osmium catalyst.

To a stirred solution of compound 41(214mg, 0.1mmol) in t-BuOH under argon was added a solution of 4-methylmorpholine N-oxide (0.47mL, 50 wt% aqueous solution) and water (0.2mL)And (4) liquid. A2.5 wt.% solution of osmium tetroxide in t-butanol (0.51mL) was added and the mixture was stirred in a water bath at room temperature for 5 hours. The mixture was evaporated in vacuo to a syrup, which was mixed with H₂O (3X 10mL) was azeotroped to remove 4-methylmorpholine. The residue was dried by addition and evaporation of EtOH (2 × 10mL) to give a residue which was purified by column chromatography on silica gel with 20% EtOAc in hexanes to give the desired product and its isomers as a solid (196mg, 79%). Proton NMR showed the ratio of the desired product to its isomer to be about 5: 1. The pure product (91mg, 37.4% from the starting material) was obtained as a crystalline solid after recrystallization of the mixture from a hexane/ethyl acetate mixture.¹H NMR(DMSO-d₆)δ1.18(t，J＝7.2Hz，3H，-OCH₂ CH ₃ )，1.24(s，3H，CH₃)，1.25(s，3H，CH₃)，1.28(s，3H，2-CH₃) 3.67(t, J ═ 7.2Hz, 1H), 3.85, 4.06 and 4.12(m, 4H), 4.97(s, 1H, 2-OH, D)₂O interchangeable), 5.14(D, J ═ 7.6Hz, 2-OH, D₂O is exchangeable).

Example 8

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-yl ] -2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42)

Potassium ferricyanide is used as an oxidizing agent and is provided with an osmium catalyst.

A100 mL round bottom flask equipped with a magnetic stirrer was charged with 5mL t-butanol, 5mL water, and K₃Fe(CN)₆(0.98g)、K₂CO₃(0.41g) and K₂OsO₂(OH)4(3.2 mg). The two clear phases formed were stirred at room temperature; the lower aqueous phase was bright yellow. At this point methanesulfonamide (95mg) was added. The mixture was cooled to 0 ℃ during which time a portion of the salt precipitated, 214mg (1mmol) of compound 41 were immediately added and the homogeneous slurry was stirred vigorously at 0 ℃ for 24 hours. To the mixture was added solid sodium sulfite (1.5g) with stirring at 0 ℃, and then the mixture was warmed to room temperature and stirred for 30 to 60 minutes. Ethyl acetate (10mL) was added, the layers were separated, and the aqueous phase was further washed with waterAnd (4) extracting the EtOAc. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by column chromatography on silica gel with 20% EtOAc in hexanes to provide the product as a solid (190mg, 77%). Proton NMR showed the ratio of the desired product to its isomer to be about 5: 1. The pure diol product (102mg, 41% from starting material) was obtained as a crystalline solid after recrystallization of the mixture from hexane/ethyl acetate. Of the product¹The H NMR spectrum is identical to that of an authentic sample.

Example 9

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-yl ] -2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42)

Tert-butyl hydroperoxide is an oxide and an osmium catalyst is present at room temperature.

Into a 50mL flask equipped with a magnetic stirrer were charged 2mL of acetone, 214mg (1mmol) of Compound 41, and 65mg of Et₄NOAc·4H₂O and 0.3mL of tert-butyl hydroperoxide (5-6M in decane). Stirred at room temperature until Et is obtained₄Clear solution of NOAc, the resulting solution was cooled in an ice bath and 5mL of OsO was added in one portion₄(2.5% by weight in t-BuOH). The solution immediately turned a brownish purple color. After 1 hour the ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 14 hours. The remaining reaction steps are exactly the same as described above. After flash column chromatography 178mg (72%) of the product is obtained as a solid. In an extension of¹In H NMR, a slight bulge was observed at δ 1.26, indicating that less than 4% of the isomer was present in the product.

Example 10

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-yl ] -2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42)

Tert-butyl hydroperoxide as an oxidizing agent at 0 ℃ with osmium catalyst.

Into a 250mL flask equipped with a magnetic stirrer were charged 20mL of acetone, 2.14g (10mmol) of Compound 41, and 650mg of Et₄NOAc·4H₂O and 3mL of tert-butyl hydroperoxide (5-6M in decane). Stirred at room temperature until Et₄The NOAc had dissolved, the resulting solution was cooled in an ice bath, and 5mL of OsO was added in one portion₄(2.5% by weight in t-BuOH). The solution immediately turned a brownish purple color. The reaction mixture was stirred at 0 ℃ for 6.5 h (monitored by TLC, hexane: ethyl acetate 4: 1, Rf 0.18). Ether (40mL) was added at 0 deg.C, and the resulting mixture was reconstituted with 5mL of 10% NaHSO₃The solution is treated once. The ice bath was removed and stirring was continued for 1 hour. To the mixture was added EtOAc (100mL) and H₂O (50 mL). After layer separation, the aqueous phase was extracted with EtOAc. The organic layer was washed with brine and dried over magnesium sulfate (MgSO)₄) Drying and concentrating. The residue was purified by flash column chromatography with 20% EtOAc in hexanes to give the product as a solid (2.16g, 87%). By violence¹H NMR analysis, no contamination of the isomer was detected in the product.

Example 11

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-yl ] -2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42)

Tetradecyltrimethylammonium permanganate (TDTAP) is used as the oxidant.

To compound 41(214mg, 1mmol) in t-BuOH (10mL) and CH at room temperature₂Cl₂To a stirred solution (2mL) was added a solution of KOH (6mg, 0.1mmol) in water, followed by multiple additions of TDTAP (0.420g, 1.12mmol) in small portions over a period of 5 minutes. After 5 min, TLC showed the reaction was complete. The solution was quenched with 10mL of saturated sodium bisulfite. The reaction mixture was concentrated in vacuo. The residue was extracted with ethyl acetate (3X 15mL) and washed with (Na)₂SO₄) Drying, evaporating to obtain white solid, and dissolving the solid in 5mL CH₂Cl₂The solution was passed through a silica gel column topped with celite, and washed with ethyl acetate (50 ml). The filtrate was dried in vacuo to give a viscous oil (174mg, 71% yield) as an 8: 1 mixture, in which the major isomer was the title compound.

Example 12

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-yl ] -2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42)

Potassium permanganate as oxidant and 18-crown-6-ether-A at-40 deg.c.

To compound 41(214mg, 1mmol) in CH at-40 deg.C₂Cl₂(10mL) and 18-crown-6-Ether (37.5mg, 0.1mmol) in several portions₄(158mg, 1mmol) and the mixture was stirred at the same temperature for 2 hours. During this time, the reaction mixture turned dark brown. After completion of the reaction, the mixture was quenched with saturated sodium bisulfite solution (10 mL). The resulting colorless mixture was filtered through a frit and the filtrate was extracted with ethyl acetate (2X 25ml) and washed with (Na)₂SO₄) Drying and concentrating to give a viscous oil containing 10-20% unreacted olefin starting material and the desired diol and its isomer (6: 1 ratio of diol to isomer) ((S))¹H NMR). The olefin starting material was removed after passing through a small pad of silica gel using 5% ethyl acetate: hexane. A6: 1 mixture of the desired diol was eluted from the column with 20% ethyl acetate/hexane to give a white solid (200 mg-80%) after evaporation of the solvent.

Example 13

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-yl ] -2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42)

Potassium permanganate as oxidant has 18-crown-6-ether-B at-10 deg.c.

To compound 41(214mg, 1mmol) in CH₂Cl₂To the solution (10ml) 37.5mg (0.1mmol) 18-crown-6-ether were added and the mixture was cooled to-10 ℃. Adding KMnO in multiple batches₄(237mg, 1.5mmo1), the mixture was stirred at-10 ℃ for 2 hours. During this time the reaction mixture became dark brown and the mixture was treated with a saturated solution of sodium bisulfite (10 mL). The resulting mixture was filtered through a frit and the filtrate was extracted with ethyl acetate (2X 25ml) and washed with (Na)₂SO₄) Drying and evaporation gave a white solid (240mg, 94.4%) containing the desired product and its isomers in a 6: 1 ratio of desired product to its isomers.

Example 14

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-yl ] -2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42)

Potassium permanganate as oxidant in 1: 9H₂O/t-BuOH.

To compound 41(214mg, 1mmol) in t-BuOH (9mL) and H at 0 deg.C₂KMnO was added to a solution of O (1mL) in several portions₄(237mg, 1.5mmol) and the mixture is stirred at the same temperature for 2 hours. Then (79mg, 0.5mmol) of KMnO was added₄The mixture was stirred for a further 30 minutes. After working up as described above, 128mg (50%) of an isomeric mixture are obtained as a white solid in a ratio of 8: 1 of isomers, the main component of which is the desired product.

Example 15

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-yl ] -2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42)

Potassium permanganate as oxidant in the ratio of 9 to 1₂O/t-BuOH.

To compound 41(214mg, 1mmol) in H at 0 deg.C₂KMnO was added to a solution of O (9mL) and t-BuOH (1mL) in multiple portions₄(237mg, 1.5mmol) and the mixture was stirred at the same temperature for 30 minutes. During this time, the mixture turned dark brown. To the mixture was added a saturated sodium hydrogen sulfite solution (10mL), the mixture was filtered, and the filtrate was extracted with ethyl acetate (3X 25mL) and washed with (Na)₂SO₄) Drying and concentration gave a 4: 1 mixture of diol isomers as a white solid (128mg, 50%) with the title compound as the major component.

Example 16

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-yl ] -2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42)

Potassium permanganate as oxidant at 0 deg.c in H₂And (4) in O.

Mixing KMnO₄(158mg, 1.0mmol) in H₂A solution in O (10mL) was added to Compound 41(214mg, 1mmol), and the mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was quenched with saturated sodium bisulfite solution (10mL) and the mixture was worked up as described above. The white solid obtained (80mg, 32%) was a 4: 1 mixture of diol isomers, the main component of which was the title compound.

Example 17

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-yl ] -2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42)

Potassium permanganate is used as oxidant in acetone.

To a solution of compound 41(214mg, 1mmol) in acetone (10mL) was added _ (37.5mg, 0.1mmol) and the reaction mixture was cooled to 0 ℃. Adding KMnO to the cold solution in multiple portions₄(237mg, 1.5mmol) and the reaction mixture was stirred at the same temperature for 2 hours. During this time, the reaction mixture turned dark brown. The reaction mixture was quenched with saturated sodium bisulfite solution (10ml) at which time the solution became colorless. The reaction mixture was extracted with ethyl acetate (3X 25ml) and after drying and evaporation of the mixture, a white solid (245mg, 96.4%) was obtained in a ratio of 10: 1.

Example 18

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-yl ] -2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42)

Potassium permanganate is used as oxidant in the mixture of acetone and pyridine.

To a solution of compound 41(214mg, 1mmol) in a mixture of acetone (9mL) and pyridine (1mL) at 0 deg.C was addedKMnO₄(158mg, 1.0mmol) and stirred at the same temperature for 1 hour. After working up the reaction mixture as described above, 164mg (67%) of a white solid were obtained as virtually pure product. Is acute¹H NMR analysis indicated that the crude white solid contained about 6% of the diastereomer of the title compound.

Example 19

(2S, 3R) -3- [ (4R) -2, 2-dimethyl- [1, 3]Dioxolan-4-yl radical]-2, 3-dihydroxy-2-methyl-propionic acid ethyl ester (42) in RuCl₃/CeCl₃/NaIO₄In the system

In a 50mL round bottom flask equipped with a magnetic stir bar, NaIO was stirred₄(321mg, 1.5mmol) and CeCl₃·7H₂A mixture of O (37mg, 0.1mmol) in 0.45mL of water was gently heated until a bright yellow suspension formed. After cooling to 0 deg.C, EtOAc (1.25mL) and acetonitrile (1.5mL) were added and the suspension was stirred for 2 minutes. 0.1M RuCl was added₃(25. mu.L) of an aqueous solution, and the mixture was stirred for 2 minutes. A solution of compound 41(214mg, 1mmol) in EtOAc (0.25mL) was added in one portion and the resulting slurry was stirred at 0 ℃ for 1 h. Adding solid Na₂SO₄(0.5g) then EtOAc (3mL) was added. The solid was filtered off and the filter cake was washed several times with EtOAc. The filtrate was saturated with Na₂SO₃The solution was washed, and the organic layer was washed with (Na)₂SO₄) Drying and concentrating to dryness. The residue was purified by column chromatography on silica gel with 20% EtOAc in hexanes to give a syrup (150mg, 60%).¹H NMR indicated that the ratio of the desired product to its isomer was about 1.6: 1.

Example 20

Reduction and acylation of Compound 49

To a solution of 3, 5-dibenzoyl-2-fluoro-2-deoxy-2-methyl-D-ribono-lactone (49, 23g, 61.77mmol, scheme 6) in anhydrous THF (400ml) at-20 deg.C to-10 deg.C was added LiAl (t-OBu)₃H (75mL of a 1M solution in THF, 75.0mmol) for 15 minutes, and the solution formed is stirred at the same temperatureLiquid until all starting material is consumed. After 5 hours, about 10-20% of the starting material remained, so that, when TLC indicated that all starting material had been consumed, 10mLLIAl (t-OBu) was added at the same temperature₃H (10mmol) and stirred for 1 hour. DMAP (7.5g) and Ac were added to the reaction mixture₂O (58.2g, 616mmol), the solution was stirred at-10 ℃ for about 2-3 hours. After completion of the reaction (indicated by TLC), the reaction mixture was diluted with ethyl acetate (400ml) and 200ml water. The organic layer was separated and the aqueous layer was washed with ethyl acetate (2X 100 ml). The combined organic layers were washed with water (3X 150ml), brine and anhydrous Na₂SO₄And (5) drying. After removal of the solvent under reduced pressure and co-evaporation with toluene (2 × 100mL), the crude acetate was obtained as a clear brown oil. The oil was passed through a silica gel column (50g) and washed with 20% ethyl acetate/hexanes until all of the acetate was recovered. The solvent was evaporated under reduced pressure to give the desired acetate (54, 32g) as a colorless oil.

Example 21

1- (2-deoxy-2-fluoro-2-methyl-3-5-O-dibenzoyl-beta-D-ribofuranosyl) -N4-benzoylcytosine (55)

To N⁴-benzoylcytosine (20.39g, 94.74mmol) in a suspension of 400ml HMDS (NH) was added₄)₂SO₄(250mg) and heated under reflux for 4 hours. Excess HMDS was removed under reduced pressure. The oily residue was dissolved in chlorobenzene (1L). To this solution was added a solution of acetate (25g) in chlorobenzene (250mL) and SnCl₄(190.4mmol, 49g), the mixture was stirred at room temperature for 2 hours and then heated at about 65 ℃ for 16 hours. The reaction mixture was cooled to 0 ℃ and NaHCO was added thereto₃(96g, 1.14mol) and ethyl acetate (500ml), followed by careful addition of water (20 ml). The mixture was stirred at room temperature for 30 minutes. The mixture was filtered under vacuum and the residue was washed with ethyl acetate. The organic layer was washed with water, brine (2X 250mL), and anhydrous Na₂SO₄And (5) drying. The solvent was removed under reduced pressure to obtain a pale yellow-brown solid. The solid was dissolved in MeOH (250mL), heated at reflux for 30 min, cooled to room temperature, and filteredThe desired product (55, 8.0g) was obtained as an off-white solid.

Example 22

1- (2-deoxy-2-fluoro-2-C-methyl-beta-D-ribofuranosyl) cytosine (14)

A suspension of compound 55 from example 21 (16.7g, 30.8mmol, scheme 6) was treated with methanolic ammonia (750mL, 7M in MeOH), stirred at room temperature for 12 h, and concentrated to dryness under reduced pressure to afford a pale yellow solid. THF (400mL) was added to the solid, heated at reflux for 30 minutes, and cooled to room temperature. The solid formed was collected by filtration and washed with THF to afford compound 14 as an off-white powder (6.7g, 88%).

Claims (9)

1. A compound of the following formula 49B:

in the formula:

R²is hydrogen;

R³is (C)₁-C₆) An alkyl group;

R⁵and R⁶Independently of each other H, acetyl, benzoyl, 4-benzenePhenylbenzoyl, 2-, 3-or 4-nitrobenzoyl, 2-, 3-or 4-chlorobenzoyl or toluoyl; and

nu is F.

2. A process for preparing a compound of formula 49B, comprising the steps of:

in the formula:

R²is hydrogen;

R³is (C)₁-C₆) An alkyl group;

R⁵and R⁶Independently is H, acetyl, benzoyl, 4-phenylbenzoyl, 2-, 3-or 4-nitrobenzoyl, 2-, 3-or 4-chlorobenzoyl or toluoyl; and

nu is F;

(a) treating a compound of formula 51B or 52B with an acid in at least one solvent:

in formula 51B:

R¹is (C)₁-C₆) An alkyl group;

R²is hydrogen;

R³is (C)₁-C₆) An alkyl group;

R⁴independently is H, aryl, arylalkyl or (C)₁-C₆) An alkyl group; and

nu is F; and

m is tetraalkylammonium or tetraethylammonium;

in formula 52B:

R¹is (C)₁-C₆) An alkyl group;

R²is hydrogen;

R³is (C)₁-C₆) An alkyl group;

R⁴independently is H, aryl, arylalkyl or (C)₁-C₆) An alkyl group; and

nu is F;

(b) azeotropically distilling in benzene or toluene in the presence of an acid to provide a compound of formula 53B; and optionally

In the formula:

R²is hydrogen;

R³is (C)₁-C₆) An alkyl group; and

nu is F;

(c) protecting a compound of formula 53B with a protecting reagent and a base in a solvent.

3. A compound having the following general formula 51B as described in claim 2:

in the formula (I), the compound is shown in the specification,

R¹is methyl;

R²is hydrogen;

R³is (C)₁-C₆) An alkyl group;

R⁴is an ethyl group;

nu is F; and

m + is tetraalkylammonium or tetraethylammonium.

4. A compound having the following general formula 52B as described in claim 2:

in the formula (I), the compound is shown in the specification,

R¹is methyl;

R²is hydrogen;

R³is (C)₁-C₆) An alkyl group;

R⁴is an ethyl group;

nu is F.

5. The method of claim 2, wherein the acid in step (a) or step (b) is selected from one or more of the following: HCl, H₂PO₃、H₂SO₄、TsOH、CH₃CO₂H、CF₃CO₂H and HCO₂H。

6. The method of claim 2, wherein the solvent in step (a) is selected from one or more of the following: MeOH, EtOH, i-PrOH, CH₃CN, THF and water.

7. The method of claim 2, wherein compound 53B of step (c) is protected in a solvent with a protecting reagent selected from one or more of the group consisting of: acetyl chloride, acetic anhydride, benzoic anhydride, benzoyl chloride, toluoyl chloride, 4-phenylbenzoyl chloride, 2, 3, or 4-nitrobenzoyl chloride and 2, 3, or 4-chlorobenzoyl chloride

In the formula R²Is H;

R³is (C)₁-C₆) An alkyl group; and

nu is F.

8. The method of claim 7, wherein the base is selected from one or more of the following: imidazole, pyridine, 4- (dimethylamino) pyridine, triethylamine, diisopropylethylamine, and 1, 4-diazabicyclo [2, 2, 2] octane.

9. The method of claim 7, wherein the solvent is selected from one or more of the following: pyridine, dichloromethane, chloroform, 1, 2-dichloroethane and tetrahydrofuran.