CN1222157A

CN1222157A - Processes for high-yield diastereoselective synthesis of dideoxynucleosides

Info

Publication number: CN1222157A
Application number: CN97195517A
Authority: CN
Inventors: S-H·陈; L·秀艳
Original assignee: Vion Pharmaceuticals Inc
Current assignee: Vion Pharmaceuticals Inc
Priority date: 1996-06-14
Filing date: 1997-06-02
Publication date: 1999-07-07

Abstract

The present invention relates to methods for substantially enhancing the stereoselective synthesis of beta -anomeric nucleoside analogs. In methods according to the present invention, the introduction of a phenylseleno group onto a blocked lactone sugar precursor may be selected so that the desirable phenylseleno substituent is introduced on the side of the blocked lactone away from the blocking group. This stereospecific introduction of the phenylseleno group in sugar precursor allows the synthesis of nucleoside analogs and in particular, 2',3',-dideoxy- and 2',3'-dideoxy-2',3'-didehydronucleoside analogs in very high yield. In certain preferred embodiments, the preferred phenylseleno blocked lactone is obtained in an amount representing approximately 90% or more of the total amount of the stereoisomers obtained. In even more preferred embodiments, the amount of the preferred stereoisomer is at least 95%, even more preferably at least about 97% of the total amount of phenylseleno blocked lactone produced.

Description

The method of the synthetic di-deoxynucleoside of high yield cis-selectivity

Invention field

The present invention relates to have the cis-selectivity preparation method of optically active cis-nucleotides and nucleoside and nucleoside analog and derivative.By novel method of the present invention the solid control of the specific isomer of required cis-nucleotides and nucleoside is synthesized has very high optical purity and has higher yields.The invention still further relates to the wherein production of useful as intermediates.

Technical background

As 3 of anti-hiv agent '-azido--3 '-appearance of deoxythymidine shown slough 3 '-nucleosides of hydroxyl is in biologically importance.And, 2 ', 3 '-dideoxy (dd) nucleoside analog and 2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxy (D ₄) discovery of nucleoside analog with potential antiviral activity also promoted the development of the method for the searching of more superior treatment reagent and synthetic these nucleosides of high yield.Reference, for example: De Clercq, E.J.Chemother.Supp.A1989,23,35; Balzarini, etc., molecule pharmacology (Mol.Pharmacol.) 1987,32,162.

As the result of sugar and base portion system modification, many 2 ', 3 '-the di-deoxynucleoside derivative has been approved for clinical anti-virus infection.Comprising D-β-ddI (2 ', 3 '-didanosine), D-β-ddC (2 ', 3 '-zalcitabine, Mitsuya and Broder, institute of NAS prints " S.Proc.Natl.Acad.Sci.U.S.A. " 1986,83,1911) and D-β-D4T (2 ', 3 '-two dehydrogenations-2 ', 3 '-Didansine, Mansuri etc., pharmaceutical chemistry magazine " J.Med.Chem. " 1989,32,461).In the recent period, the isomer that has occurred the nucleoside analog-natural D-nucleosides of many L-configurations as the antiviral agent of anti-HBV of potential and HIV.These analogues comprise (-) SddC (3TC) [(2-methylol-1,3-oxygen thiophene alkane (Oxathiolan)-4-yl) cytosine(Cyt)]; (-) FSddC (FTC) [(2-methylol-1,3-oxygen thiophene alkane (Oxathiolan)-4-yl)-and 5-flurocytosine, Chang, C-N., Deng, journal of biological chemistry (J.Biol.Chem.) 1992,267,13938-13942 and Doong, S-L. etc., periodical " Proc.Natl.Acad.Sci.U.S.A. " 1991,88 of institute of NAS, 8495-8499]; β-L-ddC (β-L-2 ', 3 '-zalcitabine, Lin, T-S., etc., tetrahedron communication " Tetrahetron Lett. " 1994,35,3477 and Lin, T-S., etc., pharmaceutical chemistry magazine (J.Med.Chem.) 1994,37,798-803); β-L-FddC (β-L-5-fluoro-2 ', 3 '-zalcitabine, Lin, T-S., etc., pharmaceutical chemistry magazine (J.Med.Chem.) 1994,37,798-803) and β-L-FD4C (β-L-5-fluoro-2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenation cytidines, Lin, T-S etc., pharmaceutical chemistry magazine (J.Med.Chem.) 1996,39,1757.

Compare with corresponding D-configuration, these non-naturals L-nucleosides above-mentioned have higher antiviral activity (for example, especially anti-HBV and HIV) and cell growth inhibiting and Mitochondrial DNA synthetic aspect, it has also reduced host toxicity.In the middle of these L-nucleosides of being discussed, find the tool activity (Lin. etc., pharmaceutical chemistry magazine " J.Med.Chem. " 1996,39,1757) of β-L-FD4C antagonism HBV.In fact, the effectiveness of the anti-HBV of β-L-FD4C approximately is 10 times of (-) SddC (3TC), and recently, it has been used for the combined therapy of anti-HIV and HBV by the FDA approval.The tangible medicine potentiality of the antiviral activity that β-L-FD4C and β-L-FddC are splendid and other nucleoside analog have further guaranteed as primary antiviral agent (comprising anti-HBV and anti-HIV) and the development that is used for this class medicament of other purpose.

The evaluation synthetic the earliest and antiviral activity of β-L-FD4C is to be finished by a science group of Yale University under Lin and doctor Cheng leader.Yale's synthesis step comprises that 12 steps and total yield are less than 0.74%.In this synthesis step, what efficient was minimum may be to introduce this step of 5 FU 5 fluorouracil by trans-N-glycosylation, and it only obtains about 10% required β-isomery intermediate.Although in the research of searching to the potential anti-viral nucleoside of host toxicity minimum, a kind of main breakthrough has been represented in this research that Yale University carries out, the initial synthetic method of this low yield is unsuitable for scale production.Therefore, a large amount of β-L-FD4C is used to expand the scale of production in order to prepare, clinical trial and final commercialization, needs a more effective synthetic method.

The object of the invention

One of purpose of the present invention is to provide a kind of effectively synthetic nucleoside analog with pharmaceutical activity, especially 2 ', 3 '-dideoxy-(dd) and 2 ', 3 '-dideoxy-2 ', 3 '-method of nucleoside analog of dideoxy-(d4).

Another object of the present invention is to provide a kind of Stereoselective method, be used to prepare the nucleosides intermediate, especially can be used to significantly promote 2 ', 3 '-dideoxy-and 2 ', 3 '-dideoxy-2 ', the stereoselectivity synthetic intermediates preparation of 3 '-two dehydrogenation nucleoside analogs.

A bright purpose again of this be to provide chemosynthesis 2 ', 3 '-dideoxy-and 2 ', 3 '-dideoxy-2 ', the intermediate of 3 '-two dehydrogenation nucleoside analogs, it can be used for the suitable locational stereoselectivity that significantly increase is incorporated into purine or pyrimidine nucleoside base in this intermediate.

These and/or other purpose of the present invention can be clear that from following description of the invention.The present invention's general introduction

The present invention relates to significantly to increase the Stereoselective synthesizing process of the nucleoside analog of β-isomery.In the methods of the invention, when phenylseleno be introduced on the protected lactone sugar precursor of hydroxyl (below formula 4 or wherein protected hydroxyl be the three-dimensional enantiomer of β-orientation rather than α-orientation), unexpected high yield and the highly-solid selectively of obtaining.In some preferred embodiments, the amount that contains the lactone (ribose precursor) of phenylseleno on α-face be at least the α that generated and β product total amount about 90% or more.Even in a more preferred embodiment, the amount that the α-face that obtains contains the phenylseleno lactone is 95% of the α that produced and a β product total amount, even more preferably is at least about 97%.The stereospecificity of this reaction is an afterclap, and makes that the synthesis yield of β-L-nucleoside analog with pharmaceutical activity is very high.

A preferred sequence according to synthetic β-L-nucleoside analog, the lactone (5a of Fig. 1 and as implied above) that contains phenylseleno can transform saccharogenesis, and can be used for the nucleoside base orientation is directed to sugar (being generally ribose) thereby goes up making that the concentration ratio alpha-isomer that generates β-isomer nucleosides is much higher.

This method can be used for synthesis of nucleoside analogue, especially 2 ', 3 '-dideoxy-and 2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenation nucleoside analogs.

The inventive method solves and has overcome the difficulty and the shortcoming of prior art and provide high yield preparation to have the method for optically active cis-nucleotides and nucleoside and nucleoside analog and following formula I and (II) derivative. Wherein X is CH or CH ₂Y is purine or pyrimidine base or analogue or derivatives thereof.

Target of the present invention provides increases D-or L-β or α-isomery nucleosides stereoselectivity synthetic method, especially phenylseleno is incorporated into the method for (as shown in Figure 1) in the protected lactone of hydroxyl (4) next by glutamic acid derivative.

Step of the present invention is that (as: structure that N-phenylseleno-phthalic imidine or similar volume are bigger is the selenium-containing compound of ArSeX by the compound that will comprise phenylseleno, wherein Ar is the phenyl of phenyl or replacement, as tert-butyl-phenyl or nitrophenyl, X be bigger leavings group (as: ^-OAc, ^-OC (O) CF ₃, ^-SCN, ^-SO ₂Ar, NR ₂With the inferior imide of N-O-phthalic) finish with the protected lactone of hydroxyl (4) reaction that comes by D-or L-glutamic acid derivative, consequently stereoselectivity has been synthesized the protected lactone of hydroxyl (5) that needed phenylseleno replaces and has been made final required β-isomery nucleosides have unexpected high yield.It should be noted that synthetic what obtain is the L-nucleosides by D-L-glutamic acid, and synthetic what obtain is the D-nucleosides by L-L-glutamic acid.

Discovery below the present invention has utilized: promptly using N-phenylseleno phthalic imidine to introduce phenylseleno on the alpha-position carbon of the ketone of hydroxyl protected lactone 4 (above and Fig. 1) is to have strange high stereoselectivity, and this introducing occurs in the lactone away from the one side that influenced by protected hydroxylic moiety.

Of the present invention preferred aspect, the present invention has following advantage: promptly need not to use expensive starting raw material or adopt complicated step to separate the nucleosides (or its derived analogs) that enantiomer just can prepare a large amount of formula I.The yield that the inventive method is produced nucleosides is suitable for expansion scale and commercialization production, and product has high purity and high optical activity.The present invention also has the following advantages: promptly by selecting suitable and facile starting raw material (selecting D-L-glutamic acid under the situation of L-nucleosides or select L-L-glutamic acid under the situation of D-nucleosides) simply, can control the configuration (L-or D-nucleosides) of the nucleosides that is generated at an easy rate.

Brief description of drawings

Accompanying drawing 1 is according to preferred chemical synthesis route of the present invention, and the stereoselectivity that is used for β-L-Fd4C and β-L-FddC is synthetic.

The present invention say describe in detail bright:

For describing the present invention, be applicable to whole specification to give a definition.

Term as used in this specification " nucleosides ", " nucleoside analog " or " nucleoside derivates " Refer to have the nucleosides of following feature: namely include purine or pyrimidine bases and described base is connected On the ribose and obtain of the present invention 2 ', 3 '-di-deoxynucleoside or 2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenation nucleosides. Nucleoside analog of the present invention can be D-form (" D ") nuclear Glycosides or be preferably (" L ") nucleosides of L-configuration. Preferred nucleoside analogues produced according to the invention Thing comprises β-L-2 ', 3 '-dideoxycytidine (β-L-ddC), β-L-5-fluoro-2 ', 3 '-Dideoxycytidine (β-L-FddC) and β-L-5-fluoro-2 ', 3 '-dideoxy-2 ', 3 '-two take off The hydrogen cytidine (β-L-Fd4C). Because the anti-HIV that it is unique and anti-HBV activity are, so preferred Be β-L-5-fluoro-2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenation cytidines (β-L-Fd4C).

The term that uses in this specification " L-nucleosides " and " D-nucleosides " refer to comprise have specific The nucleoside analog of the ribofuranose base section of chemical structure. The ribose part of L-nucleosides of the present invention The L-configuration is non-native configurations, on the contrary the nucleosides cytidine of self-assembling formation, adenosine, thymidine, The ribose part of finding in guanosine and uridine and other material then has natural D-form.

Term " pyrimidine " is to comprise such as uracil, thymidine and cytimidine and they for description The logical class of methylated with relevant analog (comprising pseudouracil and other chemical compound lot) assorted Cycle compound. The term pyrimidine comprises the pyrimidine analogue of the pyrimidine base that imitates this natural formation, although Its structure (kind of atom and arrangement) is similar to the alkali of natural formation, but they are not to increase to be exactly Some function and character that the alkali of natural formation has have been lacked. These analogs comprise that those pass through Replace CH partly to derive and next derivative with nitrogen-atoms. (as: 5-aza-pyrimidine class is such as 5-nitrogen Assorted cytimidine). Comprise also that in this term scope wherein ring substituents is connected to each other or is removed or quilt Conventional substituting group known in the art is such as halogen, hydroxyl, amino, C_1-6The alkali that alkyl etc. are modified or Analog. Preferred pyrimidine analogue comprises the cytimidine analog, and its 5-position is substituted, especially Replaced by halogen. Especially preferred pyrimidine base is 5-flurocytosine. Can be used for pyrimidine of the present invention Alkali, analog and derivative are normally known in those skilled in the art.

Term " purine " be for describe inclusion compound as: hypoxanthine, xanthine, adenine, The logical heterocyclic compounds of guanine and their analogs. Comprise those derivatives by replacing the CH part or derive and with CH Partial Replacement nitrogen-atoms with nitrogen-atoms. (as: 7-deazapurine class, Such as 7-denitrogenation adenine or 7-deazaguanine) or the derivative of CH part and nitrogen-atoms transposition (as: 7-denitrogenation, 8-azapurine (7-deaza, 8-azapurines). The derivative of these alkali or class Like thing refer to the upper substituting group of its ring be connected to each other or be removed or by this area conventional substituting group such as halogen Element, hydroxyl, amino, C_1-6Those compounds that alkyl etc. are modified.

Term " protected hydroxyl " refers to the hydroxyl in any one or a plurality of nucleosides precursor, its quilt Protection and adverse effect do not take place, if but need, can under selective conditions, remove and protect and swim Thereby further react from going out hydroxyl. The hydroxyl protecting group that can be used for this purpose comprises: for example Trisubstituted silicyl is such as t-butyldimethylsilyl, triphenyl silicyl, the tert-butyl group Diphenylmethyl silylation and trityl, methoxyl group trityl and pivaloyl group etc. Protection Base can be selected from monosilane base class, ether protection base class and ester protection base class widely. Selected protecting group Sterically hindered sterically hinderedly have a β-face that hinders from the protected lactone of hydroxyl (accompanying drawing 1 4) The α face of introducing the phenylseleno effect and impelling at lactone is introduced phenylseleno. Although protection listed above Base all is preferred, and especially preferred t-butyldiphenylsilyl, but anyly examines at lactone (the protected position of hydroxyl finally becomes produce last to the protected position of the hydroxyl of sugar precursor 4 5 of nucleoside analog '-position) provide volume all to help from α-face than the similar group of large-substituent (namely in the one side opposite with protected hydroxyl) introduces the orientation of phenylseleno.

Term " protected purine " or " protected pyrimidine " are used for describing the nitrogen on the base wherein Or the oxygen base is protected and make its purine that adverse reaction does not take place or pyrimidine. The guarantor who can be used for this purpose To protect base be well known in the art and comprise, for example trimethyl silyl, dimethyl hexyl monosilane Base, t-butyldimethylsilyl, trityl group, alkyl and acyl group and other many guarantors Protect base.

Term " phenylseleno " is used for describing group or the part that comprises phenylseleno, and it is introduced in by paddy Propylhomoserin is derived and the next protected lactone of hydroxyl (described in the compound 4 and specification of accompanying drawing 1) Upper and finally the nucleoside base orientation is imported to sugar (ribose) thus upper the generation finally has medicine Play a significant role in active β-L-or the D-nucleoside analog process. Phenylseleno of the present invention is with formula ArSe represents that wherein Ar is the phenyl of phenyl or replacement, comprises, for example tert-butyl-phenyl, nitro Phenyl etc. Phenylseleno is to utilize the compound of formula ArSeX to be incorporated into the protected lactone of hydroxyl (4) On, wherein Ar is the phenyl of aforesaid phenyl or replacement, and X is leaving group, and it has foot Thereby the directed ArSe base of introducing in enough big volume stereocpecificity ground is to the protected lactone of hydroxyl (4) α-face on. X is preferably^-OAc、 ^-OC(O)CF ₃、 ^-SCN、 ^-SO ₂Ar、NR ₂Or N-phthalimide, N phlhalimide most preferably wherein, Ar represents the substituting group that volume is bigger, such as tert-butyl-phenyl or other bulky phenyl (not being phenyl), X can be halogen, such as Cl^-、Br ^-Or I^-。

Key feature of the present invention is to use the bigger phenylseleno compound of volume (most preferably N-phenylseleno phthalimide) at the protected lactone of hydroxyl (such as the compound 4 of accompanying drawing 1) Thereby the alpha-position of ketone imports phenylseleno and obtains replacement lactone highly-solid selectively, high yield (5a). The result obtains the lactone 5 of high yield like this (at least about 90% and obtain 97% or more in some situation High required stereoisomer 5a) is unexpected, especially considers with phenylseleno bromine or phenylseleno Chlorine to lactone 4 import phenylselenos almost be do not have stereoselective. In the present invention, very unexpected Be: utilize N-phenylseleno phthalimide (or similarly phenylseleno compound) to import phenylseleno The yield of the stereoisomer that obtains wanting is about 75%, has greatly improved the existing of former report Low selective (α/β=2.5: 1) and low yield (10%) (Chu etc., organic chemistry magazine in the technology " J.Org.Chem. " 1990,55,1418).

Another feature of the present invention is the optimization of each the step reaction condition after phenylseleno is introduced Thereby guaranteed the high yield (＞90%) in each step.

Producing in the method for optimizing of L-nucleosides according to the inventive method, pure D-Glu step by step Be converted into the protected lactone of hydroxyl shown in the formula 4 in the accompanying drawing 1, and then with it and N-benzene selenium Thereby base-phthalimide reaction obtains the lactone shown in the formula 5a in specific manner. Then should in The ester reduction generates the mixture 6 of diastereoisomer sugar, carries out then acetyl groupization and and silicyl The 5-flurocytosine condensation of changing generates 2 '-nucleoside analog (compound of accompanying drawing 1 of phenylseleno-replacement 8), it can with reducing agent process to generate hydroxyl protected 2 ', 3 '-di-deoxynucleoside (dd) Analog 11 or with the mixture of hydrogen peroxide in pyridine or relevant oxidizer treatment analog 8 obtain hydroxyl protected 2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenation nucleosides (d4) are similar Thing 9. With method well known in the art the protected

nucleoside analog

9 and 11 of hydroxyl is removed protection Generate corresponding β-L-5-fluoro-2 ', 3 '-dideoxycytidine (β-L-FddC) and β-L-5-fluoro-2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenation cytidines (β-L-Fd4C).

The same just as noted, thus main aspect of the present invention is the phenylseleno Stereoselective to be incorporated on the alpha-position carbon of ketone of the protected lactone 4 of hydroxyl generate the protected lactone 5a of hydroxyl.Lactone 4 can obtain by any synthetic method in the prior art, but is preferably begun to carry out by L-glutamic acid according to synthetic route shown in Figure 1.It should be noted that accompanying drawing 1 listed synthetic route is used for from the synthetic L-nucleosides of D-L-glutamic acid.If the synthetic target compound is the D-nucleosides, then should be L-L-glutamic acid according to the starting raw material of accompanying drawing 1 described general synthetic route.The listed step of the synthesis step preferred (but and unnecessary) of producing final product and be the D-nucleosides and accompanying drawing 1 is identical.

Derive and the lactone 5a or the corresponding enantiomerism lactone that come are to be used for synthetic effectively L-and the D-2 ' with pharmaceutical activity of the present invention by L-L-glutamic acid (it be with generate D-nucleosides), 3 '-dideoxy-(dd) and 2 ', 3 '-dideoxy-2 ', the useful intermediates of nucleosides of 3 '-two dehydrogenations-(d4).

The synthetic precursor of the lactone 5 that replaces as phenylseleno, lactone 4 can be synthetic by synthetic method of the prior art, still preferably synthesizes as starting raw material with D-or the L-L-glutamic acid with enantiomeric pure.In preferred method as shown in Figure 1,, D-L-glutamic acid is reacted generation lactonic acid 1 in the presence of acid, then with its esterification in suitable pure and mild acid for synthetic lactone 4.To generate the ester 2 of lactone.Then, utilize any common hydride reducer, (comprise metal-AlH as one or more (comprising sodium borohydride, lithium borohydride, hydroboration 4-butyl amine) or the hydride of various aluminium in the various hydroborates ₄, metal-AlH (OR) ₃Deng) ester reduction partly generates lactone alcohol 3.Then with lactone alcohol 3 and the compound reaction that can on alcohol, form the bigger protecting group R of volume, t-butyldiphenylsilyl chlorine for example, it plays the effect of protecting free hydroxyl group that it is not reacted in follow-up synthesis step.Protecting group R can be the bigger silyl of volume, as triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl (being drawn in the compound 4 in the accompanying drawing 1) etc.; The ester group that volume is bigger is as pivaloyl [Me ₃CC (O) ^-] wait the ether bigger with volume, as trityl group ether (trityl) or p-methoxyphenyl diphenyl methyl ether (methoxytriyl).The phenylseleno compound that the hydroxyl protecting group of these large volumes and volume are bigger has combined together, causes on the alpha-position carbon of the lactone part of the protected lactone 4 of hydroxyl and α-face highly-solid selectively ground to introduce phenylseleno.

In generating the protected lactone 5a of the hydroxyl step that phenylseleno replaces, lactone 4 at first with highly basic, as the reaction of two (trimethyl silyl) Lithamide, then with the silyl protecting group, as reactions such as trimethylsilyl chloride.Two (trimethyl silyl) sodium amides or potassium and alkalescence is enough strong sloughs the highly basic of the proton on the alpha-position carbon of ketone group of lactone 4 with activation, also can be used in this reaction as butyllithium, diethylamino lithium (LDA) and other highly basic.Then, formed enol intermediate is stablized by trimethyl silyl.Behind the silylation, thereby the enol intermediate of trimethyl silylization and the reaction of N-phenylseleno phthalic imidine are introduced phenylseleno on the alpha-position carbon of carbonyl.Those of ordinary skill in the art is easy to recognize, the compound that also can adopt other method to utilize N-phenylseleno phthalic imidine or similarly comprise phenylseleno, on the alpha-position carbon of the carbonyl of lactone part, introduce phenylseleno, but its efficient is lower than the method that employing is described in detail above usually.

The lactone 5a that phenylseleno is replaced changes into suitable dideoxy-or dideoxy-two dehydrogenation nucleoside analog then.This normally finishes with following method, and the carbonyl that is about to lactone transforms (normally by reduction) intermediate that one-tenth has reactive behavior, and it can be by glycosylation and purine or pyrimidine base condensation.This can finish by many approach, changes into acetoxyl (compound 7) but preferable methods is a hemiacetal hydroxyl with ribose (as the compound 6 of accompanying drawing 1), then purine or pyrimidine base is condensed on the acetylizad C-1 carbon of ribose.If pursue preferable methods, shown in the listed synthetic route of accompanying drawing 1, thereby available DIBAL-H becomes secondary alcohol that the lactone 5a that phenylseleno replaces is reduced into hemiacetal 6 carbonyl reduction.Other many reductive agents also can be used for carbonyl reduction is become alcohol as the hydride reagent of hydroborate reagent or aluminium and other the original reagent of going back, but preferred DIBAL-H, because adopt this reagent to make that this reaction almost is (98% yield) that quantitatively carries out.Then hemiacetal 6 is changed into the acetylizad ribose 7 of C-1.Although, normally at acid cleaner, under the existence as amine, also can use many other acetylation reagents, in preferred synthetic schemes, acetylization reaction carries out in diacetyl oxide/triethylamine miscellany.

In condensation reaction, utilize acetylizad ribose 7 that pyrimidine or purine bases are condensed on the acetylizad ribose.In the preferred method shown in the accompanying drawing 1, at Lewis acid, as [three fluosulfonic acid trimethyl silyl esters (trimethylsilyltriflate)] (TMSOTf), SnCl ₄, TiCl ₂(OR) ₂, TiCl (OR) ₃Or TiCl ₄And under many other lewis acidic existence well known in the art, the 5-flurocytosine alkali of two-trimethyl silylization quantitatively is condensed on acetylizad (or the compound of other esterification is as compound of benzoylization etc.) ribose 7.Preferably at trifluoromethanesulfonic acid trimethyl silyl ester (trimethylsilyltriflate) thus (TMSOTf) in the presence of carry out condensation reaction and generate 2 '-nucleoside analog 8 that α-phenylseleno replaces.For prepare 2 ', 3 '-di-deoxynucleoside analogue 12, preferably at AlBN ₃Or EtB/O ₂Existence down use hydride reducer, preferably with tri-n-butyl tin hydrogen (n-Bu ₃SnH) reduction nucleoside analog 8, thus remove 5 then '-hydroxyl protecting group of position generate preferred compound β-L-5-fluoro-2 ', 3 '-zalcitabine (β-L-FddC).Perhaps with nucleoside analog 8 and suitable oxygenant (superoxide for example; as be dissolved in hydrogen peroxide in the pyridine; or metachloroperbenzoic acid and many other superoxide) reaction generates 2 '; 3 '-dideoxy-2 '; 3 '-two dehydrogenation nucleoside analogs 10; thereby with its processing remove hydroxyl protecting group obtain β-L-5-fluoro-2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenation cytidines (β-L-FD4C).

Although described preferred chemical synthesis process above, any those of ordinary skills all will recognize, adopt displaced or similar step also can obtain same result.For example, those of ordinary skill in the art is easy to replace certain reagent wherein and all solvents of in fact being used to obtain as accompanying drawing 1 listed intermediate are all replaceable.For example: the ester 2 of lactone 1 and lactone can form reagent with any suitable lactone at an easy rate or mixed reagent forms and available suitable alcohol, comprises that methyl alcohol and propyl alcohol obtain ester.In fact, the hydroborating reagent sodium borohydride can replace with the hydride of other any suitable hydroborate or aluminium and also can use any suitable solvent to replace ethanol.The orientation that the hydroxyl protecting group that any volume is bigger also can be used to prevent the further reaction of hydroxyl and help phenylseleno is introduced.

Except (two) trimethyl silyl Lithamide, also can adopt many highly basic, for example BuLi and LDA finish the reaction that phenylseleno is introduced on the alpha-position carbon of the carbonyl of lactone 4 stereospecificity ground.This reaction is by forming that enol carries out and the silyl protecting group; as trimethyl silyl and other protecting group, all can be used to the stable enol structure that will add phenylseleno as t-butyldimethylsilyl and other similar silyl protecting group.When selecting the silyl protecting group, those of ordinary skills understand for this reason: the selection of silyl protecting group be based on this silyl have the ability of stable enol intermediate and it be easier to relatively remove.The phenylseleno phthalic imidine of Shi Yonging is preferred phenylseleno reagent in the present invention, but any phenylseleno reagent that comprises the bigger leavings group of the volume that is similar to phthalimide-based as described above group also can adopt.This territory those of ordinary skill can be at an easy rate by modifying that phenyl substituent change leavings group (ArSeX) thus size influence the stereoselectivity of phenylseleno introducing.

Following β-L-FddC (β-L-5-fluoro-2 ', 3 '-zalcitabine and β-L-FD4C (β-L-5-fluoro-2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenation cytidines) synthetic is to be used for explaining actually operating of the present invention, and should not be construed as restriction to four corner of the present invention, especially relevant obvious changes is routine, replacement and similar step and method include within the scope of the invention.

Embodiment

Embodiment 1

The preferred embodiments of the invention are summarised in the accompanying drawing 1 and will elaborate below.Those numberings in the synthetic route of being given in reference compound numbering and the accompanying drawing 1 are identical.In this embodiment.Target compound 12 β-L-5-fluoro-2 ', 3 '-zalcitabine (β-L-FddC) and 10 β-L-5-fluoro-2 ', 3 '-dideoxy-2 ', (β-L-FD4C) synthetic is that finish and total yield is respectively 25% and 27% through ten steps to 3 '-two dehydrogenation cytidines.The yield of the step that efficient is minimum in this route is 75% (from 4 to 5a).The average yield in per step is about 88%, and this makes the synthetic route of this cover be used for commercialization production is feasible.Material and method

All reagent is unless otherwise indicated all from commercial sources.Solvent is before use all through distillation.Fusing point adopts the MelTemp device to measure and do not proofread and correct.Hydrogen NMR spectrum is measured on Varian EM390 or Bruker WM250, is unit record and with (CH with ppm (deta) ₃) ₄Si as a reference.UV spectrum is measured with Beckman 25 spectrophotometers.Thin-layer chromatography (TLC) analysis is to adopt the pre-smear of EM Silica Gel60 of Merk company to carry out.Column chromatography adopts the EM Silica gel. and the standard organic solvent of Merk company.The detailed reaction conditions and the sign of each intermediate (comprise ¹H NMR, ¹³The ultimate analysis data of C NMR and LRMS or HRMS and compound 8-12) all provide in this section.

The preparation of the ester 2 of preparation process lactone

In the suspension of D-L-glutamic acid (50.0g) in water (70ml), adding dense HCl (70ml) under 0 ℃, in the time of 2hr, slowly add NaNO then ₂(35.0g) solution in water (75ml).Make reaction rise to room temperature and restir 15hr then.Decompression (being lower than 50 ℃) solvent evaporated.Reaction mixture stirs with EtOAc (150ml) then.Elimination is insoluble all to divide and with EtOAc (2 * 50ml) washing solids.Merging filtrate and dry (Na ₂SO ₄).Vacuum-evaporation removes to desolvate and obtains the light yellow thick crude product lactone 1 of 45g (～100%).

The p-TsOH (1.0g) of above-mentioned thick product acid and catalytic amount is dissolved in EtOH (65ml) and the benzene (150ml) solution backflow 5hr.Air distillation removes to desolvate and rises to 79 ℃ until boiling point (b.p.).Reaction mixture is cooled to room temperature, uses benzene (500ml) dilution then.Gained reaction mixture water, 10%Na ₂CO ₃Na is used in solution and washing then ₂SO ₄Dry.Steaming desolventizes and resistates is distilled under high vacuum and obtains the required ester-lactone (2) of 35.0g (two step yields be 65%).The analysis of the ester 2 of lactone:

¹H NMR of 2 (CDCl ₃, 300MHz): δ 4.87 (m, 1H), 4.14 (q, 2H), 2.55-2.23 (m, 4H), 1.22 (t, 3H). the preparation of lactone alcohol 3

Under 0 ℃, in about 10min, (add NaBH among the 17.3g, ethanolic soln 109.5mmol) (72ml) to described ester-lactone 2 ₄Ethanolic soln (2.90g) (48ml).The gained reaction mixture at room temperature stirs 1hr.HCl termination reaction with 10% is 3 up to the pH value of solution value under 0 ℃ then.The elimination solid, concentrating under reduced pressure filtrate.Then with resistates and MeOH coevaporation three times.Then with resulting resistates silica gel chromatography (10-20%EtOH/CH ₂Cl ₂) purifying obtains the required alcohol 3 of 9.5g (75%), colourless liquid.The analytical data of lactone alcohol 3

¹H NMR of 3 (CDCl ₃, 300MHz): δ 4.72 (m, 1H), 3.99 (dd, J=3.1Hz, J '=12.7Hz, 1H), 3.72 (dd, J=4.8Hz, J '=12.6Hz, 1H), 2.76-2.18 (m, 4H). the preparation of the silyl ether of lactone 4

Under 0 ℃ to compound 3 (5.10g, add in dichloromethane solution 43.97mmol) imidazoles (3.89g, 57.16mmol) and tertiary butyl chloride for diphenylmethyl silane (13.30g, 12.58ml).Be reflected at 0 ℃ and stir 1hr down, at room temperature stir 2hr then.With reaction mixture CH ₂Cl ₂(150ml) dilution and water (3 * 40ml) and salt solution (40ml) wash.Dry organic layer also under reduced pressure concentrates, and obtains resistates, and resistates is purified with chromatogram (20-30%EtOAc/ hexane) obtains the required silyl ether 4 of 15.2g (97%), light yellow dope.The analytical data of the silyl ether of lactone 4

¹H NMR of 4 (CDCl ₃, 300MHz): δ 7.70-7.39 (m, 10H), 4.61 (m, 1H), 3.90 (d, J=3.3Hz, J '=11.4Hz, 1H), 3.70 (dd, J=3.3Hz, J '=11.4Hz, 1H), 2.70 (m, 1H), 2.53 (m, 1H), 2.26 (m, 2H), 1.08 (s, 9H). the preparation of lactone 5a phenylseleno thing

Under nitrogen protection, (1M, 32.2ml 32.20mmol) join among the THF of 6ml, and are cooled to-78 ℃ will to be dissolved in two (trimethyl silyl) Lithamides among the THF.In 45 minutes and under-78 ℃, (10.36g 29.30mmol) slowly joins in the above-mentioned solution will to be dissolved in the silyl ether 4 of the lactone among the 20ml THF.After adding 1 hour, in about 5 minutes, drip TMSCl (5.0ml, 64.46mmol).Then miscellany was stirred 1 hour down in-78 ℃, rise to room temperature then and stirred 2 hours.Then reaction mixture is cooled to-78 ℃ and in about 1 hour time, added N-phenylseleno phthalic imidine (11.0g 36.40mmol), continues to stir 3 hours down at-78 ℃, is warming up to room temperature then and stirs 30 minutes by the powder filling tube.NaHCO with reaction mixture impouring 150ml ₃In solution and the 300ml ether, use NaHCO then ₃Extract 2 times and use NaCl solution extraction 1 time.Water layer is used the 100ml extracted with diethyl ether again, merges organic layer and uses MgSO ₄Drying is filtered and removal of solvent under reduced pressure.Crude product obtains 11.20g trans-isomer(ide) (yield 75%) with the column chromatography purifying.Also obtain a spot of cis-isomeride 200mg (1%).The analytical data of the phenylseleno thing 5a of lactone

¹H NMR of 5a (CDCl ₃, 300MHz): δ 7.75-7.32 (m, 15H), 4.40 (m, 1H), 4.16 (dd, J=5.4Hz, J '=9.2Hz, 1H), 3.90 (dd, J=2.9Hz, J '=11.5Hz, 1H), 3.66 (dd, J=3.1Hz, J '=11.5Hz, 1H), 2.7S (m, 1H), 2.33 (m, 1H), 1.10 (s, 9H). ¹³C NMR of 5a (CDCl ₃, 75MHz): δ 176.1,135.8,135.7,135.6,132.9,132.5,130.1,129.5,129.1,128.0,127.2,78.8,65.0,37.3,32.5,27.0, the preparation of 19.3. lactonaphthol 6

Under-78 ℃, (1.63g, (2.35ml 1.5M) handles toluene solution 3.20mmol) (10ml), after 1 hour, adds DIBAL-H (0.32ml) again with DIBAL-H with the phenylseleno thing 5a of lactone.After 30 minutes, be reflected at-78 ℃ down with saturated sodium tartrate potassium solution (40ml) termination reaction.Reaction mixture rises to room temperature and (2 * 50ml) extract with EtOAc.Merging organic layer also washs until obtaining clear solution with the sodium-potassium tartrate saturated solution again.Organic layer that drying obtains and reduction vaporization.Resistates obtains the required lactonaphthol 6 of 1.60g (98%) through chromatogram purification (10-20%EtOAc/ hexane).The analytical data of lactonaphthol 6

¹H NMR of 6 (CDCl ₃, 300MHz): δ 7.80-7.26 (m, 15H), 5.64-5.44 (m, 1H), 4.45 (m, 1H), 4.10-3.52 (m, 4H), 2.79-2.00 (m, 2H), 1.13-1.06 (m, 9H) preparation of the acetic ester 7 of .1 ' sugar

Under 0 ℃, to lactonaphthol 6 (4.50g, add in dichloromethane solution 8.80mmol) (18ml) triethylamine (1.59ml, 11.44mmol) and diacetyl oxide (1.08ml, 11.44mmol).The DMAP that also adds catalytic amount.Be reflected at 0 ℃ and stirred 1 hour down, at room temperature stirred then 12 hours.Use NaHCO ₃Saturated solution (20ml) termination reaction, and use CH ₂Cl ₂(2 * 100ml) extraction gained reaction mixtures.Merge organic layer and wash dry and concentrating under reduced pressure with salt.Resistates by short unmodified packed column purifying (adopting 15% ethyl acetate/hexane) as eluent obtain 4.75g (98%) corresponding 1 '-sugared acetic ester derivative 7, heavy-gravity oily matter.1 '-analytical data of sugared acetic ester

¹H NMR (300MHz, CDCl ₃): δ 7.74-7.20 (m, 15H), 6.44-6.22 (m, 1H), 4.44-3.52 (m, 4H), 2.58-2.08 (m, 2H), 1.86﹠amp; 1.55 (s, 1H), 1.02﹠amp; 0.92 (s, 9H) .FAB quality C ₂₉H ₃₅O ₄SiSe (MH ⁺), calculated value: 554, experimental value: 554.The preparation of the phenylseleno thing 8 of nucleosides

With 5-flurocytosine (1.11g, 8.58mmol) and ammonium sulfate (40mg) in (TMS) ₂Miscellany reflux among the NH 2 hours obtains limpid solution.Reaction mixture is cooled to room temperature and under vacuum, removes and desolvate.The gained white solid is (two-TMS-5-FC) under high vacuum dry 30 minutes.

Add 1 upward among preparation two-TMS-5-FC '-sugared acetic ester derivative 7 (4.75g, 8.58mmol) dichloroethane solution (30ml), in above-mentioned solution, adding TMSOTf (1.99ml, dichloroethane solution 10.30mmol) (10ml) under 0 ℃ then.Reaction mixture stirred 30 minutes down at 0 ℃, and then at room temperature stirred 90 minutes.At this moment, use NH ₄Cl saturated solution (30ml) termination reaction is also used ethylene dichloride (250ml) extraction.Organic layer salt water washing, dry and concentrating under reduced pressure.Gained is remaining with chromatogram purification (60-80%EtOAc/ hexane, 10%EtOH/CH then ₂Cl ₂) obtain the required product of 5.40g (100%), white foam shape product.The analytical data of nucleosides phenylseleno thing 8

¹H?NMR?of?8(300?MHz,CDCl ₃):δ8.00(d,J=5.5Hz,1H),7.66-7.25(m,15H),6.13(dd,J=1.4Hz,J′=4.9Hz,1H),4.32(m,11～),4.11(d,J=11.2Hz,1H),3.85(dd,J=6.5Hz.J′=11.6Hz,1H),3.69(dd,J=2.3Hz,J′=11.8Hz,1H),2.47(m,1H),2.06(m,1H),1.11(s,9H).

¹³C NMR of 8 (CDCl ₃, 75MHz): δ 156.2,156.0, and 151.9,137.8,135.8,135.7,135.5,134.6,132.6,132.3,130.2,130.0,129.4,128.6,128.1,127.9,126.9,126.1,125.7,91.3,80.5,65.1,44.9,32.3,27.1,19.3.FAB quality C ₃₁H ₃₅FN ₃O ₃SiSe (MH ⁺), calculated value: 624, experimental value: 624.The preparation of the silyl ether 9 of two dehydrogenation nucleosides

Under 0 ℃, to phenyl selenide 8 (437mg, add in THF solution 0.702mmol) 30wt.% aqueous hydrogen peroxide solution (0.22ml, 7.02mmol).Being reflected at 0 ℃ stirred 1 hour down.At this moment, and adding pyridine under 0 ℃ (0.57ml, 7.02mmol).Reaction was at room temperature stirred 3 hours, and then with EtOAC (50ml) and Et ₂O (10ml) diluting reaction miscellany is used NaHCO then ₃Saturated solution and salt water washing, organic layer Na ₂SO ₄Drying obtains resistates at reduction vaporization then, and resistates is by silica gel chromatography (5-10%EtOH/CH ₂Cl ₂) obtain the silyl ether 9 of two required dehydrogenation nucleosides of 280mg (86%).The analytical data of the silyl ether 9 of two dehydrogenation nucleosides

¹H NMR of 9 (CDCl ₃, 300MHz): δ 8.95 (broad peak, 1H), 7.74-7.34 (m, 10H), 6.98 (d, J=1.5Hz, 1H), 6.10 (d, J=5.9Hz, 1H), 5.92 (d ,=5.7Hz, 1H), 5.83 (broad peaks, 1H), 4.85 (s, 1H), 3.95 (dd, J=3.1Hz, J '=11.6Hz, 1H), 3.77 (dd, J=3.4Hz, J '=11.7Hz, 1H), 1.05 (s, 9H). ¹³C NMR of 9 (CDCl ₃, 75MHz): δ 158.6,158.4,154.4,138.4,135.7,135.2,133.1,132.9,132.7,130.1,130.0,127.9,127.7,125.4,125.0,91.2,87.2,65.3,27.0,19.3.FAB quality C ₂₅H ₂₉FN ₃O ₃Si (MH ⁺), calculated value: 467, experimental value: the preparation of the silyl ether 10 of 467 di-deoxynucleosides

Preparation (a) under 0 ℃, with 5 '-(0.71g, (3.81ml, 1M 3.81mmol) handle THF solution (26ml) 1.53mmol) silyl ether 9 with tetrabutyl ammonium fluoride (TBAF).Be reflected at 0 ℃ and stirred 30 minutes down, at room temperature stirred then 2 hours, at this moment, solvent removed in vacuo.The resistates that obtains with silica gel chromatography (from the 80%EtOAc/ hexane to 10-20%EtOH/CH ₂Cl ₂) purifying obtain the required product β of 331mg (95%)-L-5-fluoro-2 ', 3 '-dideoxy-2 ', (β-L-FD4C) 10, the white foam shape for 3 '-two dehydrogenation cytidines.

(321mg, (0.449ml 2.72mmol), stirs under the room temperature after 5 hours, at 0 ℃ of reagent that adds second part down to add triethylamine-trihydrofluoride in THF solution 0.690mmol) to the silyl ether 9 that is cooled to 0 ℃ in preparation (b).Reaction mixture at room temperature stirred 15 hours, solvent removed in vacuo then, and resistates is with column chromatography purifying (5-10-20%EtOH/CH ₂Cl ₂) obtain the required product β of 146mg (94%)-L-5-fluoro-2 ', 3 '-dideoxy-2 ', (β-L-FD4C) 10 for 3 '-two dehydrogenation cytidines.

β-L-5-fluoro-2 ', 3 '-dideoxy-2 ', the analytical data of 3 '-two dehydrogenation cytidines (B-L-FD4C) 10:

¹H NMR of 10 (DMSO-d6,300MHz): δ 8.01 (d, J=7.2Hz, 1H), 7.77 (broad peaks, 1H), 7.52 (broad peak, 1H), 6.81 (d, J=1.1Hz, 1H), 6.30 (dd, J=1.2Hz, J '=5.9Hz, 1H), 5.86 (dd, J=1.3Hz, J '=5.9Hz, 1H), 5.07 (broad peak, 1H), 4.76 (s, 1H), 3.31-3.60 (m, 2H) .FAB quality C ₉H ₁₁FN ₃O ₃(MH ⁺), calculated value: 228, experimental value: 228.The preparation of the silyl ether 11 of di-deoxynucleoside

To compound 8 (323mg, 0.519mmol) and add tributyl tin hydrogen in the benzole soln (5ml) of the degassing of the AIBN of catalytic amount (0.279ml, 1.038mmol), reaction mixture is heated to and refluxed 1.5 hours.Then, reaction mixture is cooled to room temperature, solvent removed in vacuo.Resistates silica gel chromatography purifying (5-10%EtOH/CH ₂Cl ₂) obtain the silyl ether 11 of the required di-deoxynucleoside of 240mg (100%).The analytical data of the silyl ether 11 of di-deoxynucleoside

¹H NMR of 11 (CDCl ₃, 300Mhz): δ 8.17 (d, J=4.2Hz, 1H), 7.71-7.28 (m, 10H), 6.40 (broad peak, 1H), 5.98 (d, J=6.0Hz, 1H), 4.16-4.09 (m, 2H), 3.75-3.70 (m, 1H), 2.60-1.78 (m, 4H) .FAB quality C ₉H ₁₃FN ₃O ₃(MH ⁺), calculated value: 230, experimental value: 230.β-L-5-fluoro-2 ', 3 '-zalcitabine (β-L-FddC) 12 preparation

Under 0 ℃, (add Et among the 240mg, THF solution (10ml) 0.52mmol) to compound 11 ₃N-(HF) ₃(0.339ml, 2.08mmol).Reaction mixture at room temperature stirred 3 hours.At this moment, add the removal monosilane base reagent of other six equal portions, and reaction mixture at room temperature stirred spend the night.Removal of solvent under reduced pressure then, the gained resistates is with chromatogram purification (10-20%, EtOH/CH ₂Cl ₂), obtain the required β-L-FddC12 of 95mg (78%), white foam shape material.β-L-5-fluoro-2 ', 3 '-zalcitabine 12 (analytical data of β-L-FddC):

¹H NMR of β-L-FddC (DMSO-d6,300Mhz): δ 8.26 (d, J=7.4Hz, 1H), 7.65 (broad peak, 1H), 7.43 (broad peak, 1H), 5.83 (m, 1H), 5.15 (broad peak, 1H), 4.01 (m, 1H), 3.72 (d, J=11.7Hz, 1H), 3.52 (d, J=11.9Hz, 1H), 2.27-2.20 (m, 1H), 1.91-1.75 (m, 3H).

Embodiment 2

Prior art is synthesized lactone phenylseleno thing 5a

Below carry out according to prior art from the synthetic lactone phenyl selenide (5a) of lactone silyl ether (4).Chu etc., organic chemistry magazine (J.Org.Chem.) 55,1418 (1990) and Ryl etc., synthetic (Synthesis) 874 (1977).Importantly this technology utilizes the phenylseleno bromine that phenylseleno is incorporated on the enol ether.Its stereoselectivity and the inventive method of introducing phenylseleno is compared, and its specificity will be far smaller than method of the present invention.

Under-78 ℃, with lactone 4 (12.50g, 35.27mmol) THF solution (106ml) with LiHMDS (35.30ml, 1M) handled 15 minutes, in about 2 minutes, add pure TMSCl (4.48ml then, 35.27mmol), then the gained reaction mixture was stirred 30 minutes down at-78 ℃, and then at room temperature stirred 2 hours.Use NH then ₄Cl saturated solution termination reaction.Reaction solvent is removed in the decompression lower section.(3 * 100ml) extract the gained reaction mixture with EtOAc.Merge organic layer and use salt water washing and Na ₂SO ₄Dry.Evaporation.Resistates is with silica gel chromatography purifying (10-20%EtOac/ hexane), obtain 10.80g (60%) required 2 '-the isomer 5b of phenylseleno thing 5a and 4.40g (24%).

At room temperature, with 2 '-(4.40g, (3.10ml 20.74mmol) handled 24 hours THF solution (35ml) 8.64mmol) β-phenylseleno derivative 5b with DBU.The lower section of reducing pressure is then removed and to be desolvated, and reaction mixture dilutes with EtOac (150ml) and uses NaHCO ₃Saturated solution and salt water washing.Dry organic layer, evaporation and purifying obtain the S.M. (5b) of 2 of 2.3g (52%) '-α-phenylseleno thing 5a and 1.3g (30%) recovery.

Analytical data:

¹H?NMR?of?5a(CDCl ₃,300MHz):δ7.75-7.32(m,15H),4.40(m,1H),4.16(dd,J=5.4Hz,J′=9.2Hz,1H),3.90(dd,J=2.9Hz,J＇=11.5Hz,1H),3.66(dd,J=3.1Hz,J′=11.5Hz,1H),2.75(m,1H),2.33(m,1H),1.10(s,9H). ¹³C?NMR?of?5a(CDCl ₃,75MHz):δ176.1,135.8,135.7,135.6,132.9,132.5,130.1,129.5,129.1,128.0,127.2,78.8,65.0,37.3,32.5,27.0,19.3.

¹H?NMR?of?5b(CDCl ₃,300MHz):δ7.70-7.26(m,15H),4.54(m,1H),4.07(dd,J=9.5Hz,1H),3.76-3.63(m,2H),2.68(m,1H),2.27(m,1H),1.10(s,9H). ¹³C?NMR?of?5b(CDCl ₃,75MHz):δ175.8,135.7,135.5,133.0,132.9,130.0,129.4,128.9,127.9,127.5,78.8,64.8,37.1,31.8,26.9,19.4.

The purpose that it should be understood that the foregoing description and scheme is mode with example, and present invention is described.Should not be considered as any type of restriction of the present invention.Various modifications that those of ordinary skills can do aforesaid method or change also in design scope of the present invention and be included in the essence and intension scope of the application and its claim.

Claims

1. the diastereo-isomerism of the lactone shown in the production formula (5a) is method optionally, Wherein R is the hydroxyl protecting group (A) that is selected from t-butyldiphenylsilyl, triphenyl silyl, t-butyldimethylsilyl, trityl, methoxyl group trityl and pivaloyl, and it may further comprise the steps: 1) with the protected lactone of hydroxyl of formula (4)

With the reaction of the highly basic of significant quantity, in second step, introduce silyl protecting group (B) then thus obtain the enol ether product of silyl protection; 2) will be by the silyl that step 1 obtains enol ether product of protecting and phenylseleno compound reaction with formula ArSeX, wherein Ar is the phenyl of phenyl or replacement, X is selected from ^-OAc, ^-C (O) CF ₃, ^-SCN, ^-SO ₂Ar, NR ₂And N phlhalimide, the compound of production 5a.

2. according to the process of claim 1 wherein that described alkali is selected from butyllithium, diethylamino lithium, (two) trimethyl silyl Lithamide, (two) trimethyl silyl sodium amide and (two) trimethyl silyl potassium amide.

3. according to the process of claim 1 wherein that described silyl protecting group (B) is a trimethyl silyl.

4. the diastereo-isomerism of the L-nucleosides shown in production formula I method optionally,

Wherein Y is purine or pyrimidine base, and X is CH or CH ₂, it may further comprise the steps: 1) by the compound shown in the compounds accepted way of doing sth (5a) shown in the formula (4)

Wherein R is the bigger hydroxyl protecting group of volume, and it is selected from t-butyldiphenylsilyl, triphenyl silyl, t-butyldimethylsilyl, trityl, methoxyl group trityl and pivaloyl,

It is by in the first step highly basic of described compound (4) with significant quantity being reacted; thereby in second step, introduce the enol ether that the silyl protecting group generates the silyl protection then; thereby then with the enol ether of described silyl protection and the lactone of the phenylselenoization of the compound reaction production (5a) that contains phenylseleno with formula ArSeX; wherein Ar is the phenyl of phenyl or replacement, and X is selected from ^-OAc, ^-OC (O) CF ₃, ^-SCN, ^-SO ₂Ar, NR ₂And N phlhalimide; 2) lactone part with compound (5a) is reduced into hemiacetal (6);

3) with the compound of the esterification of hemiacetal (6) esterification production (7), Wherein T is an ester group; 4) purine or pyrimidine base are condensed to the compound (7) of described esterification thus go up the nucleosides of production (8):

Wherein Y is purine or pyrimidine base, with its further oxidation or the nucleosides that can generate formula I that reduces.

5. according to the method for claim 4, after the further oxidation of nucleosides of wherein said formula (8), by remove hydroxyl protection promptly obtain 2 of formula (10) ', 3 '-dideoxy-2 ＇, 3 ＇-two dehydrogenation nucleosides.

6. according to the method for claim 4, wherein Y is a pyrimidine base.

7. according to the method for claim 5, wherein said pyrimidine base is a cytosine(Cyt).

8. according to the method for claim 5, wherein said pyrimidine base is a 5-flurocytosine.

9. according to the method for claim 4, it further may further comprise the steps: 2 of the production 12 of the nucleosides of formula (8) reduction soon ', 3 '-the di-deoxynucleoside derivative.

10. according to the method for claim 9, wherein Y is a pyrimidine base.

11. according to the method for claim 10, wherein pyrimidine base is a cytosine(Cyt).

12. according to the method for claim 10, wherein pyrimidine base is a 5-flurocytosine.

13. according to the method for claim 9, wherein X is a N phlhalimide.

14. according to the method for claim 9, wherein said highly basic is selected from butyllithium, diethylamino lithium, (two) trimethyl silyl Lithamide, (two) trimethyl silyl sodium amide and (two) trimethyl silyl potassium amide.

15. according to the method for claim 9, wherein said silyl protecting group is a trimethyl silyl.

16. according to the method for claim 9, wherein said reduction step (2) is to carry out in the presence of borohydride reduction agent or hydride reducer.

17. the diastereo-isomerism of the lactone shown in the production formula (5c) is method optionally,

Wherein R is for being selected from t-butyldiphenylsilyl, triphenyl silyl, t-butyldimethylsilyl, trityl, methoxyl group trityl and pivaloyl, and it comprises that following step bag is rapid:

1) with the protected lactone of hydroxyl of formula (4a)

With the highly basic reaction of significant quantity, then by in second step, introducing the enol ether product that silyl protecting group (B) obtains the silyl protection;

2) with the enol ether product of the silyl that obtains in the step 1 protection and the compound of the phenylseleno compound reaction production 5c with formula ArSeX, wherein Ar is the phenyl of phenyl or replacement, and X is selected from ^-OAc, ^-OC (O) CF ₃, ^-SCN, ^-SO ₂Ar, NR ₂And N phlhalimide.

18. according to the method for claim 17, wherein said alkali is selected from butyllithium, diethylamino lithium, (two) trimethyl silyl Lithamide, (two) trimethyl silyl sodium amide and (two) trimethyl silyl potassium amide.

19. according to the method for claim 17, wherein said silyl protecting group (B) is a trimethyl silyl.