AU610865B2 - Process to produce 2',3'-dideoxynucleosides - Google Patents

Description

I I AUSTRALIA Patents Act COPLTME SPECIFICATICN

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: APPLICANT'S REFERENE: CT-1882A Name(s) of Applicant(s): Bristol-Myers/Company Address(es) of Applicant(s): 345 Park Avenue, New York, New York, UNITED STATES OF AMERICA.

4 Address for Service is: PHILLIPS ORMCNDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Complete Specification for the invention entitled: PRCESS TO PRODUCE 2' ,3'-DIDEOYNUCLEOSIDES Our Ref 87240 POF Code: 1490/1490 The following statement is a full description of this invention, including the best method of performing it known to applicant(s):

I

1- PROCESS TO PRODUCE 2',r 3' DIDEOXYNUCLEOSIDES BACKGROUND OF THE INVENTION Field of the Invention This invention relates to an improved process to produce 2',3'-dideoxynuclesides. Further, this invention relates to novel and~ a- and A-(L)-2',3'-dideoxy- 4 Ot 0 nucleosides.

0 too 0 0 Background Related References 4 Typically, 2' 3'-dideoxycytidline (ddC) is synthesized from 2'-deoxycytidine 1' 2 This is a general method for the synthesis of 2I,3t-didooxynucleosides. The starting 130 0 0 .0 materials for this synthesis are, however, extremely 00expensive and riot available in bulk. The reagents required for this deoxygenation, furthermore, are also quite costly.

44 Other preparations involve the usi of cytidine or protected cytidine, which is then subjected to stepwise di-deoxygenation. The original synthesis of Hlorwitz4 used a cyclonucleoside as intermediate and involved many steps, The racemic mixture ol" 0-(D,L)-2'03'-.dideoxyadenosine 2.c' (ddA) has been described in the literature by M.J. Robbins, -2r 1 i o 0 o o .0 0 to0o o o 0 0Q o 00 ft Most of the other procedures involve reduction of the nucleoside to a 2',3'-unsaturated intermediate, which is 5,6,7,8,9, 10 then catalytically hydrogenated 67,,9, A more complex approach that involves a Perkow reaction has also been described 11 A number of these methods are summarized 12 in a U.S. Patent More recently, a photoreductive synthesis of dideoxynucleosides, also from nucleosides, has appeared 3 Some of the above methods apply to 2',3'-dideoxyuracil, but this is easily converted into 14 o1 ddC 1 Finally, a synthesis of dideoxynucleosides, which are racemic and also anomeric, from a variety of tetrahydrofurans, via a photochemical chlorination, is described in the Russian literaturel. Cytidine is an expensive starting material for multi-kilo preparations of ddC. In addition, the substituted tetrahydrofurans used by the Russian authors, although rather inexpensive, are racemic and are also anomeric mixtures and would produce ddC as a mixture of difficultly separable enantiomers. Also, o. L-dideoxynucleosides are unavailable from natural nucleosides. This is the only method known to make them.

3 SUMMARY OF THE INVENTION In summary, this invention comprises a process for producing 2',3'-dideoxynucleosides represented by the formula thereby produced, and their use as antiviral and antibiotic agents, especially as antiviral agents effective against the acquired immune deficiency syndrome (AIDS) infectious S1agents.

C The earlier application, U.S. Serial No. 028,817 filed 20 March 1987 discloses broadly the process defined herein as the invention. More particularly, the description of the invention and original SCHEMES I and iI set forth structural Sfcrmulas which clearly indicate that producti produced according to the process of the inventiion may possess the base in the P-position or the a-position. But, those formulas less explicitty define the stereochemical orientation with respect to the hydroxIethyl moiety pendant to the pentofuranose ring at the 4-position. The original *\js to the pentofuranos3e ring at the 4-position. The original 4 actual examples illustrate 2',3'-dideoxynucleosides produced according to the invention starting from (D)-Y-carboxy-ebutyrolactone. We have now illustrated the process starting from (L)-e-carboxy-&-butyrolactone to produce each of the possible enantiomers separately. The process according to this invention comprises a chiral synthesis of each enantiomer and avoids the additional step of separating enantiomers.

In another aspect, this invention comprises o (L)-dideoxynucleosides. Particularly, this invention comprises "%10 (L)-dideoxynucleosides produced by- -the process according to 0 0(a oo this invention.

0 00 In still another aspect, this invention comprises S"o certain intermediates useful in the above-described process of the formulas o RO o0 R 0 wherein A is an 0-activating group as defined below and X is S0 a leaving group selected from F, Cl, Br and I, preferably o 2fl from Cl and Br.

O 0 larry al DETAILED DESCRIPTION OF THE INVENTION The present invention is a process for producing a dideoxynucleoside represented by the formula R 0 wherein B is a base selected from the group of purine and pyrimidine bases and R is a member selected from H and hydrc"-y-protectIng groups, which comprises the 9steps of; converting a member of the group consisting of Land D- t-carboxy-t'-butyrolactone of the formula 00 0 Formula 1 -6 to a 5-O';hydroxy-protecting group- T-butyro 1ac tone of the formula 0'"1a0 Formula 2 wherein R is a hydroxy-protecting group; converting the intermediate from step Formula 2, to the 5-O-hydroxy-protecting group-methyl-2,3-dideoxy- D- or -L-pentofuranose of the formula 0 4 R 0- 0)~11 t4TOOPAOH, Formula 3 wherein R, is a hydroxy-protecting gr-oup; converting the intermediate fr~om step Formula to the 1-0- activating- group- 5-0- hydroxy-protecting o0 group- 2, 3-dideoxy-D- or -L-pentofuranose of the formula Formnula 4 wherein R, is a hydroXy-protectingg'roup, and A is an 0-activating group selected from al)~ylcarbonylo 7t arylcarbonyl, alkyithiocarbonyl, aryithiocarbonyl, alkylsulfonyl, arylsulfonyl and carbonate groups wherein the alkyl moiety may be an unsubstituted or substituted C 1

-C

3 alkyl group and the aryl moiety may be an unsubstituted or substituted phenyl group and wherein the substituent on the alkyl and aryl moieties may be selected from 1 to 3 groups selected from halo and alkoxy groups; converting the intermediate from step Formula 4, by reaction with a compound having one of the formulas HX and TMSX to the group-2,3-dideoxy-D- or -L-pentofurnose of the formula RO8 aono 2 u 'R ooo Formula on a wherein R is a hydroxy-protecting group and X is a leaving group selected from F, 01, Br and It reacting the intermediate from step Formula with an activated base selected from purine and a pyrimidine bases, wherein the base has been activated by means of reacting the pendant amvino and hydroxy groups on the nucleus of the given base with An activating compound selected from silylating and aceatyb'ating and benzoylatinq agents, in the pt-esence of one o4 a Bronsttd acid and a i-tz, Lewis acid; and recovering the 2',31-dideoxynucJleoside from step above.

The process for producing two representative dideoxynucleosides according to this invention is outlined in Scheme I below.

Scheme I 0 0 0 0 0 0 "113 a 40 9QOH (D)C H-:0 R 0)

(Q)

3.

R O 0 x Ac 0 RO O Ac 4 -4

NHTMS

ddC

QTMS

b X 8r KTM RO 43 NH The starting material, T-carboxy-l-butyrolactone may be conveniently obtained from L- or D-glutanic acid by utilizing conventional techniqgues reported in the chemical 16 literature A combination of chemical reactions produce a suitably blocked 2,3-dideoxypentofuranose, 3, This compound and its derivatives are known in the literature, Thus, the conversion of the starting material, T'-carboxy-T~-butyrolactone, to a c group-methyl-l-butyr'olactone, step involves the reduction of the T-carboxy group to a hydrogymethyl group followed by reaction with a hydroxy-protecting group reagent* For eXAMple, the reduction of the 1-carbo~y o group and )r-oteotion of the resulting T-hycdroxymethyl group by means of the benzyl grou~p (PhICK 2 step was achieved by the sqccessive reaction of the starting compound 4)f For'mula, 1. with BH 3 ,SMe 2 and PhC 1 2 Br~''1 The prim~Ary alcohol functional group may be protected as an ether, such as a trialkyl or di'alyl aryl or diary'.

alkyl or triaryl silyl,, unsUbstitu-ted and substituted a bonzyl, unsubstituted and substituted alkyl, or ally! ether, or4 an ester, such as a benzoyl, mesitoyl, pivaloyll unsvbstituted or substituted acetyl, or ~a'boaetr a caboat -ser converting a member of the group consisting of Land D-T-carboxy-r-butyrolactone of the formwla /2 See "Protective Groups in Organic Synthesis," T. W. Greene, Johnx Wiley, tNew. York 1981 for more detailed description of pro\"-ecting groups and the chemistry relating to the same.

In a more preferred embodiment, there was uged as the hydroxy-protecting group for the primary alcohol group at the 5 -position the benzyl group, and most preferably the benzoyl group, becauise of their stability and well-kcnown preparation.

The conversion of the 5-O-hydroxy-protecting group-rbutyrolactone, to the S-Q-hydromy-protecting group-2,3dideoxypentofuranose haVinq Formula 3 in step was achieved by reactit.ig the intermediate having Formula 2 with NaH and HC0 2 E~t ,ollowed by HQ1l It will be understood by z e illed in the art to which this invention relates that any one of a number of reducing agents may be used to carry out either or both of steps and independently in successi.on) or at the same time. Other useful reducing agents besides BIT3'sme 2 used in steps and as described above ~'irclude NaSli 4 Nar3Ii 4 plus LiCl or Al~d 3

BF

3 LiA lH 4 1 LiA!H(QMe) 3 LiAli(O-t-Bu) 3 (Sia)ZBH (disiamyl borane) and other aialkylbora1nes, and thd lilte. We prefer to use (Sia) 2 B1 os the reducing agent because of Its convenient handling and reactivity.

The step (cu) conversion of the intermediate having Formula 3 to the intermediate having Formula 4 bearing an t"activated" hydrQxy group at th4 C(l) position of the group-2,3-dideoxy-D- or -L-pentofuranose of the formula

I

/3

I

t 2,3-idideoxypentofuranose ring system may be achieved by any reagent effective to convert this hydroxy group to a group which may be displaced readily by Cl or Br upon reaction with HCI or HBr or, preferably, TMSBr or TMSC1 catalytic amunt of TMSI. ("TMS" represents the tetramethylsilyl group). Such a group which be so displaced readily include O-activating groups selected from alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, arylthiocarbonyl, alkylsulfonyl, arylsulfonyl and carbonate groups wherein the to alkyl moiety may be an unsubstituted or substituted C 1

-C

3 alkyl group and the aryl moiety may be an unsubstituted or 0 substituted phenyl group and wherein the substituent on the o"no alkyl and aryl moieties may be selected from 1 to 3 groups o selected from halo and C 1

-C

3 alkoxy groups, More preferably, this activating group is selected from o corresponding (to the above) acetoxy and benzoyloxy groups and, most preferably, acetoxy. Step was conveniently So carried-out using acetic anhydride/pyridine reagent.

The step displacement of the 1-0-activating group S functional group with a leaving group selected from C1 and 0 00 S" Br was achieved by treatment of 4 with HC1 (or HBr) in SGCHCl at low temperature to give the furanosyl halides and Sb, which are present in solution as a mixture of anomers (a and B).

12 and TMSX; reacting the intermediate from step Formula I I I ;i i _I :i i 0 01.

o 0 0 0 0 00 06 0 0 0 0 00 C~o 0 0 0 0 ~U 0 In step of the process according to this invention, the intermediate having Formula 5 from step above was reacted with a suitably activated base, wherein the base is selected from purine and pyrimidine bases and wherein such base has been activated by reaction with well-known activating reagents to obtain a silylated, acetylated or benzoylated or other acylated base, in the presence of a suitable polar or non-polar solvent and, optionally, in the presence of a Lewis acid such as, for example, boron halides, aluminum halides, titanium halides, tin (IV) chloride, zinc halides, trimethylsilyl bromide, iodide, triflate and any other species well-known to be used in glycosylation reactions or in the presence of a Bronsted acid such as hydrogen chloride, bromide or iodide.

Especially useful in this step is the use of silylated purines and pyrimidines in the presence of non-polar solvents such as, for example, benzene, toluene, chloroform, dichloromethane, dichloroethane and carbon tetrauhloride.

Examples of useful polar solvents include others iuch as t tetrahydrofuran and dioxane, nitriles such as acetonitrile, dimethylformamide, and dimethylsulfoxide. An example of a useful procedure to carry out step is disclosed in Brundidge et al., U.S. Patent Patent 4,625,020 which discloses the coupling of silylated pyrimidines, wherein active hydrogens of hydrcxy and amino groups are blocked by silyl groups such as the 13 trimethylsilyl group, with a 2-deoxy-2-fluoroarabinofuranosyl halide. As this referenced procedure was applied to step according to the present invention, a purine or pyrimidine base having all active hydroxy and amino hydrogens blocked by the trimethylsilyl group was reacted with an intermediate having Formula Thus, treatment of intermediate having Formula 5 with a silylated base as defined above in CH 2 C1 2 and CHCI 3 gave protected 2',3-dideoxynucleosides as a mixture of anomers \c (P;a 1:1 to 3:1) in good yields (from about 49% to about P. 74%).

9 4 o" Alternatively, in another embodiment according to this So0 invention, when in step the group is acetyl, the S. intermediate from step may be reacted with an activated base in the presence of a Lewis acid as in step so as to o 6 obtain the dideoxynucleoside product without proceeding Sthrough step o Generally, in order to obtain final products having antiviral, antimetabolic, antineoplastic, and anti-human 1o immunodeficiency viruses (anti-HIV) activity, following the Scoupling reaction of step and prior to recovery of Sproduct in step the process according to the present invention includes the additional step of removing the 14 ne roulowving statement is a ruiJ aescription or tnis invention, iiuup the best method of performing it known to applicant(s): -1 t group. Suitable procedures to remove this pro-atcting group are well-known in the field to which this invention relates and examples are disclosed in frProtective Groups in Organic Synthesis" by T. W. Greene, John Wiley, New York, 1981 mentioned above. When the protecting group is the especially preferred benzyl or benzoyl group, it can :e easily removed by catalytic hydrogenation (H 2 /PdCl 2 or treatment with ammonia in methanol, (NH3/MeOH), respectively.

I) The 2',3'-dideoxynucleoside product, unprotected or oQ protected, was conveniently recovered by collecting the p reaction mixture from step or from the additional step wherein the 5-0-protecting group was removed, removing insoluble reactants and additives by filtration through Celite, and purifying the resulting product by column o 2 4 I chromatography, for example on a silica gel column using a 0 mixture of about 1-5% methanol in chloroform as eluent.

I The resulting anomers (B and a) were separated using chromatographic and crystallization techniques well-known in 4 o the field to which this invention relates. The desired 4 4, active 0-anomer generally was obtained in greater 4 proportions than the apparently biologically inactive, or at leas. less biologically active, a-anomer, Thus, the process according to the present invention affords a stereospecific synthesis for producing 2',3'-dideoxynucleosides including and (L)-a-compounds, 15 jb i 2- 1 The following is a general procedure for separating and a anomers: the mixture of anomers is applied to a silica gel HPLC column and eluted with a gradient mixture of ethyl acetate and hexane at high pressure (flow rate of 100-500 mi/mmn). Appropriate fractions are pooled and the solvent removed, e.g. by evaporation under reduced pressure, to afford the pure anomers.

As is mentioned above, the base component, B, of the 2'.3'-dideoxynuc leo side produced according to the process of to the present invention is selected from purine and pyrimidine (3 Is 'Fc-4Aror' bases. When derived from purine bases, 44pes-otat-JA' O~fB 4,are the following; 6-amino-purin-9-yl (adenin-9-yl) 2-aminopurin-.9--y' 2, 6-diaminopurin-9-yl 2-aitino-6-hydroxypurin-9-yl (guanin-9-yl) 6,-hydroxypurin-9-yl In addition to the above, the B component may be 2-halapurin-9-yl, 6-halopur-in-9-yl, or 2, 6-dihalopurin-9-yl, in which event the base component need not be activated, for example, completely sill. ed in order to undergo the condensation or coupling reaction in step When derived from pyrimidine bases, vap esentIative -E 9 are kthe following: 16 -3- 2, 4-dihydroxypyrimidin-1-yl 5-xethyl-2, 4-dihydroxypyrimidiri- -yl 5-ethyl-2, 4-dihydroxypyrimidin- 1-yl 2-hydroxy-4-aminopyrimidin-1-yl 5-vinyl-2, 4-dihydroxypyrimidini- -yl 5-halovinyl-2 4-dihydroxypyrimidin-1-yl 5-halomethyl-2 ,4-dihydroxypyriridin-1-yI 5-haloethyl-2, 4-dihydroxypyriridin-1-yl The above-mentioned 5-methyl and 5-ethyl substituents 04 (0 are representative of 5-alkcyl substituents and the 0 substituent is representative of 5-alkenyl substituents.

0 4 Examples of halo-groups on the 5-halovinyl (or a t 5-haloalkenyl) group include 1 to 3 or even 4 F, Cl, and Br 0 00 0 groups.

Thus, the process according to this invention is useful 0 ~for the preparation of a variety 2' 3'-dideoxynuc leo sides, S00 0 ,both pyrimidine and purine nucleosides, having antiviral, 00 00antimetabolic, and antineoplastic activity as well as 0 0 activity against human immunodeficiency viruses.

1-4) The following examples illustrate but a few P representative embodiments of the process according to this invention and are not to be construed as limiting in scope.

All parts and percentages are by weight and temper~atures are in degrees Celsius unless otherwise specified, 17 -4- II-- The following Scheme II is in reference to the following examples 1-9.

SCHEME II AC 2

-PY

AMS

TMSO P1 10

IV

P dC 1) H 2 =2 1 PdCl

H

2

HOH

ay0 a 1 NH 2

VII

00 0 Oft #0 *09 r.

00) 0 0 ft 00 tO o4 o O 0 e 90000 0 0 4 0 00 0 0 00 00I o o 0 00 to 0 o 000 Pho P 1^ 0TY-0 Ac II J~HX IT a)X=Cl b)X=Br VIII J3:ol:1 0 00 *9 0 0000b 0 0 0 409 0 00 X=Br

~TME

TMS

CHC1 3 X=Br Ph"N IX P: o, 3:1 -l 8- A1 EXPER IMENTAL Example 1: 1-0-AcetYl-5-0-Benzyl-2,3-dideoxy-D-pentofuranose A solution of 1.00 g (0.0048 mole) of 5-0-Benzyl-2,3-dideoxy- D-pentofuranose, I, prepared according to the literature 15 1, in 2 mL dry pyridine and 1 mL acetic anhydride was stirred at room temperature for 2.5 hrs. The reaction mixture was poured onto ice, stirred, and extracted with dichioromethane. The organic layer was washed with 1N :44 10 hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The dichioromethane solution was dried over sodium sulfate, filtered and evapor~ated to dryness, yielding 1,20 g 0 0 0 Q (100%) of 1-0-acetyI-5-0-benzyl-2,3-dideoxy-2-pentofuranose as a colorless liquid. Chromatography on silica gel with a mixture of ethyl acetate and hexane afforded pure II, The nuclear magnetic resonance spectrum was consistent for the a desired structure and indicated that II is a 3:2 mixture of anomers; Crude II is, however, essentially pure and was normally used as such in the next step.

Example 2: 5-0-Benzyl-2,3-dideoxv-D-pentofuranosyI chloride (IIla), To a solution of 0.128 g (0.00051 mole) of 1-0-acetvl-S-0benzyl-2..3-dideoxy-D-pentofuralose in 1 mtL dichloromethane 19- -6i at 0 0 C, 4 mL of a 0.125 N solution of hydrogen chloride (0,00051 mole) in d' iloromethane were added. After 1 hr at 000, a nuclear magnetic resonance spectrum of a portion of this solution indicated complete conversion to the moisturesensitive 5-0-benzyl-2,3-dideoxy-D-pentofuranosyl chloride (IIIa). The above solution was used directly in the coupling experiments.

Example 3: 5. o-Benzyl-2, 3-d deoxy-D-pentofuranosyl bromide (IIIb). To 9 t9 t a solution of 0.0965 g (0,000384 mole) of 1-0-acetyl-5-0a 9r benzyl-2,3-dideoxy-D-pentofturanose in 1 mi dichloromethane at -30 0 C, 1 mL of a 0,36 N solution of hydrogen bromide (0.00036 mole) in dichloromethane was added. After 15 mine a nuclear magnetic resonance spectrum of a portion of this o solution indicated complete conversion to the moisture- 000 O* sensitive 5-0-benzyl-2,3-dideoxy-R-pentofuranosyl bromide (IlIb). The above solution was used diretly in the coupling experiments, 9 0 a soExample 4: 0909994 5'-0-Benzvl-2',3 -dideoxyuridine A suspension of 0,24 g (0.00214 mole) uracil, 0.52 mL (0.00247 mole) hexamethyldisilazane and 0,025 g (0,00019 mole) ammonium sulfate in 8 mL dry acetonitrile was refluxed under Argon for 2 hrs, The mixture was cooled, evaporated to dryness, 20 -1 7 replacing the solvent with 5 mL dry dichloromethane, and yielding a 0.428 M solution of 0,0-bis-trimethylsilyluracil.

To a solution of 0.104 g (0.000384 mole) of 5-0-benzyl-2,3dideoxy-D-pentofuranosyl bromide in 2 mL dichloromethane at 0 C, 2 niL of a 0.428 M solution of bis-trimethylsilyl uracil (0,000856 mole) in dichloromethane were added and the temperature was allowed to rise slowly to 25 0C. After an overnight period at room temperature, the reaction was quenched with 0.2 mL methanol and filtered through Celite, washing with 30:1 dichloromethane-methanol.

The crude product was chromatographed on silica gel, using 75% ethyl acetate in hegane, to yield 0,105 g of a mixti-re of 5 1-0-benzyl,-2' 3'-dlideoxyuridi ie and its C(1) epimer (a-anomer) 2:l).

The nuclear magnetic resonance spectrum was consistent with the structure, The 0 and a anomers are separable by chromatography on silica gel 0 Example 'Vo 2",8'-Dideoxi~ridjine A suspension of 0.425 g (0.00024 mole) pre-reduoed palladium obkloride and 0,080 g (0.000265 mole) of 510bny-'3-ie~uiln (ai and A anorners) -21 .4 8in 1.5 mL dry methanol was hydrogenated in a Parr shaker with 15 p.s.i. of hydrogen for 1 hr. The catalyst was removed by filtration through Celite, the filtrate was neutralized with 0,70 g of a Dowex WGR resin for 15 min. at room temperature, filtered again and evaporated. The crude product was purified by silica gel chromatography, eluting with methanol in dichloromethane, yielding 0,0545 g of 2',3'dideoXyuridine, together with the a anomer (A:c~ 2:1).

44 44* 44 44 4 4 44 '44 44 0 4 '4 44 0 '4 4 '4 04 V 4 4 4 4" 4 '4 4 4 44 '4 4 44 4 4* .4 The nuclear magnetic resonance spectrum of the major component of the mixture was in agreement with literature daa6,15, Example 6,: 5'-0-Benzvl-2',3'1-dideoxYcvtidine k suspension of 0,363 g (0.00327 mole) cytosirne, 0.78 mL~ (0,0037 mole) hexamethyldisilazane and 0,038 g (0,00029 mole) ammnonium sulfate in 10 mL dry acetonitrile was teflwged Under Argon for 2 hrs, The mixture Was cooled, the solvent evaporated, replaced with 5 mL dichioromethane and allowed to settle, to yield a 0,654 M solUtion of OON-bis-trimothylsilyl cytosine.

To a solution of 0.92 g (0,0004 mnole) of 5-0-benzyl-20 3-dideo,~y-D-pentofur~anosyl chlori.de in 4 niL dichioromethane at 0 0 C# 1,26 ni of a 0.654 M solution of bis-trimethyleityl 22 9 -'19 I i r;l- a I cytosine (0,00082 mole) were added and the temperature was allowed to rise slowly to 25 0 C. After an overnight period at room temperature, the reaction was quenched with 0.2 mL methanol and filtered through Celite, washing with 20:1 dichloromethane-methanol. The crude product was chromatographed on silica gel, eluting with 5% methanol in methylene chloride, to yield 0.090 g of a mixture of 5'-0-benzyl-2',3'-dideoxycytidine and its C(1) epimer (a anomer) (O:ct 2;1).

00 ap o .c~a ao a a Sa o 0 0 a a iS 00 0 a The nuclear magnetic resonance spectrum was consistent with the assigned structure, The B and a anomers were resolved on a silica gel plate, although separation of the anomers is 20, 21 not yet completed 2 0 21 Example 7, 21 ,3'bideoxygytidine (VIIT, A su!pension of 0,070 g (0.000395 mole) pre-reduced palladium chloride and 0,040 g (0.000132 mole) 5'-0-benzyl-2',3 t -dideoxycytidine (a and B anomers) in 1,5 mL dry methanol was hydrogentated in a Parr shaker with 15 psAiS of hydrogen for 1 hr,.

C The catalyst was removed by fl£trstion through Celite, the filtrate was neutralized with 0,1 g of an Amberlite IRA 23 10 I II, i i resin for 15 min at room temperature, filtered aga34tz 4',qd evaporated. The crude product was purified by silPe r,4 chromatography, eluting with 25% methanol in dichlorpo methane, yielding 0,020 g of 2',3'-dideoxy-ytielIn, together with the a anomer 2:1).

The nuclear magnetic resonance spectrum of the major component of the mixture was in agreement with literature data Example 8; 5',-O-BenzYl-2' ,-3'-deoxqth 'idine (VIII), A suspension of 0,252 g (0,002 mole) thymine, 05 mL (Q,0024 mole) heXamethyl-diil3azane and 0.01 g (00Q1QI mole) iodotrimethylsilarw was refluxed for 48 hrs,, then cooled, This soll'tion of t-b-trimhylsi ly. thymine was added to a solution of 0,271 g (0,001 mole) 5--benzyl-213-dideoxy- 2-pentofuranosyl bromide in 12,1 mt, dry chloroform at -78 0

C,

*0 00 0o 0 0 00 0 0P CO 0Q9 0, 0 o 00 01 O 0 0o 0 00 0g 00000 The mixture Was slowly allowed to reach room temperature and stirred overnight, The reaction was quenched with 05 mL methaftolo diluted with dichloromethane, washed with water and brine and dried over sodium sulfate, The crude product was chromatographed on silica gel, 24 11 eluting with 4:1 ethyl acetate/hexane. The yield of benzyl-3'-deoxythymidine (both anomers obtained, 1) was 0.180 g The nuclear magnetic resonance spectrum was consistent with the structure. Altiough separation of the anomers was not carried out, chromatographic methods are successfully 20,21 employed for these separations in nucleoside chemistry Examp.e 9: ,3'-dideoyadeo nosine (IX, A suspension of t 0.270 9 (0.002 mole) adenine, 0,5 mL (0,0024 mole) 9 9 hexamethyldisilazane and 0,01 g (0,0001 mole) iodotrimethylsilane ias refluxed for 18 hrs, then cooled, This solution of N,N-bis-trimethylsilyl adenine was added to a solution of 0,271 g (0,001 mole) 99, 2,3-dideoxy-p-pentofuranosyl bromide in 12.1 mL dry chloroform at -7 0 C, The mixture was slowly allowed to re;.ch room temperature and stirred overnight. The reaction 0~ 9 was quenched with 0.5 mL methanolo diluted with dichloromethane, washed with water and brine and dried over aodium sulfate. The crude product Was chromatogtaphed on silica gel, eluting with 8% methanol in dichiotomethane.

The yield of 5'-Q-benzyl-2' ,3'-dideoiyadenosine (C ratio 3:1) was 0.158 g I ZIIIY1PYI~~.- The nuclear magnetic resonance spectrum was consistent with the structure. Although separation of the anomers shown in SCHEME II is not yet completed, this may be achieved by the chromatographic methods typically used in 20,21 nucleoside chemistry 20 The following SCHEME III is in reference to the following examples 10-14 and 16 and 17. The biological activity of representatives of the novel compounds is set forth in the accompanying Table Biological Activity Against Human Immunodeficiency Virus (HIV).

9e .0 0 9 99 oi S26 -26- SCHEME III BzOH {Ac 1 O/ py 0Or/ Ac ,jTMSX b) X=Br Bz Benzoyl 44 0 400 04 q 4q~ 44 4 0 44 4 44 00 44 4 4 4 o 0400 0 4

NTMS

xBr~ N2 BzoJ 4H MeW 1 0 0 00 4 0 4

HO

Nl 3IV B xvr XIV A

JM

-27- I~ 0 4 o 04 0 0 0 4 0B 4L 4, 4 2, 4 Example (L)-5-0-Benzovl-2,3-dideoxypentofuranose, X. To 200 mL of a M solution of disiamylborane in THF solution at 0 0 C was added dropwise under nitrogen a solution of 15.07 (0.068 mole) of in 40 mL of dry tetrahydrofuran. After 20 min at 0 C the reaction was warmed to 22 0 C. The reaction was stirred at 220C for 1 1/2 hrs, then worked up by slowly adding 12 mL of water and refluxing for 30 min. The reaction mixture was 1o cooled to 0 0 C followed by the slow addition of 24 mL of hydrogen peroxide maintaining the pH between 7-8 with IN sodium hydroxide. After the addition the reaction was evaporated under reduced pressure on a rotovapor at 30°C to an oily residue. This was partitioned be:ween 500 mL dichloromethane and 150 mL water. The aqueous layer was extracted with 2 X 100 mL dichloromethane and then the combined organic layers were washed with 50 mL water, dried over anhydrous sodium sulfate and evaporated to an oil.

Yield 15.Og of 5-O-benzoyl-2,3-dideoxypento- 1- furanose. The H-NMR was consistent for structure and the oil was used directly in the next step.

28

I'

15 Example 11: 1-0-Acetyl-(L)-5-0-benzoyl-2,3-dideoxypentofuranose. XI.

A solution of -5-0-benzoyl-2 ,3-dideoxypentofuranose (12.0g 0.054 mole) in 24 mL of pyridine and 12 mL of acetic anhydride was stirred at 22 0C for 2 1/2 hrs then worked up by adding 100 g of ice then 600 mL of ethylacetate. The reaction mixture was then washed with 3 X 100 mL IN hydrochloric acid 4 X 100 mL saturated Aqueous sodium bicarbonate and 100 mL of brine. The organic layer was dried over sodium sulfate and evaporated to yield a pale 0 yellow ojil. This could be used as is or chrontatographed on 0silica gel 35% EtOAcf/hexane. Yield: 8.6g of 1 )-5-0-benzoyl-2,3-dideoxy-pentofuranose. Its 1'ThR was consistent for structure. Other fractions contained the desired material but were impure.

0000%Example-12: 51-o-benzoyl-2' 3'-didecoxyadeno sine. XII..

-5-0-benzoyl-2,3-pentofuranose (2 .97g, 0.01125 mole) was dissolved in 20 mL of 1,2-dichloroethane. To this -44 wa added 1.4 M of trmtyslyboie Thi was~ stirred at 22 C for 20 min prior to the addition of 28.93 mL of a 0.428 M solution of bis-silyladenine in 1,2-dichlorpethane. The solution was stirred for 120 hrs at 220 C. The reaction was then worked up by cooling to 0 0

C,

followed by pouring into 50 mt of cold saturated aqueous sodium bicarbonate. The reaction mixture Was partitioned 29r -16- i i i ii between 300 mL dichloromethane and 2 X 50 mL of water. The organic layer was dried and evaporated to yield a colorless oil 3.3g of a mixture of products.

Example 13: Separation of axand 0 anomers of 9-(L)-5'-O-benzoyl-2',3'dideoxyadenosine (XIII, A and B).

This material was separated using a Waters LC-500 chromatography system on a Waters C-18 prep pak cartridge equilibrated and eluted with 60% MeOH/H20 as solvent. The Io sample was dissolved in 4 mL of methanol and injected.

Elution was carried out at 0.1 L/min using a refractive index detector. Fractions were collected and analyzed by 1 HPLC. Similar ones were pooled, evaporated to 1/3 volume and partitioned between 3 X 500 mL of dichloromethane. The pooled organic layers were dried and evaporated to yield pure 9-(B)-(L)-5'-0-benzoyl-2',3'-dideoxyadenosine) 660mg (NMR consistent with structure] and pure benzoyl-2',3'-dideoxyadenosine 560 mg [NMR consistent with structure.] There was also obtained a mixture of the benzoyl-2',3'-dideoxyadenosine) g).

30 Example .14: 3'-dideoxvadenosine (XIV A).

0-benzoyl-2' ,3'-dideoxyadeno sine) (270 mg, .0008 mole) was dissolved in 5 mL of methanol. To this was added mL of methanol saturated with ammonia. This wae stoppered and vented to a bubbler. After 16 hr the reaci-ion was complete and then was evaporated. The residue was chromatographed on a silica gel column packed and eluated with 10%. methanol in dichloromethane. A gradient was run to (0 20% methanol in dichloromethane. Desired pure fractions a Ott were pooled and evaporated. The residue was crystallized 0 from methanol to yield 1,60 mg of 00 dideox'yadeno sine). (NMR was consistent for stru~cture.] 0 a 13. Calculaited for C 51.05, H 5,57, N 29.77 Found C 51,15, H 5,63, Nq 29.67 C,0 3'-dideoxyadenosine (XIV B).

9-(ca)-(Ei)-51-0-Benzoyl-2 t ,3'-dideoxyadenosine) (250 mg, 4.00074 mole) was dissolved in 5 mL~ of methanol. To this was addjed 20 mL of methanol saturated with ammonia. This was 2o stoppered and vented to a bubbler. After 16 hours the eaction was evaporated and chromatographed on a silica gel clumn packed and eluted with 10%. methanol in, chloromethane, A gradient was run to 20% methanol in d~chloromethane. Desired pure fractions were pooled and evaporated then crystallized from methanol to yield 170 mg 31 -18-

I

p7,

I

I.

I

I

0 dOe 0 0 o 0 U C~ 00 0 U 00 00 01 0 I

I~I

00 0

III

of 3' -dideoxyadeno sine). IH NI4R consistent with structure.] Calculated for C 51.05, H 5.57, N 29.77 Found C 51.04, H 5.59, N 29.64 Example Separation of a, -0-benzoyl-2' ,3'-dideoxyadeno sine

(XV-A).

The mixture from the coupling reaction containing 0bno 2 ,3 dideoxyadeno sine was reverse phase chromatographed on a Waters LC-500 chromatography system using a Waters prep pak C-18 column and 50% Me0H/H 2 0 to elute. This material was dissolved in 2 mL of methanol and injected. Flow rate of 1 L/min Was used, After eluting 1.5 L of solvent the 4 L of mobile phase was gradually deluted with 60% MeOH/H 2 0 The fractioQns containing mainly the ca-(D)-5'-0-benzoyl isomer were then evaporated. The residcue was then rechromatographed on a flash column X 14" packed with C-18 and eluted with m~thanol/water to a gradient of 65% methanol/water.

Fractions were collected and pure ones pooled and evapot~ated to 1/3 volume. This was then extracted 5 X 100 mL with dichioromethane and the pooled organic layers were dried over anhydrous sodium sulfate and evaporated. This material 32 19 was crystallized f rom acetone to yield -5 -0 'benzoyl- 21,3'-dideoxyadenosine. [NMR was consistent for structure.]

~N

RV B NH 2 9-C-(D)-2',3'-dideoxyadenosine (XV B).

The material 9-(ct-()-5-o-benzoyl-2' ,3'-dideoxyadenosine) 220 mg (0.00065 mole) was dissolved in 8 mL of methanol saturated with ammonia. This was stirred in a closed system for 16 hrs. The reaction was then evaporated and chromatQgraphed on a silica gel column packed and elute -d with 12% methanol in dichloromethane. Fractions were collected and pure ones pooled and evaporated. The residue was crystallized from methanol to yield 9-(a)-(D)-2',3-'dideoxyadenosine) 114 mg 1'H NMR was consistent with structure.] 2 Example 16: Ioyl-2' ,3-did eoxycytidine (XVI).

l-0-acetyl-5-(L)--0-benzoyl-2,3--pentLofuranose 2,815 g DO (10.66 mm) was dissolved in 20 mL of 1,4--dichloroethane. To this was added 1.8 mL of trimethylsilylbromode k.l5.46 mm) (1.45 eq.) under Argon at 22 0 C. this was stirred at 22 0 C for min followed by cooling to a solid mass at -78 0 C. To this 33 i was then added 50 mL a solution of a .31 molar solution of bissilylcytosine (15.65 mm). The bath was removed and the reaction was allowed to warm to 22°C. After 16 hrs the reaction was worked up by pouring into 50 mL of cold saturated aqueous sodium bicarbonate. This was partitioned with 300 mL dichloromethane (CH 2 C1 2 and the organic layer was washed with 50 mL of water. The organic layer was dried over anhydrous sodium sulfate and evaporated to yield 3.36 g of a mixture containing a,O-(L)-5'-O-benzoyl-2',3'ts lo dideoxycytidine.

o t SB Example 17: o os Separation of a,g-(L)-5'-0-benzoyl-2',3'-dideoxycytidine (XVII A).

The material isolated from the coupling reaction was S separated on a Waters LC-500 chromatography system using a 0 reverse phase C-18 chromatography cartridge (Waters C-18 o4 prep pak) equilibrated and eluted with 35% MeOH/65% pH .01 M ammonium phosphate buffer. The column was eluted at .1 L/min using a gradient over a total of 6 L to o 0 MeOH/50% pH 6.5 buffer.

Fractions were collected and analyzed by TLC on S10 2 plates with 5% MeOH/CH 2 Cl 2 using 2 developments. Fractions containing mainly the first spot on TLC were pooled and evaporated. To further purify, the material was then flash 34 chromatographed on a C-18 column 1" X 14" eluted with buffer pH 6.5. After pooling the desired pure fractions and evaporating to 1/3 the volume, the material was partitioned between 3 X 500 mL dichloromethane (CH 2 C12).

The combined organic layer were dried and evaporated to yield 380 mg of B-(L)-5'-O-benzoyl-2',3'-dideoxycytidine.

[NMR consistent for structure.] Similarly, the fractions from the LC-500 chromatograph g containing mainly the second spot were pooled and 1o evaporated. This material was further purified on a flash 0 q -s 0o a C-18 column 1" X 14" packed and eluted with 40% g o pH 6,5 buffer, After pooling the desired pure fractions 0 o they were evaporated to 1/3 volume and the material was partitioned between 3 X 500 mL of dichloromethane. The Co combined organic layers were dried and evaporated to yield Va 506 mg of a-(L)-5'-0-benzoyl-2',3'-dideoxycytidine. 1 H NMR oo co consistent with structure.] 0 a B-(L)-2',3'-dideoxvcytidine (XVII B).

S

-(L)-5'-0-benzoyl-2',3'-dideoxycytidine (250 mg, 0.00079 mole) was dissolved in 5 mL of methanol and 20 mL of methanol saturated with ammonia was added. The reaction was vented through a bubbler. The reaction was stirred at 22 0

C

for 16 hrs. The reaction was complete and then evaporated, The rsridue was crystallized from ethanol/ether to yield 35 -22 P-(L)-2",3'-dideoxycytidine (132 mri, H1H NMR was consistent for structure.] a-(L)-2',3'-dideoxycytidine (XVII C).

a-(L)-5'Y0-benzoyl-2',3'-dideoxycytidine (250 mg, 0.00079 mole) was disgolved in 5 mL of methanol and to this was added 20 mL of methanol saturated with ammonia. The reaction was vented to a bubbler, After stirring 16 hours at 22 0 C the reaction was complete, The reaction was then evaporated and triturated with ether to leave an oil, This was crystallized from methanol/ether to yield a dideoxycytidine (140 mg, [H NMR was consistent for structure.] S0 Example 18; 0 00 Separation of -0-benzoi.2 ,3 dideoxVcytidine 0 d 0 0 0 0

(XVIIIA.

00 q j S. The mixture of -0-benzoyl-'2 ,3'-dideoxyytidine was flash chromatovaphed on a reverse phase C-18 column (1" 0 e X-14") packed and eluted with 40% MeH/pH 6,5 .01 M ammonium 0 o r, phosphate buffer, Fractions were (ollected and analyzed by TLC on silica gel plates using 5% methanol in dichloromethane as solvent using two developments.

Fractions containing mainly the second spot were pooled and evaporated, then rechromatographed on the same column in the rame way. This yielded pure fractions which were pooled and 36 h evaporated. The residue was dissolved in 5% methanol in dichloromethane and filtered through glass wool (to eliminate buffer salts). The filtrate was evaporated to yield 0-(D)-5'-0-benzoyl-2',3'-dideoxycytidine 190 mg. H NMR consistent with structure.] Also obtained during this separation in an analogous manner were pure a-D-ddC and the same mixture as originally started with.

ct-(D)-2'-3'-dideoxycytidine (XVIII B) a-(D)-5'-0-benzoyl-2',3'-dideoxycytidine 80 mg (0.00025 mole) was dissolved in 5 mL of methanol followed by the addition of 10 mL of methanol saturated with ammonia. The reaction was vented through a bubbler. After 16 hours the reaction was complete and was then evaporated. the residue was triturated with ether to yield 50 mg dideoxycytidine. H ',MR consistent with structure,] Example 19: 0 0 oOH O NH 2 N d, eaminase 2 L 4 n o

HQ

rr 37 F i' 24 To 45mg (.00019 Mole) of 9-a-(L)-2',3'-dideoxydenosine was added 3m1 of distilled H12 0 and 45mg of adenosine deaminase (Sigmna, Type II, E The reaction was stirred at 22 0 C for 18 hours. At this time HPLC analysis (20% MeOH/ph ammnonium phosphate buffer, c-18 column) indicated the reaction to be 97% complete, The H12 0 was then evaporated, followed by combining this reaction with a previous scale reaction. The was then chromatographei on a silica .00 gel column packed and eluted with 10% MeOH/CH 2 C1 2 0 1 Fractions were collected, analyzed and pu~re ones pooled to yield 42 mig (.00018 Mole) of 9-ca-L-2'3-dideoxyinosine yield) nip >250 0 C. (NMI? was consistent for structure,] 0 Ot .1 38 Table Biolocgical Activity Aqainst Human Immnnrodficiencv Virus (HIV). ul/mi Compound Formula, Compound Name ID so TCID 50 l I a-D-ddc (Ex, XVIII B) <0.11 0 o o~ 44 o o~

C.

L-ddc (E8xi XVII B) 1 22.0 10.0 >100.

(Ex. XVII1c) 39

REFERENCES:

1. Samukov, Ofitserov, V.I. Bioorg. Khim. 1983, 9, 132.

2. Prisbe, Martin, J.C. synth. Commun. 1985, 401.

3, Horwitz, Chua, Noel, Donatti, J.T. J.

Org. Chem. 1967, 32, 817.

4. Robbins, M.J. et at., J. Am. Chem. Soc. 1976, 98, 8213.

Marumoto, Honjo, M. Chem, Pharm, Bull. 1974, 22, 128.

6. Frukawa, Y. et al. Chem. Pharm, Bull. 1970, 18, 554, 7. McCarthy, J.R. et al, J. Am. Chem, Soc. 1966, 88, 1549.

8. Robins, M.J. et al. Tet, Lett, 1984. 25, 367, 04 0$ 0 9, David, Sennyey, G. Carbohydrate Res, 1980, 82, Adachi, T. et al, J, Org. Chem. 1979, 44, 1404, 11. Thiem, Rasch, D. Nucleosides and Nucleotides 1985, 0o00 04, 487.

K 12, Verheyden, J.PH.; Moffatt, J,G, US 3,817,982 (1974).

004 13. Saito, et at. J, Am. Chem. Soc. 1986, 108, 3115.

14, Lin, Ts. et al, J. Med. Chem. in the press, Kaulina, L.T. et al, Khi. GeteroSik% 3oedin. 1982, 0a 101.

S16. Taniguchi, Koga, Yamada, S, Tetrahedron 1974, 3 3547, 17. Ravid, Silverstein, Smith, bR Tetrahedron, 1978, 34, 1449', 18. Hubbard, A.J. et al. Nucleic Acid Res. 1984, 17, 6827.

3 19. Stone, Little, R.D. J. Am. Chem, Soc. 1985, 107, 2495, Bobek, Martin, V. Tetrahedron Letters 1978, 1919.

JM

-27- 21. Woenckhaus, Jeck, R. Liebigs Ann. Chem. 1970, 736, 126.

141

Claims (13)

1. A process for producing a 2',3'-dideoxynucleoside represented by the formula wherein B is a base selected from the group of purine and pyrimidine bases and R is a member selected from H and hydroxy-protecting groups, which comprises the steps of; 00 uo 4 0 0 6 converting a member of the group consisting of L- and D-1-carboxy-T-butyrolactone of the form.Lla 0 00 0 0 0 Formula 1 to a 5-0-hydroxy-protecting group-methyl-t-butyrolactone of o the formula 00* Formula 2 wherein R is a hydroxy-protecting group, by reacting the compoulid of Formula 1 with carboxy group reducing agent -42 0 30 I U q followed by reacting the resulting hydroxymethyl group with a hydroxy-protecting group reagent; converting the intermediate from step Formula 2, -to the 5-0-hydroxy-protecting group-methyl-2,3-dideoxy-D- or -L-pentofuranose of the formula 44 44 4 #44 44 44 o 444 44 4 o 4 4 0 44 44 J 4~:o4o 44 4 0 0 0 ~0 0 ~4 0 ~4 to 4 '~4 44 44 44 4 4 o 44 44 ~L~o OH Formula 3 wherein R is a hydroxy-protecting group, by reacting the compound of Formula 2 with a carbonyl group reducing agent; converting the intermediate from step Formula 3, to a 1-0- ac tivating- group- 5-0-hydroxy-protecti ng group- 2, 3-dideoxy-D- or -L-pentofuranose of the formula RO OA Formula 4 wherein R is a hydroxy-protecting group and A is an 0-activating group selected from alkylcarbonyl, arylcarbony., alkylt'hiocarbonyl, arylthiocarbonyl, alltylsulfonyl, arylsulfonyl and carbonate groups, wherein the alkyl. moiety may be an unsubstituted or substituted C 1 C 3 alkyl group and the aryl moiety may be an unsiUbstituted or substituted phenyl group and wherein the 43 31 substituent on the alkyl and aryl moieties may be selected from 1 to 3 groups selected from halo and C 1 -C 3 alkoxy groups, by reacting the compound of Formula 4 with an acylating or sulfonating or carbonylating agent corresponding to the group A above; 00 00 0 0 00 oa 0 icl o 0 no 0 00 0. 00 converting the intermediate from step Formula 4, by reaction with a compound having one of the formulas HX and TMSX to the l-leaving-group-5-O-protecting group-2,3- dideoxy-D- or -L-pentofuranose of the formula RO Formula wherein R is a hydroxy-protecting group and X is a leaving group selected from F, Cl, Br and I by reacting the compound of Formula 4 with a compound having one of the formulas HX and TMSX; reacting the intermediate from step Formula with an activated base selected from purine and pyrimidine bases, wherein the base has been activated by means of reacting the pendant amino and hydroxy groups on the nucleus of the given base with an activating compound selected from silylating and acetylating and benzoylating agents, in the presence of one of a Bronsted acid and a Lewis acid and in 44 32 the presence of a solvent selected from polar and non-polar solvents; and recovering the dideoxynuc leo side from step (e) above.

2. A process according to claim 1 wherein the reducing agent used in steps and is selected from 0BH 3 (B 2 H 6 BH 3 SMe 2 ,NaBH 4 NaBH 4 Plus one of LiCl and AlCl1 3 and BF 3 LiAlHi 4 LiAlH(OMe) 3 arid LiAlH(O-t-BU) 3 and 0 0 0dialkylboranes including (Sia 2 BH.. 00 14D 3, A process according to any one of claims I or 2 wher'ein the reducing agent used in step is BH 3 or BH 3 .SMe. p 0c 4. A process according to any one of claims I, to 3 wherein the hydroxy-protecting group used in step is selected from o a 0 unsubstituted and substituted benzyl, trialkylsilyl, allkylarylsilyl, unsubstituted and substituted aJlkyl, vinyl, 0 0 b~nzoyl, mesitoyl, pivaloyl, unsubstituted and substituted acetoxy, and carbonate groups, A process according to any one of claims I. to 4 wherein the Iq hydroxy-protecting group is benzyl. 45 33

6. A process according to any one of claims 1 to 5 wherein the O-activating group used in step is selected from alkylcarbonyl and arylcarbonyl.

7. A process according to any one of claims 1 to 6 wherein the 0-activating group used in step is selected from acetyl and benzoyl.

8. A process according to any one of claims 1 to 7 wherein in step t the base, B, component is selected from purine and pyrimidine bases wherein the bases are activated by c reaction with a halotrialkylsilane as the silylating agent wherein the halo is selected from bromo and iodo .adk 2 the bases a"e selected from halopurine bases which are o asufficiently reactive with the protecting group-2 ,3'-dideoxypentofuranose having Formula so as not to require activation of the base by reaction with an activating compound, oin rc<c; i3 r see Ce,) S9.- A process according to any one of claims 1 to 8 wherein the base component, B, is selected from purine and pyrimidine bases that are activated by reaction with a halotrimethylsilane 7- and wherein the reaction in step is carried out in a non-polar selected from CHCl3, CHC1 2 CLCH 2 -CH 2 C1, and -46 L -34- A process 'according to any one of claims 1 to 9 wherein the base, B, component is selected from the group of purine bases consisting of 6-aminopurin-9-yl, 2-aminopurin-9-y., 2, 6-diaminopurin-9-yl, 2-amino-6-hydroxypurin-9-yl and 6-hydroxypurin-9-yl and the group of pyrimidine bases consisting of 2,6-dihydroxypyrimidin-3-yl, 5-methyl-2, 6- dihydroxypryimidin-3-yl, 2-hydroxy-6-aminopyrimidin-3-yl, -vinyl 6-dihydroxypyrimdi n- 3 -yl, 5-halovinyl-2, 6- dihydroxypyrimidin-3-yl, 5-halomethyl-2, 6-dihydroxy- ccpyrimidin-3-yl, and 5-haloethyl-2.6-dihydroxypryriniidin- 3-yl.

11. A process according to any one of claims 1 to 10 including the additional step, following step (el and before %tep of removing the 5-0-hydroxy-protecting group, 12 A rcs0codn0oayoe fcam o1 hri h 12 AC pressen ad tH anydronesi ofclimf t b y w ronpth res-hyctiroy.poetn ru sslce rmbny n 47 -48-

13. A compound having the formula D ddA A compound having the formula D ddC An (L)-21,31-.dideoxynucleoside having the formula o, 0 000 0 0 H UL wherein B is a member selected from the group consisting of purine and pyrimidine bases as defined herein.

16. A compound according to claim 15 having the formula L~ ddA 0 00~ 0 3 00 00 0 0

17. A compou~nd according to claim 15 having the formula NH 2 A compound according to claim 15 having the formuila 0 H O r,

18. DMW/2368U -49- 4

19. A compound according to claim 15 having the formula NH 2 a ddC 0 LH 0 A compound according to claim 15 having the formula L caJ ddI HN

21. A process as claimed in claim 1 substantially as hereinbefore described with reference to any one of the examples,

22. A compound as claimed in any one of claims 13, 14 or 00 15 substantially as hereinbefore described with reference to 01 any one of the examples. S 0 0 o 0 O 0 0 1) V DATEM: 25 February 1991 PHILLIPS QRMONDE FITZPATRICK Patent Attorneys for: f BRISTOL-MYERS SQUIBB COMPANY 44 00 0 00 0 AZ DMW/2368U