United States Patent (19) (11 3,878,194 Moffatt et al. (45) Apr. 15, 1975

54 NOVEL PHOSPHORYLATED 58) Field of Search...... 260/211.5 R PHOSPHONIUM YLIDS (75) Inventors: John G. Moffatt; Gordon H. Jones, (56) References Cited both of Los Altos, Calif. UNITED STATES PATENTS 73 Assignee: Syntex (U.S.A.) Inc., Palo Alto, 3,583,974 6/197 Jones et al...... 260/21 15 R Calif. Primary Examiner-Johnnie R. Brown 22 Filed: Oct. 15, 1971 Attorney, Agent, or Firm-Lawrence S. Squires; 21 ) Appl. No.: 189,562 William B. Walker Related U.S. Application Data (57) ABSTRACT (60) Division of Ser. No. 709,234, Feb. 29, 1968, Pat. No. 3,662,03, which is a continuation-in-part of Ser. No. Novel phosphorylated phosphonium ylids are pre 654,056, June 18, 1967, abandoned. pared by reacting a monosubstituted phosphonium ylid with an appropriately disubstituted phosphoryl (52) U.S. Cl...... 260/21 1.5 R; 260/954; 7786; halide or thiophosphoryl halide. The novel ylids are 71/87; 260/956; 195/28 N; 252/46.6; useful as intermediates in the preparation of phos 260/968; 260/247.7 D; 260/252; 424/200; phonic acid or thiophosphonic acid derivatives there 260/254; 260/256.4 E; 424/80; 260/293.4 from and as intermediates for the preparation of insec B; 260/293.4 R 424/203; 260/502.4 Ri ticides, herbicides, oil additives and 5,6'-dideoxyhex 260/551 P; 424/219; 260/927 R; 260/932 ofuranosylnucleoside 6'-phosphonic acid. 51 Int. C. C07d 51150; C07d 105/04; C07f 9/54 8 Claims, No Drawings 3,878, 194 2 NOVEL PHOSPHORYLATED PHOSPHONM A primary object of the present invention is to pro Y1)S vide a new class of phosphorylated phosphonium ylids This is a livision of application Ser. No (“. . filed which can be reacted with a wide variety of aldehydes Feb. 29, 9 (S. ninw l S. P. t. No. 3 (Yes, which is a and ketones, thereby providing unsaturated phs sph)- continuation-in-part of application Sel. N. (n54.56. S nate or thiophosphonate derivatives thereof. Another filed July N, 1967, and now alanck met object of the invention is to provide a process for react This invention relates to a new class of the Shinry la ing the novel phosphorylated phosphonium ylid with a led phosphynium y lils and to a rice SS fir the Tearl nucleoside 5'-aldehyde to form the corresponding 5.6- tion of 5 ,6'-dides vy hexofuranos y nullet Side ( - '-clideoxyhe N-5'-enofuranosylnucleosicle 6'- ( phosphonate. The latter unsaturated nucleoside is cata phosphonic acids there with. More particularly, the in lytically hydrogenated or chemically reduced and then vention relates to a new class of hushtty lated phos converted to a corresponding 5,6'-dide Nyhex phonium ylids having the following formula: ofuranosylnucleoside 6'-phosphonic acid by hydrolysis, hydrogenolysis, anionic dealkylation, or enzymatic ile 5. tion or combinations thereof. The novel phosphorylated phosphonium ylids of For mula (A ) are prepared according to the following Teac tin:

() R Y l R Y 7 RNP-cil R - X-1 a- RSr-c-f- wherein / N each of R. R. and R is lower alkyl, aryl or Suhsti R3 22 R R 22 tuted aryl: (l) (II) (A) R. R. and R together are tri-N-piperidyl, tri-N- morpholiny kr tricyclohexyl. R is hydrogen low crulkyl cyclohexyl, aryl. Or Substi where in X is chlor) or bromo; and all other substitu ents are as defined hereinabove. tute aryl. in the practice of the above sequence, a monosubsti Y is xygen if sulfur. tuted phosphonium yid ( ) is condensed under sub each of 7 and Z is the group OR. SR" stantially anhydrous conditions with an appropriately 1. / N disubstituted phosphoryl halide or thiophosphoryl hal N , N O, or ide (l) in a non-reactive organic solvent such as tetra N. Y-1 hydrofuran, dioxane, dimethylformanide, dimethyl or NR'R' in which each of R and R" is lower alkyl, 35 sulfoxide, benzene, diethyl ether, hexane, and the like, lower alkenyi. aryl r substituted aryl, and each of R and mixtures thereof, at a temperature of about 0°C to and R is low cr alkyl, of aryl, and the reflux temperature of the solvent, for a period of about 2 to about 12 hours. Preferably, the condens:- Z and Z together are the group tion is performed in diethyl ether, hexane, tetrahydro O O S () Y Y N furan, benzene, or mixtures thereof, with an appropri IR. R9. or R / / / ately disubstituted phosphoryl chloride or thiophos O S. phoryl chloricle ( II), i.e. wherein X is chloro. Further in which R" is alkylene or arylene. more, reactions of the monosubstituted phosphonium The term 'lower alkyl means a straight (rhranched ylid (l), wherein R is hydrogen, alkyl or cyclohexyl, chain hydrocarhon group containing from 1 to 6 car are preferably performed at room temperature for a pe bon atoms, inclusive. Such as methyl ethyl. n-propyl. riod of about 5 minutes to about 1 hour; and reactions i-butyl, t-butyl, and the like. The term lower alkenyl of the monosubstituted phosphonium ylid (l), wherein means an alkyl group containing one carbon carbon R" is aryl or substituted aryl are preferably performed double bond such as allyl and the like. The term aryl at the reflux temperature of the solvent for a period of means a hydrocarbon group consisting of one or more about 2 hours or longer. aromatic rings and containing from 6 to 2 carbon Although the molar proportion of the monosuhsti atoms. inclusive, such as phenyl. benzyl. (y-toly, m tuted phosphonium yid ( ) to the disubstitute phos tolyi. p-tolyl. 3.5-xylyl, pentamethylphenyl, naphthyl, phoryl halide or thiophosphoryl halide (II) is not criti and the like. The term 'substituted aryl means an aryl cal, a preferred embodiment of two moles of the mono group having one or more halo. nitro, alkoxy, or dial 5 5 substituted phosphonium ylid per mole of the disubsti kylamino Suhstituents in the aromatic ring such as p tuted phosphoryl halide or thiophosphoryl halide () is chlorohenzyl. p-bromohenzyl, 2,4,6-trichlorophenyl, convenient. p-nitrophenyl, p-nitrobenzyl, p-anisyl, p in the practice of the above sequence, the reaction is methoxybenzyl, p-dinnethylaminophenyl. and the like. advantageously performed in the presence of an inert The term lower alkylene means the group) --(CH atmosphere such as a nitrogen atmosphere, an argon - in which in has a value of from to 4, inclusive. atmosphere, and the like. In addition, the mont Suhsti Such as ethylene. trimethylene and tetru methylene. Said tuted phosphonium ylid ( ) is generated in situ hy con group can be further substituted with one or more alkyl ventional techniques known to those skilled in the art. orary groups such as in 2.2-dimethyltrimethylene, 1,2- Included among the monosubstituted phosphonium diphenylethylene and the like. The terhn 'arylene' ylids ( ) which can be condensed with the disubstituted means an aryl group having two sites of attachment phosphoryl halide or thiophosphoryl halide (l) are such as ()-phenylene and the like. methylenetrialkyl? including cycloalkyl)phosphoranes 3,878, 194 3 4 such as methylenetri-n-butyl) phosphorine, methylen like, disubstituted chloridodithioates such as S.S. etrimethylphosphorane, methylenetricyclohexylphos diethyl phosphorochloridodithioate, S.S.-dibutyl phorane, and the like: methylenealkylarylphospho phosphorochloridodithioate, and the like, disubstituted ranes such as methylene ethyldiphenylphosphorane, n chloridotrithioles such as tiethyl phosphorochlorido ethylenennethyldiphenylphosphorane. methyleneciphe trithioate, and the like. disubstituted phosphoro nyl-t-butylphosphorane, and the like: methylenetriaryl bromidothioates such as O.O-diethyl phosphoro phosphoranes such as methylene triphenylphospho bromidothioate. O,O-diphenyl phosphorobromidothio rane, methylene tri-p-tolylphosphorine. methylenetri ite and the like disubstitute phosphorodiamidic chlo p-a I isyphosphorne, and the like: ilky liclenetrialkyl rides such as tetraethylphosphorcycliamidic chloricle. phosphoranes such iS ethyliclene- (n- () phosphorodimorpholidic chloride, N.N'-dimethylphos butyl phosphorane, and the like, alkyliclenealkylaryl phorodinalidic chloride, tetramethyl phosphorodia phosphoranes such as ethylidene methyldiphenylphos midic chlorile, and the like, disubstituted phos phorane, and the like: alkyl idenetriurylphosphorunes phorodian idic bromides such as phosphorodimorphol such as ethylidenetriphenylphosphorane, propylidenet idic bronhide and the like: mixed disubstituted phos riphenylphosphorane, butyliciene triphenylphospho 5. phoramidochloridates such as O-phenyl N,N-diethyl rune, penty licene triphenylphosphorane, cyclohexylme phosphoramidochloridate, O-ethyl N,N-diethylphos thylene triphenylphosphorane, {3-phenylethylidenetri phoramidochloridate, O-isopropyl N,N-dimethylphos phenylphosphorane, 3-methylbutylide metriphenylphos phoramidochloridate, and the like; mixed disubstituted phorane, and the like, arylmethylenetrialkylphospho phosphoramidochloridothioates such as S-butyl N,N- rank S. Such as benzylic enetrimethylphosphorane, benz diethylphosphoramidochloridothioate, O-ethyl N,N- yielenetricyclohexylphosphorane, and the like: arylme diethylphosphoramidochloridothioate, O-2,4,5- thylenetriary phosphoranes such as henzylidenetri trichlorophenyl N,N-dimethylphosphoramido phenylphosphorane, p-nitrobenzyliclene triphenylphos chloridothioate, and the like. phorane, p-methoxybenzylidenetriphenylphosphorane, Additionally, other disubstituted phosphoryl halides benzylidenediphenyl-p-dimethylaminophenylphospho or thiophosphoryl halides ( ) are obtained by conven rane, and the like; and methylenetri-N-morpholinyl tional techniques as described hy G. N. Kosolapoff. phosphorane. methylenetri-N-piperidylphosphorane, Organophosphorus Compounds, John Wiley & Sons, and the like. Inc., New York ( 1950), Chapters 9 and 10. For exam Additionally, other monosubstituted phosphonium ple, the disubstituted phosphoryl halides or thiophos ylids ( ) are prepared according to conventional proce 3) phoryl halides, i.e. when Z' and Z' together are the dures as described by S. Trippett, Advances in Or group (OR), or (SR"), are prepared by adding 2 moles ganic Chemistry, Interscience Publishing Co., New of a hydroxy or mercup to containing compound to 1 York 1960). Vol. 1, pages 83-102; S. Trippett, Quar mole of phosphoryl chloride, phosphoryl bromide, thi terly Review, Vol. 6-7, pages 4 () ()-44() (1962-1963); ophosphoryl chloride, or thiophosphoryl bromide in an A.W. Johnson, 'Ylid Chenistry, Academic Press, 35 essentially anhydrous non-reactive solvent such as New York (1966); and A. Maercker, Organic Reac chloroform. benzene, ether, tetrahydrofuran, dioxane, tions. Vol. 4, John Wiley & Sons, Inc., New York or mixtures thereof, and the like, at a temperature of ( 1965). from about room temperature to the reflux tempera Included among the disubstituted phosphoryl halides ture of the solvent for a period of about 1 to 12 hours, or thiophosphoryl halides (ll) which can be used to 40 as shown by the following equations and as described prepare the novel phosphorylated phosphonium ylids on pages 2 1-2 3 of the latter reference: {A} are disubstituted phosphorochloridates such as di methyl phosphorochloridate, di-ethyl phosphorochlori date, di-ully phosphorochloridate, di-is-butyl phos phort) chloridate, diphenyl phosphorochloridate, di-o- 45 Y Y tolyl phosphorochloridate, di-m-tolyl phosphorochlori 1x, -- 2RSOH -- x (or): - 2HX clate, di-p-tolyl phosphorochloridate, -phenylene Y y phosphorochloridate, trimethylene phosphorochlori ix. -- 2ER6'SH -- x (sR). - 2HX, date, di-3.5-xylyl phosphorochloridate, di-(p- nitrophenyl phosphorochloridate, 1,2- 5) diphenylethylene phosphorochloridate. 22 R" being lower alkyl and all other substituents being dimethyltrimethylene phosphorochloridate, ethyl p as defined hereinabove. When the reaction is per nitrophenyl phosphorochloridate, dibenzyl phosphoro formed at the lower temperature, i.e. about room tem chloridate, di- p-nitrobenzyl) phosphorochloridate, s 5 perature, it is convenient to use the moles of teritary di- pent an ethylphenyl) phosphorochloridate, di-(p- base such as 2,4,6-collidine. 2.6-lutidine, N.N- bromohenzyl) phosphorochloridate, and the like; di dimethylaniline and the like to remove the liberated Substituted phosphorobromidates such as dimethyl acid HX. Included among the hydroxy containing com phosphorobromidate, diphenyl phosphorobromidate, pounds which can he reacted with the phosphorus hal methyl phenyl phosphorohromidate, -phenylene ide phosphorohromidate, and the like, disubstituted chlo ht rid this fates such as O,O-tiethyl phosphor chloridkot hi cate. O,O-limethyl phosphorochloridothioate. O,O- Y cliphenyl phosphorochloridothicate, O.O-di?p PX chlorobenzyl) phosphorochloriclothioate, O.S.-diethyl are alcohols such as methanol, ethanol. n-propanol, phosphorochloridothioate, O-ethyl-O-p-nitrophenyl iso-butanol, n -amyl alcohol, and the like: phenols such phosphorochloridothioate, O-methyl-O-2,4,5- as phenol, o-cresol, m-cresol, p-cresol, p-cresol. 3.5- trichlorophenyl phosphorochloridothioate, and the xylenol, pent annethyl phenol, 4-chlorophenol, and the

3,878, 194 5 6 like; and mercaptains such as methan ethiol, ethane are different, are prepared by varying the molar pro thiol, n-propanethiol, and the like. portions of reactants and proceeding in a two-step re Other disubstituted phosphoryl halides and thiophos action sequence, as shown by the following equitions: phoryl halides, i.e. wherein Z' and Z together are Y Y (SR) in which R" is aryl or substituted aryl are pre Px, -- R5OH - XP (or) -- IX pared by first adding 3 moles of the sodium salt of a thiophenol to 1 mole of phosphoryl chloride, phos Y Y phoryl bromide, thiophosphoryl chloride, or thiophos Px, -- R'SH - X. (SR) -- X phoryl bromide, to obtain a trithioester incl second Y Y treating the trithioester with one mole of acetyl chlo 1) x, -- 2HNRRS - x, Norri') -- R7RsNH. HX ride or acetyl bromide as shown in the following equa Y y O tions and as described on page 218 of the latter refer (SR6') + 2CHCOX - XP (SR 6') 2CH's R' ence. Y Y Y Y 15 3RG'SNa -- fix, - P (SR6')3 + 3Nax x. For) -- 2NHR7Rs - XP (OR8) (NR7RS) -- R7R 8NH. HX Y Y O P (sR'), - CHCOX - x (sR'). -- ch,és Re", () Y R" being aryl or substituted aryl; and all other sub x, Nor'R'') -- 2NHR7RS' -- stituents are as defined hereinabove. Included among the thiophenols which can be reacted in the above manner, are thiophenol, thio-o-cresol, thio-p-cresol, and the like, The disubstituted phosphorodiamidic halides, i.e. 2 5 each of R" and R' being lower alkyl; and each wherein each of Z' and Z is the group of R" and R" being aryl; and all other substituents being as described herein above. Y In addition, the disubstituted phosphoryl halides or NCY ), Y-/ thiophosphoryl halides, i.e. wherein Z' and Z' together or NR'R'', are prepared by adding four moles of a sec are the group O O S onclary amine to one mole of either phosphoryl chlo N R, O N R ride, phosphoryl bromide, thiophosphoryl chloride, or / thiophosphoryl bromide, in an essentially anhydrous O S 35 non-reactive organic solvent such as chloroform, ben are prepared by adding one mole of a dihydroxy con Zene, ether, tetrahydrofuran, dioxane, or mixtures taining compound, a dimercapto containing compound thereof, and the like. at a temperature of from about or a monohydroxy monomercapto compound to one room temperature to the reflux temperature of the sol mole of phosphoryl chloride, phosphoryl bromide, thi vent, for a period of about 1 to 12 hours, as shown by 40 ophosphoryl chloride, or thiophosphoryl bromide the following equation and as described on pages 279 under essentially the same anhydrous conditions as de and 281-282 of the latter reference: scribed above, and as shown by the following equa Y tl(S: PX -- 4HN r-H) Y/ > YPX -- R(OH) - XPOR.Y --2HX x-P(O) + K. DHHx Y Y Ix, -- R9(SH) - XP SR - 2HX r N X3 - 4HN O --> 50 Y-1 YPx, -- R(SH)(OH) - xiosY R + 2HX, Y M Y N x-P(x O -- 26 NHHX all substituents being as defined above. When the reac N -/ /2 Y-/ tion is performed at the lower temperature, i.e. at about Y Y room temperature, it is convenient to use two moles of 55 a tertiary amine such as 2,4,6-collidine, 2,6-lutidine, all substituents being as defined hereinabove. Included N,N-dimethylaniline, and the like, to remove the liber among the secondary amines which can be reacted with ated acid HX, included among the compounds of the the phosphorus halide formulas R'(OH) R' SH), and R'? SH)(OH) which 60 can be reacted with the phosphorus halide Y Px, are piperidine, morpholine; dialkyl amines such as di are dihydroxy compounds such as ethylene glycol, tri methylamine, diethylamine, di-n-propylamine, and the methylene glycol, tetramethylene glycol, 2,2- like: diarylamines such as diphenylamine and the like: dimethyltrimethylene glycol, 1,2-diphenylethylene gly and mixed alkyl aryl amines such as N-methylaniline col, catechol, and the like; dimercapto compounds and the like. such as .2-ethanedithiol. 1.3-propanedithiol, 1.4- The mixed disubstituted phosphoryl halides or thio butanedithiol, l.2-henzenedithiol, and the like; and phosphoryl halides (II), i.e. wherein each of Z' and Z monohydroxy monomercapto compounds such as 3,878, 194 7 8 -nnercitkuthanol. - mercaptopropanol. nnnith 1 verted to a corresponding ylict (A') by treatment with t cate chos, and the like thise as descrihed here inah (ve for the unalkylated salt As a first it initive. Sime if the in v c phosphery : ( W tec nhc Sphi rus, y is the pesent is entin are re The triSuhstituted phosphines fill which can be used narck curing to the till wing Tucactic in Scuuc Ince s to repare some if the novel phosphery lated phospho inium ylids (A" and A' ' ) are lescrihed in the literature cited above. R 1 R Y 1. The disubstituted halomethylphosphonic acids or Y / \e 12. -- XCEP - R2-P-CH halomethylphosphonothic ic acids \ } are prepared by / N /e N t cluding a phenol, a Secondary innine. r m hinations R3 Z' R3 X thereof. in a stepwise manner. to chlorinnethylphos (III) (IV) (W) phonic acid dichloride, bronomethylphosphonic acid clichloride, chloromethylphosphonothioic dichloride, bromomethylphosphonothioic dichloride. R Y 21 R A" bromomethylphosphonic acid dihronicle. RN se c^ R-P==CHIP bromomethylphosphonothioic acid dibromide, and the R?k ke Yar R? y like, either alone or in the presence of a non-reactive organic solvent such as tetrahydrofuran, dioxane, ben (WI) (A') Zene, or the like, or mixtures thereof, at reflux for a pe () riod of about 4 to 12 hours. The molar proportions of Y materials are varied, and the reaction is to be per formed in a slep-wise manner depending on the partic RSP-c-R YA" ular material (IV) heing prepared by procedures such / Y R3 R 22 is described hereinablve the preparation of the mixed (A') disubstituted phosphoryl halides or thiophosphoryl ha ides ( ). As a second alternative, some of the novel phosphor wherein R' is lower alkyl or cyclohexyl: each of y late phosphorus y lids of the present invention. i. e. A." and Z' is the group OR 3) where in Y is oxygen, are prepared according to the fol lowing reaction:

‘(Y ). O 35 or NR'R' in which R” is aryl or substituted aryl, and all other Suhstituents being as defined hereina hove. In the practice of this alternative method : trisubsti tuted phosphine ( ) is allowed to react under substan tially anhydrus conditions with in appropriately di () substituted hillomethylphosphonic acid or halomethyl phosphonothioic acic (IV) in a non-reactive organic solvent such as tetrahydrofuran. dioxane, benzene, di methylformamide, and the like, or mixtures thereof, at room temperature to the reflux temperature of the sol 5 vent for a period of about 15 minutes to 24 hours, to afford a phosphorylated phosphonium halide salt (V). The latter silt V) is converted to a corresponding wherein all substituents are as defined hereinabove. phosphorylated phosphonium ylid (A') by treatment In the practice of the second alternative method, the with an aqueous solution if a base, said solution on s monosubstituted phosphonium ylid ( ) is allowed to tionally intaining in organic silvent such as : lower react under substantially anhydrous conditions with an monohydric alcohol such as methanel. ethanol in the appropriately tetrasubstituted pyrophosphate (VII) in like: ; cyclic water-miscible ther such as dioxane, tut a non-reactive organic solvent such as tetrahydrofuran, rahydrfuran and the like. Bases particularly useful for ether, benzene. n-hexane. and the like, or mixtures this purpose tire potassium hydroxide. sodium hydrox thereof, at room temperature to the reflux temperature ide, sodium ethoxide. Skidium carbonate, pyridine, and (if the solvent for a periend of 15 minutes to about 3 the like. The conversion is effected at rom tempera hours. ture for a perioc of 5 minutes to 24 hours, period of The tetrasubstituted pyrophosphates (Vll) are pre 15 minutes heing preferrel. ared hy first hydrolyzing the disubstituted phosphoryl The thus-khtained novely lic A' ) is alkylatel, if cle halile tyr thiophosphoryl hillicle ( II) in an aqueous sired, by treatment with a halide of the formula RX media at reflux for a period of a hut one-half to two in a non-reactive (rganic solvent such as ethyl acetate, hours to afford an intermediary disubstituted phos benzene, dioxane, dimethylformamide and the like, at phoric acid. and second condensing said disubstituted an elevated temperature, c.g. the reflux temperature of phosphoric acid in the presence of a carbodiimide such the solvent for a period of about 5 minutes to 3 hours 65 as dicyclohexylcarbodiimide, di-p-tolylcarbodiimide. to afford a corresponding alkylated phosphorylated and the like. in an essentially anhydrous non-reactive phosphonium salt (VI). The latter salt (VI) is con organic solvent such as benzene. ether. dioxane, and

3,878,194 9 the like, such as described by H. G. Khorana and A. R. Todd, J. Chen. Sec. 2257 (1956). As a third alternative, some of the novel phosphory lated phosphonium ylids of the present invention, i.e. those of Formula (A) in which R" is lower alkyl or cy 5 clohexyl, are prepared according to the following reac wherein each of tion sequence:

() R Y2 *Re. X 21 R2 PsiCH-P - RX - RNi-CH-F/ / Y /e N R3 23 R3 X R4' Z2 is an aldehyde and ketone, respectively; R' being hy 15 drogen or R'; and all other substituents being as de fined herein. In the practice of the latter reaction sequence, the RSP-c-k^R Y 2, 1 phosphorylated phosphonium ylid (A) is allowed to Y. l. Y., react with a carbonyl compound of Formulas (VIIIA) R3 R4 2. and (VIIIB), respectively, either alone or in an inert or ganic solvent such as tetrahydrofuran, dioxane, dimeth ylformamide, dimethyl sulfoxide, methanol, ethanol, acetonitrile, or mixtures thereof, and the like, at a tem perature of 25°C to the reflux temperature of the sol all substituents being as defined hereinabove. vent but preferably at about 25°C for a period of from In the practice of the third alternative method, the l to 48 hours, to form a corresponding a g-unsaturated novel unalkylated phosphorylated phosphonium ylid phosphonate or thiophosphonate derivative (IX). (A), wherein R is hydrogen), is converted to the cor responding novel alkylated phosphorylated phospho Any aldehyde, i.e. nium ylid (A), wherein R is lower alkyl or cyclo 3) R10 R10 N hexyl), by treatment with a halide of the formula R'X Yc-o or ketone, i.e. C=O, followed by basic treatment with an aqueous solution M / of a base as described hereinabove in the first alterna H R11 tive method. The phosphorylated phosphonium ylids (A) are valu 35 can be reacted with the phosphorylated phosphonium able intermediates which can be reacted with a wide variety of aldehydes and ketones, thereby providing un ylids of the present invention to form a corresponding saturated phosphonate and thiophosphonate deriva o,6-unsaturated phosphonate or thiophosphonate de tives thereof. Thus, the present invention provides a rivative thereof, i.e. valuable synthetic route for the preparation of phos 40 phonic acids and thiophosphonic acids therefrom, as Rio Y Z.1 R10 Y Zi shown by the following reaction sequence: DC--KR4 Z2 or R11DC--K k Yz. For example, the carbonyl compounds of Formulas (VIIIA) and (VIIIB) may be any aldehyde or ketone of R10 the aliphatic, alicyclic, aromatic, or heterocyclic series. Included among the aliphatic, alicyclic and aromatic DC-0 groups which R'' and R' can represent are alkyl (in H R10 Y 21 (VIIIA) cluding saturated and unsaturated, straight and -- (A) --> Yc-c- M branched chain alkyl and cycloalkyl) and aryl (includ ing alkaryl and aralkyl) groups, such as methyl, ethyl, re R?6 k Y propyl, isopropyl. n-butyl, sec-butyl, amyl, hexyl, hep c=o (IX) tyl, octyl, allyl, methallyl, cyclobutyl, cyclopentyl, cy R11 clohexyl, methylcyclohexyl, cycloheptyl, cyclohexenyl, (WIIIB) / phenyl, tolyl, xylyl, benzyl, and the like, as well as fused / ring structures, such as indanyl, indenyl, naphthyl, ace naphthyl, phenanthryl, and cyclopentanopolyhydro phenanthryl rings, and the like, all of which can either 60 be unsubstituted or substituted with one or more nonin terfering substituents, e.g., hydroxyl groups; hydroxyl R YA R10 Y OH derivatives, such as alkoxy, e.g. methoxy and acyloxy, DCH-CH-K Yo-c-k/ e.g. acetoxy groups; nitro groups; amino groups; alkyl R11 k 22 R?6 k Yoh amino groups, such as methylamino, dimethylamino (X) (XI) and diethylamino groups; halogen, e.g. fluorine or chlo rine; carbonyl derivatives; such as enol ether, acetal and ketal groups, and the like. 3,878,194 1 12 The thus-obtained c.f3-unsaturated phosphonate in which R" is arylene; and (IX), i.e. wherein Y is oxygen, is catalytically hydroge all other substituents being as defined hereinabove, nated at room temperature by conventional technique are valuable intermediates in the preparation of nu such as in the presence of a palladium on an inert Sup cleoside 6'-phosphonic acids. For example, when port catalyst such as palladium-on-barium sulfate, R in the general formula palladium-on-calcium carbonate and the like, in : lower alcoholic solvent such as methanol, ethanol and R10 the like, to form a corresponding saturated phospho Yo nate (X). Alternatively, the cy,g-unsaturated phosphonate (IX) H is reduced by treatment with diimide at room tempera given above for an aluehyde, represents a particular ture in an inert non-reactive solvent such as methanol, class of substituted tetrahydrofurfuryl groups, i.e. those ethanol, ethyl acetate and the like, or mixtures thereof, having the structures: for a period of about one to about 24 hours to afford the corresponding Saturated phosphonate (X). H H The thus-obtained c.f3-unsaturated thiophosphonates R12 o=& R12 { X}, i.e. wherein Y is sulfur, which adversely affects 0 1. the efficiency of the palladium catalyst, as well as the or f3-unsaturated phosphonate (X) having one or more > k"> groups such as nitro, ally and the like, which would be simultaneously reduced, are reduced by the diimide method as described above to afford the corresponding wherein R' is a substituted or unsubstituted pyrimidine Saturated thiophosphonate and phosphonates (X). or purine base, e.g. uracil-l-yl, cytosin-1-yl, 4-chloro Each of the Z and Z' groups in the thus-obtained 1,2-dihydropyrimidin-2-on-1-yl, 5 bromouracil-1-yl, 5 a p3-saturated phosphonate or thiophosphonate (X) is 2 5. bromocytosin-1-yl, 5-chlorouracil-1-yl, 5-chlorocytosin removed by hydrolysis, hydrogenolysis, anionic deal |-yl, 5-iodouracil-1-yl, 5-iodocytosin-1-yl, 5-fluorouracil kylation, enzymatic action, or combinations thereof, 1-yl, 5-fluorocytosin-1-yl, thymin-1-yl, 5-methylcytosin uncler a variety of clifferent conditions to afford the l-yl, 5-trifluoromethyluracil-1-yl, 5-trifluoromethyl cy fi-Saturated phosphonic acid or phosphonothicic acid cytosin-1-yl, 5-aminouracil-l-yl, 5-aminocytosin-1-yl, 5 (X). The variety of conditions is dependent upon the 3) methylaminouracil-1-yl, 5-methylaminocytosin-1-yl. 5 nature of the Z and Z' groups so that the removal of hydroxyuracil-l-yl, 6-azauracil-l-yl, 6-azacytosin-1-yl, the first group and then a second group can be effected 4-chloro-6-azal-1,2-dihydropyrimidin-2-on-1-yl, 6 in a step-wise manner or the removal of both groups azathymin-1-yl, hypoxanthin-9-yl, adenin-9-yl, 6 can be effected in a one-step procedure as will be dis dimethylaminopurin-9-yl, 2-chloroadenin-9-yl, 6 cussed in more detail below. chloropurin-9-yl, 6-mercaptopurin-9-yl, guanin-9-yl, Alternatively, the or p3-unsaturated phosphonate or xanthin-9-yl, 2,6-dichloropurin-9-yl, 2,6-bis(me thiophosphonate (IX) is converted to the correspond thylamino)purin-9-yl, 8-azaadenin-9-yl, 8-azaguanin ing or f3-unsaturated phosphonic acid (XI) by hydroly 9-yl, 7-deazaadenin-9-yl, and the like; sis, hydrogenolysis, unionic clealkylation, enzymatic ac each of R' and R' is hydrogen, hydroxy, alkoxy or tion, or combinations thereof, and the latter ag-unsatu acyloxy, rated phosphonic acid or thiophosphonic acid (XI) is each of R'' and R'' is hydrogen, hydroxy, alkoxy or converted to saturated phosphonic acid or thiophos acyloxy; and phonic acid (XII) as described hereinabove. R'' and R together are acetal or ketal group, e.g. Furthermore, the phosphorylated phosphonium ylids isopropylidenedioxy, p-anisylidenedioxy, and the having the formula: like, the starting material is a nucleoside 5'- aldehyde and will be converted by reaction with the latter ylid using the process of the present in vention to the corresponding intermediary 5", 6'- R2-R P-CH-P94 dideoxyhex-5'-enofuranosylnucleoside 6'- 5 () phosphonate wherein 21 O each of Z''' and Z' is the group OR, SR', F-CH=CH o " 55 -- M ^ K N o Y- Y-1 a k">f i. or NR'R' in which each of R and R' is lower alkyl, lower alkenyl, aryl 60 and arabinohex-5'-enfuranosyl nucleoside 6'- or substituted aryl, and phosphonate, respectively each of R'' and R'' is lower alkyl. 2, 17 O. Z''' and Z' together are the group N

O o, 3,878, 194 13 14 wherein all substituents are as defined hereinabove. OR in which R is phenyl, substituted phenyl or naph The intermediary a, (3-unsaturated phosphonates are thyl, the nucleoside 6'-phosphonic acid can be pre converted by catalytic hydrogenation or diimide reduc pared by subjecting the nucleoside 6'-phosphonate to tion as described herein above to afford a correspond transesterification by treatment with a primary alcohol ing saturated phosphonate, i.e. nucleoside 6'- 5 in dipolar organic solvent in the presence of a base fol phosphonates having the formulas: lowed by anionic dealkylation in the case of dialkyl phosphonates or hydrogenolysis in the case of cliaralkyl phosphonates. Suitable primary alcohols include the saturated aliphatic alcohols such as methanol, ethanol, () 2.2.2-trichloroethanol, and the like of up to about six 21 O zo carbon atoms and aralkyl alcohols such as benzyl alco Y2CH-CH, O R2 P-CH-y O R12 hol, methylbenzyl alcohol, £3-phenylethanol, 3-phenyl z6 K D Z?' R13' l-propanol. 4-phenyl-l-butanol, and the like. Suitable --- --~ bases for generating the alkoxide or aralkoxide include i. ir the alkali metal hydrides, alkali metals, alkali metal t butoxides, triethylamine, and the like. The reaction is carried out under anhydrous conditions in a dipolar or ganic solvent such as dimethylformamide, dimethyl wherein all substituents are as defined hereinabove. sulfoxide, and the like. As exemplified by the following procedures, both of Where each of Z' and Z' represents the group SR" the Z' and Z' groups in the latter compound can be in which each of R" is lower alkyl, aryl or substituted removed hy hydrolysis, hydrogenolysis, anionic deal aryl, the alkylthio, arylthio or substituted arylthio kylation, enzymatic action or combinations thereof, to groups are removed in a stepwise manner by treatment afford a corresponding nucleoside 6'-phosphonic acid, with a mild alkali such as alkali metal bicarbonate or an 1. t. 2 5 alkali metal carbonate in an aqueous organic solvent such as aqueous methanol, acetone, and the like, at room temperature for a period of about 30 minutes to 6 hours to remove the first group and then by treatment HO. O. with an aqueous acetone solution containing a molar HO 3) equivalent of iodine to remove the second group, as de P-CH-CH O R12 scribed by A. Z. Nussbaum et al., J. Ann. Chen. Soc., 87 2513–4 (1965). Where Z' and Z' together represent KG the group R14 R13 3. 5 R’ O wherein all substituents are as defined herein above. For example, where each of Z' and Z' represents the in which R" is arylene such as o-phenylene, the o-ary group OR in which R is lower alkyl, the alkyl groups 40 lene group is removed in a step-wise manner by treat are removed by heating with an iodide salt such as so ment with water to form an intermediary o dium iodide, in an aprotic dipolar solvent, such as di hydroxyphenyl monoester and second by treatment methylformamide, at a temperature of about 140°C to with an aqueous solution of bromine, essentially hypo 150°C for about 16 to 48 hours. Where each of Z' and bromus acid, to cleave the o-hydroxyphenyl group, as Z' represents the group OR in which R is aryl or sub 45 described by T. A. Khawaja and C. E. Reese, J. Anu. stituted aryl, the aryl or substituted aryl groups are re Chen. Soc., 88, 3446-7 (1966). Where each of Z' moved by alkaline hydrolysis in a step-wise manner by and Z' represents the group reacting first at room temperature in an aqueous or ganic solution of a strong alkali metal hydroxide such ( Y. as lithium hydroxide or sodium hydroxide in aqueous Y dioxane, tetrahydrofuran, acetonitrile, and the like, for about 30 minutes to 2 hours. The second OR group is the morpholinyl groups are removed by aqueous hydro removed by refluxing with saturated aqueous barium lysis with an acidic ion-exchange resin such as sulpho hydroxide solution for 30 minutes to two hours. Alter nated polystyrene beads cross-linked with 8% divinyl natively, the second OR group is removed by enzy 55 benzene or with an aqueous inorganic acid such as hy matic action by incubation in the presence of a snake drochloric acid. Where each of Z' and Z' represents venom phosphodiesterase such as that present in the the gf oup venom of Crotaletts a claimanteus and the like. Where / > each of Z' and Z' represents the group OR in which N R’ is a lower alkenyl or aryl group, more specifically an 60 allyl group, a benzyl group or a substituted benzyl or NR'R'', the piperidyl groups or the dialkylamino group, the allyl, benzyl or substituted benzyl groups are groups are removed by aqueous hydrolysis with an removed by hydrogenolysis at room temperature over acidic ion-exchange resin in the acid form or with an a palladium on an inert support catalyst such as a aqueous inorganic acid such as aqueous hydrochloric palladium-on-barium sulfate catalyst under a slight pos 65 acid. itive pressure of hydrogen for a period of about 2 to 6 Alternatively, removal of the Z'' and Z' groups can hours. Where each of Z' and Z' represents the group be effected by one of the procedures described herein 3,878, 194 16 above prior to the catalytic hydrogenation or clinicle reduction procedure, is described hereinabove, to ob EXAMPLE tain the nucleoside 6'-phosphonic acids. To a mixture of 7.14 g. (20 mmoles) of methyltri The novel phosphorylated phosphonium ylids of the phenylphosphonium bromide in 100 ml. of ether, present invention are versatile reagents useful in con 5 cooled to 20°C and under a nitrogen atmosphere, is verting carbonyl compounds into phosphonates, free added 2.6 ml of a 1.6M solution of n-butyl lithium in phosphonic acids or phosphonic acid salts. They are hexane (20 mmoles). The mixture is allowed to stand useful as in termediates in the preparation of, for exam at 20°C for additional a hour, at which time a yellow ple, insecticides, herbicides, oil additives, cetergents, solution of methylene triphenylphosphorane is present. lubricant and oil additives, flame retardants, anti () To this mixture is then added dropwise a solution of oxidants and nucleoside phosphonates, phosphonic 2.68 g. ( () mmoles) of diphenyl phosphorochloridate acids and phosphonic acid salts. Insecticicles such as in 50 ml. of ether over a period of 5 minutes, and the the alkyl p-nitrophenylalkylphosphonates and thioan resulting reaction mixture is allowed to stand for a pe alogs thereof can be prepared by condensing acetalde riod of 15 minutes. The reaction mixture is then ex hyde, propanal, butanal, and the like, with the appro 15 tracted with two 100 ml. portions of 3N hydrochloric priately substituted phosphorylated phosphonium ylid, acid. The combined acid extracts are washed with namely wherein Y is oxygen or sulfur, Z is O-ethyl and ether, and then carefully neutralized by the dropwise Z' is O-p-nitrophenyl, followed by reducing the inter addition of 4N aqueous sodium hydroxide to afford a mediary cy, g-unsaturated phosphonate or thiophos precipitate. The precipitate is collected by filtration, phonate by the diimide reduction. Herbicides such as washed with water and then hexane to yield diphenyl the diesters of octylphosphonic acid can be prepared triphenylphosphoranylidenemethylphosphonate which by condensing heptanal with the appropriately substi is further purified by recrystallization from ethyl aceta tuted phosphorylated phosphonium ylid, namely te:hexane. wherein Y is oxygen and each of Z and Z is the group In a similar manner by repeating the above procedure OR in which R is lower alkyl, aryl or substituted aryl with one exception, namely substituting first methyldi followed by catalytic hydrogenation or diimide reduc phenyl-t-butylphosphonium bromide, second tetrame tion of the intermediary a f3-unsaturated phosphonate. thylphosphonium bromide, third methyltricyclohexyl Oil additives such as the dialkylstyrylphosphonates can phosphonium bromide, and fourth dimethyldiphenyl be prepared by condensing benzaldehyde with the ap phosphonium bromide for methyltriphenylphos propriately substituted phosphorylated phosphonium 30 phonium bromide, there are generated in situ the cor ylid, namely wherein Y is oxygen and each of Z' and Z' responding intermediary monosubstituted phospho is the group OR in which R is lower alkyl. The nucleo nium ylids first methylened phenyl-t- side 6'-phosphonic acids prepared according to the butylphosphorane, second methylenetrimethylphos process of this invention and derivatives prepared phorane, third methylenetricyclohexylphosphorane, there from are isosteric with the natural nucleoside 5'- 35 and fourth methylenemethyldiphenylphosphorane for phosphates and derivatives thereof and can be used in methylene triphenylphosphorane in the above proce the same manner as and as a replacement for the latter dure, and there are obtained the corresponding di compounds. The nucleoside 6'-phosphonic acids and phenyl phosphoranylidenemethylphosphonates, derivatives thereof differ from the known nucleoside namely first diphenyl diphenyl-t- 5'-phosphates and derivatives thereof in that the for 40 butylphosphoranylidenemethylphosphonate, second mer contains a P-CH-C group in place of the natu diphenyl trimethylphosphoranylidenemethylphosphon ral P-O-C group, thereby conferring greater meta ate, third diphenyl tricyclohexylphosphoranylideneme bolic stability to the former. The nucleoside 6'- thylphosphonate, and fourth diphenyl methyldiphenyl phosphonic acids and derivatives thereof are not sensi phosphoranylidenemethylphosphonate. tive to cell wall phosphatase and hence are not cleaved 45 into the parent materials during entrance into the cell. EXAMPLE 2 The nucleoside 6'-phosphonic acids and derivatives To a mixture of 1.78 g. of methyltriphenylphos thereof are also useful intermediates for the prepara phonium bromide in 25 ml. of ether, cooled to 20°C tion of cyclic 3',6'-phosphonates. This conversion can and under a nitrogen atmosphere, is added 3.10 ml. of be accomplished by treating the nucleoside 6"- l.6M solution of n-butyl lithium in hexane. The mix phosphonic acid with a dehydrating agent, e.g. a carbo ture is allowed to stand at 20°C for an additional 4 diimide such as N.N'-dicyclohexylcarbodimide, hour, at which time a yellow solution of methylenetri N,N'-di-p-tolylcarbodiimide, and the like in a basic sol phenylphosphorane is present. To this mixture is then vent such as pyridine according to the procedure of added dropwise a solution of 0.74 g. of di-o-tolyl phos Smith et al., J. An. Chen. Soc., 83, 698, (1961); U.S. 55 phorochloridate in 10 ml. of cther, and the resulting re Pat. No. 3,300,479, French 2883M ( 1964); or French action mixture is allowed to stand at room temperature 3249M (1965). The cyclic 3',6'-phosphonates can be for a period of 15 minutes. The reaction mixture is then used in the same manner as and as a replacement for partitioned between 50 ml. of water and 50 ml. of ben nucleoside cyclic 3',5'-phosphonates such as adenosine Zene. The aqueous layer is separated and extracted 3',5'-cyclic phosphate which are useful, for example, with several portions of benzene. Then the combined for the control of steroid production, the treatment of organic phase and extracts are washed with water and hypotension and as vasodilators. The cyclic 3',6'- dried over magnesium sulfate. After removing the mag phosphonates being much less susceptible to hydrolysis nesium sulfate by filtration, the organic phase is evapo than are the cyclic 3',5'-phosphates have the advantage rated to dryness under reduced pressure to afford a col of a longer biological half life. orless oil. The oil is recrystallized from ethyl acetate:- The following examples are set forth to illustrate the hexane to afford di-o-tolyl triphenylphosphoranyliden present invention. emethylphosphonate as a white crystalline solid. 3,878,194 17 In a similar manner by repeating the above procedure -Continued with one exception, namely substituting first di-m-tolyl Phosphonium Salts Phosphorylating Pructs phosphorochloridate, second di-p-tolyl phosphoro Agents chloridate, and third di-3,5-xylyl phosphorochloridate methyltriphenyl- tetra-(p-nitro- di-(p-nitro phosphonium hronicle phenyl) pyrophosphate phenyl) tri for the di-o-tolyl phosphorochloridate in the above pro phenylphosphor cedure, there are obtained the corresponding lilryl tri any idcnemethyl phenylphosphoranylidenemethylphosphonates, namely phosphonate di-m-tolyl triphenylphosphoranyliciencmethylphos methyltriphenyl dihenvy phosphor)- dibenwyl tri phosphonium hronicle chloridate phenylphosphor phonate, di-p-tolyl triphenylphosphoranylidenemethyl any idencmethyl phosphonate and di-3.5-xylyl triphenyl phosphornyi () phosphonate methyltriphenyl di-(p-bromohenzyl) Ji-p-hromo denemethylphosphosphonate, respectively. phosphonium bromile phosphorochloridate benzyl) triphenyl phosphoranylilene methylphosphonate EXAMPLE 3 methyltriphenyl diphenyl phosphoto dipheny tri phosphonium bromile chlorid thicate phenylphospher 15 any lidlene methyl To 00 ml of anhydrous liquid ammonia, previously thiophosphonate cooled in a Dry Ice-acetone bath and under an inert at methyltriphenyi di-(p-nitrobenzyl) li-p-nitro mosphere of argon, are added ().5 g. of metallic sodium phosphonium bromile phosphorochloridate benzyl) triphenyl phosphoranylidene and a few grains of ferric nitrate, and the resulting mix methylphosphonate ture is allowed to stir until it turns grey. Then 3.57 g. methyltriphenyi- o-phenylene phos- o-phenylene tri phosphonium bromide phorobromidate phenylphosphor ( 10 mmoles) of methyltriphenylphosphonium bromide anylidlene methyl is added to the mixture. After stirring the mixture for phosphonate 15 minutes, the ammonia is removed by evaporation methyltriphenyl 2,2-dimethyltri 2,2-dimethyltri phosphonium hromile methylene phosphort methylene tri leaving behind a residue. To this residue is then added chloridate phenylphosphor. 100 ml, of anhydrous tetrahydrofuran, and the result any idenennethyl. ing mixture is held at reflux for 20 minutes to expell any 2 5 ph sphate residual ammonia, then cooled and filtered through a sintered glass filter of medium porosity. To the filtrate EXAMPLE 4 is then added 1.34 g (5 mmoles) of diphenyl phos phorochloridate and this mixture is then held at room To 00 ml. of anhydrous liquid ammonia, previously temperature for a period of 30 minutes. The reaction cooled in a Dry Ice-acetone bath and under an inert at mixture is then filtered and the filtrate evaporated to mosphere of argon, are added 0.5 g. of metallic sodium dryness to yield diphenyl triphenylphosphoranylidene and a few grains of ferric nitrate, and the resulting mix ture is allowed to stir until it turns grey. Then 3.57 g. methylphosphonate which is further purified by recrys ( 10 mmoles) of methyltriphenylphosphonium bromide tallization from ethyl acetate:hexane. is added to the mixture. After stirring the mixture for In a similar manner by repeating the above procedure 15 minutes, the ammonia is removed by evaporation with the phosphonium salts and phosphorylating agents leaving behind a residue. To this residue is then added indicated in the table, there are obtained the following 100 ml. of anhydrous tetrahydrofuran, and the result products: ing mixture is held at reflux for 20 minutes to expell any 4) residual ammonia, then cooled and filtered through a sintered glass filter of medium porosity. To the filtrate Phosphonium Salts Phosphorylating Priucts is then added 1.27 g. (5 mmoles) of phosphorodimor Agents pholidic chloride and this mixture is then held at 40°C ethyltriphenylphs (Jiphenylphosphorty- diphenyl -tri for a period of 1 hour. The reaction mixture is then fil phonium bronicle chittilite phenylphosphor 45 tered and the filtrate evaporated to dryness to yield tri anylidenelethyl phosphonate phenylphosphoranylidenemethylphosphonodimor methyltriphenylphos diethyl phosphort diethyl tri pholidate which is further purified by recrystallization phonium bromicle chloridate phenylphosphor anylidenemethyl from ethyl acetate: hexane. phosphinate In a similar manner by repeating the above procedure dimethyldiphenyl diethyl phosphoro diethyl methyldi with the phosphonium salts and phosphorylating agents phosphonium bronicle chloridate phenylphosphor any idenemethyl indicated in the table, there are obtained the following phosphonate products: Phosphonium Salts Phosphorylating Products Agents methyltriphenylphos phosphorodimorpho- triphenylphosphor phonium bromide idic bromide anylidenemethylphos phonodimorpholidate methyltriphenylphos diethyl phosphoro diethyl triphenyl phonium bromide chiotidothioate phosphoranylidene methylthiophosphonate methyltriphenylphos N,N'-dimethylphos triphenylphosphor phonium bromide phorodianalidic any idenemethylphos chloride phonodi(N-methyl anilidate) methyltriphenylphos O,O-diphenyl phos diphenyl triphenyl phonium bromide phorochloridothio phosphoranylidene ate methylthiophosphonate tetramethylphosphonium O,O-diphenyl phos diphenyl trimethyl bromide phorochloridothio phosphoranylidene ae methylthiophosphonate methyltri-n-butyl phosphorodimorpho tri-n-butylphosphor phosphonium bromide lidic bromide anylidenemethylphos phonodimorpholidate 3,878, 194 19 20 EXAMPLE S EXAMPLE 7 To a solution of 2.84 g. ( () mnoles) of 2',3'-O- isopropylideneuricline in 25 ml. of anhydrous dimethyl sulfoxide are added 6.2 g. (30 mmoles) of dicyclohex To 100 ml of anhydrous liquid ammonia, previously 5 cooled in a Dry lice-acetone bath and under an inert at ylcarbodiimide. (), 8 ml. ( 10 mmoles) of pyridine and mosphere of arguin, are added 0.5 g. of metallic sectium ().4 ml. (5 mmoles) of trifluoroacetic acid. The result ing Solution is allowed to stand at 25°C for 6 hours, dur and a few grains of ferric nitrate, and the resulting mix ing which time dicyclohexylure a precipitates from the ture is allowed to stir until it turns grey. Then 4.34 g. solution. At the end of the reaction, dicyclohexylu rea ( i () mmoles) of benzyltriphenylphosphonium bronhide () is removed by filtration and washed with several por is added to the mixture. After stirring the mixture for tions of fresh, anhydrous dimethyl sulfoxide. To the 15 minutes, the ammonia is removed by evaporation combined filtrate and washings, is added 5.08 g. ( () leaving behind a residue. To this residue is then added mnoles) of diphenyl triphenylphosphoruny licleneme 100 ml. of anhydrous tetrahydrofuran, and the result thylphosphonate, and the resulting mixture is allowed ing mixture is held at reflux for 20 minutes to expell any to stand at 37°C for 6 hours. At this point, 200 ml. of residual ammonia, then cooled and filtered through a ethyl alcetate is added, and the organic phase is washed sintered glass filter of medium porosity. To the filtrate with three 100 ml. portions of water, dried, filtered, is then accled 1.34 g. (5 mm les) of ciphenyl phos and evaporated under reduced pressure to afford a pale phorochloridate and this mixture is then held at 65°C yellow oil. A solution of the thus-obtained oil in chloro for a period of 2 hours. The reaction mixture is then fil 2 form is chromatographed on eight meter X 20 cm. tered and the filtrate evaporated to dryness to yield di glass plates coated with a 1.3 mm. layer of silicic acid. phenyl triphenylphosphoranylidenebenzylphosphonate After development of the plates with ethyl acetate, two which is further purified by recrystallization from ethyl ultraviolet absorbing products are eluted from the acette: hexane. plates with ethyl acetate. After removing the solvent from the faster moving product, there is obtained di phenyl -(5,6-dideoxy-2,3-O-isopropylidene-g-D- in a similar manner by repeating the above procedure ribo-hex-5-enofuranosyl)uracit 6'-phosphonate which with the phosphonium Salts and phosphorylating agents is purified by recrystallization from aqueous ethanol. indicated in the table, there are obtained the following After removing the solvent from the slower moving proclucts. 3. product, there is obtained triphenylphosphine oxide.

Phosphonium Salts Phosphorylating Products Agents benzyltriphenyl- diethyl phosphoro- diethyl triphenyl phosphonium bromide chloriciate phosphoranyl idene benzylphosphonate benzyldimethylphenyl diphenyi phos- diphenyl dimethyl phosphonium bromide phorochloridate phenylphosphoranyl idenebenzylphosphonate p-nitrobenzyl tri- diphenyl phos- diphenyl triphenyl phenylphosphonium photochloridothio- phosphoranylidlene bronicle ae p-nitrobenzylthio phosphonate benzyltricyclohexyl- di-p-tolyl phos- di-p-tolyl tri phosphonium bromide pharochloridate cyclohexylphos phoranylidenebenzyl phosphonate

EXAMPLE 6 in a similar manner by repeating the above procedure 50 with two exceptions, namely substituting a molar amount of each of 2',3'-O-isopropylideneadenosine A mixture of 0.36 g. ( mmole) of 2',3'-O- and diethyl triphenylphosphoranylidenemethylphos anisylide neuricline-5'-aldehyde prepared in accor phonate for 2',3'-O-isopropylicleneuridine and di dance with U.S. Pat. No. 3.248,380 and ().508 g. ( ! phenyl triphenylphosphoranylidene methylphosphon nnnnole) of uliphenyl triphenylphosphoranyl idenenne ate, respectively, there is obtained the corresponding thylphosphonate in 10 ml of tetrahydrofuran is al product, namely diethyl (9-(5,6-dideoxy-2,3-O- lowed to stand at 37°C for a period of 16 hours. The re isopropy idenef3-D-ribo-hex-5-enofuranosyl)adenine action mixture is then chromatographed on a 1 meter 6'-phosphonate. X 21 cm. glass plate coated with a 1.3 mm. layer of Si licic acid. After development of the plate in the Solvent () mixture, is propanol: chloroform 9). the main ultra EXAMPLE 8 violet absorhing hand (Rf ().5) is eluted with acetone. A solution of 512 mg. ( 1 mmole) of diphenyl ( 1-(5,6- After removing the solvent by evaporation under re dicleoxy-2,3-O-isopropylidene-p3-D-ribo-hex-5- (Euced pressure, there is obtained diphenyl l-(2,3-O- enofuranosyl)-uraci 6'-phosphonate in 3() m. of anisylidene 5,6-dideoxy-3-D-ribo-hex-5- 65 methanol is hydrogenated at 20°C in the presence of enofuranosyl)uracil 6'-phosphonate as a white, homo 0.2 g of a pre-reduced 5% palladiumon-barium sulfate geneous foam. catalyst and under a slight positive pressure of hydro 3,878, 194 21 22 gen for two hours, at which time, the uptake of hydro teus venom in 0.5M tris(hydroxymethyl)aminome gen reached the theoretical value. The catalyst is re thane buffer at pH 8, 40pu 1, of a 1M tris(hdyroxyme moved by filtration through diatomaceous earth and thyl)aminoethane buffer at pH 8, is incubated at 37°C washed with methanol. The combined filtrate and for 24 hours. After this reaction time, the incubation washings are evaporated to dryness under reduced mixture is then diluted with 25 ml. of water and chro pressure to yield diphenyl ( -(5,6-dideoxy-2,3-O- matographed on a 1.5 X 20 cm. column containing 25 isopropylidene-g-D-ribo-hexofuranosyl)uracil 6'- g. of diethylaminoethyl cellulose in the bicarbonate phosphonate is a white foam. form. The column is washed with 200 ml of water and In a similar manner by repeating the above procedure then eluted with a linear gradient ((), ()()2 -0.2M) of with one exception, namely substituting a molar aqueous triethylammonium bicarbonate at pH 7.5. The amount of diethyl (9-(5,6-dideoxy-2,3-O- main ultraViolet absorbing peak is collected an evapo isopropylidene-g-ribo-hex-5-enofuranosyl)-adenine) rated to dryness under reduced pressure to yield the 6'-phosphonate for diphenyl 1-(5,6-dideoxy-2,3-O- histriethylammonium salt of 1-(5.6-dideoxy-g-D-ribo isopropylidene-3-D-ribo-hex-5-enofuranosy uracil hexofuranosyl)uracil 6-phosphonic acic. 6'-phosphonate, there is obtained the corresponding 5. product, namely diethyl (9-(5,6-dideoxy-2,3-O- EXAMPLE 2 isopropylidlene-3-D-ribo-hexofuranosyl)adenine 6'- By repeating the procedure of Example 7 with two phosphonate. exceptions, namely substituting 3'-O-acetylthymidine and dibenzyl triphenylphosphoranylidenemethylphos EXAMPLE 9 phonate for 2',3'-O-isopropylideneuricline and di A solution of 0.50 g. of diphenyl 1-(5,6-dideoxy-2,3- phenyl triphenylphosphoranylidenemethylphosphon O-isopropylidene-f3-D-ribo-hexofuranosyl)uracil 6'- ate, respectively, there is obtained dibenzyl 1-(3-O- phosphonate in 20 ml. of 80% acetic acid is heated at acetyl-2,5,6-trideoxy-g-D-erythro-hex-5- 100°C for 2 hours. The solvent is then removed by enufuranosyl) thymine 6'-phosphonate. evaporation under reduced pressure to yield a residue of diphenyl 1-(5,6-dideoxy-g-D-ribo EXAMPLE 3 hexofuranosyl)u racil 6'-phosphonate which is purified A solution of 0.54 g. of dibenzyl ( - 3-O-acetyl by repeated dissolution and evaporation from several 2,5,6-trideoxy-6-D-erythro-hex-5- quantities of ethanol. enofuranosyl)thymine 6'-phosphonate in 25 ml. of In a similar manner by repeating the above procedure methanol is reduced at 25°C in the presence of 200 mg. with one exception, namely substituting diethyl 9 of a pre-reduced 5% palladium-on-barium sulfate cata (5,6-dideoxy 2,3-O-isopropylidene-3-D-ribo lyst and under a slight positive pressure of hydrogen for hexofuranosyl)adenine 6'-phosphonate for diphenyl a period of three hours. The catalyst is removed by fil 1-(5,6-dideoxy-2,3-O-isopropylidene-g-D-ribo tration through diatomaceous earth, and washed with hexofuranosyl)u racil 6'-phosphonate, there is ob 35 methanol. The combined filtrate and washings are tained the corresponding product, namely diethyl (9- evaporated to dryness under reduced pressure to yield (5,6-dideoxy-6-D-ribo-hexofuranosyl)adenine) 6'- 1-(3-O-acetyl-2,5,6-tricleoxy-3-D- phosphonate. erythrohexofuranosyl)thymine 6'-phosphonic acid. A solution of the 0.5 g. of the latter material in 5 ml. EXAMPLE () 40 of concentrated ammonium hydroxide is held at 25°C To a solution of 119 mg. (0.25 mmole) of diphenyl for a period of 30 minutes. After removing the solvent - 5,6-dideoxy-3-D-ribo-hexofuranosyl)uracil) 6'- by evaporation under reduced pressure, the residue is phosphonate in () ml. of dioxane and 10 ml. of water chromatographed on a 3.0 x 30 cm. column of diethyl is added 1 m. of 1N aqueous solution of lithium hy aminoethyl cellulose in the bicarbonate form. The col droxide. The resulting solution is allowed to stand at 45 umn is washed with 250 ml. of water and then eluted 20°C for 1 hour at which time the pH of the solution is with a linear gradient (0.002-0.2M) of aqueous trie adjusted to 7 by the addition of an acid-ion exchange thylammonium bicarbonate at pH 7.5. The major ultra resin. After removing the resin by filtration, the filtrate violet absorbing peak is collected and evaporated to is reduced to dryness under reduced pressure to afford dryness under reduced pressure to yield the bistrie a residue. A solution of the thus-obtained residue in 10 thylammonium salt of 1-(2,5,6-trideoxy-(3-D-erythro ml. of water is chromatographed on a 1 meter X 20 cm. hexofuranosyl)thymine 6'-phosphonic acid. glass plate coated with a 1.3 mm. layer of microcystal line cellulose. After developing the plates in the solvent EXAMPLE 14 mixture, isopropanol:ammonium hydroxide: water A mixture of 1.76 g. of diethyl (9-(5,6-dideoxy-2,3- (7: 1:2), the ultraviolet absorbing material, having an O-isopropylidene-g-D-ribohexofuranosyl)adenine 6'- RF value of 0.5 to 0.6, is eluted with water. After re phosphonate and 1.8 g. of sodium iodide in 10 ml. of moval of the water by evaporation under reduced pres dimethylformamide is heated at 150°C for 20 hours. sure, there is obtained phenyl l (5,6-dideoxy-3-D- After cooling the reaction mixture, there is added 50 ribo-hexofuranosyl)-uracil 6'-phosphonic acid as a ml. of acetone. The resulting precipitate is collected chromatograpically homogeneous foam. 60 and washed with several portions of acetone. The pre cipitate is then dissolved in water and passed through EXAMPLE a column containing the free acid-form of an ion One milliliter of a solution containing 40 mg. (0.1 exchange resin. The thus-obtained acidic eluate is con mnole) of phenyl f 1-(5,6-dideoxy-g-D-ribo centrated under reduced pressure to one-half the origi hexofuranosyl)uracil 6'-phosphonic acid, 60pul, of 65 nal volume and then heated at 100°C for 4 hours to give 0.01 M aqueous magnesium chloride, 40p. i. of a solu an aqueous solution of 9-(5,6-dideoxy-g-D-ribo tion containing 10 mg/ml. of crude Crotaleus adaman hexofuranosyl)adenine 6'-phosphonic acid. For puri 3,878, 194 23 24 fication, if desired, the pH of the eluate is adjusted to pyridine is added 54 g. of glacial acetic acid (90 8.5 with aqueous Sodium hydroxide Solution and the mmole). The yellow suspension is stirred under anhy resulting mixture is chromatographed on a 4.0 x 40 cm. drous conditions in an argon atomosphere for 24 hours column of diethylaminoethyl cellulose in the bicarbon and then the pyridine is removed by evaporation under ate form using a linear graclient (()()()2 to ().2M) of trie 5 reduced pressure. The yellow residue is partitioned be thylammonium bicarbonate as eluant to afford the bis tween water (25 () ml.) and ethyl acetate (250 ml.) and triethylaminonium salt of 9-(5,6-dideo Xy-p3-D-ribo the water phase is further extracted with ethyl acetate hexofuranosyl)adenine 6'-phosphonic acid. 2 X 250 ml.). The organic phase are combined, An aqueous solution of the latter compound is passed washed with water (500), dried over magnesium sul through a column of cation-exchange resin in the acid () filte. filtered and evaporated to dryness to give a pale form, and th pH of the eluate is adjusted to 8.5 hy the yellow foam. This is dissolved in about 20 ml of hot dropwise addition of aqueous soclium hydroxide solu henzene and on cooling deposits white crystals which tion, The eluate is then concentrated to a volume of ap are collected to give diphenyl (9-( 5,6-diodeoxy-2,3-o- proximately 10 ml., and added to 5 () nn. (facetone to isopropylidene-g-D-ribo-hexofuranosyl)adenine 6'- yield the disodium salt of 9-(5,6-clideoxy-3-D-ribo 15 phosphonate. hexofuranosyl)ale nine 6'-phosphonic acid as a white powder. EXAMPLE 9 A solution of 5.14 g. ( 10 mmole} of diphenyl 1-(5,6- EXAMPLE 5 dideoxy-2,3-O-isopropylidene-- To a mixture of 5 2 mg. ( 1 mmole) of diphenyl 1 2) -D-ribo-hexofuranosyl)uracil) 6'-phosphonate in 50 (5,6-dideoxy-2,3-O-isopropylidene-g-D-ribo-hex-5- ml. of dimethylsulfoxide is added rapidly at room tem enofuranosyl)uracil 6'-phosphonate, 500 mg. of po perature to a solution of 2.0 g. (42 mmoles) of sodiuim tassium azodicarboxylate in 20 ml. of methanol, is hydride (50% dispersion in mineral oil) in 20 ml, each ldced dropwise 300 mg. of glacial acetic acid, and the of benzyl alcohol and climethyl sulfoxide. After 5 min rection mixture is held at room temperature for a pe utes, the slightly yellow solution is poured into 250 ml. riod of 24 hours. After this reaction time, the mixture of water containing 3 nil. of glacial acetic acid. The re is evaporated to dryness under reduced pressure and sulting suspension is extracted with ethyl acetate (3 x the residue partitioned between 50 ml of ethyl acetate 200 ml.) and the combined extracts are washed with and 5 () ml. of water. The aqueous layer is separated and aqueous sodium bicarbonate and then water. The or extracted with several portions of ethyl acetate. The 3 () ganic phase is then dried over magnesium sulfate, fil combineti ethyl cetate layer and extracts are dried tered and evaporated to dryness to give a pale yellow (ver magnesium sulfate, evaporated to dryness under oil. A solution of this oil is chloroform (25 ml.) is then reduced pressure to yield cliphenyl 1-(5,6-dideoxy applied to the top of a silica gel column (35 x 4.5 cm.), 2,3-O-isopropylidene-p3-D-ribo-hexofuranosyl)uracil Development of the column with 1250 ml. chloroform 6'-phosphonate. 35 and 650 ml. of ethyl acetate followed by elution with In a similar manner, by repeating the procedures of 1000 ml. 10% methanol in ethyl acetate gives dibenzyl Examples 9, () and 11, the latter material is converted 1-(5,6-dideoxy-2,3-O-isopropylidene-g-D-ribo to the his triethylammonium sult of 1-(5,6-dideoxy-g- hexofuranosyl)uracil 6'-phosphonate. D-ribo-hexofuranosyl)uracil 6'-phosphonic acid. EXAMPLE 20 EXAMPLE 16 A solution of 4.52 g. of dibenzyl 1-(5,6-dideoxy-2,3- A mixture of 92.7 g of triphenylphosphine and ()(). O-isopropylidene-g-D-ribo-hexofuranosyl)uracil 6'- g. diphenyl chloromethylphosphonate is heated at 175 phosphonate in 100 ml. of methanol is added to a pre for 32 hours. The resultant solid mass is dissolved in reduced suspension of 2 g. of 5% palladium-on-barium about 7()() m. water and about 500 m. ether and the sulfate in 100 ml. of methanol. The resultant mixture phases are separated. The ether layer is further ex is stirred at room temperature under 1 atmosphere of tracted with about 250 ml, water. The combined acque hydrogen for 50 minutes at which time the theoretical ous phases are hrought to pH 8 by the cautious addition volume of hydrogen has been consumed. The catalyst of () N sodium hydroxide and the precipitate removed is removed by filtration through diatomaceous earth by filtration and dried to give diphenyl triphenylphosp and the combined filtrate and washings are evaporated horanylidene methylphosphonate which is crystallized to dryness to yield a white foam which is redissolved in from ethyl acetate. 50 ml. of water. The aqueous solution is passed down an acid ion-exchange columne (2.5 X 20 cm.) which is EXAMPLE 7 washed with Water. The first 225 ml. of column eluant A solution of 508 mg. of diphenyl triphenylphosphor is heated at 100°C for 1 hour and then evaporated to anyl idenemethylphosphonate in 10 ml. of methanol is dryness under reduced pressure. The residue is reevap heated under reflux for 3() minutes. Removal of the orated several times from methanol solution and is then methanol by evaporation under reduced pressure gives dissolved in 50 ml. of hot ethanol. The solution on cool a residual syrup which is crystallized from a mixture of ing deposits a white microcrystalline solid to yield ( - ethyl acetate and hexane to give dimethyl triphenylph 6) (5,6-dideoxy-g-D-ribo-hexofuranosyl)uracil) 6'- osphorny idenemethylphosphonate. phosphonic acid. EXAMPLE | 8 EXAMPLE 2 To a stirred mixture of 4.82 g. (9mmole) of diphenyl The proces of Example 7 is repeated using an equiv (9-(5,6-dideoxy-2,3-O-isopropylidene-g-D-ribo-hex-5- 65 alent amount of 1-(N4,O'-3'-tribenzoyl-g-D- enofuranosyl)adenine 6'-phosphonate and 9.0 g. of arabinofuranosyl) cytosine as the starting material and potassium azodicarboxylate (45 mmole) in 35 ml. of there is obtained diphenyl (1-(5,6-dideoxy N4, O2',3'

3,878,194 25 26 -tribenzoyl-g-D-arabino-hex-5- EXAMPLE 23 enofuranosyl)cylosine 6'-phosphonate. This conver The process of Example 19 is repeated with the ex sion can be illustrated as follows wherein B represents ception of using an equivalent amount of methanol in benzoyl and db is phenyl: place of benzyl alcohol and there is obtained dimethyl 1-(5,6-dideoxy-2,3-O-isopropylidene-3-D-ribo hexofuranosyl)uracil 6'-phosphonate. Similarly, by using ethanol there is obtained diethyl 1-(5,6-clideoxy-2,3-O-isopropylidene-(3-D-ribo hexofuranosyl)uracil) 6'-phosphonate. () By subjecting the above compounds to the dealkyla tion procedure of Example 14, there is obtained the di Sodium salt of 1-(5,6-dideoxy-6-D-ribo hexofuranosyl)uracil 6'-phosphonic acid. What is claimed is: 5 1. A process for preparing 5,6'-dideoxy-hex-5'- enonucleosides 6'-phosphonates, which comprises re acting a nucleoside 5'-aldehyde selected from the group having the formulas: O 2O (bo)P-CH=CH O= NN/ H O- R12 o=& R12 k'sOB and R13 |- -- Similarly, by using 1-(2',3'-di-O-benzoyl-g-D- R14 R13 R4' arabino-furanosyl) thymine and -(2',3'-di-o-benzoyl {3-D-arabinofuranosyl)uracil in the process of Example 7, there is obtained diphenyl ( 1-(5,6-dideoxy-2',3'-di wherein O-benzoyl-g-D-arabino-hex-5-enofuranosyl)thymine R' is selected from the group consisting of uracil 6'-phosphonate and diphenyl 1-(5,6-dideoxy-2',3'-di 1-yl, cytosin-1-yl, 4-chloro-1,2-dihydropyrimidin O-benzoyl-g-D-arabino-hex-5-enofuranosyl)uracil 6'- 2-on-1-yl, 5-bromouracil-1-yl, 5-hromocytosin phosphonate, respectively. 35 1-yl, 5-chlorouracil-1-yl, 5-chlorocytosin-1-yl. 5 By repeating the process of Example l8, the above iodouracil-l-yl, 5-iodocytosin-1-yl. 5-fluorouracil compounds are reduced to the corresponding arabino 1-yl, 5-fluorocytosin-1-yl, thymin-1-yl, 5 hexofuranosyl derivatives, that is, diphenyl 1-(5,6- methylcytosin-1-yl, 5-trifluoromethyluracil-1-yl, dideoxy-N,O' " -tribenzoyl-g-D-arabino 5-trifluoromethylcytosin-1-yl, 5-aminouracil-1-yl, hexofuranosyl)cytosine 6'-phosphonate, diphenyl l 40 5-aminocytosin-1-yl, 5-methylaminouracil-1-yl, 5 (5,6-dideoxy-2',3'-di-O-benzoyl-g-D-arabino methylaminocytosin-1-yl, 5-hydroxyuracil-1-yl, 6 hexofuranosyl)thymine 6 "phosphonate and diphenyl azauracil-l-yl. 6-azacytosin-1-yl, 4-chloro-6-aza 1-(5,6-dideoxy-2',3'-di-O-benzoyl-g-D-arabino 1,2-dihydropyrimidin-2-on-1-yl, 6-azathymin-1-yl, hexofuranosyl)uracil 6'-phosphonate which are sub hypoxanthin-9-yl. adenin-9-yl, 6 jected to the processes of Examples 19 and 20 to give 45 dimethylaminopurin-9-yl, 2-chloroadenin-9-yl, 6 1-(5,6-dideoxy-3-D-arabino-hexofuranosyl)cytosine chloropurin-9-yl, 6-mercaptopurin-9-yl, guanin 6'-phosphonic acid, -(5,6-dideoxy-6-D-arabino 9-yl, xanthin-9-yl, 2,6-dichloropurin-9-yl. 2,6- hexofuranosyl)thymine 6'-phosphonic acid and l bis(methylamino)purin-9-yl, 8-azaadenin-9-yl, 8 (5,6-dideoxy-g-D-arabino-hexofuranosyl)uracil) 6'- azaguanin-9-yl, and 7-deazaadenin-9-y; and phosphonic acid. 5) R', R'R'', and R'' are independently selected from the group of hydrogen, hydroxy, methoxy, acetoxy, and EXAMPLE 22 benzoyloxy, or The process of Example 9 is repeated using an R'' and R together form acetal, isopropylidenedioxy equivalent amount of diphenyl (9-(5,6-dideoxy-2,2-O- or p-anisylidenedioxy isopropylidene-g-D-ribo-hexofuranosyl)adenine 6'- with a phosphorylated ylid having the formula phosphonate and diphenyl 1-(3-O-acetyl-2.5,6- trideoxy-g-D-erythro-hexofuranosyl)thymine) 6'- phosphonate as the starting material and there is ob tained dibenzyl (9-(5,6-dideoxy-2,3-O-isopropylidene (3-D-ribo-hexofuranosyl)adenine 6'-phosphonate and dibenzyl I-(3-O-acetyl-2,5,6-trideoxy-6-D-erythro hexofuranosyl)thymine 6'-phosphonate, respectively, which are subjected to the process of Example 20 to wherein yield 9-(5,6-dideoxy-g-D-ribo R, R and R are independently selected from the hexofuranosyl)adenine 6'-phosphonic acid and - 65 group of lower alkyl having from 1 to 6 carbon (2.5,6-trideoxy-6-D-erythro-hexofuranosyl)thymine atoms, aryl having from 6 to 12 carbon atoms, or 6'-phosphonic acid, respectively. substituted aryl selected from the group of p 3,878,194 27 28 chlorobenzyl, p-bromobenzyl, 2,4,6- 9-yl, xanthin-9-yl, 2,6-dichloropurin-9-yl, 2,6- trichlorophenyl, p-nitrophenyl, p-nitrobenzyl, p bis(methylamino)purin-9-yl, 8-azaadenin-9-yl, 8 anisy, p-methoxybenzyl, und p azaguanin-9-yl, and 7-deazaadenin-9-y; and dimethylaminophenyl or R*, R', R', R'' are independently selected from the R", R and R* together are tri-N-piperidyl, tri-N- group of hydrogen, hydroxy, methoxy, acetoxy, and morpholinyl, or tricyclohexyl, and henzoyloxy, or Z''' and Z' are independently selected from the R'' and R together form acetal, isopropylidene group of -OR, -SR", dioxy or p-anisy idenedioxy; and Z' and Z' are each the group -OR wherein ^ -- () R is selected from the group of phenyl, toluoyl, -N -N O 2,4,6-trichlorophenyl, p-nitrophenyl, p Y Y-/ dimethylaminophenyl and naphthyl with an aryl alkyl primary alcohol selected from the or -NR'R'' in which group of benzyl alcohol or methylbenzyl alcohol in the R° and R" are independently selected from the group presence of a base selected from the group of alkaline of lower alkyl having from 1 to 6 carbon atoms. metal hydrides, alkali metals, alkali metal t-butoxies, lower alkenyl having from 2 to 6 carbon atoms, ary and triethylamine, in an aqueous dipolar organic sol having from 6 to 12 carbon atoms or substituted vent thereby yielding the corresponding diarylalkyl nu aryl as defined here in above, and cleoside 6'-phosphonate and hydrogenating said diary R" and R'' are independently lower alkyl having lalkyl nucleoside 6'-phosphonate in the presence of a from to 6 carbon atoms or hydrogenolysis catalyst under reactive conditions Z' and Z' together form the group thereby yielding the corresponding nucleosides 6'- phosphonic acid. O 3. The process according to claim 1 wherein each of Ype, Z' and Z' is the group OR in which R is phenyl:. / O 4. The process according to claim 3 wherein each of R. R. and R is phenyl. in which 5. The process according to claim 2 wherein said nu R" is arylene having from 6 to 12 carbon atoms: cleoside 6'-phosphonate is a diphenyl nucleoside 6'- in a substantially anhydrous non-reactive organic sol phosphonate, said alcohol is benzyl alcohol, said base vent under reactive conditions thereby forming the cor is an alkali metal hydride and said catalytic hydrogenol responding 5,6'-dideoxy-hex-5'-eno-nucleoside 6'- ysis is carried out with a palladium catalyst. phosphonate. 6. The process of claim 1 wherein said 5'-aldehyde 2. A process for preparing 6'-phosphonic acid nu nucleoside has the formula: cleosides which comprises reacting a 6'-phosphonite nucleoside selected from the group having the formulas O=CH O Ri2

4) k"> if O Z 1. O N N a P-CH, Hylos R: DP2CH-itl, o R' a k-) a 2 k > wherein . s R 45 R' is as defined in claim 1 and R'' and Rare each acetoxy or together form the group isopropylidenedioxy or p-anisylidenedioxy. 7. The process of claim 1 wherein said 5'-aldehyde wherein nucleoside has the formula: R' is selected from the group consisting of uracil l-yl, cytosin-1-yl. 4-chloro-1,2-dihydropyrimidin 2-on-1-yl. 5-bromouracil-1-yl, 5-bromocytosin 1-yl, 5-chlorourucil-1-yl, 5-chlorocytosin-1-yl, 5 OscCH Ri: iodcuracil-1-yl, 5-iodocytosin-1-yl, 5-fluorouracil 1-yl. 5-fluorocytosin-1-yl, thymin-1-yl, 5. 55 methylcytosin-1-yl, 5-trifluoromethyluracil-1-yl, ki> 5-trifluoromethylcytosin-1-yl, 5-aminou racil-l-yl, 5-aminocytosin-1-yl, 5-methylaminocytosin-1-yl, wherein 5-methylaminocytosin-l-yl, 5-hydroxyuracil-1-yl, R' is as defined in claim 1 and 6-azauracil-1-yl, 6-azacytosin-1-yl 4-chloro-6-aza O R'' and R'' are each benzoyloxy. 1,2-dihydropyrimidin-2-on-1-yl, 6-azathymin-1-yl, 8. The process of claim 1 wherein said reaction is hypoxanthin-9-yi, adenin-9-yl, 6 conducted at temperatures in the range of about from dimethylaminopurin-9-yi, 2-chloroadenin-9-yl, 6 25°C to the reflux temperature of said organic solvent. chloropurin-9-yl, 6-mercaptopurin-9-yl, guanin k sk : k