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              Name Sanilvudine;Stavudine;BMY-27857;d4T;DTH;ddeThd;Zerit
              Chemical Name 3-Deoxy-2-thymidinene
              CAS 3056-17-5
              Related CAS
              Formula C10H12N2O4
              Formula Weight 224.21814
              Stage 上市-1994
              Company Bristol-Myers Squibb (Originator), INSERM (Originator)
              Activity/Mechanism AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, Reverse Transcriptase Inhibitors
              Syn. Route 19
              Route 1
              1) the first method ever reported involves the mesylation of thymidine (i) to give dimesylate (ii), which is treated with sodium hydroxide in ethanol to yield oxetane (iii). finally, (iii) is converted to stavudine by means of potassium tert-butoxide in dmso.this process has been modified in order to obtain large quantities or to obtain [2-14c]-stavudine starting from [2-14c]-thymidine.2) a second closely related method, but using a different protecting group strategy, involves tritylation of the primary hydroxyl group of thymidine to give (iva), which is then mesylated to give (va). elimination with tbaf/thf or t-buok/dmso yields compound (vi), which is finally deprotected with acetic acid.3) a third synthesis starting from thymidine involves its protection with monomethoxytrityl chloride or picolyl chloride to give (ivb) or (ivc), respectively, which are mesylated to give (vb) or (vc). these are treated with phenyl diselenide and lithium aluminum hydride in tetrahydrofuran to yield compounds (viib) or (viic), which are treated with m-chloroperbenzoic acid in dichloromethane to afford (viiib) or (viiic). finally, (viiib) is deprotected with methylamine in water and (viiic) is deprotected with acetic acid.
              List of intermediates No.
              n-(3-aminopropyl)-n-methyltetrahydro-2-furancarboxamide (i)
              2-(3-benzoylphenyl)propionic acid (iva)
              3-[(4-oxopentanoyl)oxy]-2-phenylpropionic acid (ii)
              2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1h-indol-3-yl]-1-(1h-imidazol-1-yl)-1-ethanone (iii)
              (2r,3s,4s,5r,6s)-2-(aminomethyl)-6-methoxytetrahydro-2h-pyran-3,4,5-triol (ivb)
              2-nitrophenyl 1-(2-chloroethyl)-2-oxo-1-hydrazinecarboxylate (ivc)
              n-(2-chloroethyl)-n-[[(2r,3s,4s,5r,6s)-3,4,5-trihydroxy-6-methoxytetrahydro-2h-pyran-2-yl]methyl]urea (va)
              10-methoxy-5h-dibenzo[b,f]azepine (vb)
              10-methoxy-5h-dibenzo[b,f]azepine-5-carbonyl chloride (vc)
              10-methoxy-5h-dibenzo[b,f]azepine-5-carboxamide (via)
              5-cyano-5h-dibenzo[b,f]azepine (viib)
              5-cyano-10-nitro-5h-dibenzo[b,f]azepine (viic)
              ethyl (e)-3-(2-bromophenyl)-2-propenoate (viiib)
              (e)-3-(2-bromophenyl)-2-propen-1-ol (viiic)
              Reference 1:
                  martin, j.c.; hitchcock, m.j.m.; starrett, j.e. jr.; ghazzouli, i.; mansuri, m.m.; ho, h.-t.; sommadossi, j.-p.; brankovan, v.; synthesis, anti-hiv activity, and biological properties of 2,3-didehydro-2,3-dideoxythymidine (d4t). nucleosides nucleotides 1989, 32, 461-6.
              Reference 2:
                  starret, j.e. jr.; mansuri, m.m.; martin, j.c.; fuller, c.e.; howell, h.g. (bristol-myers squibb co.); production of 2,3-dideoxy-2,3-didehydronucleosides. ep 0334368 .
              Reference 3:
                  lin, t.-s.; prusoff, w.h. (yale university); pharmaceutical compsn. comprising 3-deoxythymidin-2-ene (3-deoxy-2,3-didehydrothymidine) in treating patients infected with retrovirus. ep 0273277 .
              Reference 4:
                  mansuri, m.m.; ghazzouli, i.; starrett, j.e. jr.; hitchcock, m.j.; sterzycki, r.z.; brankovan, v.; lin, t.s.; august, e.m.; prusoff, w.h.; sommadossi, j.p.; et al.; 1-(2,3-dideoxy-beta-d-glycero-pent-2-enofuranosyl)thymine. a highly potent and selective anti-hiv agent. j med chem 1989, 32, 2, 461-6.
              Reference 5:
                  lin, t.-s.; gao, y.-s.; august, e.m.; prusoff, w.h.; qian, h.-y.; synthesis of [2-14c]3-deoxythymidin-2-ene (d4t) and [5-125i]3-azido-2,3-dideoxy-5-iodouridine: potent inhibitors of human immunodeficiency virus (hiv-1). j label compd radiopharm 1989, 27, 6, 669-74.
              Reference 6:
                  da rooge, m.a.; noel, m.; horwitz, j.p.; chua, j.; klundt, i.l.; nucleosides. ix. the formation of 2,3-unsaturated pyrimidine nucleosides via a novel beta-elimination reaction. j org chem 1966, 31, 205-11.
              Reference 7:
                  chattopadhyaya, j.; agback, p.; vial, j.m.; a new synthesis of 1-(2,3-dideoxy-beta-d-glycero-pent-2-enofuranosyl)-thymine. a highly potent and selective anti-hiv agent. nucleosides nucleotides 1990, 9, 2, 245-58.
              Reference 8:
                  baba, m.; de clercq, e.; pauwels, r.; herdewijn, p.; balzarini, j.; vanderhaeghe, h.; broder, s.; 3-substituted 2,3-dideoxynucleoside analogues as potential anti-hiv (htlv-iii/lav) agents. j med chem 1987, 30, 8, 1270-8.
              Reference 9:
                  robinson, c.; castaner, j.; stavudine. drugs fut 1994, 19, 10, 925.

              Route 2
              4) reaction of thymine (ix) with 1-o-acetyl-2,3,5-tri-o-benzoylribose (x) and hexamethyldisilazane, trimethylsilyl chloride and trifluoromethanesulfonic acid in acetonitrile, followed by cleavage of the protecting groups with sodium methoxide in methanol gives 5-methyluridine (xi). compound (xi) is converted to (xii) by means of 2-acetoxyisobutyryl bromide in acetonitrile, subsequent reaction of (xii) with zinc-copper in dimethylformamide yields (xiii), which is finally deprotected with sodium methoxide in methanol.5) 5-methyluridine (xi) can also be converted to (xiv) by means of trimethylorthoacetate in acetic acid.compound (xiv) is then treated with hydrobromic acid to give (xv), which is treated with zinc in acetonitrile and edta or is successively treated with acetic anhydride, zirconium oxide and tributylamine.
              List of intermediates No.
              1-bromo-2-[(e)-3-bromo-1-propenyl]benzene (ix)
              2,3-dihydro-1-benzofuran-5-ol (x)
              6-[(e)-3-(2-bromophenyl)-2-propenyl]-2,3-dihydro-1-benzofuran-5-ol (xi)
              2-[(e)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1-propenyl]benzonitrile (xii)
              (2s,3s)-3-(ethoxycarbonyl)-2-oxiranecarboxylic acid (xiii)
              2-ethyl 3-(4-nitrophenyl) (2s,3s)-2,3-oxiranedicarboxylate (xiv)
              2-amino-n-isopentyl-4-methylpentanamide (xv)
              Reference 1:
                  ineyama, t.; shiragami, h.; izawa, k.; uchida, y.; synthesis of 1-(2,3-dideoxy-beta-d-glycero-pent-2-enofuranosyl)thymine (d4t; stavudine) from 5-methyluridine. nucleosides nucleotides 1996, 15, 1-3, 47.
              Reference 2:
                  ebata, t.; matsushita, h.; mizutani, n.; itoh, k. (japan tobacco inc.); process for producing 2,3-dideoxy-2,3-didehydronucleoside. wo 9202516 .
              Reference 3:
                  shiragami, h.; uchida, y.; izawa, k. (ajinomoto co., inc.); nucleoside derivs. and production thereof. ep 0519464 .
              Reference 4:
                  tortolani, d.r.; brodfuehrer, p.r.; starrett, j.e. jr.; martin, j.c.; howell, h.g.; mansuri, m.m.; wos, j.a.; preparation of 1-(2,3-ideoxy-beta-d-glycero-pent-2-enofuranosyl)thymine (d4t) and 2,30-dideoxyadenosine (dda): general methods for the synthesis of 2,3-olefinic and 2,3-dideoxy nucleoside analogues active against hiv. j org chem 1989, 54, 4780-5.
              Reference 5:
                  robinson, c.; castaner, j.; stavudine. drugs fut 1994, 19, 10, 925.

              Route 3
              6) another route involves acetylation of the anhydro derivative (xvi) to give (xvii), which is converted to (xviii) by treatment with sodium bromide in sulfuric acid and submitted to elimination with zinc and sodium hydroxide.
              List of intermediates No.
              2,3-oxiranedicarboxylic acid; oxirane-2,3-dicarboxylic acid; epoxysuccinic acid (xvi)
              (2s,3s)-2,3-oxiranedicarboxylic acid (xvii)
              diethyl (2s,3s)-2,3-oxiranedicarboxylate (xviii)
              Reference 1:
                  ikeda, t.; asamura, k. (yamasa shoyu co., ltd.); process for producing 1-(2,3-dideoxy-beta-d-glycero-pent-enofuranosyl)thymine. wo 9209599 .
              Reference 2:
                  robinson, c.; castaner, j.; stavudine. drugs fut 1994, 19, 10, 925.

              Route 4
              other methods based on the modification of carbohydrates have also been described:7) protection of readily available (s)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (xix) with tert-butyldiphenylsilyl chloride gives ether (xx), which is converted to the seleno derivative (xxi) on treatment with lithium hexamethyldisilazide and trimethylchlorosilane in tetrahydrofuran, followed by reaction with phenylselenylbromide. reduction of (xxi) with diisobutylaluminum hydride in toluene followed by acetylation gives compound (xxii), which is reacted with (xxiii) and trimethylsilyltriflate in dichloroethane to afford stereoselectively compound (xxiv). the latter is finally submitted to elimination and deprotected by successive treatment with hydrogen peroxide in pyridine and tetrabutylammonium fluoride in tetrahydrofuran.8) a related route involves treatment of (xx) with lithium diisopropylamide in tetrahydrofuran and diphenylsulfide in hmpa to give (xxv), which is reduced and acetylated to yield (xxvi). compound (xxvi) is treated with (xxiii) in the presence of tin tetrachloride in dichloromethane to afford (xxvii), which is oxidized with sodium periodate and submitted to elimination by treating in toluene-pyridine, to yield compound (xxviii). finally, compound (xxviii) is deprotected with tetrabutylammonium fluoride in tetrahydrofuran.9) a third procedure begins with the protection of (xix) as a tert-butoxycarbonyl ester to yield (xxix), reduction with diisobutylaluminum hydride in tetrahydrofuran to afford (xxx) and elimination after treatment with thionyl chloride in dichloromethane and potassium tert-butoxide in tetrahydrofuran to give (xxxi). subsequent reaction of compound (xxxi) with thymine (ix) in the presence of hexamethyldisilazane and trimethylsilyl chloride and n-chlorosuccinimide in tetrahydrofuran gives compound (xxxii), which is treated with potassium tert-butoxide in tetrahydrofuran and deprotected with sodium methoxide in methanol.
              List of intermediates No.
              2-[(3,4-dihydro-2h-thiochromen-8-yloxy)methyl]oxirane (xix)
              1-bromo-2-[(e)-3-bromo-1-propenyl]benzene (ix)
              2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether (xx)
              (2s)-2-[[(2,2-dimethylpropanoyl)oxy]amino]-4-methyl-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-pentanone (xxi)
              (2s)-2-amino-4-methyl-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-pentanone (xxii)
              3-(1,3-benzodioxol-5-yl)-2-bromopropionic acid methyl ester (xxiii)
              2-sulfanylpropionic acid; 2-mercaptopropionic acid (xxiv)
              2-[2-(1,3-benzodioxol-5-yl)-1-(methoxycarbonyl)ethylsulfanyl]propionic acid (xxv)
              8-methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6-carboxylic acid methyl ester (xxvi)
              8(s)-methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(r)-carboxylic acid methyl ester (xxvii)
              2-hydroxy-2-phenylacetic acid methyl ester (xxviii)
              8(s)-methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(r)-carboxylic acid 1(r)-(methoxycarbonyl)-1-benzyl ester (xxix)
              8(s)-methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(r)-carboxylic acid (xxx)
              4-aminobenzylphosphonic acid diethyl ester (xxxi)
              3-chloro-4-fluorobenzoyl chloride (xxxii)
              Reference 1:
                  kim, c.u.; martin, j.c. (bristol-myers squibb co.); processes for preparation of nucleoside derivs. ep 0501511 .
              Reference 2:
                  hammoudeh, a.j.; haft, j.i.; conte, p.j.; a general method for controlled glycosylation stereochemistry in the synthesis of 2-deoxyribose nucleosides. tetrahedron lett 1990, 31, 2, 1815-8.
              Reference 3:
                  robinson, c.; castaner, j.; stavudine. drugs fut 1994, 19, 10, 925.
              Reference 4:
                  babu, j.r.; beach, j.w.; ahn, s.k.; jeong, l.s.; chu, c.k.; huang, huang, h.; lee, s.j.; a highly stereoselective glycosylation of 2-(phenylselenyl)-2,3-dideoxyribose derivative with thymine: synthesis of 3-deoxy-2,3-didehydrothymidine and 3-deoxythymidine. j org chem 1990, 55, 1418-20.

              Route 5
              finally, the first total synthesis of stavudine has also been described:starting from epoxide (xxxiii), readily available in four steps from crotonaldehyde, compound (xxxiv) is obtained after reaction with selenophenol and diethylaluminum fluoride in dichloromethane. reaction of (xxxiv) with hydrochloric acid in methanol-dichloromethane gives (xxxv), which is acetylated to give (xxxvi). introduction of silylated thymine (xxiii) catalyzed by tert-butyldimethylsilyl triflate in dichloromethane affords compound (xxxvii), which is converted to (xxxviii) on treatment with m-chloroperbenzoic acid in dichloromethane. deprotection of (xxxviii) provides an anomeric mixture of stavudine and its alpha-anomer (xxxix).
              List of intermediates No.
              2-([(2s,3s)-3-[(butoxycarbonyl)amino]-2-methyl-4-oxoazetidinyl]oxy)acetic acid (xxxvii)
              3-(1,3-benzodioxol-5-yl)-2-bromopropionic acid methyl ester (xxiii)
              (3-chloro-4-fluorophenyl)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone (xxxiii)
              1-(3-chloro-4-fluorobenzoyl)-4-piperidinone (xxxiv)
              (3-chloro-4-fluorophenyl)(1-oxa-6-azaspiro[2.5]oct-6-yl)methanone (xxxv)
              (3-chloro-4-fluorophenyl)[4-fluoro-4-(hydroxymethyl)-1-piperidinyl]methanone (xxxvi)
              2-[[1-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-piperidinyl]methyl]-1h-isoindole-1,3(2h)-dione (xxxviii)
              Reference 1:
                  gardiner, j.m.; jung, m.e.; synthesis of antiviral nucleosides from crotonaldehyde. part 3. total synthesis of didehydrodideoxythymidine (d4t). tetrahedron lett 1992, 33, 27, 3841-4.
              Reference 2:
                  robinson, c.; castaner, j.; stavudine. drugs fut 1994, 19, 10, 925.

              Route 6
              a new asymmetric synthesis of stavudine has been described:the regioselective epoxidation of allyl alcohol (i) by means of titanium tetraisopropoxide and alpha,alpha-dimethylbenzylperoxide, catalyzed by diisopropyl d-tartrate, followed by esterification with pivaloyl chloride yields the epoxide (ii), which is then condensed with lithium acetylide catalyzed by boron trifluoride ethearate in thf, yielding the acetylenic alcohol (iii). the cyclization of (iii) catalyzed by mo(co)6 and trimethylamine oxide affords the dihydrofuran (iv), which is condensed with n,n-bis(trimethylsilyl)thymine (v) and i2 to give the iodonucleoside (vi). finally, this compound is dehydroiodinated and deprotected with sodium methoxide in methanol.
              List of intermediates No.
              4-aminobenzylphosphonic acid diethyl ester (iv)
              [4-(aminomethyl)-4-fluoro-1-piperidinyl](3-chloro-4-fluorophenyl)methanone (i)
              ethyl 6-chloro-5-methyl-2-pyridinecarboxylate (ii)
              [5-methyl-6-(methylamino)-2-pyridinyl]methanol (iii)
              6-(dimethylamino)-2-pyridinecarbaldehyde (v)
              6-(2-furyl)-2-pyridinecarbaldehyde (vi)
              Reference 1:
                  gleason, m.m.; mcdonald, f.e.; asymmetric syntheses of stavudine (d4t) and cordycepin by cycloisomerization of alkynyl alcohols to endocyclic enol ethers. angew chem. int ed engl 1995, 34, 3, 350.

              Route 7
              a new synthesis of stavudine has been reported:the condensation of thymine (i) with methyl 2-deoxyribofuranoside (ii) by means of n-bromosuccinimide (nbs) followed by protection with tbdps-cl gives the intermediate (iii), which is cyclized by means of trimethylsilyl triflate (tms-otf), yielding the cyclothymidine derivative (iv). the deprotection of (iv) with tetrabutylammonium fluoride affords the unprotected compound (v), which is finally treated successively with triflate anhydride, 1,8-diazabicyclo[5.4.0]undec-7-ene (dbu) and zn/acetic acid.the unprotected intermediate compound (v) can also be obtained by cyclization of thymidine (vi) by means of nbs in dmf, catalyzed by trifluoroacetic acid.
              List of intermediates No.
              n-(3-aminopropyl)-n-methyltetrahydro-2-furancarboxamide (vi)
              1-bromo-2-[(e)-3-bromo-1-propenyl]benzene (i)
              benzyl (4s)-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate (ii)
              benzyl (2s,4s)-4-allyl-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate (iii)
              benzyl (2s,4r)-4-benzyl-2-(tert-butyl)-5-oxo-4-(2-oxoethyl)-1,3-oxazolidine-3-carboxylate (iv)
              methyl (2s)-2-amino-4-phenylbutanoate (v)
              Reference 1:
                  lowe, r.f.; lipshutz, b.h.; stevens, k.l.; a novel route to the anti-hiv nucleoside d4t. tetrahedron lett 1995, 36, 16, 2711.

              Route 8
              the synthesis of [1-14c]-labeled stavudine has been published:the reaction of labeled d-ribofuranose (i) first with methanol and acetyl chloride and then with benzoyl chloride gives 2,3,5-tri-o-benzoyl-1-o-methyl-d-ribofuranoside (ii), which is acetylated with acetic anhydride and acetic acid to 1-o-acetyl-2,3,5-tri-o-benzoyl-beta-d-ribofuranoside (iii). the condensation of (iii) with thymine (iv) by means of hexamethyldisylazane (hmds), trimethylsilyl chloride (tms-cl) and trifluoromethanesulfonic acid, followed by a basic hydrolysis with naome affords 1-(beta-d-ribofuranosyl)thymine (v), which is treated with methanesulfonyl chloride in pyridine giving the trimesylate (vi). the reaction of (vi) with sodium benzoate in hot dmf yields the benzoylated internal ether (vii), which is treated with acetyl bromide in acetic acid/hbr affording 1-[2-bromo-2-deoxy-5-o-benzoyl-3-o-(methanesulfonyl)-beta-d-ribofuranos yl]thymine (viii). the reaction of (viii) with zn in the same solvent as before gives 5-o-benzoylstavudine (ix), which is finally debenzoylated with naoch3 in methanol.
              List of intermediates No.
              (2r)-2-[(methoxycarbonyl)amino]-4-(4-methoxyphenyl)butyric acid (i)
              1-bromo-2-[(e)-3-bromo-1-propenyl]benzene (iv)
              6-[(e)-3-(2-bromophenyl)-2-propenyl]-2,3-dihydro-1-benzofuran-5-ol (v)
              benzyl (3r)-3-benzyl-1-[(1s)-1-(hydroxymethyl)-3-phenylpropyl]-2-oxopyrrolidinylcarbamate (ii)
              5-amino-1,3,4-thiadiazole-2(3h)-thione (vi)
              methyl (2s)-3-(2,3,4,5,6-pentafluorophenyl)-2-([[(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)amino]carbonyl]amino)propanoate (vii)
              1-(2-pyridinyl)piperazine (viii)
              ethyl (e)-3-(3,5-dimethoxyphenyl)-2-methyl-2-propenoate (ix)
              methyl (3r,4r,5s)-4-amino-5-azido-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate (iii)
              n-(2-chloroethyl)-n-{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}-n-[(1r)-1-phenylethyl]amine; n-(2-chloroethyl)-2-methoxy-n-[(1r)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-1-ethanamine (i)
              4-(2-{[2-(9h-fluoren-9-yl)acetyl]amino}ethyl)benzoic acid (ii)
              2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1r)-1-phenylethyl]amino}ethyl 4-(2-{[2-(9h-fluoren-9-yl)acetyl]amino}ethyl)benzoate (iii)
              (6ar,9s)-6a,7-dimethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (v)
              (6ar,9s)-9-isocyanato-6a,7-dimethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline; (6ar,9s)-6a,7-dimethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl isocyanate (vi)
              2-amino-1,3-benzenediol (vii)
              2-amino-3-{[tert-butyl(dimethyl)silyl]oxy}phenol (viii)
              (7s,11s,12r,13s,14r,15r,16r,17s,18s)-32-{[tert-butyl(dimethyl)silyl]oxy}-2,15,17-trihydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,37-trioxo-8,27,38-trioxa-24,34-diazahexacyclo[,7~.0~5,36~.0~26,35~.0~28,33~]octatriaconta-1(36),2,4 (ix)
              Reference 1:
                  discordia, r.p.; synthesis of 1-[c-14]-stavudine(r) (d4t). j label compd radiopharm 1996, 38, 7, 613.

              Route 9
              an improved process for the preparation of high purity stavudine in a good yield was reported:the reaction of 5-methyluridine (i) with mesyl chloride and nmm in acetone, followed by a treatment with 6n naoh gives the 2,2-anhydro-5-methyluridine derivative (ii), which is treated successively with potassium benzoate in dmf, hbr in acetic acid, and finally with zn in dmf to yield 2,3-anhydro-5-o-benzoylthymidine (iii). finally, this compound is debenzoylated with hot butylamine.
              List of intermediates No.
              6-[(e)-3-(2-bromophenyl)-2-propenyl]-2,3-dihydro-1-benzofuran-5-ol (i)
              ethyl (e)-3-(3,5-dimethoxyphenyl)-2-methyl-2-propenoate (iii)
              pyridinium (3s,5r,7r,8r,9s,10s,13r,14s,17r)-7-(acetyloxy)-3-({3-[(4-aminobutyl)amino]propyl}amino)-17-[(1r)-1,5-dimethyl-4-(sulfonatooxy)hexyl]-10,13-dimethylhexadecahydro-1h-cyclopenta[a]phenanthrene (ii)
              Reference 1:
                  reddy, j.p.; quinlan, s.l.; reid, j.g.; renner, d.a.; weaver, d.g.; stark, d.r.; chen, b.-c.; independent syntesis and fate studies of impurities in process intermediates of the anti-aids drug d4t. org process res dev 1998, 2, 3, 203.

              Route 10
              the sulfonation of 5-methyluridine (i) with mscl and nmm in acetone gives the trimesylate (ii) which is treated with sodium benzoate in hot acetamide to yield the cyclic benzoylated anhydro compound (iii). the reaction of (iii) with acetyl bromide in methanol/ethyl acetate affords the bromo derivative (iv), which is debrominated with zn in the same solvent with a catalytic amount of hoac to furnish the unsaturated sugar derivative (v). finally this compound is debenzoylated with hot butylamine.
              List of intermediates No.
              6-[(e)-3-(2-bromophenyl)-2-propenyl]-2,3-dihydro-1-benzofuran-5-ol (i)
              5-amino-1,3,4-thiadiazole-2(3h)-thione (ii)
              methyl (2s)-3-(2,3,4,5,6-pentafluorophenyl)-2-([[(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)amino]carbonyl]amino)propanoate (iii)
              1-(2-pyridinyl)piperazine (iv)
              ethyl (e)-3-(3,5-dimethoxyphenyl)-2-methyl-2-propenoate (v)
              Reference 1:
                  chen, b.-c.; et al.; 5-benzoyl-2alpha-bromo-3-o-methanesulfonylthymidine: a superior nucleoside for the synthesis of the anti-aids drug d4t(stavudine). tetrahedron lett 1995, 36, 44, 7957.

              Route 11
              the reaction of 5-methyluridine (i) with 1,1-dimethoxycyclopentane (ii) by means of tsoh in hot dichloroethane gives the corresponding cyclic ketal (iii), which is protected with 4-methoxybenzyl bromide and nah in dme yielding the n,o-diprotected compound (iv). elimination of the ketal protecting group of (iv) with dichloroacetic acid in water affords n3,o5-bis(4-methoxybenzyl)-5-methyluridine (v), which is treated with pph3, i2 and imidazole in hot toluene/acetonitrile to provide 2,3-didehydro-2,3-dideoxy-n3,o5’-bis(4-methoxybenzyl)-5-methyluridine (vi). finally this compound is deprotected with ammonium cerium (iv) nitrate in acetonitrile/water.
              List of intermediates No.
              6-[(e)-3-(2-bromophenyl)-2-propenyl]-2,3-dihydro-1-benzofuran-5-ol (i)
              3-[4-(1-naphthyl)phenyl]-beta-alanine (ii)
              methyl 3-amino-3-[4-(1-naphthyl)phenyl]propanoate (iii)
              methyl 3-({2-[(tert-butoxycarbonyl)amino]acetyl}amino)-3-[4-(1-naphthyl)phenyl]propanoate (iv)
              methyl 3-[(2-aminoacetyl)amino]-3-[4-(1-naphthyl)phenyl]propanoate (v)
              4-[(4-methyl-2-pyridinyl)amino]butanoic acid (vi)
              Reference 1:
                  luzzio, f.a.; menes, m.e.; a facile route to pyrimidine-based nuceloside olefins: application to the synthesis of d4t(stavudine). j org chem 1994, 59, 24, 7267.

              Route 12
              the reaction of 2-deoxy-d-ribose (i) with meoh and hcl gives the methylglycoside (ii), which is selectively silylated with tbdpscl and dmap in pyridine to yield the monosilylated glycoside (iii). the reaction of (iii) with tscl in pyridine affords the 3-tosylate (iv), which is condensed with the bis(trimethylsilyl)thymine (vi) by means of tms-otf in mecn to provide 5-o-(tert-butydiphenylsilyl)-3-o-tosylthymidine (vii). finally this compound is treated with tbaf in refluxing thf.
              List of intermediates No.
              benzyl (4s)-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate (ii)
              methyl 3-{[2-({4-[(4-methyl-2-pyridinyl)amino]butanoyl}amino)acetyl]amino}-3-[4-(1-naphthyl)phenyl]propanoate (i)
              (2e,5s,6e)-2-allyl-5-{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienyl trityl ether; 4-{(1e,3s,5e)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-6-[(trityloxy)methyl]-1,5,8-nonatrienyl}-2-methyl-1,3-thiazole (iii)
              (4e,7s,8e)-7-{[tert-butyl(dimethyl)silyl]oxy}-8-methyl-9-(2-methyl-1,3-thiazol-4-yl)-4-[(trityloxy)methyl]-4,8-nonadien-1-ol (iv)
              tert-butyl(dimethyl)silyl (1s,3e)-7-iodo-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-[(trityloxy)methyl]-3-heptenyl ether; 4-{(1e,3s,5e)-3-{[tert-butyl(dimethyl)silyl]oxy}-9-iodo-2-methyl-6-[(trityloxy)methyl]-1,5-nonadienyl}-2-methyl-1,3-thiazole (v)
              (2r)-n-{(z,2s,6e,9s,10e)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienylidene}-2-methoxy-1-pyrrolidinamine; n-{(z,2s,6e,9s,10e)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienylidene}-n-[(2r)-2-methoxypyrrolidinyl]amine (vi)
              Reference 1:
                  kofoed, t.; larsen, e.; pedersen, e.b.; synthesis of 2,3-anhydro-2-deoxyuridines and 2,3-didehydro-2,3-dideoxyuridines using polymer supported fluoride. synthesis 1995, 1121.

              Route 13
              the benzoylation of thymidine (i) with benzoyl chloride, pph3 and diad in thf gives the 5-o-benzoylthymidine (ii), which is converted into the anhydro compound (iii) by reaction with pph3 and diad in dmf. the reaction of (iii) with phseh in refluxing dmf affords the phenylselenium derivative (iv), which is treated with h2o2 and hoac in thf to provide the benzoylated anhydrothymidine (v). finally this compound is debenzoylated by means of naome in methanol.
              List of intermediates No.
              n-(3-aminopropyl)-n-methyltetrahydro-2-furancarboxamide (i)
              4-[(2s,3s)-3-(3,5-dimethoxyphenyl)-2-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[,5)]decane-3,3-dione (v)
              (2s,6e,9s,10e)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienenitrile (ii)
              (2s,6e,9s,10e)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienal (iii)
              (7s,10r,11s,12s,16e,19s)-7-{[tert-butyl(dimethyl)silyl]oxy}-11-hydroxy-2,2,3,3,8,8,10,12,21,21,22,22-dodecamethyl-19-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-16-[(trityloxy)methyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one (iv)
              Reference 1:
                  becouarn, s.; czernecki, s.; valery, j.-m.; efficient transformation of thymidine into 2,3-didehydro-2,3-dideoxy-thymidine (d4t) involving opening of a 2,3-anhydro derivative by phenylselenol. nucleosides nucleotides 1995, 14, 6, 1227.

              Route 14
              the reaction of 5-methyl-5-o-(triphenylmethyl)uridine (i) with mscl and pyridine gives the dimesylate (ii), which is treated with li2te in thf to yield the tritylated derivative (iii) of the target compound.
              List of intermediates No.
              10-methoxy-5h-dibenzo[b,f]azepine-5-carboxamide (iii)
              (7s,10r,11s,12s,16e,19s)-7,11-bis{[tert-butyl(dimethyl)silyl]oxy}-2,2,3,3,8,8,10,12,21,21,22,22-dodecamethyl-19-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-16-[(trityloxy)methyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one (i)
              (5s,8r,9s,10s,14e,17s)-9-{[tert-butyl(dimethyl)silyl]oxy}-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,19,19,20,20-dodecamethyl-17-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-14-[(trityloxy)methyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one (ii)
              Reference 1:
                  clive, d.l.j.; et al.; synthesis of 2,3-didehydro-2,3-dideoxynucleosides by reaction of 5-protected nucleoside 2,3-dimesylates with telluride dianion: a general route from cis vicinal diols to olefins. j org chem 1996, 61, 21, 7426.

              Route 15
              finally this compound can be deprotected by conventional methods:(a) the acylation of 1,2-o-isopropylidene-alpha-d-xylofuranose (i) with benzoyl chloride and pyridine gives the 5-o-benzoyl derivative (ii), which is acylated again with ac2o in pyridine to yield the 3-o-acetyl-5-o-benzoyl derivative (iii). the reaction of (iii) with ac2o in acetic acid affords the triacetyl derivative (iv) which is condensed with fully silylated thymine (v) by means of sncl4 in acetone to provide the corresponding adduct (vi). the selective hydrolysis of the acetate groups of (vi) with sulfuric acid in hot acetonitrile gives 1-(5-o-benzoyl-beta-d-xylofuranosyl)thymine (vii), which is treated with mscl and pyridine to yield the dimesylate (viii). the reaction of (viii) with nai in refluxing dimethoxyethane affords, after column chromatography, 5-o-benzoyl-3-deoxy-2,3-dideoxythymidine (ix), which is finally deprotected with naome in methanol.(b) the reaction of the 5-o-benzoyl derivative (ii) with mscl and pyridine gives the mesylate (x), which is acylated with ac2o in hoac to yield 1,2-di-o-acetyl-5-o-benzoyl-3-o-(methylsulfonyl)-alpha-d-xylofuranose (xi). the condensation of (xi) with the fully silylated thymine (v) by means of sncl4 in acetone affords the expected adduct (xii), which is treated with h2so4 in hot mecn to provide 1-(5-o-benzoyl-3-o-(methylsulfonyl)-beta-d-xylofuranosyl)thymine (xiii). finally this compound is treated with mscl and pyridine to yield the dimesylate (viii), already reported.(c) the 1-(5-o-benzoyl-beta-d-xylofuranosyl)thymine (vii) can also be treated with tscl and pyridine to give the ditosylate (xiv), which is then treated with nai in refluxing dimethoxyethane to yield 5-o-benzoyl-3-deoxy-2,3-dideoxythymidine (ix), already reported.
              List of intermediates No.
              ethyl (e)-3-(3,5-dimethoxyphenyl)-2-methyl-2-propenoate (ix)
              tert-butyl(dimethyl)silyl (1s,3e)-7-iodo-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-[(trityloxy)methyl]-3-heptenyl ether; 4-{(1e,3s,5e)-3-{[tert-butyl(dimethyl)silyl]oxy}-9-iodo-2-methyl-6-[(trityloxy)methyl]-1,5-nonadienyl}-2-methyl-1,3-thiazole (v)
              (3s,6r,7s,8s,12e,15s,16e)-3,7,15-tris{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12-[(trityloxy)methyl]-12,16-heptadecadienoic acid (i)
              (3s,6r,7s,8s,12e,15s,16e)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12-[(trityloxy)methyl]-12,16-heptadecadienoic acid (ii)
              (4s,7r,8s,9s,16s)-4,8-bis{[tert-butyl(dimethyl)silyl]oxy}-5,5,7,9-tetramethyl-16-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-[(trityloxy)methyl]oxa-13-cyclohexadecene-2,6-dione (iii)
              (4s,7r,8s,9s,16s)-4,8-dihydroxy-13-(hydroxymethyl)-5,5,7,9-tetramethyl-16-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione (iv)
              (1r,3s,7s,10r,11s,12s,16r)-7,11-dihydroxy-16-(hydroxymethyl)-8,8,10,12-tetramethyl-3-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (vi)
              (1r,4s,5r,8s,9r,10s,12r,13r)-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[,13~.0~8,13~]hexadecan-10-ol (vii)
              (1r,4s,5r,8s,9r,10s,12r,13r)-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[,13~.0~8,13~]hexadec-10-yl benzoate (viii)
              (1r,4s,5r,8s,9r,10r,12r,13r)-10-allyl-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[,13~.0~8,13~]hexadecane (x)
              2-[(1r,4s,5r,8s,9r,10r,12r,13r)-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[,13~.0~8,13~]hexadec-10-yl]-1-ethanol (xi)
              2-[(1r,4s,5r,8s,9r,10r,12r,13r)-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[,13~.0~8,13~]hexadec-10-yl]ethyl methanesulfonate (xii)
              (1s,2s,3r,4s,7r,10s,15s)-4-(acetyloxy)-1,9,15-trihydroxy-10,14,17,17-tetramethyl-11,12-dioxo-6-oxatetracyclo[,10~.0~4,7~]heptadec-13-en-2-yl benzoate (xiii)
              (1s,2s,3r,9s)-3-[(2r,3s)-3-(acetyloxy)-2-(2-oxoethyl)oxetanyl]-1,5,9-trihydroxy-4,8,11,11-tetramethyl-6-oxobicyclo[5.3.1]undeca-4,7-dien-2-yl benzoate (xiv)
              Reference 1:
                  spirikhin, l.v.; mustafin, a.g.; tolstikov, g.a.; abdrakhumanov, l.b.; gataullin, r.r.; transformations of beta-d-xylofuranosyl nucleosides. synthesis of 3-deoxy-2,3-didehydrothymidine (d4t). russian j org chem 1996, 32, 12, 1787.

              Route 16
              the reaction of gamma-lactone (i) with n-(phenylsulfanyl)phthalimide (ii) by means of lihmds in thf gives the 2,2-bis(phenylsulfanyl)lactone (iii), which is reduced with dibal in thf to yield 5-o-(tert-butyldiphenylsilyl)-2,3-dideoxy-2,2-bis(phenylsulfanyl)-d-ribose (iv). the reaction of (iv) with acetic anhydride affords the acetylated ribose (v), which is condensed with bis(trimethylsilyl)thymine (vi) by means of tms-otf in acetonitrile to provide the glycosylated thymine (vii). the oxidation of (vii) with 1 mol of mcpba in dichloromethane gives the sulfinyl compound (viii), which is treated with tributylamine in refluxing xylene to yield the 2,3-didehydro compound (ix). the oxidation of (ix) with mcpba in dichloromethane gives the phenylsulfonyl derivative (x), which is desulfurized with sodium amalgam in methanol, yielding the silylated intermediate (xi). finally, this compound is desilylated with tbaf in thf.
              List of intermediates No.
              2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether (i)
              2-hydroxy-2-phenylacetic acid methyl ester (xi)
              tert-butyl(dimethyl)silyl (1s,3e)-7-iodo-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-[(trityloxy)methyl]-3-heptenyl ether; 4-{(1e,3s,5e)-3-{[tert-butyl(dimethyl)silyl]oxy}-9-iodo-2-methyl-6-[(trityloxy)methyl]-1,5-nonadienyl}-2-methyl-1,3-thiazole (vi)
              5-methyl-3-phenyl-1h-inden-1-one (ii)
              (3r)-5-methyl-3-phenyl-2,3-dihydro-1h-inden-1-ol (iii)
              (3r)-5-methyl-3-phenyl-2,3-dihydro-1h-inden-1-one (iv)
              (4r)-6-methyl-4-phenyl-3,4-dihydro-2h-chromen-2-one (v)
              (4r)-6-methyl-4-phenyl-3,4-dihydro-2h-chromen-2-ol (viii)
              nitrilomethane (ix)
              nitrilomethane (x)
              ethyl iminoformate (vii)
              Reference 1:
                  kawakami, h.; et al.; condensation reaction between 2,2-diphenylthio-2,3-dideoxyriboside and silyvated pyrimidine bases. nucleosides nucleotides 1992, 11, 9, 1673.
              Reference 2:
                  ebata, t.; matsushita, h.; kuno, h.; niihata, s.; synthesis of 2,3-didehydro-2,3-dideoxy nucleosides from 2,2-bis (phenylthio) nucleoside analogs. bull chem soc jpn 1995, 68, 8, 2327.

              Route 17
              the reaction of 5-methyluridine (i) with trcl and pyridine gives the 5-o-trityl derivative (ii), which is oxidized with naio4 in ethanol/water to yield the dialdehyde (iii). the wittig reaction of (iii) with methyltriphenylphosphonium bromide (iv) and t-buok in toluene to afford the bis vinyl compound (v), which is submitted to a ring closing metathesis reaction catalyzed by a ru catalyst in dichloromethane to provide the unsaturated nucleoside (vi). finally, this compound is deprotected by means of acoh in water to furnish the target stavudine.
              List of intermediates No.
              10-methoxy-5h-dibenzo[b,f]azepine-5-carboxamide (vi)
              6-[(e)-3-(2-bromophenyl)-2-propenyl]-2,3-dihydro-1-benzofuran-5-ol (i)
              6-amino-8,11-dihydroxy-7h-benzo[e]perimidin-7-one (iv)
              (7s,10r,11s,12s,16e,19s)-7,11-bis{[tert-butyl(dimethyl)silyl]oxy}-2,2,3,3,8,8,10,12,21,21,22,22-dodecamethyl-19-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-16-[(trityloxy)methyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one (ii)
              Reference 1:
                  ewing, d.f.; et al.; synthesis of acyclic bis-vinyl pyrimidines: a general route to d4t via metathesis. tetrahedron 2003, 59, 7, 941.

              Route 18
              the reaction of 3-deoxythymidine (i) with mscl and tea in acetone gives the mesylate (ii), which is treated with aq. naoh at 45-50 c to yield the anhydro compound (iii). finally, this compound is treated with koh in refluxing tert-butanol to afford the target stavudine.
              List of intermediates No.
              n-(3-aminopropyl)-n-methyltetrahydro-2-furancarboxamide (i)
              2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1h-indol-3-yl]-1-(1h-imidazol-1-yl)-1-ethanone (iii)
              Reference 1:
                  paramashivappa, r.; et al.; simple and efficient method for the synthesis of 2,3-didehydro-3-deoxythymidine (d4t). tetrahedron lett 2003, 44, 5, 1003.

              Route 19
              the reaction of 5-methyluridine (i) with trityl chloride (ii) and pyridine gives the 5-o-trityl analogue (iii), which is submitted to an oxidative cleavage of the vicinal dihydroxy group by means of naio4 in etoh/water to yield the dialdehyde (iv). the double wittig olefination of (iv) by means of methyltriphenylphosphonium bromide (v) and t-buok in toluene affords the bis alkene (vi), which is submitted to a ring closing metathesis by means of the grubbs catalyst in dichloromethane to provide the unsaturated nucleoside (vii). finally, this compound was deprotected by means of 80% acoh to furnish the target stavudine.
              List of intermediates No.
              10-methoxy-5h-dibenzo[b,f]azepine-5-carboxamide (vii)
              6-[(e)-3-(2-bromophenyl)-2-propenyl]-2,3-dihydro-1-benzofuran-5-ol (i)
              (3s)-3-(3-methylphenyl)-2,3-dihydro-1h-1,2-benzisothiazole-1,1-dione (ii)
              6-amino-8,11-dihydroxy-7h-benzo[e]perimidin-7-one (v)
              (7s,10r,11s,12s,16e,19s)-7,11-bis{[tert-butyl(dimethyl)silyl]oxy}-2,2,3,3,8,8,10,12,21,21,22,22-dodecamethyl-19-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-16-[(trityloxy)methyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one (iii)
              Reference 1:
                  ewing, d.; glacon, v.; mackenzie, g.; postel, d.; len, c.; a novel approach to unsaturated acyclic nucleoside analogues and the first synthesis of d4t by ring closure metathesis. tetrahedron lett 2002, 43, 19, 3503.




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