合成路线1

The protection of the amino group of ethyl 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetate (I) with trityl chloride (B) by means of triethylamine in CH2Cl2 gives ethyl 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino acetate (II), which is hydrolyzed to the corresponding acid (III) with NaOH in refluxing dioxane-water. The condensation of (III) with 7-aminocephalosporanic acid (IV) by means of dicyclohexylcarbodiimide in CH2Cl2 containing triethylamine affords 7-(2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamido]cephalosporanic acid (V). The elimination of the trityl group is performed with hot 55% formic acid yielding the corresponding free acid, which is finally treated with NaHCO3 in water.

合成路线2

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 Grubb's catalyst in dichloromethane to provide the unsaturated nucleoside (VII). Finally, this compound was deprotected by means of 80% AcOH to furnish the target Stavudine.

合成路线3

The reaction of the commercially available (1S-cis)-2-cyclopentan-1,4-diol 4-acetate (I) with methyl pyrocarbonate and DMAP in THF gives the carbonate ester (II), which by reaction with nitromethane (III), triisopropyl phosphite and a Pd catalyst, yields (1R-cis)-1-acetoxy-4-(nitromethyl)-2-cyclopentene (IV). The hydrolysis of (IV) by means of Ts-OH in methanol affords the corresponding alcohol (V), which by treatment with O3, NaOMe and NaBH4 in methanol provides (1R-cis)-4-(hydroxymethyl)-2-cyclopenten-1-ol (VI). The selective monotritylation of the primary OH group of (VI) with trityl chloride (VII) in pyridine gives the trityl ether (VIII), which is condensed with 2-amino-6-chloropurine (IX) by means of Pd(PPh3)4 in THF to yield the adduct (X). The destritylation of (X) with HOAc/water affords the hydroxymethyl compound (XI), which is finally dechlorinated by hydrolysis with hot HCl or NaOH to provide the target (-)-carbovir. Alternatively, the dechlorination of (XI) can be performed by reaction of (XI) with liquid ammonia at 75-80 C in a Parr bomb to give the diaminopurine (XII), which is finally submitted to an enzymatic deamination with adenosine deaminase (from calf intestinal mucosa).

合成路线4

The cyclization of benzonitrile (I) with sodium azide by means of ZnCl2 in hot DMF gives 5-phenyltetrazole (II), which is condensed with trityl chloride (III) by means of TEA in THF to yield 5-phenyl-2-(triphenylmethyl)tetrazole (IV). The condensation of (IV) with 4-iodotoluene (V) by means of n-BuLi, ZnCl2, (PPh3)2NiCl2 and CH3MgCl in THF affords 5-(4'-methylbiphenyl-2-yl)-2-triphenylmethyltetrazole ?VI), which is finally brominated with N-bromosuccinimide (NBS) and AIBN in refluxing acetic acid to provide the target intermediate 5-[4'-(bromomethyl)biphenyl-2-yl]-2-(triphenylmethyl)tetrazole (VII).

合成路线5

Protection of (R)-glycidol (I) with trityl chloride (II) and TEA in dichloromethane gives the trityl ether (III), which is condensed with vinylmagnesium bromide (IV) in THF to yield the pentenol (V). The alkylation of (V) with allyl bromide (VI) by means of NaH in THF affords the allyl ether (VII), which is oxidized with O3 in methanol/dichloromethane, giving dialdehyde (VIII). Reduction of (VIII) with NaBH4 in ethanol provides diol (IX), which is treated with mesyl chloride and TEA in dichloromethane to afford the fully protected alcohol (X). Cyclization of (X) with 3,4-bis(3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione (XI) by means of Cs2CO3 in DMF yields the hexacyclic compound (XII), which is N-demethylated by reaction with KOH in refluxing ethanol to give the hexacyclic furan derivative (XIII), which is then treated with hexamethyldisilazane (HMDS) in hot methanol to afford the hexacyclic demethylated pyrrole (XIV). Elimination of the trityl protecting group of (XIV) with HCl in dichloromethane gives the methanol derivative (XV), which is treated with Br2, pyridine and triphenyl phosphite in dichloromethane to yield the bromomethyl derivative (XVI). Finally, this compound is treated with dimethylamine in DMF to provide LY-333531. Alternatively, compound (XV) is treated with methanesulfonic anhydride and pyridine in THF, giving the mesylate (XVII), which is then treated with dimethylamine as before.

合成路线6

The condensation of 3-(4-morpholinylmethyl)-2H-1-benzopyran-8-ol (VI) with 2(R)-(p-toluenesulfonyloxymethyl)-4-(triphenylmethyl)morpholine (XVI) by means of K2CO3 in DMF gives the protected target compound (XVII), which is finally deprotected with acetic acid and salified with methanesulfonic acid. The intermediates benzopyran (VI) and morpholine (XVI) have been obtained as follows: Benzopyran (VI): The reaction of 8-methoxy-4H-1-benzopyran-3-carboxylic acid (I) with SOCl2 in refluxing toluene gives the acyl chloride (II), which is condensed with morpholine (III) in dioxane yielding the methanone (IV). The reaction of (IV) with BBr3 in dichloromethane affords the 1-(8-hydroxy-2H-1-benzopyran-3-yl)-1-(4-morpholinyl)methanone (V), which is reduced with LiAlH4 in THF giving the desired intermediate benzopyran (VI). Morpholine (XVI): The reaction of benzyl (S)-glycicyl ether (VII) with benzylamine (VIII) gives 1-(benzylamino)-3-(benzyloxy)-2(R)-propanol (IX), which is cyclized with chloroacetyl chloride (X) and triethylamine in dichloromethane yielding the morpholinone (XI). The reduction of (XI) with LiAlH4 in ethyl ether affords the fully protected morpholine (XII), which is debenzylated with H2 over Pd/C in ethanol giving 2(R)-(hydroxyethyl)morpholine (XIII). The reaction of (XIII) with trityl chloride (XIV) and TEA in dichloromethane yields the N-tritylmorpholine (XV), which is finally tosylated with tosyl chloridde and pyridine affording the desired intermediate morpholine (XVI).

合成路线7

L-Histidine methyl ester (I) was protected as the bis(tritylated) derivative (II) upon treatment with triphenylmethyl chloride and Et3N. Reduction of the ester function of (III) with LiAlH4 afforded alcohol (III), which was coupled with cyclohexylmethyl bromide (IV) in the presence of NaH in DMF, yielding the cyclohexylmethyl ether (V). Finally, cleavage of the trityl protecting groups of (V) with HCl in THF provided the title compound as the dihydrochloride salt.

合成路线8

The reaction of ethyl acetoacetate (I) with NaNO2 in acetic acid-water gives ethyl 2-(hydroxyimino)-3-oxobutyrate (II), which is cyclized with thiourea (III) by means of SO2Cl2 in methylene chloride yielding ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate (IV). The treatment of (IV) with trityl chloride (V) and triethylamine in DMF affords ethyl 2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetate (VI), which by condensation with tert-butyl 2-bromo-2-methylpropionate (VII) by means of K2CO3 in DMSO is converted into ethyl 2-(2-tert-butoxycarbonyl-2-propyloxymino)-2-(2-tritylaminothiazol-4-yl)acetate (VIII). The hydrolysis of (VIII) with NaOH in refluxing methanol gives 2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (IX), which by condensation with tert-butyl 7-aminocephalosporanate (X) by means of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide in DMF yields tert-butyl 7-[2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]cephalosporanate (XI). The hydrolysis of (XI) with trifluoroacetic acid in anisole affords 7-[2-(2-aminothiazol-4-yl)-2-(2-carboxy-2-propyloxyimino)acetamido]cephalosporanic acid (XII), which is finally treated with pyridine (A) and NaI.

合成路线9

Esterification of urocanic acid (I) by means of HCl in MeOH affords methyl ester (II), which is then hydrogenated over Pd/C in MeOH to provide compound (III). Protection of the imidazole ring of (III) with triphenylmethyl chloride (trityl chloride) (IV) and Et3N in acetonitrile yields derivative (V), whose carboxylate moiety is reduced with LiAlH4 in refluxing THF to give alcohol (VI). Trityl removal from compound (VI) with HCl in refluxing EtOH furnishes hydrochloride (VII), which is finally converted into the desired product by condensation in refluxing acetonitrile with isocyanate (VIII) (which in turn can be obtained either by treatment of carboxylic acid (IX) with diphenyl phosphorazidate (DPPA) and Et3N in refluxing dioxane or by reaction of amine (X) with diphosgene (XI) and catalytic charcoal in refluxing ethyl acetate).

合成路线10