合成路线1

The bromination of 7-methylnaphtho[2,3-d][1,3]benzodioxole-6-carboxylic acid methyl ester (XVII) with NBS and AIBN in refluxing CCl4 gives the bromomethyl derivative (XVIII), which is treated with allyl alcohol (XIX) and NaH in THF yielding the corresponding allyl ether (XIX). The condensation of (XIX) with the chiral auxiliary (XX) by means of triethylamine and pyridine in acetonitrile affords the oxazolidine (XXII), which is treated with (PPh3)3RhCl and 1,4-diazabicyclo[2.2.2]octane in refluxing propanol giving the carbinol (XXIII). The protection of (XXIII) with TBDMS-Cl, Et3N and DMAP provides the silyl ether (XXIV), which is arylated with 3,4,5-trimethoxyphenyllithium (XXV) in THF giving intermediate (XXVI). Opening of the oxazoline ring of (XXVI) with TFA and acetic anhydride yields the carboxylic ester (XXVII), which is treated with Ti(O-i-Pr)4 in hot ethanol to afford the lactone (XXVIII). The reaction of (XXVIII) with NaOH in methanol, methylation with diazomethane and silylation with TBDMS-Cl gives the carboxylic ester (XXIX), which is treated with NBS in DMSO/THF to afford the chiral bromohydrine (XXX). The debromination of (XXX) with Bu3SnH and AIBN in refluxing toluene provides the hydroxyester (XXXI).

合成路线2

1) The trans-esterification of methyl acetoacetate (I) with allyl alcohol (II) gives the allyl ester (III), which is treated with p-toluenesulfonyl azide (IV) and triethylamine in acetonitrile to yield the diazo derivative (V). The reaction of (V) with tert-butyl-dimethylsilyl triflate (VI) and triethyl amine in dichloromethane affords the enol silyl ether (VII), which is condensed with 3-[1-(tert-butyldimethyl-silyloxy)ethyl-4 acetoxyazetidin-2-one (VIII) by means of ZnCl2 in dichloromethane giving 3-[l-(tertbutyldimethylsilyloxy)ethyl]-4-(4-allyloxy-3-diazo-2,4-dioxobutyl)azetidin-2-one (IX). The cyclization of (IX) by means of rhodium acetate in refluxing benzene yields allyl 6alpha-[l(R)-hydroxyethyl]-2-oxocarbapenam-3-carboxylate (X), which is condensed with 2-(mercaptomethyl)pyridine (XI) by means of diphenyl chlorophosphate and diisopropylamine in acetonitrile affording allyl 6alpha-[l(R)-hydroxy-ethyl]-2-(2-pyridylmethylthio)carbapen-2-em-3-carboxylate (XII). The hydrolysis of (XII) with tetrakis-triphenylphosphine-palladium, triphenylphosphine and potassium 2-ethylhexanoate in dichloromethane gives the potassium salt (XIII), which is finally quaternized with methyl triflate and p-toluenesulfonic acid in acetone.

合成路线3

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.

合成路线4

The reaction of D-glucopyranose (A) with allyl alcohol (B) by means of HCl gives glucoside (C), which is treated with acetaldehyde diethylacetal (D) and TsOH in dichloromethane to yield the 4,6-O-ethylideneglucoside (E). Reaction of (E) with benzyl bromide (F), by means of NaH in DMF, affords the 2,3-di-O-benzyl-4,6-O-ethylideneglucoside (G), which is treated with potassium tert-butoxide and with HgO, HgCl2 to give the fully protected sugar (III).

合成路线5

An improved procedure, amenable to the industrial synthesis of the precursor (I) was further developed. Heck coupling of p-chloroiodobenzene (III) with allyl alcohol (IV) in the presence of tetramethylammonium chloride and a catalytic amount of palladium acetate provided 3-(p-chlorophenyl)propanal (V) along with minor amounts of its branched isomer (VI). Further reduction of this mixture with NaBH4 led to the respective alcohols (VII) and (VIII). Only the desired alcohol (VII) underwent bromination to the desired bromide (IX) in the presence of PBr3 in hot toluene, whereas the branched alcohol (VIII) was dehydrohalogenated to olefin (X). Subsequent alkylation of pyridazinedione (XI) with the above reaction mixture afforded the pure intermediate

合成路线6

The enantioselective epoxidation of allyl alcohol (I) with 2-phenylisopropyl hydroperoxide (II) and Ti(iPrO)4 in the presence of D-diisopropyl tartrate gives the chiral epoxide (III), which is esterified with pivaloyl chloride to yield the pivalate (IV). The opening of the epoxide ring of (IV) by means of lithium acetylide (V) and BF3/Et2O affords the alkynyl alcohol (VI), which is cyclized by means of Mo(CO)6 and trimethylamine oxide to provide the chiral dihydrofuran (VII). The oxidation of (VII) with OsO4 and 4-methylmorpholine-N-oxide (NMMO) gives the diol (VIII), which is treated with Ac2O to yield the diacetate (IX). The condensation of (IX) with N6-benzoyl-N6,7-bis(trimethylsilyl)adenine (X) by means of Tms-OTf affords the nucleoside (XI). Finally, this compound is deprotected by means of NaOMe in methanol.

合成路线7

The asymmetric 1,3-dipolar cycloaddition of the nitrile oxide resulting from 4-bromo-N-hydroxybenzenecarboximidoyl chloride (I) to allyl alcohol (II) in the presence of (R,R)-diisopropyl tartrate and diethylzinc afforded the (R)-5-(hydroxymethyl)isoxazoline (III). After conversion of (III) to the mesylate (IV), treatment with ammonium hydroxide in a sealed vessel provided primary amine (V), which was then acetylated with Ac2O and pyridine to give amide (VI). Further treatment of (VI) with hexamethylditin and dichlorobis(triphenylphosphine) palladium yielded the trimethylstannyl derivative (VII). Reaction of N-Boc-4-piperidone (VIII) with lithium diisopropylamide and N-phenyl-trifluoromethanesulfonimide at low temperature furnished the corresponding vinyl triflate (IX). Subsequent coupling of (IX) with stannyl derivative (VII) in the presence of tris(dibenzylideneacetone)dipalladium and triphenylarsine gave rise to the N-Boc-tetrahydropyridylphenylisoxazole (X). The Boc group of (X) was then deprotected using trifluoroacetic acid, and the deprotected tetrahydropyridine (XI) was condensed with acetoxyacetyl chloride (XII), yielding the acetoxyacetamide (XIII). The acetate ester of (XIII) was finally hydrolyzed by means of K2CO3 in MeOH.

合成路线8

The asymmetric 1,3-dipolar cycloaddition of the nitrile oxide resulting from 4-bromo-N-hydroxybenzenecarboximidoyl chloride (I) to allyl alcohol (II) in the presence of (R,R)-diisopropyl tartrate and diethylzinc afforded the (R)-5-(hydroxymethyl)isoxazoline (III). Treatment of 4-bromopyridine (IV) with hexamethylditin and dichlorobis(triphenylphosphine)palladium yielded 4-trimethylstannylpyridine (V). Subsequent coupling of bromophenylisoxazoline (III) with stannylpyridine (V) in the presence of tris(dibenzylideneacetone)-dipalladium and tri(2-furyl)phosphine gave rise to the pyridylphenylisoxazole (VI). After conversion of (VI) to the mesylate (VII), treatment with ammonium hydroxide in a sealed vessel provided primary amine (VIII). Finally, acetylation of (VIII) with Ac2O and pyridine furnished the title amide.

合成路线9

Hydrolysis of diester (I) with KOH in water/EtOH at 55 C gives the dicarboxylic acid (II), which is subjected to cyclization by refluxing with propionic anhydride to provide anhydride (III). Cyclic anhydride (III) is opened with allyl alcohol (XI) in diethyl ether in the presence of (­)-quinine as asymmetric inducer to yield (­)-1,2-cis-4-methylenecyclopentane-1,2-dicarboxylic acid monoallyl ester (­)-(XII), which is then converted into the amide derivative (­)-(XIII) by activation of the carboxylic acid group with isobutyl chloroformate in ethyl acetate in the presence of N-ethylmorpholine at ­6 C, followed by reaction with aqueous ammonia. Removal of the allyl group of (­)-(XIII) with triphenylphosphine, tetrakis(triphenylphosphine)palladium and 2-ethylhexanoic acid sodium salt in ethyl acetate affords (­)-1,2-cis-2-(aminocarbonyl)-4-methylenecyclopentane-1-carboxylic acid sodium salt (­)-(XIV). Compound (­)-(XIV) is subjected to a Hofmann rearrangement with KOH and KOCl in water to provide a crude aqueous solution containing PLD-118, which is finally purified by protection of the free amine group with N-(9-fluorenylmethoxycarbonyloxy)succinimide by means of Na2CO3 in dioxane followed by Fmoc removal with piperidine in diethyl ether.

合成路线10

Treatment of D-glucosamine•HCl (VI) with ethyl trifluoroacetate and NaOMe produced the trifluoroacetamide (VII), which was subsequently acetylated with Ac2O yielding the tetraacetate (VIII). Displacement of the anomeric acetoxy group of (VIII) by allyl alcohol (IX) in the presence of SnCl4 furnished the allyl glucoside (X). After methanolysis of the acetate ester groups of (X), the resultant triol (XI) was protected as the acetonide (XII) by treatment with 2,2-dimethoxypropane and camphorsulfonic acid. Alkylation of the free hydroxyl group of (XII) with tosylate (V) under Williamson's ether synthesis conditions produced adduct (XIII). Selective hydrolysis of the acetonide moiety of (XIII) was accomplished by treatment with hydrofluoric acid to give diol (XIV). The primary hydroxyl of (XIV) was then converted to tosylate (XV) upon treatment with p-toluenesulfonyl chloride and DMAP.

合成路线11

Aldehyde (II) was prepared by mono-benzylation of 1,4-butanediol (I) followed by Swern oxidation. Subsequent addition of ethynylmagnesium bromide (III) to the aldehyde function of (II) provided propargyl alcohol (IV). Kinetic resolution of the racemic alcohol (IV) by lipase-mediated acetylation in the presence of vinyl acetate produced a mixture of the (S)-acetate (V) and the unreacted (R)-alcohol (VI). The required (S)-propargyl acetate (V) was subjected to partial hydrogenation using Lindlar catalyst to furnish allyl acetate (VII), which was further hydrolyzed to the chiral alcohol (VIII). After protection of (VIII) as the silylated derivative (IX), reductive removal of the benzyl ether using lithium naphthalenide afforded the primary alcohol (X). This was then treated with methanesulfonyl chloride and triethylamine to give mesylate (XI). Ozonolysis of the double bond of (XI), followed by reductive work-up with dimethyl sulfide, yielded aldehyde (XII). This was reacted with hydroxylamine hydrochloride and Et3N in allyl alcohol (XIII) to produce the intermediate nitrone (XIV), which underwent simultaneous 1,3-dipolar cycloaddition to allyl alcohol to furnish the isoxazolopyridine (XV) as a mixture of three diastereoisomers. This mixture was then subjected to hydrogenolytic N-O bond fission, producing piperidine (XVI).

合成路线12

Aldehyde (II) was prepared by mono-benzylation of 1,4-butanediol (I) followed by Swern oxidation. Subsequent addition of ethynylmagnesium bromide (III) to the aldehyde function of (II) provided propargyl alcohol (IV). Kinetic resolution of the racemic alcohol (IV) by lipase-mediated acetylation in the presence of vinyl acetate produced a mixture of the (S)-acetate (V) and the unreacted (R)-alcohol (VI). The required (S)-propargyl acetate (V) was subjected to partial hydrogenation using Lindlar catalyst to furnish allyl acetate (VII), which was further hydrolyzed to the chiral alcohol (VIII). After protection of (VIII) as the silylated derivative (IX), reductive removal of the benzyl ether using lithium naphthalenide afforded the primary alcohol (X). This was then treated with methanesulfonyl chloride and triethylamine to give mesylate (XI). Ozonolysis of the double bond of (XI), followed by reductive work-up with dimethyl sulfide, yielded aldehyde (XII). This was reacted with hydroxylamine hydrochloride and Et3N in allyl alcohol (XIII) to produce the intermediate nitrone (XIV), which underwent simultaneous 1,3-dipolar cycloaddition to allyl alcohol to furnish the isoxazolopyridine (XV) as a mixture of three diastereoisomers. This mixture was then subjected to hydrogenolytic N-O bond fission, producing piperidine (XVI).

合成路线13

Synthesis of intermediate (3S)-(XI): Iodination of 4-chloro-2-nitrotoluene (I) with NaI, I2 and H2SO4 yields (II), which is then treated with dimethyl oxalate (A) in toluene in presence of KOMe or alternatively NaOMe, in MeOH to afford (III). Cyclization of (III) is performed by a first treatment with SnCl2 in dimethoxyethane followed by TiCl3/H2O to provide indole (IV), which is converted into (VI) by reaction with alcohol (V) in presence of NaHCO3, benzyltriethyl ammonium chloride and Pd(OAc)2, followed by a treatment with sodium thiosulfate. The reaction of aldehyde (VI) with KOtBu and triethyl phosphonoacetate (B) in THF yields ethyl ester (VIIa-b), which is then converted into iodo derivative (VIIIa-b) by means of NaI and NCS in DMF. Cyclization of (VIIIa-b) by treatment with Pd(PPh3)4 in DMF and Ag3PO4/H2O affords tetrahydrobenzindole (IX), which is reduced by means of Sm, and I2 in MeOH/THF to give (X). Alternatively (X) is obtained by simultaneous cyclization and reduction of (VIIIa-b) by treatment with SnBu3H and AIBN in chlorobenzene. Finally ethyl ester (X) is selectively hydrolyzed with HCl in HOAc to provide (XI) in its racemic form. Enantiomer (3S)-(XI) can be isolated by separation of the corresponding diasteromers obtained by reaction of (XI) with L-(-) norphedrine in isopropanol followed by hydrolysis with HCl in EtOAc and THF.

合成路线14

D,L-Glutamic acid (I) was sequentially protected as the gamma-allyl ester (III), upon treatment with allyl alcohol (II) and chlorotrimethylsilane, followed by conversion to the trichloroethyl carbamate (V) by means of chloroformate (IV), and then reaction of (V) with benzyl bromide to afford the alpha-benzyl ester (VI). Deprotection of the trichloroethyl carbamate of (VI) by treatment with zinc dust and HOAc and subsequent condensation of the resulting amine with decanoyl chloride (VII) furnished amide (VIII). The allyl ester of (VIII) was then selectively cleaved by using tetrakistriphenylphosphine palladium(0) and morpholine to give carboxylic acid (IX). trans-1,2-Diaminocyclohexane (X) was protected as the mono tert-butyl carbamate (XI) and then coupled with acid (IX) in the presence of diethylphosphoryl cyanide to yield amide (XII). After acidic Boc cleavage of (XII), coupling of the resulting amine with 2,5-diphenyloxazole-4-carboxylic acid (XIII) by means of bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP) afforded (XIV). Finally, hydrolysis of the benzyl ester of (XIV) with LiOH provided the corresponding carboxylic acid.

合成路线15

D,L-Glutamic acid (I) was sequentially protected as the gamma-allyl ester (III), upon treatment with allyl alcohol (II) and chlorotrimethylsilane, followed by conversion to the trichloroethyl carbamate (V) by means of chloroformate (IV), and then reaction of (V) with benzyl bromide to afford the alpha-benzyl ester (VI). Deprotection of the trichloroethyl carbamate of (VI) by treatment with zinc dust and HOAc and subsequent condensation of the resulting amine with decanoyl chloride (VII) furnished amide (VIII). The allyl ester of (VIII) was then selectively cleaved by using tetrakistriphenylphosphine palladium(0) and morpholine to give carboxylic acid (IX). trans-1,4-Diaminocyclohexane (X) was protected as the mono tert-butyl carbamate (XI) and then coupled with acid (IX) in the presence of diethylphosphoryl cyanide to yield amide (XII). After acidic Boc cleavage of (XII), coupling of the resulting amine with 2,5-diphenyloxazole-4-carboxylic acid (XIII) by means of bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP) afforded (XIV). Finally, hydrolysis of the benzyl ester of (XIV) with LiOH provided the corresponding carboxylic acid.

合成路线16

Reaction of betulin (I) and 2,2-dimethylsuccinic acid (II) in refluxing pyridine, followed by HPLC separation of the two products obtained, affords derivative (III). Protection of the carboxylic group of (III) is then performed by formation of the corresponding allyl ester derivative (V) by reaction with allyl bromide (IV) and K2CO3 in acetone. Separately, 2,2-dimethylsuccinic acid (II) is treated with allyl alcohol (VI) in refluxing pyridine to give an isomeric mixture of compounds from which allyl succinate derivative (VII) is chromatographically isolated. Formation of the corresponding acid chloride (VIII) is finally performed by treatment of (VII) with (COCl)2 in refluxing benzene. Condensation between alcohol (V) and acid chloride (VIII) by means of DMAP in CH2Cl2 provides compound (IX), which is finally converted into the target product by removal of the allyl protecting groups by means of Pd(Ph3P)4 and morpholine.

合成路线17

Esterification of N-benzyloxycarbonyl-(R)-tryptophan (I) with allyl alcohol (II) using DCC gave ester (III). The cyclization of (III) to afford diastereoselectively the pyrroloindole derivative (IV) was achieved in trifluoroacetic acid as the solvent. A second N-benzyloxycarbonyl protecting group was then introduced at the indoline nitrogen of (IV), yielding (V). Mannich reaction of the lithium anion of (V) with Eschenmoser's salt provided the (dimethylamino)methyl compound (VI). Ring opening of (VI) to the indole (VII) was performed with sulfuric acid in aqueous methanol. The allyl ester of (VII) was then removed by means of morpholine and palladium catalyst to produce acid (VIII), which was coupled with (S)-alpha-methylbenzylamine (IX) to give amide (X). After hydrogenolysis of the two benzyloxycarbonyl protecting groups of (X), the free amine (XI) was acylated with 2-benzofuranylmethyl chloroformate to furnish the title carbamate.

合成路线18

Condensation of dibromide (I) with allyl alcohol (II) in the presence of NaH gives rise to a mixture of mono- and diallylated compounds (III) and (IV) which, without separation, is subjected to Arbuzov reaction with triethyl phosphite, to furnish the desired phosphonate (V). Electrophilic fluorination of (V) using N-fluorobenzenesulfonimide provides the difluoro phosphonate (VI). Then, basic hydrolysis of phosphonate (VI) affords acid (VII). Compound (VII) is attached to a functionalized non-crosslinked polystyrene soluble polymer under Mitsunobu conditions to produce the polymer-bound phosphonate (VIII). Then, removal of the allyl group in the presence of p-toluenesulfinic acid and Pd(PPh3)4 yields the benzylic alcohol (IX). Oxidation of (IX) employing the Dess-Martin periodinane reagent leads to aldehyde (X) (1).

合成路线19