合成路线1

6-(Tritylamino)penicillanic acid (I) is converted into the azetidinone (II), which is treated with p-toluenesulfonic acid to yield the tosylate (III). The chlorination of (III) with Cl2 in carbon tetrachloride affords the 4-chloroazetidinone (IV), which is condensed with propargyl alcohol (V) by means of AgBF4 in THF to give the propargyl ether (VI) as a mixture of cis and trans isomers that is separated by chromatography. The acylation of (VI) with phenylacetyl chloride (VII) and pyridine affords the amide (VIII).

合成路线2

Starting compound (I) is hydroxylated microbiologically by means of Botryodiplodia malorum to 3,7-dihydroxy-15beta,16beta-methylene-5-androsten-17-one (VIII), which is selectively acylated with pivalic anhydride to the monoacyl derivative (IX). Epoxidation of (IX) with tert-butyl hydroperoxide in hot toluene yields the epoxide (X), which by reaction with triphenylphosphine and CCl4 is converted to the chloroepoxide (Xl). The reactive elimination of Cl with Zn-acetic acid followed by hydrolysis with KOH yields 3,5-dihydroxy-15beta,16beta-methylene-6-androsten-17-one (XII), which is submitted to cyclopropanation with methyrene iodide and Zn/Cu in glyme yielding 3,5-dihydroxy-6beta,7beta:15beta,16beta-dimethyleneandrostan-17-one (XIII). The reaction of (XIII) with propargyl alcohol (XIV) by means of potassium ethoxide in THF affords the 17-(3-hydroxy-1-propyn-1-yl) derivative (XV), which is reduced with H2 over Pd/CaCO3 in THF to the corresponding 3-hydroxypropyl derivative (XVI). Finally, this compound is oxidized and cyclized by means of pyridinium dichromate to (VII) ), which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanohenzoquinone in refluxing dioxane.

合成路线3

The reaction of trimethylene glycol (I) with PCl3 gives 2-chloro-1,3,2-dioxaphosphorinane (II), which is condensed with propargyl alcohol (III) by means of triethylamine in acetonitrile to give a mixture of 2-allenyl- and 2-propargyl-2-oxo-1,3,2-dioxaphosphorinane (IV and V). The reaction of this mixture with isobutylamine in acetonitrile affords 2-(2-isobutylamino-1-propenyl)-2-oxo-1,3,2-dioxaphosphorinane (VI). The hydrolysis of the enamine (VI) with malonic acid gives 2-acetonyl-2-oxo-1,3,2-dioxaphosphorinane (VII), which is condensed with isobutyl-(2-nitrobenzylidene)amine (VIII) to yield 2-[1-(2-nitrobenzylidene)-2-oxopropyl]-2-oxo-1,3,2-dioxaphosphorinane (IX). Finally, this compound is cyclized with methyl 3-aminocrotonate (X) in refluxing acetonitrile.

合成路线4

The condensation of 3,5-dihydroxy-15beta, 16beta-methyleneandrost-6-ene-17-one (I) with propargyl alcohol (II) by means of potassium ethoxide in THF gives 17alpha-(3-hydroxypropynyl)-15beta, 16beta-methyleneandrost-6-ene-3beta,5beta,17beta-triol (III), which is hydrogenated with H2 over RaNi in methanol yielding the 3-hydroxypropyl derivative (IV). The oxidation, with simultaneous cyclization and dehydration of (IV) with pyridine - CrO3, affords 15beta,16beta-methylene-3-oxo-17alpha-pregna-4,6-diene-21,17-carbolactone (V), which is treated with thioacetic acid in methanol - water to give the 7alpha-acetylthio derivative (VI). Finally, this compound is dehydrogenated with dicyano-dichloro-benzoquinone (DDQ) in refluxing benzene.

合成路线5

Z-4105 was prepared according to the reaction sequence as follows: The isoxazole intermediate (III) was obtained by one-pot 1,3-dipolar cycloaddition between acetonitrile oxide, in situ generated from chlorooxime (II), and propargyl alcohol. The oxidation of compound (III) with potassium permanganate gave the acid (IV), which was subsequently converted into the acid chloride (V) by Burdett's method. Finally, Z-4105 was synthesized from (V) and gamma-aminobutyric acid by means of Schotten-Baumann procedure.

合成路线6

This compound has been obtained by different ways: 1. The fermentation of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) or 3beta-acetoxy-15beta,16beta-methylene-5-androsten-17-one (II) with Botryodiplodia malorum gives the corresponding 3beta,7beta-dihydroxy derivative (III), which is regioselectively silylated with Tbdms-Cl and imidazole to yield the 3-beta-silylated compound (IV). The epoxidation of (IV) by means of tert-butyl hydroperoxide catalyzed by VO(acetonylacetonate)2 complex affords the corresponding epoxide (V), which is treated with PPh3 and CCl4 in dichloromethane to provide the 7-alpha-chloro derivative (VI). The desilylation of (VI) with HCl in THF/methanol gives the 3beta-hydroxy compound (VII), which is treated with Zn in AcOH/THF to yield 3beta, 5beta-dihydroxy-15beta,16beta-methylene-6-androsten-17-one (VIII) (1). The cyclopropanation of (VIII) with diiodomethane and Zn in hot ethyleneglycol dimethylether gives 3beta,5beta-dihydroxy-6beta,7beta:15beta,16beta-bismethyleneandrostan-17-one (IX), which is condensed with propargyl alcohol (X) by means of K-OEt in THF, yielding 17alpha-(3-hydroxy-1-propynyl)-6beta,7beta:15beta,16beta-bismethyleneandrostan-3,5beta,17beta-triol (XI). The hydrogenation of (XI) with H2 over Pd/C in THF/methanol/pyridine affords the corresponding 17alpha-(3-hydroxypropyl) derivative (XII), which is finally oxidized, lactonized and dehydrated by means of CrO3 in hot pyridine/water. 2. Alternatively, the 17alpha-(3-hydroxypropyl) derivative (XII) can be oxidized with RuCl3 and NaBrO3 in hot acetonitrile/water, giving the hydroxy carbolactone (XIII), which is finally dehydrated by means of Ts-OH in THF. 3. Similar synthetic pathways have been described replacing the Tbdms protecting group with either dimethyl(3-methylbutyl)silyl or tribenzylsilyl groups.

合成路线7

The intermediate, the furanone derivative (VIII) has been obtained as follows: The reaction of propargyl alcohol (XIII) with dihydropyran and Ts-OH gives the tetrahydropyranyl ether (XIV), which is treated with ethylmagnesium bromide to yield the corresponding magnesium derivative (XV). The reaction of (XV) with propionaldehyde (XVI) in THF affords the secondary alcohol (XVII), which is benzoylated with benzoyl chloride and triethylamine affording the benzoate (XVIII). The deprotection of (XVIII) with Ts-OH gives the primary alcohol (XIX), which is oxidized with pyridinium chlorochromate (PCC) to the corresponding aldehyde (XX). The Diels-Alder reaction of (XX) with 5-ethoxy-4-methyloxazole (XXI) in refluxing toluene yields 4-(1-benzoyloxypropyl)-2-ethoxyfuran-3-carbaldehyde (XXII), which is reduced with NaBH4 in methanol to the carbinol (XXIII). The controlled oxidation of (XXIII) with MnO2/HCl affords 4-(1-benzoyloxypropyl)-5-hydroxy-3-(hydroxymethyl)furan-2(5H)-one (XXIV), which is finally treated with SOCl2 and DMF in chloroform to afford the target intermediate (VIII).

合成路线8

3) The tosylation of (S)-lactic acid ethyl ester (XVIII) with tosyl chloride and triethylamine gives the corresponding tosylate (XIX), which is reduced with NaBH4, diisobutylaluminum hydride (DIBAL) or borane.THF complex yielding 2(S)-(tosyloxy)-1-propanol (XX). The epoxidation of (XX) with KOH in water or NaH in DMSO/THF affords (R)-propylene oxide (XXI), which is condensed with 1-(benzyloxy)-2-propynyl (XXII) [obtained by benzylation of propargyl alcohol (XXIII) with benzyl chloride and NaOH] by means of butyllithium in THF or lithium amide in DMSO to give 6-benzyloxy-4-hexyn-2(R)-ol (XXIV). The acetylation of (XXIV) with acetic anhydride yields the corresponding acetate (XXV), which is reduced with H2 over Raney Nickel in ethanol to afford the expected 2(R),6-hexanediol derivative (XXVI). The debenzylation of (XXVI) by hydrogenation with H2 over Pd/C in acetic acid gives 5(R)-acetoxy-1-hexanol (XXVII), which is treated with SOCl2 to yield the corresponding hexyl chloride (XXVIII). The condensation of (XXVIII) with 3,7-dimethylxanthine (X) by means of sodium methoxide in DMSO affords the 5'-O-acetyllisofylline (XXIX), which is finally deacetylated by treatment with HCl in methanol/water. 4) The 5(R)-acetoxy-1-hexanol (XXVII) can also be obtained as follows: The addition of chiral epoxide (XXI) to acetaldehyde ethyl propargyl acetal (XXX) by means of lithium amide in DMSO gives 6-(1-ethoxyethoxy)-4-hexyn-2(R)-ol (XXXI), which is acetylated with acetic anhydride as before to the acetate (XXXII). The hydrogenation of (XXXII) with H2 over Raney Nickel in ethanol yields the corresponding saturated acetate (XXXIII), which is finally deprotected with aqueous HCl to the expected 5(R)-acetoxy-1-hexanol (XXVII) already reported.

合成路线9

1) The esterification of 4-fluoro-3-hydroxybenzoic acid (I) with trimethyl orthoformate and sulfuric acid gives the methyl ester (II), which is condensed with propargyl bromide (III) by means of K2CO3 in acetone, yielding the corresponding ether (IV). The cyclization of (IV) by heating at 220 C in N,N-diethylaniline affords 8-fluoro-2H-1-benzopyran-5-carboxylic acid methyl ester (V), which is hydrolyzed with NaOH in refluxing ethanol to the corresponding free acid (VI). The reaction of (VI) with thionyl chloride and then with ammonia affords the carboxamide (VII), which is nitrated with NaNO2 and iodine, giving the 8-fluoro-3-nitro-2H-1-benzopyran-5-carboxamide (VIII). The hydrogenation of the double bond of (VIII) with NaBH4 in isopropanol yields the 3,4-dihydro compound (IX), which is then further reduced at the nitro group with H2 and RaNi in ethanol/THF, providing racemic 3-amino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (X). Optical resolution of (X) with L-(+)-tartaric acid gives the 3(R)-amino derivative (XI), which is alkylated with cyclobutanone (XII) and sodium cyanoborohydride in methanol/acetic acid to afford robalzotan (XIII). Finally, this compound is treated with L-(+)-tartaric acid (XIV) in THF/ethyl ether.

合成路线10

Addition of tributyltin hydride to the triple bond of propargyl alcohol (I) in the presence of AIBN provided a mixture of (Z)-(II) and (E)-3-(tributylstannyl)-2-propen-1-ol (III), which were separated by column chromatography. The desired (E)-allyl alcohol (III) was further converted to the corresponding chloride (IV) by treatment with PPh3 in refluxing CCl4. Alkylation of the nortropane derivative (V) with chloride (IV) in the presence of celite-supported KF furnished the N-(tributylstannyl)propenyl nortropane (VI). The target iodinated compound was then prepared by treatment of (VI) with N-iodosuccinimide.

合成路线11

The desired product is finally obtained by first formation of a mixed anhydride (XVI) by reaction of the cyclohexylphenyl glycolic acid (IV) with isobutylchloroformate (XV) in cyclohexane in the presence of Et3N, followed by treatment with 4-N,N-diethylamino butynol (XVII) (obtained on turn from reaction of propargyl alcohol (XVIII) with diethylamine (XIX) in the presence of paraformaldehyde and CuCl.

合成路线12

Treatment of propargyl alcohol (I) with two equivalents of butyllithium in THF, followed by chlorotrimethylsilane, and then with methanol and a catalytic amount of distannoxane, gave 3-(trimethylsilyl)-2-propyn-1-ol (II). Partial reduction of acetylenic triple bond with sodium bis(2-methoxyethoxy)aluminum hydride afforded the expected (E)-olefin (III), which on treatment with methanesulfonyl chloride and triethylamine in dichloromethane provided mesylate (IV). Finally, alkylation of 1-deoxynojirimycin (V) with mesylate (IV) in the presence of triethylamine gave the title compound.

合成路线13

Synthesis of 261501: The optical resolution of trans-3-penten-2-ol (IX) with porcine pancreatic lipase (PPL) and trifluoroethyl laurate in ethyl ether gives the (S)-trans-isomer (X), which is condensed with propargyl alcohol (XI) by means of tetrabutylammonium hyrogensulfate and NaOH in water, yielding the corresponding ether (XII). Rearrangement of (XII) by means of BuLi in THF affords (3R,4R,5E)-4-methylhept-5-en-1-yn-3-ol (XIII), which is silylated with Tbdms-Cl and imidazole to afford the corresponding silyl ether (XIV). The reaction of (XIV) with BH3 in THF provides the aldehyde (XV), which is condensed with phosphonate (XVI) by means of tetramethylguanidine (TMG) in THF to give the nonadienoic ester (XVII). Ozonolysis of (XVII), followed by reaction with Zn/HOAc yields the aldehyde (XVIII), which is condensed with benzyltriphenylphosphonium chloride (XIX) by means of BuLi in THF to afford the 8-phenyloctadienoic ester (XX). The hydrolysis of (XX) with LiOH in acetone/water furnishes the corresponding free acid (XXI), which is condensed with 3-chloro-4-methoxy-L-phenylalanine trichloroethyl ester (XXII) by means of pentafluorodiphenylphosphinate (FDPP) and DIEA in DMF to give the corresponding amide (XXIII). The desilylation of (XXIII) with aqueous HF in acetonitrile affords the hydroxyamide (XXIV), which is esterified with the intermediate 2(S)-[3-(tert-butoxycarbonylamino)-2,2-dimethylpropionyloxy]-4-methylpentanoic acid (VIII) by means of DCC and DMAP in dichloromethane gives the corresponding ester (XXV).

合成路线14

Reduction of cyanoazatricycloheptane (I) with diisobutylaluminum hydride produced aldehyde (II), which was treated with KCN and ammonia yielding aminonitrile (III). Cyclization of (III) with sulfur monochloride in DMF gave the 3-chloro-1,2,5-thiadiazole (IV). Displacement of the halogen atom of (IV) with sodium hydrogen sulfide, followed by alkylation with propyl bromide afforded the propyl thioether (V), which was oxidized to sulfone (VI) using oxone(R). The arylpropynol intermediate (IX) was prepared by coupling of 1-bromo-3,5-difluorobenzene (VII) with propargyl alcohol (VIII) in the presence of PdCl2(PPh3)2 and CuI. Reaction of sulfone (VI) with arylpropynol (IX) in the presence of NaH in THF provided the target ether (X). Finally, treatment of (X) with oxalic acid in acetone furnished the corresponding oxalate salt.

合成路线15

The intermediate succinimidinyl carbonate (XI) has been obtained as follows: The reaction of 2,3-dihydrofuran (XII) with N-iodosuccinimide (NIS) and propargyl alcohol (XIII) in dichloromethane gives trans-3-iodo-2-(propargyloxy)tetrahydrofuran (XIV), which is cyclized by means of Bu3SnH and AIBN in hot toluene yielding the methylenic compound (XV). The ozonolysis of (XV) with O3, followed by reduction with NaBH4 in ethanol affords the racemic alcohol (XVI), which is submitted to an enantioselective acylation with Ac2O and lipase 30 to obtain the chiral alcohol (3R,3aS,6aR)-(XVI). Finally, this compound is treated with disuccinimidinyl carbonate and triethylamine in acetonitrile to provide the target intermediate (XI).

合成路线16

Palladium-catalyzed coupling of 3-bromopyridine (I) with propargyl alcohol (II) produced 3-(3-pyridyl)propargyl alcohol (III). Reaction of alcohol (III) with diketene (IV) in the presence of DMAP gave the acetoacetate ester (V), which was subsequently treated with ammonia in THF to furnish the enamino ester (VI). The title dihydropyridine derivative was then obtained by Hantzsch's synthesis upon condensation between ethyl 4-(2-isopropylimidazo[4,5-c]pyridin-1-yl)benzoylacetate (VII), enamino ester (VI) and 3,3-diphenylpropanal in refluxing EtOH.

合成路线17

Reaction of 2-nitro-5-chlorophenylhidrazyne (I) with ethyl 2-cyano-3-ethoxypropenoate (II) in EtOH and catalytic HOAc affords derivative (III), which is simultaneously hydrolyzed and cyclized to the triazine system (IV) in aqueous NaOH. Treatment of (IV) with SOCl2 followed by addition of alcohol (V) in chloroform allows obtention of the desired product.

合成路线18

The condensation between 4-iodoaniline (I) and diethyl ethoxymethylenemalonate (II) at 130 C, followed by cyclization in diphenyl ether at 250 C, furnished ethyl 4-hydroxy-6-iodoquinoline-3-carboxylate (III). Subsequent reaction of ester (III) with 4-chlorobenzylamine (IV) at 180 C produced the corresponding amide (V). Finally, coupling of (V) with propargyl alcohol (VI) in the presence of CuI and palladium catalyst afforded the desired (hydroxypropynyl)quinoline.

合成路线19

Alkylation of the lithio-dianion of propargyl alcohol (XIII) with 6-bromo-1-hexene (XIV), followed by in situ reduction of the resultant disubstituted acetylene with lithium metal gave the allylic alcohol (XV). Asymmetric Sharpless epoxidation of (XV) using tert-butyl hydroperoxide in the presence of L-(+)-diisopropyl tartrate afforded the (S,S)-epoxy alcohol (XVI). This was reduced to the chiral diol (XVII) employing Red-Al® in THF. After formation of the bis-mesylate (XVIII), oxidative cleavage of the terminal double bond by means of NaIO4 in the presence of ruthenium catalyst furnished the carboxylic acid (XIX). The mesylate groups were finally displaced by sodium disulfide to produce the desired cyclic disulfide compound.

合成路线20

The cuprous chloride-catalyzed Mannich reaction between propargyl alcohol (I), hexahydroazepine (II) and formaldehyde furnished aminobutynol (III), which was further converted to the corresponding chloride (IV) upon treatment with SOCl2. The title compound was then synthesized by alkylation of the anion of 9-benzylfluorene (V) with chloride (IV) in DMSO.

合成路线21

This compound has been obtained by two related ways: The demethylation of levorphanol (I) by the deGraw and Engstrom procedure (ethyl chloroformate and K2CO3 in refluxing chloroform and hydrolysis with NaOH) gives norlevorphanol (II), which is alkylated with propargyl bromide (III) and K2CO3 in hot DMF to yield the N-propargyl derivative (IV). The hydrostannylation of (IV) with HSnBu3 and Et3B in THF affords a mixture of the trans-(V) and cis-(VI) tributyltin precursors that are separated by column chromatography. Finally, the desired trans-isomer (V) is iodinated with I2 in CHCl3 to provide the target iodoallyl morphinan derivative. Alternatively, the hydrostannylation of propargyl alcohol (VI) by conventional methods gives the (E)-3-(tributylastannyl)allyl alcohol (VII), which is treated with CCl4 and PPh3 to yield the corresponding allyl bromide (VIII). Finally, the N-alkylation of norlevorphanol (II) with the allyl bromide (VIII) affords the already reported trans-(tributylstannyl)precursor (V).

合成路线22

The mixed carbonate ester intermediate (X) has been obtained as follows: The reaction of dihydrofuran (I) with propargyl alcohol (II) and N-iodosuccinimide (NIS) gives the propargyl ether (III), which is cyclized by means of tributyltin hydride and AIBN in refluxing toluene to yield the perhydrofuro[2,3-b]furan (IV). The oxidation of the methylene group of (IV) with ozone in methanol/dichloromethane affords the bicyclic ketone (V), which is reduced with NaBH4 in ethanol to provide racemic (VI). The digestion of (rac)-(VI) with immobilized lipase 30 and acetic anhydride in DME provides a mixture of the (3R)-alcohol (VII) and the (3S)-acetoxy derivative (VIII) that is separated by chromatography. Finally, the (3R)-(VII) alcohol is condensed with disuccinimidyl carbonate (IX) and TEA in acetonitrile to give the target mixed carbonate ester intermediate (X).

合成路线23

Propargyl alcohol (I) is oxidized with CrO3 under reduced pressure to give propynal (II), which is treated with sodium thiosulfate to afford the aldehyde dithionite (III). Subsequent cyclization of (III) in liquid ammonia gives rise to isothiazole (IV). The lithiated derivative of (IV) is formylated by means of DMF to provide aldehyde (V), which is further reduced to alcohol (VI) employing NaBH4 in THF (1). Bromination of alcohol (VI) in the presence of CBr4/PPh3 leads to 5-bromomethylisothiazole (VII). This is then converted into the phosphonium salt (VIII) upon treatment with triphenylphosphine in refluxing acetonitrile. Wittig condensation of (VIII) with the formyl pyrrolidine (IX) produces the ethenylpyrrolidine derivative (X). The mesylate group of (X) is displaced with potassium thioacetate to produce thioester (XI), which is subsequently hydrolyzed to thiol (XII) with methanolic NaOH. Condensation of thiol (XII) with the enol phosphate (XIII) in the presence of diisopropylethylamine affords the protected carbapenem derivative (XIV). This is finally deprotected with Bu3SnH and palladium catalyst to furnish the title compound (1,2)

合成路线24

In an alternative synthesis of (IV), alkylation of propargyl alcohol (V) with benzyl bromide in a two-phase system gives ether (VI). Subsequent addition of paraformaldehyde to the lithium acetylide derived from (VI) furnishes alcohol (VII). Selective reduction of acetylene (VII) to the trans olefin (VIII) is accomplished by means of Red-Al in cold THF. The allylic alcohol (VIII) is then esterified with (4-methoxyphenyl)acetic acid (III) in the presence of DCC to form ester (IV).

合成路线25