合成路线1

A shorter synthetic pathway is through the condensation of the above chlorohydrin (II) with m-cyanobenzyloxyaniline (X), prepared by alkylation of p-nitrophenol (VIII) with m-cyanobenzyl bromide (VII) in the presence of KI and further reduction of the nitro group with Fe-NH4Cl, then cyclization with ethyl carbonate. Cimoxatone can also be obtained by opening glycidol (XI) with m-cyanobenzyloxyaniline (X) in ethanol under reflux, and cyclizing with ethyl carbonate (A) to obtain a 5-hydroxymethyl-2-oxazolidinone (XIII), which is methylated by CH3I under phase-transfer catalysis.

合成路线2

N-carbobenzyloxy-L-glutamic acid (I) is converted to the anhydride (II). Reaction of (II) with benzyl alcohol gives a mixture of half esters from which the halt ester (III) is isolated as the dicyclohexylamine salt. (III) is esterified with 4-nitrophenol (IV) with the aid of dicyclohexyl carbodiimide and the product (V) is reacted with taurine (VI). Deprotection of the resulting peptide (VII) by catalytic debenzylation affords glutaurine.

合成路线3

The reaction of 4-nitrophenol (I) with acetic anhydride in aqueous NaOH gives the corresponding acetate (II), which is submitted to a Fries migration with AlCl3 in nitrobenzene at 140 C to yield the acetophenone (III). The condensation of (III) with epichlorohydrin (IV) by means of K2CO3 affords the adduct (V), which is treated with tert-butylamine (VI) in water to obtain the aminoisopropanol derivative (VII). The reduction of the nitro group of (VII) with H2 over Pd/C in methanol gives the corresponding amino derivative (VIII), which is finally condensed with N,N-diethylcarbamoyl chloride (IX) by means of TEA in THF to yield the target urea.

合成路线4

The reaction of 4-nitrophenol (I) with 2-chloroethyl isocyanate (II) in pyridine leads to the activated carbamate (III), which is nitrosated by reacting with nitrosyl chloride in pyridine at -20 C to yield 4-nitrophenyl N-(2-chloroethyl)-N-nitrosocarbamate (IV). The nitrosated molecule (IV) is reacted with 2-(methylthio)ethylamine (V) in THF at ordinary temperature affording the sulfure urea (VI), which is then oxidized to the sulfonyl compound (VII) by hydrogen peroxide in formic acid at 50 C.

合成路线5

The estrification of L-trans-epoxysuccinic acid hemi-ethyl ester (I) with 4-nitrophenol (II) by means of dicyclohexylcarbodiimide (DCC) gives the corresponding p-nitrophenyl ester (III), which is then condensed with N-isoamyl L-leucinamide (IV).

合成路线6

The optical resolution of racemic 2-benzylsuccinic acid (XV) using the chiral amines (R)-1-phenylethylamine (VII), (R)-1-(1-naphthyl)ethylamine (XIV) or (S)-1-phenyl-2-(4-tolyl)ethylamine (XVI) is carried out by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl, providing the desired enantiomer 2(S)-benzylsuccinic acid (XVII). Reaction of (XVII) with SOCl2 gives the corresponding acyl chloride (XVIII), which is treated with 4-nitrophenol (XIX) and TEA in dichloromethane to yield the activated diester (XX). The regioselective reaction of (XX) with cis-perhydroisoindole (V) in dichloromethane affords the monoamide (XXI), which by reaction with HCl and methanol provides the corresponding methyl ester (XXII). This ester is hydrolyzed with NaOH to the previously described chiral succinamic acid (XIII), which is finally converted into its calcium salt.

合成路线7

Treatment of 4-nitrophenol (I) with propyl iodide derivative (II) and K2CO3 in DMF, followed by reduction with hydrazine hydrate, FeCl3 and activated carbon affords (III). Conversion of aniline derivative (III) into phenylcarbamate (IV) by means of PhOCOCl and treatment of (IV) with hydrazine hydrate yields semicarbazide (V), which is then subjected to cyclization with formamidine (VI) to give triazolone derivative (VII). Benzyl (S)-lactate (VIII) is converted to triflate (IX) by means of Tf2O in the presence of DIEA and its reaction with triazolone (VII) and NaH in DMF provides derivative (X). Debenzylation of (X) by hydrogenolysis over Pd/C followed by treatment with oxalyl chloride in CH2Cl2/DMF furnishes chloride (XI), which reacts with 1,3-difluorobenzene (XII) in CH2Cl2 in the presence of AlCl3 to yield intermediate (XIII).

合成路线8

The intermediate aniline (IV) was synthesized by Mitsunobu coupling between N-Boc-4-piperidinol (I) and p-nitrophenol (II), followed by catalytic hydrogenation of the resultant nitrophenyl ether (III). 7-Formyl-2-naphthalenecarbonitrile (VI) was prepared by oxidation of the bromomethyl(naphthalene) (V) employing either trimethylamine N-oxide or dimethylsulfoxide in the presence of silver tetrafluoroborate. Reductive alkylation of aniline (IV) with aldehyde (VI) by means of sodium triacetoxyborohydride produced the secondary amine (VII), which was subsequently acylated with ethyl 2-(Chlorosulfonyl)acetate (VIII) to furnish sulfonamide (IX). The required amidine (X) was then obtained by Pinner reaction of nitrile (IX) with ethanolic HCl, followed by treatment with ammonium acetate. The deprotected piperidine moiety of (X) was further subjected to condensation with ethyl acetimidate to give the bis-amidine compound (XI). The ethyl ester group of (XI) was finally hydrolyzed under acidic conditions, yielding the target carboxylic acid.

合成路线9

Coupling of carbapenem phosphate (VIII) with thiol (XIII) using diisopropylethylamine gave rise to sulfide (XIX). Hydrogenolysis of the p-nitrobenzyl group of (XIX) with simultaneous azide reduction in the presence of Pd/C provided (XX). Treatment of p-nitrobenzyl chloroformate (XXI) with p-nitrophenol (XXII) afforded the nitrophenyl carbonate (XXIII), which was coupled with L-valine (XXIV), yielding carbamate (XXV). Activation of (XXV) with N-hydroxy succinimide and DCC then produced the succinimidyl ester (XXVI). Amine (XX) was coupled with succinimidyl ester (XXVI) to furnish amide (XXVII). The p-nitrobenzyl ester was finally removed by hydrogenation over Pd/C to provide the title compound.

合成路线10

The reaction of 4-bromothiophene-2-carbaldehyde (I) with triethyl orthoformate gives the corresponding acetal (II), which is treated with NaOMe, CuO and KI in hot methanol yielding 5-methoxythiophene-2-carbaldehyde diethylacetal (III). The hydrolysis of (III) with HCl in methanol affords the carbaldehyde (IV), which is condensed with the phosphonate (V) by means of NaH in THF to provide the ethyl acrylate (VI). The hydrolysis of (VI) with KOH in methanol gives the acrylic acid (VII), which is esterified with 4-nitrophenol, TEA and 2-chloro-1-methylpyridinium iodide in dichloromethane yielding the activate ester (VIII). The condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the adduct (XI), which is treated with HBr in acetonitrile to open the cyclopropane ring and provide the bromomethyl compound (XII). The aromatization of (XII) with p-nitrophenyl chloroformate (XIII) and TEA in dichloromethane affords the activated carbonate ester (XIV), which is finally treated with 1-methylpiperazine (XV) to furnish the target carbamate.

合成路线11

The condensation of 5-(benzyloxy)-2,2,4,6,7-pentamethyl-3,4-dihydrobenzofuran-3-ylmethyl methanesulfonate (I) with 2-(methylamino)ethanol (II) by heating at 120 C gives the tertiary amine (III), which is treated with SOCl2 in benzene yielding the chloroethylamino compound (IV). The condensation of (IV) with 4-nitrophenol (V) by means of K2CO3 in hot DMF affords the 4-nitrophenoxy compound (VI), which is reduced with H2 over Pd/C in ethyl acetate to the corresponding 4-aminophenoxy compound (VII). The condensation of (VII) with ethyl acrylate (VIII) by means of NaNO2 and HBr in methanol/water gives the 2-bromopropionic ester (IX), which is cyclized with thiourea (X) by means of NaOAc in refluxing ethanol yielding the thiazolidinedione (XI). Finally, this compound is debenzylated with HCl in hot acetic acid.

合成路线12

The esterification of 3-(benzoylsulfanyl)-2(S)-methylpropionic acid with 4-nitrophenol (II) by means of DCC in dichloromethane gives the corresponding ester (III), which is condensed with S-(4-cyclohexylbenzyl)-L-cysteine (IV) (obtained by alkylation of L-cysteine (V) with 4-cyclohexylbenzyl bromide (VI)) to yield the corresponding amide (VII). Finally, this compound is debenzoylated by a treatment with aqueous NH4OH.

合成路线13

The reaction of 2-chloropyrimidine (I) with NaOMe in methanol gives 2-methoxypyrimidine (II), which is iodinated with N-iodosuccinimide (NIS) and trifluoroacetic anhydride in refluxing THF to yield 5-iodo-2-methoxypyrimidine (III). The condensation of (III) with methyl acrylate (IV) by means of Pd(OAc)2, K2CO3 and Bu4NCl at 120 C affords 3-(2-methoxypyrimidin-5-yl)acrylic acid methyl ester (V), which is hydrolyzed with KOH in methanol to provide the free acid (VI). The esterification of (VI) with p-nitrophenol (VII) by means of DCC and DMAP in dichloromethane gives the activate ester (VIII). The condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the adduct (XI), which is treated with HBr in acetonitrile to open the cyclopropane ring and provide the bromomethyl compound (XII). The aromatization of (XII) with p-nitrophenyl chloroformate (XIII) and TEA in dichloromethane affords the activated carbonate ester (XIV), which is finally treated with 1-methylpiperazine (XV) to furnish the target carbamate.

合成路线14

The reaction of 2-chloropyrimidine (I) with NaOMe in methanol gives 2-methoxypyrimidine (II), which is iodinated with N-iodosuccinimide (NIS) and trifluoroacetic anhydride in refluxing THF to yield 5-iodo-2-methoxypyrimidine (III). The condensation of (III) with methyl acrylate (IV) by means of Pd(OAc)2, K2CO3 and Bu4NCl at 120 C affords 3-(2-methoxypyrimidin-5-yl)acrylic acid methyl ester (V), which is hydrolyzed with KOH in methanol to provide the free acid (VI). The esterification of (VI) with p-nitrophenol (VII) by means of DCC and DMAP in dichloromethane gives the activate ester (VIII). Finally, the condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the target compound.

合成路线15

The reaction of 4-nitrophenol (I) with 1,5-dibromopentane (II) and NaOH in refluxing water gives the aryl ether (III), which is finally condensed with pyrrolidine (IV) in refluxing ethanol.

合成路线16

Alkylation of 5-methoxy-2-methylindole (I) with iodomethane and NaH afforded the 1,2-dimethyl derivative (II). Subsequent Vilsmeier formylation of (II) employing N-methylformanilide and POCl3 furnished aldehyde (III). Nitration of (III) to (IV), followed by reduction with Sn and HCl gave aminoindole (V), which was oxidized to the corresponding quinone (VI) by using a buffered solution of Fremy's salt. Aldehyde (VI) reduction with NaBH4 provided alcohol (VII). This was optionally converted to the chloromethyl derivative (VIII) upon treatment with SOCl2. The title p-nitrophenyl ether was either obtained by alkylation of 4-nitrophenol (IX) with chloride (VIII) or by Mitsunobu coupling of 4-nitrophenol (IX) with indole alcohol (VII).

合成路线17

8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid (I) was activated as the corresponding nitrophenyl ester (III) upon treatment with p-nitrophenol (II) and EDC. The p-nitrophenyl ester (III) was then coupled with 4-amino-3,5-dichloropyridine (IV) in the presence of NaH to produce amide (V). The pyridine ring of (V) was finally oxidized to the title N-oxide by treatment with peracetic acid.

合成路线18

The protection of the OH group of 4-hydroxy-3,5-dimethoxybenzaldehyde (I) with benzyl bromide and K2CO3 DMF gives the benzyl ether (II), which is condensed with ethyl 2-azidoacetate (III) by means of NaOMe in methanol to yield the 2-azido acrylic acid derivative (IV). The cyclization of (IV) in refluxing xylene affords the indole carboxylate (V), which is deprotected by hydrogenation with H2 over PtO2 in THF/methanol to provide 6-hydroxy-5,7-dimethoxy-1H-indole-2-carboxylic acid methyl ester (I). The condensation of (VI) with 1,2-dibromoethane (VII) by means of K2CO3 in DMF gives the 2-bromoethoxy derivative (VIII), which is treated with sodium azide in DMF to yield the 2-azidoethoxy compound (IX). The hydrolysis of the ester group of (IX) with NaOH in THF/water affords the carboxylic acid (X), which is esterified with 4-nitrophenol (XI) by means of DCC and DMAP in dichloromethane to provide the activated ester (XII). The condensation of (XII) with the tetracyclic compound (XIII) by means of NaH in DMF gives the adduct (XIV), which is finally reduced at the azido group with H2 over Pd/C in THF/HOAc to yield the target compound.

合成路线19

Treatment of p-nitrophenol (I) with 1-chloroethyl chloroformate (II) in the presence of pyridine afforded carbonate (III). Subsequent displacement of the chlorine atom of (III) with mercuric acetate in HOAc provided the acetoxy derivative (IV). This was then condensed with (R)-alpha-methylhistamine (V) in HMPT to furnish the title compound.

合成路线20

Coupling between 2-chloro-5-nitropyridine (I) and 4-nitrophenol (II) affords the diaryl ether (III). Subsequent catalytic hydrogenation of both nitro groups of (III) gives rise to diamine (IV). This is finally acylated with (S)-2,2-dimethylcyclopropanecarbonyl chloride (V) to furnish the title diamide.

合成路线21

Alkylation of 2,5-dichlorothiophenol (I) with bromoacetaldehyde diethyl acetal (II) produced thioether (III). Benzothiophene (IV) was then obtained by cyclization of (III) under Friedel-Crafts conditions in the presence of polyphosphoric acid. Metalation of benzothiophene (IV) with BuLi at -78 C, followed by addition of sulfur dioxide gave rise to the sulfinic acid (V). This was converted to the sulfonyl chloride (VI) by chlorination with N-chlorosuccinimide, and further treatment of (VI) with ammonium hydroxide provided the sulfonamide (VII). Addition of formaldehyde to the benzothiophene-2-sulfonamide (VII), followed by condensation with trimethyl phosphite, furnished the dimethyl (sulfonamidomethyl)phosphonate (VIII). The phosphonate ester function of (VIII) was then hydrolyzed by means of bromotrimethylsilane, producing phosphonic acid (IX). This was finally coupled to 4-nitrophenol (X) using trichloroacetonitrile in hot pyridine to afford the title mono-phosphonate ester.

合成路线22

Two new syntheses for amoscanate have been described: 1) The reaction of 4-isothiocyanatobenzoyl chloride (I) with sodium azide (II) gives 4-isothiocyanatobenzoyl azide (III), which by heating in chlorobenzene is converted into 4-isothiocyanatophenyl isocyanate (IV). Finally this compound is condensed with 4-nitrophenol (V) by heating at 190 C. 2) By condensation of 1,4-phenylenebisisothiocyanate (VI) with 4-nitrophenol (V) at 190 C as before.

合成路线23

Aspartic acid (I) was esterified with benzyl alcohol to afford the beta-benzyl ester (II). Dakin-West reaction of (II) with Ac2O and Et3N yielded the amido ketone (III). Acidic hydrolysis of (III), followed by re-esterification with EtOH, furnished amino ester (IV), which was acylated with acyl chloride (V), producing amide (VI). Cyclization between the amide and ketone groups of (VI) using Ac2O as the dehydrating reagent gave rise to the isoxazole (VII). The ester group of (VII) was then reduced to alcohol (VIII) with NaBH4 in the presence of AlCl3. Coupling of alcohol (VIII) with 4-nitrophenol (IX) to furnish ether (X) was effected either by Mitsunobu coupling or via previous conversion of (VIII) to the corresponding tosylate, followed by condensation with phenol (IX) under Williamson's ether synthesis conditions. Catalytic hydrogenation of the nitro group of (X) led to the aniline (XI). Finally, acylation of (XI) with trifluoromethanesulfonic anhydride provided the target sulfonamide.

合成路线24

5-Nitrobenzofuran-2-carboxylic acid (I) is coupled to 4-nitrophenol (II) in the presence of EDC to produce the p-nitrophenyl ester (III). Subsequent acylation of the duocarmycin derivative (IV) with active ester (III) leads to amide (V). Cyclopropane ring opening in (V) with HCl in DMF furnishes the chloromethyl derivative (VI). The nitro group of (VI) is then reduced by catalytic hydrogenation, yielding amine (VII). Acylation of (VII) with 7-nitroindole-2-carboxylic acid (VIII) affords the corresponding amide (IX)

合成路线25

Addition of formaldehyde to 5,7-dichlorobenzothiophene-2-sulfonamide (I), followed by condensation with trimethyl phosphite, furnished the dimethyl (sulfonamidomethyl) phosphonate (II). The phosphonate ester function of (II) was then hydrolyzed by means of bromotrimethylsilane, producing phosphonic acid (III). This was finally coupled to 4-nitrophenol (IV) using trichloroacetonitrile in hot pyridine to afford the title mono-phosphonate ester.

合成路线26

Reduction of 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionic acid (I) with LiAlH4 afforded alcohol (II), which was further brominated to (III) using PBr3. Alkylation of p-nitrophenol (IV) by the alkyl bromide (III) gave ether (V). Then, reduction of the nitro group of (V) to the aniline (VI) was accomplished by means of hydrazine in the presence of Raney nickel.

合成路线27