合成路线1

The condensation of ethyl 4-(bromomethyl)cinnamate (I) with imidazole (II) by means of NaH in DMF give ethyl 4-(1-imidazolylmethyl)cinnamate (III), wich is hydrolyzed with NaOH in methanol - water, and acidified with HCl.

合成路线2

By reaction of 2-naphthyl bromomethyl ketone (I) with imidazole (II) in DMF, followed by a treatment with HCl in ether.

合成路线3

The reduction of 2,4-dichlorophenacyl chloride with NaBH4 gives 1-(2,4-dichlorophenyl)-2-chloroethanol (II), which is condensed with imidazole (III) to yield 1-(2,4-dichlorophenyl)-2-(N-imidazolyl)ethanol (IV). Finally, this compound is condensed with 4-(phenylthio)benzyl chloride (V) [prepared by chloromethylation of diphenyl sulfide (VI) with formaldehyde and HCl] using NaH as condensing agent.

合成路线4

The chlorohydrin (II) is obtained by the reaction of p-chlorobenzylmagnesium chloride (I) with epichlorohydrin (A) in ether. This is then converted to the crystalline alcohol (III) by reaction with sodium imidazole (B) in DMF. On treatment with thionyl chloride is converted to the corresponding chloro compound (IV). When (IV) is reacted with 2,6-dichloro thiophenol (C) in the presence of anhydrous potassium carbonate in acetone, the free base of butoconazole is formed. Neutralization of the free base (V) with nitric acid gives butoconazole.

合成路线5

The Oxidation of 1-octyn-3-ol (I) with chromium trioxide gives the 3-oxooctyne (II), which by reaction with imidazole (III) yields (E)-1-(3-oxoocten-1-yl)imidazole (IV). Reduction of this compound with sodium borohydride gives (E)-1,3-hydroxyocten-1-yl)imidazole (V) . Finally, the latter is etherified with benzyl chloride (VI).

合成路线6

The condensation of 2-methyl-3-(1H-imidazol-1-ylmethyl)indole (III) with acrylonitrile (IV) by means of benzyltrimethylammonium hydroxide (B) in dioxane gives 1-(2-cyanoethyl)-2-methyl-3-(1H-imidazol-1-ylmethyl)indole (V), which is then hydrolyzed with KOH in water. The reaction of compound (III) with methyl acrylate (VI) in the same conditions as before gives 1-(2-methoxy-carbonylethyl)-2-methyl-3-(1H-imidazol-1-ylmethyl)indole (VII), which is also hydrolyzed. Compound (III) can be obtained from 2-methylindole (I).

合成路线7

A new synthesis of dazoxiben has been described: The condensation of methyl 4-hydroxybenzoate (I) with 1,2-dibromoethane (II) by means of NaOH gives methyl 4-(2-bromoethoxy)benzoate (III), which is hydrolyzed with H2SO4 to the corresponding free acid (IV). Finally, this compound is condensed with imidazole (V) in refluxing butanol.

合成路线8

This compound can be obtained in several different ways: 1) The condensation of imidazole (I) with 4-(2-chloroethoxy)benzamide (II) by means of NaH in DMF gives 1-[2-(4-carbamoylphenoxy)ethyl]imidazole (III), which is hydrolyzed by refluxing with 5N aqueous HCl. 2) Esters of 4-(2-chloroethoxy)benzoic acid (IV) can also be used instead of (II) in the first step of the synthesis. 3) This compound can also be obtained by direct condensation of imidazole (I) with 4-(2-chloroethoxy)benzoic acid (IV) by means of NaH in THF.

合成路线9

The condensation of imidazole (I) with 4-(phenethyl)phenacyl chloride (II) in DMF gives 1-[4-(phenethyl)phenacyl]imidazole (III), which is then reduced with NaBH4 in refluxing methanol.

合成路线10

The diazotation of 2-amino-4-chloroanisole (I) with NaNO2 and HCl in water gives the corresponding diazonium salt (II), which is then condensed with imidazole (III) by means of NaOH and sodium acetate in water.

合成路线11

The reduction of 4-phenylbenzophenone (I) with NaBH4 in ethanol gives 4-phenylbenzhydrol (II), which is then condensed with imidazole (III) by means of SOCl2 in acetonitrile.

合成路线12

The condensation of ethyl 4-(bromomethyl) cinnamate (I) with imidazole (II) by means of NaH in DMF gives ethyl 4-(1-imidazolylmethyl) cinnamate (III), which is hydrolyzed with NaOH in methanol / water, and acidified with HCl.

合成路线13

The reaction of 2,4-dichlorophenacyl chloride (I) with imidazole (A) gives the ketone (II), which is reduced with sodium borohydride to yield the alcohol (III). Conversion of the alcohol (III) to the chloro derivative (IV) with thionylchloride followed by reaction with p-chlorobenzyl mercaptan (V) affords sulconazole.

合成路线14

The esterification of 2,4-dichloromandelic acid (I) with methanol and sulfuric acid gives the corresponding methyl ester (II), which by treatment with NH3 in methanol yields 2,4-dichloromandelamide (III). The alkylation of (III) with allyl chloride (IV) and NaH in THF affords 2-allyloxy-2-(2,4-dichlorophenyl)acetamide (V), which is hydrolyzed with refluxing aqueous HCl giving 2-allyloxy-2-(2,4-dichlorophenyl)acetic acid (VI). The reduction of (VI) with LiAlH4 in refluxing ether yields 2-allyloxy-2-(2,4-dichlorophenyl)ethanol (VII), which is esterified with methanesulfonyl chloride in pyridine to afford 2-allyloxy-2-(2,4-dichlorophenyl) ethanol methanesulfonate (VIII). Finally, this compound is condensed with 1H-imidazole (IX) in refluxing DMF.

合成路线15

The bromination of 2,4-dichloroacetophenone (X) with Br2 in refluxing methanol gives 2,4-dichlorophenacyl bromide (XI), which is condensed with 1H-imidazole (IX) in methanol to yield 2,4-dichloro-alpha-(1-imidazolyl)acetophenone (XII). The reduction of (XII) with NaBH4 in refluxing methanol affords 1-(2,4-chlorophenyl)-2-(1-imidazolyl)ethanol (XIII), which is finally alkylated with allyl chloride (IV) and NaH in refluxing DMF.

合成路线16

The cyclization of 2,4-dichlorophenacyl bromide (I) with glycerol (II) gives cis-2-(2,4-dichlorophenyl)-2-bromomethyl-4-hydroxymethyl-1,3-dioxolane (III), which is then benzoylated with benzoyl chloride (A) yielding cis-2-(2,4-dichlorophenyl)-2-bromomethyl-4-benzoyloxymethyl-1,3-dioxolane (IV). The condensation of (IV) with 1H-imidazole (V) affords cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-4-benzoyloxymethyl-1,3-dioxolane (VI), which is then debenzoylated in basic medium giving cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-4-hydroxymethyl-1,3-dioxolane (VII). The reaction of (VII) with methanesulfonyl chloride (B) yields cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methanesulfonate (VIII). Finally, this compound is condensed with 1-acetyl-4-(4-hydroxyphenyl)piperazine (IX) by means of NaH in benzene - DMSO. Compound (IX) is obtained by reaction of 4-(1-piperazinyl)phenol dihydrobromide (X) with acetic anhydride by means of K2CO3 in refluxing acetic acid.

合成路线17

The reaction of 4-(5-iodo-2-methylbenzoyl)-3,5-dimethylbenzoic acid (I) with imidazole (II) by means of K2CO3, KF and Cu in DMF at 135 C gives 4-[5-(1-imidazolyl)-2-methylbenzoyl]-3,5-dimethylbenzoic acid (III), which is then reduced with NaBH4 in hot aqueous NaOH.

合成路线18

The reaction for preparing the esters is shown schematically by the condensation of 1-methyl-5-(4-methylbenzoyl)pyrrol-2-acetic acid and 7-(2-oxyethyl)theophylline as a general example, giving rise to the formation of the 1-methyl-5-(4-methylbenzoyl)pyrrol-2-acetate of 7-(2-oxyethyl)theophylline.

合成路线19

The cyclization of 3,4-diaminobenzophenone (I) with acetylimidic acid ethyl ester (II) in refluxing methanol gives 5-benzoyl-2-methylbenzimidazole (III), which is reduced with NaBH4 in methanol yielding 5-(alpha-hydroxybenzyl)-2-methylbenzimidazole (IV). Finally, this compound is condensed with imidazole (V) in refluxing acetonitrile.

合成路线20

A new synthesis for flutrimazole has been reported: The Grignard condensation of 2-fluorobenzophenone (I) with 4-fluorophenylmagnesium bromide (II) gives the corresponding triphenylcarbinol (III), which by reaction with refluxing SOCl2 is converted to the trityl chloride (IV). Finally, this compound is condensed with imidazole (V) in acetonitrile.

合成路线21

The reduction of 2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (I) with NaBH4 in methanol gives the corresponding alcohol (II), which is treated with refluxing SOCl2 to yield 2,4,5-trichloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (III). Finally, this compound is condensed with imidazole (IV) in refluxing DMF and salified with nitric acid in isopropanol/diisopropyl ether.

合成路线22

A process useful for the industrial preparation of eberconazole has been reported: The Wittig condensation of 2-(methoxycarbonyl)benzyl(triphenyl)phosphonium bromide (I) with 3,5-dichlorobenzaldehyde (II) by means of NaH in DMF gives 2-[2-(3,5-dichlorophenyl)vinyl]benzoic acid methyl ester (III), which is hydrolyzed with NaOH in methanol to the corresponding free acid (IV). The hydrogenation of (IV) with H2 over Pd/C in methanol affords 2-[2-(3,5-dichlorophenyl)ethyl]benzoic acid (V), which is cyclized to 2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (VI) by means of polyphosphoric acid. The reduction of (VI) with NaBH4 yields the corresponding carbinol (VII), which is treated with SOCl2 affording the chloride (VIII). Finally, this compound is condensed with imidazole (IX) in refluxing DMF.

合成路线23

The reaction of 2-bromo-2'-hydroxyacetophenone (I) with sodium methylmercaptide in methanol gives 2'-hydroxy-2-(methylthio)acetophenone (II), which is condensed with imidazole (III) by means of SOCl2 in dichloromethane to afford (E)-1-[1-(2-hydroxyphenyl)-2-(methylthio)vinyl]-1H-imidazole (IV), along with some of the (Z)-isomer. Finally, (IV) is condensed with pentyl bromide (V) by means of KOH in DMF.

合成路线24

The condensation of 5-chloro-2-nitroaniline (I) with imidazole (II) by means of KOH in DMSO gives 5-(1-imidazolyl)-2-nitroaniline (III). Hydrogenation of (III) over Pd/C in 1N HCl gives the diamine (IV), which is condensed with oxalic acid (V) in 4N HCl yielding 6-(1-imidazolyl)quinoxaline-2,3(1H,4H)-dione hydrochloride (VI). Finally, this compound is nitrated with HNO3/H2SO4.

合成路线25

Swern oxidation of protected (hydroxymethyl)pyrrolidine (I), followed by Wittig condensation of the resulting aldehyde (II) with methylene triphenylphosphorane provided vinylpyrrolidine (III). Hydroboration of (III) with 9-borabicyclo[3.3.1]nonane and subsequent oxidative treatment with sodium perborate gave alcohol (IV). Interconversion of the N-benzyl protecting group for an allyloxycarbonyl group was achieved by catalytic hydrogenation and then treatment of the deprotected amine (V) with allyloxycarbonyl chloride (VI). Alcohol (VII) was activated as the corresponding mesylate (VIII), which was condensed with imidazole (IX) in the presence of t-BuOK to afford the N-alkylated imidazole (X). Acid deprotection of the silyl ether of (X) yielded the corresponding secondary alcohol, which was further converted to mesylate (XI). Subsequent displacement in (XI) by potassium thioacetate furnished the thioacetate ester (XII).

合成路线26

Reaction of the Grignard reagent derived from 4-chlorobenzyl bromide (I) with allyl bromide (II) gives 4-(4-chlorophenyl)but-1-ene (III), which is epoxidized with peracetic acid in dichloromethane to yield 4-(4-chlorophenyl)-1,2-epoxybutane (IV). Opening of (IV) with the anion of imidazole (V) gives 1-[4-(4-chlorophenyl)-2-hydroxybutyl]imidazole (VI), which is oxidized under Swern conditions to 4-(4-chlorophenyl)-1-(1-imidazolyl)-2-butanone (VII). Ketone (VII) is then reacted with (S)-solketal tosylate [(S)-1,2-O-isopropylideneglycerol-3-O-tosylate] (VIII) in the presence of p-toluenesulfonic acid in toluene to give a mixture of stereoisomers, and (2S,4S)-cis-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-ylmethyl)-4-(p-toluenesulfonyloxy)methyl-1,3-dioxolane (IX) is then separated by crystallization. Finally, (IX) is treated with 4-aminothiophenol (X) in the presence of potassium carbonate in acetone.

合成路线27

The reduction of benzoin (XIII) with NaBH4 in ethanol/water gives the diol (XIV), which by a pinacol rearrangement by means of H2SO4 in hot acetic acid yields the diphenylacetaldehyde (XXV). The cyclization of (XV) with methyl vinyl ketone (XVI) by means of KOH in ethanol affords the cyclohexenone (XVII), which is reduced first with H2 over Pd/C in THF and then with NaBH4 in ethanol/water giving the 4,4-diphenylcyclohexanol (IX). The reaction of (IX) with PCl3 in THF yields the dichlorophosphite (XVIII), which is treated with imidazole (XIX) in THF affording the bis imidophosphite (XX). The condensation of (XX) with the previously obtained penta tert-butyl acetate compound (VI) in THF/heptane gives the imidophosphite (XXI), which is oxidized with sodium periodate yielding the phosphoric acid diester (XXII). Finally, the hydrolysis of (XXII) with HCl in ether/water eliminates the tert-butyl groups affording the desired chelating ligand (XII).

合成路线28

The reaction of bromobenzene (I) with 14CO2 by means of Mg in ether gives the corresponding benzoic acid (II), which is treated with SOCl2 and DMAP to yield the benzoyl chloride (III). The homologation of (III) with diazomethane in ether affords the phenacyl chloride (IV), which is enantioselectively reduced with borane and a chiral borolidine catalyst in THF to give (R)-2-chloro-1-phenylethanol (V). The cyclization of (V) by means of NaOH in ethyl ether yields the oxirane (VI), which by reaction with ammonia is converted into the (R)-2-amino-1-phenylethanol (VII). The condensation of (VII) with 4'-chlorobiphenyl-4-carboxylic acid (VIII) by means of CDI in DMF provides the amide (IX), which is cyclized to the oxazoline (X) by means of methanesulfonic anhydride and TEA in THF. Finally, this compound is condensed with imidazole (XI) by heating at 125 C.

合成路线29

The reaction of (R)-2-phenyloxirane (I) with ammonia in ethanol gives 2-amino-1(R)-phenylethanol (II), which is condensed with 4'-chlorobiphenyl-4-carboxylic acid (III) by means of isobutyl chloroformate and TEA in DMF yielding the amide (IV). The cyclization of (IV) by means of methanesulfonic anhydride in pyridine affords the oxazoline (V), which is finally condensed with imidazole by heating at 120 C.

合成路线30

The esterification of 2(S)-amino-2-phenylethanol (VII) with hot sulfuric acid gives the expected O-sulfate (VIII), which by treatment with hot aqueous NaOH yields the aziridine (IX). The condensation of (IX) with imidazole (VI) by heating at 120 C affords 2(R)-(1-imidazolyl)-2-phenylethan-1-amine (X). Finally, this compound is condensed with 4'-chlorobiphenyl-4-thiocarboxylic acid 2-pyridylthioester in DMF.

合成路线31

The title compound has been obtained by two related ways: Condensation of glycine ethyl ester (II) with 2,4-difluoronirobenzene (I) provided the N-arylglycine (III), which was further reduced to the phenylenediamine derivative (IV) by catalytic hydrogenation. Acylation of diamine (IV) with ethyl chloroglyoxylate, followed by ring closure in refluxing ethanol, yielded the quinoxalinedione (V). Subsequent electrophyllic nitration of (V) furnished the 6-nitroquinoxaline (VI). The fluoride group of (III) was then displaced with imidazole (VII) in hot DMF yielding the imidazolyl quinoxaline (VIII). Finally, basic hydrolysis of the ethyl ester function of (VIII) gave the target carboxylic acid.

合成路线32

The Vilsmeier-Haack formylation of 3-beta-acetoxyandrost-5-en-17-one (I) with POCl3/DMF provides the desired chloro aldehyde (III) along with minor amounts of the vinyl chloride (II), which are separated by column chromatography. Condensation of (III) with imidazole (IV) by means of K2CO3 in hot DMF yields derivative (V), which by decarbonylation of its 16-formyl group employing a modified Wilkinson’s catalyst gives (VI). The hydrolysis of the acetate group of (VI) with KOH in methanol affords the corresponding alcohol (VII), which is finally oxidized with aluminum isopropoxide and 1-methyl-4-piperidone in refluxing xylene.

合成路线33

Pyridone (XII) was converted to its dianion with LDA and then alkylated with propyl bromide to give the butyl pyridone (XIII). This was converted into bromopyridine (XIV) by subsequent treatment with PBr3. The nitrile group of (XIV) was then reduced to aldehyde (XV) using diisobutylaluminum hydride. The aldehye (XV) underwent a Heck reaction with tert-butyl acrylate (XVI) using tri-o-tolylphosphine and a palladium catalyst to provide unsaturated ester (XVII). Further condensation of the aldehyde group of (XVII) with (S,S)-pseudoephedrine (XVIII) produced the chiral oxazolidine (XIX). Alcohol (XI) was then protected as the silyl ether (XXI) using tert-butyldimethylsilyl chloride. After its conversion to the organolithium reagent with tert-butyllithium, addition to pyridyl acrylate (XIX) gave intermediate (XXII), and further acidic work-up removed the chiral auxiliary to afford aldehyde (XXIII).

合成路线34

The reaction of imidazole (I) with tert-butoxycarbonyl anhydride in ethyl acetate, followed by acetylation with acetic anhydride gives the cis-ethylenediamine derivative (II), which is isomerized to its trans isomer (III) with I2 in THF. The cyclization of (III) with hydrazone (IV) by means of Na2CO3 in hot acetonitrile yields the tetrahydropyridazine (V), which s deprotected at the amino group with HCl in ethyl acetate affording the amine (VI). The condensation of (VI) with the protected thiourea (VII) by means of HgCl2 and Et3N in DMF gives the protected guanidine (VIII), which is hydrolyzed at the ester group with KOH in methanol/water providing the carboxylic acid (IX). Finally, this compound is deprotected with TFA in dichloromethane. The intermediate, the hydrazone derivative (IV) has been obtained by condensation of 2-ethylbutyryl hydrazide (X) with 3-bromo-2-oxobutyric acid ethyl ester in ethyl ether catalyzed by acetic acid.

合成路线35

Condensation of alpha-chloro-(3,4-dimethoxyphenyl)acetonitrile (I) with p-thiocresol (II) in the presence of K2CO3 gave thioether (III). Alternatively, thioether (III) was obtained by reaction of the anion of (3,4-dimethoxyphenyl)acetonitrile (IV) with p-tolyl disulfide (V). Subsequent alkylation of (III) with 1-bromo-5-chloropentane using NaH in DMSO produced the 5-chloropentyl derivative (VI). This was then condensed with tetrahydroisoquinoline (VII) to yield the tertiary amine (VIII). Alkylation of the phenolic hydroxyl group of (VIII) with 2-chloroethyl tosylate produced the 2-chloroethyl ether (IX). Finally, reactionof (IX) with imidazole (X) and NaH in DMF furnished the title compound.

合成路线36

By condensation of 5-sulfamoyl-2-methoxybenzoic acid (I) with 1-propyl-2-aminomethylpyrrolidine (II) by means of phosgene and imidazole in dry benzene.

合成路线37

Regioselective addition of dimethylsulfoxonium methylide to 5-alpha-pregnane-3,20-dione (I) gave the epoxide (II). Opening of the epoxide ring of (II) with sodium methoxide produced the hydroxy ether (III). Bromination of (III) with Br2 in the presence of a catalytic amount of HBr afforded bromo ketone (IV). This was then condensed with imidazole (V) in refluxing acetonitrile to furnish the title compound.

合成路线38

Alkylation of imidazole (I) with 1,7-dibromoheptane (II) by means of potassium (metal) in refluxing THF furnishes N,N'-bis-(1-imidazolyl)heptane (III), which is treated with trichloroacetyl chloride (IV) in CH2Cl2 to provide derivative (V). Nitration of (V) by means of nitric acid/sulfuric acid in Ac2O/CH2Cl2 yields compound (VI), which is then converted into intermediate (VIII) by coupling in DMF/THF with substituted pyrrole (VII). In turn, (VII) can be obtained as follows: Treatment of N-methylpyrrole (IX) with trichloroacetyl chloride (IV) in CH2Cl2 affords derivative (X), which is nitrated to yield compound (XI) in the same conditions as for nitration of (V). The last step involves coupling of (XI) with 3-(dimethylamino)propylamine (XII), followed by reduction of the nitro moiety by hydrogenation over Pd/C in DMF/MeOH. Finally, the target product can be obtained by first hydrogenation of intermediate (VIII) over Pd/C in DMF/MeOH, followed by reaction with DCC and HOBt in DMF to allow coupling with carboxylic acid (XIV), which can be obtained by saponification of ethyl ester (XIII) in EtOH.

合成路线39

The dihydroxypyrimidine (IX) was converted to the 2-chloro derivative (XI) by chlorination with phosphoryl chloride and N,N-dimethylaniline, followed by treatment of the resultant dichloropyrimidine (X) with NaOAc/HOAc in aqueous EtOH. Nucleophilic displacement in chloropyrimidine (XI) with (S)-3-methylmorpholine (VIII) furnished adduct (XII). Subsequent chlorination of (XII) in hot POCl3 gave rise to the chloropyrimidine (XIII). This was then displaced with imidazole (XIV) to produce the target imidazolyl pyrimidine, which was isolated as the benzenesulfonate salt.

合成路线40

The reaction of imidazole (I) with phosgene (II) in hot benzene gives carbonyldiimidazole (III), which is condensed with 5-sulfamoyl-2-methoxybenzoic acid (IV) in THF yielding 1-(5-sulfamoyl-2-methoxybenzoyl)imidazole (V). Finally this compound is condensed with 1-methyl-2-aminomethylpyrrolidine (VI) in THF at room temperature

合成路线41

Reaction of p-chlorophenacyl bromide (I) with imidazole (II) affords 4'-chloro-2-(1-imidazolyl)acetophenone (III). Sodium borohydride reduction gives the corresponding alcohol (IV) which is then alkylated with 2,6-dichlorobenzyl chloride (V) to give orconazole (VI). Treatment of (VI) with nitric acid yield the title compound

合成路线42

Dexanabinol (I) was brominated using carbon tetrabromide in the presence of triphenylphosphine. The resultant allylic bromide (II) was then condensed with the lithium salt of imidazole (III) to produce the title compound.

合成路线43

Alkylation of 5,6-diphenyl-2-pyrazinol (I) with mesylate derivative (II) furnishes the pyrazinyl ether (III). The aldehyde function of (III) is then reduced to alcohol (IV) employing NaBH4 in EtOH. Chlorination of alcohol (IV) by means of SOCl2 in the presence of catalytic DMF leads to the benzyl chloride (V). This is finally condensed with imidazole (VI) in hot DMF to yield the title compound

合成路线44

This compound has been obtained by two similar ways: The condensation of 6-iodo-1-methyl-1H-indole (I) with imidazole (II) by means of copper trifluoromethanesulfonate, 1,10-phenanthroline, Cs2CO3 and dibenzylideneacetone gives 6-(1-imidazolyl)-1-methyl-1H-indole (III), which is condensed with oxalyl chloride (IV) in dichloromethane to yield the adduct (V). Finally, this compound is cyclized with 2-(1-methyl-1H-indol-3-yl)acetimidic acid isopropyl ester (VI) by means of TEA in dichloromethane to afford the target pyrrolinedione. Alternatively, indole (I) and imidazole (II) are condensed by means of Pd2(dba)3, BINAP and tBu-ONa to give 6-(1-imidazolyl)-1-methyl-1H-indole (III), which is condensed with methoxalyl chloride (VII) in dichloromethane to yield the adduct (VIII). The reduction of (VIII) with NaH2PO2 affords the methyl acetate derivative (IX), which is treated with NH4OH to provide the acetamide derivative (X). Finally, this compound is cyclized with the methoxalyl derivative (XI) (obtained by condensation of 1-methyl-1H-indole (XII) with methoxalyl chloride (VII)) by means of tBu-ONa in THF to afford the target pyrrolinedione.

合成路线45

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合成路线51

The nitration of imidazole (I) with HNO3 and H2SO4 at 100 °C gives 4-nitroimidazole (II) , which by a second nitration with HNO3 and Ac2O, and optionally AcOH, affords 1,4-dinitroimidazole (III) . Rearrangement of dinitroimidazole intermediate (III) in refluxing xylene or chlorobenzene generates 2,4-dinitroimidazole (IV), which then undergoes selective nitro group displacement with HCl in refluxing chlorobenzene/water to yield 2-chloro-4-nitroimidazole (V) . Condensation of imidazole (V) with epoxide (VI) by means of Et3N in hot ethyl acetate gives the adduct (VII), which is hydrolyzed using K2CO3 in MeOH providing the vicinal diol (VIII). Selective monomesylation of diol (VIII) by means of MsCl in the presence of pyridine affords the primary mesylate (IX), which is then treated with DBU in ethyl acetate to give epoxide (X). Finally, this compound is cyclized with the 4-substitutedphenol (XI) by means of NaH in DMF .