合成路线1

Esterification of 3,4-dichlorophenylacetic acid (I) with HCl/EtOH at reflux followed by radical bromination of the resulting ethyl ester (II) with NBS in the presence of HBr or (PhCOO)2 in refluxing CCl4 provides ethyl α-bromo-(3,4-dichlorophenyl)acetate (III). Tandem Michael addition and cyclization of ethyl bromoacetate (III) with ethyl acrylate (IV) by means of NaH and a catalytic amount of EtOH in ethyl ether gives diethyl cis-1-(3,4-dichlorophenyl)-1,2-cyclopropanedicarboxylate (V). After saponification with KOH in EtOH/H2O, the resulting diacid (VI) is cyclized with urea in refluxing xylene to yield the bicyclic imide (VII). Subsequent reduction of imide (VII) with BH3/THF or sodium bis(2-methoxyethoxy)aluminum hydride (Vitride, Red-Al) affords racemic 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (VIII) , which is finally treated with HCl in Et2O and submitted to enantiomeric separation by chiral chromatography .
Cyclocondensation of (3,4-dichlorophenyl)acetonitrile (X) with racemic epichlorohydrin (XIa) in the presence of NaNH2 in THF gives 1-(3,4-dichlorophenyl)-2-(hydroxymethyl)cyclopropanecarbonitrile as a diastereomeric mixture enriched in the cis-isomers (XIIa). Oxidation of alcohol (XIIa) with H5IO6 and CrO3 gives the carboxylic acid (XIII), which by esterification with MeOH in the presence of SOCl2 affords the methyl ester (XIV). Finally, reductive cyclization of the cyano ester (XIV) using BH3·Me2S in refluxing THF affords 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (VIII) .
In a stereospecific route, cyclization of nitrile (X) with (S)-epichlorohydrin (XIb) by means of NaHMDS in THF provides the cis-cyclopropanecarbonitrile (XIIb) as the major diastereoisomer, which is then reduced to aminoalcohol (XV) by means of BH3·Me2S. Chlorination of alcohol (XV) with SOCl2 in isopropyl acetate leads to the chlorinated amine (XVI), which is finally cyclized in the presence of NaOH, and then crystallized with HCl .

合成路线2

The reaction of 3-trifluoromethylbenzaldehyde (I) with morpholine (II) and potassium cyanide by means of p-toluenesulfonic acid in refluxing THF gives alpha-(3-trifluoromethylphenyl)-4-morpholineacetonitrile (III), which is condensed with ethyl acrylate (IV) by means of KOH in THF yielding gamma-cyano-gamma-(3-trifluoromethylphenyl)-4-morpholinebutyric acid ethyl ester (V). The cyclization of (V) with hydrazine in refluxing ethanol affords 4,5-dihydro-6-(3-trifluoromethylphenyl)-3(2H)-pyridazinone (VI), which is dehydrogenated by treatment with Br2 in hot acetic acid to give 6-(3-trifluoromethylphenyl)-3(2H)-pyridazinone (VII). The reaction of (VII) with POCl3 at 100 C affords 3-chloro-6-(3-trifluoromethylphenyl)pyridazine (VIII), which is finally cyclized with acetylhydrazine (IX) in refluxing n-butanol.

合成路线3

A synthesis of deuterium-labeled acrivastine has been published. The reaction of 2,6-dibromopyridine (I) with butyllithium in ethyl ether gives the monolithium salt (II), which is condensed with perdeuterated 4-methylbenzaldehyde (III) in the same solvent to yield the methanol (IV). The oxidation of (IV) with pyridinium chlorochromate in dichloromethane affords the corresponding ketone (V), which is condensed with ethyl acrylate (VI) by means of palladium acetate, triphenylphosphine and tributylamine at 130 C to give 3-[6-([2H]-4-methylbenzoyl)pyridin-2-yl]acrylic acid ethyl ester (VII). The Wittig condensation of (VII) with triphenyl[2-(1-pyrrolidinyl)ethyl]phosphonium bromide (VIII) by means of butyllithium in THF affords a cis:trans mixture that is submitted to chromatography yielding the (E,E)-isomer (IX), which is finally hydrolyzed with NaOH in ethanol, at room temperature.

合成路线4

5-Chloromercuri-2'-deoxyuridine (II) is prepared from 2'-deoxyuridine (I) by reaction with mercuriacetate and natrium chloride (1). Condensation of (II) with ethylacrylate (A) and lithium palladium chloride gives (E)-5-(2-carbethoxyvinyl)-2'-deoxyuridine (III), which is readily hydrozyled to (E)-5-(2-carboxyvinyl)-2'-deoxyuridine (IV) under basic conditions (0.5M NaOH). The final step involves the reaction of (IV) with N-bromosuccinimide to produce (E)-5-(2-bromovinyl)-2'-deoxyuridine.

合成路线5

The reaction of 4-methoxybenzylmagnesium bromide (I) with 1,3,4-trimethylpyridinium bromide (II) in ether, followed by a Diels-Alder condensation with ethyl acrylate (III) gives ethyl 3-(4-methoxybenzyl)-2,4,8-trimethyl-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate (IV), which is cyclized by means of HF yielding ethyl 1,2,3,4,4a,5,10,10a-octahydro-7-methoxy-1,4a,5-trimethyl-2,5-methanobenzo[g]quinoline-3-carboxylate (V). Acylation of (V) with hexanoyl chloride (VI) and butyllithium-diisopropylamine in THF affords the corresponding acyl derivative (VII), which is submitted to a reductive ring opening with formic acid in refluxing mesytilene giving 1,2,3,4,5,6-hexahydro-8-methoxy-3,6,11-trimethyl-11-(3-oxo-1-octyl)-2,6-methano-3-benzazocine (VIII). Finally, this compound is demethylated with 48% HBr and treated with methanesulfonic acid.

合成路线6

1) The microbiological oxidation of 3beta-hydroxyandrost-5-en-17-one (I) gives 1alpha,3beta-dihydroxyandrost-5-en-17-one (II), which is silylated with tert-butyldimethylsilyl (TBS) chloride and imidazole to the bis(silyloxy) compound (III). The dehydrogenation of (III) by bromination with N-bromosuccinimide (NBS) and dehydrobromination with 2,4,6-trimethylpyridine (TMPyr) yields 1alpha,3beta-bis(tert-butyldimethylsilyloxy)androsta-5,7-dien-17-one (IV). The Wittig condensation of (IV) with ethyltriphenylphosphonium bromide (V) by means of NaH in DMS gives the corresponding ethylidene derivative (VI), which is treated first with 9-borabicyclo[3.3.1]nonane (9-BBN) and then with H2O2 and NaOH in THF yielding a mixture of the 20(S)- and 20(R)-isomers of 1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregna-5,7-dien-20-ol that was separated by preparative TLC. The 20(S)-isomer (VII) was condensed with 1-bromo-3-butene (VIII) by means of NaH in refluxing xylene affording 20(S)-(3-butenyloxy)-1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregna-5,7-diene (IX), which is oxidized with O2 gas in DMF/water catalyzed by Cu2Cl2 and PdCl2 to give the corresponding 3-oxobutoxy derivative (X). The Grignard alkylation of (X) with methylmagnesium bromide in THF afforded the 20(S)-(3-hydroxy-3-methylbutoxy) derivative (XI), which was submitted to UV irradiation with a 200 W high-pressure mercury lamp in ethanol yielding the silylated 22-oxavitamin D3 derivative (XII). Finally, this compound is desilylated by a treatment with tetrabutylammonium fluoride (TBAF) in THF. 2) The addition of ethyl acrylate (XIII) to the previously reported pregna-5,7-dien-20(S)-ol (VII) by means of tetrabutylammonium hydroxide/NaOH in water/toluene gives the 2-(ethoxycarbonyl)ethoxy derivative (XIV), which by alkylation of the carbonyl function with methyllithium yields the 3-hydroxy-3-methylbutoxy derivative (XI), already obtained. 3) The addition of N,N-dimethylacrylamide (XV) to the previously reported pregna-5,7-dien-20(S)-ol (VII) by means of NaH gives the corresponding propionamide derivative (XVI), which by a Grignard alkylation with methylmagnesium bromide and CeCl3 is converted into the 3-hydroxy-3-methylbutoxy derivative (XI), already obtained.

合成路线7

By condensation of 3-(4-acetamido-2-methoxyphenoxy)propyl p-toluenesulfonate with 1-(2-fluorophenyl)piperazine (II). The starting products are obtained as follows: a) The addition of 4-acetamido-2-methoxyphenol (III) to ethyl acrylate (IV) gives ethyl-3-(4-acetamido-2-methoxyphenoxy)propionate (V), which is reduced with LiAlH4 to the corresponding alcohol and tosylated with tosyl chloride to the starting compound (I). b) The condensation of benzylamine (VI) with ethyl bromoacetate (VII) by means of K2CO3 gives N,N-bis(ethoxycarbonyl methyl)benzylamine (VIII), which is reduced with LiAlH4 and treated with SOCl2 to afford N,N-bis(2-chloroethyl)benzylamine (IX). The cyclization of (IX) with 2-fluoroaniline (X) yields 1-benzyl-4-(2-fluorophenyl)piperazine (XI), which is finally debenzylated by hydrogenation with H2 over PdIC to give piperazine (II).

合成路线8

The cyclization of N-(ethoxycarbonyl)glycine ethyl ester (I) with ethyl acrylate (II) by means of NaH in refluxing benzene gives 4-oxopyrrolidine-1,3-dicarboxylic acid diethyl ester (III), which is selectively decarboxylated with refluxing aqueous 6N HCl yielding 3-oxopyrrolidine-1-carboxylic acid ethyl ester (IV). The Friedlander cyclization of (IV) with 2-aminobenzaldehyde (V) affords the pyrroloquinoline derivative (VI), which is decarboxylated in basic medium to afford 2,3-dihydro-1H-pyrrolo[3,4-b]quinoline (VII). The condensation of (VII) with the furanone derivative (VIII) by means of pyridine in acetonitrile affords the acylated pyrroloquinoline (IX), which is cyclized by means of NaOAc in acetic acid providing the tetracyclic intermediate (X). The dechlorination of (X) with H2 over Pd/C in ethanol affords the expected methyl derivative (XI), which is debenzoylated with sodium methoxide in methanol to give the secondary alcohol (XII). Finally, this compound is oxidized with pyridinium chlorochromate (PCC) in dichloromethane.

合成路线9

The condensation of 4-O-benzyl-L-tyrosine methyl ester (I) with 4-methoxybenzaldehyde (II) in methanol gives the imine (III), which is oxidized with MCPBA yielding the oxaziridine (IV). The reaction of (IV) with NH2OH affords the 4-O-benzyl-N-hydroxy-L-tyrosine methyl ester (V), which is condensed with cyclohexane-1,4-dione monobutyleneketal (VI) in ethanol giving the imine oxide (VII). The cyclization of (VII) with ethyl acrylate (VIII) in refluxing toluene yields the spiranic isoxazolidine (IX). The hydrogenolysis of the O-N bond of (IX) with H2 over Pd/C, followed by lactam formation by means of AcOH affords the spiranic hydroxypyrrolidinone (X), which is alkylated at the phenolic OH with 3-methyl-2-butenyl bromide (XI) and Cs2CO3 in hot acetone providing the phenolic ether (XII). The reaction of (XII) with tosyl chloride, TEA and DMAP gives the tosylate (XIII), which is treated with sodium azide in DMF to affords the azide (XIV). The reduction of (XIV) with LiAlH4 followed by reductive methylation of the resulting amine with formic acetic anhydride and LiAlH4 provides the methyl-amino derivative (XV).

合成路线10

The condensation of 4-O-benzyl-L-tyrosine methyl ester (I) with 4-methoxybenzaldehyde (II) in methanol gives the imine (III), which is oxidized with MCPBA yielding the oxaziridine (IV). The reaction of (IV) with NH2OH affords the 4-O-benzyl-N-hydroxy-L-tyrosine methyl ester (V), which is condensed with cyclohexane-1,4-dione monobutyleneketal (VI) in ethanol giving the imine oxide (VII). The cyclization of (VII) with ethyl acrylate (VIII) in refluxing toluene yields the spiranic isoxazolidine (IX). The hydrogenolysis of the O-N bond of (IX) with H2 over Pd/C, followed by lactam formation by means of AcOH affords the spiranic hydroxypyrrolidinone (X), which is alkylated at the phenolic OH with 3-methyl-2-butenyl bromide (XI) and Cs2CO3 in hot acetone providing the phenolic ether (XII). The reaction of (XII) with tosyl chloride, TEA and DMAP gives the tosylate (XIII), which is treated with sodium azide in DMF to affords the azide (XIV). The reduction of (XIV) with LiAlH4 followed by reductive methylation of the resulting amine with formic acetic anhydride and LiAlH4 provides the methylamino derivative.

合成路线11

The condensation of adenine (I) with ethyl acrylate (II) by means of NaOEt in refluxing ethanol gives 3-(6-amino-1,6-dihydro-9H-purin-9-yl)propionic acid ethyl ester (III), which is treated with NaNO2 and HOAc to yield 3-(6-oxo-1,6-dihydro-9H-purin-9-yl)propionic acid ethyl ester (IV). Finally, this compound is treated with 1-(3-aminopropyl)-2-pyrrolidinone (V) in refluxing acetonitrile to afford the target propionamide.

合成路线12

The methylation of N-(tert-butoxycarbonyl)-L-tyrosine methyl ester (I) with methyl iodide and KOH gives the protected 4-O-methyl-L-tyrosine methyl ester (II), which is deprotected with TFA yielding (III). The Grundke oxidation of (III) affords the N-hydroxy derivative (IV), which is cyclocondensed with cyclohexane-1,4-dione monoethylene ketal (V) and ethyl acrylate (VI) in refluxing toluene to afford the spiroisoxazolidinone (VII). The reductive rearrangement of (VII) with H2 over Pd/C in acetic acid provides the spiropyrrolidinone (VIII), which is treated successively with tosyl chloride and with sodium azide to obtain the azido derivative (IX). The reduction of (IX) with H2 over Pd/C, protection of the resulting amine with Boc2O, and methylation of the resulting carbamate with NaH and methyl iodide affords the N-methylcarbamate (X). The reduction of the methoxycarbonyl group of (X) with LiBH4 in THF gives the carbinol (XI), which is oxidized with Dess-Martin periodinane to the aldehyde (XII). The rearrangement of (XII) by means of potassium tert-butoxide, followed by deprotection of the carbamate group yields the 7,10a-methanopyrrolo[1,2-a]azocin-8-one derivative (XIII), which is reduced at the carbonyl group with LiAlH4 in THF affords the 8(R)-hydroxy derivative (XIV). The protection of the amino group of (XIV) with benzyloxycarbonyl chloride and triethylamine yields the carbamate (XV).

合成路线13

The condensation of adenine (I) with ethyl acrylate (II) by means of sodium ethoxide in methanol gives 3-(9-adenyl)propionic acid ethyl ester (III), which is treated with NaNO2/acetic acid yielding 3-(6-oxo-1,6-dihydro-9H-purin-9-yl)propionic acid ethyl ester (IV). The hydrolysis of (IV) with KOH in water affords the corresponding free acid (V), which is esterified with 4-chlorophenyl trifluoroacetate (VI) in pyridine giving the expected 4-chlorophenyl ester (VII). The condensation of ester (VII) with ethyl 4-aminobenzoate (VIII) by heating (35-40 C) in DMSO yields 4-[3-(6-oxo-1,6-dihydro-9H-purin-9-yl)propionamido]benzoic acid ethyl ester (IX), which is finally hydrolyzed with KOH in water.

合成路线14

The reaction of 1,3,5-tribromobenzene (I) with 4-fluorobenzaldehyde (II) by means of BuLi in ethyl ether gives the benzhydrol (III), which is condensed with ethyl acrylate (IV) by means of palladium acetate and tri o-tolylphosphine in refluxing acetonitrile yielding the phenylenebisacrylate (V). The acetylation of (V) with acetic anhydride and DMAP in dichloromethane affords the acetate (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate providing the bispropanoate (VII). Selective hydrolysis of (VII) with NaOH in ethanol gives the monoacid (VIII), which is treated with oxalyl chloride in dichloromethane yielding the monoacyl chloride (IX). The reaction of (IX) with NH4OH affords the corresponding amide (X), which is treated with NaOCl and NaOH to perform degradation of the amide group and simultaneous hydrolysis of the ester group providing the amino acid (XI). Finally, this compound is sulfonated with 4-chlorophenylsulfonyl chloride (XII) and NaOH.

合成路线15

The reaction of 3-bromo-5-iodobenzoic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which by a Friedel-Crafts condensation with fluorobenzene (II) by means of AlCl3 in refluxing dichloromethane yields the benzophenone (IV). The condensation of (IV) with ethyl acrylate (V) by means of palladium acetate and triethylamine in refluxing acetonitrile affords the cinnamic acid derivative (VI), which is condensed with N-vinylphthalimide (VII) by means of palladium acetate and diisopropylamine in refluxing xylene to provide the unsaturated adduct (VIII). The reduction of the carbonyl group of (VIII) with triethylsilane and TFA gives the diphenylmethane derivative (IX), which is hydrogenated with H2 over Pd/C in ethyl acetate to yield the saturated diphenylmethane derivative (X). Elimination of the phthalimido group of (X) with hydrazine affords (XI) with a primary amino group. that is sulfonated with 4-chlorophenylsulfonyl chloride (XII) and triethylamine in THF to provide the sulfonamide (XIII). Finally, the ester group of (XIII) is hydrolyzed with aqueous NaOH.

合成路线16

The reaction of phenylalanine methyl ester (I) with benzaldehyde (II) and TEA in dichloromethane gives the aldimine (III), which is condensed with allyl bromide (IV) by means of n-BuLi in THF yielding the adduct (V). Treatment of (V) with HCl in methanol cleaves the benzylidene protecting group to afford the alpha-allylphenylalanine methyl ester (VI), which is reprotected with Boc2O and NaHCO3 in THF providing the carbamate (VII). The ozonolysis of (VII) with O3 in MeOH/CH2Cl2 gives the aldehyde (VIII), which is cyclized with hydrazine in refluxing THF yielding the tetrahydropyridazinone (IX). Hydrogenation of (IX) with H2 over PtO2 in methanol affords the hexahydropyridazinone (X), which is cyclocondensed with ethyl acrylate (XI) and formaldehyde to furnish the pyrazolopyridazine (XII). Hydrolysis of the ester group of (XII) with LiOH in THF/water gives the acid (XIII), which is finally condensed with N-omega(4-methoxytrityl)-L-arginylchloromethane (XIV) by means of isobutyl chloroformate and NMM in THF yielding, after working up, a diastereomeric mixture of amides, from which the target diastereomer is obtained by column chromatography.

合成路线17

The reaction of phenylalanine methyl ester (I) with benzaldehyde (II) and TEA in dichloromethane gives the aldimine (III), which is condensed with allyl bromide (IV) by means of n-BuLi in THF yielding the adduct (V). Treatment of (V) with HCl in methanol cleaves the benzylidene protecting group to afford the alpha-allylphenylalanine methyl ester (VI), which is reprotected with Boc2O and NaHCO3 in THF providing the carbamate (VII). The ozonolysis of (VII) with O3 in MeOH/CH2Cl2 gives the aldehyde (VIII), which is cyclized with hydrazine in refluxing THF yielding the tetrahydropyridazinone (IX). Hydrogenation of (IX) with H2 over PtO2 in methanol affords the hexahydropyridazinone (X), which is cyclocondensed with ethyl acrylate (XI) and formaldehyde to furnish the pyrazolopyridazine (XII). Hydrolysis of the ester group of (XII) with LiOH in THF/water gives the acid (XIII), which is finally condensed with the argininol derivative (XIV) by means of EDC, HOBT and DIEA in THF yielding the corresponding amide (XV). Finally, the secondary alcohol of (XV) is oxidized with Dess Martin periodinane (DMP) to afford, after working up, a diastereomeric mixture of amides, from which the target diastereomer is obtained by HPLC chromatography.

合成路线18

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19

Acetate (XI) was coupled with the bis-silylated uracil (XII) in the presence of trimethylsilyl triflate to give the 1:1 mixture of glycosylated products (XIII). The benzyl protecting groups of (XIII) were removed with BCl3, and the resulting mixture of diols was separated by preparative RP-HPLC. The desired isomer (XIV) was acetylated with Ac2O to give the diacetate ester (XV). After iodination of (XV) using LiI and ammonium cerium nitrate, the acetate groups were removed by treatment with methanolic NaOMe to afford 5-iodouracil (XVI). Subsequent Heck reaction of (XVI) with methyl acrylate (XVII) in the presence of Pd(OAc)2 and PPh3 produced ester (XVIII) together with some deiodinated product. Hydrolysis of the ester function of (XVIII) gave carboxylic acid (XIX), which was finally treated with N-bromosuccinimide and K2CO3 in DMF to yield the target bromovinyl compound.

合成路线20

Michael addition of ethyl acrylate (II) to the indenopyrrolocarbazole (I) provided (III). Lactam N-protection of (III) with dimethoxybenzhydrol yielded N-protected ethyl ester (IV), which was reduced with LiBH4 to give alcohol (V). Subsequent bromination of (V) with N-bromosuccinimide yielded (VI), which was first submitted to palladium-catalyzed carbonylation in methoxyethanol and then N-deprotected with trifluoroacetic acid and thioanisole to furnish (VII). Finally, reduction of ester (VII) with DIBAL furnished the diol intermediate (VIII).

合成路线21

Methylation of 5-iodovanillin (I) with dimethyl sulfate and K2CO3 afforded dimethoxy derivative (II). This was condensed with 3-anilinopropionitrile (III) in the presence of potassium tert-butoxide yielding the enamino nitrile (IV). Subsequent cyclization of (IV) with guanidine hydrochloride (V) produced diaminopyrimidine (VI). Cinnamate derivative (VIII) was then obtained by palladium-catalyzed coupling of (VI) with ethyl acrylate (VII).

合成路线22

Treatment of ethyl acrylate (I) with N-benzylmethylamine (II) affords aminopropionate derivative (III), which is then subjected to Grignard reaction with 3-bromoflurobenzene (IV) by means of Mg and catalytic iodine in refluxing THF and crystallized as a hydrochloride salt by treatment with HCl to provide propylamino derivative (V). Alcohol (V) is converted into allylamine (VI) by elimination induced by heating with HCl/HOAc, and finally the target product is obtained by hydrogenation of (VI) catalyzed by Pd(OH)2/C in EtOH.

合成路线23

Palladium-catalyzed coupling of 5-bromopyrimidine (I) with ethyl acrylate (II) afforded pyrimidinyl acrylate (III), which was hydrogenated over Pd/C to give (IV). Claisen condensation of (IV) with ethyl formate furnished oxoester (V). This was then cyclized with thiourea (VI) to produce the intermediate thiouracil (VII).

合成路线24

2-Aminobenzonitrile (XV) was acylated with 2-bromoisobutyryl bromide (XVI) to afford the cyano amide (XVII). Halogen-metal exchange with ethylmagnesium bromide followed by intramolecular addition to the cyano group of (XVII) gave rise to the quinoline dione (XVIII). This was reduced to the tetrahydroquinoline (XIX) by means of LiAlH4 and AlCl3. Iodination of (XIX) with benzyltrimethylammonium iodine dichloride furnished (XX), which was coupled with ethyl acrylate (XXI) in the presence of palladium acetate, yielding the unsaturated ester (XXII). After catalytic hydrogenation of the olefin (XXII) to propionyl ester (XXIII), sulfonation and treatment with POCl3, intermediate sulfonyl chloride (XXIV) was obtained.

合成路线25

Michael addition of ethyl acrylate (II) to the indenopyrrolocarbazole (I) provided (III). Lactam N-protection of (III) with dimethoxybenzhydrol yielded N-protected ethyl ester (IV), which was reduced with LiBH4 to give alcohol (V). Subsequent bromination of (V) with N-bromosuccinimide yielded (VI), which was first submitted to palladium-catalyzed carbonylation in methoxyethanol and then N-deprotected with trifluoroacetic acid and thioanisole to furnish (VII). Finally, reduction of ester (VII) with DIBAL furnished the diol intermediate (VIII).

合成路线26

Michael addition of ethyl acrylate (I) to glycine ethyl ester (II) produces the amino diester (III), which is protected as the allyl carbamate (IV) by treatment with allyl chloroformate. Dieckmann cyclization of diester (IV) in the presence of NaH leads to pyrrolidinone (V). After reduction of (V) to the corresponding alcohol (VI) with NaBH4, dehydration by means of methanesulfonyl chloride and pyridine furnishes the conjugated ester (VII). Acid (VIII), obtained by alkaline hydrolysis of (VII), is then condensed with magnesium tert-butyl malonate in the presence of CDI to produce keto ester (IX). Chlorination of (IX) with sulfuryl chloride, followed by acidic decarboxylation gives rise to chloro ketone (X). This is then condensed with ammonium dithiocarbamate to generate the 2-mercapto thiazole (XI)

合成路线27

合成路线28

Jones oxidation of 2-fluoro-4-methyl-1-nitrobenzene (XVIII) with CrO3 and H2SO4, followed by acetylation with Ac2O in AcOH yields the gemdiacetate (XIX), which by deacetylation with HCl in AcOH at 115 °C provides 3-fluoro-4-nitrobenzaldehyde (XX). Horner-Wadsworth-Emmons reaction of aldehyde (XX) with ethyl (diethoxyphosphoryl)acetate (XXI) using NaH in THF affords the unsaturated ester (XXII), which by fluoride substitution with methylamine (XXIII) in DMSO provides the nitro-aniline derivative (XXIVa) . Alternatively, condensation of 2,4-dichloro-1-nitrobenzene (XXV) with methylamine (XXIII) using Et3N in DMSO or THF yields 5-chloro-N-methyl-2-nitroaniline (XXVI), which is then subjected to Heck coupling with ethyl acrylate (XXVIIa), methyl acrylate (XXVIIb) or butyl acrylate (XXVIIa) in the presence of Pd(OAc)2, LiCl and DIEA in DMAc at 110 °C , or Pd2dba3, t-Bu3P and (c-Hex)2NMe at 110 °C to give the corresponding arylacrylates (XXIVa), (XXIVb) or (XXIVc). Reduction of the nitro group in compounds (XXIVa), (XXIVb) or (XXIVc) by means of SnCl2.2H2O in EtOH at 80 °C , H2 over Raney-Ni in toluene/MeOH or Na2S2O4 and K2CO3 in EtOH/H2O produces the corresponding diaminophenylacrylates (XXVIIIa) , (XXVIIIb) or (XXVIIIc) , which are finally condensed with 1-aminocyclo-butanecarboxylic acid hydrochloride (XXIX) in CH2Cl2 to provide the benzimidazole intermediates (IIIa) , (IIIb) or (XXX), the free base of intermediate (II) .
Similarly, intermediate (II) can be obtained by condensation of the diaminophenylacrylate (XXVIIIc) with N-Boc-1-aminocyclobutanecarboxylic acid (XXXI) using DCC in toluene, followed by N-deprotection and cyclization of the resulting amino amide (XXXII) with HCl in BuOH at 75 °C .