合成路线1

The cyclization of 4-benzoyloxycyclohexanone (I) with ethyl 2-bromomethylacrylate (II) and propylamine (III) in refluxing toluene gives ethyl 1-propyl-6-benzoyloxy-1,2,3,4,5,6,7,8-octahydroquinoline-3-carboxylate (IV), which is reduced with sodium cyanoborohydride in methanol yielding the corresponding decahydro derivative (V). Debenzoylation of (V) with NaOH in methanol affords the hydroxyquinoline (VI), which is oxidized with CrO3-pyr giving ethyl 1-propyl-6-oxodecahydroquinoline-3-carboxylate (VII). The reaction of (VII) with dimethylformamide dimethylacetal (VIII) in refluxing toluene yields ethyl 1-propyl-6-oxo-7-(dimethylaminomethylene)decahydroquinoline-3-carboxylate (IX), which is cyclized with hydrazine in ethanol affording ethyl 5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline-7-carboxylic acid (X). The reduction of (X) with LiAlH4 in THF gives the corresponding hydroxymethyl derivative (XI), which is esterified with methanesulfonyl chloride to the mesyl ester (XII). Finally, this compound is treated with methyl mercaptane and NaH in DMF.

合成路线2

The protection of (XI) with dihydropyran as usual affords the bistetrahydropyranylether (XII), which is deacetylated with K2CO3 in methanol to the 5-hydroxyester (XIII). Total hydrolysis of (XIII) with aqueous KOH gives the diacid (XIV), which is submitted to a dehydrative decarboxylation with N,N-dimethylformamide dimethyl acetal (A) in CHCl3 yielding the protected carbacyclin (XV). Finally, this compound is deprotected with aqueous acetic acid and hydrolyzed with KOH.

合成路线3

The condensation of ethyl acetate (I) with 4-picoline (II) by means of n-butyllithium in THF gives 1-(4-pyridyl)propanone (III), which by reaction with the dimethylacetal of dimethylformamide (IV) in refluxing HMPT is converted into 4-dimethylamino-3-(4-pyridyl)-3-buten-2-one (V). Finally, this compound is cyclized with cyanacetamide (VI) by means of sodium methoxide in refluxing DMF.

合成路线4

1) The condensation of N,N'-di(benzyloxycarbonyl)actinamine (I) with the L-glucose nitrosodimer (II) in DMF gives the oxime adduct (III), which is cyclized by means of aqueous HCl yielding the hemiketal triacetate (IV). The treatment of (IV) with anhydrous KHCO3 in acetonitrile affords the enone acetate (V), which is deacetylated with K2HPO4 in methanol to give N,N'-di(benzyloxycarbonyl)dehydrospectinomycin (VI). The hydrogenation of (VI) with H2 over Pd/BaSO4 in pyridine - isopropanol yields free spectinomycin (VII), which is protected again with benzyloxycarbonyl chloride as usual to give N,N'-di(benzyloxycarbonyl)spectinomycin (VIII). The formylation of (VIII) with formic acid - acetic anhydride gives the 2,6-di-O-formyl derivative (IX), which by treatment with acetic anhydride and dimethylaminopyridine (DMAP) is converted into the enol acetate (X). The reaction of (X) with dibromodimethylhydantoin (DBMH) in refluxing CCl4 under visible light illumination affords the unsaturated ketone (XI), which is treated with dimethylformamide dimethyl acetal in hot DMF, yielding the dimethylaminovinylene compound (XII).

合成路线5

The reaction of 4-benzoyloxycyclohexanone (I) with pyrrolidine (II) by means of p-toluenesulfonic acid in refluxing benzene gives the corresponding enamine (III), which is cyclized with acrylamide (IV) in refluxing dioxane yielding the mixture of hexahydroquinolones (V) and (VI). Benzylation of this mixture with benzylbromide (A) and NaH in THF affords the mixture of N-benzylquinolones (VII) and (VIII), which is reduced with LiAlH4 to the mixture of N-benzylhexahydroquinolines (IX) and (X). The reduction of this mixture with sodium cyanoborohydride in THF affords trans-1-benzyl-6-hydroxydecahydro quinoline (XI), which by reaction with BN in CH2Cl2 is converted to trans-1-cyano-6-hydroxydecahydro quinoline (XII). Oxidation of (XII) with CrO3/pyridine in CH2Cl2 gives the corresponding quinolone (XIII), which by reaction with dimethylformamide dimethyl acetal (XIV) in refluxing benzene is converted to 1-cyano-6-oxo-7-(dimethylaminomethylene)decahydroquinoline (XV). The cyclization of (XV) with hydrazine in refluxing methanol affords 5-cyano-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline (XVI), which by a reductive cleavage with Zn and acetic acid gives 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline (XVII). Finally, this compound is alkylated with propionaldehyde (B) and sodium cyanoborohydride in methanol.

合成路线6

The demethylation of 1-(4-methoxyphenyl)acetone (I) by means of AlCl3 gives the corresponding 4-hydroxy compound (III), which is condensed with epichlorohydrin (III), yielding the expected oxiranylmethyl ether (IV). The addition of 1-(2-methoxyphenyl)piperazine (V) to the epoxide ring of (IV) affords the isopropyl alcohol derivative (VI), which is condensed with dimethylformamide dimethylacetal (VII) to afford the dimethylaminobutenone (VIII). Finally, this compound is cyclized with 2-cyanoacetamide (IX) by means of sodium ethoxide, providing the target pyridone.

合成路线7

The condensation of N-(3-acetylphenyl)acetamide (I) with dimethylformamide dimethylacetal (II) at reflux temperature gives N-[3-[3-(dimethylamino)-2-propenoyl]phenyl]acetamide (III), which is alkylated with NaH and ethyl iodide to the corresponding N-ethyl derivative (IV). Finally, this compound is cyclized with 3-aminopyrazole-4-carbonitrile (V) in refluxing acetic acid.

合成路线8

Three related new synthetic routes for E-1020 have been reported: 1) The cyclization of 2-bromoacetaldehyde diethylacetal (I) with 2-aminopyridine-5-carboxylic acid methyl ester (II) by means of HCl in hot water gives imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (III), which is reduced with dibutylaluminum hydride in dichloromethane to the corresponding aldehyde (IV). The condensation of (IV) with nitroethane (V) by means of butylamine in refluxing ethanol affords 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine (VI), which is treated with Fe-FeCl2-HCl in hot ethanol-water to give 1-(imidazo[1,2-a]pyridyl-6-yl)-2-propanone (VII). The condensation of (VII) with dimethylformamide dimethylacetal (VIII) in hot DMF yields 4-(dimethylamino)-3-(imidazo[1,2-a]pyridin-6-yl)-3-buten-2-one (IX), which is finally cyclized with cyanacetamide (X) by means of sodium methoxide in hot DMF. 2) The cyclization of acetal (I) with 2-amino-5-bromopyridine (XI) as before gives 6-bromoimidazo[1,2-a]pyridine (XII), which is condensed with potassium acetylacetonate (XIII) by means of KI and Cu2I2 in hot DMF yielding the adduct (XIV). The cleavage of (XIV) with NaOH and then with HCl gives the propanone (VII), already obtained. 3) The condensation of the bromo derivative (XII) with 3-chloro-2-methylpropene (XV) by means of ethylmagnesium bromide in hot THF gives 6-isobutenylimidazo[1,2-a]pyridine (XVI), which is ozonolyzed with O3 in methanol-water-HCl to yield the propanone (VII), already obtained.

合成路线9

1) The condensation of 6-bromoimidazo[1,2-a]-pyridine (I) with 2-(chloromethyl)propene (II) by means of Mg and ethyl bromide in THF gives 6-(2-methyl-2-propenyl)imidazo[1,2-a]pyridine (III), which is ozonolyzed with O3 yielding 1-(imidazo[1,2-a]-pyridin-6-yl)-2-propanone (IV). The condensation of (IV) with dimethylformamide dimethylketal (V) in hot DMF affords 4-(dimethylamino)-3-(imidazo[1,2-a]-pyridin-6-yl)-3-buten-2-one (IV), which is finally cyclized with 2-cyanoacetamide (VII) by means of sodium methoxide in hot DMF.

合成路线10

2) The condensation of imidazo[1,2-a]pyridine-6-carboxaldehyde (VIII) with nitroethane (IX) by means of butylamine in refluxing ethanol gives 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine (X), which is treated with FeCl2 and concentrated HCl in refluxing ethanol to afford propanone (IV), already obtained.

合成路线11

A preparative-scale synthetic route for T-614 has been reported: The reaction of 4-chloro-3-nitroanisole (I) with potassium phenolate in hot DMF gives 4-phenoxy-3-nitroanisole (II), which is reduced to the corresponding 3-amino compound (III) by treatment with Fe and HCl. The reaction of (III) with mesyl chloride in pyridine affords the sulfonamide (IV), which is acylated with 2-aminoacetonitrile (V) and AlCl3 in nitrobenzene/HCl giving the 2-aminoacetophenone (VI). Formylation of (VI) at the NH2 with acetic formic anhydride yields the formamide (VII), which is demethylated with AlCl3 and NaI in acetonitrile affording the phenol (VIII). Finally, this compound is cyclized with dimethylformamide dimethylacetal in DMF.

合成路线12

The protection of cytidine (I) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (II) and dimethylformamide dimethylacetal (A) in pyridine gives the fully protected cytidine (III), which is oxidized with oxalyl chloride in DMSO/dichloromethane yielding the 2'-deoxy-2'-oxo derivative (IV). The reaction of (IV) with fluoromethyl phenyl sulfone (B) by means of diethyl chlorophosphate and lithium hexamethyldisylazide in THF affords the fluorovinyl sulfone (V) as a mixture of (E) and (Z) isomers that is separated by flash chromatography. The (Z)-isomer (V) is treated with tributyl tin hydride and AIBN in refluxing benzene to give the fluorovinyl stannane (VI), which is finally treated with KF in refluxing methanol to afford the target compound.

合成路线13

The protection of labeled cytidine (I) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (II) and dimethylformamide dimethylacetal (A) in pyridine gives the fully protected cytidine (III), which is oxidized with oxalyl chloride in DMSO/dichloromethane yielding the 2'-deoxy-2'-oxo derivative (IV). The reaction of (IV) with fluoromethyl phenyl sulfone (B) by means of diethyl chlorophosphate and lithium hexamethyldisylazide in THF affords the fluorovinyl sulfone (V) as a mixture of (E) and (Z) isomers that is separated by flash chromatography. The (Z)-isomer (V) is treated with tributyl tin hydride and AIBN in refluxing benzene to give the fluorovinyl stannane (VI), which is finally treated with KF in refluxing methanol to afford the labeled target compound.

合成路线14

The protection of cytidine (I) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (II) and dimethylformamide dimethylacetal (A) in pyridine gives the fully protected cytidine (III), which is oxidized with oxalyl chloride in DMSO/dichloromethane yielding the 2'-deoxy-2'-oxo derivative (IV). The reaction of (IV) with labeled fluoromethyl phenyl sulfone (V) by means of diethyl chlorophosphate (B) and lithium hexamethyldisylazide in THF affords the fluorovinyl sulfone (VI) as a mixture of (E) and (Z) isomers that is separated by flash chromatography. The (Z)-isomer (VI) is treated with tributyl tin hydride and AIBN in refluxing benzene to give the fluorovinyl stannane (VII), which is finally treated with KF in refluxing methanol to afford the labeled target compound.

合成路线15

A new synthesis of T-3761 has been described: The esterification of 2,3,4,5-tetrafluorobenzoic acid (I) with ethyl bromide and K2CO3 in DMSO gives the corresponding ethyl ester (II), which is condensed with tert-butyl cyanoacetate (III) by means of K2CO3, yielding 4-(cyanomethyl)-2,3,5-trifluorobenzoic acid ethyl ester (V) through the intermediate (IV). The cyclopropanation of (V) with 1,2-dibromoethane and benzyltriethylammonium chloride and NaOH in water/dichloromethane affords 4-(1-cyanocyclopropyl)-2,3,5-trifluorobenzoic acid, which by treatment with H2O2 and NaOH is converted to 4-(1-carbamoylcyclopropyl)-2,3,5-trifluorobenzoic acid (VII). Degradation of amide (VII) with Cl2 and NaOH gives the corresponding 4-aminocyclopropyl derivative (VIII), which is acetylated with acetic anhydride to the acetamide (IX). The reaction of (IX) with SOCl2 yields the acid chloride (X), which is condensed with malonic acid monoethyl ester potassium salt (XI) by means of triethylamine to afford 2-[4-(1-acetamidocyclopropyl)-2,3,5-trifluorobenzoyl]acetic acid ethyl ester (XII). The consecutive reaction of (XII) first with dimethylformamide dimethylacetal (XIII) in acetic acid and then with 2(S)-aminopropanol (XIV) gives the benzoylacrylic intermediate (XV), which, without isolation, is treated with K2CO3 in DMSO at 100 C to afford the ethyl ester of the acetylated T-3761 (XVI). Finally, this compound is deprotected by successive treatment first with ethanolic NaOH and then with hot 6N HCl.

合成路线16

A new synthesis for T-3761 has been described: The esterification of 2,3,4,5-tetrafluorobenzoic acid (I) with SOCl2 and ethanol gives ethyl 2,3,4,5-tetrafluorobenzoate (II), which is condensed with di-tert-butyl malonate (III) by means of NaH in DMF and decarboxylated with HCl/trifluoroacetic acid to 4-(carboxymethyl)-2,3,5-trifluorobenzoic acid ethyl ester (IV). Esterification of (IV) with diphenyldiazomethane in ether affords the corresponding ester (V), which is methylenated with bis(dimethylamino)methane (VI) and acetic anhydride in DMSO to give 4-[1-(diphenylmethoxycarbonyl)vinyl]-2,3,5-trifluorobenzoic acid ethyl ester (VII). The cyclopropanation of (VII) with trimethylsulfoxonium iodide and potassium tert-butoxide [(CH3)2SO=CH2] yields the cyclopropane compound (VIII), which is selectively hydrolyzed with trifluoroacetic acid to 4-(1-carboxycyclopropyl)-2,3,5-trifluorobenzoic acid ethyl ester (IX). The decarboxylative amination of (IX) with ethyl chloroformate, sodium azide and benzyl alcohol gives 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoic acid ethyl ester (X), which is saponified with NaOH in dioxane/ethanol to the corresponding acid (XI). The condensation of (XI) with the magnesium salt of malonic acid mono-tert-butyl ester (XII) by means of carbonyldiimidazole (Im2CO) in THF affords the benzoylacetic ester (XIII), which is treated first with dimethylformamide dimethylacetal (XIV) in refluxing benzene and then with 2-amino-1-propanol (XV) to yield 2-[4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoyl]-3-(2-hydroxy-1-methylethylamino)-2-propenoic acid ethyl ester (XVI). The cyclization of (XVI) by means of K2CO3 in hot DMF gives the pyridobenzoxazine (XVII), which is saponified with NaOH in ethanol/dioxane to the corresponding free acid (XVIII). Finally, the amino group of (XVIII) is deprotected by hydrogenation with H2 over Pd/C

合成路线17

Reaction of 4-acetylpyridine (I) with hot dimethylformamide dimethyl acetal (II) gives the enamino ketone (III), which is then condensed with (3-amino-1H-pyrazol-4-yl)(2-pyridyl)methanone (IV) in boiling acetic acid. Intermediate (IV), (3-amino-1H-pyrazol-4-yl)(2-pyrid-yl)methanone, is obtained by condensation of 3-oxo-3-(2-pyridyl)propionitrile (V) with dimethylformamide dimethyl acetal (II) to provide 2-(dimethylaminomethylene)-3-oxo-3-(2-pyridyl)propionitrile (VI), which is finally coupled with aminoguanidine nitrate (VII) by means of 10N NaOH in refluxing EtOH

合成路线18

The title compound has been obtained by several related ways: The reaction of 2-chloro-3-nitropyridine (I) with methylboronic acid by means of Pd(PPh3)4 and K2CO3 in hot dioxane gives 2-methyl-3-nitropyridine (III), which is condensed with dimethylformamide dimethylacetal (IV) to yield 2-[2-(dimethylamino)vinyl]-3-nitropyridine (V). The oxidation of (V) by means of NaIO4 affords 3-nitropyridine-2-carbaldehyde (VI), which is condensed with semicarbazide (VII) to provide the corresponding semicarbazone (VIII). Finally, the nitro group of (VIII) is reduced with SnCl2 or Na2S to furnish the target 3-aminopyridine-2-carbaldehyde semicarbazone. 2-Methyl-3-nitropyridine (III) can also be obtained by condensation of 2-chloro-3-nitropyridine (I) with diethyl malonate (II) by means of Na, followed by decarboxylative hydrolysis with H2SO4 at 125 C. The direct oxidation of 2-methyl-3-nitropyridine (III) with SeO2 in dioxane gives carbaldehyde (VI), which is treated with ethyleneglycol (IX) and Ts-OH to yield the cyclic acetal (X). The reduction of (X) with H2 over Pd/C in ethanol affords 3-aminopyridine-2-carbaldehyde ethylene ketal (XI), which is treated with semicarbazide (VI) and HCl to afford the target 3-aminopyridine-2-carbaldehyde semicarbazone. The condensation of 2-chloro-3-nitropyridine (I) with tributyl vinyl tin (XII) Pd(PPh3)4 and PPH3 in refluxing toluene gives 3-nitro-2-vinylpyridine (XIII), which is oxidized with O3 and Me2S in methanol to yield 3-nitropyridine-2-carbaldehyde (VI). This compound is condensed with semicarbazide (VII) and reduced to the target compound as already described.

合成路线19

The condensation of 1-(3-pyridyl)ethanone (I) with dimethylformamide dimethylacetal (II) gives 3-(dimethylamino)-1-(3-pyridyl)-2-propen-1-one (III), which is cyclized with 1-(2-methyl-5-nitrophenyl)guanidine (IV) [obtained by reaction of 2-methyl-5-nitroaniline (V) with cyanamide (VI)] in refluxing isopropanol to yield the pyrimidine derivative (VII). Reduction of the nitro group of (VII) with H2 over Pd/C in THF affords the corresponding amino compound (VIII), which is finally condensed with 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride (IV) in pyridine.

合成路线20

2',4',6'-Trimethoxyacetophenone (I) was condensed with dimethylformamide dimethylacetal (II) in refluxing DMF to afford the enamino ketone (III). Subsequent cyclization of (III) with N1-dicyclopropylmethyl-N1-propyl-guanidine hydrochloride (IV) in the presence of t-BuOK produced the target pyrimidine.

合成路线21

Condensation of 3-pyridylacetonitrile (I) with dimethyl-formamide dimethylacetal (II) afforded dimethylaminomethylene compound (III), which was cyclized to isoxazole (IV) by treatment with hydroxylamine.HCl in AcOH at 100 C. Quaternization with iodomethane provided pyridinium salt (V), and subsequent reduction with NaBH4 in MeOH produced tetrahydropyridine (VI). Then, methylation with iodomethane in the presence of KOH gave a mixture of monomethylated (VII) and dimethylated (VIII) compounds, which were separated by column chromatography. Finally, the major methylamino compound (VII) was converted to the oxalate salt.

合成路线22

The methylation of 2,6-difluorophenol (I) with methyl iodide and K2CO3 in DMF gives 2,6-difluoroanisole (II), which by treatment with butyllithium and CO2 yields 2,4-difluoro-3-methoxybenzoic acid (III). The methylation of (III) with diazomethane in ether affords the methyl ester (IV), which by reaction with BBr3 in dichloromethane results in 2,4-difluoro-3-hydroxybenzoic acid methyl ester (V). The alkylation of (V) with chlorodifluoromethane and K2CO3 in DMF gives 3-(difluoromethoxy)-2,4-difluorobenzoic acid methyl ester (VI), which is treated with sodium azide in DMSO, yielding the azido derivative (VII). The reduction of (VII) with H2 over Pd/C in ethanol affords 3-amino-2,4-difluorobenzoic acid methyl ester (VIII), which is hydrolyzed with NaOH in ethanol, giving the free acid (IX). The reaction of (IX) with NaNO2 and HBr yields 4-bromo-3-(difluoromethoxy)-2-fluorobenzoic acid (X), which is condensed with the magnesium salt of malonic acid monoethyl ester (XI) by means of CDI in THF, affording the 3-oxopropionate (XII). The reaction of (XII) with dimethylformamide dimethylacetal (XIII) and cyclopropylamine (XIV) by means of acetic anhydride in dichloromethane gives the 3-(cyclopropylamino)acrylate (XV), which is cyclized by means of K2CO3 in hot DMSO, yielding quinolone (XVI). The condensation of (XVI) with the isoindolylboronic acid derivative (XVII) - obtained by reaction of 5-bromo-1(R)-methyl-2-tritylisoindoline (XIX) with triisopropyl borate and butyllithium in THF - by means of bis(triphenylphosphine)palladium(II) chloride as catalyst in refluxing toluene affords the protected compound (XVIII), which is finally deprotected with HCl in ethanol.

合成路线23

The reaction of 2-amino-5-nitrobenzoic acid (I) with N,N-dimethylformamide dimethylacetal (II) by heating at 100 C gives the formamidine (III), which is cyclized with 3-bromoaniline (IV) in refluxing acetic acid yielding 4-(3-bromophenyl)-6-nitroquinazoline (V). The reduction of (V) with Fe and acetic acid affords the amine (VI), which is finally acylated with 2-butynoic acid by means of isobutyl chloroformate and N-methylmorpholine in THF.

合成路线24

The cyclization of acetyl cyclopropane (I) with 2-nitroacetamide (II) and formamide dimethylacetal (III) by means of p-tolulenesulfonic acid gives the nitro-pyridinone (IV) (1), which is reduced with H2 over Pd/C affording 3-amino-6-propylpyridin-2(1H)-one (V). The protection of the amino group of (V) with benzyl chloroformate affords the carbamate (VI), which is condensed with tert-butyl bromoacetate (VII) by means of NaH in THF giving substituted acetate ester (VIII). The deprotection of (VIII) by hydrogenolysis with H2 over Pd/C in ethyl acetate yields intermediate (IX) with a free amino group, which is treated with benzylsulfonyl chloride (X) and pyridine to afford the sulfonamide (XI). Hydrolysis of the ester group of (XI) with HCl in ethyl acetate gives the carboxylic acid (XII), which is condensed with the pyridylmethylamine (XIII) by means of EDC and HOBT to afford the carboxamide (XIV). Finally, this compound is deprotected with HCl as usual.

合成路线25

The condensation of pyruvic aldehyde dimethyl acetal (I) with dimethylformamide dimethyl acetal (II) afforded ketoenamine (III), which was condensed with N-methyl guanidine (IV) to give pyrimidine (V). Acid hydrolysis of the acetal function of (V) yielded pyrimidine carboxaldehyde (VI), which was converted to the imine (VIII) by treatment with 1-Boc-4-aminopiperidine (VII). Isonitrile (XII) was prepared by condensation of 4-fluorobenzaldehyde (IX) with formamide and p-thiocresol (X), followed by dehydration of the resulting formamide (XI) by means of POCl3 and Et3N. Reaction of isonitrile (XII) with imine (VIII) in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) produced imidazole (XIII). Finally, acid deprotection of the Boc group of (XIII) provided the title compound.

合成路线26

The reaction of 3-methoxybenzoylacetone (I) with dimethylformamide dimethylacetal (II) gives the dimethylaminomethylene derivative (III), which is cyclized with 2-cyanoacetamide (IV) by means of sodium ethoxide in ethanol yielding the pyridinone (V). The condensation of (V) with dimethylformamide dimethylacetal (II) affords the dimethylaminovinylpyridinone (VI), which is cyclized by means of ammonium acetate in DMF providing the 1,6-naphthyridine (VII). The hydrolysis of the cyano group of (VII) with NaOH gives the corresponding carboxylic acid (VIII), which is finally cyclized with N-hydroxyacetamidine (IX) by means of carbonydimidazole (CDI).

合成路线27

Reaction of 2-hydroxy-4-methoxypyridine-3-carbonitrile (X) with 85% phosphoric acid at 180 C gives 2,4-dihydroxypyridine (XI), which is nitrated with HNO3 in hot acetic acid to yield 2,4-dihydroxy-3-nitropyridine (XII). The reaction of (XII) with POCl3 in hot toluene affords 4-chloro-3-nitropyridin-2(1H)-one (XIII), which is condensed with the previously described amine (II) by means of DIEA in isopropanol to afford the aminopyridinol (XIV). Chlorination of (XIV) with POCl3 in toluene gives the previously described 4-amino-2-chloro-3-nitropyridine derivative (III), which is condensed with the described cyclopentanecarboxamide (IV) by means of K2CO3 in toluene, yielding the already known 2,4-diamino-3-nitropyridine (V). The reduction of (V) with ammonium formate over Pt/C or with Zn and ammonium acetate affords the described 2,3,4-triaminopyridine (VI), which is treated with HCl in THF in order to eliminate the acetonide group, providing the deprotected triaminopyridine derivative (XV). Finally, this compound is cyclized with formamidine (VII), triethyl orthoformate (XVI) or dimethylformamide dimethylacetal (XVII) in a suitable solvent.

合成路线28

The condensation of 2-(2,6-dichlorophenyl)acetonitrile (I) with 3,6-dichloropyridazin-3-yl)acetonitrile (III), wich is condensed with 2,4-difluorothiophenol (IV) by means of NaH in THF to yield the thioether (V). The partial hydrolysis of the cyano group of (V) with conc. H2SO4 at 100 CC affords the acetamide (VI), wich is finally cyclized with N,N-dimethylformamidedimethylacetal (VII) in refluxing toluene te provide the target pyrimido-pyridazine derivative.

合成路线29

Malonic acid monoethyl ester (I) is converted into beta-ketoester (III) by formation of the corresponding trimethylsilyl ester with TMSCl and pyridine in ether followed by deprotonation with n-BuLi and acylation with cyclopropanecarbonyl chloride (II) in DME. Treatment of (III) with refluxing N,N-dimethylformamide dimethyl acetal (IV) affords enamine (V). Quinoline-5-amine (VI) is first subjected to diazotation by treatment with NaNO2 in H2O/HCl, reduced with SnCl2.2H2O in HCl and isolated as the corresponding dihydrochloride salt (VII) by treatment with HCl. Condensation of enamine (V) with hydrazine (VII) in the presence of Et3N in refluxing EtOH yields pyrazole ester (VIII), which is converted into acylguanidine (X) either by direct heating with guanidine (IX) in EtOH or by first transformation into the corresponding carboxylic acid (XI) by saponification with NaOH in refluxing MeOH, followed by treatment with refluxing thionyl chloride and reaction with guanidine hydrochloride (XII) under Schotten-Baumann conditions in refluxing THF/NaOH. Finally, treatment of the free base (X) with HCl in THF allows isolation of the corresponding monohydrochloride-monohydrate salt .

合成路线30

Alkylation of 4-hydroxy-5-methoxy benzoic acid methyl ester (I) with 3-chloropropyl p-toluene sulfonate (III) by means of K2CO3 and methyl-tricapryl ammonium chloride (Aliquat 128) in refluxing acetone affords compound (III), which is then nitrated by means of HNO3 in HOAc to furnish 2-nitro derivative (IV). Reduction of the nitro moiety of (IV) by means of Fe in H2O/MeOH in the presence of ammonium chloride yields 2-amino compound (V), which is subjected to reaction with refluxing dimethylformamide dimethylacetal (VI) to provide amidine (VII). Condensation of (VII) with acetonitrile by means of n-BuLi in hexane/THF/HOAc gives substituted quinoline-carbonitrile (IX), whose hydroxyl group is replaced by a chlorine by treatment of (IX) with refluxing POCl3 to afford compound (X). Coupling of (X) with 2,4-dichloro-5-methoxyaniline (XI) in 2-ethoxyethanol in the presence of pyridine hydrochloride yields compound (XII), which is finally converted into the desired compound by condensation with 1-methylpiperazine (XII) by means of NaI in refluxing ethylene glycol dimethyl ether.

合成路线31

The alkylation of 4-hydroxy-3-methoxybenzoic acid methyl ester (I) with 3-(4-morpholinyl)propyl chloride (II) and tetrabutylammonium chloride in refluxing butanone gives 3-methoxy-4-[3-(4-morpholinyl)propoxy]benzoic acid methyl ester (III), which is nitrated with HNO3 in hot acetic acid to yield 5-methoxy-4-[3-(4-morpholinyl)propoxy]-2-nitrobenzoic acid methyl ester (IV). The reduction of (III) with H2 over Pd/C in methanol/ethyl acetate to afford the corresponding 2-amino ester (V), which is condensed with dimethylformamide dimethylacetal (VI) by heating at 100 C to provide the 2-(dimethylaminomethyleneamino) derivative (VII). The cyclization of (VII) with acetonitrile (VIII) by means of BuLi and CO2 in THF gives 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-oxo-1,4-dihydroquinoline-3-carbonitrile (IX), which is treated with refluxing SOCl2 to yield the 4-chloroquinoline derivative (X). Finally, this compound is condensed with 2-bromo-5-methoxyaniline by means of pyridine hydrochloride in 2-ethoxyethanol or NaH in THF (or DMF).

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Heating of 5-acetylpyrimidine (I) with N,N-dimethylformamide dimethylacetal (II) affords 3-(dimethylamino)-1-(5-pyrimidinyl)-2-propen-1-one (III), which is cyclized with 1-(2-methyl-5-nitrophenyl)guanidine —prepared in situ by adding NaOH to the guanidine nitrate (IV) in 2-propanol at 120 °C— to provide 1-methyl-4-nitro-2-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]benzene (V). The nitro group of compound (V) is then reduced to the corresponding aniline (VI) by catalytic transfer hydrogenation in the presence of formic acid and Pd/C in THF/MeOH. Benzylic bromination of 4-methyl-3-(trifluoromethyl)benzoic acid (VII) using sodium bromate and sodium bisulfite in isopropyl acetate gives 4-(bromomethyl)-3-(trifluoromethyl)benzoic acid (VIII), which is converted to the acid chloride (IX) by treatment with (COCl)2 and catalytic DMF in CH2Cl2. Acid chloride (IX) is then coupled with aniline (VI) in the presence of K2CO3 in dioxane to yield the 4-(bromomethyl)benzamide (X), from which the bromide group is finally displaced with (–)-(S)-3-(dimethylamino)pyrrolidine (XI) in the presence of K2CO3 in anhydrous DMF (1, 2). Scheme 1

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Mitsunobu reaction of apocynin (XIII) with the cyclopropylmethanol derivatives (XIa-c) in the presence of DEAD, PPh3 and DIEA in THF affords the aryl ethers (XXVIIa-c), which by nitration with HNO3 in Ac2O yields the 6-nitrophenyl derivatives (XXVIIIa-c). Condensation of ketones (XXVIIIa-c) with dimethylformamide dimethylacetal (XXIX) in DMF at 100 °C furnishes keto-enamines (XXXa-c), which upon Leimgruber-Batcho reaction using Fe in AcOH at 80 °C produces quinoline derivatives (XXXIa-c). Chlorination of 4-hydroxyquinolines (XXXIa-c) with POCl3 at 85 °C gives their corresponding chlorides (XXXIIa-c). These compounds are alternatively obtained by Mitsunobu condensation of 4-chloro-7-hydroxy-6-methoxyquinoline (XXXIII) with alcohols (Xia-c) using DEAD and PPh3 in CH2Cl2 at 0 °C. Condensation of chlorides (XXXIIa-c) with 6-hydroxy-N-methyl-1-naphthamide (V) by means of DMAP in 2,6-lutidine at 140 °C yields ethers (XIIa-c), whose N-carbamates are cleaved by means of HBr in AcOH .

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In one method, condensation of decitabine (I) with N,N-dimethylformamide dimethylacetal (II) gives the formamidine derivative (III), which by enzymatic acetylation with vinyl acetate in the presence of immobilized lipozyme in acetonitrile/1,4-dioxane yields the primary acetate (IV). Condensation of the deoxyribofuranose derivative (IV) with 2-cyanoethyl N,N,N’,N’-tetraisopropylphosphorodiamidate (V) in CH2Cl2 provides the phosphorodiamidate (VI), which then condenses with the deoxyguanosine derivative (VII) in CH2Cl2 to afford the trisubstituted phosphite (VIII) . oxidation of phosphite (VIII) with t-BuOOH provides the corresponding phosphate (IX), which is fully deprotected by means of NH3 in MeOH, and finally salified using naoAc in H2O/EtoH .

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Uracil intermediate (I) is obtained as follows. Condensation of 2-fluoro-4-iodophenyl isocyanate (XIII) with cyclopropylamine (XIV) in Et2O , or alternatively reaction of 2-fluoro-4-iodoaniline (XV) with CDI in the presence of Et3N in DMF, followed by condensation with cyclopropylamine (XIV) affords disubstituted urea (XVI). Cyclization of urea (XVI) is treated with malonic acid (XVII) in the presence of AcCl in Ac2O at 60 °C affords the pyrimidine trione (XVIII), which is chlorinated using POCl3 in the presence of PhNMe2 and a catalytic amount of H2O at 90 °C to provide a mixture of 6-chloropyrimidine (XIX) and the corresponding regioisomer. Finally, chloropyrimidine (XIX) is treated with methylamine (XX) in EtOH at 80 °C .
In an alternative procedure, acylation of urea (XVI) with cyanoacetic acid (XXI) by means of MsCl in DMF yields the N-(cyanoacetyl)urea (XXII), which cyclizes in aqueous NaOH at 80 °C to yield the amino-pyrimidine derivative (XXIII). Condensation of amine (XXIII) with dimethylformamide dimethylacetal (XXIV) in DMF affords formamidine (XXV), which is finally reduced using NaBH4 in EtOH/t-BuOH .

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Condensation of ethyl 3-(dimethylamino)acrylate (XVIII) with (benzyloxy)acetyl chloride (XIX) by means of pyridine in CH2Cl2 gives ethyl 2-[(benzyloxy)acetyl]-3-(dimethylamino)-2-propenoate (XX), which by cyclocondensation with ethyl oxalyl chloride (XXI) in the presence of LiHMDS in THF at –78 °C followed by heating with NH4OAc and AcOH affords pyridone derivative (XXII). Alkylation of pyridone (XXII) with bromoacetaldehyde dimethyl acetal (XXIII) and Cs2CO3 in DMF yields diethyl 1-(2,2-dimethoxyethyl)-3-(benzyloxy)-1,4-dihydropyridine-2,5-dicarboxylate (XXIV), which can also be obtained by condensation of diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (XXV) with 2,2-dimethoxyethylamine (XXVI) in EtOH. Hydrolysis of acetal (XXIV) with H2SO4 and HCOOH in CH2Cl2 yields aldehyde (XXVII), which upon cyclocondensation with 3(R)-amino-1-butanol (XI) by means of AcOH in refluxing MeOH/toluene provides the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XXVIII). Hydrolysis of ester (XXVIII) with NaOH in THF/MeOH/H2O gives the corresponding free acid (XXIX), which is finally condensed with 2,4-difluorobenzylamine (XIV) in the presence of HATU and NMM in DMF .
Propenoate (XX) can also be prepared by condensation of ethyl 4-chloroacetoacetate (XXX) with PhCH2OH in the presence of t-AmONa to give benzyl ether (XXXI), which then reacts with N,N-dimethylformamide dimethyl acetal (XXXII) in toluene .

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Condensation of methyl 4-chloroacetoacetate (XXXIII) with PhCH2OH in the presence of t-AmONa in THF gives the benzyl ether (XXXIV), which is then condensed with N,N-dimethylformamide dimethyl acetal (XXXII) in dioxane to give methyl 2-[(benzyloxy) acetyl]-3-aminoacrylate (XXXV). Cyclocondensation of acrylate (XXXV) with dimethyl oxalate by means of t-BuONa provides the pyranone derivative (XXXVII), which is then reacted with aminoacetaldehyde dimethyl acetal (XXVI) at reflux to yield pyridone (XXXVIII). Hydrolysis of acetal (XXXVIII) with H2SO4 and HCOOH affords aldehyde (XXXIX), which upon cyclocondensation with 3(R)-amino-1-butanol (XI) in the presence of AcOH in refluxing MeOH/toluene gives the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XL). Finally, methyl ester (XL) is condensed with 2,4-difluorobenzylamine (XIV) in the presence of AcOH in toluene .
Alternatively, coupling of methyl ester (XXXVIII) with 2,4-difluorobenzylamine (XIV) by means of AcOH in toluene/MeOH gives amide (XLI), which upon acetal hydrolysis with H2SO4 and HCOOH in toluene yields aldehyde (XLII). Finally, aldehyde (XLII) is submitted to cyclocondensation with 3(R)-amino-1-butanol (XI) in the presence of AcOH in refluxing MeOH/toluene .

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Condensation of methyl 4-methoxyacetoacetate (XLIII) with N,N-dimethylformamide dimethyl acetal (XXXII) produces methyl 3-(dimethylamino)-2-(methoxyacetyl)-2-propenoate (XLIV), which by reaction with 2,2-dimethoxyethylamine (XXVI) in MeOH affords the N-(dimethyoxyethyl)enamine (XLV). Cyclization of enaminoketone (XLV) with dimethyl oxalate (XXXVI) by means of LiH at 40 °C gives the dimethyl pyridone-dicarboxylate (XLVI), which by selective hydrolysis with LiOH yields the monocarboxylic acid (XLVII). Hydrolysis of acetal (XLVII) with MsOH and AcOH in acetonitrile at 58-65 °C followed by in situ cyclization of the resulting aldehyde (XLVIII) with 3(R)-amino-1-butanol (XI) in acetonitrile at 64 °C affords the pyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XLIX). Activation of acid (XLIX) with CDI in DME at 80 °C and subsequent coupling with 2,4-difluorobenzylamine (XIV) gives amide (L), which is finally O-demethylated with either MgBr2 in hot acetonitrile or LiBr in refluxing THF .