合成路线1

The condensation of p-anisidine (IV) with 3-chloropropionyl chloride (V) by means of TEA in hot toluene, hot 2-butanone or DMF gives the corresponding amide (VI), which is then cyclized by means of AlCl3 in N,N-dimethylacetamide at 150-60 C and treated with NaBH4 in water to yield the desired 6-hydroxy-1,2,3,4-tetrahydroquinolin-2-one intermediate (III).

合成路线2

4-Methoxyaniline (I) is reacted with 2'-bromo-4-methoxypropiophenone (II) to afford the indole (III). The ethyl group is introduced by deprotonation with sodium hydride in DMF followed by addition of ethyl bromide. The ether cleavage of (IV) with BBr3 yields the hydroxy derivative (V), which is converted to the acetate by using acetic acid an hydride in pyridine.

合成路线3

The synthesis of tritium-labeled taxol [3''-3H]-taxol has been described: The reaction of baccatin III (I) with chlorotriethylsilane in pyridine gives the protected compound (II), which is condensed with cis-1-benzoyl-4-(3-bromophenyl)-3-(triethylsilyloxy)azetidin-2-one (III) by means of butyllithium in THF, yielding 3''-bromo-2',7-bis-O-(triethylsilyl)taxol (IV). The deprotection of (IV) with pyridine and 48% HF in THF affords 3''-bromotaxol (V), which is finally debrominated with tritium by means of Pd/C and triethylamine in THF. The starting azetidinone (III) is obtained as follows: The condensation of 3-bromobenzaldehyde (VI) with 4-methoxyaniline (VII) in refluxing benzene gives the enamine (VIII), which is cyclized with acetoxyacetyl chloride (IX) by means of triethylamine in dichloromethane, yielding cis-3-acetoxy-4-(3-bromophenyl)-1-(4-methoxyphenyl)azetidin-2-one (X). The reaction of (X) with ceric ammonium nitrate (CAN) in acetonitrile affords cis-3-acetoxy-4-(3-bromophenyl)azetidin-2-one (XI), which is deacetylated with KOH in THF-water giving cis-4-(3-bromophenyl)-3-hydroxyazetidin-2-one (XII). The silylation of (XII) with chlorotriethylsilane in pyridine yields cis-4-(3-bromophenyl)-3-(triethylsilyloxy)azetidin-2-one (XIII), which is finally benzoylated with benzoyl chloride (XIV) and butyllithium in THF to afford the desired azetidinone (III).

合成路线4

This compound can be prepared by two different methods: 1) By cyclocondensation of p-anisidine (I) with 2-oxocyclohexanecarboxylate (II) to 7-methoxy-1,2,3,4-tetrahydroacridone (III), which by treatment with refluxing POCl3 is converted to 9-chloro-7-methoxy-1,2,3,4-tetrahydroacridine (IV). This compound is converted to final product by treatment with NH3 in refluxing p-cresol. 2) By cyclocondensation of 5-methoxyisatin (V) and cyclohexanone (VI) in concentrated aqueous ammonia at 150 C to 7-methoxy-1,2,3,4-tetrahydroacridine-9-carboxamide (VII), followed by a Hoffman degradation with potassium hypobromite.

合成路线5

The nitrosation of p-anisidine (I) with NaNO2 and HCl in water gives 4-methoxyphenyldiazonium chloride (II), which is condensed with 4-(4-methyl-1-cyclohexenyl)morpholine (III) yielding 2-(4-methoxyphenylhydrazono)-4-methylcyclohexanone (IV). The cyclization of (IV) by means of H2SO4 in refluxing ethanol affords 6-methoxy-4-methyl-1,2,3,4-tetrahydro-9H-carbazol-1-one (V), which is condensed with refluxing ethyl formate and NaH to give the corresponding 2-(hydroxymethylene) derivative (VI). The alkylation of (VI) with isopropyl iodide and K2CO3 yields the corresponding 2-(isopropoxymethylene) derivative (VII), which is methylated with CH3Li in ether to afford 6-methoxy-1,4-dimethyl-3,4-dihydrocarbazole-2-carboxaldehyde (VIII). The aromatization of (VIII) with MnO2 in refluxing benzene gives the corresponding carbazole (IX), which is condensed with malonic acid by means of piperidine in refluxing pyridine to afford 3-(6-methoxy-1,4-dimethylcarbazol-2-yl)-2-propenoic acid (X). The reaction of (X) with ethylchloroformate and sodium azide and acetone gives the corresponding azide (XI), which is cyclized by means of tributylamine in diphenyl ether at 250 C yielding 9-methoxy-5,11-dimethyl-1,2-dihydro-6H-pyrido[4,3-b]carbazol-1-one (XII). The reaction of (XII) with refluxing POCl3 affords 1-chloro-9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (XIII), which is finally treated with refluxing 2-(diethylamino)propylamine (XIV).

合成路线6

Reaction of 4-methoxyaniline (XXI) with ethyl acetoacetate (XXII) by means of triethanolamine in refluxing xylene gives the acetoacetanilide (XXIII), which is cyclized by means of hot triethanolamine and H2SO4 to yield 6-methoxy-4-methylquinolin-2(1H)-one (I), which is treated with refluxing POCl3 to provide 2-chloro-6-methoxy-4-methylquinoline (XXIV). Reaction of compound (XXIV) with SO2Cl2 in hot AcOH affords 2,5-dichloro-6-methoxy-4-methylquinoline (XXV), which is treated with MeONa in refluxing methanol to furnish 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Alternatively, the reaction of compound (XXIV) with MeONa as before gives 2,6-dimethoxy-4-methylquinoline (XXVII), which is treated with SO2Cl2 in hot AcOH to give the already described 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Nitration of compound (XXVI) with KNO3 and P2O5 gives the 8-nitroquinoline derivative (XXVIII), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH in hot NMP to yield the diaryl ether (VII). Finally, the nitro group of compound (VII) is reduced with hydrazine over Pd/C.

合成路线7

The condensation of 4-methoxyaniline (I) with 2,6-dichloro-3-nitrobenzoic acid (II) by means of DIEA or N,N-dimethylaniline at 75 C gives 6-chloro-2-(4-methoxyphenylamino)-3-nitrobenzoic acid (III), which is cyclized in refluxing POCl3 to yield the acridone (IV). Finally, this compound is condensed with N-[3-(dimethylamino)propyl]hydrazine (V) in THF/methanol to afford the target 2,6-dihydro-pyrazolo[3,4,5-kl]acridine.

合成路线8

Reaction of benzyloxyacetyl chloride (I) with (-)-trans-2-phenylcyclohexanol (II) afforded chiral ester (III). Subsequent removal of the benzyl group by hydrogenolysis, followed by protection with triisopropylsilyl chloride and imidazole in DMF provided silyl ether (IV). Treatment of (IV) with LDA in THF at -85 C generated the corresponding enolate, which was cyclocondensed with imine (VII), (obtained from 3-methylbutenal (V) and p-anisidine (VI)), to produce azetidinone (VIII). Then, the N-p-methoxyphenyl group was removed by treatment with cerium ammonium nitrate in cold ACN-H2O, and the resulting azetidinone (IX) was coupled with di-tert-butyl dicarbonate in the presence of DMAP and Et3N to yield (X).

合成路线9

The acylation of 4-methoxyaniline (I) with pivaloyl chloride (II) and TEA in CH2Cl2 gives the anilide (III), which is condensed with ethyl trifluoroacetate (IV) by means of n-BuLi in THF yielding the trifluoroacetyl derivative (V). The hydrolysis of the amido group of (V) with 6N HCl in refluxing DMF affords the 2-aminoacetophenone (VI), which is condensed with cyclopropylacetylene (VII) by means of n-BuLi in THF to give the tertiary alcohol (VIII). Finally, this compound is cyclized with phosgene and DIPEA in toluene yielding the racemic form of target compound.

合成路线10

Treatment of 5-nitroisoquinoline (I) with hydroxylamine and KOH produced 5-nitro-8-aminoisoquinoline (II). Subsequent hydrogenation of (II) over Pd/C gave diamine (III), which was then oxidized to the dichloroquinone (IV) by means potassium chlorate and concentrated HCl. Finally, displacement of the 7-chloro atom of (IV) with p-anisidine (V) in refluxing EtOH yielded the title compound.

合成路线11

Diazotization of p-anisidine (I), followed by coupling of the resulting diazonium salt (II) with 3-tert-butyl-4-hydroxyanisole (III) produced azobenzene (IV). Subsequent protection of the hydroxyl group of (IV) with chloromethyl methyl ether in the presence of NaH afforded the methoxymethyl derivative (V). Aniline (VI) was then obtained by catalytic hydrogenation of (V) over Pd/C. Condensation of aniline (VI) with triphosgene, followed by reaction with 3-picolylamine (VII) gave rise to urea (VIII). The methoxymethyl protecting group of (VIII) was finally removed by treatment with methanolic HCl.

合成路线12

The diazonium salt (VI), prepared by diazotization of p-anisidine (V), was added to 4-methoxy-2-tert-butylphenol (VII) yielding the azo adduct (VIII). Protection of the phenolic hydroxyl group of (VIII) was carried out by alkylation with methoxymethyl chloride and NaH to give methoxymethyl ether (IX). Then, reductive cleavage of the diazo group of (IX) by hydrogenation over Pd/C furnished aniline (X) (1). Subsequent reaction of (X) with triphosgene and triethylamine in cold CH2Cl2 produced isocyanate (XI), which was condensed with amine (IV) to afford urea (XII). After acid deprotection of the methoxymethyl group of (XII), treatment with phosphoric acid in EtOH provided the title triphosphate salt.

合成路线13

Condensation of 1-benzyl-3-hydroxy-1H-pyrazole-5-carboxylic acid methyl ester (I) with 3-(dimethylamino)-1-propanol (II) by means of 1,1'-(azodicarbonyl)dipiperidine and tributylphosphine under Mitsunobu conditions afforded the dimethylaminopropyl ether (III). After basic hydrolysis of the methyl ester group of (III), the resultant carboxylic acid (IV) was coupled with 4-methoxyaniline (V) using HATU to furnish the title amide.

合成路线14

Ring opening of cyclohexene oxide (I) with phenylmagnesium bromide in the presence of CuI, followed by acetylation of the resulting alcohol (II) gave the racemic trans-2-phenylcyclohexyl acetate (III). Enzymatic resolution of (III) using porcine liver acetone powder yielded the desired (-)-alcohol (II) along with unreacted (+)-acetate (III). Condensation of the sodium alkoxide of benzyl alcohol with bromoacetic acid (IV) afforded benzyloxyacetic acid (V), which was then coupled with the chiral alcohol (-)-(II) to give ester (VI). Hydrogenolysis of the O-benzyl group of (VI), followed by silylation of the resulting hydroxyacetate ester (VII) with triisopropylsilyl chloride, furnished (VIII). Imine (XI) was prepared by condensation of 3-methyl-2-butenal (IX) with p-anisidine (X). The asymmetric cyclocondensation reaction of the lithium enolate derived from ester (VIII) with imine (XI) yielded the chiral beta-lactam (XII). Oxidative removal of the p-methoxyphenyl protecting group of (XII) and then reprotection of the lactam N atom with Boc2O furnished the intermediate N-Boc lactam (XIII).

合成路线15

Condensation of p-anisidine (I) with 2-oxazolidinone (II) in hot 2-(2-methoxyethoxy)ethanol affords the N-aryl ethanediamine (III). This is then coupled with the succinimidyl ester of N-Z-L-leucine (IV) to furnish amide (V). The N-carbobenzoxy group of (V) is further removed by catalytic hydrogenation, providing amine (VI), which is finally acylated by 4-(benzyloxy)benzoic acid (VII) by means of HATU to yield the title compound.

合成路线16

Ullmann condensation between o-chlorobenzoic acid (I) and p-anisidine (II) produces the diphenylamine carboxylic acid (III), which is further cyclized to the 2-methoxyacridone (IV) by heating in polyphosphoric acid. N-Alkylation of acridone (IV) with 1-bromo-4-chlorobutane (V) in the presence of KOH under phase-transfer conditions furnishes the N-(chlorobutyl)acridone (VI). Finally, nucleophilic substitution of the chloro group of (VI) with N-(2-hydroxyethyl)piperazine (VII) gives rise to the title compound.

合成路线17

The intermediate chloro hydrazone (I) is prepared by he following method. Diazotization of p-anisidine (XII) employing sodium nitrite in cold aqueous HCl yields the ntermediate diazonium salt (XIII), which undergoes Japp-Klingemann reaction with ethyl 2-chloroacetoacetate (XIV) in the presence of NaOAc to produce the target hydrazone (I) (1, 2). Scheme 2.

合成路线18

合成路线19

Treatment of 2-aminobenzonitrile (V) with N,N-dimethylacetamide dimethylacetal (VI) at 115 °C yields N’-(2-cyanophenyl)-N,N-dimethylacetamidine (VII), which by cyclization with 4-methoxyaniline (VIII) in AcOH/acetonitrile at 118 °C gives N-(4-methoxyphenyl)- 2-methylquinazolin-4-amine (IX). Finally, the secondary amine group in compound (IX) is methylated by means of NaH in DMF .
Intramolecular cyclization of the acetamidine (II) with 4-methoxy-N-methylaniline (IV) in the presence of AlCl3 in NMP at 200 °C (5).