合成路线1

Alkylation of 5-hydroxyisoquinoline (I) with bromide (II) in DMF at 80 C afforded isoquinolinium salt (III). This was reduced to tetrahydroisoquinoline (IV) by catalytic hydrogenation in the presence of Pd/C. Finally, Mannich reaction with formaldehyde and perhydroazepine (V) in THF-water at r.t. provided the target compound.

合成路线2

The esterification of 4,4-bis(4-hydroxyphenyl)pentanoic acid (I) with diazomethane in ethyl ether/methanol gives the methyl ester (II), which is treated with phenylmagnesium bromide in THF to yield 4,4-bis(4-hydroxyphenyl)-1,1-diphenyl-1-pentanol (III). The reduction of (III) with H2 over Pd/C in methanol affords 4,4-bis(4-hydroxyphenyl)-1,1-diphenylpentane (IV), which is finally condensed with azepane (V) and formaldehyde in hot ethanol/water.

合成路线3

The reaction of 4-hydroxybenzyl alcohol (V) with ethyl 2-bromoacetate (XI) by means of K2CO3 gives the phenoxyacetate (XII), which is then treated with SOCl2 in THF to obtain the benzyl chloride (XIII). Reaction of (XIII) with the indole derivative (VII) by means of NaH in DMF yields the adduct (XIV), whose ester group is reduced with LiAlH4 in THF to afford the 2-hydroxyethoxy compound (XV). Treatment of (XV) with CBr4 and PPh3 in THF provides the 2-bromoethoxy compound (XVI), which is converted into compound (XVIIII) by reaction with hexamethyleneimine (homopiperidine) (XVII) in THF. Finally, compound (XVIII) is debenzylated by hydrogenation with either H2 over Pd/C in ethanol/THF or with cyclohexadiene and Pd/C in THF/EtOH.

合成路线4

By condensation of N-(perhydroazepin-1-ylcarbonyl)-L-leucine (V) with 4-O-benzyl-L-tyrosine tert-butyl ester (VIII) by means of HOBT and diisopropylethylamine in DMF. The two peptide intermediates (V) and (VIII) have been obtaines a follows: L-Leucine fragment (V): The carbonatation of perhydroazepine (I) with CO2 and pyridine followed by reaction with SOCl2 gives perhydroazepin-1-ylcarbonyl chloride (II), which is condensed with L-leucine benzyl ester (III) yielding the N-acylated leucine ester (IV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in THF to afford the target intermediate (V). Tyrosine fragment (VIII): By esterification of 4-O-benzyl-L-tyrosine (VI) with isobutylene (VII) by means of sulfuric acid in dioxane.

合成路线5

Hexahydroazepine (I) was coupled with N-Boc-glycine (II) by means of EDC and HOBt, and the resulting amide (III) was reduced with LiAlH4 to give diamine (IV). Subsequent coupling of (IV) with 3,4-dichlorophenylacetic acid (V) in the presence of DCC afforded amide (VI). Finally, reduction of (VI) with aluminum hydride in THF provided the title compound.

合成路线6

The reaction of 2-chloro-5-nitroaniline (I) with NaNO2 in HCl and HOAc, followed by addition of CuCl2 and SO2 yields sulfonyl chloride (II). Reaction of (II) with NH4OH affords sulfonamide (III), which is then treated 3-methylaniline (IV) in 3-chlorotoluene to furnish intermediate (V). Final conversion of (V) into the target product is achieved by treatment in H2O/acetone with NaOH and carbamimidothioate (VIII), which can be obtained by reaction of dimethyl N-cyanodithioiminocarbonate (VI) with amine (VII) in EtOH.

合成路线7

The alkylation of 6-chloro-2-fluoropurine (I) with isopropanol (II) under Mitsunobu conditions gives 6-chloro-2-fluoro-9-isopropylpurine (III), which is regioselectively alkylated at the 6 position with 4-methoxybenzylamine (IV) to yield 2-fluoro-9-isopropyl-N6-(4-methoxybenzyl)adenine (V). Finally, the 2-fluoro position of (V) is aminated with perhydroazepine (VI) in n-butanol at high temperature in a sealed tube to afford the target trisubstituted purine.

合成路线8

The cuprous chloride-catalyzed Mannich reaction between propargyl alcohol (I), hexahydroazepine (II) and formaldehyde furnished aminobutynol (III), which was further converted to the corresponding chloride (IV) upon treatment with SOCl2. The title compound was then synthesized by alkylation of the anion of 9-benzylfluorene (V) with chloride (IV) in DMSO.

合成路线9

The reaction of 1,3-benzodioxol-5-ylmethylamine (I) with acryloyl chloride (II) by means of TEA gives the acrylamide (III), which is reductocondensed with perhydroazepine (IV) by means of LiAlH4 or BH3/THF in THF to yield the secondary amine (V). Finally this compound is condensed with 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) by means of BuLi in diethyl ether to afford the target tertiary amine. The intermediate 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) has been obtained by two related ways: The condensation of 3.5-difluorobenzoyl chloride (VII) with malonic acid monoethyl ester (VIII) by means of BuLi gives 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX), which is cyclized with hydroxylamine in HOAc to yield 3-(3,5-difluorophenyl)isoxazol-5-ol (X). Finally this compound is treated with POCl3 to afford the desired 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) intermediate. Alternatively, the reaction of 3,5-difluoroacetophenone (XI) with diethyl carbonate (XII) by means of NaH yields also the already reported intermediate 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX)

合成路线10