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The reaction of 5-methoxy-2-tetralone (I) with benzenethiosulfonic acid S-phenyl ester and sodium acetate in methanol gives 1,1-bis(phenylsulfanyl)-2-tetralone (II), which is condensed with 2-(bromomethyl)acrylic acid tert-butyl ester (III) by means of n-BuLi and diisopropylamine (DIA) in THF to yield the acrylic acid derivative (IV). Desulfurization of (IV) with Al/Hg in THF/water affords compound (V), which is treated with O-methylhydroxylamine and Na2HPO4 in methanol, providing the methoxyimino compound (VI). The reduction of (VI) with Zn/HOAc provides the methoxyamino compound (VII). The cyclization of (VII) by means of potassium hydrogen phosphate gives 1,6-dimethoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylic acid tert-butyl ester as a diastereomeric mixture that is separated by chromatography to furnish the desired diastereomer (VIII). Hydrolysis of the tert-butoxy ester group of (VIII) by means of TFA yields the carboxylic acid (IX), which is treated with diazomethane to afford the methyl ester (X). Selective demethoxylation of (X) with Zn/HOAc provides the octahydrobenzoquinoline (XI).

合成路线2

The methylation of 1,6-naphthalenediol (I) with dimethyl sulfate gives 1,6-dimethoxynaphthalene (II), which by reaction with sodium-ethanol is converted to 5-methoxy-2-tetralone (III). The condensation of (III) with propylamine - p-toluenesulfonic acid and subsequent hydrogenation with H2 over Pt affords 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (IV). which is demethylated with HBr to 5-hydroxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (V). Finally, this compound is reductively alkytated with 2-thienylacetic acid (VI) using boranetrimethylamine complex to yield N-0437.

合成路线3

The overall synthetic approach to N-0923 is described: Methylation of 1,6-dihydroxynaphthalene (I) with dimethyl sulfate provides 1,6-dimethoxynaphthalene (II), which is converted to 5-methoxy-2-tetralone (III) by reduction with sodium in ethanol. Reductive amination of (III) with propylamine results in the racemic 5-methoxy-2-N-propylaminotetralin (IV), from which the (-)-enantiomer (V) is obtained by fractional crystallization of the dibenzoyl-L-tartaric acid (L-DBTA) salt. Demethylation with aqueous hydrobromic acid affords (-)-(S)-5-hydroxy-2-N-propylaminotetralin (VI), which is reductively alkylated with thienylacetic acid in the presence of trimethylaminoborane to (-)-(S)-5-hydroxy-2-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin (VII). Treatment with anhydrous hydrogen chloride in ether provides N-0923.

合成路线4

Ketoester (II) was prepared by condensation of dimethyl carbonate with 5-methoxy-2-tetralone (I) in the presence of NaOMe. The alkylation of (II) with allyl bromide using two equivalents of LDA at -78 C proceeded selectively on the C-3 position to give (III). Further decarbomethoxylation of (III) was carried out with LiCl in moist DMSO at high temperature, and the resulting ketone (IV) was converted to ethylene ketal (V) with ethylene glycol and p-TsOH. Then, hydroboration of (V) with disiamyl borane (VI) in cold THF, followed by oxidation of borane (VII) with H2O2-NaOH furnished the primary alcohol (VIII). After Jones oxidation of alcohol (VIII), the resulting acid (IX) was esterified with MeOH and H2SO4 to give ketoester (X). Subsequent cyclization of (X) with benzylamine (XI) and AcOH in refluxing benzene afforded the intermediate tricyclic enamide (XII), which was sequentially reduced with LiAlH4 to enamine (XIII), and then with NaBH4 in the presence of AcOH to furnish a mixture of cis and trans octahydrobenzo[g]quinolines (XIV). Separation of the major trans isomer by flash chromatography was followed by hydrogenolysis of the benzyl group over Pd/C, yielding the secondary amine (XV), whitch was N-alkylated with propargyl bromide (XVI) in hot DMF to give (XVII).

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