合成路线1

The cyclization of 2-aminobenzophenone (I) with 3-amino-2-chloropyridine (II) by means of NaOH in methylene chloride-water gives 6-phenyl-11H-[2,3-b][1,4]benzodiazepine (III), which is then condensed with (3-chloropropyl)dimethylamine by means of NaH in hot DMF, followed by a treatment with fumaric acid in isopropanol.

合成路线2

This compound can be prepared by two related ways: 1) The reaction of 2-nitrobenzoic acid (I) with PCl5 at 50 C gives the corresponding acyl chloride (II), which by a Friedel-Craft's condensation with benzene and AlCl3 yields 2-nitrobenzophenone (III). The reduction of (III) with H2 over Pd/C in ethanol affords 2-aminobenzophenone (IV), which is acylated with acetic anhydride sodium acetate to give 2-acetamidobenzophenone (V). The cyclization of (V) by means of sodium methoxide in refluxing ethanol yields 4-phenylquinoline-2(1H)-one (VI), which by reaction with SOCl2-DMF in hot CHCl3 is converted to 2-chloro-4-phenylquinoline (VII). Finally, this compound is condensed with N-ethylpiperazine (VIII) at 130 C. 2) Quinoline (VII) is condensed with piperazine (IX) as before to give 4-phenyl-2-(1-piperazinyl)quinoline (X), which is finally alkylated with ethyl iodide and sodium carbonate in refluxing butanone.

合成路线3

2-Aminobenzophenone (I) is acylated with bromoacetyl bromide followed by reaction with ammonia to form the [1,4]benzodiazepine. N1-Methylation produces 1,3-dihydro-1-methyl-5-phenyl-2H-[1,4]benzodiazepin-2-one (II). Treatment with isoamyl nitrate and t-BuOK gives an oxime, which is reduced by catalytic hydrogenation to racemic 3-amino-benzodiazepine (III), which is isolated as the crystalline benzenesulfonic acid salt. Crystallization-induced asymmetric transformation yields 3(S)-(-)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-[1,4]benzodiazepin-2-one (IV). Acylation with indole-2-carbonylimidazolide produces MK-329.

合成路线4

Friedländer cyclization between 2-aminobenzophenone (I) and 2-oxobutyric acid (II) by means of NaOMe in MeOH gives carboxylic acid (III), which is then converted into the corresponding acid chloride (IV) by reaction with SOCl2 in CH2Cl2. Finally, the target product is obtained by reaction of (IV) with N-methylbenzylamine (V) by means of Et3N.

合成路线5

Sulfonylation of anthranilic acid (I) with p-toluenesulfonyl chloride under Schotten-Baumann conditions furnishes N-tosyl anthranilic acid (II). After conversion of acid (II) to the corresponding acid chloride (III), Friedel-Crafts condensation with benzene in the presence of AlCl3 leads to the benzophenone (IV). The N-tosyl group of (IV) is then removed upon heating with concentrated sulfuric acid to provide 2-aminobenzophenone (V). Acylation of amine (V) with 4-(aminosulfonyl)benzoyl chloride (VI) yields amide (VII). This is finally cyclized to the target indole compound under McMurry conditions employing an in situ generated low valent titanium reagent.

合成路线6