合成路线1

1) The cyclization of 4-cyanophenol (I) with 3-chloro-3-methylbutine (II) by means of benzyltrimethylammonium hydroxide in methanol-CH2Cl2 gives 6-cyano-2,2-dimethyl-2H-benzo[b]pyran (III), which is treated with N-bromosuccinimide in DMSO to afford 6-cyano-trans-3-bromo-3,4-dihydro-2,2-dimethyl 2H benzo[b]pyran-4-ol (IV). Epoxidation of (IV) by means of NaOH in dioxane-water yields 6-cyano-3-(4-dihydro-3,4-epoxy-2,2-dimethyl-2H-benzo[b]pyran (V), which is finally treated with 4-aminobutyric acid (VI) and NaHCO3 in refluxing ethanol. 2) By reaction of epoxide (V) with 2-pyrrolidone (X) by means of NaH in DMSO.

合成路线2

The reaction of epoxide (V) with ammonia in ethanol gives 4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-trans-2H-benzo[b]pyran-3-ol (VII), which is condensed with 4-chlorobutyryl chloride (VIII) by means of NaOH in CHCl3 yielding 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(4-chlorobutyrylamino)-2H-benzo[blpyran 3-ol (IX). Finally, this compound is cyclized by means of NaH in THF.

合成路线3

Compound can be prepared in three different ways all starting from 4-methoxybenzylamine (I) [prepared by methylation of 4-hydroxybenzonitrile (V) with dimethyl sulfate in aqueous NaOH to afford 4-methoxybenzonitrile (VI), which is then hydrogenated with H2 over Raney-Ni in ethanol]: 1) By condensation of 4-methoxybenzylamine (I) with N,N',S-trimethylisothiourea hydroiodide (C) in refluxing ethanol, followed by treatment with H2SO4. 2) By reaction of 4-methoxybenzylamine (I) with diethyl iminocarbonate (A) in water to give diethyl N-(4-methoxybenzyl)iminocarbonate (II), followed by treatment with methylamine in water - ethanol - H2SO4. 3) By reaction of 4-methoxybenzylamine (I) with methyl isothiocyanate (B) in ether to yield N-(4-methoxybenzyl)-N'-methylthiourea (III), which is then methylated with MeI in refluxing methanol affording N-(4-methoxybenzyl)-N',S-dimethylisothiourea (IV). Finally, this compound is treated first with methylamine in refluxing methanol and then with H2SO4.

合成路线4

The condensation of 2-bromo-5-methoxybenzoic acid (IX) with 4-hydroxybenzonitrile (X) by means of K2CO3, Cu and Cu2I2 in n-pentanol gives 2-(4-cyanophenoxy)-5-methoxybenzoic acid (XI), which is cyclized and hydrolyzed with hot H2SO4 to give the starting product (I). Alternatively, compound (XI) can be cyclized and partially hydrolyzed with hot polyphosphoric acid giving 7-methoxy-9-oxoxanthene-2-carboxamide (XII), which is finally hydrolyzed with H2SO4.

合成路线5

By condensation of 4-(2-quinolinylmethoxy)benzaldeyde (I) with 2-hydroxy-5(1H-tetrazol-5-yl)acetophenone (II) by means of KOH in ethanol/water. The intermediates (I) and (II) have been obtained as follows: Benzaldehyde (I): By condensation of 2-(chloromethyl)quinoline (III) with 4-hydroxybenzaldehyde (IV) by means of K2CO3 in hot DMF. Acetophenone (II): The acetylation of 4-hydroxybenzonitrile (V) with acetic anhydride/sulfuric acid and AlCl3 gives 5-cyano-2-hydroxyacetophenone (VI), which is then cyclized with sodium azide and ammonium chloride in hot DMF.

合成路线6

The esterification of (S)-3-amino-2-(benzyloxycarbonylamino)propionic acid (I) with methanol/HCl gives the expected methyl ester (II), which is protected with di-tert-butyl dicarbonate and triethylamine in chloroform to the fully protected compound (III). The debenzylation of (III) by treatment with formic acid over Pd/C in methanol yields the 2-amino compound (IV), which is acylated with butyl chloroformate and NaHCO3 in THF affording 2(S)-(n-butoxycarbonylamino)-3-(tert-butoxycarbonylamino)propionic acid methyl ester (V).The selctive deacylation of (V) with trifluoroacetic acid in dichloromethane affords the 3-amino-2(S)-(n-butoxycarbonylamino)propionic ester (VI), which is acylated with 3-(chloromethyl)benzoyl chloride (VII) and triethylamine in dichloromethane giving the benzamido ester (VIII). The condensation of (VIII) with 4-hydroxybenzonitrile (IX) by means of NaH or K2CO3 yields the precursor (X), which is finally treated first with HCl in methanol, and then with NH3 in the same solvent to providde the target compound.

合成路线7

Mitsunobu coupling of 1,5-pentanediol (II) with two molecules of 4-hydroxybenzonitrile (I) in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine afforded diether (III). Subsequent reduction of the nitrile groups of (III) using LiAlH4 gave the bis(benzylamine) derivative (IV), which was coupled with 3-cyanobenzenesulfonyl chloride (V) to provide sulfonamide (VI). The nitrile groups of (VI) were finally converted to the required bis amidino derivative by treatment with Weinreb reagent, prepared from trimethylaluminum and ammonium chloride.

合成路线8

合成路线9