合成路线1

Condensation of ethyl nicotinate (XI) with 3-chlorophenylacetonitrile (XII) by means of sodium ethoxide in ethanol gives 2-(3-chlorophenyl)-3-oxo-3-(3-pyridyl)propionitrile (XIII), which by refluxing with concentrated HBr yields 2-(3-chlorophenyl)-1-(3-pyridyl)ethanone (XIV). The reduction of (XIV) with hydrazine hydrate and NaOH in diethylene glycol at 235-40 C affords 3-(2-phenylethyl) pyridine (XV), which is oxidized with H2O2 in hot acetic acid to provide the corresponding N-oxide (XVI). Reaction of (XVI) with NaCN and dimethyl sulfate in water affords the previously described 3-(2-phenylethyl)pyridine-2-carbonitrile (V), which can be worked up as previously described or cyclized with polyphosphoric acid (PPA) at 180 C to give 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (XVII). The condensation of (XVII) with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF yields the corresponding carbinol (XVIII), which is dehydrated with PPA at 170 C to afford the previously reported 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII).

合成路线2

Benzocycloheptapyridinone (I) was reduced to alcohol (II) with NaBH4 in MeOH. Subsequent treatment of (II) with SOCl2 in toluene gave the tricyclic chloride (III). Finally, alkylation of N-acetyl piperazine (IV) with chloride (III) in the presence of Et3N in boiling THF provided the title compound.

合成路线3

The reaction of 2-cyano-3-methylpyridine (I) with H2SO4 in t-BuOH gives the N-tert-butylamide (II), which is treated with two equivalents of BuLi and the corresponding dianion alkylated with 3-chlorobenzyl chloride to afford amide (III). The treatment of (III) with POCl3 gives nitrile (IV), which is cyclized to ketone (V) by subsequent treatment with CF3SO3H and aqueous HCl. Reaction of ketone (V) with the Grignard derivative prepared from chloride (VI) affords alcohol (VII), which is finally dehydrated by H2SO4 to give UR-12592, as shown in Scheme 20491401a.

合成路线4

Ketone (I) was reduced with sodium borohydride in methanol to alcohol (II), which was then converted into chloride (III) on treatment with thionyl chloride in cooled toluene. Alkylation of piperazine (IV) with chloride (III) in the presence of triethylamine gave V. Finally, piperazine (V) was condensed with 4-pyridylacetic acid (VI) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC), 1-hydroxybenzotriazole (HOBt), and N-methylmorpholine in DMF to afford the target amide.

合成路线5