合成路线1

After protection of 4-bromobenzaldehyde (I) with triethyl orthoformate in MeOH, the resultant bromo ketal (II) was converted to the corresponding Grignard reagent (III) with magnesium in THF. Conjugate addition of (III) to the steroid epoxide (IV) in the presence of CuCl gave rise to the 11-beta-aryl steroid (V). Introduction of a 17-spiro oxirane moiety into ketone (V) to yield (VI) was accomplished by reaction with the sulfur ylide generated from trimethylsulfonium iodide and potassium tert-butoxide. Subsequent epoxide opening in (VI) with NaOMe gave rise to the methoxy alcohol (VII), which was further alkylated with iodomethane under Williamson's ether synthesis conditions to provide the dimethoxy derivative (VIII). Acid hydrolysis of both ketal groups of (VIII) with concomitant alcohol dehydration led to the dienone (IX). The aldehyde function of (IX) was finally converted to the target oxime by treatment with hydroxylamine hydrochloride in pyridine.

合成路线2

1) The reaction of 4-bromobenzaldehyde (I) with trimethylorthoformate (II) and p-toluenesulfonic acid in methanol gives ketal (III), which is condensed with 2-pyridylmagnesium bromide in THF, yielding 4-(2-pyridyl)benzaldehyde (IV). The reaction of (IV) with tert-butyl carbazate (V) in refluxing ethanol affords hydrazone (VI), which is reduced with H2 over Pd/C in methanol to the hydrazine (VII). The condensation of (VII) with the epoxide (VIII) in hot isopropanol gives the expected addition product (IX), which by treatment with HCl or formic acid results in the fully deprotected intermediate (X). Finally, this compound is condensed with N-(methoxycarbonyl)-L-tert-leucine (XI) by means of O-(2-oxo-1,2-dihydro-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU) in dichloromethane or DMF.

合成路线3

4-Bromobenzaldehyde dimethyl acetal (I) was converted to the corresponding Grignard reagent and then coupled with 2-bromothiazole (II) in the presence of [1,3-bis(diphenylphosphino)propane]nickel chloride to afford 4-(2-thiazolyl)benzaldehyde dimethylacetal (III). After acid hydrolysis of the acetal group of (II), the resulting aldehyde was condensed with tert-butyl carbazate to give hydrazone (IV), which was further reduced to the benzylhydrazine (V) employing NaBH3CN and p-toluenesulfonic acid. Opening of the Boc-protected epoxide (VI) with hydrazine (V) gave hydrazinoalcohol (VII). Both Boc groups of (VII) were removed by treatment with formic acid to yield diamino compound (VIII). Finally, coupling of (VIII) with N-methoxycarbonyl-L-tert-leucine (IX) by means of O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetra fluoroborate (TPTU) provided the title bisamide.

合成路线4