合成路线1

The ketalization of 2beta-ethoxy-3alpha-hydroxy-5alpha-pregnane-11,20-dione (I) with ethylene glycol (A) by means of p-toluenesulfonic acid in refluxing benzene gives the corresponding 20,20-ethylenedioxy derivative (II), which is treated with hydroxylamine hydrochloride and NaOH refluxing ethanol to yield 20,20-ethylenedioxy-2beta-ethoxy-3alpha-hydroxy-5alpha-pregnan-11-one 11-oxime (III). The reduction of (III) with Na in refluxing propanol (B) affords 11alpha-amino-20,20-ethylenedioxy-2beta-ethoxy-3alpha-hydroxy-5alpha-pregnan (IV), which is finally methylated with methyl iodide and K2CO3 or with formaldehyde and formic acid, and hydrolyzed with HCl or H2SO4.

合成路线2

1,2-Epoxy-3-(2-cyanophenoxy)propane (I) is added to one equivalent of N-(2-aminoethyl)-4-benzyloxyphenylacetamide (II) in n-propanol and heated to reflux for 18 h, giving N-[2-(3-o-cyanophenoxy-2-hydroxypropylamino)ethyl]-4-benzyloxyphenylacetamide (III). Hydrogenolysis of the 4-benzyl moiety of (III) may be performed under mild conditions (e.g., hydrogen gas with palladium on carbon in ethanol at room temperature) to yield ICI-141292.

合成路线3

Hydrogenation of D-4-hydroxyphenyl glycine (I) over Raney-Ni in NaOH affords 4-hydroxycyclohexylglycine (II), which is condensed with sulfonyl chloride (III) in dioxane in the presence of Et3N to yield derivative (IV). Carboxylic acid (IV) is converted into benzyl ester (VI) by treatment with benzyl bromide (V) by means of N,N'-dicyclohexylamine (DCHA) in DMF and (VI) is then oxidized by treatment with NaBr, 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaClO2 in CH2Cl2/H2O to provide ketone (VII). Condensation of (VII) with n-propanol (VIII) by means of PhSiH3 and TFA gives a mixture of compounds from which trans-(IX) is cromatographically separated. Then ketone (IX) reacts with 4-picolyl chloride (X) and K2CO3 in DMF to furnish compound (XI). Hydrogenation of benzyl acetate (XI) over Pd/C in EtOH/HCl affords acetic acid derivative (XII), which is coupled to O-t-butylhydroxylamine hydrochloride by means of HOBt, N-methylmorpholine and N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (EDC·HCl) in CH2Cl2. Finally, removal of the t-Bu group with HCl (gas) in dichloroethane/EtOH yields the desired compound.

合成路线4

The known 3,5-dimethylpyrrole-2,4-dicarboxylic acid 2-benzyl ester 4-t-butyl ester (I) is subjected to benzyl group hydrogenolysis over Pd/C to provide the corresponding pyrrole-2-carboxylic acid (II). Subsequent coupling of acid (II) with 1-propanol (III) in the presence of trifluoroacetic anhydride furnishes the 2-propyl ester (IV). The 4-t-butyl ester of (IV) is then cleaved by means of trifluoroacetic acid, yielding the pyrrole-4-carboxylic acid (V). This is finally coupled to 3,3-dimethyl-2-butanol (VI) by using trifluoroacetic anhydride to furnish the target pyrrole diester.

合成路线5