The Grignard reaction of the protected epoxide (I) with 4-(dimethylamino)phenylmagnesium bromide (II) gives the 11-substituted compound (III), which is submitted to an Oppenhauer oxidation with cyclohexanone and aluminum isopropoxide yielding the 17-keto derivative (IV). The photochemical epimerization of the 13beta-methyl of (IV) with a high pressure mercury lamp in dioxane affords the epimer (V), which is condensed with 1-tetrahydropyranyloxy-2-propyne (VI) by means of butyllithium in THF to give the acetylenic alcohol (VII). Finally, this compound is reduced with hydrogen over Pd/C in ethanol and deprotected and dehydrated by treatment with hot aqueous acetic acid.
The Wittig condensation of 2-phenylpyrazolo[1,5-a]pyridine-3-carboxaldehyde (I) with trimethylphosphonoacetic acid methyl ester (II) by means of NaH in hot toluene gives 3(E)-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid methyl ester (III), which is hydrolyzed with NaOH in methanol - water yielding the corresponding free acid (IV). The reaction of (IV) with SOCl2 in DMF affords the acyl chloride (V), which is finally condensed with 2(R)-(2-hydroxyethyl)piperidine (VI) by means of bis(trimethylsilyl)acetamide and triethylamine in dichloromethane.
FK-352 can be obtained by two related ways: 1) The Wittig condensation of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (I) with trimethyl phosphonoacetate (II) by means of NaH in hot toluene gives 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid methyl ester (III), which by hydrolysis with aqueous NaOH yields the expected free acid (IV) (1). The reaction of (IV) with SOCl2 and DMF in dichloromethane affords the corresponding acyl chloride (V), which is condensed with 2-[2(R)-piperidinyl]acetic acid ethyl ester (VI) by means of triethylamine in dichloromethane affording the acylated piperidine (VII). Finally, this compound is hydrolyzed with NaOH in refluxing methanol. 2) The free acid precursor (IV) can also be obtained by condensation of 2-phenylpyrazolo[1,5-a]pyridine (VIII) with 3-(dimethylamino)acrylic acid ethyl ester (IX) by means of AlCl3 in methylene chloride giving the ethyl ester (X), which is hydrolyzed to the free acid (IV) by treatment with aqueous NaOH.
A new synthesis of FK-453 has been published: The cyclization of 1-aminopyridinium iodide (I) with 3-phenylpropynoic acid ethyl ester (II) by means of KOH in DMF gives 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (III), which is decarboxylated with 47% aqueous HBr yielding 2-phenylpyrazolo[1,5-a]pyridine (IV). The Vilsmayer formylation of (IV) with POCl3 and DMF affords 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (V), which by a Horner-Emmonds condensation with 2-(diethoxyphosphoryl)acetic acid ethyl ester and NaH in THF is converted into 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid ethyl ester (VII). The hydrolysis of (VII) with NaOH in methanol gives the free acid (VIII), which by reaction with SOCl2 in dichloromethane yields the corresponding acyl chloride (IX). The condensation of (IX) with 2-(2-hydroxyethyl)piperidine (X) by means of triethylamine in dichloromethane affords FK-453 as a racemic mixture (XI), which is finally submitted to optical resolution.
A new practical synthesis of FK-453, suitable for large scale manufacture is described: Bromination of cinnamic aldehyde (I) with Br2 in HOAc gives the dibromoderivative (II), which is treated with NaHSO3 and triethylamine yielding alpha-bromocinnamic aldehyde (III). The reaction of (III) with triethyl orthoformate affords the corresponding acetal (IV), which is treated with KOH in hot ethanol to give the acetylenic acetal (V). Acidic hydrolysis of the acetal (V) with sulfuric acid in refluxing water affords phenylpropargyl aldehyde (VI), which by a Horner-Emmons condensation with the phosphonate (VII) by means of KOH in DMSO gives 5-phenylpent-2(E)-en-4-ynoic acid ethyl ester (VIII). The 1,3-dipolar cycloaddition of (VIII) with 1-aminopyridinium iodide (IX) by means of KOH and K2CO3 in the same solvent yields 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid ethyl ester (X), which is hydrolyzed with NaOH in hot methanol affording the corresponding free acid (XI). Reaction of (XI) with SOCl2 and DMF gives the activated acyl chloride (XII), which is condensed with the silylated chiral piperidineethanol (XIII) [obtained by silylation of the chiral piperidineethanol (XIV) with N,N'-bis(trimethylsilyl)urea (BSU)] by means of Et3N and DMAP in CH2Cl2, yielding the silylated target compound (XV). Finally, this compound is desilylated by means of K2CO3 in methanol.