合成路线1

Heating of 3,6-dichloropyridazine (I) with hydrazine hydrate at 100 C gives 6-chloro-3-pyridazinylhydrazine (II). The hydrazino group is protected by transforming it with camphor (III) to the camphorhydrazone (IV), which is aminated by heating with morpholine to give the morpholinylhydrazone (V). After liberating the hydrazine function by acidic hydrolysis in a biphasic system, the resulting 6-morpholino-3-pyridazinylhydrazine (VI) is reacted either with tert-butylacetoacetate (VII) or with tert-butylpropiolate (VIII) to yield RGH-5526.

合成路线2

A synthesis of [14C]-labeled fluvastatin has been described: The acylation of fluorobenzene (I) with [14C]-bromoacetyl chloride (II) by means of AlCl3 gives the expected phenacyl bromide (III), which is condensed with N-isopropylaniline (IV) in hot ethanol yielding the tertiary amine (V). The cyclization of (V) by means of anhydrous ZnCl2 in refluxing ethanol affords the indole (VI), which is alkylated with 3-(N-methyl-N-phenylamino)acroleine (VII) by means of POCl3 in refluxing acetonitrile giving 3-[3-(4-fluorophenyl)-1-isopropylindol-2-yl]acroleine (VIII). The reductocondensation of (VIII) with tert-butyl acetoacetate (IX) by means of NaH and BuLi in THF yields 7-[3-(4-fluorophenyl)-1-isopropylindol-2-yl)-5-hydroxy-3-oxo-6-heptenoic acid tert-butyl ester (X), which is further reduced with NaBH4 and diethyl(methoxy)borane in THF to the dihydroxy compound (XI) as a mixture of the two syn-enantiomers (XI). Finally, this compound is hydrolyzed with NaOH in methanol to the expected sodium salt.

合成路线3

The Friedel-Crafts condensation of fluorobenzene (I) with chloroacetyl chloride (II) by means of AlCl3 gives the phenacyl chloride (III), which is cyclized with N-isopropylaniline (IV) by means of ZnCl2 to yield 3-(4-fluorophenyl)-1-isopropyl-1H-indole (V). The condensation of (V) with 3-(N-methyl-N-phenylamino)acrolein (VI) by means of POCl3 in acetonitrile affords 3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrolein (VII), which is further condensed with tert-butyl acetoacetate (VIII) by means of BuLi and NaH in THF to provide 7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6(E)-heptenoic acid tert-butyl ester (IX). The reduction of the ketonic group of (IX) with NaBH4 catalyzed by Et2B-OMe as chelating agent gives the diol (X) with a syn configuration. Finally, the tert-butyl ester group of (X) is hydrolyzed with NaOH in ethanol/water to afford the target fluvastatin sodium.

合成路线4

In an alternative route to the title compound, dinitro derivative (XV) was converted into the benzofuroxan (XVI) by treatment with sodium azide in hot DMSO. Furazan ring opening by means of tert-butyl acetoacetate (XVII) under basic conditions generated the quinoxaline N,N'-dioxide (XVIII). The Pummerer-like rearrangement of the N-oxide (XVIII) in the presence of trifluoroacetic anhydride gave rise to the unstable trifluoroacetoxymethyl quinoxaline (XIX), which was further converted to bromide (XX) upon heating with LiBr in acetone. Alkylation of N,N-di-Boc-hydroxylamine (III) with bromide (XX) provided the protected O-alkyl hydroxylamine (XXI). Reduction of the remaining N-oxide group of (XXI) and simultaneous N-Boc groups cleavage by means of boron tribromide furnished quinoxaline (XXII). The fully deprotected quinoxaline (IX) was then obtained by acidic treatment of (XXII). Condensation of keto amide (XIII) with hydroxylamine (IX) in the presence of tetrabutylammonium bisulfate produced the oxime adduct (XXIII). Finally, the title compound was obtained by deformylation of (XXIII) under acidic conditions.

合成路线5

Nitrosation of tert-butyl acetoacetate (I) with NaNO2/AcOH produces the oximino ester (II). Reductive cyclization of (II) with ethyl acetoacetate (III) in the presence of Zn/AcOH leads to the pyrrole dicarboxylate (IV). Selective decarboxylation of the t-butyl ester of (IV) under acidic conditions, followed by Vilsmeier formylation of the intermediate ethyl 2,4-dimethylpyrrole-3-carboxylate furnishes the pyrrole aldehyde (V). Alternatively, this compound is directly obtained from (IV) upon treatment with trimethyl orthoformate and trifluoroacetic acid. Basic hydrolysis of the ethyl ester group of (V) yields the pyrrolecarboxylic acid (VI). This is coupled to 2-(diethylamino)ethylamine (VII) to afford the corresponding amide (VIII).

合成路线6

Nitrosation of tert-butyl acetoacetate (I) with NaNO2 in cold AcOH leads to oxime (II), which is further condensed with benzyl acetoacetate (III) in the presence of Zn and ammonium acetate, to produce pyrrole (IV). The 4-benzyl ester of (IV) is selectively removed by catalytic hydrogenolysis over Pd/C, yielding the pyrrole-4-carboxylic acid (V). Subsequent coupling of acid (V) with 3,3-dimethyl-2-butanol (VI) employing trifluoroacetic anhydride furnishes the target pyrrole diester.

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合成路线9