合成路线1

The reaction of 1-aminoindolin-2-one (I) with phenylacetone (A) by means of acetic acid in refluxing ethanol gives 1-(alpha-methylphenethylidiene-imino)indolin-2-one (II), which by reaction with refluxing ethanolic hydrogen chloride affords ethyl alpha-(2-methyl-3-phenylindol-7-yl)acetate (III). The ozonolysis of (III) in acetic acid yields ethyl 2-acetamido-3-benzoylphenyl-acetate (IV), which is cyclized by refluxing with HCl in acetic acid to give 7-benzoylindolin-2-one (V). Finally, of the ester (III) with KOH in refluxing water affords the corresponding acid (this compound is hydrolyzed with NaOH in refluxing water). The hydrolysis of the ester (III) with KOH in refluxing water affords the corresponding acid (VI), which can be ozonolyzed as before yielding 2-acetamido-3-benzoylphenylacetic acid (VII). This acid can be cyclized to (V) by refluxing with HCl in acetic acid as before.

合成路线2

1) Reductive amination of phenylacetone (I) with ammonium acetate and sodium cyanoborohydride (I) gives d,l-amphetamine (II), which is separated by distillation at reduced pressure from a secondary amine byproduct resulting from reaction of amphetamine with phenylacetone. Iodination of the N-acetyl-protected amine followed by acid hydrolysis yields a mixture of ortho-meta and para substituted iodoamphetamine, from which the para-isomer can be obtained by crystallization of the salt (IV) from hydrochloric acid. Reductive condensation of the primary amine salt with acetone and sodium cyanoborohydride then yields ofetamine (V). The free base is converted to the hydrochloride salt (VI) by treatment with dry HCl gas in ether. The acetate salt may be prepared by treatment of the free base with glacial acetic acid in ether, followed by addition of hexane or petroleum ether to precipitate the product.

合成路线3

Aminothiophene (III) was prepared by condensation of phenylacetone (I) with ethyl cyanoacetate (II), followed by treatment with sulfur and diethylamine. Subsequent condensation of (III) with diethyl ethoxymethylenemalonate (IV) at 120 C provided the enaminomalonate (V). the partial hydrolysis of (V) with KOH in EtOH-dioxan provided monoacid (VI), which was cyclized by means of PPE to the thienopyridine (VII). Alkylation of (VII) with 2,6-difluorobenzyl chloride (VIII) and K2CO3 yielded predominantly the N-benzylated compound (IX), which was selectively nitrated at the phenyl ring to produce (X) (2). Radical bromination of the 3-methyl group of (X) gave bromomethyl compound (XI).

合成路线4

The cyclization of phenylacetone (I) with ethyl cyanoacetate (II) by means of HOAc and AcONH4 in refluxing benzene, followed by a treatment with sulfur in hot ethanol gives 2-amino-4-methyl-5-phenylthiophene-3-carboxylic acid ethyl ester (III). The condensation of (III) with diethyl ethoxymethylene malonate (IV) by heating at 120 C yields the adduct (V), which is submitted to a selective hydrolysis with KOH in hot ethanol to afford the carboxylic acid (VI). The cyclization of (VI) by means of PPE at 120 C provides the thienopyridine (VII), which is nitrated with NaNO3 and H2SO4 to give the 4-nitrophenyl derivative (VIII). The alkylation of the hydroxy-thienopyridine (VIII) with 2,6-difluorobenzyl chloride (IX) by means of NaH in DMF yields the benzylated thienopyridinone (X), which is brominated with NBS and AIBN in refluxing CCl4 to afford the bromomethyl derivative (XI). The condensation of (XI) with N-benzyl-N-methylamine (XII) by means of TEA in DMF provides the tertiary amine (XIII). The reduction of the nitro group of (XIII) by means of Fe and HCl in ethanol gives the 4-aminophenyl derivative (XIV), which is acylated with trifluoroacetic anhydride and TEA to yield the acetamide (XV). The reaction of (XV) with N,O-dimethylhydroxylamine (XVI) and TEA in CH2Cl2 affords the methoxyamide (XVII).

合成路线5