合成路线1

Acetylsalicylic acid (I) was converted to acid chloride (II) by refluxing in a SOCl2 solution. Condensation of acid chloride (II) with guaiacol (III) either in the absence or in the presence of tertiary amines gave rise to the target orthoester derivative. Alternatively, the title compound has been prepared by treatment of acetylsalicylic acid (I) with several acid anhydrides, followed by guaiacol (III).

合成路线2

Acetylsalicylic (I) acid was refluxed in SOCl2 to give acetylsalicylyl chloride (II), which is condensed with maltol (III) by means of triethylamine in chloroform to afford aspalatone.

合成路线3

Full protection of 8-aminooctanoic acid (I) with TMSCl in refluxing CH2Cl2 yields derivative (II), which is then coupled to acetylsalicyloyl chloride (III) by means of Et3N to provide compound (IV). Finally, the desired product is obtained by saponification of (IV) with NaOH. Alternatively, another route can be followed for the synthesis of the target compound: Curtius rearrangement of nonanedioic acid monomethyl ester (V) with DPPA and Et3N in toluene, followed by treatment with tert-BuOH, affords Boc-amino ester (VI), whose Boc group is then removed by means of HCl in dioxane to yield deprotected ester (VII). Coupling of (VII) with acetylsalicyloyl chloride (III) by means of Et3N in THF/DMF gives compound (VIII), which is finally saponified with NaOH.

合成路线4

A mixture of 3-hydroxybenzyl alcohol (I) with 48% hydrobromic acid in dichloromethane is stirred at room temperature to give the corresponding benzyl bromide (II), which is immediately dissolved in acetonitrile. Silver nitrate is added proportionally to the crude solution (II) at room temperature to obtain derivative (III). A mixture of (III), potassium carbonate and ethyl acetate is cooled under nitrogen at 0 C and slowly treated with a solution of O-acetylsalicyloyl chloride (IV) in ethyl acetate to yield crude NCX-4016. The pure product is obtained by crystallization from isopropyl ether. The three-step prepaation is described in the Scheme 25203601a.

合成路线5

Basic treatment of 3-hydroxybenzyl alcohol (I) with either NaOH in dichloromethane, Et3N in toluene or K2CO3 in acetone, followed by reaction with acetylsalicyloyl chloride (II) in the respective solvents, gives 2-acetoxybenzoic acid 3-(hydroxymethyl)phenyl ester (III). NCX-4016 is obtained by nitration of compound (III) with steaming nitric acid in dichloromethane in the presence of either sulfuric acid, acetic anhydride or methanesulfonic acid.

合成路线6

Alternatively, coupling of 3-hydroxybenzaldehyde (I) with acetylsalicyloyl chloride (II) by means of Et3N in dichloromethane affords 2-acetoxybenzoic acid 3-formyl-phenyl ester (IV), which is then reduced by hydrogenation over Pd/C in ethyl acetate to provide alcohol (III). Chlorination of alcohol (III) by treatment with thionyl chloride in DMF gives the chloromethyl derivative (V), which is finally converted to NCX-4016 by treatment with AgNO3 in refluxing acetonitrile.

合成路线7

A synthesis of the racemic compound was later reported: 3-Hydroxy-4-nitrobenzaldehyde (I) was reduced to the benzyl alcohol (II) with NaBH4 and then converted to diacetate (III) with Ac2O in pyridine. Selective deacetylation of the aryl ester of (III) with KHCO3 in MeOH produced phenol (IV), which was then acylated with acetylsalicyloyl chloride (V) to yield (VI). The catalytic hydrogenation of the nitro group of (VI) in the presence of Raney-Ni was accompanied by migration of the salicyloyl unit to the amino group to yield salicylamide (VII) (accompanied by some byproduct resulting from the cleavage of the phenolic acetate). The resultant mixture of mono- and diacetate was converted to triol (VIII) by hydrolysis in aqueous NaOH. Then, the aminophenol ring of (VIII) was selectively oxidized with Fremy's salt to quinone (IX). Finally, the quinone was treated with H2O2 in the presence of NaHCO3 to furnish the racemic epoxide.

合成路线8

The condensation of 4-(tert-butyldimethylsilyloxymethyl)aniline (I) with 2-(acetoxy)benzoyl chloride (II) by means of TEA in dichloromethane gives the corresponding amide (III), which is oxidized with DMP in dichloromethane to yield the benzoquinone (IV). The reaction of (IV) with H2O2 and K2CO3 affords the epoxide (V), which is finally desilylated with HF and pyridine in THF to provide the target compound.

合成路线9

Conversion of 10-undecen-1-ol (I) into the primary amine (IV) was effected by Mitsunobu coupling of (I) with phthalimide (II), followed by hydrazinolysis of the resulting N-(10-undecenyl)phthalimide (III). Amine (IV) was then acylated with O-acetylsalicyloyl chloride (V) to give salicylamide (VI). Oxidative cleavage of the terminal olefin to the carboxylic acid (VII) was achieved using potassium permanganate under phase-transfer conditions. The O-acetyl group was finally removed by treatment with NaOH.

合成路线10

The silylation of 10-aminodecanoic acid with Tms-Cl in refluxing dichloromethane gives the bis-silylated compound (II), which is treated with acetylsalicyl chloride (III) and TEA to yield the salicylamide (IV). Finally, this compound is hydrolyzed with NaOH.

合成路线11