合成路线1

The protection of aniline (I) with di-tert-butyl dicarbonate in THF gives the carbamate (II), which is treated with BuLi and 14C labeled CO2 in THF yielding 2-(tert-butoxycarbonylamino)benzoic acid (III). The deprotection of (III) with TFA in dichloromethane affords labeled 2-aminobenzoic acid (IV), which is diazotized with NaNO2 /HCl and treated with Na2S, S and NaOH to give the disulfide (V). The reaction of (V) with refluxing SOCl2 yields the acid dichloride (VI), which is condensed with L-isoleucine tert-butyl ester (VII), by means of N-methylmorpholine (NMM) in dichloromethane to afford the final intermediate (VIII). Finally, this compound is deprotected with TFA in dichloromethane to give the labeled target compound.

合成路线2

The protection of aniline (I) with di-tert-butyl dicarbonate in THF gives the carbamate (II), which is treated with BuLi and 14C labeled CO2 in THF yielding 2-(tert-butoxycarbonylamino)benzoic acid (III). The deprotection of (III) with TFA in dichloromethane affords labeled 2-aminobenzoic acid (IV), which is diazotized with NaNO2 /HCl and treated with Na2S, S and NaOH to give the disulfide (V). The reaction of (V) with refluxing SOCl2 yields the acid dichloride (VI), which is condensed with L-isoleucine tert-butyl ester (VII), by means of N-methylmorpholine (NMM) in dichloromethane to afford the intermediate (VIII). The deprotectionof (VIII) with TFA in dichloromethane to give the labeled dimeric isoleucine derivative (IX), which is finally cyclized to the target benazoisothiazolone by oxidative cyclization with Br2 in dichloromethane.

合成路线3

The enantioselective reduction of phenacyl bromide (I) with BH3.S(CH3)2 in THF catalyzed by the chiral borolidine (II) (obtained by reaction of (1R,2S)-1-amino-2-indanol (III) with BH3.S(CH3)2 in THF) gives the (R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (IV), which is reduced with H2 over PtO2 in THF/toluene yielding the corresponding amino derivative (V). The reaction of (V) with formic acid and Ac2O affords the formamide (VI), which is condensed with the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) in THF/methanol providing the protected target compound (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol. The intermediate the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) has been obtained by reductocondensation of 1-(4-methoxyphenyl)-2-propanone (IX) and benzylamine by hydrogenation with H2 over Pd/C in methanol yielding racemic N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (X), which is submitted to optical resolution with (S)-mandelic acid to obtain the desired (R)-enantiomer (VII).

合成路线4

By reduction of a mixture of 1-(3-formylamino-4-hydroxyphenyl)-2-aminoethanol (VIII) and 1-(4-methoxyphenyl)-2-propanone (IX) with H2 over Pt in ethanol, followed by a treatment with fumaric acid (A).

合成路线5