合成路线1

The condensation of diethyl succinate (IX) with benzaldehyde (II) gives 2-benzylidenesuccinic acid (III), which is treated with refluxing Ac2O to yield the corresponding anhydride (IV). Reaction of (IV) with cis-perhydroisoindole (V) in toluene affords the monoamide (VI), which is reduced with H2 over Pd/C in ethanol to provide the racemic benzylsuccinamic acid (X). Esterification of (X) with (S)-N-benzylmandelamide (XI) by means of DCC and DMAP in dichloromethane gives a mixture of diastereomeric esters, which were separated by column chromatography on silica gel to provide the desired diastereomer (XII). The hydrolysis of (XII) with NaOH in methanol yields the chiral acid (XIII), which is finally treated first with NaOH and then with CaCl2 in water. The preceding optical resolution of racemic acid (X) can also be performed with (R)-1-phenylethylamine (VII) or (R)-1-(1-naphthyl)ethylamine (XIV) by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl.

合成路线2

The optical resolution of racemic 2-benzylsuccinic acid (XV) using the chiral amines (R)-1-phenylethylamine (VII), (R)-1-(1-naphthyl)ethylamine (XIV) or (S)-1-phenyl-2-(4-tolyl)ethylamine (XVI) is carried out by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl, providing the desired enantiomer 2(S)-benzylsuccinic acid (XVII). Reaction of (XVII) with SOCl2 gives the corresponding acyl chloride (XVIII), which is treated with 4-nitrophenol (XIX) and TEA in dichloromethane to yield the activated diester (XX). The regioselective reaction of (XX) with cis-perhydroisoindole (V) in dichloromethane affords the monoamide (XXI), which by reaction with HCl and methanol provides the corresponding methyl ester (XXII). This ester is hydrolyzed with NaOH to the previously described chiral succinamic acid (XIII), which is finally converted into its calcium salt.

合成路线3

3) The condensation of 3-(trimethylsilyl)propynal (XXIII) with the dialkaline salt of ethylacetoacetate (XXIV) in THF gives 5-hydroxy-3-oxo-7-(trimethylsilyl)-6-heptynoic acid ethyl ester (XXV), which is reduced with NaBH4/diethylmethoxyborane to the racemic 3,5-dihydroxy-7-(trimethylsilyl)-6-heptynoic acid ethyl ester (XXVI). The protection and desilylation of (XXVI) with 2,2-dimethoxypropane and p-toluenesulfonic acid yields the protected heptynoic ester (XXVII), which is saponified to the corresponding acid (XXVIII) with NaOH. The optical resolution of the racemic acid (XXVIII) by treatment with 1(R)-(1-naphthyl)ethylamine (XXIX) and crystallization of the diastereomeric salts affords the protected (3R,5S)-isomer (XXX), which is esterified with ethyl iodide and DBU to the corresponding ester (XXXI). The condensation of (XXXI) with 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI, see Scheme 5) by means of disiamylborane, NaOEt and PdCl2 in acetonitrile gives the protected (3R,5S)-NK-104 ethyl ester (XXXII).

合成路线4

Reaction of chloroacetic acid (XXII) with sodium ethoxide (XXIII) in ethanol gives 2-ethoxyacetic acid ethyl ester (XXIV), which is condensed with 4-methoxybenz-aldehyde (XXV) by means of t-BuOK in THF to yield 2-ethoxy-3-(4-methoxyphenyl)-2-propenoic acid ethyl ester (XXVI). Hydrolysis of ester (XXVI) with NaOH in hot ethanol/water affords the propenoic acid derivative (XXVII), which is reduced with H2 over Pd/C in ethanol to provide racemic 2-ethoxy-3-(4-methoxyphenyl)propionic acid (XXVIII). Optical resolution of mixture (XXVIII) is performed by salt formation with 1(S)-(1-naphthyl)ethylamine (XXIX) followed by crystallization to give the diastereomeric salt (XXX), which is treated with NaOH, followed by acidification with HCl to yield 2(S)-ethoxy-3-(4-methoxyphenyl)propionic acid (XXXI). Demethylation of compound (XXXI) by reaction with NaOH and octanethiol in NMP affords 2(S)-ethoxy-3-(4-hydroxyphenyl)propionic acid (XXXII), which is esterified with ethanol/HCl to provide the corresponding ethyl ester (XXXIII). Condensation of ester (XXXIII) with the bismesylate (II) by means of either K2CO3 in 2-butanone or Na2CO3 in acetone provides 2(S)-ethoxy-3-[4-[2-[4-(methanesulfonyloxy)-phenyl]ethoxy]phenyl]propionic acid ethyl ester (XXI), which is finally hydrolyzed with NaOH or LiOH in acetone/water.

合成路线5

Reaction of 1(R)-(1-naphthyl)ethylamine (I) with 3-[3-(trifluoromethyl)phenyl]propionaldehyde (II) by means of titanium tetraisopropoxide gives the corresponding imine (III), which is finally reduced with NaBH3CN in ethanol.

合成路线6

合成路线7