合成路线1

The cyclization of 2,2'-di(benzyloxycarbonylamino)pimelic acid (I) with PCl5 in methylene chloride gives the bis-N-carboxy anhydride (II), which by reaction with tert-butyl carbazate (A) is converted into the bis(tert-butyloxycarbonylhydrazide) compound (III). The enzymatic hydrolysis of (III) with an aminopeptidase from Streptomyces sapporonensis affords the mono-tert-butoxycarbonylhydrazide (IV), which by selective protection of the amino group with benzyloxycarbonyl chloride (B) under copper chelate conditions yields the selectively protected hydrazide (V). Full protection of (V) with tert-butoxycarbonyl anhydride (C) affords the fully protected monohydrazide (VI), which is condensed with benzyl glycinate (VII) to give the protected dipeptide (VIII). Hydrogenolysis of (VIII) with H2 over Pd/C in methanol-acetic acid yields the di-tert-butoxycarbonyldipeptide (IX), which is condensed with 2-acetoxypropanoylalanylglutamic acid monobenzyl ester (X) by means of isobutoxycarbonyl chloride (D) yielding the protected FK-156 (XI).

合成路线2

Alternatively, ecadotril can be obtained by an analogous route: Treatment of the already reported methyl beta-hydroxy-alpha-methylene-benzenepropionate (XVI) with sulfuric acid and acetic anhydride provides 2-benzylidene-3-acetoxypropionate methyl ester (XIXa-b), which is then subjected to hydrolysis with NaOH in MeOH/H2O to give carboxylic acid (XXa-b). Hydrogenation of (XXa-b) over Pd/C in MeOH/H2O in the presence of Et3N yields racemic 3-hydroxy-2-benzylpropionic acid (XXI), from which isomer (S)-(XXIII) is isolated by formation of a diastereomeric salt with (1R,2S)-(+)-cis-1-amino-2-indanol (XXII) in 2-propanol at 70 C followed by crystallization and decomposition of the salt with HCl. Coupling of compound (S)-(XXIII) with benzyl glycinate (XIV) by means of Et3N, HOBt and DCC in THF gives N-(3-hydroxy-2(S)-benzylpropionyl)-glycine benzyl ester (XXIV), which is then converted into the corresponding methanesulfonyloxy derivative (XXV) by reaction with methanesulfonyl chloride in toluene in the presence of pyridine followed by treatment with HCl. Finally, treatment of (XXV) with LiBr in refluxing acetone provides N-(3-bromo-2(S)-benzylpropionyl)glycine benzyl ester (XXVI), which is converted into ecadotril by reaction with potassium thioacetate in methyl isobutyl ether at 50 C.

合成路线3

The condensation of 4-(pivaloyloxy)benzenesulfonyl chloride (I) with the glycine benzyl ester (II) in pyridine gives N-[2-[4-(pivaloyloxy)phenylsulfonamido]benzoyl]glycine benzyl ester (III), which is then debenzylated by hydrogenolysis with H2 over Pd/C in methanol. The starting compounds (I) and (II) are obtained as follows: 1) The condensation of pivaloyl chloride (IV) with 4-hydroxybenzenesulfonic acid (V) by means of NaOH in THF - water gives 4-(pivaloyloxy)benzenesulfonic acid (VI), which is then treated with SOCl2 to afford the corresponding acyl chloride (I). 2) The condensation of 2-nitrobenzoyl chloride (VII) with glycine benzyl ester (VIII) by means of triethylamine in dichloromethane gives N-(2-nitrobenzoyl)glycine benzyl ester (IX), which is then reduced with Fe - HCl in THF - water to the amino derivative (II).

合成路线4

Coupling of N-Boc-glycine (VI) with glycine benzyl ester hydrochloride (VII) by means of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) gave the protected dipeptide (VIII). After deprotection of the Boc group of (VIII) with HCl, the resulting amine (IX) was condensed with the thioacylating compound (V) to furnish thioamide (X). Finally, the Boc and benzyl protecting groups of (X) were cleaved using HF.

合成路线5

Coupling of N-Boc-L-leucine (XVII) with glycine benzyl ester (XVIII), followed by acidic N-Boc group cleavage, affords the dipeptide benzyl ester (XIX), which is submitted to coupling with N-Boc-L-isoleucine (XX) and further benzyl ester hydrogenolysis to give rise to the N-Boc tripeptide (XXI). Then, assembly between (XXI) and pentapeptide (XVI) is accomplished by means of EDC/HOBt, providing the protected peptide (XXII). Hydrogenolysis of the benzyl groups of (XXII), followed by Boc group cleavage with trifluoroacetic acid, leads to the fully deprotected octapeptide (XXIII).

合成路线6

The title compound was obtained by solution-phase peptide synthesis. Acylation of L-aspartic acid beta-benzyl ester (II) with the succinimidyl ester of N-Boc-gamma-benzyl-L-glutamic acid (I) led to the protected dipeptide (III). Removal of the Boc protecting group of (III) by means of trifluoroacetic acid afforded amine (IV), which was subsequently condensed with N-Cbz-L-alanine succinimidyl ester (V) to furnish tripeptide (VI). Coupling of (VI) with glycine benzyl ester (VII) using DCC and HOBt gave the fully protected peptide (VIII). The N-Cbz and benzyl ester groups of (VIII) were finally removed by catalytic hydrogenation over Pd/C to provide the target tetrapeptide.

合成路线7