合成路线1

7) [12b-14C]-Org-5222: The condensation of labeled sarcosine methyl ester (XVI) (prepared from sarcosine (XV) with SOCl2 and methanol) with 2-(5-chloro-2-phenoxyphenyl)acetyl chloride (XVIII) (prepared from the corresponding acid (XVII) and SOCl2) yields the acylated sarcosine (XIX), which is cyclized by means of potassium tert-butoxide in toluene to the pyrrolidinedione (XX). A further cyclization of (XX) with polyphosphoric acid affords [3a-14C]-11-chloro-2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (XXI), which is reduced with Mg in methanol to the trans-isomeric amide (XXII) (along with the cis-isomer, which is separated by HPLC). Finally, the amide (XXII) is reduced with LiAlH4/AlCl3 in ethyl ether.

合成路线2

The reaction of 6-methoxy-5-(trifluoromethyl)naphthalene-1-carboxylic acid (I) with SOCl2 in refluxing DMF gives the corresponding acyl chloride (II), which is condensed with methyl N-methylglycinate (III) by means of hydroxybenzotriazole and dicyclohexylcarbodiimide in DMF yielding methyl N-[[5-(trifluoromethyl)-6-methoxy-1-naphthyl]carbonyl]-N-methylglycinate (IV). The reaction of (IV) with P2S5 refluxing pyridine affords methyl N-[[5-(trifluoromethyl)-6-methoxy-1-naphthyl]thioxomethyl]-N-methylglycinate (V), which is finally hydrolyzed with NaOH in methanol water. The synthesis of [14C]-labeled tolrestat has also been described.

合成路线3

The intermediate chiral aldehyde (XIV) has been obtained as follows: Acylation of sarcosine methyl ester (II) with 3,5-dichlorobenzoyl chloride (I) provides the N-benzoyl aminoester (III). The dilithium derivative of 3,4-dichlorophenylacetic acid (IV) is condensed with ester (III) to furnish, after acidic work-up, the N-benzoyl amino ketone (V). Subsequent alkylation of (V) with 1-bromo-3-methyl-2-butene (VI) affords (VII). Treatment of ketone (VII) with hydroxylamine yields a mixture of E- and Z- oximes, from which the Z-isomer (VIII) is isolated by column chromatography. Resolution of racemic (VIII) is then accomplished by two procedures. Coupling of (VIII) with N-Boc-D-phenylglycine (IX) produces a diastereomeric mixture of O-acyl oximes, from which isomer (X) can be separated by recrystallization. Hydrazinolysis of the N-acyl oxime (X) furnishes the target (R)-enantiomer (XI). Alternatively, oxime (VIII) is acylated by pivaloyl chloride, and subsequently separated into enantiomers by means of chiral chromatography. The desired isomer (XII) is then subjected to hydrazinolysis, yielding (XI)

合成路线4

Coupling of Boc-d-nitroarginine (I) with sarcosine methyl ester (II) in the presence of EDC and HOBt gave dipeptide (III). Subsequent deprotection of the Boc group of (III) afforded amine (IV), which was coupled with benzylsulfonyl chloride (V), yielding sulfonamide (VI). Then, saponification of the methyl ester of (VI) with LiOH furnished carboxylic acid (VII).

合成路线5

Acylation of sarcosine methyl ester (I) with 3,5-dichlorobenzoyl chloride (II) produced the corresponding amide (III). Claisen condensation of (III) with the dianion of 3,4-dichlorophenylacetic acid (IV), generated in the presence of lithium hexamethyldisilazide, gave, after acid decarboxylation, ketone (V). The lithium enolate of ketone (V) was then alkylated with 1-bromo-3-methyl-2-butene (VI) to afford (VII). Treatment of ketone (VII) with hydroxylamine produced a geometric mixture of oximes from which the desired (E)-isomer (VIII) was isolated by column chromatography. Resolution of the racemic (VIII) was achieved by coupling with N-Boc-D-phenylglycine (IX) followed by fractional crystallization of the desired diastereoisomer (X). Hydrazinolysis of the oxime ester then furnished the chiral intermediate (XI).

合成路线6