合成路线1

3) The reaction of diethyl malonate (XVIII) with 3-methylbutanal (XIX) by means of dipropylamine in acetic acid gives the corresponding 2-(3-methylbutylidene)malonate derivative (XX), which is treated with KCN to yield the corresponding addition compound (XXI). The decarboxylative hydrolysis of (XXI) with KOH affords 3-cyano-5-methylhexanoic acid (XXII), which is reduced with H2 over Ni to yield racemic pregabalin (XXIII). Finally, this racemate is submitted to optical resolution with (S)-(+)-mandelic acid.

合成路线2

5) The condensation of 3-methylbutanal (XIX) with cyanoacetic acid ethyl ester (XXXII) or cyanoacetamide (XXXIII) by means of dipropylamine in refluxing hexane, followed by treatment with refluxing 6N HCl, gives 3-isobutylglutaric acid (XXXIV). This compound is converted into the corresponding anhydride (XXXV) by treatment with refluxing acetic anhydride. The reaction of the anhydride (XXXV) with NH4OH affords the glutaramic amide (XXXVI), which is submitted to optical resolution with (R)-(+)-1-phenylethylamine, yielding the (S)-enantiomer (XXXVII). Finally, this compound is submitted to a Hoffmann degradation with Br2/NaOH.

合成路线3

Cyclization of 2,2-dichloroisobutyraldehyde (I) - obtained by reaction of isovaleraldehyde (II) with chlorine in DMF - with 2-benzyloxyacetaldehyde (III) - produced by reaction of 2-butene-1,4-diol (IV) with benzyl chloride by means of NaOH in water, followed by ozonolysis in MeOH and finally reduction with triphenylphosphine in ethyl acetate - and aqueous NH4OH in methanol gives the imidazole derivative (VI), which is iodinated with I2 and NaOH in dichloromethane to yield the 5-iodoimidaz-ole derivative (VII). Condensation of compound (VII) with bis(3,5-dichlorophenyl)disulfide (VIII) by means of LiH in DMSO affords the dichlorophenylsulfanyl imidazole (IX), which is alkylated with 4-(chloromethyl)pyridine (X) and K2CO3 in DMF to provide the fully substituted imidazole (XI). Debenzylation of compound (XI) with conc. HCl in refluxing ethanol gives the carbinol (XII), which is finally treated with trichloroacetyl isocyanate and triethylamine in methanol/water.

合成路线4

Hydrogenation of 6-methylpyridine-2-carboxylic acid (I) over Pd/C in aqueous ammonia afforded the corresponding piperidine (II). Subsequent condensation of (II) with isovaleraldehyde (III), followed by catalytic hydrogenation with Pd/C provided the N-isopentyl piperidine (IV), which was finally coupled with O-benzyltyrosine tert-butyl ester (V) in the presence of benzotriazolyl tetramethyluronium hexafluorophosphate (HBTU) to furnish the target amide.

合成路线5

Piperazine-2-carboxylic acid (VIII) was prepared by catalytic hydrogenation of pyrazine (VII). Sequential protection of the N-4 of (VIII) with 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile and the N-1 with benzyl chloroformate provided the diprotected piperazinecarboxylic acid (X), which was subsequently esterified with diazomethane to give the methyl ester (XI). The N-benzyloxycarbonyl group of (XI) was selectively deprotected by hydrogenation in the presence of Pd/C to yield the N-Boc-piperazine (XII). Reductive alkylation of (XII) with isovaleraldehyde (XIII) afforded the corresponding N-isoamyl piperazine (XIV). After acid removal of the N-Boc group of (XIV) to yield (XV), a second reductive alkylation with acetone (XVI) produced the dialkyl piperazine (XVII). Hydrolysis of the methyl ester group of (XVII) under acidic conditions gave acid (XVIII). This was finally coupled with the intermediate piperidine (VI) in the presence of HBTU to provide the title compound.

合成路线6

The condensation of tert-butoxycarbonylproline (I) with methylamine (II), isovaleraldehyde (III) and ethyl isocyanoacetate (IV) in methanol gives Boc-Pro-Me-Leu-Gly-OEt (V), which is separated from its diastereoisomer by chromatography over silica gel. The reaction of (V) with ammonia in cold methanol yields the corresponding amide (VI). Finally this compound is deprotected by treatment with dry HCl in ethyl acetate

合成路线7