合成路线1

The condensation of 1-(3-pyridyl)ethanone (I) with dimethylformamide dimethylacetal (II) gives 3-(dimethylamino)-1-(3-pyridyl)-2-propen-1-one (III), which is cyclized with 1-(2-methyl-5-nitrophenyl)guanidine (IV) [obtained by reaction of 2-methyl-5-nitroaniline (V) with cyanamide (VI)] in refluxing isopropanol to yield the pyrimidine derivative (VII). Reduction of the nitro group of (VII) with H2 over Pd/C in THF affords the corresponding amino compound (VIII), which is finally condensed with 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride (IV) in pyridine.

合成路线2

Chlorination of 3-acetylpyridine (V) with N-chlorosuccinimide in HCl-AcOH gave (chloroacetyl)pyridine (VI). Subsequent enantioselective reduction of (VI) using (-)-B-chlorodiisopinocampheylborane yielded (R)-chlorohydrin (VII), which was cyclized to pyridyloxirane (VIII) with K2CO3 in boiling acetone. Opening of epoxide (VIII) with 4-aminophenethylamine (IX) produced amino alcohol (X). After protection as the tert-butyl carbamate (XI), coupling with sulfonyl chloride (IV) furnished sulfonamide (XII). Finally, Boc deprotection of (XII) using TFA produced the title compound.

合成路线3

The chlorination of 2-acetylpyridine (I) with N-chlorosuccinimide in ethereal HCl gives 2-(chloroacetyl)pyridine (II), which is reduced with (-)-B-chlorodiisopinocampheylborane [(-)-DIP-Cl] in THF yielding (R)-2-chloro-1-(2-pyridyl)ethanol (III). The epoxidation of (III) with K2CO3 in refluxing acetone affords the epoxide (IV), which is condensed with 4-(2-aminoethyl)aniline (V) in refluxing methanol providing (R)-2-[2-(4-aminophenyl)ethylamino]-1-(2-pyridyl)ethanol (VI). The selective protection of the secondary amino group of (VI) with tert-butoxycarbonyl anhydride in THF gives the carbamate (VII) (1), which is condensed with 4-[2-(2-cyclopentylethyl)oxazol-5-yl]phenylsulfonyl chloride (VIII) in pyridine yielding the sulfonamide (IX). Finally, this compound is deprotected with trifluoroacetic acid.

合成路线4

3-Acetylpyridine (I) was converted to the hydrochloride salt and then chlorinated with N-chlorosuccinimide to afford (chloroacetyl)pyridine (II). Asymmetric reduction of (II) by means of (-)-B-chlorodiisopinocampheylborane in THF produced the (R)-alcohol (III), which was cyclized to oxirane (IV) upon heating with K2CO3 in acetone. Epoxide (IV) opening with 4-aminophenethyl amine (V) in boiling MeOH gave aminoalcohol (VI). Then, selective protection of the aliphatic amine of (VI) as the tert-butyl carbamate yielded the target intermediate (VII). In a similar procedure, 2-chloro-5-acetylpyridine (VIII) was brominated employing dibromobarbituric acid in THF to afford bromide (IX), which was enantioselectively reduced to the (R)-alcohol (X). After cyclization of (X) to epoxide (XI), its opening with 4-nitrophenethyl amine (XII) yielded aminoalcohol (XIII). This was protected as the N-Boc derivative (XIV) and then, hydrogenation of the nitro group of (XIV) with concomitant halogen hydrogenolysis in the presence of Raney Nickel provided an alternative access to intermediate (VII).

合成路线5

3-Acetylpyridine (I) was chlorinated employing N-chlorosuccinimide, and the resulting chloroketone (II) was enantioselectively reduced with (-)-B-chlorodiisopinocampheylborane (DIP-Cl) to furnish the chiral chlorohydrin (III). Intramolecular cyclization of (III) in the presence of K2CO3 in refluxing acetone produced (R)-(3-pyridyl)oxirane (IV). Further ring opening with 4-aminophenethylamine (V) gave rise to diaminoalcohol (VI), which was selectively proteced with Boc2O at the aliphatic amino group, yielding carbamate (VII). In a related alternative procedure, 2-chloro-5-acetylpyridine (VIII) was brominated to (IX) by means of dibromobarbituric acid (DBBA), followed by reduction of bromoketone (IX) with (-)-DIP-Cl. The resulting (R)-bromohydrin (X) was converted to epoxide (XI) by treatment with NaOH, and subsequent ring opening with 4-nitrophenethylamine (XII) provided aminoalcohol (XIII). Protection of the amino group of (XIII) with Boc2O afforded carbamate (XIV). Further reduction of the nitro group of (XIV) with simultaneous hydrogenolysis of the halogen atom furnished the target intermediate (VII).

合成路线6

Chlorination of 3-acetylpyridine (I) by means of N-chlorosuccinimide (NCS) and HCl/HOAc in ethyl ether affords chloroacetyl derivative (II), which is then reduced with (-)-B-chlorodiisopinocampheylborane ((-)-DIP-Cl) and Et3N in THF to yield ethanol (III). Alcohol (III) is treated with K2CO3 in refluxing acetone to provide (R)-(3-pyridyl)oxirane (IV), which is then condensed with 4-aminophenethylamine (V) to give derivative (VI). N-Protection of (VI) by means of Boc2O in THF furnishes Boc derivative (VII), which is coupled to benzenesulfonyl chloride (VIII) in CH2Cl2 in the presence of pyridine to afford benzene sulfonamide (IX), which is then treated with H2S and Et3N in pyridine to yield thiocarboxamide derivative (X). Derivative (X) is then condensed in refluxing EtOH with chloromethylketone (XII), which can be obtained by reaction of 4-(trifluoromethyl)benzoyl chloride (XI) first with diazomethane (CH2N2) and then with HCl in ether. Finally, the N-Boc group is removed by means of TFA in CH2Cl2 to provide the target compound.

合成路线7

MGCD-0103 can be prepared as follows. Reaction of 4-(aminomethyl)benzoic acid methyl ester hydrochloride (I) with pyrazole-1-carboxamidine hydrochloride (II) affords guanidine (III). 3-Acetylpyridine (IV) is then heated with dimethylformamide dimethyl acetal to furnish the enaminone (V), which is cyclized with guanidine (III), giving the pyridyl pyrimidine (VI). After saponification of the methyl ester (VI) by means of LiOH, the resulting carboxylic acid (VII) is coupled with o-phenylenediamine (VIII) to provide the title compound (1). Scheme 1.

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