合成路线1

The condensation of 4(R)-phenyloxazolidin-2-one (I) with 2(E)-pentenoyl chloride (II) by means of BuLi in THF gives 3-[2(E)-pentenoyl]-3(R)-phenyloxazolidin-2-one (III), which is treated with 3-[bis(trimethylsilyl)amino]phenylmagnesium bromide (IV) and CuBr in DMSO/THF regioselectively yielding the addition product (V). Elimination of the silyl groups of (VII) in mild acidic conditions and treatment of the resulting amine with benzyl bromide affords the dibenzylated amine derivative (VI), which is regioselectively acylated with 2-methoxy-2-methyl-1,3-dioxolane (V) and TiCl4 in dichloromethane under basic conditions giving the dione (VIII). The condensation of (VIII) with 1-phenyl-3-hexanone (IX) by means of Ti(OBu)Cl3 in dichloromethane as before yields the hydroxy-dione (X), which is cyclized by means of potassium tert-butoxide in THF to afford the dihydropyrone (XI). The debenzylation of (XI) by hydrogenation with H2 over Pd/C in methanol/ethyl acetate gives the free amine (XII), which is finally sulfonated with 5-(trifluoromethyl)pyridine-2-sulfonyl chloride (XIII) in pyridine/dichloromethane

合成路线2

2) The previously obtained dione (VIII) can also be condensed with 1-phenyl-4-pentyn-1-one (XIV) by means of Ti(OBu)Cl3 in dichloromethane as before yielding the unsaturated hydroxy-dione (XV), which is cyclized by means of potassium tert-butoxide in THF to afford the dihydropyrone (XVI). The hydrogenation of the triple bond of (XVI) with simultaneous debenzylation by means of H2 over Pd/C in methanol/ethyl acetate gives the previously obtained free amine derivative (XII).

合成路线3

1) The condensation of 1-phenylhexan-3-one (I) with ethyl acetate by means of butyllithium and diisopropylamine in THF gives racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ethyl ester (II), which is hydrolyzed with NaOH in methanol to the corresponding free acid (III). The optical resolution of (III) with (1R,2S)-(-)-norephedrine (IV) followed by treatment with aqueous HCl yields the chiral (R)-acid (V), which is treated with 4-biphenylyloxymethyl chloride (VI) and diisopropylethylamine in toluene affording the protected ester (VII). The reduction of the ester group of (VII) with diisobutylaluminum hydride (DIBAL) in toluene gives the monoprotected diol (VIII), which is oxidized at the primary hydroxy group with 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy radical (TEMPO) and NaOCl yielding the corresponding aldehyde (IX). The condensation of (IX) with (R)-3-(3-nitrophenyl)pentanoic acid methyl ester (X) by means of sodium hexamethyldisilazide (NaHMDS) in THF gives the hydroxyester (XI) as a mixture of four diastereomers. This mixture is oxidized with pyridinium chlorochromate (PCC) in dichloromethane to afford the ketoester (XII) also as a mixture of two diastereomers. Elimination of the biphenylyloxymethyl protecting group with H2SO4 in methanol yields the hydroxy ketoester (XIII).

合成路线4

The hydroxy ketoester (XIII) (Scheme 24009402a), which is cyclized by means of NaOH in methanol/water affording the dihydropyranone (XIV). The reduction of the nitro group of (XIV) with hydrogen over Pd/C in THF gives the corresponding aniline (XV), which is finally amidated with 5-(trifluoromethyl)pyridine-2-sulfonyl chloride and pyridine in DMSO.

合成路线5

2) The chiral intermediate (X) has been obtained by two different ways: a) The Knovenagel condensation of dimethyl malonate (XVII) with 3-nitrobenzaldehyde (XVIII) gives the corresponding benzylidenemalonate (XIX), which is alkylated with diethyl zinc and CuBr in DMSO yielding 2-[1-(3-nitrophenyl)propyl]malonic acid dimethyl ester (XX). The partial decarboxylation of (XX) with 6N HCl affords racemic 3-(3-nitrophenyl)pentanoic acid (XXI), which is esterified with methanol/HCl to the racemic methyl ester (XXII). Finally, this racemate is resolved by chromatography over a chiral (R,R)Whelk-O1 column giving the desired intermediate (X). b) The regioselective acetylation of 1-(3-nitrophenyl)-1-propanol (XXIII) with isopropenyl acetate (XXIV) catalyzed by Amano P30 lipase gives a mixture of the (S)-acetate (XXV) and unreacted (R)-alcohol (XXVI). After separation, (XXVI) was mesylated with mesyl chloride as usual yielding mesylate (XXVII), which was condensed with the sodium salt of diethyl malonate (XXVIII) affording the chiral malonic ester (XXIX). Partial decarboxylation of (XXIX) with 6N HCl gives the chiral pentanoic acid (XXX), which is finally esterified to the desired intermediate (X) with methanol/HCl.

合成路线6

A new synthesis of PNU-140690 has been developed: The condensation of 1-phenyl-3-hexanone (I) with methyl acetoacetate (II) by means of NaH in THF, followed by cyclization gives the hydroxypyrone (III), which by condensation with 3-nitrobenzaldehyde (IV) by means of AlCl3 in THF yields the benzylidene-pyrone (V). The alkylation of (V) with Et3Al, CuBr-Me2S in THF affords intermediate (VI), which is reduced at the nitro group with H2 over Pd/C in methanol giving the racemic amine (VII). The optical resolution of the N-benzyloxycarbonyl derivative of (VII) with chiral HPLC yielded the desired (R,R)-enantiomer (VIII), which was finally sulfonated with 5-(trifluoromethyl)pyridine-2-sulfonyl chloride (IX) in pyridine/dichloromethane.

合成路线7

合成路线8

合成路线9