1) The condensation of 2-(1,3-dixolan-2-yl)ethylamine (I) with ethyl 2-bromo-2-(4-fluorophenyl)acetate (II) by means of triethylamine in acetonitrile gives ethyl 2-[2-(1,3-dioxolan-2-yl)ethylamino]-2-(4-fluorophenyl)acetate (III), which is acylated with isobutyryl chloride (IV) and triethylamine in dichloromethane yielding the corresponding amide (V). Saponification of the ester (V) with NaOH in methanol/water affords the free acid (VI), which is cyclized with N,3-diphenylpropynamide (VII) [obtained in the reaction of 3-phenylpropynoic acid (VIII) with aniline (IX) by means of dicyclohexylcarbodiimide (DCC)] by heating at 90 C in acetic anhydride giving 1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenylpyrrole-3-carboxamide (X). The hydrolysis of the dioxolane group of (X) with HCl yields the corresponding aldehyde (XI), which is condensed with methyl acetoacetate (XII) by means of NaH in THF affording 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid methyl ester (XIII). The reduction of the carbonyl group of (XIII) with tributylborane and NaBH4 in THF gives the (3R*,5R*)-dihydroxy ester (XIV), which is saponified with NaOH in water yielding the corresponding free acid (XV). The lactonization of (XV) by heating in refluxing toluene affords the (R*,R*)-lactone (XVI), which is submitted to optical resolution by reaction with (R)-1-phenylethylamine (XVII) followed by fractional crystallization thus obtaining the amide (XVII) as the pure (R,R,R)-enantiomer. The hydrolysis of the amide (XVIII) with NaOH, followed by heating in refluxing toluene gives the (R,R)-lactone (XIX), which is finally treated first with NaOH in methanol/water, and then with CaCl2 or calcium acetate.
2) The condensation of the previously described aldehyde (XI) with (S)-(+)-2-acetoxy-1,1,2-triphenylethanol (XX) by means of lithium diisopropylamide (LDA) in THF gives 5-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-3(R)-hydroxypentanoic acid 2-hydroxy-1(S),2,2-triphenylethyl ester (XXI), which is trans-esterified with sodium methoxide in methanol/THF yielding the expected methyl ester (XXII). The condensation of (XXII) with tert-butyl acetate (XXIII) by means of LDA in THF affords (R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl) pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid tert-butyl ester (XXIV), which is reduced with triethylborane and NaBH4 in THF, hydrolyzed with NaOH, lactonized by heating in refluxing toluene and finally submitted to fractional crystallization in order to separate the two diastereomers of the obtained lactone, (R,R) and (R,S). The (R,R)-diastereomer (XIX), already obtained, is finally treated with NaOH and then with CaCl2.
8) The synthesis of the 4-(4-fluorophenyl)-2-isobutyryl-4-oxo-N-phenylbutyramide (XXXII) is carried out as follows: The condensation of 4-methyl-3-oxo-N-phenylpentanamide (XLIV) with benzaldehyde (XLV) gives 2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide (XLVI), which is then condensed with 4-fluorobenzaldehyde (XLVII) by means of triethylamine in hot ethanol. 9) The cyclization of (XXXII) with intermediate (XLII) (preceding synthesis) in refluxing toluene yields the protected dehydroxyheptanoate (XLIII), which is deprotected with HCl in methanol and finally hydrolyzed with NaOH and treated with calcium acetate in water.
3) The condensation of 4-cyano-3(R)-hydroxybutyric acid ethyl ester (XXXV) with N,N-diphenylacetamide (R1 = R2 = Ph in XXVI) by means of LDA in THF gives 6-cyano-5(R)-hydroxy-3-oxo-N,N-diphenylhexanamide (XXVII), which is reduced with diethylmethoxyborane and NaBH4 in THF yielding 6-cyano-3(R),5(R)-dihydroxy-N,N-diphenylhexanamide (XXVIII). The protection of the two OH groups of (XXVIII) with acetone dimethylketal (XXIX) and methanesulfonic acid affords the 1,3-dioxane (XXX), which by reduction of its CN group by hydrogenation with H2 over RaNi in methanol/liquid ammonia gives intermediate (4R,6R)-2-[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]-N,N-diphenylacetamide (XXXI). The cyclization of (XXXI) with 4-(4-fluorophenyl)-2-isobutyryl-4-oxo-N-phenylbutyramide (XXXII) (its synthesis is in section 6, Scheme 18007204a) in refluxing toluene yields the protected dihydroxyheptanamide (XXXIII), which is deprotected with HCl in methanol to afford (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxy-N,N-diphenylheptanamide (XXXIV). Finally, this compound is hydrolyzed with NaOH and treated with calcium acetate in water. 4) The preceding reaction pathway can be repeated using other substituents for R1 and R2 in acetamide (XXVI) such as R1 = R2 = CH2Ph; R1 = R2 = Et; R1 = Bu, R2 = Me; R1 = t-Bu, R2 = CH2Ph; R1,R2 = -(CH2)5-.
5) The hydrolysis of methyl (Et or Bu) 3(R)-(tert-butyldimethylsilyloxy)-4-cyanobutyrate (XXV) with NaOH gives the corresponding free acid (XXXVI), which is condensed with malonic acid mono-tert-butyl ester magnesium salt (XXXVII) by means of carbonyldiimidazole (CDI) yielding tert-butyl 5(R)-(tert-butyldimethylsilyloxy)-6-cyano-3-oxohexanoate (XXXVIII). The desilylation of (XXXVIII) with tetrabutylammonium fluoride in acetic acid affords the expected hydroxylated ketoester (XXXIX), which is reduced with diethylmethoxyborane and NaBH4 in methanol giving tert-butyl 6-cyano-3(R),5(R)-dihydroxyhexanoate (XL). The protection of the two OH groups of (XL) with acetone dimethylketal (XXIX) and methanesulfonic acid affords the 1,3-dioxane (XLI) (6), which by reduction of its CN group by hydrogenation with H2 over Pd/C gives intermediate (4R,6R)-2-[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLII). 6) The (4R,6R)-2-[6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLI) can also be obtained by reaction of (4R,6R)-2-[6-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLVIII) with tosyl chloride to give the corresponding tosylate (XVIX), which is then treated with NaCN. 7) The tert-butyl 6-cyano-5(R)-hydroxy-3-oxohexanoate (XXXIX) can also be obtained by condensation of methyl 4-cyano-3(R)-hydroxybutyrate (L) with tert-butyl acetate (XXIII) by means of LDA in THF.
The synthesis of ring labeled [14C]-atorvastatin has been described: The Grignard reaction of phenylmagnesium chloride (I) with [14C]-labeled CO2 (II) in THF/ethyl ether gives the benzoic acid (III), which is reduced with LiAlH4 in ethyl ether to the benzyl alcohol (IV). The oxidation of (IV) with pyridinium dichromate affords the benzaldehyde (V), which is condensed with the isobutyrylacetamide (VI) by means of beta-alanine in acetic acid yielding a mixture of the cis- and trans-benzylidene derivatives (VII). The condensation of (VII) with 4-fluorobenzaldehyde (VIII) by means of triethylamine and a thiazolium bromide catalyst affords the 1,4-dione (IX), which is cyclized with the chiral amino ester (X) in hot heptane/toluene/THF providing the protected pyrroloheptanoic ester (XI). The deprotection of (XI) in acidic medium, followed by the hydrolysis of the ester group with NaOH affords the sodium salt (XII), which is finally treated with calcium acetate in THF/water.
The synthesis of atorvastatin [14C]-labeled on the side chain has been described: The reaction of [14C]-labeled sodium acetate (I) with phthaloyl chloride (II) in refluxing xylene gives the acyl chloride (III), which is treated with 1,2,2-triphenyl-1(S),2-ethanediol (IV) in dichloromethane yielding the expected monoacetate (V). The condensation of (V) with the pyrrolepropionaldehyde (VI) by means of lithium diisopropylamide (LDA) in THF affords the chiral beta-hydroxyester (VII), which is transesterified with sodium methoxide in methanol providing the corresponding methyl ester (VIII). The condensation of (VIII) with tert-butyl acetate (IX) by means of LDA in THF gives the beta-oxo-delta-hydroxyester (X), which is regioselectively reduced to the dihydroxyester (XI) by means of BEt3, NaBH4 and H2O2 in THF. The hydrolysis of (XI) with NaOH in THF/water, followed by acidification yields the free acid (XII), which is heated in refluxing toluene in a Dean-Stark trap to provide lactone (XIII). The reaction of (XIII) with NaOH in THF/methanol gives the corresponding sodium salt (XIV), which is finally treated with CaCl2 in the same solvent.
The synthesis of atorvastatin has been described: The condensation of benzaldehyde (I) with the isobutyrylacetamide (II) by means of beta-alanine in acetic acid yields a mixture of cis- and trans-benzylidene derivatives (III). The condensation of (III) with 4-fluorobenzaldehyde (IV) by means of triethylamine and a thiazolium bromide catalyst affords the 1,4-dione (V), which is cyclized with the chiral amino ester (VI) in hot heptane/toluene/THF to provide the protected pyrroloheptanoic ester (VII). The deprotection of (VII) in acidic medium, followed by the hydrolysis of the ester group with NaOH affords the sodium salt (VIII), which is finally treated with calcium acetate in THF/water.
The 6-cyanohexanoic ester (VII), intermediate in the synthesis of 180072 (see intermediate (XLI) in scheme no. 18007204a) has been obtained as follows: the reaction of 1,6-heptadien-4-ol (I) with BuLi, CO2, and I2 in THF gives the cyclic carbonate (II), which is treated with Ts-OH in acetone to yield the acetonide (III). The reaction of the iodine atom of (III) with KCN in hot DMSO affords the nitrile (IV), which is oxidized at the terminal double bond with OsO4 and NaIO4, or O3 and Me2S, to provide the carbaldehyde (V). The oxidation of (V) with CrO3/H2SO4 in acetone gives the carboxylic acid (VI), which is finally esterified with tert-butanol by means of DCC and DMAP in dichloromethane, yielding the target ester intermediate (VII).