Pitavastatin calcium, Itavastatin calcium, Nisvastatin, NKS-104, NK-104, Livalo

合成路线:8) Open form: The silylation of (S,S)-tartaric acid diisopropyl ester (LXI) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF gives the bissilylated compound (LXII),which is condensed with the disodium salt of tert-butyl acetoacetate (LXIII) in THF,yielding (S,S)-7-(tert-butoxycarbonyl)-2,3-bis (tert-butyldimethylsilyloxy)-4,6-dioxoheptanoic acid isopropyl ester (LXIV).The selective reduction of (LXIV) with DIBAL in THF affords the monohydroxylated compound (LXV),which is further reduced with diethylmethoxyborane in THF to the dihydroxylated compound (LXVI).The protection of the OH groups of (LXVI) with 2,2-dimethoxypropane and p-toluenesulfonic acid gives the 1,3-dioxane derivative (LXVII),which is desilylated with TBAF in THF to the gem-diol (LXVIII).Oxidation of the diol (LXVIII) with sodium metaperiodate in water/ethyl ether affords the aldehyde (LXIX),which is then condensed with 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-ylmethyl(diphenyl)phosphine oxide (LXX) by means of lithium 2,2,6,6-tetramethylpiperidine (TMPip-Li) or butyllithium in THF,giving the protected tert-butyl ester (XXII).Finally,this compound is deprotected and hydrolyzed with trifluoroacetic acid in dichloromethane.9) The phosphine oxide (LXX) has been obtained as follows: 2-Cyclopropyl-4-(4-fluorophenyl)-3-(hydroxy-methyl)quinoline (LIX,Scheme 5) was treated with PBr3,yielding the corresponding bromomethyl derivative (LXXI),which was then treated with diphenyl(ethoxy)phosphorane in refluxing toluene.

合成路线:10) Lactone form: The reduction of 7-phenyl-3,5-dioxo-6(E)-heptenoic acid methyl ester (LXXII) with diethylmethoxyborane and NaBH4 in THF/methanol gives the (3R*,5S*,6E)-dihydroxy ester (LXXIII),which by reaction with acetone dimethylacetal and p-toluenesulfonic acid yields the acetonide (LXXIV).The ozonolysis of (LXXIV) with O3 and dimethylsulfide in methanol affords the aldehyde (LXXV),which is condensed with 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-ylmethylphosphonic acid diethyl ester (LXXVI) by means of butyllithium to give the acetonide of the methyl ester (LXXVII).Finally,this compound is treated with trifluoroacetic acid to yield the lactone (XLVI).The phosphonate (LXXVI) has been obtained by reaction of the bromomethyl derivative (LXXI) with triethylphosphite (8).

参考文献标题:Condensed pyridines mevalonolactone intermediates and their preparation method
文献作者:Yanagawa,E.; Minami,T.; Obara,Y.; Kaiyama,T.(Nissan Chemical Industry,Ltd.; Sagami Chemical Research Center)
参考来源:JP 1993310700


合成路线:2) Lactone form: The regioselective opening of (R)-2-(tert-butyldimethylsilylethynyl)oxirane (XIV) with KCN in ethanol gives 3(S)-hydroxy-5-(tert-butyldimethylsilyl)-4-pentynenitrile (XV),which is condensed with tert-butyl bromoacetate (XVI) by means of Zn in refluxing THF to afford the 5(S)-hydroxyketoester (XVII).The controlled reduction of (XVII) with NaBH4/diethylmethoxyborane yields the 3(R),5(S)-dihydroxy ester (XVIII),which is deprotected with 2,2-dimethoxypropane and p-toluenesulfonic acid in THF/methanol to the protected heptynoic ester (XIX).The desilylation of (XIX) with tetrabutylammonium fluoride (TBAF) in THF affords the protected heptynoic ester (XX),which is condensed with 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI,see Scheme 5) to give the protected NK-104 tert-butyl ester (XXII).Finally,this compound is treated with trifluoroacetic acid in dichloromethane.

参考文献标题:A new synthesis of HMG-CoA reductase inhibitor NK-104 through hydrosilylation-cross coupling reaction
文献作者:Takahashi,K.; Minami,T.; Ohara,Y.; Hiyama,T.
参考来源:Tetrahedron Lett 1993,34(51),8263-6


合成路线:3) The condensation of 3-(trimethylsilyl)propynal (XXIII) with the dialkaline salt of ethylacetoacetate (XXIV) in THF gives 5-hydroxy-3-oxo-7-(trimethylsilyl)-6-heptynoic acid ethyl ester (XXV),which is reduced with NaBH4/diethylmethoxyborane to the racemic 3,5-dihydroxy-7-(trimethylsilyl)-6-heptynoic acid ethyl ester (XXVI).The protection and desilylation of (XXVI) with 2,2-dimethoxypropane and p-toluenesulfonic acid yields the protected heptynoic ester (XXVII),which is saponified to the corresponding acid (XXVIII) with NaOH.The optical resolution of the racemic acid (XXVIII) by treatment with 1(R)-(1-naphthyl)ethylamine (XXIX) and crystallization of the diastereomeric salts affords the protected (3R,5S)-isomer (XXX),which is esterified with ethyl iodide and DBU to the corresponding ester (XXXI).The condensation of (XXXI) with 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI,see Scheme 5) by means of disiamylborane,NaOEt and PdCl2 in acetonitrile gives the protected (3R,5S)-NK-104 ethyl ester (XXXII).

合成路线:6) Synthesis of the quinoline (XXI): Anthranilic acid (LI) is tolylated with tosyl chloride and treated with PCl5 in 1,2-dichloroethane to give the corresponding acyl chloride (LII),which is submitted to a Friedel Crafts condensation with fluorobenzene (LIII)/AlCl3 yielding 2-amino-4'-fluorobenzophenone (LIV).The cyclization of (LIV) with ethyl 2-(cyclopropylcarbonyl)acetate (LV) [obtained by condensation of cyclopropyl methyl ketone (LVI) and diethyl carbonate (LVII) with H2SO4] by means of p-toluenesulfonic acid yields 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carboxylic acid ethyl ester (LVIII),which is submitted to a decarboxylative iodination with I2 and acetyl peroxide to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI).7) Synthesis of the quinoline (XXXVII): The reduction of the quinolinecarboxylate (LVIII) with LiAlH4 in THF gives the corresponding methanol derivative (LIX),which is then treated with diphenyl disulfide (LX) and tri-butylphosphine in pyridine to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII).

参考文献标题:A novel synthetic method of HMG-CoA reductase inhibitor NK-104 via a hydroboration-cross-coupling sequence
文献作者:Iwasaki,H.; Miyachi,N.; Yanagawa,Y.; Ohara,Y.; Hiyama,T.
参考来源:Tetrahedron Lett 1993,34(51),8267-70


合成路线:1NK-104 in its open and lactone forms has been synthesized by several different ways:1) Lactone form: The reaction of 1(R),7,7-trimethylbicyclo[2.2.1]heptan-2-one (I) with 1-naphthylmagnesium bromide (II) gives the tertiary alcohol (III),which by reaction with SOCl2 and then with NaHCO3 yields 2-(1-naphthyl)-1(R),7,7-trimethylbicyclo[2.2.1]heptene (IV).Hydroboration of (IV) with BH3 followed by oxidation with H2O2 affords 4(S),7,7-trimethyl-3exo-(1-naphthyl)bicyclo[2.2.1]heptan-2exo-ol (V),which is submitted to transesterification with methyl acetoacetate (VI) and dimethyl-aminopyridine (DMAP) to give the corresponding ester (VII).The condensation of (VII) with N-methoxy-N-methyl-3-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-2(E)-propenamide (VIII) by means of NaH yields the corresponding chiral 3,5-dioxoheptenoic acid ester (IX),which is selectively reduced first with diisobutylaluminum hy-dride acid (DIBAL) and then with diethylmethoxyborane and sodium borohydride affording the 3(R),5(S)-dihydroxyheptenoic ester (X).Finally,this compound is saponified with NaOH and treated with acetic acid/sodium acetate.The intermediate amide (VIII) is obtained by condensation of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde (XI) with N-methoxy-N-methylacetamide (XII) by means of butyllithium to the hydroxy propionamide (XIII),which is then dehydrated with methanesulfonyl chloride and triethylamine in the usual way).

合成路线:2) Lactone form: The regioselective opening of (R)-2-(tert-butyldimethylsilylethynyl)oxirane (XIV) with KCN in ethanol gives 3(S)-hydroxy-5-(tert-butyldimethylsilyl)-4-pentynenitrile (XV),which is condensed with tert-butyl bromoacetate (XVI) by means of Zn in refluxing THF to afford the 5(S)-hydroxyketoester (XVII).The controlled reduction of (XVII) with NaBH4/diethylmethoxyborane yields the 3(R),5(S)-dihydroxy ester (XVIII),which is deprotected with 2,2-dimethoxypropane and p-toluenesulfonic acid in THF/methanol to the protected heptynoic ester (XIX).The desilylation of (XIX) with tetrabutylammonium fluoride (TBAF) in THF affords the protected heptynoic ester (XX),which is condensed with 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI,see Scheme 5) to give the protected NK-104 tert-butyl ester (XXII).Finally,this compound is treated with trifluoroacetic acid in dichloromethane.

合成路线:3) The condensation of 3-(trimethylsilyl)propynal (XXIII) with the dialkaline salt of ethylacetoacetate (XXIV) in THF gives 5-hydroxy-3-oxo-7-(trimethylsilyl)-6-heptynoic acid ethyl ester (XXV),which is reduced with NaBH4/diethylmethoxyborane to the racemic 3,5-dihydroxy-7-(trimethylsilyl)-6-heptynoic acid ethyl ester (XXVI).The protection and desilylation of (XXVI) with 2,2-dimethoxypropane and p-toluenesulfonic acid yields the protected heptynoic ester (XXVII),which is saponified to the corresponding acid (XXVIII) with NaOH.The optical resolution of the racemic acid (XXVIII) by treatment with 1(R)-(1-naphthyl)ethylamine (XXIX) and crystallization of the diastereomeric salts affords the protected (3R,5S)-isomer (XXX),which is esterified with ethyl iodide and DBU to the corresponding ester (XXXI).The condensation of (XXXI) with 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI,see Scheme 5) by means of disiamylborane,NaOEt and PdCl2 in acetonitrile gives the protected (3R,5S)-NK-104 ethyl ester (XXXII).

合成路线:4) Lactone form: The condensation of 2(S)-(chloromethyl)oxirane (XXXIII) with trimethylsilylacetylene (XXXIV) by means of butyllithium and BF3 ethearate in THF gives 5-chloro-4(S)-hydroxy-1-(trimethylsilyl)-1-pentyne (XXXV),which is cyclized with KOH in THF to the chiral epoxide (XXXVI).The condensation of (XXXVI) with 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII,see Scheme 5) by means of butyllithium in THF affords the silylated heptynol (XXXVIII),which is desilylated with K2CO3 in methanol to the terminal acetylene (XXXIX).The carboxylation of (XXXIX) with CO by means of PdCl2/CuCl2 in methanol yields the heptynoic acid ester (XL),which is selectively reduced with H2 over the Lindlar catalyst in methanol to the cis-heptenoic ester (XLI).The cyclization of (XLI) with PPTS in refluxing toluene affords the (S)-unsaturated lactone (XLII),which is oxidized with m-chloroperbenzoic acid to the corresponding sulfinyl derivative (XLIII).

合成路线:Elimination of thiophenol from (XLIII) by means of CaCO3 in refluxing toluene gives the unsaturated lactone (XLIV) with the (E)-vinylene bond.The alpha,beta-epoxidation of the unsaturated lactone (XLIV) with H2O2 and NaOH in methanol/dichloromethane affords the monoepoxy lactone (XLV) regioselectively,which is finally submitted to a regioselective ring opening with diphenyl diselenide and NaBH4 in THF.

合成路线:6) Synthesis of the quinoline (XXI): Anthranilic acid (LI) is tolylated with tosyl chloride and treated with PCl5 in 1,2-dichloroethane to give the corresponding acyl chloride (LII),which is submitted to a Friedel Crafts condensation with fluorobenzene (LIII)/AlCl3 yielding 2-amino-4'-fluorobenzophenone (LIV).The cyclization of (LIV) with ethyl 2-(cyclopropylcarbonyl)acetate (LV) [obtained by condensation of cyclopropyl methyl ketone (LVI) and diethyl carbonate (LVII) with H2SO4] by means of p-toluenesulfonic acid yields 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carboxylic acid ethyl ester (LVIII),which is submitted to a decarboxylative iodination with I2 and acetyl peroxide to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI).7) Synthesis of the quinoline (XXXVII): The reduction of the quinolinecarboxylate (LVIII) with LiAlH4 in THF gives the corresponding methanol derivative (LIX),which is then treated with diphenyl disulfide (LX) and tri-butylphosphine in pyridine to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII).

合成路线:8) Open form: The silylation of (S,S)-tartaric acid diisopropyl ester (LXI) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF gives the bissilylated compound (LXII),which is condensed with the disodium salt of tert-butyl acetoacetate (LXIII) in THF,yielding (S,S)-7-(tert-butoxycarbonyl)-2,3-bis (tert-butyldimethylsilyloxy)-4,6-dioxoheptanoic acid isopropyl ester (LXIV).The selective reduction of (LXIV) with DIBAL in THF affords the monohydroxylated compound (LXV),which is further reduced with diethylmethoxyborane in THF to the dihydroxylated compound (LXVI).The protection of the OH groups of (LXVI) with 2,2-dimethoxypropane and p-toluenesulfonic acid gives the 1,3-dioxane derivative (LXVII),which is desilylated with TBAF in THF to the gem-diol (LXVIII).Oxidation of the diol (LXVIII) with sodium metaperiodate in water/ethyl ether affords the aldehyde (LXIX),which is then condensed with 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-ylmethyl(diphenyl)phosphine oxide (LXX) by means of lithium 2,2,6,6-tetramethylpiperidine (TMPip-Li) or butyllithium in THF,giving the protected tert-butyl ester (XXII).Finally,this compound is deprotected and hydrolyzed with trifluoroacetic acid in dichloromethane.9) The phosphine oxide (LXX) has been obtained as follows: 2-Cyclopropyl-4-(4-fluorophenyl)-3-(hydroxy-methyl)quinoline (LIX,Scheme 5) was treated with PBr3,yielding the corresponding bromomethyl derivative (LXXI),which was then treated with diphenyl(ethoxy)phosphorane in refluxing toluene.

合成路线:10) Lactone form: The reduction of 7-phenyl-3,5-dioxo-6(E)-heptenoic acid methyl ester (LXXII) with diethylmethoxyborane and NaBH4 in THF/methanol gives the (3R*,5S*,6E)-dihydroxy ester (LXXIII),which by reaction with acetone dimethylacetal and p-toluenesulfonic acid yields the acetonide (LXXIV).The ozonolysis of (LXXIV) with O3 and dimethylsulfide in methanol affords the aldehyde (LXXV),which is condensed with 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-ylmethylphosphonic acid diethyl ester (LXXVI) by means of butyllithium to give the acetonide of the methyl ester (LXXVII).Finally,this compound is treated with trifluoroacetic acid to yield the lactone (XLVI).The phosphonate (LXXVI) has been obtained by reaction of the bromomethyl derivative (LXXI) with triethylphosphite (8).

参考文献标题:NK-104
文献作者:Castar,J.; Sorbera,L.A.; Leeson,P.A.
参考来源:Drugs Fut 1998,23(8),847-859


合成路线:8) Open form: The silylation of (S,S)-tartaric acid diisopropyl ester (LXI) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF gives the bissilylated compound (LXII),which is condensed with the disodium salt of tert-butyl acetoacetate (LXIII) in THF,yielding (S,S)-7-(tert-butoxycarbonyl)-2,3-bis (tert-butyldimethylsilyloxy)-4,6-dioxoheptanoic acid isopropyl ester (LXIV).The selective reduction of (LXIV) with DIBAL in THF affords the monohydroxylated compound (LXV),which is further reduced with diethylmethoxyborane in THF to the dihydroxylated compound (LXVI).The protection of the OH groups of (LXVI) with 2,2-dimethoxypropane and p-toluenesulfonic acid gives the 1,3-dioxane derivative (LXVII),which is desilylated with TBAF in THF to the gem-diol (LXVIII).Oxidation of the diol (LXVIII) with sodium metaperiodate in water/ethyl ether affords the aldehyde (LXIX),which is then condensed with 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-ylmethyl(diphenyl)phosphine oxide (LXX) by means of lithium 2,2,6,6-tetramethylpiperidine (TMPip-Li) or butyllithium in THF,giving the protected tert-butyl ester (XXII).Finally,this compound is deprotected and hydrolyzed with trifluoroacetic acid in dichloromethane.9) The phosphine oxide (LXX) has been obtained as follows: 2-Cyclopropyl-4-(4-fluorophenyl)-3-(hydroxy-methyl)quinoline (LIX,Scheme 5) was treated with PBr3,yielding the corresponding bromomethyl derivative (LXXI),which was then treated with diphenyl(ethoxy)phosphorane in refluxing toluene.

参考文献标题:Synthesis of artificial HMG-CoA reductase inhibitors based on the olefination strategy
文献作者:Hiyama,T.; Takahashi,K.; Minami,T.
参考来源:Bull Chem Soc Jpn 1995,68(1),364-72


合成路线:2) Lactone form: The regioselective opening of (R)-2-(tert-butyldimethylsilylethynyl)oxirane (XIV) with KCN in ethanol gives 3(S)-hydroxy-5-(tert-butyldimethylsilyl)-4-pentynenitrile (XV),which is condensed with tert-butyl bromoacetate (XVI) by means of Zn in refluxing THF to afford the 5(S)-hydroxyketoester (XVII).The controlled reduction of (XVII) with NaBH4/diethylmethoxyborane yields the 3(R),5(S)-dihydroxy ester (XVIII),which is deprotected with 2,2-dimethoxypropane and p-toluenesulfonic acid in THF/methanol to the protected heptynoic ester (XIX).The desilylation of (XIX) with tetrabutylammonium fluoride (TBAF) in THF affords the protected heptynoic ester (XX),which is condensed with 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI,see Scheme 5) to give the protected NK-104 tert-butyl ester (XXII).Finally,this compound is treated with trifluoroacetic acid in dichloromethane.

参考文献标题:Synthesis of an artificial HMG-CoA reductase inhibitor NK-104 via a hydrosilylation-cross-coupling reaction
文献作者:Minami,T.; Hiyama,T.; Takahashi,K.; Ohara,Y.
参考来源:Bull Chem Soc Jpn 1995,68(5),2649-56

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