Atorvastatin calcium, YM-548, CI-981, Prevencor, Tahor, Lipibec, Torvast, Sortis, Lipitor

合成路线: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.

合成路线: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.

参考文献标题:(R-(R*R*)-2-(4-Fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3 -phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid,its lactone form and salts thereo
文献作者:Roth,B.D.(Pfizer Inc.)
参考来源:EP 0409281; JP 1991058967; US 5273995


合成路线: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.

合成路线: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.

参考文献标题:Stable oral CI-981 formulation and process for preparing same
文献作者:Mills,N.; Muhammad,N.A.; Weiss,J.; Nesbitt,R.U.(Pfizer Inc.)
参考来源:EP 0680320; JP 1996505640; US 5686104; WO 9416693


合成路线: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.

参考文献标题:Form III crystalline (R-(R*,R*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methyl-ethyl) -3-phenyl-4- ((phenylamino)carbonyl)-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)
文献作者:McKenzie,A.T.(Pfizer Inc.)
参考来源:JP 1999509229; WO 9703958


合成路线: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.

参考文献标题:Crystalline [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl) -3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)
文献作者:Briggs,C.A.; Jennings,R.A.; Wade,R.A.; Harasawa,K.; Ichikawa,S.; Minohara,K.; Nakagawa,S.(Pfizer Inc.)
参考来源:JP 1999509230; WO 9703959


合成路线: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.

参考文献标题:Novel process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
文献作者:Lin,M.; Schweiss,D.(Pfizer Inc.)
参考来源:JP 1999510486; WO 9703960


合成路线: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-.

参考文献标题:Process for trans-6-[2-(substd.-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
文献作者:Butler,D.E.; Le,T.V.; Nanninga,T.N.(Pfizer Inc.)
参考来源:US 5298627

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