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【结 构 式】 
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【分子编号】15448 【品名】4-Methyl-3-oxo-N-phenylpentanamide; 4-Methyl-3-oxopentanoic acid anilide 【CA登记号】124401-38-3 |
【 分 子 式 】C12H15NO2 【 分 子 量 】205.25664 【元素组成】C 70.22% H 7.37% N 6.82% O 15.59% |
合成路线1
该中间体在本合成路线中的序号：(XLIV)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.
| 【1】 Graul, A.; Castaner, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956. |
| 【2】 McKenzie, A.T. (Pfizer Inc.); 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). JP 1999509229; WO 9703958 . |
| 【3】 Lin, M.; Schweiss, D. (Pfizer Inc.); 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). JP 1999510486; WO 9703960 . |
| 【4】 Briggs, C.A.; Jennings, R.A.; Wade, R.A.; Harasawa, K.; Ichikawa, S.; Minohara, K.; Nakagawa, S. (Pfizer Inc.); 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). JP 1999509230; WO 9703959 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXII) | 15426 | 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide | 125971-96-2 | C26H24FNO3 | 详情 | 详情 |
| (XLII) | 15444 | (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; (4R-Cis)-1,1-Dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxoane-4-acetate | 125995-13-3 | C14H27NO4 | 详情 | 详情 |
| (XLIII) | 15452 | tert-butyl 2-((4R,6R)-6-[2-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C40H47FN2O5 | 详情 | 详情 | |
| (XLIV) | 15448 | 4-Methyl-3-oxo-N-phenylpentanamide; 4-Methyl-3-oxopentanoic acid anilide | 124401-38-3 | C12H15NO2 | 详情 | 详情 |
| (XLV) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (XLVI) | 15450 | (Z)-2-isobutyryl-N,3-diphenyl-2-propenamide | 125971-57-5 | C19H19NO2 | 详情 | 详情 |
| (XLVII) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)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.
| 【1】 Woo, P.W.K.; et al.; Atorvastatin, an HMG-CoA reductase inhibitor and efficient lipid-regulating agent. Part I. Synthesis of ring-labeled [C-14] atorvastatin. J Label Compd Radiopharm 1999, 42, 2, 121. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 27910 | chloro(phenyl)magnesium | 100-59-4 | C6H5ClMg | 详情 | 详情 |
| (III) | 10202 | Benzoic acid | 65-85-0 | C7H6O2 | 详情 | 详情 |
| (III) | 45234 | benzoic acid | C7H6O2 | 详情 | 详情 | |
| (IV) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (IV) | 45235 | phenylmethanol | C7H8O | 详情 | 详情 | |
| (V) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (V) | 44663 | benzaldehyde | C7H6O | 详情 | 详情 | |
| (VI) | 15448 | 4-Methyl-3-oxo-N-phenylpentanamide; 4-Methyl-3-oxopentanoic acid anilide | 124401-38-3 | C12H15NO2 | 详情 | 详情 |
| (VII) | 15450 | (Z)-2-isobutyryl-N,3-diphenyl-2-propenamide | 125971-57-5 | C19H19NO2 | 详情 | 详情 |
| (VII) | 45236 | (Z)-2-isobutyryl-N,3-diphenyl-2-propenamide | C19H19NO2 | 详情 | 详情 | |
| (VIII) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (IX) | 15426 | 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide | 125971-96-2 | C26H24FNO3 | 详情 | 详情 |
| (IX) | 45237 | 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide | C26H24FNO3 | 详情 | 详情 | |
| (X) | 15444 | (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; (4R-Cis)-1,1-Dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxoane-4-acetate | 125995-13-3 | C14H27NO4 | 详情 | 详情 |
| (XI) | 15452 | tert-butyl 2-((4R,6R)-6-[2-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C40H47FN2O5 | 详情 | 详情 | |
| (XI) | 45238 | tert-butyl 2-((4R,6R)-6-[2-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C40H47FN2O5 | 详情 | 详情 | |
| (XII) | 27911 | sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C33H34FN2NaO5 | 详情 | 详情 | |
| (XII) | 45239 | sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C33H34FN2NaO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)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.
| 【1】 Woo, P.W.K.; et al.; Atorvastatin, an HMG-CoA reductase inhibitor and effective lipid regulating agent. Part III. Synthesis of [H-2(5)]-, [C-13(8)], and [C-13(7)],N-15]atorvastatin and their application in metabolic and pharmacokinetic studies. J Label Compd Radiopharm 1999, 42, 2, 135. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (II) | 15448 | 4-Methyl-3-oxo-N-phenylpentanamide; 4-Methyl-3-oxopentanoic acid anilide | 124401-38-3 | C12H15NO2 | 详情 | 详情 |
| (III) | 15450 | (Z)-2-isobutyryl-N,3-diphenyl-2-propenamide | 125971-57-5 | C19H19NO2 | 详情 | 详情 |
| (IV) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (V) | 15426 | 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide | 125971-96-2 | C26H24FNO3 | 详情 | 详情 |
| (VI) | 15444 | (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; (4R-Cis)-1,1-Dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxoane-4-acetate | 125995-13-3 | C14H27NO4 | 详情 | 详情 |
| (VII) | 15452 | tert-butyl 2-((4R,6R)-6-[2-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C40H47FN2O5 | 详情 | 详情 | |
| (VIII) | 27911 | sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C33H34FN2NaO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)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.
| 【1】 Woo, P.W.K.; et al.; Atorvastatin, an HMG-CoA reductase inhibitor and effective lipid regulating agent. Part III. Synthesis of [H-2(5)]-, [C-13(8)], and [C-13(7)],N-15]atorvastatin and their application in metabolic and pharmacokinetic studies. J Label Compd Radiopharm 1999, 42, 2, 135. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (II) | 15448 | 4-Methyl-3-oxo-N-phenylpentanamide; 4-Methyl-3-oxopentanoic acid anilide | 124401-38-3 | C12H15NO2 | 详情 | 详情 |
| (III) | 15450 | (Z)-2-isobutyryl-N,3-diphenyl-2-propenamide | 125971-57-5 | C19H19NO2 | 详情 | 详情 |
| (IV) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (V) | 15426 | 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide | 125971-96-2 | C26H24FNO3 | 详情 | 详情 |
| (VI) | 15444 | (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; (4R-Cis)-1,1-Dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxoane-4-acetate | 125995-13-3 | C14H27NO4 | 详情 | 详情 |
| (VII) | 15452 | tert-butyl 2-((4R,6R)-6-[2-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C40H47FN2O5 | 详情 | 详情 | |
| (VIII) | 27911 | sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C33H34FN2NaO5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)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.
| 【1】 Woo, P.W.K.; et al.; Atorvastatin, an HMG-CoA reductase inhibitor and effective lipid regulating agent. Part III. Synthesis of [H-2(5)]-, [C-13(8)], and [C-13(7)],N-15]atorvastatin and their application in metabolic and pharmacokinetic studies. J Label Compd Radiopharm 1999, 42, 2, 135. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (II) | 15448 | 4-Methyl-3-oxo-N-phenylpentanamide; 4-Methyl-3-oxopentanoic acid anilide | 124401-38-3 | C12H15NO2 | 详情 | 详情 |
| (III) | 15450 | (Z)-2-isobutyryl-N,3-diphenyl-2-propenamide | 125971-57-5 | C19H19NO2 | 详情 | 详情 |
| (IV) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (V) | 15426 | 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide | 125971-96-2 | C26H24FNO3 | 详情 | 详情 |
| (VI) | 15444 | (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; (4R-Cis)-1,1-Dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxoane-4-acetate | 125995-13-3 | C14H27NO4 | 详情 | 详情 |
| (VII) | 15452 | tert-butyl 2-((4R,6R)-6-[2-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C40H47FN2O5 | 详情 | 详情 | |
| (VIII) | 27911 | sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C33H34FN2NaO5 | 详情 | 详情 |