sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate -Drug Synthesis Database

【结构式】

【分子编号】27911

【品名】sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate

【CA登记号】

【分子式】C₃₃H₃₄FN₂NaO₅

【分子量】580.6316112

【元素组成】C 68.26% H 5.9% F 3.27% N 4.82% Na 3.96% O 13.78%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(XII)

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.

参考文献中间体

合成目标

【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2

该中间体在本合成路线中的序号：(XIV)

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.

参考文献中间体

合成目标

【1】 Woo, P.W.K.; Lee, H.T.; Atorvastatin, an HMG-CoA reductase inhibitor and effective lipid-regulating agent. Part II. Synthesis of side-chain-labeled [C-14] atorvastatin. J Label Compd Radiopharm 1999, 42, 2, 129.

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)	27912	Sodium acetate	127-09-3	C₂H₃NaO₂	详情	详情
(I)	45240	sodium acetate		C₂H₃NaO₂	详情	详情
(II)	23811	phthaloyl dichloride;1,2-Benzenedicarbonyl dichloride;o-Phthaloyl chloride	88-95-9	C₈H₄Cl₂O₂	详情	详情
(III)	19273	acetyl chloride	75-36-5	C₂H₃ClO	详情	详情
(III)	45241	acetyl chloride		C₂H₃ClO	详情	详情
(IV)	27913	(2S)-1,1,2-triphenyl-1,2-ethanediol	95061-46-4	C₂₀H₁₈O₂	详情	详情
(V)	11540	(1S)-2-hydroxy-1,2,2-triphenylethyl acetate; (R)-(+)-1,1,2-Triphenyl-1,2-ethanediol 2-acetate	95061-47-5	C₂₂H₂₀O₃	详情	详情
(V)	45242	(1S)-2-hydroxy-1,2,2-triphenylethyl acetate		C₂₂H₂₀O₃	详情	详情
(VI)	15386	5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide		C₂₉H₂₇FN₂O₂	详情	详情
(VII)	15395	(1S)-2-hydroxy-1,2,2-triphenylethyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate	134394-96-0	C₅₁H₄₇FN₂O₅	详情	详情
(VII)	45243	(1S)-2-hydroxy-1,2,2-triphenylethyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate		C₅₁H₄₇FN₂O₅	详情	详情
(VIII)	15396	methyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate		C₃₂H₃₃FN₂O₄	详情	详情
(VIII)	45244	methyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate		C₃₂H₃₃FN₂O₄	详情	详情
(IX)	15397	tert-butyl acetate	540-88-5	C₆H₁₂O₂	详情	详情
(X)	15398	tert-butyl (5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-5-hydroxy-3-oxoheptanoate		C₃₇H₄₁FN₂O₅	详情	详情
(X)	45245	tert-butyl (5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-5-hydroxy-3-oxoheptanoate		C₃₇H₄₁FN₂O₅	详情	详情
(XI)	27914	tert-butyl (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate		C₃₇H₄₃FN₂O₅	详情	详情
(XI)	45246	tert-butyl (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate		C₃₇H₄₃FN₂O₅	详情	详情
(XII)	15390	(3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid		C₃₃H₃₅FN₂O₅	详情	详情
(XII)	45247	(3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid		C₃₃H₃₅FN₂O₅	详情	详情
(XIII)	15391	5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide		C₃₃H₃₃FN₂O₄	详情	详情
(XIII)	45248	5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide		C₃₃H₃₃FN₂O₄	详情	详情
(XIV)	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
(XIV)	45249	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：(VIII)

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.

参考文献中间体

合成目标

【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：(VIII)

参考文献中间体

合成目标

【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：(VIII)

参考文献中间体

合成目标

【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

Extended Information