(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 -Drug Synthesis Database

【结构式】

【分子编号】15444

【品名】(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

【CA登记号】125995-13-3

【分子式】C₁₄H₂₇NO₄

【分子量】273.37272

【元素组成】C 61.51% H 9.96% N 5.12% O 23.41%

与该中间体有关的原料药合成路线共 6 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6

合成路线1

该中间体在本合成路线中的序号：(XLII)

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.

参考文献中间体

合成目标

【1】 Graul, A.; Castaner, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956.
【2】 Roth, B.D.; Baumann, K.L.; Butler, D.E.; Deering, C.F.; Mennen, K.E.; Millar, A.; Nanninga, T.N.; Palmer, C.W.; The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33, 17, 2283-4.
【3】 Brower, P.L.; Butler, D.E.; Deering, C.F.; Le, T.V.; Millar, A.; Nanninga, T.N.; Roth, B.D.; The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33, 17, 2279-82.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXIII)	15097	7-[(2-aminopropyl)amino]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid		C₁₇H₂₀FN₃O₃	详情	详情
(XXIX)	10722	1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane	77-76-9	C₅H₁₂O₂	详情	详情
(XXXV)	15437	methyl (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-cyanobutanoate		C₁₂H₂₃NO₃Si	详情	详情
(XXXVI)	15438	(3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-cyanobutyric acid		C₁₁H₂₁NO₃Si	详情	详情
(XXXVII)	15439	Bis(malonic acid mono-tert-butyl ester)magnesium salt		C₁₄H₂₂MgO₈	详情	详情
(XXXVIII)	15440	tert-butyl (5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-cyano-3-oxohexanoate		C₁₇H₃₁NO₄Si	详情	详情
(XXXIX)	15441	tert-butyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate		C₁₁H₁₇NO₄	详情	详情
(XL)	15442	tert-butyl (3R,5R)-6-cyano-3,5-dihydroxyhexanoate		C₁₁H₁₉NO₄	详情	详情
(XLI)	15443	tert-Butyl (4R,3R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate；tert-butyl 2-[(4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate	125971-94-0	C₁₄H₂₃NO₄	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
(XLVIII)	15445	tert-butyl 2-[(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate	124655-09-0	C₁₃H₂₄O₅	详情	详情
(XLIX)	15446	tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1,3-dioxan-4-yl]acetate		C₂₀H₃₀O₇S	详情	详情
(L)	15447	methyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate		C₈H₁₁NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XLII)

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.

参考文献中间体

合成目标

【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3

该中间体在本合成路线中的序号：(X)

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4

该中间体在本合成路线中的序号：(VI)

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5

该中间体在本合成路线中的序号：(VI)

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6

该中间体在本合成路线中的序号：(VI)

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