isopropyl (E)-3-amino-2-butenoate -Drug Synthesis Database

【结构式】

【分子编号】13331

【品名】isopropyl (E)-3-amino-2-butenoate

【CA登记号】143093-33-8

【分子式】C₇H₁₃NO₂

【分子量】143.18576

【元素组成】C 58.72% H 9.15% N 9.78% O 22.35%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(II)

By cyclocondensation of 3-chloro-6-fluoro-2-(trifluoromethyl)benzaldehyde (I), isopropyl 3-aminocrotonate (II) and methyl 4-fluoroacetylacetate (III) by heating at 110 C. The starting products are prepared as follows: Aldehyde (I) is obtained by reaction of 1-chloro-4-fluoro-3-(trifluoromethyl)benzene (IV) with N-methyl-N-phenylformamide (V) by means of butyllithium in TNF. Aminocrotonate (II) is obtained by reaction of isopropyl acetoacetate (VI) with dry ammonia in methanol. Finally, the acylation of 2,2-dimethyl-1,3-dioxane-4,6-dione (VII) with fluoroacetyl chloride (VIII) by means of pyridine in dichloromethane gives 5-(fluoroacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (IX), which is then treated with refluxing methanol to give 4-fluoroacetylacetate (III).

参考文献中间体

合成目标

【1】 Baxter, A.J.G.; Dixon, J.; Gould, K.J.; McInally, T.; Tinker, A.C. (Celltech Group plc); Pharmaceutically active dihydropyridines. EP 0125803 .
【2】 Baxter, A.J.G.; Dixon, J.; Gould, K.J.; Tinker, A.C. (Celltech Group plc); Dihydropyridine derivs.. EP 0174131; ES 8800154; ES 8801632; JP 1986065867 .
【3】 Prous, J.; Castaner, J.; FPL-62129XX. Drugs Fut 1989, 14, 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)	20356	3-chloro-6-fluoro-2-(trifluoromethyl)benzaldehyde		C₈H₃ClF₄O	详情	详情
(II)	13331	isopropyl (E)-3-amino-2-butenoate	143093-33-8	C₇H₁₃NO₂	详情	详情
(III)	20358	methyl 4-fluoro-3-oxobutanoate		C₅H₇FO₃	详情	详情
(IV)	20359	1-chloro-4-fluoro-2-(trifluoromethyl)benzene		C₇H₃ClF₄	详情	详情
(V)	20360	methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline	93-61-8	C₈H₉NO	详情	详情
(VI)	13332	isopropyl 3-oxobutanoate; Isopropyl acetoacetate	542-08-5	C₇H₁₂O₃	详情	详情
(VII)	14738	Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester	2033-24-1	C₆H₈O₄	详情	详情
(VIII)	20363	2-fluoroacetyl chloride	359-06-8	C₂H₂ClFO	详情	详情
(IX)	20364	5-(2-fluoroacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione		C₈H₉FO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Elgodipine can be obtained in three main steps: The alkylation of N-methyl-2-aminoethanol (I) with 4-fluorobenzyl chloride (II) gives 2-[N-(4-fluorobenzyl)-N-methylamino]ethanol (III), which is esterified with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (IV) yielding the corresponding acetoacetic ester (V). The condensation of (V) with 2,3-methylenedioxybenzaldehyde (VI) affords 2-[N-(4-fluorobenzyl)-N-methylamino]ethyl 2-(2,3-methylenedioxybenzylidene]acetoacetate (VII), which is finally cyclized with isopropyl 3-aminocrotonate (VIII). The intermediate aldehyde (VI) is obtained starting from 2,3-dimethoxybenzaldehyde (X), which by demethylation with HCl or HBr yields 2,3-dihydroxybenzaldehyde (XI). Finally, this compound is converted into (VI) in the usual way. The intermediate crotonate (VIII) is obtained by reaction of isopropyl acetoacetate (IX) with ammonia.

参考文献中间体

合成目标

【1】 Galiano, A.; Elgodipine Hydrochloride. Drugs Fut 1995, 20, 3, 231.
【2】 Fernandez Torija, C.; Galiano Ramos, J.A. (IIDQB (Madrid)); 1,4-Dihydropyridines, process for their preparation and their use as medicaments. AU 8820330; BE 1001055; CH 675999; EP 0302980; GB 2208861; JP 1989294675; US 4952592 .
【3】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Oxodipine. Drugs Fut 1987, 12, 7, 633.

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)	13324	2-Methylaminoethanol; 2-(Methylamino)-1-ethanol	109-83-1	C₃H₉NO	详情	详情
(II)	12354	4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene	352-11-4	C₇H₆ClF	详情	详情
(III)	13333	2-[(4-Fluorobenzyl)(methyl)amino]-1-ethanol		C₁₀H₁₄FNO	详情	详情
(IV)	13327	2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid	5394-63-8	C₇H₁₀O₃	详情	详情
(V)	13328	2-[(4-fluorobenzyl)(methyl)amino]ethyl 3-oxobutanoate		C₁₄H₁₈FNO₃	详情	详情
(VI)	13329	2,3-(Methylenedioxy)benzaldehyde; 1,3-Benzodioxole-4-carbaldehyde	7797-83-3	C₈H₆O₃	详情	详情
(VII)	13330	2-[(4-fluorobenzyl)(methyl)amino]ethyl (Z)-2-acetyl-3-(1,3-benzodioxol-4-yl)-2-propenoate		C₂₂H₂₂FNO₅	详情	详情
(VIII)	13331	isopropyl (E)-3-amino-2-butenoate	143093-33-8	C₇H₁₃NO₂	详情	详情
(IX)	13332	isopropyl 3-oxobutanoate; Isopropyl acetoacetate	542-08-5	C₇H₁₂O₃	详情	详情
(X)	17615	2,3-Dimethoxybenzaldehyde	86-51-1	C₉H₁₀O₃	详情	详情
(XI)	12380	2,3-Dihydroxybenzaldehyde	24677-78-9	C₇H₆O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

Treatment of anacardic acid (I) with diethyl sulfate produces the dialkylated derivative (II). Ester group reduction in (II) employing LiAlH4 then yields the benzylic alcohol (III), which is further oxidized to aldehyde (IV) with pyridinium chlorochromate. Condensation of aldehyde (IV) with ethyl acetoacetate (V) in the presence of piperidine and AcOH gives the benzylidene acetoacetate (VI). This is finally condensed with enamino ester (VII) under modified Hantzsh conditions to furnish the target dihydropyridine compound.

参考文献中间体

合成目标

【1】 Kumar, P.P.; et al.; Synthesis and evaluation of a new class of nifedipine analogs with T-type calcium channel blocking activity. Mol Pharmacol 2002, 61, 3, 649.

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)	61865	2-hydroxy-6-pentadecylbenzoic acid		C₂₂H₃₆O₃	详情	详情
(II)	61866	ethyl 2-ethoxy-6-pentadecylbenzoate		C₂₆H₄₄O₃	详情	详情
(III)	61867	(2-ethoxy-6-pentadecylphenyl)methanol		C₂₄H₄₂O₂	详情	详情
(IV)	61868	2-ethoxy-6-pentadecylbenzaldehyde		C₂₄H₄₀O₂	详情	详情
(V)	11819	ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate	141-97-9	C₆H₁₀O₃	详情	详情
(VI)	61869	ethyl (Z)-2-acetyl-3-(2-ethoxy-6-pentadecylphenyl)-2-propenoate		C₃₀H₄₈O₄	详情	详情
(VII)	13331	isopropyl (E)-3-amino-2-butenoate	143093-33-8	C₇H₁₃NO₂	详情	详情

Extended Information