2-cyanoethyl 3-oxobutanoate -Drug Synthesis Database

【结构式】

【分子编号】13993

【品名】2-cyanoethyl 3-oxobutanoate

【CA登记号】

【分子式】C₇H₉NO₃

【分子量】155.1534

【元素组成】C 54.19% H 5.85% N 9.03% O 30.94%

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：(VIII)

CD-832.HCl can be obtained by several different ways: 1) The cyclization of benzaldehyde (IX) with acetoacetate (V) and crotonate (VII) in refluxing isopropanol gives 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-cyanoethyl) 5-[2-(3-pyridylcarboxamido)ethyl] diester (X), which by reaction with tetrabutylammonium fluoride in THF/DMF, or with Na2S in dichloromethane/methanol, eliminates vinyl cyanide yielding the dihydropyridine monoester (XI). Finally, this compound is esterified with (XII) by means of acetyl chloride and acetic anhydride in dichloromethan). 2) The cyclization of benzaldehyde (IX) with crotonate (VI) and acetoacetate (VIII) as before also gives dihydropyridine (X). 3) The reaction of benzaldehyde (IX) with acetoacetate (V) by means of piperidinium acetate in refluxing benzene gives the corresponding 3-nitrobenzylidene derivative (XIII), which is then cyclized with crotonate (VII) to afford the previously obtained dihydropyridine (X). 4) The reaction of benzaldehyde (IX) with acetoacetate (V) by means of piperidinium acetate in refluxing benzene gives the 3-nitrobenzylidene derivative (XIII), which is then cyclized with 3-aminocrotonic acid ester (XIV) in refluxing isopropanol.

参考文献中间体

合成目标

【1】 Mealy, N.; Martel, A.M.; Castaner, J.; CD-832.HCl. Drugs Fut 1996, 21, 12, 1221.
【2】 Ogawa, T.; Hatayama, K.; Maeda, H.; Kita, Y.; Mild and facile cleavage of 2-cyanoethyl ester using sodium sulfide or tetrabutylammonium fluoride. Synthesis of 1,4-dihydropyridine monocarboxylic acids and unsymmetrical 1,4-dihydropyridine dicarboxylates. Chem Pharm Bull 1994, 42, 8, 1579-89.
【3】 Ogawa, T.; Ota, T.; Sato, S.; Sunaga, T.; Watanabe, Y.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); 1,4-Dihydropyridine derivs. EP 0370821; JP 1990223580; US 5047543 .
【4】 Kelly, R.C.; Martin, D.G.; Aristoff, P.A. (Pharmacia Corp.); Novel CC-1065 analogs. AU 8812290; EP 0340243; WO 8804659 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	13984	2-[(3-pyridinylcarbonyl)amino]ethyl 3-oxobutanoate		C₁₂H₁₄N₂O₄	详情	详情
(VI)	13985	2-[(3-pyridinylcarbonyl)amino]ethyl (E)-3-amino-2-butenoate		C₁₂H₁₅N₃O₃	详情	详情
(VII)	13987	2-cyanoethyl (E)-3-amino-2-butenoate		C₇H₁₀N₂O₂	详情	详情
(VIII)	13993	2-cyanoethyl 3-oxobutanoate		C₇H₉NO₃	详情	详情
(IX)	12646	3-Nitrobenzaldehyde	99-61-6	C₇H₅NO₃	详情	详情
(X)	13989	3-(2-cyanoethyl) 5-[2-[(3-pyridinylcarbonyl)amino]ethyl] 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate		C₂₆H₂₅N₅O₇	详情	详情
(XI)	13990	2,6-Dimethyl-4-(3-nitrophenyl)-5-([2-[(3-pyridinylcarbonyl)amino]ethoxy]carbonyl)-1,4-dihydro-3-pyridinecarboxylic acid		C₂₃H₂₂N₄O₇	详情	详情
(XII)	13991	3-(Nitrooxy)-1-propanol		C₃H₇NO₄	详情	详情
(XIII)	13998	2-[(3-pyridinylcarbonyl)amino]ethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate		C₁₉H₁₇N₃O₆	详情	详情
(XIV)	13999	3-(nitrooxy)propyl (E)-3-amino-2-butenoate		C₇H₁₂N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

A synthesis of S-12968 has been published: The cyclization of 4-[2-(2-phthalimidoethoxy)ethoxy]-3-oxobutyric acid ethyl ester (I) with 2-(2,3-dichlorobenzylidene)-3-oxobutyric acid 2-cyanoethyl ester (II) and ammonium formate in hot ethanol gives the protected racemic 1,4-dihydropyridine (III), which is submitted to a chiral preparative HPLC to obtain the (R)-(-)-enantiomer (IV). The deprotection of (IV) with aqueous methylamine affords (S)-(-)-2-[2-(2-aminoethoxy)ethoxymethyl]-4-(2,3-dichlorophenyl)-1,4-di hydropyridine-3,5-dicarboxylic acid 3-monoethyl ester (V). Finally, this compound is methylated with diazomethane in ethyl ether/methanol. The starting compound, the dichlorobenzylidene derivative (II) has been obtained as follows: The condensation of Meldrum's acid (X) with acetic acid (XII) by means of CDI and pyridine as before gives 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (XIII), which is submitted to ring opening with 3-hydroxypropionitrile (XIV) in refluxing toluene yielding 2-cyanoethyl acetoacetate (XV). Finally, the condensation of (XV) with 2,3-dichlorobenzaldehyde (XVI) by means of piperidine and hexanoic acid in refluxing benzene affords the dichlorobenzylidene derivative (II) used as the second starting compound.

参考文献中间体

合成目标

【1】 Dolle, F.; et al.; Highly efficient synthesis of [11C]S12968 and [11C]S12967, for the in vivo imaging of the cardiac calcium channels using PET. J Label Compd Radiopharm 2001, 44, 7, 481.
【2】 Crouzel, C.; Duval, R.; Hinnen, F.; Fuseau, C.; Dollé, F.; Valette, H.; Péglion, J.-L.; Synthesis of two optically active calcium channel antagonists labelled with carbon-11 for in vivo cardiac PET imaging. Bioorg Med Chem 1997, 5, 4, 749.

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)	14743	ethyl 4-[2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]-3-oxobutanoate		C₁₈H₂₁NO₇	详情	详情
(II)	14744	2-cyanoethyl (Z)-2-acetyl-3-(2,3-dichlorophenyl)-2-propenoate		C₁₄H₁₁Cl₂NO₃	详情	详情
(III)	14745	5-(2-cyanoethyl) 3-ethyl 4-(2,3-dichlorophenyl)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate		C₃₂H₃₁Cl₂N₃O₈	详情	详情
(IV)	14746	5-(2-cyanoethyl) 3-ethyl (4S)-4-(2,3-dichlorophenyl)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate		C₃₂H₃₁Cl₂N₃O₈	详情	详情
(V)	14747	(4R)-6-[[2-(2-aminoethoxy)ethoxy]methyl]-4-(2,3-dichlorophenyl)-5-(ethoxycarbonyl)-2-methyl-1,4-dihydro-3-pyridinecarboxylic acid		C₂₁H₂₆Cl₂N₂O₆	详情	详情
(X)	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
(XIII)	12273	5-Acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione		C₈H₁₀O₅	详情	详情
(XIV)	14029	Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile	109-78-4	C₃H₅NO	详情	详情
(XV)	13993	2-cyanoethyl 3-oxobutanoate		C₇H₉NO₃	详情	详情
(XVI)	14742	2,3-dichlorobenzaldehyde	6334-18-5	C₇H₄Cl₂O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

Treatment of a benzenic solution of 4-piperidone hydrate (I) with anhydrous AlCl3 provided 4,4-diphenylpiperidine (II). Then, conjugate addition of acrylonitrile (III) in the presence of triethylamine in ethanol gave the cyanoethylpiperidine (IV), which was reduced with borane in THF to afford the intermediate primary amine (V). Dihydropyridine (IX) was prepared by Hantzsch synthesis by condensation of 3-aminocrotonamide (VI), 4-nitrobenzaldehyde (VII) and cyanoethyl acetoacetate (VIII) in refluxing ethanol. Cyanoethyl ester was then cleaved with dilute KOH at 0 C to give acid (X), which was finally coupled with amine (V) by treatment with DEC to yield the target amide.

参考文献中间体

合成目标

【1】 Cox, E.D.; et al.; Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate. J Med Chem 1998, 41, 14, 2643.

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)	18178	4,4-piperidinediol	73390-11-1	C₅H₁₁NO₂	详情	详情
(II)	13154	4,4-Diphenylpiperidine		C₁₇H₁₉N	详情	详情
(III)	10847	Acrylonitrile	107-13-1	C₃H₃N	详情	详情
(IV)	18181	3-(4,4-diphenyl-1-piperidinyl)propanenitrile		C₂₀H₂₂N₂	详情	详情
(V)	18182	3-(4,4-diphenyl-1-piperidinyl)-1-propanamine; 3-(4,4-diphenyl-1-piperidinyl)propylamine		C₂₀H₂₆N₂	详情	详情
(VI)	18183	(E)-3-amino-2-butenamide		C₄H₈N₂O	详情	详情
(VII)	18184	4-Nitrobenzaldehyde	555-16-8	C₇H₅NO₃	详情	详情
(VIII)	13993	2-cyanoethyl 3-oxobutanoate		C₇H₉NO₃	详情	详情
(IX)	18186	2-cyanoethyl 5-(aminocarbonyl)-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate		C₁₈H₁₈N₄O₅	详情	详情
(X)	18187	5-(aminocarbonyl)-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid		C₁₅H₁₅N₃O₅	详情	详情

Extended Information