CD-832.HCl, -Drug Synthesis Database

【结构式】

【药物名称】CD-832.HCl

【化学名称】2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 5-(3-nitrooxypropyl) 3-[2-(3-pyridylcarbonylamino)ethyl] diester monohydrochloride

【CA登记号】129904-55-8, 129904-63-8 (free base)

【分子式】C₂₆H₂₈ClN₅O₁₀

【分子量】605.99356

【开发单位】Taisho (Originator)

【药理作用】Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Vasodilators, Calcium Channel Blockers

合成路线1 合成路线2

合成路线1

The starting products are prepared as follows: The reaction of pyridine-3-carboxylic acid methyl ester (I) with ethanolamine (II) gives the 2-hydroxyethylamide (III), which by reaction with diketene in THF yields the corresponding acetoacetic ester (V). The reaction of (V) with ammonia in THF affords the expected 3-aminocrotonate ester (VI).

参考文献中间体

【1】 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.
【2】 Mealy, N.; Martel, A.M.; Castaner, J.; CD-832.HCl. Drugs Fut 1996, 21, 12, 1221.
【3】 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
(I)	13980	methyl nicotinate; Nicotinic acid, methyl ester	93-60-7	C₇H₇NO₂	详情	详情
(II)	10259	Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol	141-43-5	C₂H₇NO	详情	详情
(III)	13982	N-(2-Hydroxyethyl)nicotinamide		C₈H₁₀N₂O₂	详情	详情
(IV)	11367	4-Methylene-2-oxetanone; Acetyl ketene	674-82-8	C₄H₄O₂	详情	详情
(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

合成路线2

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

【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

Extended Information