DHP-218, -Drug Synthesis Database

【结构式】

【药物名称】DHP-218

【化学名称】Methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydropyridine-3-carboxylate

【CA登记号】102097-78-9

【分子式】C₁₈H₂₁N₂O₇P

【分子量】408.35107

【开发单位】Nippon Shinyaku (Originator)

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

合成路线1 合成路线2

合成路线1

The reaction of trimethylene glycol (I) with PCl3 gives 2-chloro-1,3,2-dioxaphosphorinane (II), which is condensed with propargyl alcohol (III) by means of triethylamine in acetonitrile to give a mixture of 2-allenyl- and 2-propargyl-2-oxo-1,3,2-dioxaphosphorinane (IV and V). The reaction of this mixture with isobutylamine in acetonitrile affords 2-(2-isobutylamino-1-propenyl)-2-oxo-1,3,2-dioxaphosphorinane (VI). The hydrolysis of the enamine (VI) with malonic acid gives 2-acetonyl-2-oxo-1,3,2-dioxaphosphorinane (VII), which is condensed with isobutyl-(2-nitrobenzylidene)amine (VIII) to yield 2-[1-(2-nitrobenzylidene)-2-oxopropyl]-2-oxo-1,3,2-dioxaphosphorinane (IX). Finally, this compound is cyclized with methyl 3-aminocrotonate (X) in refluxing acetonitrile.

参考文献中间体

【1】 Morita, I.; Tsuda, M.; Kise, M.; Sugiyama, M.; Improved synthesis of methyl 2, 6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3, 2-dioxaphosphorinan-2-yl)-1, 4-dihydropyridine-3-carboxylate (DHP-218). Chem Pharm Bull 1988, 36, 3, 1139-42.

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)	14685	1,3-propanediol; Trimethylene Glycol	504-63-2	C₃H₈O₂	详情	详情
(II)	20567	2-chloro-1,3,2-dioxaphosphinane		C₃H₆ClO₂P	详情	详情
(III)	16664	Propargyl Alcohol; 2-propyn-1-ol	107-19-7	C₃H₄O	详情	详情
(IV)	20569	2-(1,2-propadienyl)-1,3,2lambda(5)-dioxaphosphinan-2-one		C₆H₉O₃P	详情	详情
(V)	20570	2-(1-propynyl)-1,3,2lambda(5)-dioxaphosphinan-2-one		C₆H₉O₃P	详情	详情
(VI)	20571	2-[(E)-2-(isobutylamino)-1-propenyl]-1,3,2lambda(5)-dioxaphosphinan-2-one		C₁₀H₂₀NO₃P	详情	详情
(VII)	20572	2-(2-oxopropyl)-1,3,2lambda(5)-dioxaphosphinan-2-one		C₆H₁₁O₄P	详情	详情
(VIII)	20573	2-methyl-N-[(Z)-(2-nitrophenyl)methylidene]-1-propanamine; N-isobutyl-N-[(Z)-(2-nitrophenyl)methylidene]amine		C₁₁H₁₄N₂O₂	详情	详情
(IX)	20574	2-[(Z)-1-acetyl-2-(2-nitrophenyl)ethenyl]-1,3,2lambda(5)-dioxaphosphinan-2-one		C₁₃H₁₄NO₆P	详情	详情
(X)	11372	Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate		C₅H₉NO₂	详情	详情
(XI)	12963	Malonic acid	141-82-2	C₃H₄O₄	详情	详情

合成路线2

The condensation of Cyclic acetonylphosphonate (II), obtained from bromoacetone and cyclic phosphite (I) by an Arbuzov reaction, with o-nitrobenzaldehyde in the presence of piperidine - AcOH salt in boiling benzene gives benzylidene phosphonale (III), which is cyclized with methyl 3-aminocrotonate (IV) in reflux in 2-propanol affording methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2 oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4 dihydro-pyridine-3 carboxylate.

参考文献中间体

【1】 Kimura, K.; Morita, I. (Nippon Shinyaku Co., Ltd.); 1,4-Dihydropyridine-3-carboxylate derivs.. AU 8541405; BE 0902210; EP 0159040; ES 8606276; FR 2563222; GB 2157695; JP 1985248693; US 5036059 .
【2】 Kimura, K.; DHP-218. Drugs Fut 1987, 12, 3, 212.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11370	2-Nitrobenzaldehyde	552-89-6	C₇H₅NO₃	详情	详情
	20549	1-bromoacetone	598-31-2	C₃H₅BrO	详情	详情
(I)	22929	2-methoxy-1,3,2-dioxaphosphinane		C₄H₉O₃P	详情	详情
(II)	20572	2-(2-oxopropyl)-1,3,2lambda(5)-dioxaphosphinan-2-one		C₆H₁₁O₄P	详情	详情
(III)	20574	2-[(Z)-1-acetyl-2-(2-nitrophenyl)ethenyl]-1,3,2lambda(5)-dioxaphosphinan-2-one		C₁₃H₁₄NO₆P	详情	详情

Extended Information