Efonidipine hydrochloride ethanol, NZ-105, Landel, -Drug Synthesis Database

【结构式】

【药物名称】Efonidipine hydrochloride ethanol, NZ-105, Landel

【化学名称】(±)-5-(5,5-Dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 2-(N-benzyl-N-phenylamino)ethyl ester P-oxide hydrochloride ethanol
　　　　　　(±)-5-(2,2-Dimethylpropylenedioxyphosphinyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 2-(N-benzyl-N-phenylamino)ethyl ester hydrochloride,compound with ethyl alcohol (1:1)

【CA登记号】111011-76-8, 111011-63-3 (free base;non adduct), 111011-53-1 (monoHCl salt;non-adduct)

【分子式】C₃₆H₄₅ClN₃O₈P

【分子量】714.20215

【开发单位】Nissan Chemical (Originator), Shionogi (Distributor), Zeria (Codevelopment)

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

合成路线1 合成路线2 合成路线3

合成路线1

A new synthesis of efonidipine has been described: The cyclization of 2,2-dimethylbutane-1,4-diol (I) with triethyl phosphite (II) by heating at 100 C gives 2-methoxy-5,5-dimethyl-1,3,2-dioxaphosphorinan (III), which, by treatment with iodoacetone (IV) in refluxing ether, yields 2-acetonyl-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one (V). The condensation of (V) with 3-nitrobenzaldehyde (VI) by means of piperidine in acetic acid affords 3-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-buten-2-one (VII), which is finally cyclized with 3-amino-2-propenoic acid 2-(N-benzyl-N-phenylamino)ethyl ester (VIII) in refluxing toluene.

参考文献中间体

【1】 Sakoda, R.; Kamikawaji, Y.; Seto, K.; Synthesis of 1,4-dihydropyridine-5-phosphonates and their calcium antagonistic and antihypertensive activities: Novel calcium-antagonist NZ-105 and its crystal structure. Chem Pharm Bull 1992, 40, 9, 2362.

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)	12641	Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol	126-30-7	C₅H₁₂O₂	详情	详情
(II)	12642	Trimethyl phosphite	121-45-9	C₃H₉O₃P	详情	详情
(III)	12643	2-Methoxy-5,5-dimethyl-1,3,2lambda(5)-dioxaphosphinan-2-one		C₆H₁₃O₄P	详情	详情
(IV)	12644	1-Iodoacetone		C₃H₅IO	详情	详情
(V)	12645	5,5-Dimethyl-2-(2-oxopropyl)-1,3,2lambda(5)-dioxaphosphinan-2-one		C₈H₁₅O₄P	详情	详情
(VI)	12646	3-Nitrobenzaldehyde	99-61-6	C₇H₅NO₃	详情	详情
(VII)	12647	2-[(Z)-1-Acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-1,3,2lambda(5)-dioxaphosphinan-2-one		C₁₅H₁₈NO₆P	详情	详情
(VIII)	12648	2-(benzylanilino)ethyl (E)-3-amino-2-butenoate		C₁₉H₂₂N₂O₂	详情	详情

合成路线2

A new synthesis for (4S)-efonidipine has been described: The reaction of 5,5-dimethyl-2-(2-oxopropyl)-1,3,2-dioxaphosphorinan-2-one (I) with dimorpholino(3-nitrophenyl)methane (II) by means of trifluoroacetic acid in hot toluene gives 5,5-dimethyl-2-[1-acetyl-2-(3-nitrophenyl)vinyl]-1,3,2-dioxaphosphorina n-2-one (III), which is cyclized with 3-aminocrotonic acid 2(S)-methoxy-2-phenylethyl ester (IV) in refluxing toluene; the recrystallization of the resulting product affords 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4(S)-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 2(S)-methoxy-2-phenylethyl ester (V). The protection of the NH group of (V) with chloromethyl methyl ether and NaH in THF yields the N-methoxymethyl derivative (VI), which is transesterified with 2-(N-benzyl-N-methylamino)ethanol (VII) and NaH in DMSO, giving the protected final product (VIII). Finally, this compound is deprotected with HCl in ethanol.

参考文献中间体

【1】 Seto, K.; Matsumoto, H.; Sakoda, R.; Synthesis and crystal structure of optically active 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate (NZ-105). Chem Pharm Bull 1992, 40, 9, 2377.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	12645	5,5-Dimethyl-2-(2-oxopropyl)-1,3,2lambda(5)-dioxaphosphinan-2-one	C₈H₁₅O₄P	详情	详情
(II)	12650	4-[4-Morpholinyl(3-nitrophenyl)methyl]morpholine	C₁₅H₂₁N₃O₄	详情	详情
(III)	12647	2-[(Z)-1-Acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-1,3,2lambda(5)-dioxaphosphinan-2-one	C₁₅H₁₈NO₆P	详情	详情
(IV)	12652	(2S)-2-methoxy-2-phenylethyl (E)-3-amino-2-butenoate	C₁₃H₁₇NO₃	详情	详情
(V)	12653	(2S)-2-methoxy-2-phenylethyl (4S)-5-(5,5-dimethyl-2-oxo-1,3,2lambda(5)-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate	C₂₈H₃₃N₂O₈P	详情	详情
(VI)	12654	(2S)-2-methoxy-2-phenylethyl (4S)-5-(5,5-dimethyl-2-oxo-1,3,2lambda(5)-dioxaphosphinan-2-yl)-1-(methoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate	C₃₀H₃₇N₂O₉P	详情	详情
(VII)	12655	2-(Benzylanilino)-1-ethanol	C₁₅H₁₇NO	详情	详情
(VIII)	12656	2-(benzylanilino)ethyl (4S)-5-(5,5-dimethyl-2-oxo-1,3,2lambda(5)-dioxaphosphinan-2-yl)-1-(methoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate	C₃₆H₄₂N₃O₈P	详情	详情

合成路线3

An enantioselective synthesis of efonidipine has been described: The enantioselective hydrolysis of 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-n itrophenyl)-1,4-dihydropyridine-3-carboxylic acid propionyloxymethyl ester (I) with lipase AH in 2,5-dimethyltetrahydrofuran saturated with water gives the corresponding free acid of the (S)-isomer (III), while the propionyloxymethyl ester of the (R)-isomer (II) remains undisturbed. After chromatographic separation, the (R)-ester (II) is hydrolyzed with NaOH in methanol to the (R)-acid (IV). Finally, both enantiomerically pure acids (III) and (IV) are separately esterified with 2-(N-benzyl-N-phenylamino)ethanol in the usual way.

参考文献中间体

【1】 Ebiike, H.; Achiwa, K.; Yamazaki, Y.; Lipase-catalyzed enantiosynthesis of (R)- and (S)-2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate (NZ 105). Chem Pharm Bull 1995, 43, 7, 1251.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	12657	(propionyloxy)methyl 5-(5,5-dimethyl-2-oxo-1,3,2lambda(5)-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate	C₂₃H₂₉N₂O₉P	详情	详情
(II)	12658	(propionyloxy)methyl (4R)-5-(5,5-dimethyl-2-oxo-1,3,2lambda(5)-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate	C₂₃H₂₉N₂O₉P	详情	详情
(III)	12659	(4S)-5-(5,5-Dimethyl-2-oxo-1,3,2lambda(5)-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid	C₁₉H₂₃N₂O₇P	详情	详情
(IV)	63469	(4R)-5-(5,5-dimethyl-2-oxo-1,3,2lambda~5~-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid	C₁₉H₂₃N₂O₇P	详情	详情
(V)	12655	2-(Benzylanilino)-1-ethanol	C₁₅H₁₇NO	详情	详情

Extended Information