2-(4-Benzhydryl-1-piperazinyl)-1-ethanol -Drug Synthesis Database

【结构式】

【分子编号】12674

【品名】2-(4-Benzhydryl-1-piperazinyl)-1-ethanol

【CA登记号】

【分子式】C₁₉H₂₄N₂O

【分子量】296.41244

【元素组成】C 76.99% H 8.16% N 9.45% O 5.4%

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：(XII)

A synthesis of the (R)- and (S)-isomers of manidipine hydrochloride has been described: The cyclization of 3-nitrobenzaldehyde (I) with methyl 3-aminocrotonate (II) and methylacetylacetate (III) gives 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (IV), which is alkylated with ethoxymethyl chloride and NaH yielding the 1-(ethoxymethyl) derivative (V). Selective hydrolysis of (V) with 1-(dimethylamino)-2-propanol - Na - H2O affords the monomethyl ester (VI), which is submitted to optical resolution with cinchonidine and cinchonine giving (R)-1-(ethoxymethyl-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)- 1,4-dihydropyridine-3-carboxylic acid (VIII) and the corresponding (S)-isomer (IX), respectively. The cleavage of the ethoxymethyl group of (VIII) and (IX) in acidic medium affords the corresponding free (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyrid ine-3-carboxylic acid (X) and the (S)-isomer (XI). Both compounds are esterified with 2-[4-(diphenylmethyl)piperazin-1-yl]ethanol (XII) by means of PCl5 and NaHCO3, finally yielding the (S)- and (R)-isomers of manidipine hydrochloride, respectively.

参考文献中间体

合成目标

【1】 Wada, Y.; Kajino, M.; Nagai, Y.; Meguro, K.; Nagaoka, A.; Synthesis and biological activities of optical isomers of 2-(4-diphenylmethyl-1-piperazinyl)ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (manidipine) dihydrochloride. Chem Pharm Bull 1989, 37, 8, 2225-8.

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)	12646	3-Nitrobenzaldehyde	99-61-6	C₇H₅NO₃	详情	详情
(II)	11372	Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate		C₅H₉NO₂	详情	详情
(III)	11791	methyl 3-oxobutanoate; Methyl acetoacetate	105-45-3	C₅H₈O₃	详情	详情
(IV)	12667	dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate; 2,6-Dimethyl-4-(3-nitro-ph)-1,4-2h-pyridine-3,5-dicarboxylic acid dimethyl ester	21881-77-6	C₁₇H₁₈N₂O₆	详情	详情
(V)	12668	dimethyl 1-(ethoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate		C₂₀H₂₄N₂O₇	详情	详情
(VI)	12669	1-(Ethoxymethyl)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid		C₁₉H₂₂N₂O₇	详情	详情
(VIII)	12670	(4R)-1-(Ethoxymethyl)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid		C₁₉H₂₂N₂O₇	详情	详情
(IX)	12671	(4S)-1-(Ethoxymethyl)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid		C₁₉H₂₂N₂O₇	详情	详情
(X)	12672	(4R)-5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid		C₁₆H₁₆N₂O₆	详情	详情
(XI)	12673	(4S)-5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid		C₁₆H₁₆N₂O₆	详情	详情
(XII)	12674	2-(4-Benzhydryl-1-piperazinyl)-1-ethanol		C₁₉H₂₄N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

1) The reaction of 2-(4-piperazinyl)ethanol (I) with diphenylmethyl bromide (II) by means of K2CO3 in DMF gives 2-[4-(diphenylmethyl)-1-piperazinyl] ethanol (III), which is condensed with diketene (IV) at 80 C to yield 2-[4-(diphenylmethyl)-1-piperazinyl] ethyl acetoacetate (V). The condensation of (V) with 3-nitrobenzaldehyde (VI) gives the intermediate benzylidene derivative (VII), which is finally cyclized with methyl 3-aminocrotonate (VIII) in refluxing isopropanol.

参考文献中间体

合成目标

【1】 Meguro, K.; Kawamatsu, Y.; Aizawa, M.; Nagaoka, A.; Sohda, T.; New 1,4-dihydropyridine derivatives with potent an. Chem Pharm Bull 1985, 33, 9, 3787.
【2】 Meguro, K.; Nagaoka, A. (Takeda Chemical Industries, Ltd.); Dihydropyridine derivs., their production and use. EP 0138505; JP 1985084269; US 4603135 .
【3】 Prous, J.; Castaner, J.; CV-4093. Drugs Fut 1988, 13, 3, 207.

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)	21893	2-(1-piperazinyl)-1-ethanol; 1-piperazineethanol; 1-(2-Hydroxyethyl)piperazine	103-76-4	C₆H₁₄N₂O	详情	详情
(II)	12079	Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide	776-74-9	C₁₃H₁₁Br	详情	详情
(III)	12674	2-(4-Benzhydryl-1-piperazinyl)-1-ethanol		C₁₉H₂₄N₂O	详情	详情
(IV)	21896	4-methyl-2H-oxet-2-one		C₄H₄O₂	详情	详情
(V)	21897	2-(4-benzhydryl-1-piperazinyl)ethyl 3-oxobutanoate		C₂₃H₂₈N₂O₃	详情	详情
(VI)	12646	3-Nitrobenzaldehyde	99-61-6	C₇H₅NO₃	详情	详情
(VII)	21899	2-(4-benzhydryl-1-piperazinyl)ethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate		C₃₀H₃₁N₃O₅	详情	详情
(VIII)	11372	Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate		C₅H₉NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

2) The reaction of 2-(4-piperazinyl)ethanol (I) with diphenylmethyl bromide (II) by means of K2CO3 in DMF gives 2-[4-(diphenylmethyl)-1-piperazinyl] ethanol (III), which is condensed with diketene (IV) at 80 C to yield 2-[4-(diphenylmethyl)-1-piperazinyl] ethyl acetoacetate (V). The reaction of acetoacetate (V) with NH3 in ethanol gives the corresponding aminocrotonate (IX), which is then cyclized with methyl (3-nitrobenzylidene)acetoacetate (VI) [prepared from methyl acetoacetate (X) and 3-nitrobenzaldehyde (VI)] in refluxing isopropanol.

参考文献中间体

合成目标

【1】 Meguro, K.; Kawamatsu, Y.; Aizawa, M.; Nagaoka, A.; Sohda, T.; New 1,4-dihydropyridine derivatives with potent an. Chem Pharm Bull 1985, 33, 9, 3787.
【2】 Meguro, K.; Nagaoka, A. (Takeda Chemical Industries, Ltd.); Dihydropyridine derivs., their production and use. EP 0138505; JP 1985084269; US 4603135 .
【3】 Prous, J.; Castaner, J.; CV-4093. Drugs Fut 1988, 13, 3, 207.

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)	21893	2-(1-piperazinyl)-1-ethanol; 1-piperazineethanol; 1-(2-Hydroxyethyl)piperazine	103-76-4	C₆H₁₄N₂O	详情	详情
(II)	12079	Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide	776-74-9	C₁₃H₁₁Br	详情	详情
(III)	12674	2-(4-Benzhydryl-1-piperazinyl)-1-ethanol		C₁₉H₂₄N₂O	详情	详情
(IV)	21896	4-methyl-2H-oxet-2-one		C₄H₄O₂	详情	详情
(V)	21897	2-(4-benzhydryl-1-piperazinyl)ethyl 3-oxobutanoate		C₂₃H₂₈N₂O₃	详情	详情
(VI)	12646	3-Nitrobenzaldehyde	99-61-6	C₇H₅NO₃	详情	详情
(IX)	21900	2-(4-benzhydryl-1-piperazinyl)ethyl (E)-3-amino-2-butenoate		C₂₃H₂₉N₃O₂	详情	详情
(X)	11791	methyl 3-oxobutanoate; Methyl acetoacetate	105-45-3	C₅H₈O₃	详情	详情
(XI)	12276	methyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate		C₁₂H₁₁NO₅	详情	详情

Extended Information