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【结 构 式】 
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【药物名称】Manidipine hydrochloride, Franidipine hydrochloride, CV-4093, Artedil, Iperten, Calslot 【化学名称】2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-[4-(diphenylmethyl)-1-piperazinyl]ethyl] 5-methyl diester dihydrochloride 【CA登记号】120092-68-4 (free base), 89226-50-6 (free base;no stereoch.) 【 分 子 式 】C35H40Cl2N4O6 【 分 子 量 】683.63825 |
【开发单位】Takeda (Originator), Chiesi (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Calcium Channel Blockers |
合成路线1
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.
| 【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
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.
| 【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
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.
| 【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 |
合成路线4
3) By cyclization of acetoacetate (V) with aldehyde (VI) and methyl 3-aminocrotonate (VIII) in refluxing isopropanol.
| 【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. |
合成路线5
4) By cyclization of aldehyde (VI) with aminocrotonate (IX) and methyl acetoacetate (X) in refluxing isopropanol.
| 【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. |