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【结 构 式】 
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【分子编号】12646 【品名】3-Nitrobenzaldehyde 【CA登记号】99-61-6 |
【 分 子 式 】C7H5NO3 【 分 子 量 】151.12164 【元素组成】C 55.64% H 3.33% N 9.27% O 31.76% |
合成路线1
该中间体在本合成路线中的序号：(I)1) By cyclization of 3-nitrobenzaldehyde (I) with methyl 3-aminocrotonate (II) and N-benzyl-3-pipendinyl acetylacetate (III) in refluxing THF.
| 【1】 Muto, K.; Kuroda, T.; Karasawa, A.; Yamada, K.; Nakamizo, N. (Kyowa Hakko Kogyo Co., Ltd.); 1,4-Dihydropyridine derivatives. CA 1246078; EP 0106275; ES 526441 . |
| 【2】 Muto, K.; Watanabe, M.; Hatta, T.; Sugaya, T.; Takemoto, Y.; Nakamizo, N. (Kyowa Hakko Kogyo Co., Ltd.); 1,4-Dihyropiridine derivatives. EP 0063365; JP 57171968; US 4448964 . |
| 【3】 Prous, J.; Castaner, J.; KW-3049. Drugs Fut 1986, 11, 11, 936. |
合成路线2
该中间体在本合成路线中的序号：(IV)Two new related ways for the synthesis of lercanidipine have been reported: 1) The condensation of diketene (I) with the aminoalcohol (II) gives the corresponding acetoacetate ester (III), which is allowed to react with 3-nitrobenzaldehyde (IV) by means of HCl in chloroform yielding the expected benzylidene derivative (V). Finally, this compound is cyclized with methyl 3-aminocrotonate (VI) in refluxing isopropanol. 2) By esterification of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (VIII) with alcohol (II) by means of SOCl2 in DMF/dichloromethane.
| 【1】 Catto, A.; Motta, G.; Pennini, R.; Testa, R.; Sironi, G.; Cerri, A.; Leonardi, A.; Asymmetric N-(3,3-diphenylpropyl)aminoalkyl esters of 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxylic acids with antihypertensive activity. Eur J Med Chem 1998, 33, 5, 399. |
| 【2】 Nardi, D.; Leonardi, A.; Graziani, G.; Bianchi, G. (Recordati Industria Chimica e Farmaceutica SpA); N-(3,3-diphenylpropyl)aminoethylesters of 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid, compositions and use. EP 0153016; JP 60199874; US 4772621; US 4968832 . |
| 【3】 Bianchi, G.; Leonardi, A.; REC 15/2375. Drugs Fut 1987, 12, 12, 1113. |
| 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) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (II) | 17748 | 1-[(3,3-diphenylpropyl)(methyl)amino]-2-methyl-2-propanol | C20H27NO | 详情 | 详情 | |
| (III) | 17749 | 2-[(3,3-diphenylpropyl)(methyl)amino]-1,1-dimethylethyl 3-oxobutanoate | C24H31NO3 | 详情 | 详情 | |
| (IV) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 17751 | 2-[(3,3-diphenylpropyl)(methyl)amino]-1,1-dimethylethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C31H34N2O5 | 详情 | 详情 | |
| (VI) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VII) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Compound can be prepared in two different ways: 1) By heating at 100 C a mixture of m-nitrobenzaldehyde (I), methyl beta-aminocrotonate (II) and N-benzyl-N-methylaminoethyl acetoacetate (III). 2) By cyclization of a mixture of m-nitrobenzaldehyde (I), methyl acetoacetate (IV) and N-benzyl-N-methylaminoethyl beta + aminocrotonate (V) in refluxing isopropanol.
| 【1】 Murakami, M.; et al.; BE 0811324 . |
| 【2】 Roberts, P.J.; Castaner, J.; YC-93. Drugs Fut 1977, 2, 6, 409. |
| 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) | 33898 | 2-[benzyl(methyl)amino]ethyl 3-oxobutanoate | C14H19NO3 | 详情 | 详情 | |
| (IV) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (V) | 33899 | 2-[benzyl(methyl)amino]ethyl (E)-3-amino-2-butenoate | C14H20N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The condensation of isopropyl acetoacetate (I) with 3-nitrobenzaldehyde (II) gives isopropyl 2-(3-nitrobenzylidene)acetoacetate (III), which is cyclized with methyl 3-amino-4,4-dimethoxycrotonate (IV) at 100 C yielding 5-isopropyl-3-methyl-2-(dimethoxymethyl)-6-methyl-4-(3-nitropheny)-1,4-dihydropyridine-3,5-dicarboxylate (V). The hydrolysis of the acetal group of (V) with HCl in acetone affords the corresponding 2-formyl derivative (VI), which is finally treated with hydroxylamine and acetic anhydride in acetic acid at 100 C.
| 【1】 Satu, Y. (Fujisawa Pharmaceutical Co., Ltd.); 1,4-Dihydropyridine derivatives and pharmaceutical method of the same. BE 0879263; DE 2940833; FR 2438654; GB 2036722; US 4284634; US 4338322 . |
| 【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; FR-34,235. Drugs Fut 1983, 8, 9, 776. |
| 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) | 13332 | isopropyl 3-oxobutanoate; Isopropyl acetoacetate | 542-08-5 | C7H12O3 | 详情 | 详情 |
| (II) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (III) | 12595 | isopropyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C14H15NO5 | 详情 | 详情 | |
| (IV) | 31096 | methyl (E)-3-amino-4,4-dimethoxy-2-butenoate | C7H13NO4 | 详情 | 详情 | |
| (V) | 31097 | 5-isopropyl 3-methyl 2-(dimethoxymethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C21H26N2O8 | 详情 | 详情 | |
| (VI) | 31098 | 5-isopropyl 3-methyl 2-formyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C19H20N2O7 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)1) The condensation of ethyl acetoacetate (I) with 3-nitrobenzaldehyde (II) in toluene gives ethyl 2-(3-nitrobenzylidene)acetoacetate (III), which is then cyclized with methyl 3-aminocrotonate (IV) [prepared from methyl acetoacetate (V) with NH3 and p-toluenesulfonic acid]; the reaction is carried out in refluxing ethanol.
| 【1】 Wehinger, E.; Stoepel, K.; Vater, W.; Meyer, H.; Bossert, F.; Synthesis and comparative pharmacological studies of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylates with non-identical estes function. Arzneim-Forsch Drug Res 1981, 31, 3, 407-409. |
| 【2】 Serradell, M.N.; Castaner, J.; Grau, M.; Blancafort, P.; Nitrendipine. Drugs Fut 1983, 8, 6, 508. |
| 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) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (II) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (III) | 30721 | ethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C13H13NO5 | 详情 | 详情 | |
| (IV) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (V) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)2) This compound can also be obtained by direct cyclization of ethyl acetoacetate (I) with 3-nitrobenzaldehyde (II) and 3-aminocrotonate (IV) in refluxing ethanol.
| 【1】 Meyer, H.; Bossert, F. (Bayer AG); Verfahren zur Herstellung con neuen unsymmetrischen 1,4-Dihydropyridindicarbosaureestern. CA 934758; CH 571492; DD 104520; DE 2117573; NL 7204695 . |
| 【2】 Serradell, M.N.; Castaner, J.; Grau, M.; Blancafort, P.; Nitrendipine. Drugs Fut 1983, 8, 6, 508. |
| 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) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (II) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (IV) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)By cyclization of 3-nitrobenzaldehyde (I) with 3-nitratopropyl-3-aminocrotonate (II) and 2-nitratopropyl acetoacetate (III) in refluxing benzene. The starting products (II) and (III) are obtained as follows: The reaction of diketene (IV) with 3-bromopropanol (V) by means of sodium acetate at 50 C gives 3-bromopropyl acetoacetate (VI), which by reaction with AgNO3 in refluxing acetonitrile is converted to 3-nitratopropyl acetoacetate (VII). Finally, this compound is treated with NH3 in THF to afford the aminocrotonic ester (II). The reaction of diketene (IV) with 2-chloropropanol (VIII) as before gives 2-chloropropyl acetoacetate (IX), which is treated with AgNO3 as before to yield acetoacetate (III).
| 【1】 Hatayama, K.; Sawada, J.; Nakazato, A.; Ogawa, T.; Ito, S. (Taisho Pharmaceutical Co., Ltd.); 1,4-Dihydropyridine derivs.. EP 0092936; US 4472411 . |
| 【2】 Prous, J.; Castaner, J.; CD-349. Drugs Fut 1988, 13, 7, 610. |
| 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) | 13999 | 3-(nitrooxy)propyl (E)-3-amino-2-butenoate | C7H12N2O5 | 详情 | 详情 | |
| (III) | 22628 | 2-(nitrooxy)propyl 3-oxobutanoate | C7H11NO6 | 详情 | 详情 | |
| (IV) | 21896 | 4-methyl-2H-oxet-2-one | C4H4O2 | 详情 | 详情 | |
| (V) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (VI) | 22631 | 3-bromopropyl 3-oxobutanoate | C7H11BrO3 | 详情 | 详情 | |
| (VII) | 22632 | 3-(nitrooxy)propyl 3-oxobutanoate | C7H11NO6 | 详情 | 详情 | |
| (VIII) | 22633 | 2-chloro-1-propanol | 78-89-7 | C3H7ClO | 详情 | 详情 |
| (IX) | 22634 | 2-chloropropyl 3-oxobutanoate | C7H11ClO3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Hantzsch condensation of 2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethyl acetylacetate (III) with methyl 3-aminocrotonate (II) and 3-nitrobenzaldehyde (I) in eftuxing isopropanol affords title compound.
| 【1】 Zumin Tricerri, S.; Casagrande, C.; De Marchi, F.; Nicola, M. (Pierrel SpA); Dihydropyridines with an antagonistic activity to . EP 0097821; US 4894460 . |
| 【2】 Bani, M.; Favara, D.; P-0285. Drugs Fut 1988, 13, 4, 321. |
合成路线9
该中间体在本合成路线中的序号：(VI)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.
| 【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10
该中间体在本合成路线中的序号：(I)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11
该中间体在本合成路线中的序号：(VI)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12
该中间体在本合成路线中的序号：(VI)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13
该中间体在本合成路线中的序号：(VI)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14
该中间体在本合成路线中的序号：(VI)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. |
合成路线15
该中间体在本合成路线中的序号：(I)By cyclocondensation of 3-nitrobenzaldehyde (I) with methyl 3-aminocrotonate (II) and 1-benzyl-3-(acetoacetoxy)pyrrolidine (III) in refluxing isopropanol. The pyrrolidine (III) is obtained as follows: The condensation of 2-hydroxysuccinic acid (IV) with benzylamine (VI), which is reduced with LiAlH4 in dry THF yielding N-benzyl-3-hydroxypyrrolidine (VIII). Finally, this compound is condensed with diketene (VII) by means of sodium acetate at 80 C.
| 【1】 Tamazawa, K.; Takeuchi, M.; Arima, H.; Synthesis of 14C-and 2H-labeled (3S)-1-benzyl-3-py. J Label Compd Radiopharm 1988, 25, 2, 161. |
| 【2】 Kojima, T.; Takenaka, T. (Yamanouchi Pharmaceutical Co., Ltd.); 1,4-Dihydropyridine-3,5-dicarboxylic acid ester de. DE 2904552; US 4220649 . |
| 【3】 Prous, J.; Castaner, J.; YM-09730-5. Drugs Fut 1988, 13, 7, 634. |
| 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) | 22742 | 2-Oxobutyric acid 1-benzylpyrrolidin-3-yl ester | C15H19NO3 | 详情 | 详情 | |
| (IV) | 22743 | Hydroxysuccinic acid; Malic acid; Hydroxybutanedioic acid | 617-48-1 | C4H6O5 | 详情 | 详情 |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 22745 | 1-Benzyl-3-hydroxypyrrolidine-2,5-dione | C11H11NO3 | 详情 | 详情 | |
| (VII) | 22746 | 1-benzyl-3-pyrrolidinol | C11H15NO | 详情 | 详情 | |
| (VIII) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(IV)The reaction of diketene (I) with 2-bromoethanol (II) by means of dimethylaminopyridine (DMAP) in dichloromethane gives acetoacetic acid 2-bromoethyl ester (III), which is condensed with 3-nitrobenzaldehyde (IV) by means of piperidine acetate in isopropanol yielding the corresponding 3-nitrobenzylidene derivative (V). The cyclization of (V) with methyl 3-aminocrotonate (VI) by heating at 80 C affords 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-bromoethyl) 5-methyl diester (VII), which is condensed with chloromethyl ethyl ether (VIII) by means of NaH in THF to afford the corresponding 1-ethoxymethyl derivative (IX). The reaction of diester (IX) with NaCN and tetrabutylammonium cyanide or sodium p-toluenesulfonate and benzyltriethylammonium chloride (BTEACl) in DMF gives 1-(ethoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (X). The optical resolution of (X) through the cinchonidine salt yields, after crystallization, the cinchonidine salt of the (R)-enantiomer (XI), which is treated with HCl to eliminate the cinchonidine, and esterified with 1,3-dibromopropane and K2CO3 in acetone to afford (R)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(3-bromopropyl) 5-methyl diester (XII). Finally, this compound is condensed with 4,4-diphenylpiperidine (XIII) by means of K2CO3 in DMF at 100 C.
| 【1】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Dexniguldipine hydrochloride. Drugs Fut 1997, 22, 2, 114. |
| 【2】 Amschler, H.; Flockerzi, D.; Klemm, K.; Kohl, B.; Eistetter, K.; Eltze, M.; Kolassa, N.; Sanders, K.; Schudt, C. (Byk Gulden Lomberg Chemische Fabrik GmbH); 1,4-Dihydropyridine enantiomers. AU 8816264; EP 0296316; EP 0343193; WO 8807525 . |
| 【3】 Klemm, K.; Ulrich, W.-R.; Flockerzi, D.; Sanders, K.; Beller, K.-D. (Byk Gulden Lomberg Chemische Fabrik GmbH); Optically pure (R)-(-)-niguldipine and its derivs. for treating tumor diseases. WO 8907443 . |
| 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) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (II) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (III) | 13144 | 2-bromoethyl 3-oxobutanoate | C6H9BrO3 | 详情 | 详情 | |
| (IV) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 13146 | 2-bromoethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C13H12BrNO5 | 详情 | 详情 | |
| (VI) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VII) | 63539 | 3-(2-bromoethyl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C18H19BrN2O6 | 详情 | 详情 | |
| (VIII) | 13149 | 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether | 3188-13-4 | C3H7ClO | 详情 | 详情 |
| (IX) | 13150 | 3-(2-bromoethyl) 5-methyl 1-(ethoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C21H25BrN2O7 | 详情 | 详情 | |
| (X) | 13151 | 1-(Ethoxymethyl)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C19H22N2O7 | 详情 | 详情 | |
| (XI) | 12671 | (4S)-1-(Ethoxymethyl)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C19H22N2O7 | 详情 | 详情 | |
| (XII) | 13153 | 3-(3-bromopropyl) 5-methyl (4R)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C19H21BrN2O6 | 详情 | 详情 | |
| (XIII) | 13154 | 4,4-Diphenylpiperidine | C17H19N | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(VII)Iganidipine can be obtained by two similar ways: 1) The condensation of 1-(tert-butoxycarbonyl)piperazine (I) with isobutyraldehyde (II) and formaldehyde in acetic acid gives 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2,2-dimethylpropionaldehyde (III), which is reduced with NaBH4 in isopropanol to the corresponding alcohol (IV). The condensation of (IV) with diketene (V) by mens of dimethylaminopyridine (DMAP) in dichloromethane affords the acetoacetic ester (VI), which is cyclized with 3-nitrobenzaldehyde (VII) and methyl 3-aminocrotonate (VIII) in refluxing isopropanol to give the protected dihydropyridine (IX). The elimination of the tert-butoxycarbonyl group of (IX) with HCl in ethanol yields dihydropyridine (X), which is finally alkylated with allyl chloride (XI) and triethylamine in hot THF. 2) The condensation of 3-(4-allylpiperazin-1-yl)-2,2-dimethylpropanol (XII) with diketene (V) in dichloromethane gives the corresponding acetoacetic ester (XIII), which is treated with dry NH3 in methanol to yield the 3-aminocrotonic ester (XIV). Finally, this compound is cyclized with 2-(3-nitrobenzylidene)acetoacetic acid methyl ester (XV) in hot isopropanol.
| 【1】 Robinson, C.P.; Robinson, K.A.; Castaner, J.; Iganidipine Hydrochloride. Drugs Fut 1997, 22, 1, 23. |
| 【2】 Matsui, H.; Fukata, F.M.; Mori, T.; Kakeya, N.; Kitao, K. (Kyoto Pharmaceutical Industries, Ltd.); 1,4-Dihydropyridine derivs. and pharmaceutical compsn. Thereof. AU 8812519; EP 0289746; JP 1988225355; US 4937242 . |
| 【3】 Kakeya, N.; Fukada, F.; Nishizawa, S. (Kyoto Pharmaceutical Industries, Ltd.); 3-Aminocrotonic acid ester. JP 1991099064 . |
| 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) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (II) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (III) | 13227 | tert-butyl 4-(2,2-dimethyl-3-oxopropyl)-1-piperazinecarboxylate | C14H26N2O3 | 详情 | 详情 | |
| (IV) | 13228 | tert-butyl 4-(3-hydroxy-2,2-dimethylpropyl)-1-piperazinecarboxylate | C14H28N2O3 | 详情 | 详情 | |
| (V) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (VI) | 13230 | tert-butyl 4-[3-(acetoacetoxy)-2,2-dimethylpropyl]-1-piperazinecarboxylate | C18H32N2O5 | 详情 | 详情 | |
| (VII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (VIII) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (IX) | 13233 | 3-[3-[4-(tert-butoxycarbonyl)-1-piperazinyl]-2,2-dimethylpropyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C30H42N4O8 | 详情 | 详情 | |
| (X) | 13234 | 3-[2,2-dimethyl-3-(1-piperazinyl)propyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C25H34N4O6 | 详情 | 详情 | |
| (XI) | 13235 | Allyl chloride; 3-Chloro-1-propene | 107-05-1 | C3H5Cl | 详情 | 详情 |
| (XII) | 13236 | 3-(4-Allyl-1-piperazinyl)-2,2-dimethyl-1-propanol | C12H24N2O | 详情 | 详情 | |
| (XIII) | 13237 | 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl 3-oxobutanoate | C16H28N2O3 | 详情 | 详情 | |
| (XIV) | 13238 | 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl (E)-3-amino-2-butenoate | C16H29N3O2 | 详情 | 详情 | |
| (XV) | 11375 | Methyl-2-(2-nitrobenzylidene)acetoacetate; methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate | 39562-27-1 | C12H11NO5 | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(I)This compound can be obtained by three different ways: 1) The reaction of 3-nitrobenzaldehyde (I) with methyl acetoacetate (II) by means of m-toluidine in methanol gives methyl 2-(3-nitrobenzylidene)acetoacetate (III), which is then cyclized with 3-aminocrotonic acid 3-phenyl-2(E)-propenyl ester (IV) in refluxing isopropanol. 2) By cyclization of methyl 3-aminocrotonate (V) with aldehyde (I) and acetoacetic acid 3-phenyl-2(E)-propenyl ester (VI) in refluxing isopropanol. 3) By esterification of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (VII) with 3-phenyl-2(E)-propenyl alcohol (VIII), by means of dicyclohexylcarbodiimide (DCC) in pyridine.
| 【1】 Nishitani, S.; Minamikawa, J.; Kano, M.; Otsubo, J.; Manabe, Y. (Otsuka Pharmaceutical Co., Ltd.); Process for preparing novel dihydropyridine derivs. EP 0173126 . |
| 【2】 Tamada, S.; Ei, K.; Teramoto, S.; Tanaka, T.; Nakagawa, T. (Otsuka Pharmaceutical Co., Ltd.); Dihydropyridine derivs. JP 1986140567 . |
| 【3】 Tamada, S.; Nagami, K.; Teramoto, S.; Tanaka, T.; Nakagawa, K. (Otsuka Pharmaceutical Co., Ltd.); Novel dihydropyridine derivs. and process for preparing the same. EP 0145434; ES 8604516; ES 8701726; ES 8701727; JP 1985120861; JP 1989151557; US 5034395; US 5137889 . |
| 【4】 Prous, J.; Castaner, J.; OPC-13340. Drugs Fut 1991, 16, 2, 119. |
| 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) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (III) | 12276 | methyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C12H11NO5 | 详情 | 详情 | |
| (IV) | 13947 | (E)-3-phenyl-2-propenyl (E)-3-amino-2-butenoate | C13H15NO2 | 详情 | 详情 | |
| (V) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VI) | 13949 | (E)-3-phenyl-2-propenyl 3-oxobutanoate | C13H14O3 | 详情 | 详情 | |
| (VII) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 | |
| (VIII) | 13951 | (E)-3-Phenyl-2-propen-1-ol | 104-54-1 | C9H10O | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(IX)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.
| 【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 |
合成路线20
该中间体在本合成路线中的序号：(VIII)Reaction of 2-(4-aminophenyl)ethanol (I) with bis(2-chloroethyl)amine hydrochloride (II) in butanol gives 2-[4-(1-piperazinyl)phenyl]ethanol (III), which is alkylated with diphenylbromomethane (IV) and potassium carbonate in dimethyl formamide to afford 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethanol (V). Treatment of (V) with diketene (VI) in the presence of 4-dimethylaminopyridine in tetrahydrofuran yields 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethyl acetoacetate (VII), which is finally condensed with 3-nitrobenzaldehyde (VIII) and methyl 3-aminocrotonate (IX) in isopropanol (1-5). This last condensation can be performed in two steps by reaction of compound (VII) with compound (VIII) in the presence of piperidine and acetic acid in benzene to give 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethyl 2-(3-nitrobenzylidene)acetoacetate (X), which is finally treated with (IX) in isopropanol. An alternative procedure involves condensation of 3-nitrobenzaldehyde (VIII), diketene (VI), methyl 3-aminocrotonate (IX) and 3-hydroxypropionitrile (XI) in isopropanol to give 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 2-cyanoethyl ethyl diester (XII), which is hydrolyzed with sodium hydroxide to 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (XIII). Compound (XIII) is finally esterified with compound (V) in a mixture of dimethylformamide and chloroform.
| 【1】 Ashimori, A.; Ono, T.; Inoue, Y.; Fukaya, C. (Welfide Corporation); Dihydropyridine derivs. and pharmaceutical compsns. Thereof. EP 0257616; JP 1988099042; JP 1988225356; US 4886819 . |
| 【2】 (Welfide Corporation); Use of dihydropyridines in cardiotonic pharmaceutical compsns. EP 0109039; US 4543354 . |
| 【3】 Kido, H.; Uchida, T.; Fukaya, C.; Yokoyama, K.; Uchida, Y. (Welfide Corporation); Dihydropyridine derivs. for the treatment of angiospasm. EP 0379737; JP 1990180826 . |
| 【4】 Ono, T.; Ashimori, A.; Inoue, Y.; Novel 1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive activity of 3-[4-(substituted amino)phenylalkyl]ester derivatives. Chem Pharm Bull 1991, 39, 1, 91-9. |
| 【5】 Ohe, K.; Tanaka, M.; Yokoyama, K.; Uchida, T.; Fukaya, C.; Watanabe, M.; Ohtaki, Y.; Ashimori, A.; Kagitani, M.; Synthesis and pharmacological effects of optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicrboxylate hydrochloride. Chem Pharm Bull 1991, 39, 1, 108-11. |
| 【6】 Castaner, J.; Mealy, N.; Prous, J.; AE0047. Drugs Fut 1994, 19, 7, 627. |
| 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) | 14019 | p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol | 104-10-9 | C8H11NO | 详情 | 详情 |
| (II) | 14020 | N,N-Bis(2-chloroethyl)amine hydrochloride; 2-Chloro-N-(2-chloroethyl)-1-ethanamine hydrochloride | C4H10Cl3N | 详情 | 详情 | |
| (III) | 14021 | 2-(4-Piperazinophenyl)-1-ethanol | C12H18N2O | 详情 | 详情 | |
| (IV) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (V) | 14023 | 2-[4-(4-Benzhydrylpiperazino)phenyl]-1-ethanol | C25H28N2O | 详情 | 详情 | |
| (VI) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (VII) | 14025 | 4-(4-benzhydrylpiperazino)phenethyl 3-oxobutanoate | C29H32N2O3 | 详情 | 详情 | |
| (VIII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (IX) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (X) | 14028 | 4-(4-benzhydryl-1-piperazinyl)phenethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C36H35N3O5 | 详情 | 详情 | |
| (XI) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XII) | 14030 | 3-(2-cyanoethyl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C19H19N3O6 | 详情 | 详情 | |
| (XIII) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(XII)In an alternative method, the diamino ketal (XI) was subjected to reductive alkylation with m-nitrobenzaldehyde (XII) using sodium cyanoborohydride, sodium triacetoxyborohydride, or pyridine-borane complex as the reducing reagents to produce the bis-benzylamine (XIII). Cyclization of diamine (XIII) to urea (XIV) was accomplished by means of either phosgene or triphosgene in the presence of diisopropyl ethylamine. Subsequent ketal hydrolysis in (XIV) with methanesulfonic acid in MeOH yielded the dinitro precursor (X), which was finally reduced to the title compound by the same method as above.
| 【1】 Confalone, P.N.; Smyser, T.E. (Bristol-Myers Squibb Co.); Method for preparing N,N'-disubstd. cyclic ureas. WO 9639393 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 59260 | (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-bis(3-nitrobenzyl)-1,3-diazepan-2-one | C33H32N4O7 | 详情 | 详情 | |
| (XI) | 18091 | (1S)-1-[(4R,5R)-5-[(1S)-1-amino-2-phenylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethylamine; (1S)-1-[(4R,5R)-5-[(1S)-1-amino-2-phenylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenyl-1-ethanamine | C21H28N2O2 | 详情 | 详情 | |
| (XII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (XIII) | 59261 | (1R)-1-((4S,5S)-2,2-dimethyl-5-{(1R)-1-[(3-nitrobenzyl)amino]-2-phenylethyl}-1,3-dioxolan-4-yl)-N-(3-nitrobenzyl)-2-phenyl-1-ethanamine; N-[(1R)-1-((4S,5S)-2,2-dimethyl-5-{(1R)-1-[(3-nitrobenzyl)amino]-2-phenylethyl}-1,3-dioxolan-4-yl)-2-phenylethyl]-N-(3-nitrobenzyl)amine | C35H38N4O6 | 详情 | 详情 | |
| (XIV) | 59262 | (3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethyl-5,7-bis(3-nitrobenzyl)hexahydro-6H-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one | C36H36N4O7 | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(XVIII)2) The chiral intermediate (X) has been obtained by two different ways: a) The Knovenagel condensation of dimethyl malonate (XVII) with 3-nitrobenzaldehyde (XVIII) gives the corresponding benzylidenemalonate (XIX), which is alkylated with diethyl zinc and CuBr in DMSO yielding 2-[1-(3-nitrophenyl)propyl]malonic acid dimethyl ester (XX). The partial decarboxylation of (XX) with 6N HCl affords racemic 3-(3-nitrophenyl)pentanoic acid (XXI), which is esterified with methanol/HCl to the racemic methyl ester (XXII). Finally, this racemate is resolved by chromatography over a chiral (R,R)Whelk-O1 column giving the desired intermediate (X). b) The regioselective acetylation of 1-(3-nitrophenyl)-1-propanol (XXIII) with isopropenyl acetate (XXIV) catalyzed by Amano P30 lipase gives a mixture of the (S)-acetate (XXV) and unreacted (R)-alcohol (XXVI). After separation, (XXVI) was mesylated with mesyl chloride as usual yielding mesylate (XXVII), which was condensed with the sodium salt of diethyl malonate (XXVIII) affording the chiral malonic ester (XXIX). Partial decarboxylation of (XXIX) with 6N HCl gives the chiral pentanoic acid (XXX), which is finally esterified to the desired intermediate (X) with methanol/HCl.
| 【1】 Fors, K.S.; et al.; A convergent, scalable synthesis of HIV protease inhibitor PNU-140690. J Org Chem 1998, 63, 21, 7348. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 21164 | methyl (3S)-3-(3-nitrophenyl)pentanoate | C12H15NO4 | 详情 | 详情 | |
| (XVII) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (XVIII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (XIX) | 21173 | dimethyl 2-(3-nitrobenzylidene)malonate | C12H11NO6 | 详情 | 详情 | |
| (XX) | 21174 | dimethyl 2-[1-(3-nitrophenyl)propyl]malonate | C14H17NO6 | 详情 | 详情 | |
| (XXI) | 21175 | 3-(3-nitrophenyl)pentanoic acid | C11H13NO4 | 详情 | 详情 | |
| (XXII) | 21176 | methyl 3-(3-nitrophenyl)pentanoate | C12H15NO4 | 详情 | 详情 | |
| (XXIII) | 21177 | 1-(3-nitrophenyl)-1-propanol | C9H11NO3 | 详情 | 详情 | |
| (XXIV) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (XXV) | 21179 | (1S)-1-(3-nitrophenyl)propyl acetate | C11H13NO4 | 详情 | 详情 | |
| (XXVI) | 21180 | (1R)-1-(3-nitrophenyl)-1-propanol | C9H11NO3 | 详情 | 详情 | |
| (XXVII) | 21181 | (1R)-1-(3-nitrophenyl)propyl methanesulfonate | C10H13NO5S | 详情 | 详情 | |
| (XXVIII) | 21182 | Diethyl malonate sodium salt | C7H11NaO4 | 详情 | 详情 | |
| (XXIX) | 21183 | diethyl 2-[(1S)-1-(3-nitrophenyl)propyl]malonate | C16H21NO6 | 详情 | 详情 | |
| (XXX) | 21184 | (3S)-3-(3-nitrophenyl)pentanoic acid | C11H13NO4 | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(IV)A new synthesis of PNU-140690 has been developed: The condensation of 1-phenyl-3-hexanone (I) with methyl acetoacetate (II) by means of NaH in THF, followed by cyclization gives the hydroxypyrone (III), which by condensation with 3-nitrobenzaldehyde (IV) by means of AlCl3 in THF yields the benzylidene-pyrone (V). The alkylation of (V) with Et3Al, CuBr-Me2S in THF affords intermediate (VI), which is reduced at the nitro group with H2 over Pd/C in methanol giving the racemic amine (VII). The optical resolution of the N-benzyloxycarbonyl derivative of (VII) with chiral HPLC yielded the desired (R,R)-enantiomer (VIII), which was finally sulfonated with 5-(trifluoromethyl)pyridine-2-sulfonyl chloride (IX) in pyridine/dichloromethane.
| 【1】 Turner, S.R.; Strohbach, J.W.; Tommasi, R.A.; Aristoff, P.A.; Johnson, P.D.; Skulnick, H.I.; Dolak, L.A.; Seest, E.P.; Tomich, P.K.; Bohanon, M.J.; Horng, M.M.; Lynn, J.C.; Chong, K.T.; Hinshaw, R.R.; Watenpaugh, K.D.; Janakiraman, M.N.; Thaisrivongs, S.; Tipranavir (PNU-140690): A potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. J Med Chem 1998, 41, 18, 3467. |
| 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) | 17233 | 1-phenyl-3-hexanone | C12H16O | 详情 | 详情 | |
| (II) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (III) | 32879 | 4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C16H20O3 | 详情 | 详情 | |
| (IV) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 32880 | 3-[(Z)-(3-nitrophenyl)methylidene]-6-phenethyl-6-propyldihydro-2H-pyran-2,4-dione | C23H23NO5 | 详情 | 详情 | |
| (VI) | 32881 | 4-hydroxy-3-[1-(3-nitrophenyl)propyl]-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H29NO5 | 详情 | 详情 | |
| (VII) | 32882 | 3-[1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H31NO3 | 详情 | 详情 | |
| (VIII) | 17236 | (6R)-3-[(1R)-1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H31NO3 | 详情 | 详情 | |
| (IX) | 17237 | 5-(trifluoromethyl)-2-pyridinesulfonyl chloride | C6H3ClF3NO2S | 详情 | 详情 |
合成路线24
该中间体在本合成路线中的序号：(I)The Hantzsch cyclization of 3-nitrobenzaldehyde (I), methyl acetoacetate (II) and NH4OAc in refluxing ethanol or isopropanol gives 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (III), which is reduced with H2 over sulfided carbon in ethanol or with Fe/NH4Cl in methanol/water to yield the corresponding amino derivative (IV). The reaction of (IV) with methyl chloroformate and pyridine in acetonitrile/dichloromethane affords the carbamate (V), which is treated with B-chlorocatecholborane in refluxing THF to provide the corresponding isocyanate (VI). Finally, this compound is condensed with 3-[4-(3-methoxyphenyl)piperidin-1-yl]propylamine (VII) in dichloromethane to furnish the target urea. The intermediate 3-[4-(3-methoxyphenyl)piperidin-1-yl]propylamine (VII) is obtained by condensation of 4-(3-methoxyphenyl)piperidine (VIII) with acrylonitrile (IX) in refluxing acetonitrile to give 3-[4-(3-methoxyphenyl)piperidin-1-yl]propionitrile (X), which is reduced with H2 over Raney-Ni in methanol/aq. NH3.
| 【1】 Poindexter, G.S.; et al.; Dihydropyridine neuropeptide Y Y1 receptor antagonists. Bioorg Med Chem Lett 2002, 12, 3, 379. |
| 【2】 Poindexter, G.S.; Bruce, M.; Johnson, G.; leBoulluec, K.; Sloan, C.P. (Bristol-Myers Squibb Co.); Dihydropyridine NPY antagonists: Piperidine derivs.. CA 2177110; EP 0747357; JP 1997003045; US 5668151 . |
| 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) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (III) | 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 |
| (IV) | 55440 | dimethyl 4-(3-aminophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate | C17H20N2O4 | 详情 | 详情 | |
| (V) | 55441 | dimethyl 4-{3-[(methoxycarbonyl)amino]phenyl}-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate | C19H22N2O6 | 详情 | 详情 | |
| (VI) | 55442 | dimethyl 4-(3-isocyanatophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate | C18H18N2O5 | 详情 | 详情 | |
| (VII) | 55443 | 3-[4-(3-methoxyphenyl)-1-piperidinyl]-1-propanamine; 3-[4-(3-methoxyphenyl)-1-piperidinyl]propylamine | C15H24N2O | 详情 | 详情 | |
| (VIII) | 47138 | 4-(3-methoxyphenyl)piperidine; methyl 3-(4-piperidinyl)phenyl ether | C12H17NO | 详情 | 详情 | |
| (IX) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (X) | 55444 | 3-[4-(3-methoxyphenyl)-1-piperidinyl]propanenitrile | C15H20N2O | 详情 | 详情 |
合成路线25
该中间体在本合成路线中的序号：(II)Aldol condensation of acetophenone (I) with 3-nitrobenzaldehyde (II) in the presence of sodium methoxide in methanol at room temperature afforded enone (III). Double bond hydrogenation over Pd/C in MeOH-THF, with simultaneous nitro group reduction and O-benzyl hydrogenolysis, provided hydroxy ketone (IV). This compound was acylated with acetyl chloride in the presence of triethylamine and catalytic dimethylaminopyridine(DMAP) to yield ester-amide (V), which was cyclized to chromenone (VI) on treatment with NaH in DMSO, followed by HCl in refluxing acetic acid (1). Acidic hydrolysis of amide (VI) gave amine (VII), and this was treated with triflic anhydride and triethylamine to afford the corresponding sulfonamide (VIII). Demethylation of ether (VIII) with HBr in acetic acid gave phenol (IX), and then alkylation with with 2-(chloromethyl)-5-fluorobenzothiazole (X) yielded (XI). Reduction of chromenone with L-Selectride(R) in THF at -78 C gave racemic chromanone (XII) with trans stereochemistry.
| 【1】 Chambers, R.J.; Antognoli, G.W.; Cheng, J.B.; Marfat, A.; Pillar, J.S.; Shirley, J,T,; Watson, J.W.; Development of new chromanol antagonists of leukotriene D4. Bioorg Med Chem Lett 1998, 8, 14, 1791. |
| 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) | 18126 | 1-[2-(benzyloxy)-5-methoxyphenyl]-1-ethanone | C16H16O3 | 详情 | 详情 | |
| (II) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (III) | 18128 | (E)-1-[2-(benzyloxy)-5-methoxyphenyl]-3-(3-nitrophenyl)-2-propen-1-one | C23H19NO5 | 详情 | 详情 | |
| (IV) | 18129 | 3-(3-aminophenyl)-1-(2-hydroxy-5-methoxyphenyl)-1-propanone | C16H17NO3 | 详情 | 详情 | |
| (V) | 18130 | 2-[3-[3-(acetamido)phenyl]propanoyl]-4-methoxyphenyl acetate | C20H21NO5 | 详情 | 详情 | |
| (VI) | 18131 | N-[3-[(6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)methyl]phenyl]acetamide | C20H19NO4 | 详情 | 详情 | |
| (VII) | 18132 | 3-(3-aminobenzyl)-6-methoxy-2-methyl-4H-chromen-4-one | C18H17NO3 | 详情 | 详情 | |
| (VIII) | 18133 | trifluoro-N-[3-[(6-methoxy-2-methyl-4-oxo-4H-chromen-3-yl)methyl]phenyl]methanesulfonamide | C19H16F3NO5S | 详情 | 详情 | |
| (IX) | 18134 | trifluoro-N-[3-[(6-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)methyl]phenyl]methanesulfonamide | C18H14F3NO5S | 详情 | 详情 | |
| (X) | 18135 | 2-(chloromethyl)-5-fluoro-1,3-benzothiazole | C8H5ClFNS | 详情 | 详情 | |
| (XI) | 18136 | trifluoro-N-[3-([6-[(5-fluoro-1,3-benzothiazol-2-yl)methoxy]-2-methyl-4-oxo-4H-chromen-3-yl]methyl)phenyl]methanesulfonamide | C26H18F4N2O5S2 | 详情 | 详情 | |
| (XII) | 18137 | trifluoro-N-[3-([(2R,3R)-6-[(5-fluoro-1,3-benzothiazol-2-yl)methoxy]-2-methyl-4-oxo-3,4-dihydro-2H-chromen-3-yl]methyl)phenyl]methanesulfonamide | C26H20F4N2O5S2 | 详情 | 详情 |
合成路线26
该中间体在本合成路线中的序号：(XI)In an alternative procedure, Wittig reaction of 3-nitrobenzaldehyde (XI) with isopropyltriphenylphosphonium iodide gave isobutenyl compound (XII). Then, the nitro group of (XII) was selectively reduced to aniline (XIII) by hydrogenation over Pt/C, and this was protected as the pivaloyl amide (XIV) with pivaloyl chloride. Further hydrogenation of (XIV) using Pd/C produced the isobutyl derivative (XV). Lithiation of (XV) with tert-butyllithium generated the intermediate organolithium reagent (XVI), which was subsequently converted to boronic acid (XVII). Further Suzuki coupling of (XVII) with bromosulfonamide (IV) produced biphenyl (XVIII). Reductive removal of the pivaloyl group of (XVIII) using DIBAL-H then gave the precursor (X), which was finally deprotected with HCl to afford the target compound.
| 【1】 Biphenylsulfonamide endothelin antagonists: Structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1,1'-biphe. J Med Chem 1998, 41, 26, 5198. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40672 | isopropyl(triphenyl)phosphonium | C21H22P | 详情 | 详情 | ||
| (IV) | 26893 | 2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide | C15H19BrN2O5S | 详情 | 详情 | |
| (X) | 26899 | 2'-amino-N-(3,4-dimethyl-5-isoxazolyl)-4'-isobutyl-N-[(2-methoxyethoxy)methyl][1,1'-biphenyl]-2-sulfonamide | C25H33N3O5S | 详情 | 详情 | |
| (XI) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (XII) | 26900 | 1-(2-methyl-1-propenyl)-3-nitrobenzene | C10H11NO2 | 详情 | 详情 | |
| (XIII) | 26901 | 3-(2-methyl-1-propenyl)aniline | C10H13N | 详情 | 详情 | |
| (XIV) | 26902 | 2,2-dimethyl-N-[3-(2-methyl-1-propenyl)phenyl]propanamide | C15H21NO | 详情 | 详情 | |
| (XV) | 26903 | N-(3-isobutylphenyl)-2,2-dimethylpropanamide | C15H23NO | 详情 | 详情 | |
| (XVI) | 26904 | [2-[(2,2-dimethylpropanoyl)amino]-4-isobutylphenyl]lithium | C15H22LiNO | 详情 | 详情 | |
| (XVII) | 26905 | 2-[(2,2-dimethylpropanoyl)amino]-4-isobutylphenylboronic acid | C15H24BNO3 | 详情 | 详情 | |
| (XVIII) | 26906 | N-[2'-([(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino]sulfonyl)-4-isobutyl[1,1'-biphenyl]-2-yl]-2,2-dimethylpropanamide | C30H41N3O6S | 详情 | 详情 |
合成路线27
该中间体在本合成路线中的序号：(II)Treatment of 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide (I) with EtMgBr and 3-nitrobenzaldehyde (II) in CH2Cl2 yields derivative (III), whose nitro moiety is reduced by hydrogenation over Pd/C in EtOAc to afford aminophenyl derivative (IV). Treatment of (IV) with Et3SiH in TFA provides aminobenzyl derivative (V), which is finally converted into the desired compound by treatment with pyridine and ethanesulfonyl chloride (VI) followed by reflux in HCl.
| 【1】 Altenbach, R.J.; Holladay, M.W.; Carroll, W.A.; Meyer, M.D.; Kerwin, J.F. Jr.; Kolasa, T.; Rohde, J.; Khilevich, A. (Abbott Laboratories Inc.); Imidazoles and related cpds. as alpha1A agonists. WO 0007997 . |
| 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) | 44143 | 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide | C5H8IN3O2S | 详情 | 详情 | |
| (II) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (III) | 44145 | 4-[hydroxy(3-nitrophenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide | C12H14N4O5S | 详情 | 详情 | |
| (IV) | 44146 | 4-[(3-aminophenyl)(hydroxy)methyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide | C12H16N4O3S | 详情 | 详情 | |
| (V) | 44147 | 4-(3-aminobenzyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide | C12H16N4O2S | 详情 | 详情 | |
| (VI) | 54065 | Ethanesulfonyl chloride; Ethylsulfonyl chloride | 594-44-5 | C2H5ClO2S | 详情 | 详情 |
合成路线28
该中间体在本合成路线中的序号：(II)The condensation of 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide (I) with 3-nitrobenzaldehyde (II) by means of Et-MgBr in dichloromethane gives the carbinol (III), which is reduced with triethylsilane in refluxing TFA to yield 4-(3-nitrobenzyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (IV). The reduction of the nitro group of (IV) by means of H2 over Pd/C in ethyl acetate affords the amino derivative (V), which is acylated with ethanesulfonyl chloride (VI) and pyridine in dichloromethane to give the ethanesulfonamide (VII). Finally, this compound is treated with aqueous refluxing HCl to yield the target compound.
| 【1】 Khilevich, A.; Altenbach, R.J.; Meyer, M.D.; et al.; N-[3-(1H-Imidazol-4-ylmethyl)phenyl]ethanesulfonamide (ABT-866, 1),(1) a novel alpha1-adrenoceptor ligand with an enhanced in vitro and in vivo profile relative to phenylpropanolamine and midodrine. J Med Chem 2002, 45, 20, 4395. |
| 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) | 44143 | 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide | C5H8IN3O2S | 详情 | 详情 | |
| (II) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (III) | 44145 | 4-[hydroxy(3-nitrophenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide | C12H14N4O5S | 详情 | 详情 | |
| (IV) | 58281 | N,N-dimethyl-4-(3-nitrobenzyl)-1H-imidazole-1-sulfonamide | C12H14N4O4S | 详情 | 详情 | |
| (V) | 44147 | 4-(3-aminobenzyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide | C12H16N4O2S | 详情 | 详情 | |
| (VI) | 54065 | Ethanesulfonyl chloride; Ethylsulfonyl chloride | 594-44-5 | C2H5ClO2S | 详情 | 详情 |
| (VII) | 58282 | 4-{3-[(ethylsulfonyl)amino]benzyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide | C14H20N4O4S2 | 详情 | 详情 |
合成路线29
该中间体在本合成路线中的序号：(VIII)Condensation between 3-nitrobenzaldehyde (VIII) and methyl acetoacetate (IX) in the presence of ammonium acetate under Hantzsch reaction conditions leads to dihydropyridine (X). The nitro group of (X) is then reduced by catalytic hydrogenation to the corresponding aniline (XI). Finally, condensation of aniline (XI) with the cyanoisothiourea (VII) employing HgCl2 furnishes the target N-cyanoguanidine.
| 【1】 Poindexter, G.S.; Sit, S.-Y.; Swann, R.T.; Bruce, M.A.; Morton, M.A.; Huang, Y.; Breitenbucher, J.G. (Bristol-Myers Squibb Co.); Dihydropyridine NPY antagonists: Cyanoguanidine derivs.. US 6001836; WO 9854136 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 58483 | sodium 1-(3-{[(cyanoimino)(sulfido)methyl]amino}propyl)-4-phenylpiperidine | C16H21N4NaS | 详情 | 详情 | |
| (VIII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (IX) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (X) | 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 |
| (XI) | 55440 | dimethyl 4-(3-aminophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate | C17H20N2O4 | 详情 | 详情 |
合成路线30
该中间体在本合成路线中的序号：(III)2'-Hydroxyacetophenone (I) is protected as the silyl ether (II) employing t-butyldimethylsilyl chloride and imidazole. Condensation of acetophenone (II) with 3-nitrobenzaldehyde (III) and malononitrile in the presence of ammonium acetate gives rise to the cyanopyridine (IV). The nitro group of (IV) is then reduced to the corresponding amine (V) by catalytic hydrogenation over Pd/C. 3-Piperidinylpropionic acid (VI) is then activated as the acid chloride (VII) upon treatment with oxalyl chloride. Subsequent coupling of acid chloride (VII) with amine (V) furnishes amide (VIII). Finally, desilylation of (VIII) by means of either tetrabutylammonium fluoride or HCl in dioxane leads to the title compound. (1,2)
| 【1】 Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Kadono, H.; Masuda, T.; Shimazaki, M.; Shintani, T.; Fuchikami, K.; Sakai, K.; Inbe, H.; Takeshita, K.; Niki, T.; Umeda, M.; Bacon, K.B.; Ziegelbauer, K.B.; Lowinger, T.B.; Discovery of novel and selective IKK-beta serine-threonine protein kinase inhibitors. Part 1. Bioorg Med Chem Lett 2003, 13, 5, 913. |
| 【2】 Yoshida, N.; Masuda, T.; Sakakibara, S.; Murata, T.; Yoshino, T.; Umeda, M.; Shimada, M.; Lowinger, T.B.; Komura, H.; Shintani, T.; Ziegelbauer, K.B.; Fuchikami, K.; Ikegami, Y.; Shimazaki, M. (Bayer AG); 4-Aryl pyridine derivs.. EP 1339687; JP 2002193938; WO 0244153 . |
| 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) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 64006 | 1-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-ethanone | C14H22O2Si | 详情 | 详情 | |
| (III) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (IV) | 64007 | 2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(3-nitrophenyl)nicotinonitrile | C24H26N4O3Si | 详情 | 详情 | |
| (V) | 64008 | 2-amino-4-(3-aminophenyl)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)nicotinonitrile | C24H28N4OSi | 详情 | 详情 | |
| (VI) | 64010 | 3-(1-piperidinyl)propanoic acid | C8H15NO2 | 详情 | 详情 | |
| (VII) | 64011 | 3-(1-piperidinyl)propanoyl chloride | C8H14ClNO | 详情 | 详情 | |
| (VIII) | 64009 | N-{3-[2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-cyano-4-pyridinyl]phenyl}-3-(1-piperidinyl)propanamide | C32H41N5O2Si | 详情 | 详情 |