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【结 构 式】 
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【分子编号】13154 【品名】4,4-Diphenylpiperidine 【CA登记号】 |
【 分 子 式 】C17H19N 【 分 子 量 】237.3446 【元素组成】C 86.03% H 8.07% N 5.9% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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2
该中间体在本合成路线中的序号：(II)Treatment of a benzenic solution of 4-piperidone hydrate (I) with anhydrous AlCl3 provided 4,4-diphenylpiperidine (II). Then, conjugate addition of acrylonitrile (III) in the presence of triethylamine in ethanol gave the cyanoethylpiperidine (IV), which was reduced with borane in THF to afford the intermediate primary amine (V). Dihydropyridine (IX) was prepared by Hantzsch synthesis by condensation of 3-aminocrotonamide (VI), 4-nitrobenzaldehyde (VII) and cyanoethyl acetoacetate (VIII) in refluxing ethanol. Cyanoethyl ester was then cleaved with dilute KOH at 0 C to give acid (X), which was finally coupled with amine (V) by treatment with DEC to yield the target amide.
| 【1】 Cox, E.D.; et al.; Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate. J Med Chem 1998, 41, 14, 2643. |
| 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) | 18178 | 4,4-piperidinediol | 73390-11-1 | C5H11NO2 | 详情 | 详情 |
| (II) | 13154 | 4,4-Diphenylpiperidine | C17H19N | 详情 | 详情 | |
| (III) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (IV) | 18181 | 3-(4,4-diphenyl-1-piperidinyl)propanenitrile | C20H22N2 | 详情 | 详情 | |
| (V) | 18182 | 3-(4,4-diphenyl-1-piperidinyl)-1-propanamine; 3-(4,4-diphenyl-1-piperidinyl)propylamine | C20H26N2 | 详情 | 详情 | |
| (VI) | 18183 | (E)-3-amino-2-butenamide | C4H8N2O | 详情 | 详情 | |
| (VII) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (VIII) | 13993 | 2-cyanoethyl 3-oxobutanoate | C7H9NO3 | 详情 | 详情 | |
| (IX) | 18186 | 2-cyanoethyl 5-(aminocarbonyl)-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate | C18H18N4O5 | 详情 | 详情 | |
| (X) | 18187 | 5-(aminocarbonyl)-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C15H15N3O5 | 详情 | 详情 |