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【结 构 式】 
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【药物名称】BMS-214428 【化学名称】4-[3-[N3-Cyano-N2-[3-(4-phenylpiperidin-1-yl)propyl]guanidino]phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl diester 【CA登记号】216508-01-9 【 分 子 式 】C33H40N6O4 【 分 子 量 】584.72455 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】Antiobesity Drugs, METABOLIC DRUGS, Treatment of Nutritional Disorders, Neuropeptide Y1 (NPY Y1) Antagonists |
合成路线1
Conjugate addition of acrylonitrile (II) to 4-phenylpiperidine (I) affords the piperidinopropionitrile (III). Catalytic hydrogenation of the cyano group of (III) in the presence of Raney nickel and methanolic ammonia leads to diamine (IV). This is further converted into isothiocyanate (VI) by reaction with thiocarbonyl diimidazole (V). Subsequent addition of sodium cyanamide to isothiocyanate (VI) yields the intermediate N-cyano isothiourea sodium salt (VII).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 58479 | 4-phenylpiperidine | 771-99-3 | C11H15N | 详情 | 详情 |
| (II) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (III) | 58480 | 3-(4-phenyl-1-piperidinyl)propanenitrile | C14H18N2 | 详情 | 详情 | |
| (IV) | 58481 | 3-(4-phenyl-1-piperidinyl)-1-propanamine; 3-(4-phenyl-1-piperidinyl)propylamine | C14H22N2 | 详情 | 详情 | |
| (V) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (VI) | 58482 | 1-(3-isothiocyanatopropyl)-4-phenylpiperidine; 3-(4-phenyl-1-piperidinyl)propyl isothiocyanate | C15H20N2S | 详情 | 详情 | |
| (VII) | 58483 | sodium 1-(3-{[(cyanoimino)(sulfido)methyl]amino}propyl)-4-phenylpiperidine | C16H21N4NaS | 详情 | 详情 |
合成路线2
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 |