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【结 构 式】 
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【分子编号】29204 【品名】6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone 【CA登记号】 |
【 分 子 式 】C11H13N3O 【 分 子 量 】203.24384 【元素组成】C 65.01% H 6.45% N 20.67% O 7.87% |
合成路线1
该中间体在本合成路线中的序号：(I)The optical resolution of 6-(4-aminophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one (I) with L-tartaric acid in isopropanol or D-tartaric acid in ethyl acetate gives the (R)-enantiomer (II), which is then condensed with malonodinitrile (III) by means of NaNO2 and HCl in cool water.
| 【1】 Haikala, H.O.; Nore, P.T.; Honkanen, E.J.; Pystynen, J.J.; Lonnberg, K.K.; Luiro, A.M.; Pippuri, A.K. (Orion Corporation); Heterocyclic cpds.. EP 0383449; JP 1990288868; US 5019575; US 5122524; US 5185332 . |
| 【2】 Backstrom, R.J.; Haarala, J.V.; Honkanen, E.J.; Nore, P.T.; Wikberg, T.E.I.; Haikala, H.O. (Orion Corporation); Pyridazine deriv.. GB 2251615; JP 1994504275; US 5424428; US 5512571; US 5569657; WO 9212135 . |
| 【3】 Tanninen, V.P.; Timmerbacka, M.; Kaukonen, J.; Lehtonen, J.; Hyppölä, R.; Muttonen, E. (Orion Corporation); Method for obtaining pure enantiomers of a pyridazinone deriv.. WO 9735841 . |
合成路线2
该中间体在本合成路线中的序号：(VIII)Friedel-Crafts acylation of acetanilide (I) with propionyl chloride in the presence of AlCl3 afforded 4'-(acetamido)propiophenone (II). Subsequent Mannich reaction of (II) with dimethylamine hydrochloride and formaldehyde produced the aminoketone (III). Quaternization of the tertiary amine of (III) with MeI, followed by displacement of the resulting ammonium salt (IV) with KCN yielded the intermediate ketonitrile (V). In alternative procedure, nitrile (V) was prepared by acylation of acetanilide (I) with 3-chloro-2-methylpropionyl chloride, and further displacement of the resulting beta-chloroketone (VI) with KCN. Acid hydrolysis of both nitrile and acetamido groups of (V) provided ketoacid (VII), which was cyclized with hydrazine to give pyridazinone (VIII). Finally, acylation of the amino group of (VIII) by means of pyridine-2-carbonyl chloride furnished the title amide.
| 【1】 Liu, C.M.; et al.; Synthesis and platelet aggregation inhibitory activity of 6-(4'-substituted acylaminophenyl)-4,5-dihydro-3-(2H)-pyridazinones. Acta Pharm Sin 1999, 34, 1, 23. |
| 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) | 10194 | N-Phenylacetamide; Acetanilide | 103-84-4 | C8H9NO | 详情 | 详情 |
| (II) | 29198 | N-(4-propionylphenyl)acetamide | C11H13NO2 | 详情 | 详情 | |
| (III) | 29199 | N-[4-[3-(dimethylamino)-2-methylpropanoyl]phenyl]acetamide | C14H20N2O2 | 详情 | 详情 | |
| (IV) | 29200 | 3-[4-(acetamido)phenyl]-N,N,N,2-tetramethyl-3-oxo-1-propanaminium iodide | C15H23IN2O2 | 详情 | 详情 | |
| (V) | 29201 | N-[4-(3-cyano-2-methylpropanoyl)phenyl]acetamide | C13H14N2O2 | 详情 | 详情 | |
| (VI) | 29202 | N-[4-(3-chloro-2-methylpropanoyl)phenyl]acetamide | C12H14ClNO2 | 详情 | 详情 | |
| (VII) | 29203 | 4-(4-aminophenyl)-3-methyl-4-oxobutyric acid | C11H13NO3 | 详情 | 详情 | |
| (VIII) | 29204 | 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone | C11H13N3O | 详情 | 详情 | |
| (IX) | 29205 | 2-pyridinecarbonyl chloride | C6H4ClNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Friedel-Crafts acylation of acetanilide (I) with propionyl chloride in the presence of AlCl3 afforded 4'-(acetamido)propiophenone (II). Subsequent Mannich reaction of (II) with dimethylamine hydrochloride and formaldehyde produced the aminoketone (III). Quaternization of the tertiary amine of (III) with MeI, followed by displacement of the resulting ammonium salt (IV) with KCN yielded the intermediate ketonitrile (V). In alternative procedure, nitrile (V) was prepared by acylation of acetanilide (I) with 3-chloro-2-methylpropionyl chloride, and further displacement of the resulting alpha-chloroketone (VI) with KCN. Acid hydrolysis of both nitrile and acetamido groups of (V) provided ketoacid (VII), which was cyclized with hydrazine to give pyridazinone (VIII). Finally, acylation of the amino group of (VIII) by means of pyridine-4-carbonyl chloride furnished the title amide.
| 【1】 Liu, C.M.; et al.; Synthesis and platelet aggregation inhibitory activity of 6-(4'-substituted acylaminophenyl)-4,5-dihydro-3-(2H)-pyridazinones. Acta Pharm Sin 1999, 34, 1, 23. |
| 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) | 10194 | N-Phenylacetamide; Acetanilide | 103-84-4 | C8H9NO | 详情 | 详情 |
| (II) | 29198 | N-(4-propionylphenyl)acetamide | C11H13NO2 | 详情 | 详情 | |
| (III) | 29199 | N-[4-[3-(dimethylamino)-2-methylpropanoyl]phenyl]acetamide | C14H20N2O2 | 详情 | 详情 | |
| (IV) | 29200 | 3-[4-(acetamido)phenyl]-N,N,N,2-tetramethyl-3-oxo-1-propanaminium iodide | C15H23IN2O2 | 详情 | 详情 | |
| (V) | 29201 | N-[4-(3-cyano-2-methylpropanoyl)phenyl]acetamide | C13H14N2O2 | 详情 | 详情 | |
| (VI) | 29202 | N-[4-(3-chloro-2-methylpropanoyl)phenyl]acetamide | C12H14ClNO2 | 详情 | 详情 | |
| (VII) | 29203 | 4-(4-aminophenyl)-3-methyl-4-oxobutyric acid | C11H13NO3 | 详情 | 详情 | |
| (VIII) | 29204 | 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone | C11H13N3O | 详情 | 详情 | |
| (IX) | 27850 | isonicotinoyl chloride | 39178-35-3 | C6H4ClNO | 详情 | 详情 |