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【结 构 式】 
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【药物名称】CHIR-99021 【化学名称】6-[2-[4-(2,4-Dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)pyrimidin-2-ylamino]ethylamino]pyridine-3-carbonitrile 【CA登记号】252917-06-9 【 分 子 式 】C22H18Cl2N8 【 分 子 量 】465.34836 |
【开发单位】Chiron (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Glycogen Synthase Kinase 3 (GSK-3) Inhibitors |
合成路线1
Acylation of 2,4-dimethylimidazole (I) with 2,4-dichlorobenzoyl chloride (II) in the presence of diisopropylethylamine, followed by acidic hydrolysis, provides the 2-imidazolyl acetophenone (III). Subsequent condensation of (III) with dimethylformamide dimethylacetal gives rise to the enaminone (IV)
| 【1】 Brown, S.P.; Goff, D.; Ring, D.B.; Harrison, S.D.; Subramanian, S.; Nuss, J.M.; Boyce, R.S.; Johnson, K.; Pfister, K.B.; Ramurthy, S.; Renhowe, P.A.; Seely, L.; Wagman, A.S.; Zhou, X.A. (Chiron Corp.); Inhibitors of glycogen synthase kinase 3. EP 1087963; US 6417185; WO 9965897 . |
| 【2】 Ring, D.B.; Harrison, S.D.; Nuss, J.M.; Boyce, R.S.; Johnson, K.; Pfister, K.B.; Ramurthy, S.; Seely, L.; Wagman, A.S.; Desai, M.; Levine, B.H. (Chiron Corp.); Inhibitors of glycogen synthase kinase 3. WO 0220495 . |
| 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) | 20613 | 2,4-dimethyl-1H-imidazole | 930-62-1 | C5H8N2 | 详情 | 详情 |
| (II) | 35131 | 2,4-dichlorobenzoyl chloride; 2,4-Dichlorophenacylchloride | 89-75-8 | C7H3Cl3O | 详情 | 详情 |
| (III) | 60241 | 1-(2,4-dichlorophenyl)-2-(4-methyl-1H-imidazol-2-yl)-1-ethanone | C12H10Cl2N2O | 详情 | 详情 | |
| (IV) | 60242 | 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-(4-methyl-1H-imidazol-2-yl)-2-propen-1-one | C15H15Cl2N3O | 详情 | 详情 |
合成路线2
Condensation of 2-chloro-5-cyanopyridine (V) with ethylenediamine (VI) yields the N-pyridyl ethylenediamine (VII). Subsequent reaction of amine (VII) with pyrazole-1-carboxyamidine (VIII) in refluxing acetonitrile affords guanidine (IX). Finally, condensation between guanidine (IX) and enaminone (IV) in the presence of NaOEt produces the title pyrimidine derivative
| 【1】 Brown, S.P.; Goff, D.; Ring, D.B.; Harrison, S.D.; Subramanian, S.; Nuss, J.M.; Boyce, R.S.; Johnson, K.; Pfister, K.B.; Ramurthy, S.; Renhowe, P.A.; Seely, L.; Wagman, A.S.; Zhou, X.A. (Chiron Corp.); Inhibitors of glycogen synthase kinase 3. EP 1087963; US 6417185; WO 9965897 . |
| 【2】 Ring, D.B.; Harrison, S.D.; Nuss, J.M.; Boyce, R.S.; Johnson, K.; Pfister, K.B.; Ramurthy, S.; Seely, L.; Wagman, A.S.; Desai, M.; Levine, B.H. (Chiron Corp.); Inhibitors of glycogen synthase kinase 3. WO 0220495 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 60242 | 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-(4-methyl-1H-imidazol-2-yl)-2-propen-1-one | C15H15Cl2N3O | 详情 | 详情 | |
| (V) | 57164 | 2-Chloro-5-cyanopyridine; 6-Chloro-3-cyanopyridine; 6-Chloronicotinonitrile | 33252-28-7 | C6H3ClN2 | 详情 | 详情 |
| (VI) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (VII) | 54332 | 6-[(2-aminoethyl)amino]nicotinonitrile | n/a | C8H10N4 | 详情 | 详情 |
| (VIII) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
| (IX) | 60243 | N-{2-[(5-cyano-2-pyridinyl)amino]ethyl}guanidine | C9H12N6 | 详情 | 详情 |