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【结 构 式】 
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【分子编号】68946 【品名】2,5-dioxopyrrolidin-1-yl 3-oxocyclobutanecarboxylate 【CA登记号】 |
【 分 子 式 】C9H9NO5 【 分 子 量 】211.1742 【元素组成】C 51.19% H 4.3% N 6.63% O 37.88% |
合成路线1
该中间体在本合成路线中的序号：(XXXIV)Metalation of 2-chloropyrazine (XVIII) with LTMP (prepared from BuLi and TMP) in THF, followed by formylation with DMF and subsequent reduction with NaBH4 yields (3-chloro-2-pyrazinyl)methanol (XXXI). Mitsunobu coupling of alcohol (XXXI) with phthalimide (XX) in the presence of PPh3 and DIAD in THF gives the N-substituted phthalimide (XXXII), which is then subjected to hydrazinolysis with NH2NH2 in CH2Cl2 to provide, after treatment with HCl, (3-chloro-2-pyrazinyl)methylamine dihydrochloride (XXXIII) . Coupling of amine (XXXIII) with succinimidyl ester (XXXIV) (prepared by condensation of 3-oxocyclobutanecarboxylic acid [XXXVI] with N-hydroxysuccinimide [XXXV] using DCC in isopropyl acetate [3]) in the presence of NaHCO3 in THF/H2O produces the 3-oxocyclobutanecarboxamide (XXXVII). Cyclization of amide (XXXVII) in the presence POCl3 and DMF in EtOAc affords 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (XXXVIII), which is then brominated by means of NBS in DMF to yield the 1-bromo derivative (XXXIX) . Addition of CH3MgI to ketone (XXXIX) in THF, followed by chloride substitution with NH3, gives rise to cis-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (XII) .
| 【1】 Arnold, L.D., Cesario, C., Coate, H. et al. (OSI Pharmaceuticals, Inc.). 6,6-Bicyclic ring substituted heterobicyclic protein kinase inhibitors. EP 1740591, EP 2168968, EP 2305682, EP 2308879, JP 2007531754, JP 2009197013, US 200635031, WO 005097800. |
| 【2】 Mulvihill, K.M., Castelhano, A.L. (OSI Pharmaceuticals, Inc.). Process to prepare substituted imidazopyrazine compounds. US 2007129547, WO 2007067709 |
| 【3】 Volk, B., Buck, E., Coate, H. et al. OSI-906: A novel, potent, and selective first-in-class small molecule insulin-like growth factor 1 receptor (IGF-1R) inhibitor in phase I clinical trials. 238th ACS Natl Meet (Aug 16-20, Washington) 2009, Abst MEDI 152. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 68929 | C11H13BrN4O | 详情 | 详情 | ||
| (XVIII) | 24075 | 2-chloropyrazine | 14508-49-7 | C4H3ClN2 | 详情 | 详情 |
| (XX) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (XXXI) | 68943 | (3-chloropyrazin-2-yl)methanol；3-chloro-Pyrazinemethanol；3-chloro-2-Pyrazinemethano | 89283-32-9 | C5H5ClN2O | 详情 | 详情 |
| (XXXII) | 68944 | 2-((3-chloropyrazin-2-yl)methyl)isoindoline-1,3-dione | C13H8ClN3O2 | 详情 | 详情 | |
| (XXXIII) | 68945 | (3-chloropyrazin-2-yl)methanamine dihydrochloride | C5H6ClN3.2HCl | 详情 | 详情 | |
| (XXXIV) | 68946 | 2,5-dioxopyrrolidin-1-yl 3-oxocyclobutanecarboxylate | C9H9NO5 | 详情 | 详情 | |
| (XXXV) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (XXXVI) | 68947 | 3-oxocyclobutanecarboxylic acid；(3-Oxocyclobutyl)carboxylic acid | 23761-23-1 | C5H6O3 | 详情 | 详情 |
| (XXXVII) | 68948 | N-((3-chloropyrazin-2-yl)methyl)-3-oxocyclobutanecarboxamide | C10H10ClN3O2 | 详情 | 详情 | |
| (XXXVIII) | 68949 | 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone | C10H8ClN3O | 详情 | 详情 | |
| (XXXIX) | 68950 | 3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone | C10H7BrClN3O | 详情 | 详情 |