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【结 构 式】 
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【分子编号】68929 【品名】 【CA登记号】 |
【 分 子 式 】C11H13BrN4O 【 分 子 量 】297.155 【元素组成】C 44.46% H 4.41% Br 26.89% N 18.85% O 5.38% |
合成路线1
该中间体在本合成路线中的序号：(XII)In one strategy, condensation of amine (I) with 3-methylenecyclobutanecarboxylic acid (II) in the presence of EDC and HOBt in CH2Cl2 yields amide (III), which then undergoes cyclization to the imidazo[1,5-a]pyrazine derivative (IV) upon heating with POCl3 in DMF. Oxidation of alkene (IV) by means of K2OsO4·2H2O in the presence of NMMO in THF/H2O furnishes the 1-(hydroxymethyl)cyclobutanol (V), which is then subjected to chloride displacement with NH3 in i-PrOH to produce the 8-aminoimidazo[1,5-a]pyrazine derivative (VI). Oxidative cleavage of diol (VI) by means of NaIO4 in THF/H2O yields the cyclobutanone (VII), which upon addition of MeLi in THF and subsequent separation of the obtained isomers using TLC affords linsitinib .
In another strategy, condensation of amine (I) with 3-hydroxy-3-methylcyclobutanecarbonyl chloride (VIII) in the presence of DIEA and DMAP in CH2Cl2 produces carboxamide (IX). Cyclization of amide (IX) with POCl3 at 70 °C followed by treatment with NH3 then leads to the imidazo[1,5-a]pyrazine derivative (X). Displacement of the 8-chloroimidazo[1,5-a]pyrazine derivative (X) with NH3 at 110 °C and subsequent chromatographic separation of the isomers provides linsitinib .
In the third strategy, linsitinib is obtained by Suzuki coupling of the quinolinylboronate (XI) with the 1-bromoimidazo[1,5-a]pyrazine derivative (XII) in the presence of PdCl2(dppf)·CH2Cl2 and K2CO3 at 90 °C .
| 【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】 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 |
|---|---|---|---|---|---|---|
| (I) | 68918 | (3-chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methanamine | C20H15ClN4 | 详情 | 详情 | |
| (II) | 68919 | 3-methylenecyclobutanecarboxylic acid;3-Methylenecyclobutylcarboxylic acid | 15760-36-8 | C6H8O2 | 详情 | 详情 |
| (III) | 68920 | N-((3-chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methyl)-3-methylenecyclobutanecarboxamide | C26H21ClN4O | 详情 | 详情 | |
| (IV) | 68921 | 7-(8-chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline | C26H19ClN4 | 详情 | 详情 | |
| (V) | 68922 | 3-(8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)-1-(hydroxymethyl)cyclobutanol | C26H21ClN4O2 | 详情 | 详情 | |
| (VI) | 68923 | 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)-1-(hydroxymethyl)cyclobutanol | C26H23N5O2 | 详情 | 详情 | |
| (VII) | 68924 | 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)cyclobutanone | C25H19N5O | 详情 | 详情 | |
| (VIII) | 68926 | 3-hydroxy-3-methylcyclobutanecarbonyl chloride | C6H9ClO2 | 详情 | 详情 | |
| (IX) | 68925 | N-((3-chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methyl)-3-hydroxy-3-methylcyclobutanecarboxamide | C26H23ClN4O2 | 详情 | 详情 | |
| (X) | 68927 | 3-(8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol | C26H21ClN4O | 详情 | 详情 | |
| (XI) | 68928 | 2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline | C21H22BNO2 | 详情 | 详情 | |
| (XII) | 68929 | C11H13BrN4O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)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 |