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【结 构 式】 
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【分子编号】68928 【品名】2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline 【CA登记号】 |
【 分 子 式 】C21H22BNO2 【 分 子 量 】331.222 【元素组成】C 76.15% H 6.69% Cl 3.26% N 4.23% O 9.66% |
合成路线1
该中间体在本合成路线中的序号：(XI)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：(XI)In one method, oxidation of 4-chloro-2-nitrotoluene (XXIV) with NaIO4 in the presence of DMFA in DMF at 135 °C yields 4-chloro-2-nitrobenzaldehyde (XXV). Reduction of the nitro group in compound (XXV) with Fe and HCl in EtOH/H2O, followed by Friedländer condensation of the resulting aminoaldehyde with acetophenone (XIV) using KOH at reflux gives 7-chloro-2-phenylquinoline (XXVI). Miyaura borylation of chloroquinoline (XXVI) with bis(pinacolato)diboron (XXVII) in the presence of 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride [IPr·HCl], Pd(OAc)2 and KOAc in refluxing THF furnishes boronate ester (XI).
In another method, arylation of 7-quinolinol (XXVIII) using phenyl lithium in THF, optionally after protection of the hydroxyl group with TBDMSCl in the presence of DMAP and Et3N in CH2Cl2, leads to 2-phenyl-7-quinolinol (XXIX). Quinolinol (XXIX) is then activated by Tf2O in pyr/CH2Cl2 to produce the aryl triflate (XXX), which condenses with bis(pinacolato)diboron (XXVII) in the presence of PdCl2(dppf) CH2Cl2, dppf and KOAc in 1,4-dioxane to afford the dioxaborolane derivative (XI) .
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 68928 | 2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline | C21H22BNO2 | 详情 | 详情 | |
| (XIV) | 10317 | Acetophenone | 98-86-2 | C8H8O | 详情 | 详情 |
| (XXIV) | 41485 | 4-chloro-1-methyl-2-nitrobenzene；4-chloro-2-nitrotoluene;4-chloro-1-methyl-2-nitro-benzene | 89-59-8 | C7H6ClNO2 | 详情 | 详情 |
| (XXV) | 68938 | 4-chloro-2-nitrobenzaldehyde;2-Nitro-4-chlorobenzaldehyde | 5551-11-1 | C7H4ClNO3 | 详情 | 详情 |
| (XXVI) | 68939 | 7-chloro-2-phenylquinoline | C15H10ClN | 详情 | 详情 | |
| (XXVII) | 53342 | 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester | 73183-34-3 | C12H24B2O4 | 详情 | 详情 |
| (XXVIII) | 68940 | quinolin-7-ol | C9H7NO | 详情 | 详情 | |
| (XXIX) | 68941 | 2-phenyl-7-quinolinol;2-phenylquinolin-7-ol | C15H11NO | 详情 | 详情 | |
| (XXX) | 68942 | 2-phenylquinolin-7-yl trifluoromethanesulfonate | C16H10F3NO3S | 详情 | 详情 |