(3-chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methanamine -Drug Synthesis Database

【结构式】

【分子编号】68918

【品名】(3-chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methanamine

【CA登记号】　

【分子式】C₂₀H₁₅ClN₄

【分子量】346.819

【元素组成】C 69.26% H 4.36% Cl 10.22% N 16.15%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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 .

参考文献中间体

合成目标

【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：(I)

Reduction of methyl 4-formyl-3-nitrobenzoate (XIII) by means of Fe and HCl in EtOH, followed by Friedländer condensation of the resulting aminoaldehyde with acetophenone (XIV) in the presence of KOH at 95 °C, and treatment with HCl, yields 2-phenylquinoline-7-carboxylic acid hydrochloride (XV). Reduction of acid (XV) with LiAlH4 in THF gives alcohol (XVI), which is then oxidized by means of MnO2 in CHCl3 to give 2-phenylquinoline-7-carbaldehyde (XVII). Coupling of carbaldehyde (XVII) with the metalated derivative of 2-chloropyrazine (XVIII) in the presence LTMP (prepared from BuLi and TMP) in THF yields the diaryl carbinol (XIX), which is then subjected to Mitsunobu reaction with phthalimide (XX) in the presence of PS-PPh3 and DIAD in THF to provide the N-substituted phthalimide (XXI). Hydrazinolysis of phthalimide (XXI) with NH2NH2 in EtOH/CH2Cl2 then affords amine (I).
Alternatively, carbaldehyde (XVII) can be prepared by arylation of 7-methylquinoline (XXII) with phenyl lithium in THF, followed by air oxidation to produce 7-methyl-2-phenylquinoline (XXIII). Side chain oxidation of (XXIII) using SeO2 at 160 °C provides the target aldehyde (XVII) .

参考文献中间体

合成目标

【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
(I)	68918	(3-chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methanamine		C₂₀H₁₅ClN₄	详情	详情
(XIII)	68930	methyl 4-formyl-3-nitrobenzoate;4-Formyl-3-nitrobenzoicacid methyl ester	153813-69-5	C₉H₇NO₅	详情	详情
(XIV)	10317	Acetophenone	98-86-2	C₈H₈O	详情	详情
(XV)	68931	2-phenylquinoline-7-carboxylic acid hydrochloride		C₁₆H₁₁NO₂.HCl	详情	详情
(XVI)	68932	(2-phenylquinolin-7-yl)methanol		C₁₆H₁₃NO	详情	详情
(XVII)	68933	2-phenylquinoline-7-carbaldehyde		C₁₆H₁₁NO	详情	详情
(XVIII)	24075	2-chloropyrazine	14508-49-7	C₄H₃ClN₂	详情	详情
(XIX)	68934	(3-chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methanol		C₂₀H₁₄ClN₃O	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
(XXI)	68935	2-((3-chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methyl)isoindoline-1,3-dione		C₂₈H₁₇ClN₄O₂	详情	详情
(XXII)	68936	7-methylquinoline;m-Toluquinoline	612-60-2	C₁₀H₉N	详情	详情
(XXIII)	68937	7-methyl-2-phenylquinoline	27356-39-4	C₁₆H₁₃N	详情	详情

Extended Information