Ponatinib;AP-24534, -Drug Synthesis Database

【结构式】

【药物名称】Ponatinib;AP-24534

【化学名称】3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-(trifluoromethyl)phenyl]benzamide

【CA登记号】

【分子式】C₂₉H₂₇F₃N₆O

【分子量】532.5595

【开发单位】ARIAD Pharmaceuticals, Inc. (US)

【药理作用】Multitargeted Kinase Inhibitor；Pan-BCR-ABL Inhibitor；Oncolytic

合成路线1 合成路线2

合成路线1

Bromination of 1-methyl-4-nitro-2-(trifluoromethyl)benzene (I) with NBS in the presence of AIBN in refluxing CCl4 gives the corresponding bromomethyl derivative (II), which is condensed with 1-methylpiperazine (III) by means of Et3N in CH2Cl2 to afford 1-methyl-4-[4-nitro-2-(trifluoromethyl)benzyl]piperazine (IV). Reduction of compound (IV) with Na2S2O4 in refluxing acetone/H2O yields the aniline (V), which by coupling with 3-iodo-4-methylbenzoyl chloride (VI) (prepared by chlorinating acid [VII] with SOCl2 at reflux) in the presence of DIEA and DMAP in THF provides the corresponding amide (VIII). Finally, the iodobenzene derivative (VIII) is submitted to Sonogashira coupling with 3-ethynylimidazo[1,2-b]pyridazine (IX) by means of CuI, Pd(PPh3)4 and DIEA in DMF .
Intermediate (IX) is prepared by Sonogashira coupling of 3-bromoimidazo[1,2-b]pyridazine (X) with trimethylsilyl acetylene (XI) in the presence of CuI, PdCl2(PPh3)4 and DCHA in acetonitrile at 80 °C or CuI, Pd(PPh3)4 and DIEA in DMF to give 3-[(trimethylsilyl)ethynyl]imidazo[1,2-b]pyridazine (XII), which is deprotected by cleaving the trimethylsilyl moiety by means of TBAF in THF .

参考文献中间体

【1】 Huang, W.S., Metcalf, C., Sundaramoorthi, R. et al. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-Abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J Med Chem 2010, 53(12): 4701-19.
【2】 Zou, D., Huang, W.-S., Thomas, R.M. et al. (Ariad Pharmaceuticals, Inc.).Bicyclic heteroaryl compounds. EP 1973545, JP 2009521462, US 2007191376, WO 2007075869.

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)	68863	1-methyl-4-nitro-2-(trifluoromethyl)benzene		C₈H₆F₃NO₂	详情	详情
(II)	68864	1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene		C₈H₅BrF₃NO₂	详情	详情
(III)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情
(IV)	68865	1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine		C₁₃H₁₆F₃N₃O₂	详情	详情
(V)	68866	4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline	694499-26-8	C₁₃H₁₈F₃N₃	详情	详情
(VI)	68867	3-iodo-4-methylbenzoyl chloride		C₈H₆ClIO	详情	详情
(VII)	68868	3-iodo-4-methylbenzoic acid		C₈H₇IO₂	详情	详情
(VIII)	68869	3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide		C₂₁H₂₃F₃IN₃O	详情	详情
(IX)	68870	3-ethynylimidazo[1,2-b]pyridazine		C₈H₅N₃	详情	详情
(X)	68871	3-bromoimidazo[1,2-b]pyridazine	18087-73-5	C₆H₄BrN₃	详情	详情
(XI)	23897	ethynyl(trimethyl)silane；trimethylsilyl acetylene	1066-54-2	C₅H₁₀Si	详情	详情
(XII)	68872	3-[(trimethylsilyl)ethynyl]imidazo[1,2-b]pyridazine		C₁₁H₁₃N₃Si	详情	详情

合成路线2

In a related way, Sonogashira coupling of 3-iodo-4-methylbenzoic acid (VII) with 3-ethynylimidazo[1,2-b]pyridazine (IX) in the presence of CuI, Pd(PPh3)4 and either Et3N in EtOAc or DIEA in DMF affords 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzoic acid (XIII). Finally, carboxylic acid (XIII) is chlorinated with (COCl)2 in the presence of NMM in CH2Cl2, followed by amidation with the aniline derivative (V) by means of DMAP at reflux .

参考文献中间体

【1】 Zou, D., Huang, W.-S., Thomas, R.M. et al. (Ariad Pharmaceuticals, Inc.).Bicyclic heteroaryl compounds. EP 1973545, JP 2009521462, US 2007191376, WO 2007075869.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	68866	4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline	694499-26-8	C₁₃H₁₈F₃N₃	详情	详情
(VII)	68868	3-iodo-4-methylbenzoic acid		C₈H₇IO₂	详情	详情
(IX)	68870	3-ethynylimidazo[1,2-b]pyridazine		C₈H₅N₃	详情	详情
(XIII)	68873	3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4- methylbenzoic acid		C₁₆H₁₁N₃O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)