Imatinib mesylate, GGP-57148B, STI-571, CGP-57148(free base), Gleevec, Glivec, -Drug Synthesis Database

【结构式】

【药物名称】Imatinib mesylate, GGP-57148B, STI-571, CGP-57148(free base), Gleevec, Glivec

【化学名称】4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl]benzamide methanesulfonate

【CA登记号】220127-57-1, 152459-95-5 (free base)

【分子式】C₃₀H₃₅N₇O₄S

【分子量】589.72195

【开发单位】Novartis (Orphan Drug), Novartis (Originator), M.D. Anderson Cancer Center (Not Determined), EORTC (Codevelopment), National Cancer Institute (Codevelopment)

【药理作用】Bone Cancer Therapy, Brain Cancer Therapy, Colorectal Cancer Therapy, Gastric Cancer Therapy, Leukemia Therapy, Lung Cancer Therapy, Lymphocytic Leukemia Therapy, Myeloid Leukemia Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Small Cell Lung Cancer Therapy, Abl Kinase Inhibitors, Apoptosis Inducers, Inhibitors of Signal Transduction Pathways, KIT (C-KIT) Kinase Inhibitors, PDGFRalpha Inhibitors, PDGFRbeta Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

参考文献中间体

【1】 Kompella A, Bhujanga Rao AKS, Venkaiah Chowdary N, et aL 2004. Process for the preparation of the anti-cancer drug imatinib and its analogs via aminolysis of a (chloromethyl benzamide intermediate. WO 2004108699(本专利申请人为: Natco Pharma Limited, India)
【2】 Szczepek W, Luniewski W, Kaczmarek L, et aL 2006.A process for preparation of imatinib base. W0 2006071130(本专利申请人为: Instytut Farmaceutyczny, Pol)
【3】 Szakacs Z,Beni S,VargaZ,et aL 2005. Acid-base profiling of imatinib(gleevec) and its fragments. J Med Chem,8(1): 249一255
【4】 Zimmermann J.Buchdunger E, Mett H, et aL 1997. Potent and selective inhibitors of the abl-kinase: phenylaminopyrimidine (PAP) derivatives. Bioorg Med Chem Lett,7(2): 187～191

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)	47518	2-Amino-4-nitrotoluene; 5-Nitro-o-toluidine; 4-Nitro-2-aminotoluene; 2-methyl-5-nitrophenylamine; 2-methyl-5-nitroaniline	99-55-8	C₇H₈N₂O₂	详情	详情
(II)	47517	N-(2-methyl-5-nitrophenyl)guanidine	152460-07-6	C₈H₁₀N₄O₂	详情	详情
(III)	47516	(E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one	123367-26-0	C₁₀H₁₂N₂O	详情	详情
(IV)	47519	N-(2-methyl-5-nitrophenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine; N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidinamine	152460-09-8	C₁₆H₁₃N₅O₂	详情	详情
(V)	47520	4-methyl-N(3)-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine; N-(5-amino-2-methylphenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine	152460-10-1	C₁₆H₁₅N₅	详情	详情
(VI)	49112	4-(Chloromethyl)benzoyl chloride; p-(Chloromethyl)benzoyl chloride	876-08-4	C₈H₆Cl₂O	详情	详情
(VII)	66476	4-(chloromethyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide	404844-11-7	C₂₄H₂₀ClN₅O	详情	详情
(VIII)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情

合成路线2

参考文献中间体

【1】 Kompella A, Bhujanga Rao AKS, Venkaiah Chowdary N, et aL 2004. Process for the preparation of the anti-cancer drug imatinib and its analogs via aminolysis of a (chloromethyl benzamide intermediate. WO 2004108699(本专利申请人为: Natco Pharma Limited, India)
【2】 Szczepek W, Luniewski W, Kaczmarek L, et aL 2006.A process for preparation of imatinib base. W0 2006071130(本专利申请人为: Instytut Farmaceutyczny, Pol)
【3】 Szakacs Z,Beni S,VargaZ,et aL 2005. Acid-base profiling of imatinib(gleevec) and its fragments. J Med Chem,8(1): 249一255
【4】 Zimmermann J.Buchdunger E, Mett H, et aL 1997. Potent and selective inhibitors of the abl-kinase: phenylaminopyrimidine (PAP) derivatives. Bioorg Med Chem Lett,7(2): 187～191

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)	12027	1-(3-Pyridinyl)-1-ethanone; 1-(3-Pyridinyl)ethanone	350-03-8	C₇H₇NO	详情	详情
(II)	11984	N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal	4637-24-5	C₅H₁₃NO₂	详情	详情
(III)	47516	(E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one	123367-26-0	C₁₀H₁₂N₂O	详情	详情

合成路线3

参考文献中间体

【1】 Huang AL,Xing L.Zelikovitch L,et al.2006.Multi-step process for preparing imatinib. US 2006149061.

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)	47518	2-Amino-4-nitrotoluene; 5-Nitro-o-toluidine; 4-Nitro-2-aminotoluene; 2-methyl-5-nitrophenylamine; 2-methyl-5-nitroaniline	99-55-8	C₇H₈N₂O₂	详情	详情
(II)	66477	4-(3-Pyridyl)-2-chloropyrimidine;2-Chloro-4-(3-pyridyl)pyrimidine;2-Chloro-4-(pyridin-3-yl)pyrimidine	483324-01-2	C₉H₆ClN₃	详情	详情
(III)	47519	N-(2-methyl-5-nitrophenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine; N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidinamine	152460-09-8	C₁₆H₁₃N₅O₂	详情	详情
(IV)	47520	4-methyl-N(3)-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine; N-(5-amino-2-methylphenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine	152460-10-1	C₁₆H₁₅N₅	详情	详情
(V)	47521	4-[(4-methyl-1-piperazinyl)methyl]benzoyl chloride	148077-69-4	C₁₃H₁₇ClN₂O	详情	详情

合成路线4

参考文献中间体

【1】 Kompella A, Bhujanga Rao AKS, Venkaiah Chowdary N, et aL 2004. Process for the preparation of the anti-cancer drug imatinib and its analogs via aminolysis of a (chloromethyl benzamide intermediate. WO 2004108699(本专利申请人为: Natco Pharma Limited, India)
【2】 Szczepek W, Luniewski W, Kaczmarek L, et aL 2006.A process for preparation of imatinib base. W0 2006071130(本专利申请人为: Instytut Farmaceutyczny, Pol)
【3】 Szakacs Z,Beni S,VargaZ,et aL 2005. Acid-base profiling of imatinib(gleevec) and its fragments. J Med Chem,8(1): 249一255
【4】 Zimmermann J.Buchdunger E, Mett H, et aL 1997. Potent and selective inhibitors of the abl-kinase: phenylaminopyrimidine (PAP) derivatives. Bioorg Med Chem Lett,7(2): 187～191

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)	12027	1-(3-Pyridinyl)-1-ethanone; 1-(3-Pyridinyl)ethanone	350-03-8	C₇H₇NO	详情	详情
(III)	47516	(E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one	123367-26-0	C₁₀H₁₂N₂O	详情	详情

合成路线5

The condensation of 1-(3-pyridyl)ethanone (I) with dimethylformamide dimethylacetal (II) gives 3-(dimethylamino)-1-(3-pyridyl)-2-propen-1-one (III), which is cyclized with 1-(2-methyl-5-nitrophenyl)guanidine (IV) [obtained by reaction of 2-methyl-5-nitroaniline (V) with cyanamide (VI)] in refluxing isopropanol to yield the pyrimidine derivative (VII). Reduction of the nitro group of (VII) with H2 over Pd/C in THF affords the corresponding amino compound (VIII), which is finally condensed with 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride (IV) in pyridine.

参考文献中间体

【1】 Castaner, J.; Fernandez, R.; de Bree, F.; Sorbera, L.A.; Imatinib Mesilate. Drugs Fut 2001, 26, 6, 545.
【2】 Buchdunger, E.; Mett, H.; Meyer, T.; Lydon, N.B.; Zimmermann, J.; Potent and selective inhibitors of the Abl-kinase: Phenylaminopyrimidine (PAP) derivatives. Bioorg Med Chem Lett 1997, 7, 2, 187.
【3】 Zimmermann, J. (Novartis AG); Pyrimidine derivs. and process for their preparation. EP 0564409; JP 1994087834; US 5521184 .

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)	12027	1-(3-Pyridinyl)-1-ethanone; 1-(3-Pyridinyl)ethanone	350-03-8	C₇H₇NO	详情	详情
(II)	11984	N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal	4637-24-5	C₅H₁₃NO₂	详情	详情
(III)	47516	(E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one	123367-26-0	C₁₀H₁₂N₂O	详情	详情
(IV)	47517	N-(2-methyl-5-nitrophenyl)guanidine	152460-07-6	C₈H₁₀N₄O₂	详情	详情
(V)	47518	2-Amino-4-nitrotoluene; 5-Nitro-o-toluidine; 4-Nitro-2-aminotoluene; 2-methyl-5-nitrophenylamine; 2-methyl-5-nitroaniline	99-55-8	C₇H₈N₂O₂	详情	详情
(VI)	19648	Cyanamide	420-04-2	CH₂N₂	详情	详情
(VII)	47519	N-(2-methyl-5-nitrophenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine; N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidinamine	152460-09-8	C₁₆H₁₃N₅O₂	详情	详情
(VIII)	47520	4-methyl-N(3)-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine; N-(5-amino-2-methylphenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine	152460-10-1	C₁₆H₁₅N₅	详情	详情
(IX)	47521	4-[(4-methyl-1-piperazinyl)methyl]benzoyl chloride	148077-69-4	C₁₃H₁₇ClN₂O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)