Gefitinib, ZD-1839, Iressa, -Drug Synthesis Database

【结构式】

【药物名称】Gefitinib, ZD-1839, Iressa

【化学名称】4-(3-Chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline

【CA登记号】184475-35-2, 184475-56-7 (diHCl), 184475-55-6 (mono HCl salt)

【分子式】C₂₂H₂₄ClFN₄O₃

【分子量】446.91298

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

【药理作用】Astrocytoma Therapy, Bladder Cancer Therapy , Brain Cancer Therapy, Breast Cancer Therapy, Colorectal Cancer Therapy, Gastric Cancer Therapy, Glioblastoma MultiformeTherapy, Head and Neck Cancer Therapy, Liver Cancer Therapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Prostate Cancer Therapy, Solid Tumors Therapy, Squamous Cell Carcinoma Therapy, EGFR (erbB1) Inhibitors, Inhibitors of Signal Transduction Pathways, Tyrphostins

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6 合成路线7 合成路线8

合成路线1

Monodemethylation of 6,7-dimethoxyquinazolin-4(3H)-one (I) in refluxing methanesulfonic acid in the presence of L-methionine provides 6-hydroxy-7-methoxyquinazolin-4(3H)-one (II), which is acetylated with acetic anhydride and pyridine at 100 C to give the acetate (III). Treatment of compound (III) with refluxing SOCl2 and a catalytic amount of DMF yields chloride (IV), which by condensation with 3-chloro-4-fluoroaniline (V) in boiling isopropanol affords the anilinoquinazoline (VI). Hydrolysis of the acetate group of (VI) by treatment with NH4OH in refluxing MeOH gives the 6-hydroxyquinazoline derivative (VII), which finally is alkylated with 3-(4-morpholinyl)-propyl chloride (VIII) or 3-(4-morpholinyl)propyl bromide (IX).

参考文献中间体

【1】 Gibson, K.H.; Grundy, W.; Barker, A.J.; et al.; Studies leading to the identification of ZD1839 (Iressa(TM)): An orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett 2001, 11, 14, 1911.
【2】 D'Souza, N.; Castañer, J.; Levin, M.; Iressa. Drugs Fut 2002, 27, 4, 339.
【3】 Gibson, K.H. (AstraZeneca plc); Quinazoline derivs.. EP 0823900; JP 1999504033; US 5770599; WO 9633980 .

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)	18684	6,7-dimethoxy-4(3H)-quinazolinone	13794-72-4	C₁₀H₁₀N₂O₃	详情	详情
(II)	18685	6-hydroxy-7-methoxy-4(3H)-quinazolinone	179688-52-9	C₉H₈N₂O₃	详情	详情
(III)	18686	7-methoxy-4-oxo-3,4-dihydro-6-quinazolinyl acetate	179688-53-0	C₁₁H₁₀N₂O₄	详情	详情
(IV)	18687	4-chloro-7-methoxy-6-quinazolinyl acetate	230955-75-6	C₁₁H₉ClN₂O₃	详情	详情
(V)	18688	3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline	367-21-5	C₆H₅ClFN	详情	详情
(VI)	18689	4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinyl acetate	788136-89-0	C₁₇H₁₃ClFN₃O₃	详情	详情
(VII)	18690	4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinol	184475-71-6	C₁₅H₁₁ClFN₃O₂	详情	详情
(VIII)	18691	4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine	7357-67-7	C₇H₁₄ClNO	详情	详情
(IX)	52653	4-(3-bromopropyl)morpholine	125422-83-5	C₇H₁₄BrNO	详情	详情

合成路线2

参考文献中间体

【1】 Welham MJ．2005．Process for the manufacture。gefitinib. W0 2005023783（本专利为AstraZeneca plc所有）

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)	18455	3-hydroxy-4-methoxybenzaldehyde; Isovanillin	621-59-0	C₈H₈O₃	详情	详情
(II)	54574	3-hydroxy-4-methoxybenzonitrile	52805-46-6	C₈H₇NO₂	详情	详情
(III)	66433	4-methoxy-3-(3-morpholinopropoxy)benzonitrile		C₁₅H₂₀N₂O₃	详情	详情
(IV)	66434	4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile	675126-26-8	C₁₅H₁₉N₃O₅	详情	详情
(V)	66435	2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile	675126-27-9	C₁₅H₂₁N₃O₃	详情	详情
(VI)	66436	(E)-N,N'-bis(3-chloro-4-fluorophenyl)formimidamide		C₁₃H₈Cl₂F₂N₂	详情	详情

合成路线3

参考文献中间体

【1】 Welham MJ．2005．Process for the manufacture。gefitinib. W0 2005023783（本专利为AstraZeneca plc所有）

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	66436	(E)-N,N'-bis(3-chloro-4-fluorophenyl)formimidamide		C₁₃H₈Cl₂F₂N₂	详情	详情
(VIII)	18688	3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline	367-21-5	C₆H₅ClFN	详情	详情

合成路线4

参考文献中间体

【1】 Jyothi Prasad R. 2005. An improved process for the preparation of gefitinib. WO2005023783(本专利为Natco Pharma Ltd所有）

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)	18455	3-hydroxy-4-methoxybenzaldehyde; Isovanillin	621-59-0	C₈H₈O₃	详情	详情
(II)	66437	4-methoxy-3-(3-morpholinopropoxy)benzaldehyde	861453-11-4	C₁₅H₂₁NO₄	详情	详情
(III)	66438	4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzaldehyde		C₁₅H₂₀N₂O₆	详情	详情
(IV)	66439	(Z)-4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzaldehyde oxime		C₁₅H₂₁N₃O₆	详情	详情
(V)	66434	4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile	675126-26-8	C₁₅H₁₉N₃O₅	详情	详情
(VI)	66440	4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzamide		C₁₅H₂₁N₃O₆	详情	详情
(VII)	66441	2-amino-4-methoxy-5-(3-morpholinopropoxy)benzamide		C₁₅H₂₃N₃O₄	详情	详情
(VIII)	66442	7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one		C₁₆H₂₁N₃O₄	详情	详情
(IX)	66443	4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine		C₁₆H₂₀ClN₃O₃	详情	详情
(X)	18688	3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline	367-21-5	C₆H₅ClFN	详情	详情

合成路线5

参考文献中间体

【1】 Chandregowda V,Rao GV, Reddy GC. 2007. One-pot conversion of 2-nitrobenzonitriles to quinazolin-4(3H)-ones and synthesis of gefitinib and erlotinib hydrochloride. Heterocycles,71(1): 39~48

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)	18455	3-hydroxy-4-methoxybenzaldehyde; Isovanillin	621-59-0	C₈H₈O₃	详情	详情
(II)	18691	4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine	7357-67-7	C₇H₁₄ClNO	详情	详情
(III)	66437	4-methoxy-3-(3-morpholinopropoxy)benzaldehyde	861453-11-4	C₁₅H₂₁NO₄	详情	详情
(IV)	66444	(Z)-4-methoxy-3-(3-morpholinopropoxy)benzaldehyde oxime		C₁₅H₂₂N₂O₄	详情	详情
(V)	66433	4-methoxy-3-(3-morpholinopropoxy)benzonitrile		C₁₅H₂₀N₂O₃	详情	详情
(VI)	66434	4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile	675126-26-8	C₁₅H₁₉N₃O₅	详情	详情
(VII)	66445	7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(1H)-one		C₁₆H₂₁N₃O₄	详情	详情
(VIII)	18688	3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline	367-21-5	C₆H₅ClFN	详情	详情

合成路线6

参考文献中间体

【1】 Knesl P.Roeseling D,Jordis U 2006. Improved synthesis of substituted 6,7-rdihydroxy-4iuinazolinearninest: tandutinib, erlotinib and gefitinib. Molecules, 11(4):286~297

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)	65853	5-Hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one; 5-Hydroxy-7-methoxy-3H-quinazolin-4-one		C₉H₈N₂O₃	详情	详情
(II)	66446	7-methoxy-4-oxo-1,4-dihydroquinazolin-6-yl acetate		C₁₁H₁₀N₂O₄	详情	详情
(III)	18687	4-chloro-7-methoxy-6-quinazolinyl acetate	230955-75-6	C₁₁H₉ClN₂O₃	详情	详情
(IV)	18688	3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline	367-21-5	C₆H₅ClFN	详情	详情
(V)	66447	4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate hydrochloride;6-Acetoxy-4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride	184475-70-5	C₁₇H₁₃ClFN₃O₃.HCl	详情	详情
(VI)	18690	4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinol	184475-71-6	C₁₅H₁₁ClFN₃O₂	详情	详情
(VII)	18691	4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine	7357-67-7	C₇H₁₄ClNO	详情	详情

合成路线7

参考文献中间体

【1】 Wang JQ, Gao MZ, Miller KD, et al.2006. Synthesis of (11 C) iressa as a new potential PET cancer imaging agent for epidermal growth factor receptor tyrosine kinase. Bioorg Med Chem Lett, 16 (15): 4102~4106

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)	54574	3-hydroxy-4-methoxybenzonitrile	52805-46-6	C₈H₇NO₂	详情	详情
(II)	18691	4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine	7357-67-7	C₇H₁₄ClNO	详情	详情
(III)	66433	4-methoxy-3-(3-morpholinopropoxy)benzonitrile		C₁₅H₂₀N₂O₃	详情	详情
(IV)	66434	4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile	675126-26-8	C₁₅H₁₉N₃O₅	详情	详情
(V)	66435	2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile	675126-27-9	C₁₅H₂₁N₃O₃	详情	详情
(VI)	66441	2-amino-4-methoxy-5-(3-morpholinopropoxy)benzamide		C₁₅H₂₃N₃O₄	详情	详情
(VII)	66445	7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(1H)-one		C₁₆H₂₁N₃O₄	详情	详情
(VIII)	66443	4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine		C₁₆H₂₀ClN₃O₃	详情	详情
(IX)	18688	3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline	367-21-5	C₆H₅ClFN	详情	详情
(X)	66448	4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-ol	847949-49-9	C₂₁H₂₂ClFN₄O₃	详情	详情

合成路线8

参考文献中间体

【1】 Zhu CQ, Chi YS, Deng, YL,et aL 2006.Process for preparation of 4-(3’-chloro-4'-fluoroanilino)-7-methoxy6-(3-morpholinopropoxy) quinazoline.发明专利申请公开说明书，CN 1733738

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)	13439	3,4-Dimethoxybenzoic acid	93-07-2	C₉H₁₀O₄	详情	详情
(II)	31789	4,5-dimethoxy-2-nitrobenzoic acid	4998-07-6	C₉H₉NO₆	详情	详情
(III)	66449	2-amino-5-hydroxy-4-methoxybenzoic acid		C₈H₉NO₄	详情	详情
(IV)	66450	6-hydroxy-7-methoxyquinazolin-4(1H)-one		C₉H₈N₂O₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)