AZD-6474, ZD-6474, -Drug Synthesis Database

【结构式】

【药物名称】AZD-6474, ZD-6474

【化学名称】N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazolin-4-amine

【CA登记号】338992-00-0, 338992-48-6 (HCl), 338992-53-3 (monotrifluoroacetate)

【分子式】C₂₂H₂₄BrFN₄O₂

【分子量】475.36458

【开发单位】AstraZeneca (Originator)

【药理作用】Breast Cancer Therapy, Lung Cancer Therapy, Oncolytic Drugs, Solid Tumors Therapy, Angiogenesis Inhibitors, EGFR (erbB1) Inhibitors, Inhibitors of Signal Transduction Pathways, Tyrphostins, VEGFR-2 (FLK-1/KDR) Inhibitors, VEGFR-3 (FLT4) Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

Ethyl isonipecotate (I) was protected as the N-Boc derivative (II) and then reduced to alcohol (III) using LiAlH4. Treatment of alcohol (III) with p-toluenesulfonyl chloride in the presence of DBU afforded the intermediate tosylate (IV).

参考文献中间体

【1】 Hennequin, L.F.A.; Stokes, E.S.E.; Thomas, A.P. (AstraZeneca AB; AstraZeneca plc); Quinazoline derivs. as VEGF inhibitors. WO 0132651 .

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)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(II)	49847	1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine	142851-03-4	C₁₃H₂₃NO₄	详情	详情
(III)	40399	tert-butyl 4-(hydroxymethyl)-1-piperidinecarboxylate		C₁₁H₂₁NO₃	详情	详情
(IV)	49848	tert-butyl 4-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-piperidinecarboxylate		C₁₈H₂₇NO₅S	详情	详情

合成路线2

Nucleophilic substitution of the chloroquinazoline (V) with 4-bromo-2-fluoroaniline (VI) in refluxing isopropanol provided the anilino quinazoline (VII). Subsequent cleavage of the benzyl ether group of (VII) by treatment with hot trifluoroacetic acid gave phenol (VIII), which was condensed with tosylate (IV) to furnish the ether adduct (IX). Acid deprotection of the N-Boc group of (IX) gave piperidine (X). Finally, reductive methylation of (X) using formaldehyde and sodium cyanoborohydride yielded the corresponding N-methyl piperidine.

参考文献中间体

【1】 Hennequin, L.F.A.; Stokes, E.S.E.; Thomas, A.P. (AstraZeneca AB; AstraZeneca plc); Quinazoline derivs. as VEGF inhibitors. WO 0132651 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	49848	tert-butyl 4-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-piperidinecarboxylate		C₁₈H₂₇NO₅S	详情	详情
(V)	31531	benzyl 4-chloro-6-methoxy-7-quinazolinyl ether; 7-(benzyloxy)-4-chloro-6-methoxyquinazoline		C₁₆H₁₃ClN₂O₂	详情	详情
(VI)	14723	4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline	367-24-8	C₆H₅BrFN	详情	详情
(VII)	31532	7-(benzyloxy)-N-(4-bromo-2-fluorophenyl)-6-methoxy-4-quinazolinamine; N-[7-(benzyloxy)-6-methoxy-4-quinazolinyl]-N-(4-bromo-2-fluorophenyl)amine		C₂₂H₁₇BrFN₃O₂	详情	详情
(VIII)	31533	4-(4-bromo-2-fluoroanilino)-6-methoxy-7-quinazolinol		C₁₅H₁₁BrFN₃O₂	详情	详情
(IX)	49849	tert-butyl 4-([[4-(4-bromo-2-fluoroanilino)-6-methoxy-7-quinazolinyl]oxy]methyl)-1-piperidinecarboxylate		C₂₆H₃₀BrFN₄O₄	详情	详情
(X)	49850	N-(4-bromo-2-fluorophenyl)-6-methoxy-7-(4-piperidinylmethoxy)-4-quinazolinamine; N-(4-bromo-2-fluorophenyl)-N-[6-methoxy-7-(4-piperidinylmethoxy)-4-quinazolinyl]amine		C₂₁H₂₂BrFN₄O₂	详情	详情

合成路线3

The condensation of 7-hydroxy-6-methoxy-3-(pivaloyloxymethyl)quinazolin-3(4H)-one (I) with N-(tert-butoxycarbonyl)piperidine-4-methanol (II) by means of DEAD and PPh3 in dichloromethane or K2CO3 in DMF gives the aryl ether (III), which is deprotected with TFA to yield the free piperidine (IV). The reductive methylation of (IV) with HCHO and NaBH3CN in methanol/THF affords the methylated piperidine (V), which is deprotected with NH3 in methanol to provide the quinazolinone (VI). The reaction of (VI) with SOCl2 in DMF gives the 4-chloroquinazoline (VII), which is finally condensed with 4-chloro-2-fluoroaniline (VIII) by means of NaH in DMF to yield the target quinazoline-4-amine.

参考文献中间体

【1】 Hennequin, L.F.; et al.; Novel 4-anilinoquinazolines with C-7 basic side chains: Design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors. J Med Chem 2002, 45, 6, 1300.

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)	51967	[7-hydroxy-6-methoxy-4-oxo-3(4H)-quinazolinyl]methyl pivalate		C₁₅H₁₈N₂O₅	详情	详情
(II)	40399	tert-butyl 4-(hydroxymethyl)-1-piperidinecarboxylate		C₁₁H₂₁NO₃	详情	详情
(III)	51968	tert-butyl 4-[[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-6-methoxy-4-oxo-3,4-dihydro-7-quinazolinyl)oxy]methyl]-1-piperidinecarboxylate		C₂₆H₃₇N₃O₇	详情	详情
(IV)	51969	[6-methoxy-4-oxo-7-(4-piperidinylmethoxy)-3(4H)-quinazolinyl]methyl pivalate		C₂₁H₂₉N₃O₅	详情	详情
(V)	51971	[6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4-oxo-3(4H)-quinazolinyl]methyl pivalate		C₂₂H₃₁N₃O₅	详情	详情
(VI)	51970	6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4(3H)-quinazolinone		C₁₆H₂₁N₃O₃	详情	详情
(VII)	51972	4-chloro-6-methoxy-7-quinazolinyl (1-methyl-4-piperidinyl)methyl ether; 4-chloro-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]quinazoline		C₁₆H₂₀ClN₃O₂	详情	详情
(VIII)	51973	2-Fluoro-4-chloroaniline; 4-Chloro-2-fluorobenzenamine; 4-Chloro-2-fluoroaniline	57946-56-2	C₆H₅ClFN	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)