5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydro-7-quinazolinyl trifluoromethanesulfonate -Drug Synthesis Database

【结构式】

【分子编号】63190

【品名】5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydro-7-quinazolinyl trifluoromethanesulfonate

【CA登记号】

【分子式】C₂₁H₁₁Cl₃F₄N₂O₄S

【分子量】569.7471328

【元素组成】C 44.27% H 1.95% Cl 18.67% F 13.34% N 4.92% O 11.23% S 5.63%

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：(XIII)

Radical bromination of 2,6-dibromo-4-methoxytoluene (I) affords the benzylic bromide (II), which is subsequently condensed with p-methoxybenzylamine (III) to produce the bis-benzyl amine derivative (IV). Coupling of amine (IV) with 2,6-dichlorophenyl isocyanate (V) furnishes urea (VI). Intramolecular cyclization of (VI) in the presence of K2CO3 and CuI leads to quinazolinone (VII). The p-methoxybenzyl protecting group is then removed by refluxing in trifluoroacetic acid to provide (VIII). Transmetalation of 2-chloro-4-fluoro-1-iodobenzene (IX) with isopropylmagnesium chloride, followed by condensation with trimethyl borate results in the boronic acid (X). Then, Suzuki coupling of (X) with aryl bromide (VIII) furnishes (XI). The methyl ether group of (XI) is cleaved by means of BBr3 to yield phenol (XII), which is further converted into triflate (XIII) upon treatment with either N-phenyl trifluoromethanesulfonimide or with N-(5-chloro-2-pyridyl) trifluoromethanesulfonimide.

参考文献中间体

合成目标

【1】 Stelmach, J.E.; Liu, L.; Patel, S.B.; Pivnichny, J.V.; Scapin, G.; Singh, S.; Hop, C.E.C.A.; Wang, Z.; Strauss, J.R.; Cameron, P.M.; Nichols, E.A.; O'Keefe, S.J.; O'Neill, E.A.; Schmatz, D.M.; Schwartz, C.D.; Thompson, C.M.; Zaller, D.M.; Doherty, J.B.; Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase. Bioorg Med Chem Lett 2003, 13, 2, 277.
【2】 Doherty, J.B.; Rupprecht, K.M.; Goulet, J.L.; Chen, M.-H.; Bao, J.; Liu, L.; Miao, S.; Hunt, J.A.; Hong, X.; Stelmach, J.E.; Ruzek, R.D.; Wisnoski, D.D.; Natarajan, S.R. (Merck & Co., Inc.); (Halo-benzo carbonyl)heterocyclic fused phenyl p38 kinase inhibiting agents. EP 1345603; WO 0258695 .

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)	63179	3,5-dibromo-4-methylphenyl methyl ether; 1,3-dibromo-5-methoxy-2-methylbenzene		C₈H₈Br₂O	详情	详情
(II)	63180	1,3-dibromo-2-(bromomethyl)-5-methoxybenzene; 3,5-dibromo-4-(bromomethyl)phenyl methyl ether		C₈H₇Br₃O	详情	详情
(III)	15098	4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine	2393-23-9	C₈H₁₁NO	详情	详情
(IV)	63181	N-(2,6-dibromo-4-methoxybenzyl)(4-methoxyphenyl)methanamine; N-(2,6-dibromo-4-methoxybenzyl)-N-(4-methoxybenzyl)amine		C₁₆H₁₇Br₂NO₂	详情	详情
(V)	63182	2,6-dichlorophenyl isocyanate; 1,3-dichloro-2-isocyanatobenzene		C₇H₃Cl₂NO	详情	详情
(VI)	63183	N-(2,6-dibromo-4-methoxybenzyl)-N'-(2,6-dichlorophenyl)-N-(4-methoxybenzyl)urea		C₂₃H₂₀Br₂Cl₂N₂O₃	详情	详情
(VII)	63184	5-bromo-1-(2,6-dichlorophenyl)-7-methoxy-3-(4-methoxybenzyl)-3,4-dihydro-2(1H)-quinazolinone		C₂₃H₁₉BrCl₂N₂O₃	详情	详情
(VIII)	63185	5-bromo-1-(2,6-dichlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinazolinone		C₁₅H₁₁BrCl₂N₂O₂	详情	详情
(IX)	63186	2-chloro-4-fluoro-1-iodobenzene		C₆H₃ClFI	详情	详情
(X)	63187	2-chloro-4-fluorophenylboronic acid		C₆H₅BClFO₂	详情	详情
(XI)	63188	5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinazolinone		C₂₁H₁₄Cl₃FN₂O₂	详情	详情
(XII)	63189	5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-hydroxy-3,4-dihydro-2(1H)-quinazolinone		C₂₀H₁₂Cl₃FN₂O₂	详情	详情
(XIII)	63190	5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydro-7-quinazolinyl trifluoromethanesulfonate		C₂₁H₁₁Cl₃F₄N₂O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

Quaternization of 1-ethyl-4-piperidone (XIV) with methyl iodide provides the ammonium salt (XV) which, upon treatment with tert-butylamine and NaHCO3, gives rise to 1-tert-butyl-4-piperidone (XVI). The reaction of 1-tert-butyl-4-piperidone (XVI) firstly with LiN(SiMe3)2 and subsequently with N-(5-chloro-2-pyridyl) trifluoromethanesulfonimide [(Tf)2NPyr] in THF provides the enol triflate (XVII). Reaction of triflate (XVII) with hexamethylditin in the presence of palladium catalyst furnishes 1-tert-butyl-4-(trimethylstannyl)-1,2,3,6-tetrahydropyridine (XVIII). Stille coupling between the quinazolinyl triflate (XIII) and the stannyl tetrahydropyridine (XVIII) produces adduct (XIX). Finally, hydrogenation of the tetrahydropyridine double bond of (XIX) using PtO2 as the catalyst leads to the target piperidinyl compound.

参考文献中间体

合成目标

【1】 Stelmach, J.E.; Liu, L.; Patel, S.B.; Pivnichny, J.V.; Scapin, G.; Singh, S.; Hop, C.E.C.A.; Wang, Z.; Strauss, J.R.; Cameron, P.M.; Nichols, E.A.; O'Keefe, S.J.; O'Neill, E.A.; Schmatz, D.M.; Schwartz, C.D.; Thompson, C.M.; Zaller, D.M.; Doherty, J.B.; Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase. Bioorg Med Chem Lett 2003, 13, 2, 277.
【2】 Doherty, J.B.; Rupprecht, K.M.; Goulet, J.L.; Chen, M.-H.; Bao, J.; Liu, L.; Miao, S.; Hunt, J.A.; Hong, X.; Stelmach, J.E.; Ruzek, R.D.; Wisnoski, D.D.; Natarajan, S.R. (Merck & Co., Inc.); (Halo-benzo carbonyl)heterocyclic fused phenyl p38 kinase inhibiting agents. EP 1345603; WO 0258695 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	63190	5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydro-7-quinazolinyl trifluoromethanesulfonate		C₂₁H₁₁Cl₃F₄N₂O₄S	详情	详情
(XIV)	28868	1-ethyl-4-piperidinone; N-ethyl-4-piperidinone	3612-18-8	C₇H₁₃NO	详情	详情
(XV)	51994	1-ethyl-1-methyl-4-oxopiperidinium iodide		C₈H₁₆INO	详情	详情
(XVI)	24875	1-(tert-butyl)-4-piperidinone; N-(tert-butyl)-4-piperidinone		C₉H₁₇NO	详情	详情
(XVII)	63191	1-(tert-butyl)-1,2,3,6-tetrahydro-4-pyridinyl trifluoromethanesulfonate		C₁₀H₁₆F₃NO₃S	详情	详情
(XVIII)	63192	1-(tert-butyl)-4-(trimethylstannyl)-1,2,3,6-tetrahydropyridine		C₁₂H₂₅NSn	详情	详情
(XIX)	63193	7-[1-(tert-butyl)-1,2,3,6-tetrahydro-4-pyridinyl]-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-2(1H)-quinazolinone		C₂₉H₂₇Cl₃FN₃O	详情	详情

Extended Information