FR-184280, -Drug Synthesis Database

【结构式】

【药物名称】FR-184280

【化学名称】N-[N-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-N-methylcarbamoylmethyl]-3-[6-[2(E)-(4-pyridyl)vinyl]pyridin-3-yl]-2(E)-propenamide

【CA登记号】179623-05-3

【分子式】C₃₅H₂₉Cl₂N₅O₃

【分子量】638.55908

【开发单位】Fujisawa (Originator)

【药理作用】Asthma Therapy, Bronchodilators, RESPIRATORY DRUGS, Bradykinin B2 Antagonists

合成路线1 合成路线2

合成路线1

Protection of 2,4-dichloro-3-nitrobenzyl alcohol (I) with tert-butyldiphenylsilyl chloride (TBDPSCl) in the presence of imidazole in DMF provided silyl ether (II). Then, reduction of the nitro group with hydrazine, FeCl3, and carbon gave aniline (III), which was condensed with N-phthaloylglycyl chloride (IV) to afford glycinamide (V). Alkylation with iodomethane in the presence of NaH yielded N-methylaniline (VI) and, then, the silyl ether was deprotected with tetra-n-butylammonium fluoride to produce alcohol (VII). Treatment with methanesulfonyl chloride provided mesylate (VIII), which was coupled with quinolinol (IX) in the presence of NaH in DMF to give ether (X). Subsequent removal of the N-phthaloyl group with hydrazine hydrate yielded amine (XI).

参考文献中间体

【1】 Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Inamura, N.; Asano, M.; Aramori, I.; Hatori, C.; Sawai, H.; Oku, T.; Tanaka, H.; A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 3. Discovering bioisosteres of the imidazo[1,2-a]pyridine moiety. J Med Chem 1998, 41, 21, 4062.

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)	18590	(2,6-dichloro-3-nitrophenyl)methanol		C₇H₅Cl₂NO₃	详情	详情
(II)	18591	tert-butyl[(2,6-dichloro-3-nitrobenzyl)oxy]diphenylsilane; tert-butyl(diphenyl)silyl 2,6-dichloro-3-nitrobenzyl ether		C₂₃H₂₃Cl₂NO₃Si	详情	详情
(III)	18592	3-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2,4-dichlorophenylamine; 3-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2,4-dichloroaniline		C₂₃H₂₅Cl₂NOSi	详情	详情
(IV)	10278	2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride	6780-38-7	C₁₀H₆ClNO₃	详情	详情
(V)	18594	N-[3-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2,4-dichlorophenyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetamide		C₃₃H₃₀Cl₂N₂O₄Si	详情	详情
(VI)	18595	N-[3-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2,4-dichlorophenyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-methylacetamide		C₃₄H₃₂Cl₂N₂O₄Si	详情	详情
(VII)	18596	N-[2,4-dichloro-3-(hydroxymethyl)phenyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-methylacetamide		C₁₈H₁₄Cl₂N₂O₄	详情	详情
(VIII)	18597	2,6-dichloro-3-[[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl](methyl)amino]benzyl methanesulfonate		C₁₉H₁₆Cl₂N₂O₆S	详情	详情
(IX)	18598	2-methyl-8-quinolinol	826-81-3	C₁₀H₉NO	详情	详情
(X)	18599	N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-methylacetamide		C₂₈H₂₁Cl₂N₃O₄	详情	详情
(XI)	18600	2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide		C₂₀H₁₉Cl₂N₃O₂	详情	详情

合成路线2

Methyl 6-methylnicotinate (XII) was condensed with 4-pyridinecarboxaldehyde (XIII) in AcOH-Ac2O at 120 C to produce (XIV). Then, ester group was reduced with LiAlH4 to alcohol (XV), and this was subsequently oxidized with DMSO and SO3-pyridine complex to give aldehyde (XVI). Wittig reaction with phosphorane (XVII) afforded ester (XVIII), which was saponified to yield acid (XIX). Finally, coupling of acid (XIX) with amine (XI) in the presence of EDC and HOBt provided the title amide.

参考文献中间体

【1】 Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Inamura, N.; Asano, M.; Aramori, I.; Hatori, C.; Sawai, H.; Oku, T.; Tanaka, H.; A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 3. Discovering bioisosteres of the imidazo[1,2-a]pyridine moiety. J Med Chem 1998, 41, 21, 4062.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	18600	2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide		C₂₀H₁₉Cl₂N₃O₂	详情	详情
(XII)	14160	methyl 6-methylnicotinate	5470-70-2	C₈H₉NO₂	详情	详情
(XIII)	17203	4-Pyridinecarboxaldehyde; isonicotinaldehyde	872-85-5	C₆H₅NO	详情	详情
(XIV)	18603	methyl 6-[(E)-2-(4-pyridinyl)ethenyl]nicotinate		C₁₄H₁₂N₂O₂	详情	详情
(XV)	18604	[6-[(E)-2-(4-pyridinyl)ethenyl]-3-pyridinyl]methanol		C₁₃H₁₂N₂O	详情	详情
(XVI)	18605	6-[(E)-2-(4-pyridinyl)ethenyl]nicotinaldehyde		C₁₃H₁₀N₂O	详情	详情
(XVII)	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(XVIII)	18607	methyl (E)-3-[6-[(E)-2-(4-pyridinyl)ethenyl]-3-pyridinyl]-2-propenoate		C₁₆H₁₄N₂O₂	详情	详情
(XIX)	18608	(E)-3-[6-[(E)-2-(4-pyridinyl)ethenyl]-3-pyridinyl]-2-propenoic acid		C₁₅H₁₂N₂O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)