(2,6-dichloro-3-nitrophenyl)methanol -Drug Synthesis Database

【结构式】

【分子编号】18590

【品名】(2,6-dichloro-3-nitrophenyl)methanol

【CA登记号】

【分子式】C₇H₅Cl₂NO₃

【分子量】222.02704

【元素组成】C 37.87% H 2.27% Cl 31.94% N 6.31% O 21.62%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

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

合成目标

【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

该中间体在本合成路线中的序号：(I)

Benzyl alcohol (I) was treated with mesyl chloride and triethylamine in CH2Cl2 at 0 C, and the resulting mesylate (II) was subsequently coupled with 2-methyl-8-hydroxyquinoline (III) in the presence of NaH to afford ether (IV). Reduction of the nitro group of (IV) with hydrazine in the presence of FeCl3 and carbon gave aniline (V). Pyrrole (VII) was then obtained by heating (V) with 2,5-dimethoxy tetrahydrofuran (VI) in AcOH. Further reaction of (VII) with chlorosulfonylisocyanate (VIII) at low temperature provided the 2-cyanopyrrole (IX). The cyano group of (IX) was reduced with LiAlH4 to give amine (X). This was finally condensed with pyridinylacrylic acid (XI) using EDC and HOBt to yield the target amide, which was isolated as the dihydrochloride salt.

参考文献中间体

合成目标

【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. 4. Discovery of novel frameworks mimicking the active conformation. J Med Chem 1998, 41, 23, 4587.

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)	19295	2,6-dichloro-3-nitrobenzyl methanesulfonate		C₈H₇Cl₂NO₅S	详情	详情
(III)	18598	2-methyl-8-quinolinol	826-81-3	C₁₀H₉NO	详情	详情
(IV)	18926	(E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoic acid		C₁₁H₁₁NO₃	详情	详情
(V)	18930	2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenylamine; 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]aniline		C₁₇H₁₄Cl₂N₂O	详情	详情
(VI)	12132	2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether	696-59-3	C₆H₁₂O₃	详情	详情
(VII)	19300	2,6-dichloro-3-(1H-pyrrol-1-yl)benzyl 2-methyl-8-quinolinyl ether; 8-[[2,6-dichloro-3-(1H-pyrrol-1-yl)benzyl]oxy]-2-methylquinoline		C₂₁H₁₆Cl₂N₂O	详情	详情
(VIII)	14010	ethyl 5-(2-chlorophenyl)-2-hydrazino-3,6,7,9-tetrahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate		C₁₉H₂₀ClN₅O₂S	详情	详情
(IX)	19302	1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrole-2-carbonitrile		C₂₂H₁₅Cl₂N₃O	详情	详情
(X)	19303	[1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrol-2-yl]methanamine; [1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrol-2-yl]methylamine		C₂₂H₁₉Cl₂N₃O	详情	详情
(XI)	19304	(E)-3-[6-(acetamido)-3-pyridinyl]-2-propenoic acid		C₁₀H₁₀N₂O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

Nitration of 2,6-dichlorobenzaldehyde (I) with 70% HNO3 in concentrated H2SO4 at ice-bath temperature provided the 3-nitro derivative (II). This was reduced with NaBH4 in MeOH at 10 C to the alcohol (III), which was treated with mesyl chloride and triethylamine in dichloromethane to give mesylate (IV). Alkylation of 5-hydroxyisoquinoline (V) with mesylate (IV) in the presence of NaH in DMF yielded ether (VI). Subsequent reduction of the nitro group of (VI) with hydrazine and FeCl3 provided amine (VII), which was finally acylated with Ac2O in dichloroethane at 70 C to furnish the target acetamide.

参考文献中间体

合成目标

【1】 Satoh, S.; Kayakiri, H.; Abe, Y.; et al.; A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 1. Construction of the basic framework. J Med Chem 1998, 41, 4, 564.
【2】 Yoshida, Y.; Barrett, D.; Azami, H.; Morinaga, C.; Matsumoto, Y.; Takasugi, H.; Discovery of a novel benzyloxyisoquinoline derivative with potent anti-Helicobacter pylori activity. Bioorg Med Chem Lett 1998, 8, 14, 1897.

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)	27507	2,6-dichlorobenzaldehyde	83-38-5	C₇H₄Cl₂O	详情	详情
(II)	27508	2,6-dichloro-3-nitrobenzaldehyde		C₇H₃Cl₂NO₃	详情	详情
(III)	18590	(2,6-dichloro-3-nitrophenyl)methanol		C₇H₅Cl₂NO₃	详情	详情
(IV)	19295	2,6-dichloro-3-nitrobenzyl methanesulfonate		C₈H₇Cl₂NO₅S	详情	详情
(V)	18668	5-isoquinolinol	2439-04-5	C₉H₇NO	详情	详情
(VI)	27509	2,6-dichloro-3-nitrobenzyl 5-isoquinolinyl ether		C₁₆H₁₀Cl₂N₂O₃	详情	详情
(VII)	27510	2,4-dichloro-3-[(5-isoquinolinyloxy)methyl]aniline		C₁₆H₁₂Cl₂N₂O	详情	详情

Extended Information