2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide -Drug Synthesis Database

【结构式】

【分子编号】18600

【品名】2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide

【CA登记号】

【分子式】C₂₀H₁₉Cl₂N₃O₂

【分子量】404.29528

【元素组成】C 59.42% H 4.74% Cl 17.54% N 10.39% O 7.91%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(VIII)

The condensation of 2-methylquinolin-8-ol (I) with 2,6-dichloro-3-nitrobenzyl chloride (II) by means of NaH in DMF gives the corresponding benzyl ether (III), which is reduced with Fe and HCl in methanol/water to the aniline (IV). The acylation of (IV) with 2-phthalimidoacetyl chloride (V) by means of DMAP and pyridine yields the amide (VI), which is methylated at the amidic nitrogen with NaH and methyl iodide in DMF to the N-methylanilide (VII). Elimination of the phthalimido group of (VII) with hydrazine in refluxing ethanol affords the glycine anilide (VIII), which is acylated with the acrylic acid (IX) by means of 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide (DECD) and HOBT in DMF. The intermediate substituted acrylic acid (IX) has been obtained by reaction of 6-acetamidopyridine-3-carbaldehyde (X) with malonic acid and pyridine in refluxing ethanol.

参考文献中间体

合成目标

【1】 Oku, T.; Kayakiri, H.; Satoh, S.; Abe, Y.; Sawada, Y.; Inoue, T.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Pyridopyrimidones, quinolines and fused N-heterocycles as bradykinin antagonists. EP 0807105; JP 1998507764; WO 9613485 .

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)	18598	2-methyl-8-quinolinol	826-81-3	C₁₀H₉NO	详情	详情
(II)	18928	1,3-dichloro-2-(chloromethyl)-4-nitrobenzene		C₇H₄Cl₃NO₂	详情	详情
(III)	18929	2,6-dichloro-3-nitrobenzyl 2-methyl-8-quinolinyl ether; 8-[(2,6-dichloro-3-nitrobenzyl)oxy]-2-methylquinoline		C₁₇H₁₂Cl₂N₂O₃	详情	详情
(IV)	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
(V)	10278	2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride	6780-38-7	C₁₀H₆ClNO₃	详情	详情
(VI)	18932	N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetamide		C₂₇H₁₉Cl₂N₃O₄	详情	详情
(VII)	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
(VIII)	18600	2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide		C₂₀H₁₉Cl₂N₃O₂	详情	详情
(IX)	19304	(E)-3-[6-(acetamido)-3-pyridinyl]-2-propenoic acid		C₁₀H₁₀N₂O₃	详情	详情
(X)	26413	N-(5-formyl-2-pyridinyl)acetamide		C₈H₈N₂O₂	详情	详情
(XI)	12963	Malonic acid	141-82-2	C₃H₄O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

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3

该中间体在本合成路线中的序号：(XI)

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

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
(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

合成路线4

该中间体在本合成路线中的序号：(XIII)

The target FR-165649 has been obtained by condensation of cinnamic acid (V) with amine (XIII) using EDC and HOBt as coupling agents. The two intermediates (V) and (XIII) have been obtained as follows: 1) Wittig reaction of 4-formylbenzoic acid (I) and methyl (triphenylphosphoranylidene)acetate (II) in THF gave methyl 4-carboxycinnamate (III), which was converted into amide (IV) by reaction with methylamine hydrochloride in the presence of EDC and HOBt. Further hydrolysis of the ester group with NaOH provided 4-(methylcarbamoyl)cinnamic acid (V). 2) The alkylation of 8-hydroxy-2-methylquinoline (VI) with benzylic chloride (VII) in the presence of NaH and a catalytic amount of tetrabutylammonium iodide in DMF afforded ether (VIII). Subsequent reduction of the nitro group with iron powder and HCl in refluxing aqueous methanol gave amine (IX), which was coupled with phthalimidoacetyl chloride (X) in the presence of DMAP in a mixture of N-methylpyrrolidone and pyridine to yield amide (XI). Then, alkylation at the amide N with CH3I and NaH provided (XII), and further hydrazinolysis of the phthalimido group yielded the primary amine (XIII). Finally, the target amide was obtained by condensation of cinnamic acid (V) with amine (XIII) using EDC and HOBt as the coupling reagents.

参考文献中间体

合成目标

【1】 Oku, T.; Kayakiri, H.; Satoh, S.; Abe, Y.; Sawada, Y.; Inoue, T.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Pyridopyrimidones, quinolines and fused N-heterocycles as bradykinin antagonists. EP 0807105; JP 1998507764; WO 9613485 .

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)	18922	4-formylbenzoic acid	619-66-9	C₈H₆O₃	详情	详情
(II)	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(III)	18924	4-[(E)-3-methoxy-3-oxo-1-propenyl]benzoic acid		C₁₁H₁₀O₄	详情	详情
(IV)	18925	methyl (E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoate		C₁₂H₁₃NO₃	详情	详情
(V)	18926	(E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoic acid		C₁₁H₁₁NO₃	详情	详情
(VI)	18598	2-methyl-8-quinolinol	826-81-3	C₁₀H₉NO	详情	详情
(VII)	18928	1,3-dichloro-2-(chloromethyl)-4-nitrobenzene		C₇H₄Cl₃NO₂	详情	详情
(VIII)	18929	2,6-dichloro-3-nitrobenzyl 2-methyl-8-quinolinyl ether; 8-[(2,6-dichloro-3-nitrobenzyl)oxy]-2-methylquinoline		C₁₇H₁₂Cl₂N₂O₃	详情	详情
(IX)	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
(X)	10278	2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride	6780-38-7	C₁₀H₆ClNO₃	详情	详情
(XI)	18932	N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetamide		C₂₇H₁₉Cl₂N₃O₄	详情	详情
(XII)	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
(XIII)	18600	2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide		C₂₀H₁₉Cl₂N₃O₂	详情	详情

Extended Information