2-amino-1-(4-morpholinyl)-1-ethanone -Drug Synthesis Database

【结构式】

【分子编号】35094

【品名】2-amino-1-(4-morpholinyl)-1-ethanone

【CA登记号】

【分子式】C₆H₁₂N₂O₂

【分子量】144.17356

【元素组成】C 49.99% H 8.39% N 19.43% O 22.19%

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：(XIX)

Simultaneous deprotection of the benzyl ester and the N-carbobenzoxy group of (XIII) by hydrogenolysis over Pd/C gave amino acid (XIV), which was cyclized by means of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and diisopropyl ethylamine (DIEA), yielding macrocycle (XV). Cleavage of the tert-butyl ester of (XV) with trifluoroacetic acid produced carboxylic acid (XVI), and this was converted to the O-benzyl hydroxamate (XVII) by coupling with O-benzyl hydroxylamine. Further hydrolysis of the methyl ester group of (XVII) to acid (XVIII) was followed by coupling with glycine morpholide (XIX) affording diamide (XX). The O-benzyl group of (XX) was finally removed by hydrogenation in the presence of Pd/C.

参考文献中间体

合成目标

【1】 Xue, C.-B.; Cherney, R.J.; DeCicco, C.P.; Degrado, W.F.; He, X.; Hodge, C.N.; Jacobson, I.C.; Magolda, R.L.; Arner, E.C.; Duan, J.; Nelson, D.J. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0863885; JP 2000502050; WO 9718207 .
【2】 Nelson, D.; Magolda, R.L.; Jacobson, I.C.; He, X.; Arner, E.; Cherney, R.J.; Duan, J.; Xue, C.-B.; Decicco, C.P.; Degrado, W.F. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0981521; WO 9851665 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	14640	O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene	622-33-3	C₇H₉NO	详情	详情
(XIII)	35088	17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-19-methyl-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaicosane-5,16,17-tricarboxylate		C₃₈H₅₄N₂O₁₀	详情	详情
(XIV)	35089	(2R,3S)-6-[([[(5S)-5-amino-6-methoxy-6-oxohexyl]amino]carbonyl)oxy]-3-(tert-butoxycarbonyl)-2-isobutylhexanoic acid		C₂₃H₄₂N₂O₈	详情	详情
(XV)	35090	12-(tert-butyl) 8-methyl (8S,11R,12S)-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxylate		C₂₃H₄₀N₂O₇	详情	详情
(XVI)	35091	(8S,11R,12S)-11-isobutyl-8-(methoxycarbonyl)-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-12-carboxylic acid		C₁₉H₃₂N₂O₇	详情	详情
(XVII)	35092	methyl (8S,11R,12S)-12-[[(benzyloxy)amino]carbonyl]-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8-carboxylate		C₂₆H₃₉N₃O₇	详情	详情
(XVIII)	35093	(8S,11R,12S)-12-[[(benzyloxy)amino]carbonyl]-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8-carboxylic acid		C₂₅H₃₇N₃O₇	详情	详情
(XIX)	35094	2-amino-1-(4-morpholinyl)-1-ethanone		C₆H₁₂N₂O₂	详情	详情
(XX)	35095	(8S,11R,12S)-N(12)-(benzyloxy)-11-isobutyl-N(8)-[2-(4-morpholinyl)-2-oxoethyl]-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxamide		C₃₁H₄₇N₅O₈	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXIII)

Saponification of the methyl ester (XXI) using LiOH gave the carboxylic acid (XXII). This was coupled with the glycine amide (XXIII) to produce adduct (XXIV). The desired hydroxamic acid was then obtained by trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (XXIV), followed by coupling of the resulting carboxylic acid (XXV) with hydroxylamine.

参考文献中间体

合成目标

【1】 Xue, C.-B.; et al.; Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release. J Med Chem 2001, 44, 21, 3351.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXI)	53181	12-(tert-butyl) 8-methyl (8S,11R,12S)-2,10-dioxo-11-{[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxylate	n/a	C₃₃H₄₁F₃N₂O₇	详情	详情
(XXII)	53182	(8S,11R,12S)-12-(tert-butoxycarbonyl)-2,10-dioxo-11-{[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1-oxa-3,9-diazacyclopentadecane-8-carboxylic acid	n/a	C₃₂H₃₉F₃N₂O₇	详情	详情
(XXIII)	35094	2-amino-1-(4-morpholinyl)-1-ethanone		C₆H₁₂N₂O₂	详情	详情
(XXIV)	53183	tert-butyl (8S,11R,12S)-8-({[2-(4-morpholinyl)-2-oxoethyl]amino}carbonyl)-2,10-dioxo-11-{[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1-oxa-3,9-diazacyclopentadecane-12-carboxylate	n/a	C₃₈H₄₉F₃N₄O₈	详情	详情
(XXV)	53184	(8S,11R,12S)-8-({[2-(4-morpholinyl)-2-oxoethyl]amino}carbonyl)-2,10-dioxo-11-{[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1-oxa-3,9-diazacyclopentadecane-12-carboxylic acid	n/a	C₃₄H₄₁F₃N₄O₈	详情	详情

Extended Information