2-[5-[[(benzyloxy)carbonyl]amino]-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid -Drug Synthesis Database

【结构式】

【分子编号】47808

【品名】2-[5-[[(benzyloxy)carbonyl]amino]-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid

【CA登记号】

【分子式】C₂₀H₁₇N₃O₅

【分子量】379.3722

【元素组成】C 63.32% H 4.52% N 11.08% O 21.09%

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：(VII)

The reaction of methyl pivalate (I) with hydrazine gives the expected hydrazide (II), which is cyclized with methyl or ethyl orthoformate and Ts-OH, yielding the 2-tert-butyl-1,3,4-oxadiazole (III). The condensation of (III) with N-(tert-butoxycarbonyl)-L-valinal (IV) by means of BuLi and MgBr2 in THF affords the alcohol (V), which is treated with HCl in dioxane to provide the amino alcohol (VI). The condensation of (VI) with 2-[5-(benzyloxycarbonyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl]acetic acid (VII) by means of EDC, HOBT and NMM in DMF gives the corresponding amide (VIII), which is treated with DMP or (COCl)2 in order to oxidize the secondary OH group to the ketone (IX). Finally, this compound is deprotected by means of AlCl3 and anisole or HBr in HOAc to afford the target compound.

参考文献中间体

合成目标

【1】 Yamamoto, T.; Okuma, M.; Ohmoto, K.; et al.; Development of orally active nonpeptidic inhibitors of human neutrophil elastase. J Med Chem 2001, 44, 8, 1268.
【3】 Spruce, L.W.; Gyorkos, A. (Cortech, Inc.); Serine protease inhibitors. JP 2001192398; JP 2001507679; WO 9824806 .
【2】 Ohmoto, K.; Matsuoka, S.; Sekioka, T.; Imanishi, H.; Hirota, Y.; Kawabata, K.; Nakai, H.; Yamamoto, T.; Horiuchi, T.; Odagaki, Y.; Toda, M.; Design and synthesis of new orally active nonpeptide inhibitors of human neutrophil elastase. J Med Chem 2000, 43, 26, 4927.

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)	47802	Trimethylacetic acid methyl ester; 2,2-Dimethylpropionic acid methyl ester; Methyl Trimethylacetate; pivalic acid methyl ester; methyl pivalate	598-98-1	C₆H₁₂O₂	详情	详情
(II)	47803	Pivalic acid hydrazide; 2,2-dimethylpropanohydrazide		C₅H₁₂N₂O	详情	详情
(III)	47804	2-(tert-butyl)-1,3,4-oxadiazole		C₆H₁₀N₂O	详情	详情
(IV)	47805	tert-butyl (1S)-1-formyl-2-methylpropylcarbamate		C₁₀H₁₉NO₃	详情	详情
(V)	47806	tert-butyl (1S)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl](hydroxy)methyl]-2-methylpropylcarbamate		C₁₆H₂₉N₃O₄	详情	详情
(VI)	47807	(2S)-2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanol		C₁₁H₂₁N₃O₂	详情	详情
(VII)	47808	2-[5-[[(benzyloxy)carbonyl]amino]-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid		C₂₀H₁₇N₃O₅	详情	详情
(VIII)	47809	benzyl 1-[2-([(1S)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl](hydroxy)methyl]-2-methylpropyl]amino)-2-oxoethyl]-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate		C₃₁H₃₆N₆O₆	详情	详情
(IX)	47810	benzyl 1-[2-[((1S)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-methylpropyl)amino]-2-oxoethyl]-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate		C₃₁H₃₄N₆O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVI)

The reaction of 3-(2,2-dimethoxyethyl)-2-phenyl-4-oxo-3,4-dihydropyrimidine-5-carboxylic acid (IX) with isobutyl chloroformate and hydroxylamine gives the corresponding hydroxamic acid (X), which is acylated with Ac2O in pyridine to yield the acetoxy compound (XI). The degradation of (XI) by reaction with DBU in refluxing THF affords the amine (XII), which is protected with benzyl chloroformate (XIII) and NaHCO3, providing the carbamate (XIV). The hydrolysis of the dimethylacetal group of (XIV) with HCl in hot acetic acid gives the acetaldehyde derivative (XV), which is oxidized with NaClO2 in tert-butanol/water yielding the corresponding acetic acid derivative (XVI). The condensation of (XVI) with the intermediate amine (VIII) by means of ethyl chloroformate and NMM in THF affords the amide (XVII), which is hydrogenolyzed with H2 over Pd/C in order to eliminate its carbamate protecting group and provide the target racemic 285811.

参考文献中间体

合成目标

【1】 Kojima, T.; Hachiya, K.; Ohmoto, K. (Ono Pharmaceutical Co., Ltd.); 1,3,4-Oxadiazole derivs. and process for producing the same. EP 1162199; WO 0055145 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	47823	2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanone		C₁₁H₁₉N₃O₂	详情	详情
(IX)	51960	1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarboxylic acid		C₁₅H₁₆N₂O₅	详情	详情
(X)	51961	1-(2,2-dimethoxyethyl)-N-hydroxy-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarboxamide		C₁₅H₁₇N₃O₅	详情	详情
(XI)	51962	5-[[(acetoxy)amino]carbonyl]-3-(2,2-dimethoxyethyl)-2-phenyl-4(3H)-pyrimidinone		C₁₇H₁₉N₃O₆	详情	详情
(XII)	51963	5-amino-3-(2,2-dimethoxyethyl)-2-phenyl-4(3H)-pyrimidinone		C₁₄H₁₇N₃O₃	详情	详情
(XIII)	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(XIV)	51964	benzyl 1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate		C₂₂H₂₃N₃O₅	详情	详情
(XV)	51965	benzyl 6-oxo-1-(2-oxoethyl)-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate		C₂₀H₁₇N₃O₄	详情	详情
(XVI)	47808	2-[5-[[(benzyloxy)carbonyl]amino]-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid		C₂₀H₁₇N₃O₅	详情	详情
(XVII)	51966	benzyl 1-[2-[(1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-methylpropyl)amino]-2-oxoethyl]-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate		C₃₁H₃₄N₆O₆	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

The pyrimidinone acetaldehyde (VI) is oxidized to the corresponding acid (VII) by means of sodium chlorite. Then, coupling of acid (VII) with amino ester (V) using DCC and HOBt provides the target amide.

参考文献中间体

合成目标

【1】 Zhu, S.; et al.; Synthesis and in vitro studies of novel pyrimidinyl peptidomimetics as potential antimalarial therapeutic agents. J Med Chem 2002, 45, 16, 3491.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	59028	methyl (E,4S)-2-[(acetyloxy)methyl]-4-amino-2-pentenoate	C₉H₁₅NO₄	详情	详情
(VI)	51965	benzyl 6-oxo-1-(2-oxoethyl)-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate	C₂₀H₁₇N₃O₄	详情	详情
(VII)	47808	2-[5-[[(benzyloxy)carbonyl]amino]-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid	C₂₀H₁₇N₃O₅	详情	详情

Extended Information