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【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

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.

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.

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.

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 CAS号 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