【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% |
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 |