methyl (E)-7-[4-((4S)-4-[[(4-cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-1,3-oxazol-2-yl)phenyl]-7-(3-pyridinyl)-6-heptenoate -Drug Synthesis Database

【结构式】

【分子编号】18284

【品名】methyl (E)-7-[4-((4S)-4-[[(4-cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-1,3-oxazol-2-yl)phenyl]-7-(3-pyridinyl)-6-heptenoate

【CA登记号】

【分子式】C₃₃H₄₃N₃O₄

【分子量】545.72224

【元素组成】C 72.63% H 7.94% N 7.7% O 11.73%

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：(XIII)

1,4-Benzenedimethanol (I) was monoprotected with tert-butyldimethylsilyl chloride in the presence of imidazole, and the resulting silyl ether (II) was oxidized with MnO2 in refluxing THF to aldehyde (III). This was treated with 3-lithiopyridine (IV), (generated from 3-bromopyridine and butyllithium at -78 C in Et2O), to give carbinol (V), which was oxidized with MnO2 to ketone (VI). Wittig reaction with 5-carboxypentylphosphonium bromide (VII) and t-BuOK in THF at low temperature yielded a 4:1 mixture of Z and E heptenoic acids (VIII). Subsequent reaction with diazomethane provided a mixture of esters, from which the E isomer (IX) was separated by column chromatography. Oxidation of TBDMS ether with Jones reagent provided acid (X), and this was coupled with N-(4-cyclohexylbutyl)-L-serinamide (XI) using N-(dimethylaminopropyl)-N'-ethylcarbodiimide.HCl (EDC) in the presence of HOBT and N-methylmorpholine to give amide (XII). Cyclization to oxazolidine (XIII) was effected by treatment with triphenyl phosphine and diisopropylethylamine.

参考文献中间体

合成目标

【1】 Takeuchi, K.; Kohn, T.J.; Mais, D.E.; True, T.A.; Wyss, V.L.; Jakubowski, J.A.; Development of dual-acting agents for thromboxane receptor antagonism and thromboxane synthase inhibition. 2. Design, synthesis, and evaluation of a novel series of phenyl oxazole derivatives. Bioorg Med Chem Lett 1998, 8, 15, 1943-1948.
【2】 Takeuchi, K.; Kohn, T.J.; True, T.A.; Mais, D.E.; Wikel, J.H.; Utterback, B.G.; Wyss, V.L.; Jakubowski, J.A.; Development of dual-acting agents for thromboxane receptor antagonism and thromboxane synthase inhibition. 3. Synthesis and biological activities of oxazolecarboxamide-substituted omega-phenyl-omega-(3-pyridyl)alkenoic acid derivatives and related compo. J Med Chem 1998, 41, 27, 5362.

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)	18272	[4-(hydroxymethyl)phenyl]methanol; p-Xylylene Glycol	589-29-7	C₈H₁₀O₂	详情	详情
(II)	18273	[4-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl]methanol		C₁₄H₂₄O₂Si	详情	详情
(III)	18274	4-([[tert-butyl(dimethyl)silyl]oxy]methyl)benzaldehyde		C₁₄H₂₂O₂Si	详情	详情
(V)	18276	[4-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl](3-pyridinyl)methanol		C₁₉H₂₇NO₂Si	详情	详情
(VI)	18277	[4-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl](3-pyridinyl)methanone		C₁₉H₂₅NO₂Si	详情	详情
(VIII)	18279	(E)-7-[4-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl]-7-(3-pyridinyl)-6-heptenoic acid		C₂₅H₃₅NO₃Si	详情	详情
(IX)	18280	methyl (E)-7-[4-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl]-7-(3-pyridinyl)-6-heptenoate		C₂₆H₃₇NO₃Si	详情	详情
(X)	18281	4-[(E)-7-methoxy-7-oxo-1-(3-pyridinyl)-1-heptenyl]benzoic acid		C₂₀H₂₁NO₄	详情	详情
(XII)	18283	methyl (E)-7-[4-([[(1S)-2-[(4-cyclohexylbutyl)amino]-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl)phenyl]-7-(3-pyridinyl)-6-heptenoate		C₃₃H₄₅N₃O₅	详情	详情
(XIII)	18284	methyl (E)-7-[4-((4S)-4-[[(4-cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-1,3-oxazol-2-yl)phenyl]-7-(3-pyridinyl)-6-heptenoate		C₃₃H₄₃N₃O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

Oxazolidine (XIII) was oxidized to oxazole (XIV) with nickel peroxide in the presence of 4 Å molecular sieves, and finally hydrolyzed with 1 M NaOH in THF-MeOH to the title acid.

参考文献中间体

合成目标

【1】 Takeuchi, K.; Kohn, T.J.; Mais, D.E.; True, T.A.; Wyss, V.L.; Jakubowski, J.A.; Development of dual-acting agents for thromboxane receptor antagonism and thromboxane synthase inhibition. 2. Design, synthesis, and evaluation of a novel series of phenyl oxazole derivatives. Bioorg Med Chem Lett 1998, 8, 15, 1943-1948.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	18284	methyl (E)-7-[4-((4S)-4-[[(4-cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-1,3-oxazol-2-yl)phenyl]-7-(3-pyridinyl)-6-heptenoate		C₃₃H₄₃N₃O₄	详情	详情
(XIV)	18285	methyl (E)-7-[4-(4-[[(4-cyclohexylbutyl)amino]carbonyl]-1,3-oxazol-2-yl)phenyl]-7-(3-pyridinyl)-6-heptenoate		C₃₃H₄₁N₃O₄	详情	详情

Extended Information