-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】7-[4-[4-[N-(4-Cyclohexylbutyl)carbamoyl]oxazol-2-yl]phenyl]-7-(3-pyridyl)-6(E)-heptenoic acid

【CA登记号】200399-71-9

【分子式】C₃₂H₃₉N₃O₄

【分子量】529.68533

【开发单位】Lilly (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Antiplatelet Therapy, Asthma Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, RESPIRATORY DRUGS, Restenosis Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Prostanoid TP (Thromboxane A2) Antagonists, Thromboxane Synthase Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

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

【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

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

【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

合成路线3

Addition of 3-lithiopyridine (I) to methyl 4-formylbenzoate (II) in Et2O at low temperature provided carbinol (III), which was oxidized to ketone (IV) with MnO2 in refluxing THF. Then, saponification of the methyl ester of (IV) gave acid (V). Alternatively, acid (V) was obtained by Jones oxidation of silyloxymethyl compound (VI). Serinamide (IX) was prepared by coupling of N-Boc-L-serine (VII) with 4-cyclohexylbutylamine (VIII) using EDC and HOBt, followed by deprotection of the Boc group with trifluoroacetic acid in cold CH2Cl2. Compound (IX) was then coupled with acid (V) to provide amide (X), whose cyclization in the presence of PPh3, CCl4 and i-Pr2NEt produced the oxazoline (XI). Subsequent nickel peroxide oxidation yielded oxazole (XII). Finally, Wittig reaction of (XII) with phosphonate (XIII) in the presence of KO-t-Bu furnished the title compound.

参考文献中间体

【1】 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)	18261	3-pyridinyllithium		C₅H₄LiN	详情	详情
(II)	10170	methyl 4-formylbenzoate	1571-08-0	C₉H₈O₃	详情	详情
(III)	20122	methyl 4-[hydroxy(3-pyridinyl)methyl]benzoate		C₁₄H₁₃NO₃	详情	详情
(IV)	20123	methyl 4-(3-pyridinylcarbonyl)benzoate		C₁₄H₁₁NO₃	详情	详情
(V)	20124	4-(3-pyridinylcarbonyl)benzoic acid		C₁₃H₉NO₃	详情	详情
(VI)	18277	[4-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl](3-pyridinyl)methanone		C₁₉H₂₅NO₂Si	详情	详情
(VII)	20126	(2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid		C₈H₁₅NO₅	详情	详情
(VIII)	20127	4-cyclohexyl-1-butanamine; 4-cyclohexylbutylamine		C₁₀H₂₁N	详情	详情
(IX)	18268	(2S)-2-amino-N-(4-cyclohexylbutyl)-3-hydroxypropanamide		C₁₃H₂₆N₂O₂	详情	详情
(X)	20129	N-[(1S)-2-[(4-cyclohexylbutyl)amino]-1-(hydroxymethyl)-2-oxoethyl]-4-(3-pyridinylcarbonyl)benzamide		C₂₆H₃₃N₃O₄	详情	详情
(XI)	20130	(4S)-N-(4-cyclohexylbutyl)-2-[4-(3-pyridinylcarbonyl)phenyl]-4,5-dihydro-1,3-oxazole-4-carboxamide		C₂₆H₃₁N₃O₃	详情	详情
(XII)	20131	N-(4-cyclohexylbutyl)-2-[4-(3-pyridinylcarbonyl)phenyl]-1,3-oxazole-4-carboxamide		C₂₆H₂₉N₃O₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)