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【结 构 式】 
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【分子编号】18268 【品名】(2S)-2-amino-N-(4-cyclohexylbutyl)-3-hydroxypropanamide 【CA登记号】 |
【 分 子 式 】C13H26N2O2 【 分 子 量 】242.36172 【元素组成】C 64.43% H 10.81% N 11.56% O 13.2% |
合成路线1
该中间体在本合成路线中的序号：(IX)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.
| 【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 |
合成路线2
该中间体在本合成路线中的序号：(XI)1,3-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 3:1 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.
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 18258 | [3-(hydroxymethyl)phenyl]methanol; 1,3-Benzenedimethanol | 626-18-6 | C8H10O2 | 详情 | 详情 |
| (II) | 18259 | [3-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl]methanol | C14H24O2Si | 详情 | 详情 | |
| (III) | 18260 | 3-([[tert-butyl(dimethyl)silyl]oxy]methyl)benzaldehyde | C14H22O2Si | 详情 | 详情 | |
| (IV) | 18261 | 3-pyridinyllithium | C5H4LiN | 详情 | 详情 | |
| (V) | 18262 | [3-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl](3-pyridinyl)methanol | C19H27NO2Si | 详情 | 详情 | |
| (VI) | 18263 | [3-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl](3-pyridinyl)methanone | C19H25NO2Si | 详情 | 详情 | |
| (VII) | 18264 | (5-Carboxypentyl)triphenylphosphonium bromide; (5-carboxypentyl)(triphenyl)phosphonium bromide | 50889-29-7 | C24H26BrO2P | 详情 | 详情 |
| (VIII) | 18265 | (E)-7-[3-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl]-7-(3-pyridinyl)-6-heptenoic acid | C25H35NO3Si | 详情 | 详情 | |
| (IX) | 18266 | methyl (E)-7-[3-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl]-7-(3-pyridinyl)-6-heptenoate | C26H37NO3Si | 详情 | 详情 | |
| (X) | 18267 | 3-[(E)-7-methoxy-7-oxo-1-(3-pyridinyl)-1-heptenyl]benzoic acid | C20H21NO4 | 详情 | 详情 | |
| (XI) | 18268 | (2S)-2-amino-N-(4-cyclohexylbutyl)-3-hydroxypropanamide | C13H26N2O2 | 详情 | 详情 | |
| (XII) | 18269 | methyl (E)-7-[3-([[(1S)-2-[(4-cyclohexylbutyl)amino]-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl)phenyl]-7-(3-pyridinyl)-6-heptenoate | C33H45N3O5 | 详情 | 详情 | |
| (XIII) | 18270 | methyl (E)-7-[3-((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 |