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【结 构 式】 
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【分子编号】18264 【品名】(5-Carboxypentyl)triphenylphosphonium bromide; (5-carboxypentyl)(triphenyl)phosphonium bromide 【CA登记号】50889-29-7 |
【 分 子 式 】C24H26BrO2P 【 分 子 量 】457.347002 【元素组成】C 63.03% H 5.73% Br 17.47% O 7% P 6.77% |
合成路线1
该中间体在本合成路线中的序号：(III)The condensation of 6-bromohexanoic acid (I) with triphenylphosphine in refluxing acetonitrile gives the corresponding phosphonium salt (III), which is submitted to a Wittig condensation with phenyl 3-pyridyl ketone (IV) by means of NaH in DMSO, yielding a mixture of the title product and its (Z)-isomer (V). This mixture of isomers is separated by fractional crystallization or HPLC and the isomeric compound (V) is treated with refluxing aqueous 25% HBr to perform its isomerization to CV-415.
| 【1】 Kato, K.; et al.; Thromboxane synthetase inhibitors (TXSI). Design, synthesis, and evaluation of a novel series of omega-pyridilalkenoic acids. J Med Chem 1985, 28, 3, 287-294. |
| 【2】 Terao, S.; et al. (Takeda Chemical Industries, Ltd.); Substituted vinylcarboxylic acid derivative and its preparation. JP 58219162 . |
| 【3】 Castaner, J.; Serradell, M.N.; CV-4151. Drugs Fut 1986, 11, 3, 183. |
| 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) | 27765 | 6-bromohexanoic acid | 4224-70-8 | C6H11BrO2 | 详情 | 详情 |
| (III) | 18264 | (5-Carboxypentyl)triphenylphosphonium bromide; (5-carboxypentyl)(triphenyl)phosphonium bromide | 50889-29-7 | C24H26BrO2P | 详情 | 详情 |
| (IV) | 27766 | phenyl(3-pyridinyl)methanone | 5424-19-1 | C12H9NO | 详情 | 详情 |
| (V) | 27767 | (Z)-7-phenyl-7-(3-pyridinyl)-6-heptenoic acid | C18H19NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)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 |
合成路线3
该中间体在本合成路线中的序号：(II)1) The Wittig reaction of 2,4-dichlorobenzaldehyde (I) with phosphonium bromide (II) using NaH in DMSO provided 7-(2,4-dichlorophenyl)-6-heptenoic acid (III) as a mixture of E and Z isomers. Esterification of (III) with MeOH in the presence of H2SO4 afforded (IV), which was reduced with DIBAL-H to afford alcohol (V). Subsequent hydrogenation of (V) over Pd/C gave 7-(2,4-dichlorophenyl)-1-heptanol (VI) and further Swern oxidation yielded the corresponding aldehyde (VII). Oxime (VIII) was then prepared by reaction of (VII) with hydroxylamine. Treatment with NaOCl and Et3N generated an intermediate nitrile oxide which, in the presence of dimethyl itaconate (IX), experienced a [3+2] cycloaddition to afford the isoxazole (X). Reductive opening of this heterocycle by hydrogenation in the presence of Raney Nickel and boric acid produced hydroxyketone (XI), and further reduction of (XI) using NaBH4 and CeCl3 in MeOH yielded the dihydroxy ester (XII) as a mixture of diastereoisomers. Saponification of (XII) with NaOH, followed by recrystallization of the resulting disodium salt, then furnished the racemic (3R*,5S*)-diasteroisomer (XIII).
| 【1】 Gribble, A.D.; Ife, R.J.; Shaw, A.; McNair, D.; Novelli, C.E.; Bakewell, S.; Shah, V.P.; Dolle, R.E.; Groot, P.H.; Pearce, N.; Yates, J.; Tew, D.; Boyd, H.; Ashman, S.; Eggleston, D.S.; Haltiwanger, R.C.; Okafo, G.; ATP-citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R*,5S*)-omega-substituted-3-carboxy-3,5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo. J Med Chem 1998, 41, 19, 3582. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac-XIII) | 22208 | 2-[8-(2,4-Dichlorophenyl)-2(R)-hydroxyoctyl]-2-hydroxysuccinic acid disodium salt | C20H28Cl2O4 | 详情 | 详情 | |
| (I) | 22196 | 2,4-dichlorobenzaldehyde | 874-42-0 | C7H4Cl2O | 详情 | 详情 |
| (II) | 18264 | (5-Carboxypentyl)triphenylphosphonium bromide; (5-carboxypentyl)(triphenyl)phosphonium bromide | 50889-29-7 | C24H26BrO2P | 详情 | 详情 |
| (III) | 22198 | (E)-7-(2,4-dichlorophenyl)-6-heptenoic acid | C13H14Cl2O2 | 详情 | 详情 | |
| (IV) | 22199 | methyl (E)-7-(2,4-dichlorophenyl)-6-heptenoate | C14H16Cl2O2 | 详情 | 详情 | |
| (V) | 22200 | (E)-7-(2,4-dichlorophenyl)-6-hepten-1-ol | C13H16Cl2O | 详情 | 详情 | |
| (VI) | 22201 | 7-(2,4-dichlorophenyl)-1-heptanol | C13H18Cl2O | 详情 | 详情 | |
| (VII) | 22202 | 7-(2,4-dichlorophenyl)heptanal | C13H16Cl2O | 详情 | 详情 | |
| (VIII) | 22203 | 7-(2,4-dichlorophenyl)heptanal oxime | C13H17Cl2NO | 详情 | 详情 | |
| (IX) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 详情 | 详情 |
| (X) | 22205 | methyl 3-[6-(2,4-dichlorophenyl)hexyl]-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylate | C20H25Cl2NO5 | 详情 | 详情 | |
| (XI) | 22206 | dimethyl 2-[8-(2,4-dichlorophenyl)-2-oxooctyl]-2-hydroxysuccinate | C20H26Cl2O6 | 详情 | 详情 | |
| (XII) | 22207 | dimethyl 2-[8-(2,4-dichlorophenyl)-2-hydroxyoctyl]-2-hydroxysuccinate | C20H28Cl2O6 | 详情 | 详情 |