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【结 构 式】 
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【药物名称】RPR-122818 【化学名称】3(R)-(4-Methoxyphenylsulfonyl)-2(S)-methyl-7-phenylheptanohydroxamic acid 【CA登记号】 【 分 子 式 】C21H27NO5S 【 分 子 量 】405.51704 |
【开发单位】Aventis Pharma (Originator) 【药理作用】Asthma Therapy, Bronchodilators, RESPIRATORY DRUGS, Matrix Metalloproteinase Inhibitors, Phosphodiesterase IV Inhibitors |
合成路线1
The reaction of 5-phenylpentanal (I) with triethyl 2-phosphonopropionate (II) by means of NaOEt in THF gives ethyl 2-methyl-7-phenyl-2(E)-heptenoate (III), which is hydrolyzed with NaOH in methanol/water to the corresponding free acid (IV). The reaction of (IV) with 4-methoxythiophenol (V) in hot piperidine affords 3-(4-methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (VI), which by reaction first with oxalyl chloride, then with O-trimethylsilylhydroxylamine (VII) in dichloromethane, and finally with HCl is converted into the hydroxamic acid (VIII). Finally, this compound is oxidized with oxone in methanol/water to provide the target compound as mixture of diastereomeric racemates that is separated by reversed phase HPLC.
| 【1】 Groneberg, R.D.; Neuenschwander, K.W.; Djuric, S.W.; McGeehan, G.M.; Burns, C.J.; Condon, S.M.; Morrissette, M.M.; Salvino, J.M.; Scotese, A.C.; Ullrich, J.W. (Aventis Pharma SA); Substd. (aryl, heteroaryl, arylmethyl or heteroarylmethyl) hydroxamic acid cpds.. EP 0871439; JP 2000503012; WO 9724117 . |
| 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) | 25636 | 5-phenylpentanal | C11H14O | 详情 | 详情 | |
| (II) | 18816 | ethyl 2-(diethoxyphosphoryl)propanoate | 3699-66-9 | C9H19O5P | 详情 | 详情 |
| (III) | 26081 | ethyl (E)-2-methyl-7-phenyl-2-heptenoate | C16H22O2 | 详情 | 详情 | |
| (IV) | 26082 | (E)-2-methyl-7-phenyl-2-heptenoic acid | C14H18O2 | 详情 | 详情 | |
| (V) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |
| (VI) | 26083 | 3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanoic acid | C21H26O3S | 详情 | 详情 | |
| (VII) | 26091 | O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane | 22737-36-6 | C3H11NOSi | 详情 | 详情 |
| (VIII) | 26084 | N-hydroxy-3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanamide | C21H27NO3S | 详情 | 详情 |
合成路线2
Hydroxyacid (III) was prepared by condensation of 5-phenylpentanal (I) with the dilithium anion of propionic acid (II). Cyclization of (III) upon treatment with dipyridyl disulfide and PPh3, and then with mercuric mesylate yielded an equimolar mixture of beta-lactones (IV) and (V), from which the desired cis isomer (IV) was isolated by flash chromatography. Subsequent ring opening of (IV) with the sodium salt of 4-methoxythiophenol (VI) provided carboxylic acid (VII). This was converted to acid the corresponding chloride by means of oxalyl chloride and then condensed with O-(trimethylsilyl)hydroxylamine to produce hydroxamic acid (VIII). Finally, sulfide oxidation of (VIII) with Oxone furnished the target sulfonylhydroxamic acid.
| 【1】 Burns, C.J.; Groneberg, R.D.; Morrissette, M.M.; et al.; Dual inhibition of phosphodiesterase 4 and matrix metalloproteinases by an (arylsulfonyl)hydroxamic acid template. J Med Chem 1999, 42, 4, 541. |
| 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) | 25636 | 5-phenylpentanal | C11H14O | 详情 | 详情 | |
| (II) | 26085 | 2-Lithiopropionic acid lithium salt | C3H4Li2O2 | 详情 | 详情 | |
| (III) | 26086 | 3-hydroxy-2-methyl-7-phenylheptanoic acid | C14H20O3 | 详情 | 详情 | |
| (IV) | 26087 | (3S,4R)-3-methyl-4-(4-phenylbutyl)-2-oxetanone | C14H18O2 | 详情 | 详情 | |
| (V) | 26088 | (3R,4R)-3-methyl-4-(4-phenylbutyl)-2-oxetanone | C14H18O2 | 详情 | 详情 | |
| (VI) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |
| (VII) | 26089 | (2S,3R)-3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanoic acid | C21H26O3S | 详情 | 详情 | |
| (VIII) | 26090 | (2S,3R)-N-hydroxy-3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanamide | C21H27NO3S | 详情 | 详情 |