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【结 构 式】 
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【药物名称】RPR-111905 【化学名称】(+)-(3aS,4S,6S,7aR)-2-[4-Hydroxy-4-(2-methoxyphenyl)-2-[2(S)-(2-methoxyphenyl)propionyl]perhydroisoindol-6-yl]acetonitrile 【CA登记号】 【 分 子 式 】C27H32N2O4 【 分 子 量 】448.56709 |
【开发单位】Aventis Pharma (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiallergy/Antiasthmatic Drugs, Asthma Therapy, Non-Opioid Analgesics, RESPIRATORY DRUGS, Non-Steroidal Antiinflammatory Drugs, Tachykinin NK1 Antagonists |
合成路线1
The condensation of racemic (3aRS,4RS,6SR,7aSR)-6-(hydroxymethyl)-4-(2-methoxyphenyl)perhydroisoindol-4-ol (I) with 2(S)-(2-methoxyphenyl)propionic acid (II) by means of hydroxybenzotriazole and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide in dichloromethane gives the diastereomeric amide (III), which is tosylated with tosyl chloride and submitted to chromatography yielding the (3aS,4S,6R,7aR)(S)-enantiomer (IV) as an optically pure isomer. Finally, this compound is allowed to react with potassium cyanide in hot DMSO affording RPR-111905. The starting compounds, the perhydroisoindole (I) and the propionic acid (II) have been obtained as follows: a) The cyclization of 5-(acetoxymethyl)-2-cyclohexen-1-one (V) with N-(butoxymethyl)-N-(trimethylsilylmethyl)benzylamine (VI) by means of trifluoroacetic acid (TFA) in dichloromethane gives racemic (3aRS,6SR,7aSR)-6-(acetoxymethyl)-2-benzylperhydroisoinol-4-one (VII), which is submitted to a Grignard condensation with 2-methoxyphenylmagnesium bromide (VIII) in THF yielding the racemic (3aRS,4RS,6SR,7aSR)(IX). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in hot ethanol affording the desired racemic diol (I). b) The condensation of 2-(2-methoxyphenyl)acetic acid (X) with (4S,5S)-4-methyl-5-phenyloxazolidin-2-one (XI) by means of NaH, pivaloyl chloride and butyllithium gives the acylated oxazolidinone (XII), which is methylated regioselectively with sodium hexamethyldisylazane (Na-HMDS) and methyl iodide in THF yielding the 2(S)-methyl derivative (XIII). Finally, the hydrolysis of the oxazolidinone group of (XIII) with LiOH in THF-water affords the desired 2(S)-(2-methoxyphenyl)propionic acid (II).
| 【1】 Mutti, S.; et al.; Practical enantiospecific synthesis of RPR 111905: A novel non-peptide substance P antagonist. Tetrahedron Lett 1996, 37, 48, 8743. |
| 【2】 Achard, D.; Peyronel, J.-F.; Tabart, M. (Aventis Pharma SA); Perhydroisoindole derivs. as antagonists of substance P. FR 2727411; JP 1998509970; US 5739351; WO 9616939 . |
| 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) | 19697 | (3aS,4R,6R,7aR)-6-(hydroxymethyl)-4-(2-methoxyphenyl)octahydro-1H-isoindol-4-ol | C16H23NO3 | 详情 | 详情 | |
| (II) | 19698 | (2S)-2-(2-methoxyphenyl)propionic acid | C10H12O3 | 详情 | 详情 | |
| (III) | 19699 | (2S)-1-[(4S,6R)-4-hydroxy-6-(hydroxymethyl)-4-(2-methoxyphenyl)octahydro-2H-isoindol-2-yl]-2-(2-methoxyphenyl)-1-propanone | C26H33NO5 | 详情 | 详情 | |
| (IV) | 19700 | [(3aR,5R,7R,7aS)-7-hydroxy-7-(2-methoxyphenyl)-2-[(2S)-2-(2-methoxyphenyl)propanoyl]octahydro-1H-isoindol-5-yl]methyl 4-methylbenzenesulfonate | C33H39NO7S | 详情 | 详情 | |
| (V) | 19701 | [(1R)-5-oxo-3-cyclohexen-1-yl]methyl acetate | C9H12O3 | 详情 | 详情 | |
| (VI) | 19702 | N-benzyl-N-(butoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-(butoxymethyl)(phenyl)-N-[(trimethylsilyl)methyl]methanamine | C16H29NOSi | 详情 | 详情 | |
| (VII) | 19703 | [(3aR,5R,7aS)-2-benzyl-7-oxooctahydro-1H-isoindol-5-yl]methyl acetate | C18H23NO3 | 详情 | 详情 | |
| (VIII) | 19704 | bromo(2-methoxyphenyl)magnesium | C7H7BrMgO | 详情 | 详情 | |
| (IX) | 19705 | (3aS,4R,6R,7aR)-2-benzyl-6-(hydroxymethyl)-4-(2-methoxyphenyl)octahydro-1H-isoindol-4-ol | C23H29NO3 | 详情 | 详情 | |
| (X) | 19706 | 2-(2-methoxyphenyl)acetic acid | 93-25-4 | C9H10O3 | 详情 | 详情 |
| (XI) | 19707 | (4S,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one | 17097-67-5 | C10H11NO2 | 详情 | 详情 |
| (XII) | 19708 | (4S,5S)-3-[2-(2-methoxyphenyl)acetyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C19H19NO4 | 详情 | 详情 | |
| (XIII) | 19709 | (4S,5S)-3-[(2S)-2-(2-methoxyphenyl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C20H21NO4 | 详情 | 详情 |
合成路线2
The Diels-Alder cyclization of 1-acetoxy-1,3-butadiene (XIV) with maleimide (XV) in toluene at 80 C gives racemic (3aRS,4RS,7aSR)-4-acetoxy-2,3,3a,4,7,7a-hexahydro-1H-isoindole-1,3-dione (XVI), which is reduced with LiAlH4 in THF to the racemic alcohol (XVII). Optical resolution of (XVII) with Di-p-toluoyl-L-tartaric acid in THF/ethanol/ /water yields the (3aS,4S,7aR)-isomer (XVIII), which is N-protected with tert-butoxycarbonyl anhydride to the protected compound (XIX). The Oppenauer oxidation of (XIX) catalized by aluminum isopropoxide affords the unsaturated ketone (XX), which is condensed with cyanacetic acid (XXI) by means of NaOH in toluene/water to afford the substituted cyanacetic derivative (XXII). The decarboxylation of (XXII) catalized by Cu2O in refluxing acetonitrile gives the suitably substituted ketone (XXIII), which is submitted to a Grignard condensation with 2-methoxy-phenylmagnesium bromide (XXIV) in THF yielding the alcohol (XXV) as a single isomer. The deprotection of (XXV) with HCl in THF affords compound (XXVI) with a free NH group, which is finally acylated with 2(S)-(2-methoxyphenyl)propionic acid (II) by means of SOCl2 and K2CO3 to obtain RPR-111905.
| 【1】 Mutti, S.; et al.; Practical enantiospecific synthesis of RPR 111905: A novel non-peptide substance P antagonist. Tetrahedron Lett 1996, 37, 48, 8743. |
| 【2】 Achard, D.; Peyronel, J.-F.; Tabart, M. (Aventis Pharma SA); Perhydroisoindole derivs. as antagonists of substance P. FR 2727411; JP 1998509970; US 5739351; WO 9616939 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 19710 | (1E)-1,3-butadienyl acetate | 1515-76-0 | C6H8O2 | 详情 | 详情 |
| (XV) | 19711 | 1H-pyrrole-2,5-dione | 541-59-3 | C4H3NO2 | 详情 | 详情 |
| (XVI) | 19712 | (3aR,4S,7aR)-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-yl acetate | C10H11NO4 | 详情 | 详情 | |
| (XVII) | 19713 | (3aS,4S,7aR)-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ol | C8H13NO | 详情 | 详情 | |
| (XIX) | 19715 | tert-butyl (3aS,4S,7aR)-4-hydroxy-1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate | C13H23NO3 | 详情 | 详情 | |
| (XX) | 19716 | tert-butyl (3aS,7aR)-4-oxo-1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate | C13H19NO3 | 详情 | 详情 | |
| (XXII) | 19718 | (2S)-2-[(3aR,5R,7aS)-2-(tert-butoxycarbonyl)-7-oxooctahydro-1H-isoindol-5-yl]-2-cyanoethanoic acid | C16H22N2O5 | 详情 | 详情 | |
| (XXIII) | 19719 | tert-butyl (3aS,6S,7aR)-6-(cyanomethyl)-4-oxooctahydro-2H-isoindole-2-carboxylate | C15H22N2O3 | 详情 | 详情 | |
| (XXV) | 19721 | tert-butyl (3aS,4S,6S,7aR)-6-(cyanomethyl)-4-hydroxy-4-(2-methoxyphenyl)octahydro-2H-isoindole-2-carboxylate | C22H30N2O4 | 详情 | 详情 | |
| (XXVI) | 19722 | 2-[(3aR,5S,7S,7aS)-7-hydroxy-7-(2-methoxyphenyl)octahydro-1H-isoindol-5-yl]acetonitrile | C17H22N2O2 | 详情 | 详情 |