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【结 构 式】 
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【药物名称】RPR-118031A 【化学名称】(+)-2(S)-[5-(1,3-Benzodioxol-5-ylmethoxy)-2-cyanophenoxy]-2-(2-methylphenyl)acetic acid sodium salt 【CA登记号】181038-67-5 (free acid) 【 分 子 式 】C24H18NNaO6 【 分 子 量 】439.40396 |
【开发单位】Aventis Pharma (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Pulmonary Hypertension, Treatment of, Endothelin ETA Receptor Antagonists |
合成路线1
The title compound has been prepared by two related ways. The alkylation of 2-fluoro-4-hydroxybenzonitrile (I) with 3,4-(methylenedioxy)benzyl chloride (II) afforded ether (III). This was coupled with (R,S)-2-hydroxy-2-(2-methylphenyl)acetic acid (IV) in the presence of NaH in DMSO to produce the racemic adduct (V). Resolution was then achieved by fractional crystallization of the diastereoisomeric salts with (-)-ephedrine to furnish the desired (S)-enantiomer, which was finally isolated as the corresponding sodium salt.
| 【1】 Astles, P.C.; Brown, T.J.; Halley, F.; et al.; Selective ETA antagonists. 5. Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives. J Med Chem 2000, 43, 5, 900. |
| 【2】 Porter, B.; Astles, P.C.; Bridge, A.W.; McLay, I.M.; Van Sickle, A.P.; Walsh, R.J.A.; McCarthy, C.; Morley, A.D.; Halley, F.; Harris, N.V.; Majid, T.N.; Smith, C. (Rhône-Poulenc Rorer Ltd.); Substd. phenyl cpds. as endothelin antagonists. US 6048893; US 6124343; WO 9622978 . |
| 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) | 20094 | 2,4-dihydroxybenzaldehyde | 95-01-2 | C7H6O3 | 详情 | 详情 |
| (II) | 28617 | 5-(chloromethyl)-1,3-benzodioxole | C8H7ClO2 | 详情 | 详情 | |
| (III) | 38975 | (3S,5R)-1-[(2S,4R)-5-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-4-benzyl-2-hydroxy-5-oxopentyl]-3,5-dibenzyl-2-pyrrolidinone | C42H46N2O4 | 详情 | 详情 | |
| (IV) | 38977 | 2-hydroxy-2-(2-methylphenyl)acetic acid | C9H10O3 | 详情 | 详情 | |
| (V) | 38978 | 2-[5-(1,3-benzodioxol-5-ylmethoxy)-2-cyanophenoxy]-2-(2-methylphenyl)acetic acid | C24H19NO6 | 详情 | 详情 |
合成路线2
In a related procedure, alkylation of 2,4-dihydroxybenzaldehyde (VI) with chloride (II) gave ether (VII). Subsequent conversion of the aldehyde group of (VII) into the desired nitrile (X) was effected by the following sequence, including formation of the corresponding oxime (VIII), dehydration with concomitant acetylation using Ac2O, and then hydrolysis of acetate (IX) using K2CO3. Alternatively, aldehyde (VII) was directly converted to nitrile (X) by reaction with hydroxylamine-O-sulfonic acid, followed by basic treatment. Racemic alpha-bromo-(2-methylphenyl)acetic acid (XI) was resolved via formation of the corresponding salt with (-)-ephedrine (XII). Hydroxy nitrile (X) was then alkylated with the chiral bromide (XII), and the resulting compound was finally converted to the corresponding sodium salt.
| 【1】 Porter, B.; Astles, P.C.; Bridge, A.W.; McLay, I.M.; Van Sickle, A.P.; Walsh, R.J.A.; McCarthy, C.; Morley, A.D.; Halley, F.; Harris, N.V.; Majid, T.N.; Smith, C. (Rhône-Poulenc Rorer Ltd.); Substd. phenyl cpds. as endothelin antagonists. US 6048893; US 6124343; WO 9622978 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 28617 | 5-(chloromethyl)-1,3-benzodioxole | C8H7ClO2 | 详情 | 详情 | |
| (VI) | 20094 | 2,4-dihydroxybenzaldehyde | 95-01-2 | C7H6O3 | 详情 | 详情 |
| (VII) | 38979 | 4-(1,3-benzodioxol-5-ylmethoxy)-2-hydroxybenzaldehyde | C15H12O5 | 详情 | 详情 | |
| (VIII) | 38980 | 4-(1,3-benzodioxol-5-ylmethoxy)-2-hydroxybenzaldehyde oxime | C15H13NO5 | 详情 | 详情 | |
| (IX) | 38981 | 5-(1,3-benzodioxol-5-ylmethoxy)-2-cyanophenyl acetate | C17H13NO5 | 详情 | 详情 | |
| (X) | 38982 | 4-(1,3-benzodioxol-5-ylmethoxy)-2-hydroxybenzonitrile | C15H11NO4 | 详情 | 详情 | |
| (XI) | 38983 | 2-bromo-2-(2-methylphenyl)acetic acid | C9H9BrO2 | 详情 | 详情 | |
| (XII) | 38984 | (2R)-2-bromo-2-(2-methylphenyl)ethanoic acid | C9H9BrO2 | 详情 | 详情 |