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【结 构 式】 
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【药物名称】ZD-3523 【化学名称】(R)-3-Methoxy-4-[1-methyl-5-[N-(2-methyl-4,4,4-trifluorobutyl)carbamoyl]indol-3-ylmethyl]-N-(2-methylphenylsulfonyl)benzamide 【CA登记号】136564-68-6, 136564-67-5 (undefined isomer) 【 分 子 式 】C31H32F3N3O5S 【 分 子 量 】615.67699 |
【开发单位】AstraZeneca (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Leukotriene CysLT1 (LTD4) Antagonists |
合成路线1
A modification of Leimgruber-Batcho synthesis of indoles was employed to convert 3-methyl-4-nitrobenzoic acid (I) to the 3,5-disubstituted indole (V)). In this process, the intermediate enamine (II) was alkylated with the bromobenzoate (III) prior to hydrolysis and reductive cyclization to the indole nucleus. Alkylation of (V) with iodomethane under basic conditions, followed by amide formation using (R)-4,4,4-trifluoro-2-methylbutylamine (VII) afforded the key intermediate amidoester (VIII). Hydrolysis of the methyl ester moiety of (VIII) with aqueous lithium hydroxide, followed by sulfonimide formation gave ZD 3523).
| 【1】 Bernstein, P.R.; Jacobs, R.T.; ZD 3523. Drugs Fut 1995, 20, 12, 1233. |
| 【2】 Jacobs, R.T.; Costello, G.F.; Brook, S.A.; Harrison, P.J. (AstraZeneca plc); A process for the preparation of a 3-alkylated indole, intermediates, and a process for the preparation of a derivative thereof. EP 0489547 . |
| 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) | 14771 | (4-carboxy-2-methylphenyl)(oxo)-lambda(5)-azanolate | C8H8NO4 | 详情 | 详情 | |
| (II) | 14772 | [4-carboxy-2-[(E)-2-(dimethylamino)ethenyl]phenyl](oxo)-lambda(5)-azanolate | C11H13N2O4 | 详情 | 详情 | |
| (III) | 11920 | methyl 4-(bromomethyl)-3-methoxybenzoate; 4-(Bromomethyl)-3-methoxy benzoic acid methyl ester | C10H11BrO3 | 详情 | 详情 | |
| (IV) | 14774 | (4-carboxy-2-[1-formyl-2-[2-methoxy-4-(methoxycarbonyl)phenyl]ethyl]phenyl)(oxo)-lambda(5)-azanolate | C19H18NO8 | 详情 | 详情 | |
| (V) | 14775 | 3-[2-methoxy-4-(methoxycarbonyl)benzyl]-1H-indole-5-carboxylic acid | C19H17NO5 | 详情 | 详情 | |
| (VI) | 14776 | 3-[2-methoxy-4-(methoxycarbonyl)benzyl]-1-methyl-1H-indole-5-carboxylic acid | C20H19NO5 | 详情 | 详情 | |
| (VII) | 14777 | (2R)-4,4,4-trifluoro-2-methyl-1-butanamine; (2R)-4,4,4-trifluoro-2-methylbutylamine | C5H10F3N | 详情 | 详情 | |
| (VIII) | 14778 | methyl 3-methoxy-4-[[1-methyl-5-([[(2R)-4,4,4-trifluoro-2-methylbutyl]amino]carbonyl)-1H-indol-3-yl]methyl]benzoate | C25H27F3N2O4 | 详情 | 详情 | |
| (IX) | 14779 | 3-methoxy-4-[[1-methyl-5-([[(2R)-4,4,4-trifluoro-2-methylbutyl]amino]carbonyl)-1H-indol-3-yl]methyl]benzoic acid | C24H25F3N2O4 | 详情 | 详情 | |
| (X) | 63841 | 2-methylbenzenesulfonamide | C7H9NO2S | 详情 | 详情 |
合成路线2
The synthesis of the key chiral amine component (VII) is outlined: Conversion of 4,4,4-trifluorobutyric acid (XI) to the corresponding acid chloride and subsequent reaction with the anion derived from the Evans oxazolidinone (XII) yielded the acyloxazolidinone (XIII). Treatment of (XIII) with a strong base such as sodium hexamethyldisilazide and alkylation of the resultant enolate with iodomethane at -35 C afforded a mixture of the diastereomeric acyloxazolidinones (XIV). The desired diastereomer was obtained by crystallization of the crude product. Reductive cleavage of the chiral auxiliary gave the enantiomerically pure alcohol (XV), which was converted in two steps to the desired enantiomerically pure amine hydrochloride (VII). Alternative routes to the amine, such as resolution of racemic 4,4,4-trifluoro-2-methylbutyric acid followed by amide formation and reduction to (VII) could also be utilized.
| 【1】 Bernstein, P.R.; Jacobs, R.T.; ZD 3523. Drugs Fut 1995, 20, 12, 1233. |
| 【2】 Jacobs, R.T.; Yee, Y.K.; Bernstein, P.R.; Brewster, A.G.; Sependa, G.J. (AstraZeneca plc); A process for the preparation of 2(R)-methyl-4,4,4-trifluorobutylamine, intermediates and a process for the preparation of a derivative thereof. EP 0489548 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 | |
| (XI) | 14781 | 4,4,4-Trifluorobutyric acid | 406-93-9 | C4H5F3O2 | 详情 | 详情 |
| (XII) | 14782 | [(4R,5S)-4-Methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]lithium | C10H10LiNO2 | 详情 | 详情 | |
| (XIII) | 14783 | (4R,5S)-4-Methyl-5-phenyl-3-(4,4,4-trifluorobutanoyl)-1,3-oxazolan-2-one | C14H14F3NO3 | 详情 | 详情 | |
| (XIV) | 14784 | (4R,5S)-4-methyl-5-phenyl-3-[(2R)-4,4,4-trifluoro-2-methylbutyl]-1,3-oxazolan-2-one | C15H18F3NO2 | 详情 | 详情 | |
| (XV) | 14785 | (2R)-4,4,4-trifluoro-2-methyl-1-butanol | 107103-95-7 | C5H9F3O | 详情 | 详情 |
| (XVI) | 14786 | 2-[(2R)-4,4,4-trifluoro-2-methylbutyl]-1H-isoindole-1,3(2H)-dione | C13H12F3NO2 | 详情 | 详情 |