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【结 构 式】 
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【分子编号】15345 【品名】(4S)-4-(4-aminobenzyl)-1,3-oxazolan-2-one 【CA登记号】 |
【 分 子 式 】C10H12N2O2 【 分 子 量 】192.21756 【元素组成】C 62.49% H 6.29% N 14.57% O 16.65% |
合成路线1
该中间体在本合成路线中的序号：(V)Zolmitriptan can be obtained by several related ways: 1) The esterification of L-4-nitrophenylalanine (I) with SOCl2 and methanol gives the corresponding methyl ester (II), which is reduced with NaBH4 in ethanol/water yielding (S)-2-amino-3-(4-nitrophenyl)-1-propanol (III). The cyclization of (III) with phosgene and KOH affords (S)-4-(4-nitrobenzyl)oxazolidin-2-one (IV), which is reduced with H2 over Pd/C in ethanol/water to the corresponding amino derivative (V). The diazotation of (V) with NaNO2.HCl, followed by reduction with SnCl2 in water affords the expected hydrazino derivative (VI), which is cyclized with 4-chlorobutanal diethylacetal (VII) in refluxing ethanol/water to give (S)-4-[3-(2-aminoethyl)-1H-indol-5-ylmethyl]oxazolidin-2-one (VIII). Finally, this compound is methylated with formaldehyde/sodium cyanoborohydride in methanol. 2) The reduction of L-4-nitrophenylalanine (I) to the propanol (III) can also be performed directly by treatment of (I) first with BF3.(Et)2O, followed by reduction with BH3.(CH3)2S complex in hot dimethoxyethane. 3) The cyclization of propanol (III) to oxazolidinone (IV) can also be performed with trichloromethyl chloroformate and NaOH in dichloromethane. 4) The cyclization of hydrazino derivative (VI) with 4-(dimethylamino)butanal diethylacetal (IX) in refluxing acetic acid/water directly yields zolmitriptan. 5) The condensation of hydrazino derivative (VI) with 3-cyanopropanal diethylacetal (X) in aqueous HCl gives (S)-4-[4-(N2-(3-cyanopropylidene)hydrazino]benzyl]oxazolidin-2-one (XI), which is cyclized with polyphosphate ester (PPE) in refluxing chloroform to yield (S)-4-[3-(cyanomethyl)-1H-indol-5-ylmethyl]oxazolidin-2-one (XII). Finally, this compound is reduced with H2 over Pd/C in 30% w/w ethanolic dimethylamine to afford zolmitriptan.
| 【1】 Ngo, J.; Mealy, N.; Castaner, J.; Zolmitriptan. Drugs Fut 1997, 22, 3, 260. |
| 【2】 Glen, R.C.; Martin, G.R.; Hill, A.P.; Hyde, R.M.; Woollard, P.M.; Salmon, J.A.; Buckingham, J.; Robertson, A.D.; Computer-aided design and synthesis of 5-substituted tryptamines and their pharmacology at the 5-HT1D receptor: Discovery of compounds with potential anti-migraine properties. J Med Chem 1995, 38, 18, 3566. |
| 【3】 Robertson, A.D.; Hill, A.P.; Glen, R.C.; Martin, G.R. (Glaxo Wellcome plc); Therapeutic heterocyclic cpds.. EP 0486666; EP 0636623; JP 1993502679; US 5399574; US 5466699; WO 9118897 . |
| 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) | 15341 | (2S)-2-amino-3-(4-nitrophenyl)propionic acid; 4-nitro-L-phenylalanine | 949-99-5 | C9H10N2O4 | 详情 | 详情 |
| (II) | 15342 | methyl (2S)-2-amino-3-(4-nitrophenyl)propanoate | C10H12N2O4 | 详情 | 详情 | |
| (III) | 15343 | (2S)-2-amino-3-(4-nitrophenyl)-1-propanol | C9H12N2O3 | 详情 | 详情 | |
| (IV) | 15344 | (4S)-4-(4-nitrobenzyl)-1,3-oxazolan-2-one | C10H10N2O4 | 详情 | 详情 | |
| (V) | 15345 | (4S)-4-(4-aminobenzyl)-1,3-oxazolan-2-one | C10H12N2O2 | 详情 | 详情 | |
| (VI) | 15346 | (4S)-4-(4-hydrazinobenzyl)-1,3-oxazolan-2-one | C10H13N3O2 | 详情 | 详情 | |
| (VII) | 15347 | 4-Chloro-1-ethoxybutyl ethyl ether; 4-Chloro-1,1-diethoxybutane; 4-Chlorobutyraldehyde diethyl acetal | 6139-83-9 | C8H17ClO2 | 详情 | 详情 |
| (VIII) | 15348 | (4S)-4-[[3-(2-aminoethyl)-1H-indol-5-yl]methyl]-1,3-oxazolan-2-one | C14H17N3O2 | 详情 | 详情 | |
| (IX) | 15349 | N-(4,4-diethoxybutyl)-N,N-dimethylamine; 4,4-diethoxy-N,N-dimethyl-1-butanamine | C10H23NO2 | 详情 | 详情 | |
| (X) | 15350 | 4,4-diethoxybutanenitrile; 4,4-diethoxy-butanenitrile | 18381-45-8 | C8H15NO2 | 详情 | 详情 |
| (XI) | 15351 | 4-[(E)-2-(4-[[(4S)-2-oxo-1,3-oxazolan-4-yl]methyl]phenyl)hydrazono]butanenitrile | C14H16N4O2 | 详情 | 详情 | |
| (XII) | 15352 | 2-(5-[[(4S)-2-oxo-1,3-oxazolan-4-yl]methyl]-1H-indol-3-yl)acetonitrile | C14H13N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Halogenation of the substituted aniline (VII) by means of iodine monochloride gave ortho-iodoaniline (VIII). 3-Butyn-1-ol (IX) was protected as the 1,4-bis(triethylsilyl)derivative (X) by deprotonation with butyllithium, followed by treatment with triethylsilyl chloride. Palladium-catalyzed condensation of disilylated butynol (X) with iodoaniline (VIII) furnished a mixture of the bis(silylated) tryptophol (XI) and the O-desilylated analogue (XII). Treatment of the crude mixture with methanolic HCl produced the completely desilylated indole (XIII), which was converted to mesylate (XIV) by reaction with methanesulfonyl chloride and triethylamine. Alkylation of pyrrolidine (VI) with mesylate (XIV) then yielded the target (indolylethyl)pyrrolidine, which was finally converted to the title dioxalate salt.
| 【1】 Sternfeld, F.; Guiblin, A.R.; Jelley, R.A.; et al.; Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1-yl)ethyl]indoles: Potent agonists for the h5-HT1D receptor with high selectivity over the h5-HT1B receptor. J Med Chem 1999, 42, 4, 677. |
| 【2】 Ogawa, T.; Terai, T.; Haruna, K.; Watanabe, A.; Tominaga, T.; Taguchi, H. (Senju Pharmaceuticals Co., Ltd.; Toyobo Co., Ltd.); Pharmaceutical compsn. for topical administration to the eye for treating allergic conjunctivitis. CA 2165999; EP 0719553; JP 1996231393 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 34465 | N-[(1S)-1-phenylethyl]-N-[(3R)pyrrolidinylmethyl]amine; (1S)-1-phenyl-N-[(3R)pyrrolidinylmethyl]-1-ethanamine | C13H20N2 | 详情 | 详情 | |
| (VI) | 34470 | 2-(5-[[(4S)-2-oxo-1,3-oxazolidin-4-yl]methyl]-1H-indol-3-yl)ethyl methanesulfonate | C15H18N2O5S | 详情 | 详情 | |
| (VII) | 15345 | (4S)-4-(4-aminobenzyl)-1,3-oxazolan-2-one | C10H12N2O2 | 详情 | 详情 | |
| (VIII) | 34466 | (4S)-4-(4-amino-3-iodobenzyl)-1,3-oxazolidin-2-one | C10H11IN2O2 | 详情 | 详情 | |
| (IX) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
| (X) | 16862 | triethylsilyl 4-(triethylsilyl)-3-butynyl ether; triethyl[[4-(triethylsilyl)-3-butynyl]oxy]silane | 160194-28-5 | C16H34OSi2 | 详情 | 详情 |
| (XI) | 34467 | (4S)-4-[(2-(triethylsilyl)-3-[2-[(triethylsilyl)oxy]ethyl]-1H-indol-5-yl)methyl]-1,3-oxazolidin-2-one | C26H44N2O3Si2 | 详情 | 详情 | |
| (XII) | 34468 | (4S)-4-[[3-(2-hydroxyethyl)-2-(triethylsilyl)-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one | C20H30N2O3Si | 详情 | 详情 | |
| (XIII) | 34469 | (4S)-4-[[3-(2-hydroxyethyl)-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one | C14H16N2O3 | 详情 | 详情 |