【结 构 式】 |
【药物名称】Alosetron hydrochloride, GR-68755C, Lotronex 【化学名称】5-Methyl-2-(5-methyl-1H-imidazol-4-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one hydrochloride 【CA登记号】132414-02-9, 122852-42-0 (free base), 122852-43-1 (maleate), 122852-69-1 (monoHCl) 【 分 子 式 】C17H19ClN4O 【 分 子 量 】330.82018 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】GASTROINTESTINAL DRUGS, Irritable Bowel Syndrome, Agents for, Non-Ulcer Dyspepsia, Agents for, 5-HT3 Antagonists |
合成路线1
【1】 Coates IH, North PC, Oxford AW. 1989. Preparation of(imidazolylmethyl) oxoheterocycloindoles as 5-HT3 antagonists, EP 306323 |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VII) | 15739 | 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one | C12H12N2O | 详情 | 详情 | |
(XVI) | 66072 | 4-methyl-2,3-dihydrocyclopenta[b]indol-1(4H)-one oxime | C12H12N2O | 详情 | 详情 | |
(XVII) | 66074 | 4-ethyl-5-methyl-1-(phosphinomethyl)-1H-imidazole | C7H13N2P | 详情 | 详情 | |
(XVIII) | 66073 | 4-methyl-2,3-dihydrocyclopenta[b]indol-1(4H)-one | C12H11NO | 详情 | 详情 |
合成路线2
【1】 Zhu ZH,Li RD.2001.Synthesis of alosetron hydrochloride.中国医药工业杂志,32(6):246-247 |
合成路线3
【1】 Prakash SR, Cable SR, Correa ID, et al. 1995. Synthesis o{ isotopically labeled pyridoindolane 5-HT3 receptor antagonists J Label Comp Radiopluum, 36 (10): 993~1007 |
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) | 14216 | (5-Methyl-1H-imidazol-4-yl)methanol | 29636-87-1 | C5H8N2O | 详情 | 详情 |
(XX) | 16598 | Formamide | 75-12-7 | CH3NO | 详情 | 详情 |
(XXI) | 66076 | methyl 3-chloro-5-oxohexanoate | C7H11ClO3 | 详情 | 详情 | |
(XXII) | 66077 | methyl 4-methyl-1H-imidazole-5-carboxylate | C6H8N2O2 | 详情 | 详情 | |
(XXIII) | 66078 | (4-methyl-1H-imidazol-5-yl)methanol | C5H8N2O | 详情 | 详情 |
合成路线4
1) Treatment of 4-methyl-5-hydroxymethylimidazole (I) with trimethylsilyl chloride and triethylamine followed by reaction with N,N-dimethylsulfamoyl chloride gives the protected imidazole (II). Removal of the trimethylsilyl group by means of tetrabutylammonium fluoride affords the 5-hydroxymethylimidazole (III), which is converted into the chloromethylimidazole (IV) with thionyl chloride.
【1】 Oxford, A.W.; Hagan, R.M.; Tyers, M.B.; Kilpatrick, G.J.; North, P.C.; GR-68755 Hydrochloride. Drugs Fut 1992, 17, 8, 660. |
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) | 14216 | (5-Methyl-1H-imidazol-4-yl)methanol | 29636-87-1 | C5H8N2O | 详情 | 详情 |
(II) | 15734 | N-methyl-N-[[(5-methyl-4-[[(trimethylsilyl)oxy]methyl]-1H-imidazol-1-yl)sulfinyl]oxy]methanamine; N,N-dimethyl-N-[[(5-methyl-4-[[(trimethylsilyl)oxy]methyl]-1H-imidazol-1-yl)sulfinyl]oxy]amine | C10H21N3O3SSi | 详情 | 详情 | |
(III) | 15735 | (1-[[(dimethylamino)oxy]sulfinyl]-5-methyl-1H-imidazol-4-yl)methanol | C7H13N3O3S | 详情 | 详情 | |
(IV) | 15736 | N-([[4-(chloromethyl)-5-methyl-1H-imidazol-1-yl]sulfinyl]oxy)-N-methylmethanamine; N-([[4-(chloromethyl)-5-methyl-1H-imidazol-1-yl]sulfinyl]oxy)-N,N-dimethylamine | C7H12ClN3O2S | 详情 | 详情 |
合成路线5
2) Alkylation of the tetrahydropyridoindolone (VII) with 5-chloromethyl-4-methyloxazole (VIII) in dimethoxyethane in the presence of sodium hydride affords (IX). Ammonolysis of this material is carried out by heating with formamide.
【1】 Oxford, A.W.; Hagan, R.M.; Tyers, M.B.; Kilpatrick, G.J.; North, P.C.; GR-68755 Hydrochloride. Drugs Fut 1992, 17, 8, 660. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
53911 | 1-Methyl-1-phenylhydrazine; 1-Methylphenylhydrazine | 618-40-6 | C7H10N2 | 详情 | 详情 | |
(V) | 15737 | dihydro-2,4(1H,3H)-pyridinedione | C5H7NO2 | 详情 | 详情 | |
(VI) | 15738 | 4-[(Z)-methyl(phenyl)-lambda(5)-azanylidene]dihydro-2(1H,3H)-pyridinone | C12H16N2O | 详情 | 详情 | |
(VII) | 15739 | 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one | C12H12N2O | 详情 | 详情 | |
(VIII) | 15740 | 5-(chloromethyl)-4-methyl-1,3-oxazole | C5H6ClNO | 详情 | 详情 | |
(IX) | 15741 | 5-methyl-2-[(4-methyl-1,3-oxazol-5-yl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one | C17H17N3O2 | 详情 | 详情 |
合成路线6
3) Treatment of 2-(1-methylindol-2-yl)ethanamine (X) in dichloromethane with trifluoroacetic anhydride and triethylamine yields the trifluoroacetamide (XI). This is alkylated with the chloromethylimidazole (IV) to give (XII) and then treated with aqueous potassium carbonate to generate the amino derivative (XIII). Finally, the reaction of (XIII) with phosgene and aluminum chloride in methylene chloride effects acylation and cyclization with concomitant removal of the protecting group.
【1】 Oxford, A.W.; Hagan, R.M.; Tyers, M.B.; Kilpatrick, G.J.; North, P.C.; GR-68755 Hydrochloride. Drugs Fut 1992, 17, 8, 660. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(X) | 15742 | 2-(1-methyl-1H-indol-2-yl)ethylamine; 2-(1-methyl-1H-indol-2-yl)-1-ethanamine | C11H14N2 | 详情 | 详情 | |
(XI) | 15743 | 2,2,2-trifluoro-N-[2-(1-methyl-1H-indol-2-yl)ethyl]acetamide | C13H13F3N2O | 详情 | 详情 | |
(XII) | 15744 | N-[(1-[[(dimethylamino)oxy]sulfinyl]-5-methyl-1H-imidazol-4-yl)methyl]-2,2,2-trifluoro-N-[2-(1-methyl-1H-indol-2-yl)ethyl]acetamide | C20H24F3N5O3S | 详情 | 详情 | |
(XIII) | 15745 | N-[(1-[[(dimethylamino)oxy]sulfinyl]-5-methyl-1H-imidazol-4-yl)methyl]-N-[2-(1-methyl-1H-indol-2-yl)ethyl]amine; N-[(1-[[(dimethylamino)oxy]sulfinyl]-5-methyl-1H-imidazol-4-yl)methyl]-2-(1-methyl-1H-indol-2-yl)-1-ethanamine | C18H25N5O2S | 详情 | 详情 |
合成路线7
4) Treatment of the 2-substituted indole (XII) with iodine and potassium iodide in aqueous solution in the presence of potassium carbonate yields the corresponding 3-iodo derivative (XIV). Hydrolysis of the trifluoroacetyl group with aqueous potassium carbonate gives the amino derivative (XV), which undergoes a palladium-catalyzed carbonylation reaction to form the lactam. Finally, the protecting group is removed with hydrochloric acid.
【1】 Oxford, A.W.; Hagan, R.M.; Tyers, M.B.; Kilpatrick, G.J.; North, P.C.; GR-68755 Hydrochloride. Drugs Fut 1992, 17, 8, 660. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XII) | 15744 | N-[(1-[[(dimethylamino)oxy]sulfinyl]-5-methyl-1H-imidazol-4-yl)methyl]-2,2,2-trifluoro-N-[2-(1-methyl-1H-indol-2-yl)ethyl]acetamide | C20H24F3N5O3S | 详情 | 详情 | |
(XIV) | 15746 | N-[(1-[[(dimethylamino)oxy]sulfinyl]-5-methyl-1H-imidazol-4-yl)methyl]-2,2,2-trifluoro-N-[2-(3-iodo-1-methyl-1H-indol-2-yl)ethyl]acetamide | C20H23F3IN5O3S | 详情 | 详情 | |
(XV) | 15747 | N-[(1-[[(dimethylamino)oxy]sulfinyl]-5-methyl-1H-imidazol-4-yl)methyl]-2-(3-iodo-1-methyl-1H-indol-2-yl)-1-ethanamine; N-[(1-[[(dimethylamino)oxy]sulfinyl]-5-methyl-1H-imidazol-4-yl)methyl]-N-[2-(3-iodo-1-methyl-1H-indol-2-yl)ethyl]amine | C18H24IN5O2S | 详情 | 详情 |