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【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
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
(VII) 15739 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one C12H12N2O 详情 详情
(XIX) 66075 2(1H)-Pyridinone,5,6-dihydro-4-(2-methyl-2-phenylhydrazinyl)- 139122-76-2 C12H15N3O 详情 详情

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
Extended Information