氨鲁米特 [CAS125848] 合成路线图解——原料药厂家武汉东康源.doc
药物详细合成路线NameAminoglutethimide;AG-1;Orimeten;CytadrenChemical Name3-(4-Aminophenyl)-3-ethyl-2,6-piperidinedioneCAS125-84-8Related CASFormulaC13H16N2O2StructureFormula Weight232.28467TelE-mail027-81302267 18007166089 Mr YuanchemCompany武汉东康源科技有限公司Activity/MechanismAdrenocortical Dysfunction Therapy, Breast Cancer Therapy, Cushings Syndrome, Agents for, ENDOCRINE DRUGS, Oncolytic Drugs, Prostate Cancer Therapy, Antiglucocorticoids, Aromatase InhibitorsSyn. Route1Route 1an improved procedure for the large-scale preparation of (r)-aminoglutethimide has been reported. nucleophilic substitution of 1-chloro-4-nitrobenzene (i) with methyl cyanoacetate afforded the (nitrophenyl)cyanoacetate (ii), which was alkylated with diethyl sulfate in the presence of et3n, yielding (iii). hydrolysis and decarboxylation of the cyano ester (iii) by means of k2co3 in aqueous meoh provided the arylbutyronitrile (iv). subsequent michael addition with methyl acrylate gave adduct (v). this was hydrolyzed to the cyano acid (vi), which was further resolved with (-)-cinchonidine, yielding the desired (r)-enantiomer (vii). acid-catalyzed cyclization of (vii) in boiling toluene generated the glutarimide derivative (viii). the nitro group of (viii) was finally reduced to the title amino derivative by hydrogenation over pd/c.List of intermediatesNo.(4s,7r,8s,9s,16s)-8-hydroxy-5,5,7,9,13-pentamethyl-16-(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl-4-(triethylsilyl)oxyoxa-13-cyclohexadecene-2,6-dione(i)1-methyl-2-oxo-1,2-dihydro-4-pyridinecarbaldehyde2-(2-phenyl-1h-indol-3-yl)-1-ethanamine; 2-(2-phenyl-1h-indol-3-yl)ethylamine(1as,8r,9as)-3-(acetoxy)-7-(benzyloxy)-5-(benzyloxy)methoxymethyl-8-(hydroxymethyl)-1-(4-methylphenyl)sulfonyl-1,1a,2,3,8,9a-hexahydro-9h-azireno2,3-c1benzazocin-9-one(ii)(1as,8r,9as)-7-(benzyloxy)-5-(benzyloxy)methoxymethyl-3-hydroxy-8-(hydroxymethyl)-1-(4-methylphenyl)sulfonyl-1,1a,2,3,8,9a-hexahydro-9h-azireno2,3-c1benzazocin-9-one(iii)(8r,9s,10s,12s)-6-(benzyloxy)-4-(benzyloxy)methoxymethyl-8-(hydroxymethyl)-11-(4-methylphenyl)sulfonyl-14-oxa-1,11-diazatetracyclo7.4.1.0(2,7).0(10,12)tetradeca-2,4,6-trien-9-ol(iv)(1s,6r,15s,17s)-8-(benzyloxy)-10-(benzyloxy)methoxymethyl-16-(4-methylphenyl)sulfonyl-2,4,18-trioxa-13,16-diazapentacyclo11.4.1.0(1,6).0(7,12).0(15,17)octadeca-7,9,11-trien-3-one(v)(8r,9s,10s,12s)-6-(benzyloxy)-4-(benzyloxy)methoxymethyl-9-hydroxy-11-(4-methylphenyl)sulfonyl-14-oxa-1,11-diazatetracyclo7.4.1.0(2,7).0(10,12)tetradeca-2,4,6-trien-8-ylmethyl carbamate(vi)(8r,10s,12s)-8-(aminocarbonyl)oxymethyl-6-(benzyloxy)-4-(benzyloxy)methoxymethyl-11-(4-methylphenyl)sulfonyl-14-oxa-1,11-diazatetracyclo7.4.1.0(2,7).0(10,12)tetradeca-2,4,6-trien-9-yl acetate(vii)(8r,10s,12s)-8-(aminocarbonyl)oxymethyl-6-(benzyloxy)-4-(benzyloxy)methoxymethyl-14-oxa-1,11-diazatetracyclo7.4.1.0(2,7).0(10,12)tetradeca-2,4,6-trien-9-yl acetate(viii)Reference 1: bunegar, m.j.; et al.; production of (r)-aminogluthimide: a new route from 1-chloro-4-nitrobenzene. org process res dev 1999, 3, 6, 442.
