合成路線圖解——原料藥廠家武漢東康源

1、.藥物詳細(xì)合成路線NameAminoglutethimide;AG-1;Orimeten;CytadrenChemical Name3-(4-Aminophenyl)-3-ethyl-2,6-piperidinedioneCAS125-84-8Related CASFormulaC13H16N2O2StructureFormula Weight232.28467TelE-mai18007166089 Mr YuanchemCompany武漢東康源科技有限公司Activity/MechanismAdrenocortical Dysfunction Therapy, B

2、reast 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-

3、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 (

4、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

5、(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-meth

6、yl-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,9

7、as)-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

8、,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-meth

9、ylphenyl)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)