Rizatriptan benzoate, MK-462, MK-0462, Maxalt-MLT, Maxalt
苯甲酸利扎曲坦 利扎曲坦 N,N-二甲基-2-[5-(1H-1,2,4-三唑-1-甲基)-1H-吲哚-3-基]乙氨酸硫酸盐水合物(2:1:1)Chemical Name: 3-[2-(Dimethylamino)ethyl]-5-(1,2,4-triazol-1-ylmethyl)indole benzoate
CAS No. 145202-66-0, 144034-80-0 (free base), 159776-67-7 (sulfate salt (2:1), monohydrate), 153764-00-2 (sulfate salt(10:5), heptahydrate)
项目整合开发状态: Launched-1998
项目研究机构: Kyorin (Supplier), Merck & Co. (Originator), Merck Frosst (Originator), Eisai (Marketer)
合成路线:2) The condensation of 4-nitrobenzyl bromide (VI) with 1,2,4-triazole sodium salt (VII) in DMF gives 1-(4-nitrobenzyl)-1,2,4-triazole (VIII),which is reduced with H2 over Pd/C in ethanol/ethyl acetate yielding the aniline (I).The diazotization of (I) with NaNO2/HCl followed by reduction with SnCl2 affords the corresponding hydrazine (IX),which is cyclized with 4-chlorobutanal dimethylacetal (X) by means of HCl in refluxing ethanol/water to afford 2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl] ethylamine (XI).Finally,this amine is methylated with formaldehyde,sodium cyanoborohydride and acetic acid in methanol.
📌 参考资料/链接：
参考文献标题:Imidazole,triazole and tetrazole derivs
文献作者:Baker,R.; Matassa,V.G.; Street,L.J.(Merck Sharp & Dohme Ltd.)
参考来源:EP 0497512; EP 0778275; US 5298520; US 5451588; US 5602162; US 5602163
📄 详细内容
合成路线:3) The condensation of 4-nitrobenzyl bromide (VI) with 4-amino-1,2,4-triazole (XII) in refluxing isopropanol gives 4-amino-1-(3-nitrobenzyl)-1,2,4-triazolium bromide (XIII),which is deaminated with NaNO2/HCl to afford 1-(4-nitrobenzyl)-1,2,4-triazole (VIII).The reduction of (VIII) yields amine (I),which by diazotation and reduction with Na2SO3 yields the corresponding hydrazine (IX).Finally,(IX) is cyclized with 4-(dimethylamino)butanal dimethylacetal (XIV) in acidic water.
参考文献标题:The sulphate salt of a substd.triazole,pharmaceutical compsns.thereof,and their use in therapy
文献作者:Baker,R.; Pitt,K.G.; Matassa,V.G.; Storey,D.E.; Olive,C.; Street,L.J.(Merck Sharp & Dohme Ltd.)
参考来源:EP 0573221; US 5527817; WO 9325547
合成路线:1) The iodination of 4-(1,2,4-triazol-1-ylmethyl)aniline (I) with ICl and CaCO3 in methanol/water gives the 2-iodoaniline (II),which is cyclized with 1-(triethylsilyl)-4-(triethylsilyloxy)-1-butyne (III) by means of paladium acetate and Na2CO3 in hot DMF yielding 5-(1,2,4-triazol-1-ylmethyl)-3-[2-(triethylsilyloxy)ethyl]-1H-indole (IV).The desilylation of (IV) with HCl in methanol affords the corresponding alcohol (V),which is condensed with dimethylamine by means of methanesulfonyl chloride and triethylamine to give MK-0462 free base (VI).Finally,this compound is treated with benzoic acid in isopropyl alcohol/isopropyl acetate solution.
参考文献标题:Synthesis of the 5-HT1D receptor agonist MK-0462 via a Pd-catalyzed coupling reaction
文献作者:Lieberman,D.R.; Reamer,R.A.; Reider,P.J.; Cottrell,I.F.; Chen,C.-Y.; Verhoeven,T.R.; Larsen,R.D.; Houghton,P.G.
参考来源:Tetrahedron Lett 1994,35(38),6981-4
合成路线:1) The iodination of 4-(1,2,4-triazol-1-ylmethyl)aniline (I) with ICl and CaCO3 in methanol/water gives the 2-iodoaniline (II),which is cyclized with 1-(triethylsilyl)-4-(triethylsilyloxy)-1-butyne (III) by means of paladium acetate and Na2CO3 in hot DMF yielding 5-(1,2,4-triazol-1-ylmethyl)-3-[2-(triethylsilyloxy)ethyl]-1H-indole (IV).The desilylation of (IV) with HCl in methanol affords the corresponding alcohol (V),which is condensed with dimethylamine by means of methanesulfonyl chloride and triethylamine to give MK-0462 free base (VI).Finally,this compound is treated with benzoic acid in isopropyl alcohol/isopropyl acetate solution.
合成路线:2) The condensation of 4-nitrobenzyl bromide (VI) with 1,2,4-triazole sodium salt (VII) in DMF gives 1-(4-nitrobenzyl)-1,2,4-triazole (VIII),which is reduced with H2 over Pd/C in ethanol/ethyl acetate yielding the aniline (I).The diazotization of (I) with NaNO2/HCl followed by reduction with SnCl2 affords the corresponding hydrazine (IX),which is cyclized with 4-chlorobutanal dimethylacetal (X) by means of HCl in refluxing ethanol/water to afford 2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl] ethylamine (XI).Finally,this amine is methylated with formaldehyde,sodium cyanoborohydride and acetic acid in methanol.
合成路线:3) The condensation of 4-nitrobenzyl bromide (VI) with 4-amino-1,2,4-triazole (XII) in refluxing isopropanol gives 4-amino-1-(3-nitrobenzyl)-1,2,4-triazolium bromide (XIII),which is deaminated with NaNO2/HCl to afford 1-(4-nitrobenzyl)-1,2,4-triazole (VIII).The reduction of (VIII) yields amine (I),which by diazotation and reduction with Na2SO3 yields the corresponding hydrazine (IX).Finally,(IX) is cyclized with 4-(dimethylamino)butanal dimethylacetal (XIV) in acidic water.
参考文献标题:MK-0462
文献作者:Castar,J.; Mealy,N.; Rabassseda,X.
参考来源:Drugs Fut 1995,20(7),676