Rizatriptan benzoate, MK-462, MK-0462, Maxalt-MLT, Maxalt, -Drug Synthesis Database

【结构式】

【药物名称】Rizatriptan benzoate, MK-462, MK-0462, Maxalt-MLT, Maxalt

【化学名称】3-[2-(Dimethylamino)ethyl]-5-(1,2,4-triazol-1-ylmethyl)indole benzoate

【CA登记号】145202-66-0, 144034-80-0 (free base), 159776-67-7 (sulfate salt (2:1), monohydrate), 153764-00-2 (sulfate salt(10:5), heptahydra

【分子式】C₂₂H₂₅N₅O₂

【分子量】391.47685

【开发单位】Kyorin (Supplier), Merck & Co. (Originator), Merck Frosst (Originator), Eisai (Marketer)

【药理作用】Acute Attacks of Migraine, Treatment of, ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, 5-HT1B Agonists, 5-HT1D Agonists

合成路线1 合成路线2 合成路线3

合成路线1

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.

参考文献中间体

【1】 Castañer, J.; Mealy, N.; Rabassseda, X.; MK-0462. Drugs Fut 1995, 20, 7, 676.
【2】 Lieberman, D.R.; Reamer, R.A.; Reider, P.J.; Cottrell, I.F.; Chen, C.-Y.; Verhoeven, T.R.; Larsen, R.D.; Houghton, P.G.; Synthesis of the 5-HT1D receptor agonist MK-0462 via a Pd-catalyzed coupling reaction. Tetrahedron Lett 1994, 35, 38, 6981-4.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10202	Benzoic acid	65-85-0	C₇H₆O₂	详情	详情
(I)	16860	4-(1H-1,2,4-triazol-1-ylmethyl)aniline; 4-(1H-1,2,4-triazol-1-ylmethyl)phenylamine		C₉H₁₀N₄	详情	详情
(II)	16861	2-iodo-4-(1H-1,2,4-triazol-1-ylmethyl)phenylamine; 2-iodo-4-(1H-1,2,4-triazol-1-ylmethyl)aniline		C₉H₉IN₄	详情	详情
(III)	16862	triethylsilyl 4-(triethylsilyl)-3-butynyl ether; triethyl[[4-(triethylsilyl)-3-butynyl]oxy]silane	160194-28-5	C₁₆H₃₄OSi₂	详情	详情
(IV)	16863	2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethyl triethylsilyl ether; 5-(1H-1,2,4-triazol-1-ylmethyl)-3-[2-[(triethylsilyl)oxy]ethyl]-1H-indole		C₁₉H₂₈N₄OSi	详情	详情
(V)	16864	2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]-1-ethanol		C₁₃H₁₄N₄O	详情	详情
(VI)	16865	N,N-dimethyl-2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]-1-ethanamine; N,N-dimethyl-N-[2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethyl]amine		C₁₅H₁₉N₅	详情	详情

合成路线2

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.

参考文献中间体

【1】 Castañer, J.; Mealy, N.; Rabassseda, X.; MK-0462. Drugs Fut 1995, 20, 7, 676.
【2】 Baker, R.; Matassa, V.G.; Street, L.J. (Merck Sharp & Dohme Ltd.); Imidazole, triazole and tetrazole derivs. EP 0497512; EP 0778275; US 5298520; US 5451588; US 5602162; US 5602163 .

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)	16860	4-(1H-1,2,4-triazol-1-ylmethyl)aniline; 4-(1H-1,2,4-triazol-1-ylmethyl)phenylamine		C₉H₁₀N₄	详情	详情
(VI)	16866	1-(Bromomethyl)-4-nitrobenzene; para-Nitrobenzyl bromide	100-11-8	C₇H₆BrNO₂	详情	详情
(VII)	13104	1,2,4-Triazole, sodium derivative	41253-21-8	C₂H₂N₃Na	详情	详情
(VIII)	16868	1-(4-nitrobenzyl)-1H-1,2,4-triazole		C₉H₈N₄O₂	详情	详情
(IX)	16869	1-(4-hydrazinobenzyl)-1H-1,2,4-triazole		C₉H₁₁N₅	详情	详情
(X)	16870	4-Chlorobutyraldehyde dimethylacetal; 4-Chloro-1-methoxybutyl methyl ether; 4-Chloro-1,1-dimethoxybutane		C₆H₁₃ClO₂	详情	详情
(XI)	16871	2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine; 2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]-1-ethanamine		C₁₃H₁₅N₅	详情	详情

合成路线3

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.

参考文献中间体

【1】 Castañer, J.; Mealy, N.; Rabassseda, X.; MK-0462. Drugs Fut 1995, 20, 7, 676.
【2】 Baker, R.; Pitt, K.G.; Matassa, V.G.; Storey, D.E.; Olive, C.; Street, L.J. (Merck Sharp & Dohme Ltd.); The sulphate salt of a substd. triazole, pharmaceutical compsns. thereof, and their use in therapy. EP 0573221; US 5527817; WO 9325547 .

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)	16680	methyl (2S)-2-(acetylsulfanyl)propanoate		C₆H₁₀O₃S	详情	详情
(VI)	16866	1-(Bromomethyl)-4-nitrobenzene; para-Nitrobenzyl bromide	100-11-8	C₇H₆BrNO₂	详情	详情
(VIII)	16868	1-(4-nitrobenzyl)-1H-1,2,4-triazole		C₉H₈N₄O₂	详情	详情
(XI)	16869	1-(4-hydrazinobenzyl)-1H-1,2,4-triazole		C₉H₁₁N₅	详情	详情
(XII)	16106	4H-1,2,4-triazol-4-amine; 4-Amino-4H-1,2,4-triazole; 4H-1,2,4-triazol-4-ylamine; 4-Amino-1,2,4-triazole	584-13-4	C₂H₄N₄	详情	详情
(XIII)	16873	4-amino-1-(4-nitrobenzyl)-1H-1,2,4-triazol-4-ium bromide	6085-99-0	C₉H₁₀BrN₅O₂	详情	详情
(XIV)	16874	N-(4,4-dimethoxybutyl)-N,N-diethylamine; N,N-diethyl-4,4-dimethoxy-1-butanamine		C₁₀H₂₃NO₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)