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药物详细合成路线

Name Rizatriptan benzoate;MK-462;MK-0462;Maxalt-MLT;Maxalt
Chemical Name 3-[2-(Dimethylamino)ethyl]-5-(1,2,4-triazol-1-ylmethyl)indole benzoate
CAS 145202-66-0
Related CAS 144034-80-0 (free base), 159776-67-7 (sulfate salt (2:1), monohydrate), 153764-00-2 (sulfate salt(1
Formula C22H25N5O2
Structure
Formula Weight 391.47685
Stage 上市-1998
Company Kyorin (Supplier), Merck & Co. (Originator), Merck Frosst (Originator), Eisai (Marketer)
Activity/Mechanism Acute Attacks of Migraine, Treatment of, ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, 5-HT1B Agonists, 5-HT1D Agonists
Syn. Route 3
Route 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.
List of intermediates No.
4-methoxybenzyl (7r)-7-([2-([[(1s)-2-(benzhydryloxy)-1-methyl-2-oxoethyl]oxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-3-[([1,3]thiazolo[4,5-c]pyridin-2-ylsulfanyl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-4-ethoxy-2(1h)-pyrimidinone (i)
1-[(6ar,8r,9r,9as)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6h-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-4-ethoxy-2(1h)-pyrimidinone (ii)
1-[(6ar,8r,9ar)-2,2,4,4-tetraisopropyl-9-oxotetrahydro-6h-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-4-ethoxy-2(1h)-pyrimidinone (iii)
1-[(6ar,8r,9as)-9-[(z)-fluoro(phenylsulfonyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6h-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8h)-yl]-4-ethoxy-2(1h)-pyrimidinone (iv)
1-[(6ar,8r,9as)-9-[(z)-fluoro(tributylstannyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6h-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8h)-yl]-4-ethoxy-2(1h)-pyrimidinone (v)
methyl(oxo)phenyl-lambda(4)-sulfane (vi)
Reference 1:
    casta?er, j.; mealy, n.; rabassseda, x.; mk-0462. drugs fut 1995, 20, 7, 676.
Reference 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.

Route 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.
List of intermediates No.
4-fluoro-alpha-(4-methylphenylsulfanyl)benzyl isocyanide (vii)
1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-4-ethoxy-2(1h)-pyrimidinone (i)
fluoromethyl phenyl sulfide (vi)
[(2r,3s,5r)-3-(acetoxy)-5-[4-amino-2-oxo-1(2h)-pyrimidinyl]-4-[(e)-fluoromethylidene]tetrahydro-2-furanyl]methyl acetate (viii)
[(2r,3s,5r)-3-(acetoxy)-5-[4-amino-5-iodo-2-oxo-1(2h)-pyrimidinyl]-4-[(e)-fluoromethylidene]tetrahydro-2-furanyl]methyl acetate (ix)
(2s)-1-(1,3-benzodioxol-5-yl)-2-propanol (x)
(7s)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5h-[1,3]dioxolo[4,5-g]isochromene (xi)
Reference 1:
    casta?er, j.; mealy, n.; rabassseda, x.; mk-0462. drugs fut 1995, 20, 7, 676.
Reference 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 .

Route 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.
List of intermediates No.
n-[4-(2,4-dichlorophenyl)-3-methyl-1h-pyrazol-5-yl]ethanimidamide (xii)
1-pentynylcopper (i)
fluoromethyl phenyl sulfide (vi)
[(2r,3s,5r)-3-(acetoxy)-5-[4-amino-2-oxo-1(2h)-pyrimidinyl]-4-[(e)-fluoromethylidene]tetrahydro-2-furanyl]methyl acetate (viii)
[(2r,3s,5r)-3-(acetoxy)-5-[4-amino-5-iodo-2-oxo-1(2h)-pyrimidinyl]-4-[(e)-fluoromethylidene]tetrahydro-2-furanyl]methyl acetate (xi)
acetohydrazide (xiii)
n-[(e)-[6-[(2s)-2-hydroxypropyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methylidene]acetohydrazide (xiv)
Reference 1:
    casta?er, j.; mealy, n.; rabassseda, x.; mk-0462. drugs fut 1995, 20, 7, 676.
Reference 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 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名苯甲酸利扎曲坦;英文名Rizatriptan benzoate;MK-462;MK-0462;Maxalt-MLT;Maxalt;CAS[145202-66-0]

 
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