藥物詳細合成路線

Name	Tipifarnib;NSC-702818;R-115777;Zarnestra
Chemical Name	(+)-(R)-6-[1-Amino-1-(4-chlorophenyl)-1-(1-methylimidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2(1H)-one
CAS	192185-72-1
Related CAS	192185-68-5 (racemate), 192185-70-9 (racemic; diHCl), 192185-69-6 (racemic; fumarate)
Formula	C27H22Cl2N4O
Structure
Formula Weight	489.40859
Stage	III 期臨床
Company	Janssen (Originator), National Cancer Institute (Codevelopment)
Activity/Mechanism	Bladder Cancer Therapy , Brain Cancer Therapy, Breast Cancer Therapy, Glioblastoma MultiformeTherapy, Leukemia Therapy, Lung Cancer Therapy, Melanoma Therapy, Myeloid Leukemia Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Pancreatic Cancer Therapy, Prostate Cancer Therapy, Solid Tumors Therapy, Farnesyl Transferase Inhibitors, Inhibitors of Signal Transduction Pathways
Syn. Route	1

Route 1 cyclization of 3-(3-chlorophenyl)-n-phenyl-2-propenamide (i) by means of polyphosphoric acid (ppa) at 100 c gives 4-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-2-one (ii), which is condensed with 4-chlorobenzoic acid (iii) by means of ppa at 140 c to yield 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-2-one (iv). the dehydrogenation of (iv) by means of br2 in bromobenzene at 160 c affords 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)quinolin-2(1h)-one (v), which is methylated with iodomethane and naoh/benzyltrimethylammonium chloride in thf to provide 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methylquinolin-2(1h)-one (vi). condensation of compound (vi) with 1-methylimidazole (vii) by means of butyllithium in thf gives the triaryl carbinol (viii), which is finally treated with ammonia in thf to afford r-115777. List of intermediates No. methyl 5-acetyl-2-[(2-oxotetrahydro-3-furanyl)oxy]benzoate (iii) ethyl 5-amino-1-(4-methoxybenzyl)-1h-pyrazole-4-carboxylate (vii) (4r,5r)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-[4-(4-hydroxybutoxy)phenyl]-2,3,4,5-tetrahydro-1h-1lambda~6~-benzothiepine-1,1-dione (i) 4-{4-[(4r,5r)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1h-1lambda~6~-benzothiepin-5-yl]phenoxy}butyl methanesulfonate (ii) (6r,7r)-3-[(acetyloxy)methyl]-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iv) benzhydryl (6r,7r)-3-(hydroxymethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (v) (2r)-2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)ethanoic acid (vi) diphenylmethyl 3-(chloromethyl)-7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (viii) Reference 1:     sorbera, l.a.; castaner, j.; fernandez, r.; r-115777. drugs fut 2001, 26, 5, 453. Reference 2:     venet, m.g.; angibaud, p.r.; muller, p.; sanz, g.c. (janssen pharmaceutica nv); farnesyl protein transferase inhibiting (imidazol-5-yl)methyl-2-quinolinone derivs.. ep 0865440; jp 1998511405; us 6037350; wo 9721701 .

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名替吡法尼；英文名Tipifarnib;NSC-702818;R-115777;Zarnestra；CAS[192185-72-1]

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