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药物详细合成路线

Name Zosuquidar trihydrochloride;LY-335979;RS-33295-198
Chemical Name (1aR,6S,10bS)-1,1-Difluoro-6-[4-[2(R)-hydroxy-3-(quinolin-5-yloxy)propyl]piperazin-1-yl]-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene trihydrochloride
      1-[4-(1,1-Difluoro-1,1aR,6S,10bS-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl)piperazin-1-yl]-3-(quinolin-5-yloxy)-2(R)-propanol trihydrochloride
CAS 167465-36-3
Related CAS 167354-41-8 (free base), 474276-97-6 (hydrochloride), 312905-17-2 (monohydrate), 167354-32-7 (stere
Formula C32H34Cl3F2N3O2
Structure
Formula Weight 637.00248
Stage III 期临床
Company Roche Bioscience (Originator), Lilly (Licensee)
Activity/Mechanism Breast Cancer Therapy, Leukemia Therapy, Modulators of the Therapeutic Activity of Antineoplastic Agents, Multidrug Resistance Modulators, Myeloid Leukemia Therapy, Oncolytic Drugs, P-Glycoprotein (MDR-1) Inhibitors
Syn. Route 3
Route 1
condensation of dibenzosuberenone (i) with sodium 2-chloro-2,2-difluoroacetate (ii) in diglyme at 165 c gives 10,11-(difluoromethano)benzosuberone (iii), which is reduced with nabh4 in thf/methanol to yield the corresponding syn-alcohol (iv). reaction of alcohol (iv) with hot socl2 affords a mixture of the syn- and anti-chloro derivatives (v). this mixture (v) is treated with 1-for-mylpiperazine (vi) in refluxing acetonitrile to provide a mixture of syn- and anti-4-[10,11-(difluoromethano)dibenzosuber-5-yl]piperazine-1-carbaldehyde (vi), which is separated by chromatography. the desired anti-isomer (vii) is then treated with koh in refluxing ethanol/water to give the piperazine derivative (viii), which is finally condensed with 5-[2(r),3-epoxypropoxy]quinoline (ix) in refluxing isopranol.5-[2(r),3-epoxypropoxy]quinoline (ix) is obtained by reaction of 5-hydroxyquinoline (x) with (r)-glycidyl tosylate (xi) by means of nah in dmf.
List of intermediates No.
(8-methoxy-2h-chromen-3-yl)(4-morpholinyl)methanone (xi)
(e)-2-butenyl 7-methyl-2,3-dihydro-1h-inden-4-yl ether; 4-[(e)-2-butenyloxy]-7-methylindane (vi)
n-(2-cyanopropyl)-2,4,6-triiodo-3-[[(e)-1-(4-morpholinyl)ethylidene]amino]benzamide (x)
(2r)-2-cyclopentyl-2-hydroxy-2-phenyl-n-(4-piperidinyl)ethanamide (i)
Reference 1:
    sorbera, l.a.; castaner, j.; silvestre, j.s.; bayes, m.; zosuquidar trihydrochloride.. drugs fut 2003, 28, 2, 125-136.
Reference 2:
    knaus, e.e.; vo, d.; wolowyk, m.w.; synthesis and cardioselective beta-adrenergic antagonist activity of quinolyloxypropanolamines. drug des discov 1992, 9, 1, 69.
Reference 3:
    bruno, n.a.; nelson, j.t.; wu, h.; muehldorf, a.v.; makra, f.; cheung, p.; slate, d.l.; zutshi, n.; casey, s.m.; pfister, j.r.; methanodibenzosuberylpiperazines as potent multidrug resistance reversal agents. bioorg med chem lett 1995, 5, 21, 2473.
Reference 4:
    pfister, j.r.; slate, d.l. (syntex (usa) llc); 10,11-methanodibenzosuberane derivs. used as chemosensitizing agents. ep 0695293; ep 0866063; jp 1996509223; wo 9424107 .

Route 2
reaction of alcohol (iv) with 48% hbr or with pbr3 affords the anti-bromo derivative (xii), which is condensed with pyrazine (xiii) in refluxing acetonitrile to give anti-1-[10,11-(difluoromethano)dibenzosuber-5-yl]pyrazinium bromide (xiv). reduction of compound (xiv) with nabh4 in ethyl acetate provides the piperazine derivative (viii), which is finally condensed with 5-[2(r),3-epoxypropoxy]quinoline (ix) - obtained by reaction of 5-hydroxyquinoline (x) with (r)-glycidyl 4-nitrobenzene- sulfonate (xv) by means of k2co3 in dmf - in hot ethanol.
List of intermediates No.
n-(2-cyanopropyl)-2,4,6-triiodo-3-[[(e)-1-(4-morpholinyl)ethylidene]amino]benzamide (x)
Reference 1:
    sorbera, l.a.; castaner, j.; silvestre, j.s.; bayes, m.; zosuquidar trihydrochloride.. drugs fut 2003, 28, 2, 125-136.
Reference 2:
    le tourneau, m.e.; wilson, t.m.; huff, b.e.; bush, j.k.; reutzel-edens, s.m. (eli lilly and company); process for preparing 10,11-methanobenzosuberane derivs.. wo 0075121 .

Route 3
condensation of the anti-bromo derivative (xii) with piperazine (xvi) in refluxing acetonitrile provides 1-[10,11-(difluoromethano)dibenzosuber-5-yl]piperazine as a mixture of syn- and anti-isomers (xvii), which is separated by crystallization. finally, the desired anti-isomer (viii) is condensed with 5-[2(r),3-epoxypropoxy]quinoline (ix) in hot ethanol.
List of intermediates No.
2,2,2-trifluoro-n-methyl-n-(trimethylsilyl)acetamide (xvi)
Reference 1:
    sorbera, l.a.; castaner, j.; silvestre, j.s.; bayes, m.; zosuquidar trihydrochloride.. drugs fut 2003, 28, 2, 125-136.
Reference 2:
    barnett, c.j.; wilson, t.m.; astleford, b.a.; kobierski, m.e. (eli lilly and company); process for preparing a 10,11-methanodibenzosuberane deriv.. wo 0075132 .

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Zosuquidar 三盐酸盐;英文名Zosuquidar trihydrochloride;LY-335979;RS-33295-198;CAS[167465-36-3]

 
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