Zosuquidar trihydrochloride, LY-335979, RS-33295-198, -Drug Synthesis Database

【结构式】

【药物名称】Zosuquidar trihydrochloride, LY-335979, RS-33295-198

【化学名称】(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

【CA登记号】167465-36-3, 167354-41-8 (free base), 474276-97-6 (hydrochloride), 312905-17-2 (monohydrate), 167354-32-7 (stereoisomer), 167354

【分子式】C₃₂H₃₄Cl₃F₂N₃O₂

【分子量】637.00248

【开发单位】Roche Bioscience (Originator), Lilly (Licensee)

【药理作用】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

合成路线1 合成路线2 合成路线3

合成路线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.

参考文献中间体

【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Bayes, M.; Zosuquidar Trihydrochloride.. Drugs Fut 2003, 28, 2, 125-136.
【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.
【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.
【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 .

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)	29151	5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone	2222-33-5	C₁₅H₁₀O	详情	详情
(II)	59522	sodium 2-chloro-2,2-difluoroacetate		C₂ClF₂NaO₂	详情	详情
(III)	56203	1,1-difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]cyclohepten-6(1H)-one		C₁₆H₁₀F₂O	详情	详情
(IV)	56204	(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol		C₁₆H₁₂F₂O	详情	详情
(V)	56205	6-chloro-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene		C₁₆H₁₁ClF₂	详情	详情
(VI)	23801	1-piperazinecarbaldehyde; N-Formylpiperazine	7755-92-2	C₅H₁₀N₂O	详情	详情
(VII)	56206	4-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]-1-piperazinecarbaldehyde		C₂₁H₂₀F₂N₂O	详情	详情
(VIII)	56207	1-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]piperazine		C₂₀H₂₀F₂N₂	详情	详情
(IX)	56211	(2R)oxiranylmethyl 5-quinolinyl ether; 5-[(2R)oxiranylmethoxy]quinoline		C₁₂H₁₁NO₂	详情	详情
(X)	23805	5-quinolinol	578-67-6	C₉H₇NO	详情	详情
(XI)	16242	(2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate	113826-06-5	C₁₀H₁₂O₄S	详情	详情

合成路线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.

参考文献中间体

【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Bayes, M.; Zosuquidar Trihydrochloride.. Drugs Fut 2003, 28, 2, 125-136.
【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 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	56204	(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol		C₁₆H₁₂F₂O	详情	详情
(VIII)	56207	1-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]piperazine		C₂₀H₂₀F₂N₂	详情	详情
(IX)	56211	(2R)oxiranylmethyl 5-quinolinyl ether; 5-[(2R)oxiranylmethoxy]quinoline		C₁₂H₁₁NO₂	详情	详情
(X)	23805	5-quinolinol	578-67-6	C₉H₇NO	详情	详情
(XII)	56208	(1aR,10bS)-6-bromo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene		C₁₆H₁₁BrF₂	详情	详情
(XIII)	56209	pyrazine		C₄H₄N₂	详情	详情
(XIV)	56210	1-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]pyrazin-1-ium bromide		C₂₀H₁₅BrF₂N₂	详情	详情
(XV)	56212	(2R)oxiranylmethyl 3-nitrobenzenesulfonate		C₉H₉NO₆S	详情	详情

合成路线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.

参考文献中间体

【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Bayes, M.; Zosuquidar Trihydrochloride.. Drugs Fut 2003, 28, 2, 125-136.
【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 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	56207	1-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]piperazine		C₂₀H₂₀F₂N₂	详情	详情
(IX)	56211	(2R)oxiranylmethyl 5-quinolinyl ether; 5-[(2R)oxiranylmethoxy]quinoline		C₁₂H₁₁NO₂	详情	详情
(XII)	56208	(1aR,10bS)-6-bromo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene		C₁₆H₁₁BrF₂	详情	详情
(XVI)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(XVII)	59523	1-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]piperazine		C₂₀H₂₀F₂N₂	详情	详情

Extended Information