|
【结 构 式】 
|
【分子编号】56205 【品名】6-chloro-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene 【CA登记号】 |
【 分 子 式 】C16H11ClF2 【 分 子 量 】276.7128464 【元素组成】C 69.45% H 4.01% Cl 12.81% F 13.73% |
合成路线1
该中间体在本合成路线中的序号：(V)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.
| 【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 |