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Loratadine, Sch-29851, Civeran, Versal, Lisino, Clarityne, Clarityn, Claritin

氯雷他定Chemical Name: 8-Chloro-11-[N-(ethoxycarbonyl)piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine; 4-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylic acid ethyl ester
CAS No. 79794-75-5
项目整合开发状态: Launched-1988
项目研究机构: Essex (Originator), Schering-Plough (Originator), Shionogi (Licensee)
合成路线:The condensation of S-methylisothiourea (I) with trans-4-(aminomethyl)cyclohexanecarboxylic acid (II) by means of NaOH in water gives trans-4-(guanidinomethyl)cyclohexanecarboxylic acid (III) (I),which is esterified with benzyl salicylate (IV) by means of dicyclohexylcarbodiimide (DCC) or SOCl2 yielding 2-benzyloxycarbonylphenyl trans-4-(guanidinomethyl)cyclohexanecarboxylate (V).Finally,this compound is treated with cyclodextrin in aqueous solution to afford the corresponding complex.

合成路线:1) By carboxylation of 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyctohepta[1,2-b]pyridine (I) with ethyl chloroformate (II) in refluxing benzene.

合成路线:2) By reaction of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (III) with the Grignard reagent (IV) to give the tertiary carbinol (V),which is dehydrated with 85% H2SO4 affording 8-chloro-11-piperidinylidene derivative (VI).Finally,cornpound (VI) is treated with ethyl chloroformate (II) in toluene.

合成路线:Alcoholysis of 3-methylpyridine-2-carbonitrile (I) with hot tert-butanol and H2SO4 gives the N-tert-butylcarboxamide (II),which is alkylated with 3-chlorobenzyl chloride (III) and BuLi in THF,yielding N-tert-butyl-3-[2-(3-chlorophenyl)ethyl]pyridine-2-carboxamide (IV).The reaction of (IV) with refluxing POCl3 and then with NaOH affords the corresponding nitrile (V),which is condensed with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF to give the ketone (VII).Cyclization of (VII) by means of either BF3 in HF or trifluoromethanesulfonic acid yields 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII),which is reacted with cyanogen bromide in benzene to give the N-cyano compound (IX).Finally,this compound is treated with HCl in refluxing acetic acid/water.Alternatively,8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII) is treated with ethyl chloroformate in hot toluene,affording the carbamate (X) (2),which is finally decarboxylated with KOH or NaOH in refluxing ethanol/water.
📌 参考资料/链接：
参考文献标题:Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6
文献作者:Villani,F.J.(Schering Corp.)
参考来源:US 4282233

📄 详细内容


合成路线:1) By carboxylation of 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyctohepta[1,2-b]pyridine (I) with ethyl chloroformate (II) in refluxing benzene.

合成路线:2) By reaction of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (III) with the Grignard reagent (IV) to give the tertiary carbinol (V),which is dehydrated with 85% H2SO4 affording 8-chloro-11-piperidinylidene derivative (VI).Finally,cornpound (VI) is treated with ethyl chloroformate (II) in toluene.

合成路线:The nitration of loratadine (I) (1) by means of tetrabutylammonium nitrate and trifluoroacetic anhydride (TFAA) in dichloromethane gives the 3-nitro derivative (II),which is reduced with iron filings and CaCl2 in refluxing ethanol/water to yield the 3-amino derivative (III).Treatment of compound (III) with NaNO2,HBr and Br2 provides 4-(3-bromo-8-chloro-5,6-dihydro-1H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylic acid ethyl ester (IV) (see scheme 25468001a,intermediate (I).(2)

参考文献标题:Loratadine
文献作者:Prous,J.; Castar,J.
参考来源:Drugs Fut 1987,12(6),544


合成路线:1) By carboxylation of 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyctohepta[1,2-b]pyridine (I) with ethyl chloroformate (II) in refluxing benzene.

合成路线:2) By reaction of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (III) with the Grignard reagent (IV) to give the tertiary carbinol (V),which is dehydrated with 85% H2SO4 affording 8-chloro-11-piperidinylidene derivative (VI).Finally,cornpound (VI) is treated with ethyl chloroformate (II) in toluene.

参考文献标题:N-substituted 11-(4-piperidylene)-5,6-dihydro-11H-
文献作者:Magatti,C.V.; Villani,F.J.; Wong,J.; Poper,T.L.; Vashi,D.B.
参考来源:Arzneim-Forsch Drug Res 1986,36(9),1311


合成路线:1) By carboxylation of 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyctohepta[1,2-b]pyridine (I) with ethyl chloroformate (II) in refluxing benzene.

合成路线:2) By reaction of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (III) with the Grignard reagent (IV) to give the tertiary carbinol (V),which is dehydrated with 85% H2SO4 affording 8-chloro-11-piperidinylidene derivative (VI).Finally,cornpound (VI) is treated with ethyl chloroformate (II) in toluene.
参考文献标题:Derivatives of 10,11-dihydro-5H-dibenzola[a,d]cyclheptene and related compounds.6.Aminoalkyl derivatives of the aza isosteres
文献作者:Villani,F.J.; Daniels,P.J.; Ellis,C.A.; Mann,T.A.; Wang,K.C.; Wefer,E.A.
参考来源:J Med Chem 1972,15(7),750


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