8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine -Drug Synthesis Database

【结构式】

【分子编号】17840

【品名】8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

【CA登记号】

【分子式】C₁₉H₁₉ClN₂

【分子量】310.82604

【元素组成】C 73.42% H 6.16% Cl 11.41% N 9.01%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【1】 Magatti, C.V.; Villani, F.J.; Wong, J.; Poper, T.L.; Vashi, D.B.; N-substituted 11-(4-piperidylene)-5,6-dihydro-11H-. Arzneim-Forsch Drug Res 1986, 36, 9, 1311.
【2】 Magatti, C.V.; Vashi, D.B.; Wong, J.; Poper, T.L.; Villani, F.J.; Derivatives of 10,11-dihydro-5H-dibenzola[a,d]cycl. J Med Chem 1972, 15, 7, 750.
【3】 Villani, F.J. (Schering Corp.); Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6. US 4282233 .
【4】 Prous, J.; Castaner, J.; Loratadine. Drugs Fut 1987, 12, 6, 544.

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)	17840	8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₉H₁₉ClN₂	详情	详情
(II)	16993	methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate	79-22-1	C₂H₃ClO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

N-tert-Butyl-3-methyl-2-pyridinecarboxamide (I) was treated with two equivalents of butyllithium at -40 C, and the resulting dianion was C-alkylated with 3-chlorobenzyl chloride (II) to provide the phenetylpyridine (III). Further refluxing with phosphoryl chloride afforded nitrile (IV), which was condensed with the piperidinyl Grignard reagent (V) to yield, after hydrolysis, ketone (VI). Acid-catalyzed cyclization of ketone (VI) produced the tricyclic compound (VII). Demethylation was then accomplished by conversion to the ethyl carbamate (VIII) by treatment with ethyl chloroformate, followed by hydrolysis to the N-unsubstituted piperidine (IX). Finally, acetylation of (IX) in the presence of pyridine provided the target amide.

参考文献中间体

合成目标

【1】 Billah, M.M.; Green, M.J.; Wong, J.K.; Piwinski, J.J.; West, R.E. Jr.; Ganguly, A.K.; Kreutner, W.; Dual antagonists of platelet activating factor and histamine. Identification of structural requirements for dual activity of N-acyl-4-(5,6-dihydro-11H-benzo[5,6]cyclohepta-[1,2-b]pyridin-11-ylidene)piperidines. J Med Chem 1991, 34, 1, 457.

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)	16501	N-(tert-butyl)-3-methyl-2-pyridinecarboxamide		C₁₁H₁₆N₂O	详情	详情
(II)	20642	1-chloro-3-(chloromethyl)benzene; 3-Chlorobenzyl chloride	620-20-2	C₇H₆Cl₂	详情	详情
(III)	20643	N-(tert-butyl)-3-(3-chlorophenethyl)-2-pyridinecarboxamide		C₁₈H₂₁ClN₂O	详情	详情
(IV)	20644	3-(3-chlorophenethyl)-2-pyridinecarbonitrile		C₁₄H₁₁ClN₂	详情	详情
(V)	20645	chloro(1-methyl-4-piperidinyl)magnesium		C₆H₁₂ClMgN	详情	详情
(VI)	20646	[3-(3-chlorophenethyl)-2-pyridinyl](1-methyl-4-piperidinyl)methanone		C₂₀H₂₃ClN₂O	详情	详情
(VII)	20647	8-chloro-11-(1-methyl-4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine	38092-89-6	C₂₀H₂₁ClN₂	详情	详情
(VIII)	17877	ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate	79794-75-5	C₂₂H₂₃ClN₂O₂	详情	详情
(IX)	17840	8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₉H₁₉ClN₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Isomerization of (I) in refluxing trifluoromethanesulfonic acid provided the endocyclic olefin (II). Further reaction with ethyl chloroformate and triethylamine in toluene gave carbamate (III), which was then nitrated with a cooled mixture tetra-n-butylammonium nitrate and trifluoroacetic anhydride in dicloromethane, to afford a mixture of nitrocompounds (IV) and (V). After separation by column chromatography on silica gel, nitrocompound (V )was reduced with iron powder and calcium chloride in refluxing aqueous ethanol to amine (VII). Diazotization of amine (VII) with NaNO2 in 48% HBr in the presence of bromine at -5 C gave a mixture of monobromide (VIII) and dibromide (IX), which were separated on column chromatography. The dibromocarbamate (IX) was hydrolyzed in refluxing HCl to amine (X), which was finally coupled with 4-pyridylacetic acid N-oxide (XI) by treatment with EDC and HOBT.

参考文献中间体

合成目标

【1】 Njoroge, F.G.; et al.; Potent, selective, and orally bioavailable tricyclic pyridyl acetamide N-oxide inhibitors of farnesyl protein transferase with enhanced in vivo antitumor activity. J Med Chem 1998, 41, 10, 1561.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	17840	8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine	C₁₉H₁₉ClN₂	详情	详情
(II)	17841	8-chloro-11-(4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine	C₁₉H₁₉ClN₂	详情	详情
(III)	17842	ethyl 4-(8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinecarboxylate	C₂₂H₂₃ClN₂O₂	详情	详情
(IV)	17843	ethyl 4-(8-chloro-6-nitro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinecarboxylate	C₂₂H₂₂ClN₃O₄	详情	详情
(V)	17844	ethyl 4-(8-chloro-3-nitro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinecarboxylate	C₂₂H₂₂ClN₃O₄	详情	详情
(VII)	17845	ethyl 4-(3-amino-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinecarboxylate	C₂₂H₂₄ClN₃O₂	详情	详情
(VIII)	17846	ethyl 4-(3-bromo-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinecarboxylate	C₂₂H₂₂BrClN₂O₂	详情	详情
(IX)	17847	ethyl 4-(3,5-dibromo-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinecarboxylate	C₂₂H₂₁Br₂ClN₂O₂	详情	详情
(X)	17848	3,5-dibromo-8-chloro-11-(4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine	C₁₉H₁₇Br₂ClN₂	详情	详情
(XI)	17849	2-(1-hydroxy-1lambda(5)-pyridin-4-yl)acetic acid	C₇H₉NO₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(II)

Carbamate (I) was hydrolyzed to amine (II) by treatment with an ethanolic solution of HCl, which was then isomerized to the endocyclic compound (III) on heating with trifluoromethanesulfonic acid. Compound III was protected as the carbamate (IV) by reaction with ethyl chloroformate, and further nitration was effected with tetra-n-butylammonium nitrate - trifluoroacetic anhydride (TFAA) reagent to afford nitro compound (V). Subsequent deprotection of carbamate was effected with ethanolic HCl, to give amine (VI), which was then condensed with 4-pyridylacetic acid (VII) to the amide (VIII). Reduction of the nitro group of (VIII) with tin (II) chloride yielded oxime (IX) (SCH 59948), and reaction of this compound with acetyl chloride gave the corresponding oxime acetate (SCH 60102).

参考文献中间体

合成目标

【1】 del Rosario, J.D.; et al.; Benzocycloheptapyridine farnesyl protein transferase inhibitors: Effects of substitution at position 5 and 6 on enzyme inhibition. 213th ACS Natl Meet (April 13-17, San Francisco) 1997, Abst MEDI 198.

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)	17877	ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate	79794-75-5	C₂₂H₂₃ClN₂O₂	详情	详情
(II)	17840	8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₉H₁₉ClN₂	详情	详情
(III)	17841	8-chloro-11-(4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₉H₁₉ClN₂	详情	详情
(IV)	17842	ethyl 4-(8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinecarboxylate		C₂₂H₂₃ClN₂O₂	详情	详情
(V)	17843	ethyl 4-(8-chloro-6-nitro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinecarboxylate		C₂₂H₂₂ClN₃O₄	详情	详情
(VI)	17882	8-chloro-6-nitro-11-(4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₉H₁₈ClN₃O₂	详情	详情
(VII)	17883	2-(4-pyridinyl)acetic acid	28356-58-3	C₇H₇NO₂	详情	详情
(VIII)	17884	1-[4-(8-chloro-6-nitro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinyl]-2-(4-pyridinyl)-1-ethanone		C₂₆H₂₃ClN₄O₃	详情	详情
(IX)	17885	8-chloro-11-[1-[2-(4-pyridinyl)acetyl]-4-piperidinyl]-5,11-dihydro-6H-benzo[5,6]cyclohepta[1,2-b]pyridin-6-one oxime		C₂₆H₂₅ClN₄O₂	详情	详情

Extended Information