ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】17877

【品名】ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate

【CA登记号】79794-75-5

【分子式】C₂₂H₂₃ClN₂O₂

【分子量】382.8896

【元素组成】C 69.01% H 6.05% Cl 9.26% N 7.32% O 8.36%

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：(X)

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.

参考文献中间体

合成目标

【1】 Villani, F.J.; Wong, J.K. (Schering Corp.); Antihistaminic 8-(halo)-substituted 6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines. WO 8503707 .
【2】 Castaner, J.; Leeson, P.; Graul, A.; Desloratadine. Drugs Fut 2000, 25, 4, 339.
【3】 Villani, F.J. (Schering Corp.); Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6. US 4282233 .

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)	16500	3-methyl-2-pyridinecarbonitrile	20970-75-6	C₇H₆N₂	详情	详情
(II)	16501	N-(tert-butyl)-3-methyl-2-pyridinecarboxamide		C₁₁H₁₆N₂O	详情	详情
(III)	20642	1-chloro-3-(chloromethyl)benzene; 3-Chlorobenzyl chloride	620-20-2	C₇H₆Cl₂	详情	详情
(IV)	20643	N-(tert-butyl)-3-(3-chlorophenethyl)-2-pyridinecarboxamide		C₁₈H₂₁ClN₂O	详情	详情
(V)	20644	3-(3-chlorophenethyl)-2-pyridinecarbonitrile		C₁₄H₁₁ClN₂	详情	详情
(VI)	20645	chloro(1-methyl-4-piperidinyl)magnesium		C₆H₁₂ClMgN	详情	详情
(VII)	20646	[3-(3-chlorophenethyl)-2-pyridinyl](1-methyl-4-piperidinyl)methanone		C₂₀H₂₃ClN₂O	详情	详情
(VIII)	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
(IX)	34056	8-chloro-11-(1-cyano-4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₂₀H₁₈ClN₃	详情	详情
(X)	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

合成路线2

该中间体在本合成路线中的序号：(VIII)

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)

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

合成路线4

该中间体在本合成路线中的序号：(I)

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)

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castañer, J.; Lonafarnib. Drugs Fut 2003, 28, 12, 1168.
【2】 Structure-activity relationship of 3-substituted N-(pyridinylacetyl)-4-(8-chloro-5, 6-dihydro-11H-benzo[5,6]cyclohepta[1, 2-b]pyridin-11-ylidene)piperidine inhibitors of farnesyl-protein transferase: Design and synthesis of in vivo active antitumor compou. J Med Chem 1997, 40, 26, 4290.
【3】 Prous, J.; Castañer, 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)	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)	63294	ethyl 4-(8-chloro-3-nitro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate		C₂₂H₂₂ClN₃O₄	详情	详情
(III)	63295	ethyl 4-(3-amino-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate		C₂₂H₂₄ClN₃O₂	详情	详情
(IV)	19338	ethyl 4-(3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate		C₂₂H₂₂BrClN₂O₂	详情	详情

Extended Information