N-(tert-butyl)-3-methyl-2-pyridinecarboxamide -Drug Synthesis Database

【结构式】

【分子编号】16501

【品名】N-(tert-butyl)-3-methyl-2-pyridinecarboxamide

【CA登记号】

【分子式】C₁₁H₁₆N₂O

【分子量】192.26092

【元素组成】C 68.72% H 8.39% N 14.57% O 8.32%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(II)

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：(I)

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：(II)

The reaction of 2-cyano-3-methylpyridine (I) with H2SO4 in t-BuOH gives the N-tert-butylamide (II), which is treated with two equivalents of BuLi and the corresponding dianion alkylated with 3-chlorobenzyl chloride to afford amide (III). The treatment of (III) with POCl3 gives nitrile (IV), which is cyclized to ketone (V) by subsequent treatment with CF3SO3H and aqueous HCl. Reaction of ketone (V) with the Grignard derivative prepared from chloride (VI) affords alcohol (VII), which is finally dehydrated by H2SO4 to give UR-12592, as shown in Scheme 20491401a.

参考文献中间体

合成目标

【1】 Carceller, E.; Jiménez, P.J.; Salas, J. (J. Uriach & Cia., SA); Process for the preparation of 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine. ES 9602107 .
【2】 García-Rafanell, J.; Rupatadine Fumarate. Drugs Fut 1996, 21, 10, 1032.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	20642	1-chloro-3-(chloromethyl)benzene; 3-Chlorobenzyl chloride	620-20-2	C₇H₆Cl₂	详情	详情
(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)	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)	16504	8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one; 8-Chloro-10,11-dihydro-4-aza-5H-dibenzo[a,d]cycloheptan-5-one	31251-41-9	C₁₄H₁₀ClNO	详情	详情
(VI)	16505	4-chloro-1-[(5-methyl-3-pyridinyl)methyl]piperidine		C₁₂H₁₇ClN₂	详情	详情
(VII)	16506	8-chloro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinyl]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol		C₂₆H₂₈ClN₃O	详情	详情

Extended Information