8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine -Drug Synthesis Database

【结构式】

【分子编号】17936

【品名】8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

【CA登记号】

【分子式】C₁₄H₁₁Cl₂N

【分子量】264.15348

【元素组成】C 63.66% H 4.2% Cl 26.84% N 5.3%

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：(III)

Benzocycloheptapyridinone (I) was reduced to alcohol (II) with NaBH4 in MeOH. Subsequent treatment of (II) with SOCl2 in toluene gave the tricyclic chloride (III). Finally, alkylation of N-acetyl piperazine (IV) with chloride (III) in the presence of Et3N in boiling THF provided the title compound.

参考文献中间体

合成目标

【1】 Piwinski, J.J.; Wong, J.K.; Green, M.J.; Kaminski, J.J.; Colizzo, F.; Albanese, M.M.; Ganguly, A.K.; Billah, M.M.; Anthes, J.C.; West, R.E. Jr; Dual antagonists of platelet activating factor and histamine 3. Synthesis, biological activity and conformational implications of substituted N-acyl-bis-arylcycloheptapiperazines. Bioorg Med Chem Lett 1998, 8, 24, 3469.

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)	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
(II)	17935	8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol		C₁₄H₁₂ClNO	详情	详情
(III)	17936	8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₄H₁₁Cl₂N	详情	详情
(IV)	20674	N-Acetyl piperazine; 1-(1-piperazinyl)-1-ethanone	13889-98-0	C₆H₁₂N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Ketone (I) was reduced with sodium borohydride in methanol to alcohol (II), which was then converted into chloride (III) on treatment with thionyl chloride in cooled toluene. Alkylation of piperazine (IV) with chloride (III) in the presence of triethylamine gave V. Finally, piperazine (V) was condensed with 4-pyridylacetic acid (VI) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC), 1-hydroxybenzotriazole (HOBt), and N-methylmorpholine in DMF to afford the target amide.

参考文献中间体

合成目标

【1】 Lesur, B.; et al.; New deoxynojirimycin derivatives as potent inhibitors of intestinal alpha-glucohydrolases. Bioorg Med Chem Lett 1997, 7, 3, 355-360.
【2】 Lesur, B.; Ducep, J.-B.; Danzin, C. (Merrell Pharmaceuticals, Inc.); Novel nojirimycin derivs.. EP 0453692; EP 0454580; JP 1993086072; US 5252587; US 5536732 .

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)	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
(II)	17935	8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol		C₁₄H₁₂ClNO	详情	详情
(III)	17936	8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₄H₁₁Cl₂N	详情	详情
(IV)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(V)	17938	8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₈H₂₀ClN₃	详情	详情
(VI)	17883	2-(4-pyridinyl)acetic acid	28356-58-3	C₇H₇NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XIII)

(R)-Piperazine-2-carboxylic acid, obtained by resolution of the racemic piperazine (VIII) with (-)-camphorsulfonic acid, was regioselectively protected with Boc-ON at the 4-N atom, yielding the tert-butyl carbamate (IX). Subsequent treatment with cyclohexyl chloroformate (X) produced the bis-carbamate (XI), which was further subjected to selective Boc group cleavage under acidic conditions. The resultant piperazine (XII) was condensed with the tricyclic alkyl chloride (XIII), producing a diastereomeric mixture of N-alkylated adducts from which the required isomer (XIV) was isolated by flash chromatography. Finally, coupling of acid (XIV) with the intermediate amine (VII) by means of EDC and HOBt gave rise to the title compound.

参考文献中间体

合成目标

【1】 Guzi, T.; Taveras, A.G.; Ferreira, J.A.; Desai, J.A.; Wang, J.J.S.; Lalwani, T.; Alvarez, C.; Afonso, A.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Weinstein, J.; Cooper, A.B.; Chao, J.; Rane, D.F.; Aki, C.J.; Kelly, J.M. (Schering Corp.); Tricyclic farnesyl protein transferase inhibitors. EP 1140902; WO 0037459 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	51590	N-benzyl-3-(4-methyl-1H-imidazol-1-yl)-1-propanamine; N-benzyl-N-[3-(4-methyl-1H-imidazol-1-yl)propyl]amine		C₁₄H₁₉N₃	详情	详情
(VIII)	25933	2-piperazinecarboxylic acid; Piperazine-2-carboxylic acid		C₅H₁₀N₂O₂	详情	详情
(IX)	51591	(2R)-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid		C₁₀H₁₈N₂O₄	详情	详情
(X)	51592	Carbonochloridic acid, cyclohexyl ester; Cyclohexyl chloroformate	13248-54-9	C₇H₁₁ClO₂	详情	详情
(XI)	51593	(2R)-4-(tert-butoxycarbonyl)-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid		C₁₇H₂₈N₂O₆	详情	详情
(XII)	51594	(2R)-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid		C₁₂H₂₀N₂O₄	详情	详情
(XIII)	17936	8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₄H₁₁Cl₂N	详情	详情
(XIV)	51595	(2R)-4-[(11S)-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid		C₂₆H₃₀ClN₃O₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(V)

(R)-Piperazinecarboxylic acid (I) is sequentially protected with 2-(t-butoxycarbonyloxy)imino-2-phenylacetonitrile to produce the 4N-Boc-piperazine (II), and then with cyclohexyl chloroformate, yielding the 1N-cyclohexyl carbamate (III). Selective N-Boc group cleavage in (III) under acidic conditions provides piperazine (IV). This is condensed with the tricyclic chloride (V) to furnish, after chromatographic separation of the isomers, the required intermediate (VI).

参考文献中间体

合成目标

【1】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. EP 1140904; JP 2002533335; WO 0037458 .
【2】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. US 6362188 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	16266	(2S)-hexahydro-2-pyrazinecarboxylic acid; (S)-Piperazine-2-carboxylic acid	C₅H₁₀N₂O₂	详情	详情
(II)	51591	(2R)-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid	C₁₀H₁₈N₂O₄	详情	详情
(III)	51593	(2R)-4-(tert-butoxycarbonyl)-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid	C₁₇H₂₈N₂O₆	详情	详情
(IV)	51594	(2R)-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid	C₁₂H₂₀N₂O₄	详情	详情
(V)	17936	8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine	C₁₄H₁₁Cl₂N	详情	详情
(VI)	51595	(2R)-4-[(11S)-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid	C₂₆H₃₀ClN₃O₄	详情	详情

Extended Information