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【结 构 式】

【分子编号】51595

【品名】(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

【CA登记号】

【 分 子 式 】C26H30ClN3O4

【 分 子 量 】483.99472

【元素组成】C 64.52% H 6.25% Cl 7.33% N 8.68% O 13.22%
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：(XIV)

(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2

该中间体在本合成路线中的序号：(VI)

(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 CAS号 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

合成路线3

该中间体在本合成路线中的序号：(VI)

Reduction of (R)-ethyl nipecotate (VII) with LiAlH4 yields 3-piperidinemethanol (VIII), which is further protected as the N-Boc derivative (IX) by using Boc2O. Treatment of the piperidine alcohol (IX) with p-toluenesulfonyl chloride and pyridine leads to tosylate (X). Condensation of the sodium derivative of 4-methylimidazole (XI) with tosylate (X) gives rise to a mixture of regioisomeric N-alkylated imidazoles, which are chromatographically separated after derivatization with trityl chloride. The desired isomer (XII) is then deprotected under acidic conditions, giving piperidine (XIII). Finally, EDC-mediated coupling between piperidine (XIII) and the piperazinecarboxylic acid (VI) furnishes the title amide.

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 CAS号 分子式 供应商 用于合成
(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
(VII) 12453 ethyl (3R)hexahydro-3-pyridinecarboxylate C8H15NO2 详情 详情
(VIII) 57427 (1S)-2,2-dimethylcyclopropanecarbonyl chloride C6H9ClO 详情 详情
(IX) 35221 tert-butyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate C11H21NO3 详情 详情
(X) 57428 ethyl 3-ethyl-2-pentenoate C9H16O2 详情 详情
(XI) 51586 4-Methylimidazole; 4-Methyl-1H-imidazole; 4-Methyl Imidazole 822-36-6 C4H6N2 详情 详情
(XII) 58429 tert-butyl (3S)-3-[(4-methyl-1H-imidazol-1-yl)methyl]-1-piperidinecarboxylate C15H25N3O2 详情 详情
(XIII) 58430 (3R)-3-[(4-methyl-1H-imidazol-1-yl)methyl]piperidine C10H17N3 详情 详情
Extended Information