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【结 构 式】 
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【分子编号】41837 【品名】(+)-3,10-dibromo-8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine 【CA登记号】 |
【 分 子 式 】C19H17Br2ClN2 【 分 子 量 】468.61816 【元素组成】C 48.7% H 3.66% Br 34.1% Cl 7.57% N 5.98% |
合成路线1
该中间体在本合成路线中的序号：(+)-(XIII)The starting product is the benzocyclohetapyridine (VII), already reported as intermediate (VII) in the synthesis of 25468001a. Compound (VII) is resolved into its atropaisomers by digestion with Toyobo LIP-300 enzyme in the presence of trifluroethyl isobutyrate (XII) to give a mixture of unreacted (-)-(XIII) and acylated compound (+)-(XIV) that are separated by acid extraction. The undesired atropaisomer (-)-(XIII) can be recovered by thermal razemization in diethyleneglycol dibutyl ether at 210 C and new enzymatic separation. The acid hydrolysis of the separated amide (+)-(XIV) produces the desired atropaisomer (+)-(XIII), which is reduced to the (R)-(+)-(VIII), intermediate already reported with no. (VIII) in the synthesis of 25468001a. (6,7)
| 【1】 Sorbera, L.A.; Castañer, J.; Lonafarnib. Drugs Fut 2003, 28, 12, 1168. |
| 【2】 Morgan, B.; Zaks, A.; Dodds, D.R.; Liu, J.; Jain, R.; Megati, S.; Njoroge, F.G.; Girijavallabhan, V.M.; Enzymatic kinetic resolution of piperidine atropisomers: Synthesis of a key intermediate of the farnesyl protein transferase inhibitor, SCH66336. J Org Chem 2000, 65, 18, 5451. |
| 【3】 Njoroge, F.G.; Vibulbhan, B.; Girijavallabhan, V.M. (Schering Corp.); Process for producing (8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidine. EP 1091954; JP 2002519419; WO 0001689 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (-)-(XIII) | 41836 | (-)-3,10-dibromo-8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C19H17Br2ClN2 | 详情 | 详情 | |
| (+)-(XIII) | 41837 | (+)-3,10-dibromo-8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C19H17Br2ClN2 | 详情 | 详情 | |
| (VII) | 19344 | 3,10-dibromo-8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C19H17Br2ClN2 | 详情 | 详情 | |
| (VIII) | 19345 | (11R)-3,10-dibromo-8-chloro-11-(4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C19H19Br2ClN2 | 详情 | 详情 | |
| (XII) | 41835 | 2,2,2-trifluoroethyl 2-methylpropanoate | C6H9F3O2 | 详情 | 详情 | |
| (XIV) | 41834 | 1-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-methyl-1-propanone | C23H23Br2ClN2O | 详情 | 详情 |