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【结 构 式】 
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【分子编号】25663 【品名】1-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-(4-piperidinyl)-1-ethanone 【CA登记号】 |
【 分 子 式 】C26H28Br2ClN3O 【 分 子 量 】593.78864 【元素组成】C 52.59% H 4.75% Br 26.91% Cl 5.97% N 7.08% O 2.69% |
合成路线1
该中间体在本合成路线中的序号：(IX)Benzocycloheptapyridine (I) was nitrated with NaNO3 and H2SO4 to afford (II) as the major isomer. Reduction of (II) with iron and CaCl2 gave amine (III), which was brominated to provide (IV). Removal of the amino group of (IV) was accomplished by diazotization, followed by reduction with hypophosphorous acid to give (V). Then, hydrolysis of the carbamate group in refluxing hydrochloric acid furnished piperidine (VI). Subsequent coupling of (VI) with N-Boc-piperidineacetic acid (VII) using EDC and HOBt yielded amide (VIII). After Boc deprotection of (VIII) with trifluoroacetic acid, piperidine (IX) was condensed with trimethylsilyl isocyanate to produce the corresponding urea. Finally, separation of the target (+)-atropoisomer was achieved by chiral chromatography.
| 【1】 (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem 1998, 41, 24, 4890. |
| 【2】 Bishop, W.R.; Girijavallabhan, V.M.; Njoroge, F.G.; Bryant, M.S.; Nomeir, A.A.; Doll, R.J.; Ganguly, A.K.; Kirschmeier, P.; Liu, M.; Vibulbhan, B.; Atropisomeric trihalobenzocycloheptapyridine analogues provide stereoselective FPT inhibitors with antitumor activity. Bioorg Med Chem 1999, 7, 5, 861. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19976 | isocyanato(trimethyl)silane; trimethylsilyl isocyanate | C4H9NOSi | 详情 | 详情 | ||
| (I) | 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 | |
| (II) | 19340 | ethyl 4-(3-bromo-8-chloro-9-nitro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H21BrClN3O4 | 详情 | 详情 | |
| (III) | 19341 | ethyl 4-(9-amino-3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H23BrClN3O2 | 详情 | 详情 | |
| (IV) | 19342 | ethyl 4-(9-amino-3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H22Br2ClN3O2 | 详情 | 详情 | |
| (V) | 19343 | ethyl 4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H21Br2ClN2O2 | 详情 | 详情 | |
| (VI) | 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 | |
| (VII) | 19346 | 1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid | 157688-46-5 | C12H21NO4 | 详情 | 详情 |
| (VIII) | 25662 | tert-butyl 4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxylate | C31H36Br2ClN3O3 | 详情 | 详情 | |
| (IX) | 25663 | 1-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-(4-piperidinyl)-1-ethanone | C26H28Br2ClN3O | 详情 | 详情 |