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【结 构 式】 
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【分子编号】37122 【品名】(2R,6S)-2,6-dimethylmorpholine；cis-2,6-dimethylmorpholine 【CA登记号】6485-55-8 |
【 分 子 式 】C6H13NO 【 分 子 量 】115.17536 【元素组成】C 62.57% H 11.38% N 12.16% O 13.89% |
合成路线1
该中间体在本合成路线中的序号：(I)By condensation of 3-(4-tert-amylphenyl)propionaldehyde (I) with 2,6-dimethylmorpholine (II) by heating at 100 C in toluene, followed by hydrogenation with H2 over Pd/C in the same solvent.
| 【1】 Pfiffner, A.; Bohnen, K. (Roche); Piperidines morpholines, etc., and fungicidal compsns. Thereof. US 4202894; US 4241058 . |
| 【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; RO-144,767/002. Drugs Fut 1982, 7, 7, 492. |
合成路线2
该中间体在本合成路线中的序号：(II)Condensation of 2-chloro-5-nitropyridine (I) with cis-2,6-dimethylmorpholine (II) by means of K2CO3 in DMF at 50 °C gives intermediate (III), which is hydrogenated with H2 over Pd/C in MeOH to yield amine (IV) . Coupling of amine (IV) with 3-bromo-4-methylbenzoic acid (V) using HATU and Et3N or DIEA in DMF affords the corresponding amide (VI), which is finally submitted to Suzuki coupling with 4-(trifluoromethoxy)phenyl boronic acid (VII) in the presence of Pd(PPh3)4 and Na2CO3 in toluene/EtOH/H2O , DME or DME/H2O at 135 °C.
Alternatively, Suzuki coupling of 3-bromo-4-methylbenzoic acid (V) with 4-(trifluoromethoxy)phenylboronic acid (VII) in the presence of Pd(PPh3)4 and Na2CO3 in DME/H2O gives intermediate (IX), which is finally coupled with amine (IV) using HATU and Et3N in DMF .
| 【1】 gao, W., Jiang, J., Wan, Y., Cheng, D., Han, D., Wu, X., Pan, S. (IRM, LLC). Compounds and compositions as hedgehog pathway modulators. CN 102746285, EP 2021328, EP2363393, JP 2009536220, US 2009203666, US 8178563, US 2012196849, WO 2007131201. |
| 【2】 Dierks, C., Warmuth, M., Wu, X. (IRM, LLC). Biphenylcarboxamide derivatives as hedgehog pathway modulators. CN 101820950, EP 2162190, JP 2010529963, US 2010197659, WO 2008154259. |
| 【3】 Fritze, E., Corcelle, K., grubesa, M.E. (Novartis Ag). Pharmaceutical compositions. CN 102481249, CN 103893184, EP 2456422, JP 2012533598, KR 2012097482, US 2012122866, US 8722672, WO 2011009852. |
| 【4】 Pan, S., Wu, X., Jiang, J. et al. Discovery of NVP-LDE225, a potent and selective smoothened antagonist. ACS Med Chem Lett 2010, 1(3): 130-4. |
| 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) | 29610 | 2-chloro-5-nitropyridine | 4548-45-2 | C5H3ClN2O2 | 详情 | 详情 |
| (II) | 37122 | (2R,6S)-2,6-dimethylmorpholine；cis-2,6-dimethylmorpholine | 6485-55-8 | C6H13NO | 详情 | 详情 |
| (III) | 67845 | (2R,6S)-2,6-dimethyl-4-(5-nitropyridin-2-yl)morpholine | C11H15N3O3 | 详情 | 详情 | |
| (IV) | 67844 | 6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-amine | C11H17N3O | 详情 | 详情 | |
| (V) | 67847 | 3-bromo-2-methylbenzoic acid | 76006-33-2 | C8H7BrO2 | 详情 | 详情 |
| (VI) | 67846 | 3-bromo-N-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methylbenzamide | C19H22BrN3O2 | 详情 | 详情 | |
| (VII) | 67849 | 4-(trifluoromethoxy)phenyl boronic acid | 139301-27-2 | C7H6BF3O3 | 详情 | 详情 |
| (VIII) | 67848 | N-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide | C26H26F3N3O3 | 详情 | 详情 | |
| (IX) | 67850 | 2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxylic acid | C15H11F3O3 | 详情 | 详情 |