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【结 构 式】 
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【分子编号】29610 【品名】2-chloro-5-nitropyridine 【CA登记号】4548-45-2 |
【 分 子 式 】C5H3ClN2O2 【 分 子 量 】158.5438 【元素组成】C 37.88% H 1.91% Cl 22.36% N 17.67% O 20.18% |
合成路线1
该中间体在本合成路线中的序号：(XI)Coupling of 3-hydroxypyridine (X) with 2-chloropyridine (XI) afforded the corresponding dipyridyl ether (XII). After reduction of the nitro group of (XII) with SnCl2, the resulting aminopyridine (XIII) was treated with phenyl chloroformate to give the phenyl carbamate (XIV). Finally, condensation of carbamate (XIV) with indoline (IX) produced the title carboxamide.
| 【1】 Bromidge, S.M.; Forbes, I.T. (SmithKline Beecham plc); Indoline derivs. useful as 5-HT-2C receptor antagonists. EP 0912554; WO 9748699 . |
| 【2】 Blackburn, T.P. (SmithKline Beecham plc); Pharmaceutical compsn. containing a 5HT2C antagonist and a D2 antagonist. WO 9804289 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 29608 | 5-methyl-6-(trifluoromethyl)indoline | C10H10F3N | 详情 | 详情 | |
| (X) | 29609 | 2-methyl-3-pyridinol | 1121-25-1 | C6H7NO | 详情 | 详情 |
| (XI) | 29610 | 2-chloro-5-nitropyridine | 4548-45-2 | C5H3ClN2O2 | 详情 | 详情 |
| (XII) | 29611 | 2-methyl-3-[(5-nitro-2-pyridinyl)oxy]pyridine; 2-methyl-3-pyridinyl 5-nitro-2-pyridinyl ether | C11H9N3O3 | 详情 | 详情 | |
| (XIII) | 29612 | 6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinamine; 6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinylamine | C11H11N3O | 详情 | 详情 | |
| (XIV) | 29613 | phenyl 6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinylcarbamate | C18H15N3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Coupling between 2-chloro-5-nitropyridine (I) and 4-nitrophenol (II) affords the diaryl ether (III). Subsequent catalytic hydrogenation of both nitro groups of (III) gives rise to diamine (IV). This is finally acylated with (S)-2,2-dimethylcyclopropanecarbonyl chloride (V) to furnish the title diamide.
| 【1】 Yamamoto, T.; Iino, Y.; Kobayashi, T.; Fujita, K.; Hatanaka, T.; Kodaira, A.; Takehana, K.; Konishi, A. (Ajinomoto Co., Inc.); Heterocyclic cpds. and medicinal use thereof. EP 1193255; WO 0102359 . |
| 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) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (III) | 57425 | 4-nitrophenyl 5-nitro-2-pyridinyl ether; 5-nitro-2-(4-nitrophenoxy)pyridine | C11H7N3O5 | 详情 | 详情 | |
| (IV) | 57426 | 6-(4-aminophenoxy)-3-pyridinamine; 6-(4-aminophenoxy)-3-pyridinylamine | C11H11N3O | 详情 | 详情 | |
| (V) | 57427 | (1S)-2,2-dimethylcyclopropanecarbonyl chloride | C6H9ClO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Coupling of 2-chloro-5-nitropyridine (II) with the sodium alkoxide of 5-methyl-2-phenylisoxazol-4-ylmethanol (I) gave the 2-alkoxy-5-nitropyridine (III), which was reduced to the aminopyridine (IV) by catalytic hydrogenation over Pd/C. Meerwein arylation of methyl acrylate with the diazonium salt generated from amine (IV) furnished the bromopropionate (V), which was further dehydrohalogenated in the presence of DBU to the pyridyl acrylate (VI). Ester reduction in (VI) employing DIBAL yielded the allylic alcohol (VII). This was hydrogenated to the saturated alcohol (VIII) in the presence of Pd/C. After activation of alcohol (VIII) as the corresponding mesylate (IX), displacement by KCN in hot DMF yielded nitrile (X). This was finally converted to the desired tetrazole by treatment with sodium azide and ammonium chloride.
| 【1】 Momose, Y.; Ikeda, H.; Odaka, H.; Maekawa, T.; Sohda, T.; Novel 5-substituted-1H-tetrazole derivatives as potent glucose and lipid lowering agents. Chem Pharm Bull 2002, 50, 1, 100. |
| 【2】 Sohda, T.; Ikeda, H.; Momose, Y. (Takeda Chemical Industries, Ltd.); Tetrazole derivs., their production and use. CA 2125549; EP 0629624; JP 1995053555; US 5591862 . |
| 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) | 55939 | (5-methyl-2-phenyl-1,3-oxazol-4-yl)methanol | 70502-03-3 | C11H11NO2 | 详情 | 详情 |
| (II) | 29610 | 2-chloro-5-nitropyridine | 4548-45-2 | C5H3ClN2O2 | 详情 | 详情 |
| (III) | 55940 | (5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl 5-nitro-2-pyridinyl ether; 2-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-5-nitropyridine | C16H13N3O4 | 详情 | 详情 | |
| (IV) | 55941 | 6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinamine; 6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinylamine | C16H15N3O2 | 详情 | 详情 | |
| (V) | 55942 | methyl 2-bromo-3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}propanoate | C20H19BrN2O4 | 详情 | 详情 | |
| (VI) | 55943 | methyl (E)-3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}-2-propenoate | C20H18N2O4 | 详情 | 详情 | |
| (VII) | 55944 | (E)-3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}-2-propen-1-ol | C19H18N2O3 | 详情 | 详情 | |
| (VIII) | 55945 | 3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}-1-propanol | C19H20N2O3 | 详情 | 详情 | |
| (IX) | 55946 | 3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}propyl methanesulfonate | C20H22N2O5S | 详情 | 详情 | |
| (X) | 55947 | 4-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}butanenitrile | C20H19N3O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)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 |