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【结 构 式】 
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【分子编号】19330 【品名】2,5-dibromopyridine 【CA登记号】624-28-2 |
【 分 子 式 】C5H3Br2N 【 分 子 量 】236.89356 【元素组成】C 25.35% H 1.28% Br 67.46% N 5.91% |
合成路线1
该中间体在本合成路线中的序号：(I)Reaction of 2,5-dibromopyridine (I) with an excess of 1,3-diaminopropane (II) in refluxing pyridine provided N-1-(2-pyridyl)propanediamine (III). This compound was further alkylated at the 1N with 3,4-dichlorobenzyl chloride (IV) in DMSO using NaH as the base to afford (V). From this, isothiocyanate (VI) was prepared by reaction with CS2 and DCC in THF. Subsequent coupling with trityl-protected amine (VII) yielded the thiourea (VIII). Finally, the trityl protecting group was removed by refluxing in 1 N HCl.
| 【1】 Liu, S.; Tang, C.; Ho, B.; Ankersen, M.; Stidsen, C.E.; Crider, A.M.; Nonpeptide somatostatin agonists with sst4 selectivity: Synthesis and structure-activity relationships of thioureas. J Med Chem 1998, 41, 24, 4693. |
| 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) | 19330 | 2,5-dibromopyridine | 624-28-2 | C5H3Br2N | 详情 | 详情 |
| (II) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (III) | 19332 | N-(3-aminopropyl)-N-(5-bromo-2-pyridinyl)amine; N(1)-(5-bromo-2-pyridinyl)-1,3-propanediamine | C8H12BrN3 | 详情 | 详情 | |
| (IV) | 19333 | 1,2-dichloro-4-(chloromethyl)benzene | 102-47-6 | C7H5Cl3 | 详情 | 详情 |
| (V) | 19334 | N(1)-(5-bromo-2-pyridinyl)-N(1)-(3,4-dichlorobenzyl)-1,3-propanediamine; N-(3-aminopropyl)-N-(5-bromo-2-pyridinyl)-N-(3,4-dichlorobenzyl)amine | C15H16BrCl2N3 | 详情 | 详情 | |
| (VI) | 19335 | N-(5-bromo-2-pyridinyl)-N-(3,4-dichlorobenzyl)-N-(3-isothiocyanatopropyl)amine; 5-bromo-N-(3,4-dichlorobenzyl)-N-(3-isothiocyanatopropyl)-2-pyridinamine | C16H14BrCl2N3S | 详情 | 详情 | |
| (VII) | 19336 | 3-(1-trityl-1H-imidazol-4-yl)-1-propanamine; 3-(1-trityl-1H-imidazol-4-yl)propylamine | C25H25N3 | 详情 | 详情 | |
| (VIII) | 19337 | N-[3-[(5-bromo-2-pyridinyl)(3,4-dichlorobenzyl)amino]propyl]-N'-[3-(1-trityl-1H-imidazol-4-yl)propyl]thiourea | C41H39BrCl2N6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Treatment of 2,5-dibromopyridine (XI) with NaCN/CuCN gives rise to nitrile (XII). Cycloaddition of NaN3 to the cyano group of (XII) then leads to the tetrazolyl pyridine (XIII) (1). Further methylation of tetrazole (XIII) with iodomethane and KOH produces a mixture of methylated regioisomers (XIV) and (XV). The desired 2-methyl tetrazole derivative (XIV) is finally subjected to Stille coupling with the aryl stannane (X) to furnish the title compound
| 【1】 Im, W.; Lee, T.; Cho, J.; Choi, S.; Rhee, J.; In vitro and in vivo studies of hetero-ring substituted pyridine containing oxazolidinone derivatives, including DA-7867. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1311. |
| 【2】 Lee, J.-G.; Lee, J.-J.; Park, S.-K.; Lee, T.-H.; Leem, W.-B.; Cho, J.-H.; Choi, S.-H.; Kim, D.-G.; Sung, H.-J. (Dong-A Pharmaceutical Co., Ltd.); Novel oxazolidinone derivs. and a process for the preparation thereof. WO 0194342 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 60320 | N-({3-[3-fluoro-4-(trimethylstannanyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide | C15H21FN2O3Sn | 详情 | 详情 | |
| (XI) | 19330 | 2,5-dibromopyridine | 624-28-2 | C5H3Br2N | 详情 | 详情 |
| (XII) | 60321 | 5-bromo-2-pyridinecarbonitrile | C6H3BrN2 | 详情 | 详情 | |
| (XIII) | 60322 | 5-bromo-2-(1H-1,2,3,4-tetraazol-5-yl)pyridine | C6H4BrN5 | 详情 | 详情 | |
| (XIV) | 60323 | 5-bromo-2-(1-methyl-1H-1,2,3,4-tetraazol-5-yl)pyridine | C7H6BrN5 | 详情 | 详情 | |
| (XV) | 60324 | 5-bromo-2-(2-methyl-2H-1,2,3,4-tetraazol-5-yl)pyridine | C7H6BrN5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Reaction of 2,5-dibromopyridine (I) with morpholine (II) yields 5-bromo-2-(4-morpholinyl)pyridine (III). Palladium-catalyzed coupling of (III) with trimethylsilyl acetylene (IV) leads to the ethynylpyridine (V)
| 【1】 Gomtsyan, A.; et al.; Design, synthesis, and structure-activity relationship of 6-alkynylpyrimidines as potent adenosine kinase inhibitors. J Med Chem 2002, 45, 17, 3639. |
合成路线4
该中间体在本合成路线中的序号：(I)Selective bromide displacement in 2,5-dibromopyridine (I) with NaOMe in refluxing MeOH affords 5-bromo-2-methoxypyridine (II) (1), which alternatively can be obtained by bromination of 2-methoxypyridine (III) with elemental bromine in the presence of NaOAc in EtOAc at 50 °C (2). Metalation of 5-bromo-2-methoxypyridine (II) with BuLi in THF at –75 °C followed by addition of trimethyl borate and aqueous acidic hydrolysis leads to (6-methoxy-3-pyridyl)boronic acid (IV). Subsequent Suzuki coupling of boronic acid (IV) with 2-bromopyridine (V) in the presence of Pd(OAc)2, PPh3 and K2CO3 in DME/H2O at reflux provides 6-methoxy-3,2’-bipyridine (VI) (1). In an alternative method, bipyridine (VI) can be obtained by metalation of 5-bromo-2-methoxypyridine (II) with BuLi in THF at –75 °C followed by condensation with 2-(phenylsulfonyl)pyridine (VII) . Hydrolysis of 6-methoxy-3,2’-bipyridine (VI) by means of aqueous HCl at reflux yields 5-(2-pyridyl)-2-pyridone (VIII) . In a related method, Stille coupling of 5-bromo-2-methoxypyridine (II) with (2-pyridyl)tributyltin (IX) in the presence of Pd(Ph3)4 in DMF at 120 °C followed by methoxy group hydrolysis with concentrated HBr at 110 °C leads to 5-(2-pyridyl)-2-pyridinone (VIII) . N-Arylation of pyridone (VIII) with either phenylboronic acid (X) or its trimeric anhydride 2,4,6-triphenylboroxine (XI) in the presence of Cu(OAc)2 in pyridine/DMF under air blowing conditions gives 1-phenyl-5-(2-pyridyl)-2-pyridinone (XII), which is brominated using NBS in DMF or EtOAc to yield the 3-bromopyridone derivative (XIII). Finally, this compound is subjected to Suzuki coupling with 2-(2-cyanophenyl)-1,3,2-dioxaborinane (XIV) by means of Pd(OAc)2, PPh3, CuI and K2CO3 in DME .
In a different synthetic strategy, Suzuki coupling of 5-bromo-6-methoxy-3,2’-bipyridine (XV) with 2-(2-cyanophenyl)-1,3,2-dioxaborinane (XIV) using Pd(PPh3)4 and Cs2CO3 in DMF at 140 °C gives 3-(2-cyanophenyl)-5-(2-pyridyl)-2-methoxypyridine (XVI), which undergoes methoxy group hydrolysis by means of ClSiMe3 and NaI in acetonitrile to produce the pyridone derivative (XVII). Finally, subsequent N-arylation of pyridone (XVII) with phenylboronic acid (X) in the presence of Cu(OAc)2 and Et3N in CH2Cl2 furnishes perampanel
| 【1】 Nagato, S., Naka, H., Kawano, K. et al. (Eisai R&D Management Co., Ltd.). 1,2-Dihydropyridine compounds, process for preparation of the same and use thereof. EP 1300396, EP 2053041, EP 177520, JP 2007119486, US 2004023973, US 6949571, US 2005245581, US 7563811, US 7939549, WO 2001096308. |
| 【2】 Koyakumaru, K., Matsuo, Y., Satake, Y. (Kuraray Co., Ltd., Eisai Co., Ltd.). Process for producing 5-(2’-pyridyl)-2-pyridone derivative. CA 2493036, CN 1671665, EP 1553086, JP 2004051592, KR 2005019919, US 2006004205, US 7524967, WO 2004009553. |
| 【3】 Nishiura, K., Kayano, A. (Eisai R&D Management Co., Ltd.). Method for producing 1,2-dihydropyridine-2-one compound. CA 2570177, CN 101914057, EP 1772450, WO 2006004100. |
| 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) | 19330 | 2,5-dibromopyridine | 624-28-2 | C5H3Br2N | 详情 | 详情 |
| (II) | 29862 | 5-bromo-2-methoxypyridine; 5-bromo-2-pyridinyl methyl ether | 13472-85-0 | C6H6BrNO | 详情 | 详情 |
| (III) | 54878 | 2-Methoxypyridine; Methyl 2-pyridyl ether | 1628-89-3 | C6H7NO | 详情 | 详情 |
| (IV) | 68389 | (6-methoxy-3-pyridyl)boronic acid；2-Methoxy-5-pyridinylboronic acid | 163105-89-3 | C6H8BNO3 | 详情 | 详情 |
| (V) | 29052 | 2-Bromopyridine；α-bromopyridine;α-bromoazine | 109-04-6 | C5H4BrN | 详情 | 详情 |
| (VI) | 68390 | 6'-methoxy-2,3'-bipyridine | C11H10N2O | 详情 | 详情 | |
| (VII) | 68391 | 2-(phenylsulfonyl)pyridine;2-Benzenesulfonylpyridine;2-Pyridyl phenyl sulfone | 24244-60-8 | C11H9NO2S | 详情 | 详情 |
| (VIII) | 68392 | 5-(2-pyridyl)-2-pyridone;2,3'-Bipyridin-6'(1'H)-one | 381233-78-9 | C10H8N2O | 详情 | 详情 |
| (IX) | 19686 | (2-pyridyl)tributyltin;2-(tributylstannyl)pyridine;(2-Pyridinyl)tributylstannane;2-(1,1,1-Tributylstannyl)pyridine;2-(Tri-n-butylstannyl)pyridine;2-(Tributylstannyl)pyridine;2-(Tributyltin)pyridine;2-Pyridyltri-n-butyltin;2-Pyridyltributylstannane;2-Pyridyltributyltin;Tri-n-butyl(2-pyridyl)tin;Tri-n-butyl-2-pyridylstannane;Tributyl(pyridin-2-yl)stannane;Tributyl-2-pyridylstannane;Tributyl-2-pyridyltin | 17997-47-6 | C17H31NSn | 详情 | 详情 |
| (X) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (XI) | 68393 | 2,4,6-triphenylboroxine;Benzeneboronic anhydride;Cyclic benzeneboronic anhydride;Cyclic phenylboronic anhydride;Phenylboronic acid anhydride;Phenylboronic anhydride;Triphenylboroxin;Triphenylboroxole | 3262-89-3 | C18H15B3O3 | 详情 | 详情 |
| (XII) | 68394 | 1-phenyl-5-(2-pyridyl)-2-pyridinone;1'-phenyl-[2,3'-bipyridin]-6'(1'H)-one | C16H12N2O | 详情 | 详情 | |
| (XIII) | 68395 | 5'-bromo-1'-phenyl-[2,3'-bipyridin]-6'(1'H)-one | C16H11BrN2O | 详情 | 详情 | |
| (XIV) | 68396 | 2-(2-cyanophenyl)-1,3,2-dioxaborinane;2-(1,3,2-Dioxaborinan-2-yl)benzonitrile | 172732-52-4 | C10H10BNO2 | 详情 | 详情 |
| (XV) | 68397 | 5'-bromo-6'-methoxy-2,3'-bipyridine | C11H9BrN2O | 详情 | 详情 | |
| (XVI) | 68398 | 3-(2-cyanophenyl)-5-(2-pyridyl)-2-methoxypyridine;2-(6'-methoxy-[2,3'-bipyridin]-5'-yl)benzonitrile | C18H13N3O | 详情 | 详情 | |
| (XVII) | 68399 | 2-(6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-5'-yl)benzonitrile | C17H11N3O | 详情 | 详情 |