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【结 构 式】 
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【分子编号】54878 【品名】2-Methoxypyridine; Methyl 2-pyridyl ether 【CA登记号】1628-89-3 |
【 分 子 式 】C6H7NO 【 分 子 量 】109.12772 【元素组成】C 66.04% H 6.47% N 12.84% O 14.66% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)Lithiation of 2-methoxypyridine (XVIII), followed by formylation with N-formyl-N,N',N'-trimethylethylenediamine (XIX), produced the pyridine carbaldehyde (XX), which was further iodinated to (XXI) by lithiation and subsequent treatment with iodine. Reductive condensation of aldehyde (XXI) with crotyl alcohol (XXII) in the presence of triethylsilane and trifluoroacetic acid yielded the crotyl ether (XXIII). Cyclization of (XXIII) under Heck reaction conditions led to a mixture of the ethylidene pyranopyridine (XXIV) and the major isomerized analogue (XXV). Sharpless asymmetric dihydroxylation of this reaction mixture afforded the alpha-hydroxy lactol (XXVI), which was further oxidixed to hydroxy lactone (XXVII) employing iodine and CaCO3. Demethylation of ether (XXVII) under acidic conditions generated lactam (XXVIII). Mitsunobu coupling between lactam (XXVIII) and (hydroxymethyl)quinoline (XVII) furnished adduct (XXIX). The title compound was finally obtained by Heck cyclization of (XXIX) in the presence of palladium acetate and triphenylphosphine.
| 【1】 Fang, F.G.; et al.; Convergent catalytic asymmetric synthesis of camptothecin analog GI147211C. Tetrahedron 1997, 53, 32, 10953. |
| 【2】 Fang, F.G.; Xie, S.; Lowery, M.W. (GlaxoSmithKline Inc.); Intermediates in pharmaceutical camptothecin preparation. WO 9529917 . |
| 【3】 Huie, E.M.; Fang, F.G.; Xie, S.; Comins, D.L. (GlaxoSmithKline Inc.; North Carolina State University); Preparation of a camptothecin deriv. by intramolecular cyclisation. WO 9529919 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 54877 | {7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol | C18H22IN3O3 | 详情 | 详情 | |
| (XVIII) | 54878 | 2-Methoxypyridine; Methyl 2-pyridyl ether | 1628-89-3 | C6H7NO | 详情 | 详情 |
| (XIX) | 54879 | 2-(dimethylamino)ethyl(methyl)formamide | C6H14N2O | 详情 | 详情 | |
| (XX) | 54880 | 2-methoxynicotinaldehyde | C7H7NO2 | 详情 | 详情 | |
| (XXI) | 54881 | 4-iodo-2-methoxynicotinaldehyde | C7H6INO2 | 详情 | 详情 | |
| (XXII) | 54882 | 2-Butene-1-ol; Crotyl Alcohol; trans-Propenylcarbinol | 504-61-0 | C4H8O | 详情 | 详情 |
| (XXIII) | 54883 | (E)-2-butenyl (4-iodo-2-methoxy-3-pyridinyl)methyl ether; 3-{[(E)-2-butenyloxy]methyl}-4-iodo-2-methoxypyridine | C11H14INO2 | 详情 | 详情 | |
| (XXIV) | 54884 | 4-[(E)ethylidene]-3,4-dihydro-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-[(E)ethylidene]-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine | C11H13NO2 | 详情 | 详情 | |
| (XXV) | 54885 | 4-ethyl-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-ethyl-8-methoxy-1H-pyrano[3,4-c]pyridine | C11H13NO2 | 详情 | 详情 | |
| (XXVI) | 54886 | (4S)-4-ethyl-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-3,4-diol | C11H15NO4 | 详情 | 详情 | |
| (XXVII) | 54887 | (4S)-4-ethyl-4-hydroxy-8-methoxy-1,4-dihydro-3H-pyrano[3,4-c]pyridin-3-one | C11H13NO4 | 详情 | 详情 | |
| (XXVIII) | 54888 | (4S)-4-ethyl-4-hydroxy-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione | C10H11NO4 | 详情 | 详情 | |
| (XXIX) | 54889 | (4S)-4-ethyl-4-hydroxy-7-({7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methyl)-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione | C28H31IN4O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)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 |