2,6-Diacetylpyridine -Drug Synthesis Database

【结构式】

【分子编号】48515

【品名】2,6-Diacetylpyridine

【CA登记号】1129-30-2

【分子式】C₉H₉NO₂

【分子量】163.176

【元素组成】C 66.25% H 5.56% N 8.58% O 19.61%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VII)

Treatment of (R,R)-1,2-diaminocyclohexane (I) with triphenylmethyl chloride produced the N-trityl derivative (II). Subsequent condensation of (II) with glyoxal (III) gave the bis-imine (IV), which was reduced to amine (V) using LiBH4. Cleavage of the N-trityl groups of (V) with HCl in acetone afforded tetraamine (VI). This was then condensed with 2,6-diacetylpyridine (VII) in the presence of MnCl2 to furnish the cyclic bis-imine manganese complex (VIII). Finally, transfer hydrogenation of the imine functions of (VIII) using ammonium formate and Pd/C produced the cyclic pentaamino derivative as a diastereomeric mixture. The title isomer was then purified by separative partition between H2O and CH2Cl2.

参考文献中间体

合成目标

【1】 Udipi, K.; Joardar, S.; Forster, D.; Riley, D.; Henke, S.; Brethaur, K.; Thurmond, B.; Ornberg, R. (Pharmacia Corp.); Biomaterials modified with superoxide dismutase mimics. WO 0072893 .

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)	11130	(1R,2R)-1,2-cyclohexanediamine; (1R,2R)-2-aminocyclohexylamine; cis-1,2-Diaminocyclohexane	20439-47-8	C₆H₁₄N₂	详情	详情
(II)	48511	N-[(1R,2R)-2-aminocyclohexyl]-N-tritylamine; (1R,2R)-N(1)-trityl-1,2-cyclohexanediamine		C₂₅H₂₈N₂	详情	详情
(III)	32557	glyoxal; 2-oxoacetaldehyde	107-22-2	C₂H₂O₂	详情	详情
(IV)	48512	(1R,2R)-N(1)-trityl-N(2)-((E)-2-[[(1R,2R)-2-(tritylamino)cyclohexyl]imino]ethylidene)-1,2-cyclohexanediamine; N-trityl-N-[(1R,2R)-2-[((E)-2-[[(1R,2R)-2-(tritylamino)cyclohexyl]imino]ethylidene)amino]cyclohexyl]amine		C₅₂H₅₄N₄	详情	详情
(V)	48513	(1R,2R)-N(1)-trityl-N(2)-(2-[[(1R,2R)-2-(tritylamino)cyclohexyl]amino]ethyl)-1,2-cyclohexanediamine; N-trityl-N-[(1R,2R)-2-[(2-[[(1R,2R)-2-(tritylamino)cyclohexyl]amino]ethyl)amino]cyclohexyl]amine		C₅₂H₅₈N₄	详情	详情
(VI)	48514	(1R,2R)-N(1)-(2-[[(1R,2R)-2-aminocyclohexyl]amino]ethyl)-1,2-cyclohexanediamine; N-[(1R,2R)-2-aminocyclohexyl]-N-(2-[[(1R,2R)-2-aminocyclohexyl]amino]ethyl)amine		C₁₄H₃₀N₄	详情	详情
(VII)	48515	2,6-Diacetylpyridine	1129-30-2	C₉H₉NO₂	详情	详情
(VIII)	48516	(4R,9R,14R,19R)-2,21-dimethyl-3,10,13,20,26-pentaazatetracyclo[20.3.1.0(4,9).0(14,19)]hexacosa-1(26),2,20,22,24-pentaene		C₂₃H₃₅N₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XX)

The precursor 4-bromo-2,6-diethylpyridine (V) can be prepared by several methods. Condensation of 3-oxoglutaric acid (XIII) with propionic anhydride (XIV) in the presence of H2SO4, followed by cyclization with HCl at 100 °C leads to 2,6-diethyl-4-pyranone (XV). Subsequent treatment of pyranone (XV) with NH4OH at 50 °C yields 2,6-diethyl-4-pyridinol (XVI) , which is finally brominated with PBr5 in CHCl3 or POBr3 in DMF at 120 °C .
Alternatively, substitution of 2,6-dichloropyridine (XVII) with ethylmagnesium bromide (XVIII) in the presence of NiCl2(dppp) in Et2O gives 2,6-diethylpyridine (XIX), which can also be obtained by Wolff- Kishner reduction of 2,6-diacetylpyridine (XX) with NH2NH2 in the presence of NaOH in diethylene glycol at 120 °C. Oxidation of 2,6-diethylpyridine (XIX) with mCPBA in CHCl3, followed by nitration of the resulting 2,6-diethylpyridine-1-oxide (XXI) with HNO3 and H2SO4 at 90 °C provides the 4-nitro derivative (XXII). Substitution of nitropyridine (XXII) using AcBr in AcOH at 90 °C affords 4-bromo-2,6-diethylpyridin-1-oxide (XXIII), which is finally reduced with PBr3 in CH2Cl2 .

参考文献中间体

合成目标

【1】 Gonzalez, J., Jewell, T.M., Li, H., Linton, A., Tatlock, J.H. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Inhibitors of hepatitis C virus RNAdependent RNA polymerase, and compositions and treatments using the same. EP 1781662, JP 2008509984, US 2006122399, US 7151105, US 8268835, WO 2006018725.
【2】 Li, H., Tatlock, J., Linton, A. et al. Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-(1,2,4)triazolo(1,5-a)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. J Med Chem 2009, 52(5): 1255-8.
【3】 Johnson, S., Drowns, M., Tatlock, J. et al. Synthetic route optimization of PF-00868554, an HCV polymerase inhibitor in clinical evaluation. Synlett 2010(5): 796-800.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	68333	4-bromo-2,6-diethylpyridine	877133-54-5	C₉H₁₂BrN	详情	详情
(XIII)	15530	1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid	542-05-2	C₅H₆O₅	详情	详情
(XIV)	20095	propionic anhydride	123-62-6	C₆H₁₀O₃	详情	详情
(XV)	68342	2,6-diethyl-4H-pyran-4-one		C₉H₁₂O₂	详情	详情
(XVI)	68343	2,6-diethyl-4-pyridinol;2,6-diethylpyridin-4-ol		C₉H₁₃NO	详情	详情
(XVII)	13573	2,6-Dichloropyridine	2402-78-0	C₅H₃Cl₂N	详情	详情
(XVIII)	24239	bromo(ethyl)magnesium；ethylmagnesium bromide	925-90-6	C₂H₅BrMg	详情	详情
(XIX)	68344	2,6-diethylpyridine	935-28-4	C₉H₁₃N	详情	详情
(XX)	48515	2,6-Diacetylpyridine	1129-30-2	C₉H₉NO₂	详情	详情
(XXI)	68345	2,6-diethylpyridine-1-oxide		C₉H₁₃NO	详情	详情
(XXII)	68346	2,6-diethyl-4-nitropyridine 1-oxide		C₉H₁₂N₂O₃	详情	详情
(XXIII)	68347	4-bromo-2,6-diethylpyridin-1-oxide		C₉H₁₂BrNO	详情	详情

Extended Information