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【结 构 式】 
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【分子编号】22949 【品名】6-methylnicotinaldehyde 【CA登记号】 |
【 分 子 式 】C7H7NO 【 分 子 量 】121.13872 【元素组成】C 69.41% H 5.82% N 11.56% O 13.21% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of 6-methylpyridine-3-carboxaldehyde (I) with malonic acid (II) by means of piperidine in refluxing pyridine gives 3-(6-methyl-3-pyridyl)acrylic acid (III), which is esterified with ethanol and H2SO4 as usual to afford ethyl 3-(6-methyl-3-pyridyl)acrylate (IV). The reduction of (IV) with H2 over Pd/C in ethanol affords ethyl 3-(6-methyl-3-pyridyl)propionate (V), which is cyclized with ethyl formate (VI) and thiourea (VII) by means of Na in ether-ethanol yielding 5-(6-methyl-3-pyridylmethyl)-2-thiouracil (VIII). The methylation of (VIII) with methyl iodide and NaOH in hot water gives 5-(6-methyl-3-pyridyl-methyl)-2-methylthio-4-pyrimidone (IX), which is finally condensed with 2-[(5-dimethylaminomethylfuran-2-yl)methylthio]ethylamine (X) in refluxing pyridine.
| 【1】 Brown, T.H.; Ife, R.J. (SmithKline Beecham plc); Pyrimidine compounds. DD 140252; EP 0003677; ES 477667; US 4234588; US 4649141 . |
| 【2】 de Angelis, L.; Serradell, M.N.; Castaner, J.; Blancafort, P.; SKF-93,479. Drugs Fut 1982, 7, 3, 175. |
| 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) | 22949 | 6-methylnicotinaldehyde | C7H7NO | 详情 | 详情 | |
| (II) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
| (III) | 22950 | (E)-3-(6-methyl-3-pyridinyl)-2-propenoic acid | C9H9NO2 | 详情 | 详情 | |
| (IV) | 36446 | ethyl (E)-3-(6-methyl-3-pyridinyl)-2-propenoate | C11H13NO2 | 详情 | 详情 | |
| (V) | 22951 | ethyl 3-(6-methyl-3-pyridinyl)propanoate | C11H15NO2 | 详情 | 详情 | |
| (VI) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (VII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VIII) | 36447 | 5-[(6-methyl-3-pyridinyl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C11H11N3OS | 详情 | 详情 | |
| (IX) | 36448 | 5-[(6-methyl-3-pyridinyl)methyl]-2-(methylsulfanyl)-4(3H)-pyrimidinone | C12H13N3OS | 详情 | 详情 | |
| (X) | 13851 | 2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]-1-ethanamine; N-[(5-[[(2-Aminoethyl)sulfanyl]methyl]-2-furyl)methyl]-N,N-dimethylamine | C10H18N2OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)2-Chloro-3-nitropyridine (I) is condensed with diethyl 2-(2-cyanoethyl)malonate (II) by means of NaH in refluxing THF fo give 1-cyano-3,3-bis(ethoxycarbonyl)-3-(3-nitro-2-pyridinyl)propane (III), which is hydrolyzed with NaOH io aqueous ethanol and decarboxylated in aqueous HCl to afford 2-(3-cyanopropyl)-3-nitropyridine (IV). Hydrogenation of (IV) over Pd/C in ethanol gives 3 amino-2-(3-cyanopropyl)pyridine (V), which is diazotized with NaNO2 in dilute H2SO4 and hydrolyzed to 2-(3-cyanopropyl)-3-hydroxypyridine (VI). Methylation of (VI) with MeI by means of NaH in Me2SO yields 2-(3-cyanopropyl)-3-methoxypyridine (VII), which is then reduced with LiAlH4 to provide 2-(4-amino-butyl)-3-methoxypyridine (VIII). The final stage is to condense (VIII) with 2-nitroamino-5-(6-methyl)-3-pyridinylmethyl)-4-pyrimidinone (XIII) in refluxing pyridine. Synthesis of the pyrimidinone (XIII) reagent commences with 2-methylpyridine-4-aldehyde (IX), which is condensed with malonic acid and decarboxylated in pyridine containing piperidine to afford 3-(6-methyl-3pyridinyl)acrylic acid (X). Esterification of (X) with ethanol-H2SO4, followed by reduction with H2 over Pd/C in ethanol gives ethyl (2-mcthyl-5-pyridinyl)ethanoate (XI), which with ethyl formate in the presence of NaH in glyme furnishes 1-(ethoxycarbonyl)-1-formyl-2-(2 methyl-5-pyridinyl)ethane (XII). Condensation of (XII) with nitroguanidine in ethanol in the presence of NaOEt provides the 4-pyrimidinone (XIII).
| 【1】 Durant, G.J.; Ganellin, C.R.; Sach, G.S. (SmithKline Beecham plc); Guanidines, thioureas and 1,1-diamino-2-nitroethyl. GB 1564502; US 4426526 . |
| 【2】 Durant, G.J.; Brown, T.H.; Ganellin, C.R. (SmithKline Beecham plc); Pyridylalkylpyrimidone cpds., process for preparin. EP 0017679 . |
| 【3】 Prous, J.; Castaner, J.; Icotidine trihydrochloride. Drugs Fut 1987, 12, 1, 24. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
| (I) | 10321 | 2-Chloro-3-nitropyridine | 5470-18-8 | C5H3ClN2O2 | 详情 | 详情 |
| (II) | 22941 | diethyl 2-(2-cyanoethyl)malonate | 17216-62-5 | C10H15NO4 | 详情 | 详情 |
| (III) | 22942 | diethyl 2-(2-cyanoethyl)-2-(3-nitro-2-pyridinyl)malonate | C15H17N3O6 | 详情 | 详情 | |
| (IV) | 22943 | 4-(3-nitro-2-pyridinyl)butanenitrile | C9H9N3O2 | 详情 | 详情 | |
| (V) | 22944 | 4-(3-amino-2-pyridinyl)butanenitrile | C9H11N3 | 详情 | 详情 | |
| (VI) | 22945 | 4-(3-hydroxy-2-pyridinyl)butanenitrile | C9H10N2O | 详情 | 详情 | |
| (VII) | 22946 | 4-(3-methoxy-2-pyridinyl)butanenitrile | C10H12N2O | 详情 | 详情 | |
| (VIII) | 22947 | 4-(3-methoxy-2-pyridinyl)-1-butanamine; 4-(3-methoxy-2-pyridinyl)butylamine | C10H16N2O | 详情 | 详情 | |
| (IX) | 22949 | 6-methylnicotinaldehyde | C7H7NO | 详情 | 详情 | |
| (X) | 22950 | (E)-3-(6-methyl-3-pyridinyl)-2-propenoic acid | C9H9NO2 | 详情 | 详情 | |
| (XI) | 22951 | ethyl 3-(6-methyl-3-pyridinyl)propanoate | C11H15NO2 | 详情 | 详情 | |
| (XII) | 22952 | ethyl 2-formyl-3-(6-methyl-3-pyridinyl)propanoate | C12H15NO3 | 详情 | 详情 | |
| (XIII) | 22953 | 5-(6-Methylpyridin-3-ylmethyl)-2-(nitroamino)pyrimidin-4(1H)-one | C11H11N5O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XX)2) Synthesis of etoricoxib via ketosulfone (XXIV): a) The reaction of 6-methylpyridine-3-carboxylic acid methyl ester (XVIII) with N,O-dimethylhydroxylamine and isopropylmagnesium chloride in toluene gives the N-methoxyamide (XIX), which is reduced with DIBAL to afford 6-methylpyridine-3-carbaldehyde (XX). Reaction of aldehyde (XX) with aniline and diphenyl phosphite provides the diphenyl phosphonate (XXI), which is condensed with 4-(methylsulfonyl)benzaldehyde (XXII) by means of potassium tert-butoxide in HF to yield the enimine (XXIII). Finally, this compound is hydrolyzed with HCl to give ketosulfone (XXIV). b) Condensation of N-methoxyamide (XIX) with 4-(methylsulfanyl)benzylmagnesium bromide (XXV) in toluene/THF gives 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfanyl)phenyl]ethanone (XXVI), which is finally oxidized with Na2WO4 to yield ketosulfone (XXIV). c) Oxidation of 4'-(methylsulfonyl)acetophenone (XXVII) with S8 and morpholine, followed by esterification with ethanol, affords 2-[4-(methylsulfonyl)phenyl]acetic acid ethyl ester (XXVIII); which is condensed with 6-methylpyridine-3-carboxylic acid methyl ester (XVIII) by means of t-BuMgCl in hot THF to furnish ketosulfone (XXIV).
| 【1】 Castañer, R.M.; Silvestre, J.S.; Sorbera, L.A.; Castañer, J.; Etoricoxib. Drugs Fut 2001, 26, 4, 346. |
| 【2】 Davies, I.W.; Marcoux, J.-F.; Corley, E.G.; et al.; A practical synthesis of a COX-2-specific inhibitor. J Org Chem 2000, 65, 25, 8415. |
| 【3】 Corley, E.G.; Davies, I.W.; Larsen, R.D.; Rossen, K.; Pye, P.J. (Merck & Co., Inc.); Process for synthesizing COX-2 inhibitors. US 6040319; WO 9955830 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 14160 | methyl 6-methylnicotinate | 5470-70-2 | C8H9NO2 | 详情 | 详情 |
| (XIX) | 45705 | N-methoxy-N,6-dimethylnicotinamide | C9H12N2O2 | 详情 | 详情 | |
| (XX) | 22949 | 6-methylnicotinaldehyde | C7H7NO | 详情 | 详情 | |
| (XXI) | 45706 | diphenyl anilino(6-methyl-3-pyridinyl)methylphosphonate | C25H23N2O3P | 详情 | 详情 | |
| (XXII) | 17294 | 4-(methylsulfonyl)benzaldehyde; 4-Methylsulfonyl benzaldehyde | 5398-77-6 | C8H8O3S | 详情 | 详情 |
| (XXIII) | 45710 | N-[(E)-1-(6-methyl-3-pyridinyl)-2-[4-(methylsulfonyl)phenyl]ethenyl]-N-phenylamine; N-[(E)-1-(6-methyl-3-pyridinyl)-2-[4-(methylsulfonyl)phenyl]ethenyl]aniline | C21H20N2O2S | 详情 | 详情 | |
| (XXIV) | 45711 | 1-(6-methyl-3-pyridinyl)-2-[4-(methylsulfonyl)phenyl]-1-ethanone | C15H15NO3S | 详情 | 详情 | |
| (XXV) | 45707 | chloro[4-(methylsulfanyl)benzyl]magnesium | C8H9ClMgS | 详情 | 详情 | |
| (XXVI) | 45708 | 1-(6-methyl-3-pyridinyl)-2-[4-(methylsulfanyl)phenyl]-1-ethanone | C15H15NOS | 详情 | 详情 | |
| (XXVII) | 19263 | 1-[4-(methylsulfonyl)phenyl]-1-ethanone; 4-methylsulfonylacetophenone | 10297-73-1 | C9H10O3S | 详情 | 详情 |
| (XXVIII) | 45709 | ethyl 2-[4-(methylsulfonyl)phenyl]acetate | C11H14O4S | 详情 | 详情 |