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【结 构 式】 
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【分子编号】14160 【品名】methyl 6-methylnicotinate 【CA登记号】5470-70-2 |
【 分 子 式 】C8H9NO2 【 分 子 量 】151.165 【元素组成】C 63.56% H 6% N 9.27% O 21.17% |
合成路线1
该中间体在本合成路线中的序号：(XII)c) Synthesis of metabolite M-V: The reduction of 6-methylpyridine-3-carboxylic acid methyl ester (XII) with LiAlH4 in THF gives the corresponding hydroxymethyl derivative (XIII), which is protected with chloromethyl methyl ether as before yielding the methoxymethoxymethyl compound (XIV). Hydroxymethylation of (XIV) with formaldehyde as described affords the ethanol derivative (XV), which is condensed with 4-fluoronitrobenzene (V) as before giving 5-(hydroxymethyl)-2-[2-(4-nitrophenoxy)ethyl]pyridine (XVI). The deprotection of (XVI) with HCl in refluxing methanol yields the hydroxymethyl compound (XVII), which is treated with SOCl2 in refluxing chloroform to afford the chloromethyl compound (XVIII). The reaction of (XVIII) with KCN in hot DMF gives the corresponding cyanomethyl derivative (XIX), which by reduction of the NO2 group with H2 over Pd/C in ethyl acetate yields the amino derivative (XX). The diazotation of (XX) with NaNO2 in aqueous HBr followed by condensation with methyl acrylate as before affords the 2-bromopropionate (XXI), which is cyclized with thiourea (X) as reported to give iminothiazolidinone derivative (XXII). Finally, the hydrolysis of the cyano gives Metabolite M-V.
| 【1】 Momose, Y.; Sohda, T.; Meguro, K.; Hatanaka, C.; Ikeda, H.; Oi, S.; Studies on antidiabetic agents: Synthesis and biological activities of pioglitazone and related compounds. 11th Symp Med Chem (Dec 4-5, Tokushima) 1990, Abst P-11. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| M-V | 63863 | 2-[6-(2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}ethyl)-3-pyridinyl]acetic acid | C19H18N2O5S | 详情 | 详情 | |
| (V) | 14153 | 4-Fluoronitrobenzene; 1-Fluoro-4-nitrobenzene | 350-46-9 | C6H4FNO2 | 详情 | 详情 |
| (VIII) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (X) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (XII) | 14160 | methyl 6-methylnicotinate | 5470-70-2 | C8H9NO2 | 详情 | 详情 |
| (XIII) | 14161 | (6-Methyl-3-pyridinyl)methanol | C7H9NO | 详情 | 详情 | |
| (XIV) | 14162 | Methoxymethyl (6-methyl-3-pyridinyl)methyl ether; 5-[(Methoxymethoxy)methyl]-2-methylpyridine | C9H13NO2 | 详情 | 详情 | |
| (XV) | 14163 | 2-[5-[(Methoxymethoxy)methyl]-2-pyridinyl]-1-ethanol | C10H15NO3 | 详情 | 详情 | |
| (XVI) | 14164 | 5-[(Methoxymethoxy)methyl]-2-[2-(4-nitrophenoxy)ethyl]pyridine; 2-[5-[(Methoxymethoxy)methyl]-2-pyridinyl]ethyl 4-nitrophenyl ether | C16H18N2O5 | 详情 | 详情 | |
| (XVII) | 14165 | [6-[2-(4-Nitrophenoxy)ethyl]-3-pyridinyl]methanol | C14H14N2O4 | 详情 | 详情 | |
| (XVIII) | 14166 | 2-[5-(Chloromethyl)-2-pyridinyl]ethyl 4-nitrophenyl ether; 5-(Chloromethyl)-2-[2-(4-nitrophenoxy)ethyl]pyridine | C14H13ClN2O3 | 详情 | 详情 | |
| (XIX) | 14167 | 2-[6-[2-(4-Nitrophenoxy)ethyl]-3-pyridinyl]acetonitrile | C15H13N3O3 | 详情 | 详情 | |
| (XX) | 14168 | 2-[6-[2-(4-Aminophenoxy)ethyl]-3-pyridinyl]acetonitrile | C15H15N3O | 详情 | 详情 | |
| (XXI) | 14169 | methyl 2-bromo-3-(4-[2-[5-(cyanomethyl)-2-pyridinyl]ethoxy]phenyl)propanoate | C19H19BrN2O3 | 详情 | 详情 | |
| (XXII) | 14170 | 2-[6-(2-[4-[(2-Imino-4-oxo-1,3-thiazolan-5-yl)methyl]phenoxy]ethyl)-3-pyridinyl]acetonitrile | C19H18N4O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Methyl 6-methylnicotinate (XII) was condensed with 4-pyridinecarboxaldehyde (XIII) in AcOH-Ac2O at 120 C to produce (XIV). Then, ester group was reduced with LiAlH4 to alcohol (XV), and this was subsequently oxidized with DMSO and SO3-pyridine complex to give aldehyde (XVI). Wittig reaction with phosphorane (XVII) afforded ester (XVIII), which was saponified to yield acid (XIX). Finally, coupling of acid (XIX) with amine (XI) in the presence of EDC and HOBt provided the title amide.
| 【1】 Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Inamura, N.; Asano, M.; Aramori, I.; Hatori, C.; Sawai, H.; Oku, T.; Tanaka, H.; A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 3. Discovering bioisosteres of the imidazo[1,2-a]pyridine moiety. J Med Chem 1998, 41, 21, 4062. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 18600 | 2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide | C20H19Cl2N3O2 | 详情 | 详情 | |
| (XII) | 14160 | methyl 6-methylnicotinate | 5470-70-2 | C8H9NO2 | 详情 | 详情 |
| (XIII) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (XIV) | 18603 | methyl 6-[(E)-2-(4-pyridinyl)ethenyl]nicotinate | C14H12N2O2 | 详情 | 详情 | |
| (XV) | 18604 | [6-[(E)-2-(4-pyridinyl)ethenyl]-3-pyridinyl]methanol | C13H12N2O | 详情 | 详情 | |
| (XVI) | 18605 | 6-[(E)-2-(4-pyridinyl)ethenyl]nicotinaldehyde | C13H10N2O | 详情 | 详情 | |
| (XVII) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (XVIII) | 18607 | methyl (E)-3-[6-[(E)-2-(4-pyridinyl)ethenyl]-3-pyridinyl]-2-propenoate | C16H14N2O2 | 详情 | 详情 | |
| (XIX) | 18608 | (E)-3-[6-[(E)-2-(4-pyridinyl)ethenyl]-3-pyridinyl]-2-propenoic acid | C15H12N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVIII)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 |