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【结 构 式】 
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【分子编号】25173 【品名】2-pyridinecarbaldehyde 【CA登记号】1121-60-4 |
【 分 子 式 】C6H5NO 【 分 子 量 】107.11184 【元素组成】C 67.28% H 4.71% N 13.08% O 14.94% |
合成路线1
该中间体在本合成路线中的序号：(V)A slightly modified method of Houlihan et al. is used in making the intermediate 1-amino-3-hydroxyguanidine tosylate. Thiosemicarbazide (I) (0.5 mol) and methyl p-toluenesulfonate (II) (0.5 mol) are refluxed with stirring for 18 h. The reaction mixture is then evaporated to about 250 ml in vacua, and 500 ml of ether is added. The white precipitate formed is filtered and washed with ether. The resultant S-methylisothiosemicarbazide tosylate (III) (135g) gives a melting point of 144-6 C. Cold methanolic KOH solution (0.5 mol in 250 mI) is added to a cold hydroxyamine hydrochloride solution 10.5 mol). The mixture is stirred for 1 h in a salt-ice bath. The KCl precipitate formed is removed by filtration. S-Methyl-isothiosemicarbazide tosylate (III) (0.4 mol) is added to the filtrate. The reaction mixture is stirred at room temperature for 48 h, then evaporated to dryness in vacua at 40 C. The residue is dissolved in hot ethanol (800 mI) and cooled to room temperature. A small amount of insoluble precipitate is filtered off, then the filtrate is concentrated to about 200 ml in vacuo. Ether (400 ml) is added and mixed thoroughly to precipitate out the desired intermediate. This is filtered and washed with a mixture of ether and ethanol (2:1). White crystalline product of 1-amino-3-hydroxyguanidine tosylate (IV) (50 g) is obtained with an m.p. of 136-7 C, and it decomposes at 150-5 C. To prepare title compound 0.04 mol of freshly distilled 2-formylpyridine (V) is added dropwise to a solution of 0.04 mol of 1-amino-3-hydroxyguanidine tosylate (IV) in 25 ml methanol. The reaction mixture is stirred overnight at room temperature. The solvent is evaporated in vacuo. The final resultant Schiff's base is recrystallized with a mixture of ethanol-ether (1:1). The yield of the final product is 6.48 g (46.1%).
| 【1】 Tai, A.W.; Moore, E.C.; Chun, Y.; Lien, E.J.; Roberts, J.D.; Studies of N-hydroxy-N'-aminoguanidine derivatives by nitrogen-15 nuclear magnetic resonance spectroscopy and as ribonucleotide reductase inhibitors. J Med Chem 1983, 26, 9, 1326-1329. |
| 【2】 Houlihan, W.J.; Manning, R.E. (Novartis AG); Improvements in or relating to benzylideneamino guanidine derivatives. BE 0727146; DE 1902449; ES 362712; ES 374472; ES 374475; FR 2000512; FR 2059987; FR 2061583; GB 1253548; GB 1253549 . |
| 【3】 Lien, E.J.; LT-1. Drugs Fut 1985, 10, 1, 26. |
| 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) | 29023 | 1-hydrazinecarbimidothioic acid | CH5N3S | 详情 | 详情 | |
| (II) | 23403 | Methyl p-toluenesulfonate; Methyl 4-methylbenzenesulfonate; Methyl 4-toluenesulfonate | 80-48-8 | C8H10O3S | 详情 | 详情 |
| (III) | 29025 | methyl 1-hydrazinecarbimidothioate | C2H7N3S | 详情 | 详情 | |
| (IV) | 29026 | N-hydroxy-1-hydrazinecarboximidamide | CH6N4O | 详情 | 详情 | |
| (V) | 25173 | 2-pyridinecarbaldehyde | 1121-60-4 | C6H5NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Mannich reaction of dimethyl 3-oxoglutarate (I) with methylamine and two equivalents of 2-pyridinecarboxaldehyde (II) gave piperidinone (III). Then, a further Mannich reaction with formaldehyde and methylamine furnished the bicyclic compound.
| 【1】 Kogel, B.; et al.; HZ2, a selective kappa-opioid agonist. CNS Drug Rev 1998, 4, 1, 54. |
| 【2】 Samhammer, A.; et al.; Synthesis, stereochemistry and analgesic activity of 3,7-diazabicyclo[3.3.1]nonan-9-ones and 1,3-diazaadamantan-6-ones. Arch Pharm 1989, 322, 9, 551. |
| 【3】 Haller, R.; Unholzer, H.; Stereochemistry of 3-oxa-7-aza- and 3,7-diazabicyclo[3.3.1]nonan-9-ones. Arch Pharm 1972, 305, 11, 855. |
合成路线3
该中间体在本合成路线中的序号：(IX)2-Amino-6-methylbenzoic acid (I) was reduced to alcohol (II) using LiAlH4, and then acetylated in Ac2O at 50 C. The acetyl protected compound (III) was nitrated with HNO3 in AcOH to afford (IV), which was hydrolyzed to the nitroaniline (V) with methanolic KOH. Subsequent condensation with pyrrolidine (VI) in the presence of diethyl azodicarboxylate and triphenylphosphine provided tertiary amine (VII). Hydrogenation of the nitro group of (VII) over Raney-Ni gave phenylenediamine (VIII), which was cyclized with dimethyl oxalate to produce quinoxalinedione (IX). This was finally nitrated with KNO3 in H2SO4 to furnish the title compound.
| 【1】 Kornberg, B.E.; Nikam, S.; Rafferty, M.F.; Yuen, P.-W. (Pfizer Inc.); Cyclic amine derivs. of substd. quinoxaline 2,3-diones as glutamate receptor antagonists. JP 1999506724; US 5874426; WO 9640650 . |
| 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) | 25165 | 2-amino-6-methylbenzoic acid | 4389-50-8 | C8H9NO2 | 详情 | 详情 |
| (II) | 25166 | (2-amino-6-methylphenyl)methanol | C8H11NO | 详情 | 详情 | |
| (III) | 25167 | 2-(acetamido)-6-methylbenzyl acetate | C12H15NO3 | 详情 | 详情 | |
| (IV) | 25168 | 2-(acetamido)-6-methyl-3-nitrobenzyl acetate | C12H14N2O5 | 详情 | 详情 | |
| (V) | 25169 | (2-amino-6-methyl-3-nitrophenyl)methanol | C8H10N2O3 | 详情 | 详情 | |
| (VI) | 25170 | 3-methyl-6-nitro-2-(1-pyrrolidinylmethyl)aniline | C12H17N3O2 | 详情 | 详情 | |
| (VII) | 25171 | 2-amino-4-methyl-3-(1-pyrrolidinylmethyl)phenylamine | C12H19N3 | 详情 | 详情 | |
| (VIII) | 25172 | 6-methyl-5-(1-pyrrolidinylmethyl)-1,4-dihydro-2,3-quinoxalinedione | C14H17N3O2 | 详情 | 详情 | |
| (IX) | 25173 | 2-pyridinecarbaldehyde | 1121-60-4 | C6H5NO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The Grignard reaction of 3-(cyclopentyloxy)-4-methoxybenzaldehyde (I) with vinylmagnesium bromide in THF gives the vinyl carbinol (II), which is oxidized with MnO2 in ethyl acetate yielding the propenone (III). The condensation of (III) with pyridine-2-carbaldehyde (IV) by means of 3-ethyl-5-(2-hydroxyethyl)-4-methyl-thiazolium bromide (ETB) and triethylamine affords the butanedione (V), which is finally cyclized to the target compound with p-toluenesulfonic acid in refluxing toluene.
| 【1】 Rasori, R.; Robichaud, A.; Girard, Y.; MacDonal, D.; Laliberté, F.; Huang, z.; Perrier, H.; Bayly, C.; Substituted furans as inhibitors of the PDE4 enzyme. Bioorg Med Chem Lett 1999, 9, 3, 323. |
| 【2】 Young, R.N.; MacDonald, D.; Bayly, C.; Perrier, H.; Han, Y.; Giroux, A. (Merck Frosst Canada Inc.); Aryl furan derivs. as PDE IV inhibitors. EP 1021429; US 6020339; WO 9918095 . |
| 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) | 16510 | 3-(cyclopentyloxy)-4-methoxybenzaldehyde | C13H16O3 | 详情 | 详情 | |
| (II) | 30022 | 1-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-propen-1-ol | C15H20O3 | 详情 | 详情 | |
| (III) | 30023 | 1-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-propen-1-one | C15H18O3 | 详情 | 详情 | |
| (IV) | 25173 | 2-pyridinecarbaldehyde | 1121-60-4 | C6H5NO | 详情 | 详情 |
| (V) | 30024 | 1-[3-(cyclopentyloxy)-4-methoxyphenyl]-4-(2-pyridinyl)-1,4-butanedione | C21H23NO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Tetrakis-(2-pyridyl)porphyrin (III) was prepared by condensation between pyridine-2-carboxaldehyde (I) and pyrrole (II) in refluxing propionic acid. Metallation of porphyrin (III) was performed with MnCl2, which spontaneously underwent oxidation, yielding the Mn3+ complex (IV). Subsequent N-alkylation of the pyridine rings with ethyl iodide produced the corresponding pyridinium iodide salt, which was transformed to the analogous chloride by treatment with tetrabutylammonium chloride (1). In an alternative procedure, initial quaternization of the pyridine rings of porphyrin (III) with ethyl p-toluenesulfonate afforded (V), which was further metallated with MnCl2 to give the title compound.
| 【2】 Kachadourian, R.; et al.; Synthesis and superoxide dismuting activities of partially (1-4) beta-chlorinated derivatives of manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl)porphyrin. Inorg Chem 1999, 38, 2, 391. |
| 【3】 Bloodsworth, A.; et al.; Manganese-porphyrin reactions with lipid and lipoproteins. Free Radical Biol Med 2000, 28, 7, 1017. |
| 【4】 Batinic-Haberle, I.; Fridovich, I. (Duke University); Substd. porphyrins. EP 1045851; JP 2001521939; WO 9923097 . |
| 【1】 Batinié-Haberle, I.; et al.; Relationships among redox potentials, proton dissociation constants of pyrrolic nitrogens, and in vivo and in vitro superoxide dismutating activities of magnase(III) and iron(III) water-soluble porphyrins. Inorg Chem 1999, 38, 18, 4011. |
| 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) | 25173 | 2-pyridinecarbaldehyde | 1121-60-4 | C6H5NO | 详情 | 详情 |
| (II) | 21674 | 1H-pyrrole | 109-97-7 | C4H5N | 详情 | 详情 |
| (III) | 51699 | 2,7,12,17-tetra(2-pyridinyl)-21,22,23,24-tetraazapentacyclo[16.2.1.1(3,6).1(8,11).1(13,16)]tetracosa-1,3,5,7,9,11(23),12,14,16,18(21),19-undecaene | C40H26N8 | 详情 | 详情 | |
| (IV) | 51700 | C40H24MnN8 | 详情 | 详情 | ||
| (V) | 51701 | 1-ethyl-2-[7,12,17-tris(1-ethyl-2-pyridiniumyl)-21,22,23,24-tetraazapentacyclo[16.2.1.1(3,6).1(8,11).1(13,16)]tetracosa-1,3,5,7,9,11(23),12,14,16,18(21),19-undecaen-2-yl]pyridinium | C48H46N8 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(X)3-Fluoroaniline (I) is condensed with benzyl chloroformate to give carbamate (II). Reaction of (II) with (R)-glycidol butyrate (III) in the presence of butyllithium affords oxazolidinone (IV). After conversion of alcohol (IV) to the corresponding mesylate, displacement with NaN3 provides azide (V). Reduction and acylation of (V) by means of thioacetic acid leads to acetamide (VI). Friedel-Crafts acylation of the aromatic ring of (VI) with acetic anhydride in the presence of methanesulfonic acid furnishes acetophenone (VII). Acidic hydrolysis of acetamide (VII) yields amine (VIII). This is then treated with thiophosgene, followed by methanol, to produce the thiocarbamate (IX). Finally, aldol condensation of the acetophenone (IX) with pyridine-2-carbaldehyde (X) gives rise to the target compound.
| 【1】 Selvakumar, N.; et al.; Synthesis and antibacterial activity of novel chalcone oxazolidinone hybrids. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1323. |
| 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) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (II) | 60314 | phenylmethyl 3-fluorophenylcarbamate | C14H12FNO2 | 详情 | 详情 | |
| (III) | 18385 | (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate | 60456-26-0 | C7H12O3 | 详情 | 详情 |
| (IV) | 60315 | 3-(3-fluorophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one | C10H10FNO3 | 详情 | 详情 | |
| (V) | 60317 | (R)-5-(azidomethyl)-3-(3-fluorophenyl)oxazolidin-2-one | C10H9FN4O2 | 详情 | 详情 | |
| (VI) | 60319 | N-{[3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide | C12H13FN2O3 | 详情 | 详情 | |
| (VII) | 62789 | N-{[(5S)-3-(4-acetyl-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide | C14H15FN2O4 | 详情 | 详情 | |
| (VIII) | 62790 | (5S)-3-(4-acetyl-3-fluorophenyl)-5-(aminomethyl)-1,3-oxazolidin-2-one | C12H13FN2O3 | 详情 | 详情 | |
| (IX) | 62791 | O-methyl [(5S)-3-(4-acetyl-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methylcarbamothioate | C14H15FN2O4S | 详情 | 详情 | |
| (X) | 25173 | 2-pyridinecarbaldehyde | 1121-60-4 | C6H5NO | 详情 | 详情 |