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【结 构 式】 
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【分子编号】13671 【品名】Hydroxymethylpyrone; 3-Hydroxy-2-methyl-4H-pyran-4-one；Maltol;3-Hydroxy-2-methyl-4-pyrone 【CA登记号】118-71-8 |
【 分 子 式 】C6H6O3 【 分 子 量 】126.11184 【元素组成】C 57.14% H 4.8% O 38.06% |
合成路线1
该中间体在本合成路线中的序号：(I)By reflux reaction of 3-hydroxy-2-methylpyridin-4-one (maltol) (I) with allylamine (II) solution in water for 3 h.
| 【1】 Kontoghiorghes, G.J.; Sheppard, L.N. (Royal Free Hospital); Process for producing pyrid-4-ones. EP 0335745 . |
| 【2】 Kontoghiorghes, G.J.; L1NAll. Drugs Fut 1990, 15, 3, 230. |
合成路线2
该中间体在本合成路线中的序号：(III)Acetylsalicylic (I) acid was refluxed in SOCl2 to give acetylsalicylyl chloride (II), which is condensed with maltol (III) by means of triethylamine in chloroform to afford aspalatone.
| 【1】 Underwood, M.J.; More, R.S.; The aspirin papers. Brit Med J 1994, 308, 71-2. |
| 【2】 Han, B.H.; Suh, D.-Y.; Yang, H.O.; Park, Y.-H.; Kang, Y.H.; Kim, Y.C.; Synthesis and antiplatelet effects of the new antithrombotic agent aspalatone with low ulcerogenicity. Arzneim-Forsch Drug Res 1994, 44, 10, 1122-6. |
| 【3】 Han, B.H.; Aspalatone. Drugs Fut 1995, 20, 11, 1109. |
| 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) | 16899 | 2-(Acetoxy)benzoic acid; Aspirin; Acetylsalicylic acid | 50-78-2 | C9H8O4 | 详情 | 详情 |
| (II) | 16900 | 2-(chlorocarbonyl)phenyl acetate; Acetylsalicyloyl chloride | 5538-51-2 | C9H7ClO3 | 详情 | 详情 |
| (III) | 13671 | Hydroxymethylpyrone; 3-Hydroxy-2-methyl-4H-pyran-4-one；Maltol;3-Hydroxy-2-methyl-4-pyrone | 118-71-8 | C6H6O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Bis(maltolato)oxovanadium(IV) is prepared by complexation of maltol (I) with vanadyl sulfate in refluxing aqueous solution, adjusting the pH at approx. 8.5 with KOH.
| 【1】 McNeill, J.H.; et al.; Bis(maltolato)oxovanadium(IV) is a potent insulin mimic. J Med Chem 1992, 35, 8, 1489. |
| 【2】 Orvig, C.; et al.; Reaction chemistry of BMOV, bis(maltolato) oxovanadium(IV), a potent insulin mimetic agent. J Am Chem Soc 1995, 117, 51, 12759. |
| 【3】 McNeill, J.H.; Hoveyda, H.R.; Orvig, C. (University of British Columbia); Complexed vanadium for the treatment of diabetes mellitus. JP 1994511244; US 5300496; WO 9306811 . |
合成路线4
该中间体在本合成路线中的序号：(I)Maltol (I) was protected as the benzyl ether (II) by means of benzyl chloride, and subsequently treated with 1-(2-aminoethyl)piperidine (III) in refluxing ethanol to produce the substituted pyridone (IV). The benzyl protecting group of (IV) was finally removed with boron tribromide, yielding the title hydroxypyridone, which was isolated as the dihydrobromide salt.
| 【1】 Aytemir, M.D.; et al.; New 4(1H)-pyridinone derivatives as analgesic agents. Arzneim-Forsch Drug Res 1999, 49, 3, 250. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 | |
| (I) | 13671 | Hydroxymethylpyrone; 3-Hydroxy-2-methyl-4H-pyran-4-one；Maltol;3-Hydroxy-2-methyl-4-pyrone | 118-71-8 | C6H6O3 | 详情 | 详情 |
| (II) | 12074 | 3-(Benzyloxy)-2-methyl-4H-pyran-4-one；3-(benzyloxy)-2-methylpyran-4-one | 61049-69-2 | C13H12O3 | 详情 | 详情 |
| (III) | 24646 | 2-(1-piperidinyl)-1-ethanamine | 27578-60-5 | C7H16N2 | 详情 | 详情 |
| (IV) | 31300 | 3-(benzyloxy)-2-methyl-1-[2-(1-piperidinyl)ethyl]-4(1H)-pyridinone | C20H26N2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The title gallium complex was prepared by mixing solutions of maltol (I) and a soluble gallium salt, such as gallium chloride or gallium nitrate, followed by neutralization with Na2CO3.
| 【1】 Finnegan, M.M.; et al.; Neutral water-soluble post-transition-metal chelate complexes of medical interest: Aluminum and gallium tris(3-hydroxy-4-pyronates). Inorg Chem 1987, 26, 20, 2171. |
| 【2】 Bernstein, L.R.; Powder X-ray crystallography of gallium 3-hydroxy-4-pyronates. Powder Diffr 1995, 10, 2, 140. |
| 【3】 Tanner, T.; Godfrey, C.; Noll, B.; Bernstein, L.R.; Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium biovailability. Met-Based Drugs 2000, 7, 1, 33. |
| 【4】 Bernstein, L.R. (GeoMed, Inc.); Methods and compsns. to inhibit keratinocyte proliferation. WO 9804263; WO 9804264 . |
合成路线6
该中间体在本合成路线中的序号：(I)Protection of 3-hydroxy-2-methylpyran-4-one (I) with PhCH2Br in the presence of K2CO3 in acetonitrile at 80 °C or in DMF yields 3-(benzyloxy)-2-methylpyran-4-one (II) , which, after deprotonation with LiHMDS in THF, is condensed with benzaldehyde (III) at –60 °C to afford 3-(benzyloxy)-2-(2-hydroxy-2-phenylethyl) pyran-4-one (IV). Sulfonylation of alcohol (IV) with MsCl and Et3N in THF followed by mesylate elimination by means of DBU in NMP gives alkene (V), which by oxidative cleavage with NaIO4 in the presence of RuCl3, optionally using H2S, in acetonitrile/AcOEt/water, and further oxidation of the obtained aldehyde with NaClO2 or NaClO in the presence of TEMPO, yields the pyrancarboxylic acid (VI). Condensation of the 4-pyranone (VI) with 3-aminopropane-1,2-diol (VII) in EtOH at 80 °C leads to the pyridone (VIII), which is then converted to the methyl ester (IX) using MeI and NaHCO3. Oxidative cleavage of the vicinal diol (IX) with NaIO4 and AcOH or H2SO4 in acetonitrile/water provides the pyridone-1-acetaldehyde hydrate (X), which by cyclization with 3(R)-amino-1-butanol (XI) by means of AcOH in MeOH at 90 °C or diglyme yields the pyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XII). Bromination of compound (XII) with NBS in CH2Cl2 or NMP furnishes the bromopyridone derivative (XIII), which undergoes carbonylation with CO in the presence of 2,4-difluorobenzylamine (XIV) and Pd(PPh3)4/DIEA or Pd(OAc)2/DIEA/DPPB in DMSO at 90 °C to afford carboxamide (XV). Finally, compound (XV) is deprotected by debenzylation with H2 over Pd/C .
The pyrancarboxylic acid (VI) can also be prepared by oxidation of 3-(benzyloxy)-2-methylpyran-4-one (XVI) with SeO2 in bromobenzene at 160 °C to give aldehyde (XVII) and further oxidation with NaClO2 in the presence of NH2SO3H in acetone/H2O .
| 【1】 Johns, B.A., Duan, M., Hakogi, T. (Shionogi & Co., Ltd.; GlaxoSmithKline, Inc.). Processes and intermediates for carbamoylpyridone HIV integrase inhibitors. CN 102245572, EP 2376453, JP 2012511574, KR 2011096574, US 2011263855, WO 2010068262. |
| 【2】 Yoshida, H., Taoda, Y., Johns, B.A. (Shionogi & Co., Ltd.; GlaxoSmithKline, Inc.). Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates. CN 102245182, EP 2376080, JP 012511573, KR 2011094336, US 2011282055, WO 2010068253. |
| 【3】 Johns, B.A., Kawasuji, T., Taishi, T., Taoda, Y. (Shionogi & Co., Ltd.). Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity. EP 1874117, EP 2465580, JP 2008540343, JP 2009079058, US 200931821, US 8129385, US 2012115875, WO 2006116764. |
| 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) | 13671 | Hydroxymethylpyrone; 3-Hydroxy-2-methyl-4H-pyran-4-one；Maltol;3-Hydroxy-2-methyl-4-pyrone | 118-71-8 | C6H6O3 | 详情 | 详情 |
| (II) | 12074 | 3-(Benzyloxy)-2-methyl-4H-pyran-4-one；3-(benzyloxy)-2-methylpyran-4-one | 61049-69-2 | C13H12O3 | 详情 | 详情 |
| (III) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (IV) | 68571 | 3-(benzyloxy)-2-(2-hydroxy-2-phenylethyl)-4H-pyran-4-one | C20H18O4 | 详情 | 详情 | |
| (V) | 68572 | (E)-3-(benzyloxy)-2-styryl-4H-pyran-4-one | C20H16O3 | 详情 | 详情 | |
| (VI) | 68573 | 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid | C13H10O5 | 详情 | 详情 | |
| (VII) | 12979 | 3-Amino-1,2-propanediol；3-aminopropane-1,2-diol | 616-30-8 | C3H9NO2 | 详情 | 详情 |
| (VIII) | 68574 | 3-(benzyloxy)-1-(2,3-dihydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid | C16H17NO6 | 详情 | 详情 | |
| (IX) | 68575 | methyl 3-(benzyloxy)-1-(2,3-dihydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxylate | C17H19NO6 | 详情 | 详情 | |
| (X) | 68576 | methyl 3-(benzyloxy)-1-(2,2-dihydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate | C16H17NO6 | 详情 | 详情 | |
| (XI) | 68577 | 3(R)-amino-1-butanol;(R)-3-aminobutan-1-ol | 61477-39-2 | C4H11NO | 详情 | 详情 |
| (XII) | 68581 | (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione | C19H20N2O4 | 详情 | 详情 | |
| (XIII) | 68580 | (4R,12aS)-7-(benzyloxy)-9-bromo-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione | C19H19BrN2O4 | 详情 | 详情 | |
| (XIV) | 68578 | 2,4-difluorobenzylamine | 72235-52-0 | C7H7F2N | 详情 | 详情 |
| (XV) | 68579 | (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide | C27H25F2N3O5 | 详情 | 详情 | |
| (XVI) | 12074 | 3-(Benzyloxy)-2-methyl-4H-pyran-4-one；3-(benzyloxy)-2-methylpyran-4-one | 61049-69-2 | C13H12O3 | 详情 | 详情 |
| (XVII) | 68582 | 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde | C13H10O4 | 详情 | 详情 |