|
【结 构 式】 
|
【分子编号】12074 【品名】3-(Benzyloxy)-2-methyl-4H-pyran-4-one；3-(benzyloxy)-2-methylpyran-4-one 【CA登记号】61049-69-2 |
【 分 子 式 】C13H12O3 【 分 子 量 】216.23648 【元素组成】C 72.21% H 5.59% O 22.2% |
合成路线1
该中间体在本合成路线中的序号：(I)A new synthesis of L1 has been reported: The reaction of 3-benzyloxy-2-methyl-4H-pyran-4-one (I) with methylamine and NaOH in refluxing ethanol gives 3-benzyloxy-1,2-dimethylpyridin-4(1H)-one (II), which is deprotected by hydrogenolysis with H2 over Pd/C in ethanol.
| 【1】 Dobbin, P.S.; Hider, R.C.; Porter, J.B.; Sarpong, P.; Hall, A.D.; Xiao, G.; Taylor, P.D.; Van der Helm, D.; Synthesis, physicochemical properties, and biological evaluation of N-substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: Orally active iron chelators with clinical potential. J Med Chem 1993, 36, 17, 2448. |
合成路线2
该中间体在本合成路线中的序号：(II)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3
该中间体在本合成路线中的序号：(VI)Catalytic hydrogenation of 3,5-di-tert-butyl-4-hydroxycinnamic acid (I) afforded the saturated carboxylic acid (II), which was converted into amide (IV) via the corresponding acid chloride (III). Reduction of the amide function of (IV) by means of LiAlH4 furnished the primary amine (V). This was condensed with O-benzyl maltol (VI) to produce the pyridone (VII). After hydrogenolysis of the benzyl protecting group of (VII), the title compound was isolated as the corresponding mesylate salt.
| 【1】 Malcolm, C.S.; Bebbington, D.; Monck, N.J.T.; Palmer, A.M.; Gaur, S.; Benwell, K.; Porter, R.H.P.; Harvey, V.; 3,5-Disubstituted-4-hydroxyphenyls linked to 3-hydroxy-2-methyl-4(1H)-pyridinone: Potent inhibitors of lipid peroxidation and cell toxicity. J Med Chem 2000, 43, 15, 2779. |
| 【2】 Malcolm, C.; Porter, R.; Bebbington, D.; Palmer, A.; Gaur, S.; Monck, N. (Vernalis Research Ltd.); Ortho-hydroxypyridinone derivs. as iron chelating and antioxidant agents. EP 1027335; WO 9923075 . |
| 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) | 43375 | (E)-3-[3,5-di(tert-butyl)-4-hydroxyphenyl]-2-propenoic acid | 22014-01-3 | C17H24O3 | 详情 | 详情 |
| (II) | 43376 | 3-[3,5-di(tert-butyl)-4-hydroxyphenyl]propionic acid | 20170-32-5 | C17H26O3 | 详情 | 详情 |
| (III) | 43777 | 5,5,8,8-tetramethyl-N-(2-nitrophenyl)-5,6,7,8-tetrahydro-2-naphthalenamine; N-(2-nitrophenyl)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)amine | C20H24N2O2 | 详情 | 详情 | |
| (IV) | 43378 | 3-[3,5-di(tert-butyl)-4-hydroxyphenyl]propanamide | C17H27NO2 | 详情 | 详情 | |
| (V) | 43379 | 4-(3-aminopropyl)-2,6-di(tert-butyl)phenol | C17H29NO | 详情 | 详情 | |
| (VI) | 12074 | 3-(Benzyloxy)-2-methyl-4H-pyran-4-one；3-(benzyloxy)-2-methylpyran-4-one | 61049-69-2 | C13H12O3 | 详情 | 详情 |
| (VII) | 43380 | 3-(benzyloxy)-1-[3-[3,5-di(tert-butyl)-4-hydroxyphenyl]propyl]-2-methyl-4(1H)-pyridinone | C30H39NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)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 |
合成路线5
该中间体在本合成路线中的序号：(XVI)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 |