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【结 构 式】 
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【药物名称】Dolutegravir;GSK-1349572;S-349572;S/GSK-1349572 【化学名称】(4R,12aS)-N-(2,4-Difluorobenzyl)-7-hydroxy-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 【CA登记号】 【 分 子 式 】C20H19F2N3O5 【 分 子 量 】419.3788 |
【开发单位】Shionogi-ViiV Healthcare (US) 【药理作用】HIV Integrase Inhibitor；Treatment of HIV Infection |
合成路线1
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2
Condensation of ethyl 3-(dimethylamino)acrylate (XVIII) with (benzyloxy)acetyl chloride (XIX) by means of pyridine in CH2Cl2 gives ethyl 2-[(benzyloxy)acetyl]-3-(dimethylamino)-2-propenoate (XX), which by cyclocondensation with ethyl oxalyl chloride (XXI) in the presence of LiHMDS in THF at –78 °C followed by heating with NH4OAc and AcOH affords pyridone derivative (XXII). Alkylation of pyridone (XXII) with bromoacetaldehyde dimethyl acetal (XXIII) and Cs2CO3 in DMF yields diethyl 1-(2,2-dimethoxyethyl)-3-(benzyloxy)-1,4-dihydropyridine-2,5-dicarboxylate (XXIV), which can also be obtained by condensation of diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (XXV) with 2,2-dimethoxyethylamine (XXVI) in EtOH. Hydrolysis of acetal (XXIV) with H2SO4 and HCOOH in CH2Cl2 yields aldehyde (XXVII), which upon cyclocondensation with 3(R)-amino-1-butanol (XI) by means of AcOH in refluxing MeOH/toluene provides the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XXVIII). Hydrolysis of ester (XXVIII) with NaOH in THF/MeOH/H2O gives the corresponding free acid (XXIX), which is finally condensed with 2,4-difluorobenzylamine (XIV) in the presence of HATU and NMM in DMF .
Propenoate (XX) can also be prepared by condensation of ethyl 4-chloroacetoacetate (XXX) with PhCH2OH in the presence of t-AmONa to give benzyl ether (XXXI), which then reacts with N,N-dimethylformamide dimethyl acetal (XXXII) in toluene .
| 【1】 Sumino, Y., Okamoto, K., Masui, M., Yamada, D., Ikarashi, F. (Shionogi & Co., Ltd.). Process for preparing compound having HIV integrase inhibitory activity. WO 2012018065. |
| 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) | 68577 | 3(R)-amino-1-butanol;(R)-3-aminobutan-1-ol | 61477-39-2 | C4H11NO | 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 | |
| (XVIII) | 16000 | ethyl (E)-3-(dimethylamino)-2-propenoate; Ethyl trans-3-dimethylaminoacrylate | 1117-37-9 | C7H13NO2 | 详情 | 详情 |
| (XIX) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (XX) | 68583 | (E)-ethyl 4-(benzyloxy)-2-((dimethylamino)methylene)-3-oxobutanoate | C16H21NO4 | 详情 | 详情 | |
| (XXI) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (XXII) | 68584 | diethyl 3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C18H19NO6 | 详情 | 详情 | |
| (XXIII) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (XXIV) | 68585 | 1-(2,2-dimethoxyethyl)-3-(benzyloxy)-1,4-dihydropyridine-2,5-dicarboxylate diethyl；diethyl 3-(benzyloxy)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C22H27NO8 | 详情 | 详情 | |
| (XXV) | 68586 | diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate | C18H18O7 | 详情 | 详情 | |
| (XXVI) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XXVII) | 68587 | diethyl 3-(benzyloxy)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2,5-dicarboxylate | C20H21NO7 | 详情 | 详情 | |
| (XXVIII) | 68588 | (4R,12aS)-ethyl 7-(benzyloxy)-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-carboxylate | C22H24N2O6 | 详情 | 详情 | |
| (XXIX) | 68589 | (4R,12aS)-7-(benzyloxy)-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-carboxylic acid | C20H20N2O6 | 详情 | 详情 | |
| (XXX) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (XXXI) | 68590 | ethyl 4-(benzyloxy)-3-oxobutanoate | C13H16O4 | 详情 | 详情 | |
| (XXXII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
合成路线3
Condensation of methyl 4-chloroacetoacetate (XXXIII) with PhCH2OH in the presence of t-AmONa in THF gives the benzyl ether (XXXIV), which is then condensed with N,N-dimethylformamide dimethyl acetal (XXXII) in dioxane to give methyl 2-[(benzyloxy) acetyl]-3-aminoacrylate (XXXV). Cyclocondensation of acrylate (XXXV) with dimethyl oxalate by means of t-BuONa provides the pyranone derivative (XXXVII), which is then reacted with aminoacetaldehyde dimethyl acetal (XXVI) at reflux to yield pyridone (XXXVIII). Hydrolysis of acetal (XXXVIII) with H2SO4 and HCOOH affords aldehyde (XXXIX), which upon cyclocondensation with 3(R)-amino-1-butanol (XI) in the presence of AcOH in refluxing MeOH/toluene gives the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XL). Finally, methyl ester (XL) is condensed with 2,4-difluorobenzylamine (XIV) in the presence of AcOH in toluene .
Alternatively, coupling of methyl ester (XXXVIII) with 2,4-difluorobenzylamine (XIV) by means of AcOH in toluene/MeOH gives amide (XLI), which upon acetal hydrolysis with H2SO4 and HCOOH in toluene yields aldehyde (XLII). Finally, aldehyde (XLII) is submitted to cyclocondensation with 3(R)-amino-1-butanol (XI) in the presence of AcOH in refluxing MeOH/toluene .
| 【1】 Sumino, Y., Okamoto, K., Masui, M., Yamada, D., Ikarashi, F. (Shionogi & Co., Ltd.). Process for preparing compound having HIV integrase inhibitory activity. WO 2012018065. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XL) | 68597 | (4R,12aS)-methyl 7-(benzyloxy)-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-carboxylate | C21H22N2O6 | 详情 | 详情 | |
| (XI) | 68577 | 3(R)-amino-1-butanol;(R)-3-aminobutan-1-ol | 61477-39-2 | C4H11NO | 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 | |
| (XXVI) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XXXII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XXXIII) | 68591 | methyl 4-chloro-3-oxobutanoate；Methyl 4-chloro-3-oxo-butanoate;Methyl 4-chloro-3-oxobutyrate；Methyl 4-chloroacetoacetate | 32807-28-6 | C5H7ClO3 | 详情 | 详情 |
| (XXXIV) | 68592 | methyl 4-(benzyloxy)-3-oxobutanoate | C12H14O4 | 详情 | 详情 | |
| (XXXV) | 68593 | (E)-methyl 4-(benzyloxy)-2-((dimethylamino)methylene)-3-oxobutanoate;methyl 2-[(benzyloxy)acetyl]-3-aminoacrylate | C15H19NO4 | 详情 | 详情 | |
| (XXXVI) | 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 |
| (XXXVII) | 68594 | dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate | C16H14O7 | 详情 | 详情 | |
| (XXXVIII) | 68595 | dimethyl 3-(benzyloxy)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C20H23NO8 | 详情 | 详情 | |
| (XXXIX) | 68596 | dimethyl 3-(benzyloxy)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2,5-dicarboxylate | C18H17NO7 | 详情 | 详情 | |
| (XLI) | 68598 | methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate | C26H26F2N2O7 | 详情 | 详情 | |
| (XLII) | 68599 | methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate | C24H20F2N2O6 | 详情 | 详情 |
合成路线4
Condensation of methyl 4-methoxyacetoacetate (XLIII) with N,N-dimethylformamide dimethyl acetal (XXXII) produces methyl 3-(dimethylamino)-2-(methoxyacetyl)-2-propenoate (XLIV), which by reaction with 2,2-dimethoxyethylamine (XXVI) in MeOH affords the N-(dimethyoxyethyl)enamine (XLV). Cyclization of enaminoketone (XLV) with dimethyl oxalate (XXXVI) by means of LiH at 40 °C gives the dimethyl pyridone-dicarboxylate (XLVI), which by selective hydrolysis with LiOH yields the monocarboxylic acid (XLVII). Hydrolysis of acetal (XLVII) with MsOH and AcOH in acetonitrile at 58-65 °C followed by in situ cyclization of the resulting aldehyde (XLVIII) with 3(R)-amino-1-butanol (XI) in acetonitrile at 64 °C affords the pyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XLIX). Activation of acid (XLIX) with CDI in DME at 80 °C and subsequent coupling with 2,4-difluorobenzylamine (XIV) gives amide (L), which is finally O-demethylated with either MgBr2 in hot acetonitrile or LiBr in refluxing THF .
| 【1】 Wang, H., Goodman, S.N., Mans, D., Kowalski, M. (GlaxoSmithKline, Inc.). Process for preparing carbamoylpyridone derivatives and intermediates. WO 2011119566. |
| 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) | 68577 | 3(R)-amino-1-butanol;(R)-3-aminobutan-1-ol | 61477-39-2 | C4H11NO | 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 | |
| (XXVI) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XXXII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XXXVI) | 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 |
| (XLIII) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (XLIV) | 68600 | methyl 3-(dimethylamino)-2-(methoxyacetyl)-2-propenoate;(Z)-methyl 2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate | C9H15NO4 | 详情 | 详情 | |
| (XLV) | 68601 | (Z)-methyl 2-(((2,2-dimethoxyethyl)amino)methylene)-4-methoxy-3-oxobutanoate | C11H19NO6 | 详情 | 详情 | |
| (XLVI) | 68602 | dimethyl 1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C14H19NO8 | 详情 | 详情 | |
| (XLVII) | 68603 | 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid | C13H17NO8 | 详情 | 详情 | |
| (XLVIII) | 68604 | 5-methoxy-6-(methoxycarbonyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-3-carboxylic acid | C11H11NO7 | 详情 | 详情 | |
| (XLIX) | 68606 | (4R,12aS)-7-methoxy-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-carboxylic acid | C14H16N2O6 | 详情 | 详情 | |
| (L) | 68605 | (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-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 | C21H21F2N3O5 | 详情 | 详情 |
合成路线5
Condensation of ethyl 4-chloro-3-oxobutyrate (XXX) with N,Ndimethylformamide dimethylacetal (XXXII) in EtOAc results in ethyl 2-(chloroacetyl)-3-(dimethylamino)-2-propenoate (LI), which by cyclocondensation with ethyl oxalyl chloride (XXI) by means of LiHMDS in THF affords diethyl 3-chloro-4-oxopyran-2,5-dicarboxylate (LII). Condensation of pyranone (LII) with 2,2-dimethoxyethylamine (XXVI) in EtOH gives pyridone (LIII), which is then hydrolyzed using HCOOH and H2SO4 in CH2Cl2 to yield the corresponding aldehyde (LIV). Cyclization of compound (LIV) with 3(R)-amino-1-butanol (XI) and AcOH in refluxing MeOH/toluene provides the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (LV), which by hydrolysis with KOSiMe3 in DME affords the hydroxy acid (LVI). Finally, acid (LVI) is coupled with 2,4-difluorobenzylamine (XIV) in the presence of HATU and NMM in DMF .
| 【1】 Sumino, Y., Okamoto, K., Masui, M., Yamada, D., Ikarashi, F. (Shionogi & Co., Ltd.). Process for preparing compound having HIV integrase inhibitory activity. WO 2012018065. |
| 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) | 68577 | 3(R)-amino-1-butanol;(R)-3-aminobutan-1-ol | 61477-39-2 | C4H11NO | 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 | |
| (XXI) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (XXVI) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XXX) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (XXXII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (LI) | 68607 | ethyl 2-(chloroacetyl)-3-(dimethylamino)-2- propenoate;(E)-ethyl 4-chloro-2-((dimethylamino)methylene)-3-oxobutanoate | C9H14ClNO3 | 详情 | 详情 | |
| (LII) | 68608 | diethyl 3-chloro-4-oxo-4H-pyran-2,5-dicarboxylate | C11H11ClO6 | 详情 | 详情 | |
| (LIII) | 68609 | diethyl 3-chloro-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C15H20ClNO7 | 详情 | 详情 | |
| (LIV) | 68610 | diethyl 3-chloro-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2,5-dicarboxylate | C13H14ClNO6 | 详情 | 详情 | |
| (LV) | 68612 | (4R,12aS)-ethyl 7-chloro-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-carboxylate | C15H17ClN2O5 | 详情 | 详情 | |
| (LVI) | 68611 | (4R,12aS)-7-chloro-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-carboxylic acid | C13H13ClN2O5 | 详情 | 详情 |
合成路线6
Condensation of ethyl 3-oxobutyrate (LVII) with N,N-dimethylformamide dimethylacetal (XXXII) in EtOAc affords ethyl 2-acetyl-3-(dimethylamino)-2-propenoate (LVIII), which by cyclocondensation with ethyl oxalyl chloride (XXI) by means of LiHMDS in THF provides diethyl 4-oxopyran-2,5-dicarboxylate (LIX). Condensation of pyranone derivative (LIX) with 2,2-dimethoxyethylamine (XXVI) in EtOH gives pyridone (LX), which is then brominated with NBS in DMF to yield the 3-bromopyridin-4-one derivative (LXI). Hydrolysis of acetal (LXI) using HCOOH and H2SO4 in CH2Cl2 yields the corresponding aldehyde (LXII), which is cyclized with 3(R)-aminobutan-1-ol (XI) in the presence of AcOH in refluxing MeOH/toluene to afford the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (LXIII). Finally, bromo ester (LXIII) is submitted to treatment with KOSiMe3 in DME .
| 【1】 Sumino, Y., Okamoto, K., Masui, M., Yamada, D., Ikarashi, F. (Shionogi & Co., Ltd.). Process for preparing compound having HIV integrase inhibitory activity. WO 2012018065. |
| 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) | 68577 | 3(R)-amino-1-butanol;(R)-3-aminobutan-1-ol | 61477-39-2 | C4H11NO | 详情 | 详情 |
| (XXI) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (XXVI) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XXXII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (LVI) | 68611 | (4R,12aS)-7-chloro-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-carboxylic acid | C13H13ClN2O5 | 详情 | 详情 | |
| (LVII) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (LVIII) | 68613 | ethyl 2-acetyl-3-(dimethylamino)-2-propenoate;Ethyl 2-acetyl-3-(dimethylamino)acrylate;Ethyl (2E)-2-(dimethylaminomethylidene)-3-oxobutanoate | 51145-57-4 | C9H15NO3 | 详情 | 详情 |
| (LIX) | 68614 | diethyl 4-oxopyran-2,5-dicarboxylate;diethyl 4-oxo-4H-pyran-2,5-dicarboxylate | C11H12O6 | 详情 | 详情 | |
| (LX) | 68615 | diethyl 1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C15H21NO7 | 详情 | 详情 | |
| (LXI) | 68616 | diethyl 3-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C15H20BrNO7 | 详情 | 详情 | |
| (LXII) | 68617 | diethyl 3-bromo-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2,5-dicarboxylate | C13H14BrNO6 | 详情 | 详情 | |
| (LXIII) | 68618 | (4R,12aS)-ethyl 7-bromo-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-carboxylate | C15H17BrN2O5 | 详情 | 详情 |