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【结 构 式】

【分子编号】34158

【品名】aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine

【CA登记号】22483-09-6

【 分 子 式 】C4H11NO2

【 分 子 量 】105.13688

【元素组成】C 45.7% H 10.55% N 13.32% O 30.44%
与该中间体有关的原料药合成路线共 15 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15

合成路线1

该中间体在本合成路线中的序号：(II)

The condensation of 2,3-dichlorobenzaldehyde (I) with 2,2-dimethoxyethylamine (II) in refluxing toluene gives the corresponding Schiff base (III), which is reduced with H2 over PtO2 in ethyl acetate and acetylated with acetic anhydride yielding N-(2,3-dichlororobenzyl)-N-(2,2-dimethoxyethyl)acetamide (IV). The cyclization of (IV) with AlCl3 in dichloroethane affords 7,8-dichloro-2-acetyl-1,2-dihydroisoquinoline (V), which is submitted to cyclopropanation with CHCl3, NaOH and benzyltriethylammonium chloride giving 1,1,4,5-tetrachloro-2-acetyl-1a,2,3,7b-tetrahydro-1H-cycloprop[c]isoquinoline (VI). Ring opening of (VI) by refluxing with tert-butyl alcohol yields 2-acetyl-3-(tert-butoxy)-4,8,9-trichloro-2,3-dihydro-1H-2-benzazepine (VII), which is reduced with H2 over PtO2 in methanol affording 2-acetyl-8,9-dichloro 2,3,4,5-tetrahydro-1H-2-benzazepine (VIII). Finally, this compound is desacetylated by means of refluxing aqueous HCl.

参考文献 中间体
合成目标
【1】 Perchonock, C.D.; Lantos, I.; Holden, K.G.; Finkelstei, J.A.; Facile synthesis of halo-substituted tetrahydroisoquinolines and tetrahydro-2-benzazepines via N-acetyl-1,2-dihydroisoquinolines. J Org Chem 1980, 45, 10, 1950-53.
【2】 Serradell, M.N.; Castaner, J.; LY-134046. Drugs Fut 1984, 9, 4, 268.
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) 14742 2,3-dichlorobenzaldehyde 6334-18-5 C7H4Cl2O 详情 详情
(II) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(III) 34159 N-[(Z)-(2,3-dichlorophenyl)methylidene]-2,2-dimethoxy-1-ethanamine; N-[(Z)-(2,3-dichlorophenyl)methylidene]-N-(2,2-dimethoxyethyl)amine C11H13Cl2NO2 详情 详情
(IV) 34160 N-(2,3-dichlorobenzyl)-N-(2,2-dimethoxyethyl)acetamide C13H17Cl2NO3 详情 详情
(V) 34161 1-[7,8-dichloro-2(1H)-isoquinolinyl]-1-ethanone C11H9Cl2NO 详情 详情
(VI) 34162 1-(1,1,4,5-tetrachloro-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)-1-ethanone C12H9Cl4NO 详情 详情
(VII) 34163 1-[3-(tert-butoxy)-4,8,9-trichloro-1,3-dihydro-2H-2-benzazepin-2-yl]-1-ethanone C16H18Cl3NO2 详情 详情
(VIII) 34164 1-(8,9-dichloro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-1-ethanone C12H13Cl2NO 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The reaction of 4-phenyl-1-butanol (I) with 1,6-dibromohexane (II) by means of KOH and tetrabutylammonium bisulfate gives the butyl hexyl ether (III), which is condensed with 2-aminoacetaldehyde dimethylacetal (IV) in refluxing toluene yielding 2-[6-(4-phenylbutoxy)hexylamino]acetaldehyde dimethylacetal (V). The protection of the amino group of (V) with N-(benzyloxycarbonyloxy)succinimide and triethylamine in acetone affords the carbamate (VI), which is treated with TsOH in acetone to provide the acetaldehyde derivative (VII). The condensation of (VII) with 6-bromo-2,2-dimethyl-1,3-benzodioxan (VIII) (obtained by cyclization of phenol (IX) with acetone and AlCl3) by means of Mg in THF gives the expected carbinol (X), which is deprotected with H2 over Pd/C in methanol yielding the aminoethanol derivative (XI). Finally, this compound is treated with HCl in methanol/water to open the 1,3-dioxane ring and afford the target compound.

参考文献 中间体
合成目标
【1】 Marquillas Olondriz, F.; Dalmases Barjoan, P.; Bessa Bellmunt, J. (Laboratorios Vita, SA); New derivs. of 6-(4-phenylbutoxy)hexylamine and process for producing salmeterol. ES 2142771; WO 0018722 .
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) 27291 4-phenyl-1-butanol 3360-41-6 C10H14O 详情 详情
(II) 24786 1,6-dibromohexane 629-03-8 C6H12Br2 详情 详情
(III) 31479 1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene 94749-73-2 C16H25BrO 详情 详情
(IV) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(V) 36932 N-(2,2-dimethoxyethyl)-N-[6-(4-phenylbutoxy)hexyl]amine; N-(2,2-dimethoxyethyl)-6-(4-phenylbutoxy)-1-hexanamine C20H35NO3 详情 详情
(VI) 36933 benzyl 2,2-dimethoxyethyl[6-(4-phenylbutoxy)hexyl]carbamate C28H41NO5 详情 详情
(VII) 36934 benzyl 2-oxoethyl[6-(4-phenylbutoxy)hexyl]carbamate C26H35NO4 详情 详情
(VIII) 36935 4-bromo-2-(hydroxymethyl)phenol 2316-64-5 C7H7BrO2 详情 详情
(IX) 36936 6-bromo-2,2-dimethyl-4H-1,3-benzodioxine C10H11BrO2 详情 详情
(X) 36937 benzyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl[6-(4-phenylbutoxy)hexyl]carbamate C36H47NO6 详情 详情
(XI) 36938 1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[[6-(4-phenylbutoxy)hexyl]amino]-1-ethanol C28H41NO4 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XIII)

The Grignard condensation of 1-tetralone (IX) with 4-chloro-3-methoxyphenylmagnesium bromide (X) in THF followed by a treatment with TsOH gives 4-(4-chloro-3-methoxyphenyl)-1,2-dihydronaphthalene (XI), which is oxidized with oxone and TsOH yielding the 2-tetralone (XII). The condensation of (XII) with 2-aminoacetaldehyde dimethylacetal (XIII) in toluene affords the enamine (XIV), which is reduced with BH3 / t-Bu-NH2 and AcOH in dichloromethane to give a 9:1 mixture of cis (XV) and trans (XVI) isomers that is epimerized with t-BuOK in DMSO/DMF to a 15:85 mixture from which the desired trans-diastereomer (XVI) is isolated. The cyclization of (XVI) with CH3SO3H in dichloromethane affords the tetracyclic compound (XVII), which is hydrogenated with BH3 / t-Bu-NH2 to provide the intermediate (XVIII). Finally, this compound is methylated with formaldehyde and formic acid to obtain the previously reported rac-(VIII) compound.

参考文献 中间体
合成目标
【1】 Berger, J.G.; Clader, J.W.; Chang, W.K.; Gold, E.H. (Schering Corp.); Fused benzazepines. EP 0230270; EP 0254737; JP 1988502348; WO 8704430 .
【2】 Draper, R.W.; et al.; Novel stereoselective syntheses of the fused benzazepine dopamine D1 antagonist (6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5-H-benzo[d]naphth[2,1-b]azepin-12-ol (Sch 39166): 1. Aziridinium salt based syntheses. Org Process Res Dev 1998, 2, 3, 175.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 31779 (3aS,9bR)-12-chloro-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine; (3aS,9bR)-12-chloro-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether C20H22ClNO 详情 详情
(IX) 20720 3,4-dihydro-1(2H)-naphthalenone 529-34-0 C10H10O 详情 详情
(X) 36624 bromo(4-chloro-3-methoxyphenyl)magnesium C7H6BrClMgO 详情 详情
(XI) 36625 4-(4-chloro-3-methoxyphenyl)-1,2-dihydronaphthalene; 2-chloro-5-(3,4-dihydro-1-naphthalenyl)phenyl methyl ether C17H15ClO 详情 详情
(XII) 36626 1-(4-chloro-3-methoxyphenyl)-3,4-dihydro-2(1H)-naphthalenone C17H15ClO2 详情 详情
(XIII) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(XIV) 36627 N-[1-(4-chloro-3-methoxyphenyl)-3,4-dihydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)amine; 1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-3,4-dihydro-2-naphthalenamine C21H24ClNO3 详情 详情
(XV) 36628 N-[(1R,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)amine; (1R,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-2-naphthalenamine C21H26ClNO3 详情 详情
(XVI) 36629 (1S,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(1S,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)amine C21H26ClNO3 详情 详情
(XVII) 36630 (3aS,9bR)-12-chloro-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether; (3aS,9bR)-12-chloro-11-methoxy-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepine C19H18ClNO 详情 详情
(XVIII) 36631 (3aS,9bR)-12-chloro-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether; (3aS,9bR)-12-chloro-11-methoxy-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine C19H20ClNO 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

The condensation of 2,2-dimethyl-1,3-dioxan-5-one (I) with aminoacetaldehyde dimethyl acetal (II) followed by acetylation with Ac2O/Et3N afforded the amido dioxin (III). Retro Diels-Alder reaction of dioxin (III) in warm benzonitrile generated the amidoacrolein (V), which was trapped in situ with the silyloxydiene (IV) to yield the cycloadduct (VI). Aldol cyclization between the acetamide and aldehyde functionalities of (VI) in the presence of t-BuOK produced the spiro lactam (VII). Subsequent aldol condensation between the acetal and silyl enolate functions of (VII) under acidic conditions furnished the tricyclic hydroxy ketone (VIII). Reduction of the keto group of (VIII) with NaBH(OAc)3 produced the C-4 axial alcohol (IX). Silylation of both hydroxyl groups of (IX) followed by selective cleavage of the C-2 silyl ether provided the C-4 mono silylated derivative (X). The free C-2 hydroxyl group of (X) was then oxidized to the corresponding ketone (XI) under Swern conditions. The potassium enolate of (XI) was stereoselectively alkylated with p-methoxybenzyl bromide (XII) to yield (XIII). Reduction of the keto group of (XIII) with Red-Al gave rise to the alcohol (XIV) in the undesired equatorial configuration. Inversion of the C-2 stereogenic center of (XIV) was achieved via formation of the sulfonate ester (XVI) with 4-nitrobenzenesulfonyl chloride (XV).

参考文献 中间体
合成目标
【1】 Maeng, J.-H.; Funk, R.L.; Total synthesis of the immunosuppressant FR901483 via an amidoacrolein cycloaddition. Org Lett 2001, 3, 8, 1125.
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) 46538 2,2-dimethyl-1,3-dioxan-5-one C6H10O3 详情 详情
(II) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(III) 48300 N-(2,2-dimethoxyethyl)-N-(2,2-dimethyl-4H-1,3-dioxin-5-yl)acetamide C12H21NO5 详情 详情
(IV) 48301 triisopropyl[(1-methylene-2-propenyl)oxy]silane; 1-methylene-2-propenyl triisopropylsilyl ether C13H26OSi 详情 详情
(V) 48302 N-(2,2-dimethoxyethyl)-N-(1-formylvinyl)acetamide C9H15NO4 详情 详情
(VI) 48303 N-(2,2-dimethoxyethyl)-N-[1-formyl-4-[(triisopropylsilyl)oxy]-3-cyclohexen-1-yl]acetamide C22H41NO5Si 详情 详情
(VII) 48304 1-(2,2-dimethoxyethyl)-8-[(triisopropylsilyl)oxy]-1-azaspiro[4.5]deca-3,7-dien-2-one C22H39NO4Si 详情 详情
(VIII) 48305 (1S,7R,8R)-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,9-dione C11H13NO3 详情 详情
(IX) 48306 (1S,7R,8S,9S)-7,9-dihydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one C11H15NO3 详情 详情
(X) 48307 (1S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one C17H29NO3Si 详情 详情
(XI) 48308 (1S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione C17H27NO3Si 详情 详情
(XII) 27490 1-(bromomethyl)-4-methoxybenzene C8H9BrO 详情 详情
(XIII) 48309 (1S,6S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione C25H35NO4Si 详情 详情
(XIV) 48310 (1S,6S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one C25H37NO4Si 详情 详情
(XV) 15809 4-nitrobenzenesulfonyl chloride 98-74-8 C6H4ClNO4S 详情 详情
(XVI) 48311 (1S,6S,7R,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl 4-nitrobenzenesulfonate C31H40N2O8SSi 详情 详情

合成路线5

该中间体在本合成路线中的序号：(II)

The condensation of acetonide (I) with 2-aminoacetaldehyde dimethylacetal (II) by means of Ac2O and TEA gives the acetylated enamine (III), which is cyclocondensed with the silylated butadiene (IV) in hot benzonitrile to yield the cycloadduct (V). The cyclization of (V) by means of tBu-OK in ethyl acetate/THF, followed by desilylation with TFA, affords the tricyclic lactam (VI), which is reduced with NaBH(OAc)3 to provide the dihydroxy compound (VII). The silylation of both OH groups of (VII) by means of Tbdms-Cl, followed by selective desilylation of the equatorial silyl ether with TBAF, gives the corresponding alcohol (VIII), which is submitted to a Swern oxidation to yield the ketone (IX). The condensation of (IX) with 4-methoxybenzyl bromide (X) by means of tBu-OK and Red-Al affords the hydroxylated adduct (XI); however, the resulting alcohol presents an unnatural equatorial configuration that is inverted by its esterification with 4-nitrophenylsulfonyl chloride to furnish (XII), followed by acetoxylation of (XII) with rubidium acetate and 18-crown-6, to provide the desired axial acetoxy compound (XIII). The hydrolysis of (XIII) with KOH in methanol gives the corresponding alcohol (XIV), which is silylated with Tes-Otf to yield the bis silyl ether (XV). The reduction of the double bond of (XV) with H2 over PtO2 affords the saturated compound (XVI), which is treated with triethylsilylazide and LDA to provide at the azido compound (XVII). The reduction of lactam and azido groups by means of LiAlH4, followed by protection of the resulting amino group with benzyloxycarbonyl chloride and Na2CO3, gives the benzyl carbamate (XVIII).

参考文献 中间体
合成目标
【1】 Maeng, J.-H.; Funk, R.L.; Total synthesis of the immunosuppressant FR901483 via an amidoacrolein cycloaddition. Org Lett 2001, 3, 8, 1125.
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) 46538 2,2-dimethyl-1,3-dioxan-5-one C6H10O3 详情 详情
(II) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(III) 48300 N-(2,2-dimethoxyethyl)-N-(2,2-dimethyl-4H-1,3-dioxin-5-yl)acetamide C12H21NO5 详情 详情
(IV) 48301 triisopropyl[(1-methylene-2-propenyl)oxy]silane; 1-methylene-2-propenyl triisopropylsilyl ether C13H26OSi 详情 详情
(V) 48303 N-(2,2-dimethoxyethyl)-N-[1-formyl-4-[(triisopropylsilyl)oxy]-3-cyclohexen-1-yl]acetamide C22H41NO5Si 详情 详情
(VI) 48305 (1S,7R,8R)-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,9-dione C11H13NO3 详情 详情
(VII) 48306 (1S,7R,8S,9S)-7,9-dihydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one C11H15NO3 详情 详情
(VIII) 48307 (1S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one C17H29NO3Si 详情 详情
(IX) 48308 (1S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione C17H27NO3Si 详情 详情
(X) 27490 1-(bromomethyl)-4-methoxybenzene C8H9BrO 详情 详情
(XI) 48310 (1S,6S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one C25H37NO4Si 详情 详情
(XII) 48311 (1S,6S,7R,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl 4-nitrobenzenesulfonate C31H40N2O8SSi 详情 详情
(XIII) 48313 (1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl acetate C27H39NO5Si 详情 详情
(XIV) 48314 (1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one C25H37NO4Si 详情 详情
(XV) 48315 (1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one C31H51NO4Si2 详情 详情
(XVI) 48316 (1R,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodecan-4-one C31H53NO4Si2 详情 详情
(XVII) 48317 (1S,3S,6S,7S,8R,9S)-3-azido-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodecan-4-one C31H52N4O4Si2 详情 详情
(XVIII) 48319 benzyl (1S,3S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-ylcarbamate C33H48N2O5Si 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

The cyclization of 2-methylphenyl isothiocyanate (I) with 2-aminoacetaldehyde dimethylacetal (II) in methanol gives the 1-(2-methylphenyl)imidazole-2-thiol (III), which is condensed with 3-bromopropanol (IV) by means of NaOH in refluxing water to yield the sulfide (V). The asymmetric oxidation of sulfide (V) with Ti(O-iPr)4, cumene hydroperoxide (CHP) and (R)-(-)-mandelic acid as chiral catalyst in dichloromethane affords the (S)-sulfinyl derivative (VI), which is treated with Ms-Cl to provide the expected mesylate (VII). Finally, this compound is condensed with the sodium salt of 6-hydroxy-1,2,3,4-tetrahydroquinolin-2one (VIII) to give the target compound.

参考文献 中间体
合成目标
【1】 Matsugi, M.; et al.; Catalytic asymmetric oxidation of sulfide with titanium-mandelic acid complex: Practical synthesis of (S)-3-[1-(2-methylphenyl)imidazol-2-ylsulfinyl]propan-1-ol, the key intermediate of OPC-29030. Tetrahedron 2001, 57, 14, 2739.
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) 50207 6-isothiocyanato-1-methyl-1,3-cyclohexadiene; 2-methyl-2,4-cyclohexadien-1-yl isothiocyanate C8H9NS 详情 详情
(II) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(III) 30223 1-(2-methylphenyl)-1H-imidazol-2-ylhydrosulfide; 1-(2-methylphenyl)-1H-imidazole-2-thiol C10H10N2S 详情 详情
(IV) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(V) 30239 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfanyl]-1-propanol C13H16N2OS 详情 详情
(VI) 50208 (3-hydroxypropyl)[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfoniumolate C13H16N2O2S 详情 详情
(VII) 50209 [1-(2-methylphenyl)-1H-imidazol-2-yl][3-[(methylsulfonyl)oxy]propyl]sulfoniumolate C14H18N2O4S2 详情 详情
(VIII) 50210 　 C9H8NNaO2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(X)

Alkylation of isovanillin (I) with 2-indanyl tosylate (II) produces the corresponding indanyl ether (III). Subsequent reduction of the aldehyde function of (III) with NaBH4 yields the benzylic alcohol (IV), which is converted to chloride (V) by treatment with SOCl2. Displacement of chloride (V) by KCN in hot DMF gives nitrile (VI). The phenylacetonitrile (VI) is then converted to the homologous phenylpropionitrile derivative (VII) by alkylation with iodomethane in the presence of LDA. Further cyano group reduction in (VII) by hydrogenation over Raney Ni provides amine (VIII). Condensation of amine (VIII) with diphenyl N-cyanocarbonimidate affords the N-cyano isourea (IX) which, after reaction with 2,2-dimethoxyethylamine (X), yields the cyano guanidine (XI). Finally, cyclization of (XI) under acidic conditions gives rise to the target 2-(cyanoimino)imidazole derivative.

参考文献 中间体
合成目标
【1】 Diaz, A.; Andres, J.I.; Alonso, J.M.; et al.; Synthesis and biological evaluation of imidazol-2-one and 2-cyanoiminoimidazole derivatives: Novel series of PDE4 inhibitors. Bioorg Med Chem Lett 2002, 12, 4, 653.
【2】 Freyne, E.J.E.; Fernandez-Gadea, F.J.; Andres-Gil, J.I. (Janssen Pharmaceutica NV); PDE IV inhibiting 2-cyanoiminoimidazole derivs.. WO 9814432 .
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) 18455 3-hydroxy-4-methoxybenzaldehyde; Isovanillin 621-59-0 C8H8O3 详情 详情
(II) 57734 2-Indanyl p-toluenesulphonate 17783-69-6 C16H16O3S 详情 详情
(III) 57735 3-(2,3-dihydro-1H-inden-2-yloxy)-4-methoxybenzaldehyde C17H16O3 详情 详情
(IV) 57736 [3-(2,3-dihydro-1H-inden-2-yloxy)-4-methoxyphenyl]methanol C17H18O3 详情 详情
(V) 57737 2-[5-(chloromethyl)-2-methoxyphenoxy]indane; 4-(chloromethyl)-2-(2,3-dihydro-1H-inden-2-yloxy)phenyl methyl ether C17H17ClO2 详情 详情
(VI) 57738 2-[3-(2,3-dihydro-1H-inden-2-yloxy)-4-methoxyphenyl]acetonitrile C18H17NO2 详情 详情
(VII) 57739 2-[3-(2,3-dihydro-1H-inden-2-yloxy)-4-methoxyphenyl]propanenitrile C19H19NO2 详情 详情
(VIII) 57740 2-[3-(2,3-dihydro-1H-inden-2-yloxy)-4-methoxyphenyl]-1-propanamine; 2-[3-(2,3-dihydro-1H-inden-2-yloxy)-4-methoxyphenyl]propylamine C19H23NO2 详情 详情
(IX) 57741 2-[5-(2-{[(cyanoimino)(phenoxy)methyl]amino}-1-methylethyl)-2-methoxyphenoxy]indane C27H27N3O3 详情 详情
(X) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(XI) 57742 N''-cyano-N-{2-[3-(2,3-dihydro-1H-inden-2-yloxy)-4-methoxyphenyl]propyl}-N'-(2,2-dimethoxyethyl)guanidine C25H32N4O4 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IV)

The bromo pyrazinone intermediate (VII) has been obtained as follows. The condensation of ethyl glycinate (I) with ethoxalyl chloride (II) by means of TEA in dichloroethane gives the corresponding amide (III), which is condensed with aminoacetaldehyde dimethyl acetal (IV) in isopropanol to yield the diamide (V). The cyclization of (V) by means of HCl in refluxing AcOH affords the hydroxypyrazinone (VI), which is finally treated with POBr3 in refluxing 1,2-dichloroethane to provide the target bromopyrazinone intermediate (VII) (1).

参考文献 中间体
合成目标
【1】 Selnick, H.G.; Newton, R.C.; Newton, C.L.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Thrombin inhibitors. WO 0311222 .
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) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情
(II) 17568 methyl 2-aminoacetate C3H7NO2 详情 详情
(III) 63817 ethyl 2-oxo-2-[(2-oxo-2-propoxyethyl)amino]acetate C9H15NO5 详情 详情
(IV) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(V) 63818 propyl 2-({2-[(2,2-dimethoxyethyl)amino]-2-oxoacetyl}amino)acetate C11H20N2O6 详情 详情
(VI) 63819 propyl 2-[3-hydroxy-2-oxo-1(2H)-pyrazinyl]acetate C9H12N2O4 详情 详情
(VII) 63820 propyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate C9H11BrN2O3 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XIII)

Acylation of glycine ethyl ester (X) with ethyl oxalyl chloride (XI) provides the oxalic acid mono-amide (XII). Subsequent condensation of (XII) with aminoacetaldehyde dimethylacetal (XIII) affords the diamide (XIV). Cyclization of (XIV) under acetal hydrolysis conditions leads to pyrazinone (XV). This is then brominated to (XVI) employing POBr3 in refluxing dichloroethane. Condensation of the bromopyrazinone (XVI) with amine (IX) at 120 C in a sealed vessel furnishes the aminopyrazinone (XVII). After chlorination of (XVII) with N-chlorosuccinimide, the resultant chloropyrazine ester (XVIII) is hydrolyzed to acid (XIX) under alkaline conditions

参考文献 中间体
合成目标
【1】 Selnick, H.G.; Rittle, K.E.; Barrow, J.C.; Morrissette, M.M.; Nantermet, P.G.; Staas, D. (Merck & Co., Inc.); Thrombin inhibitors. WO 0257225 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 63218 2-(2-amino-1,1-difluoroethyl)-1-pyridiniumolate C7H8F2N2O 详情 详情
(X) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(XI) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情
(XII) 63556 ethyl 2-[(2-ethoxy-2-oxoethyl)amino]-2-oxoacetate C8H13NO5 详情 详情
(XIII) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(XIV) 63557 ethyl 2-({2-[(2,2-dimethoxyethyl)amino]-2-oxoacetyl}amino)acetate C10H18N2O6 详情 详情
(XV) 63558 ethyl 2-[2,3-dioxo-3,4-dihydro-1(2H)-pyrazinyl]acetate C8H10N2O4 详情 详情
(XVI) 63219 ethyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate C8H9BrN2O3 详情 详情
(XVII) 63220 2-(2-{[4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate C15H16F2N4O4 详情 详情
(XVIII) 63221 2-(2-{[5-chloro-4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate C15H15ClF2N4O4 详情 详情
(XIX) 63222 2-(2-{[4-(carboxymethyl)-5-chloro-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate C13H11ClF2N4O4 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IV)

Acylation of glycine ethyl ester (I) with ethyl oxalyl chloride (II) affords amide (III). Subsequent reaction of (III) with aminoacetaldehyde dimethyl acetal (IV) produces the oxalic acid diamide (V). Cyclization of (V) under acidic conditions furnishes the pyrazine dione (VI), which is further brominated to (VII) employing phosphorus oxybromide.

参考文献 中间体
合成目标
【1】 Selnick, H.G.; Newton, R.C.; Newton, C.L.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Thrombin inhibitors. WO 0311222 .
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) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(II) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情
(III) 63556 ethyl 2-[(2-ethoxy-2-oxoethyl)amino]-2-oxoacetate C8H13NO5 详情 详情
(IV) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(V) 63557 ethyl 2-({2-[(2,2-dimethoxyethyl)amino]-2-oxoacetyl}amino)acetate C10H18N2O6 详情 详情
(VI) 63558 ethyl 2-[2,3-dioxo-3,4-dihydro-1(2H)-pyrazinyl]acetate C8H10N2O4 详情 详情
(VII) 63219 ethyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate C8H9BrN2O3 详情 详情

合成路线11

该中间体在本合成路线中的序号：(XXVI)

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 .

参考文献 中间体
合成目标
【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12

该中间体在本合成路线中的序号：(XXVI)

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 .

参考文献 中间体
合成目标
【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13

该中间体在本合成路线中的序号：(XXVI)

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 .

参考文献 中间体
合成目标
【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14

该中间体在本合成路线中的序号：(XXVI)

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 .

参考文献 中间体
合成目标
【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15

该中间体在本合成路线中的序号：(XXVI)

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 .

参考文献 中间体
合成目标
【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
Extended Information