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【结 构 式】 
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【分子编号】37412 【品名】methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate 【CA登记号】553-90-2 |
【 分 子 式 】C4H6O4 【 分 子 量 】118.08924 【元素组成】C 40.68% H 5.12% O 54.19% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reaction of methylhydrazin (I) with potassium thiocyanate (II) gives N-methyl-N-aminothiourea (III), which is cyclized with dimethyl oxalate (IV) by means of sodium methoxide in methanol to afford 2,5-dihydro-6-hydroxy-2-methyl-3-mercapto-5-oxo-1,2,4-triazine (V). The reaction of (V) with 7-aminocephalosporanic acid (VI) in a buffer solution at pH 6.5 gives 7-amino-3,4-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (VII), which is condensed with 2-(2-chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]acetyl chloride (VIII) at pH 2 yielding 7-]2-(2-chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (IX). Finally, this compound is hydrolyzed and treated with sodium hydroxide.
| 【1】 Neuman, M.; Cefatriaxon. Drugs Fut 1981, 6, 3, 132. |
| 【2】 Reiner, R.; et al.; Ro-13-9904/001, a novel potent and long-acting parenteral cephalosporin. J Antibiot 1980, 32, 7, 783-786. |
| 【3】 Reiner, R.; Montavon, M. (F. Hoffmann-La Roche AG); Cephalosporin derivs. and process for their preparation. DE 2922036 . |
| 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) | 12091 | 1-Methylhydrazine; Monomethyl hydrazine | 60-34-4 | CH6N2 | 详情 | 详情 |
| (II) | 37410 | Potassium thiocyanate | 333-20-0 | CKNS | 详情 | 详情 |
| (III) | 37411 | 1-methyl-1-hydrazinecarbothioamide | C2H7N3S | 详情 | 详情 | |
| (IV) | 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 |
| (V) | 37413 | 6-hydroxy-2-methyl-3-sulfanyl-1,2,4-triazin-5(2H)-one | C4H5N3O2S | 详情 | 详情 | |
| (VI) | 22747 | (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C10H12N2O5S | 详情 | 详情 | |
| (VII) | 37414 | (6R,7R)-7-amino-3-[[(6-hydroxy-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C12H13N5O5S2 | 详情 | 详情 | |
| (VIII) | 32659 | 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl chloride | 75532-64-8 | C8H7Cl2N3O3S | 详情 | 详情 |
| (IX) | 37415 | (6R,7R)-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-3-[[(6-hydroxy-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C20H19ClN8O8S3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The Grignard condensation of oxalic acid dimethyl ester (I) with 2-thienylmagnesium bromide (II) gives 2-hydroxy-2,2-bis(2-thienyl)acetic acid methyl ester (III), which is submitted to transesterification with scopine (IV) catalyzed by Na or NaOEt, providing the corresponding ester (V). Finally, (V) is quaternized with methyl bromide in dichloromethane/acetonitrile.
| 【1】 Banholzer, R.; Bauer, R.; Reichl, R. (Boehringer Ingelheim GmbH; Boehringer Ingelheim Pharma KG); Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the cpds.. DE 3931041; EP 0418716; JP 1993502438; US 5610163; WO 9104252 . |
| 【2】 Norman, P.; Rabasseda, X.; Castaner, J.; Graul, A.; Tiotropium Bromide. Drugs Fut 2000, 25, 7, 693. |
| 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) | 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 |
| (II) | 32082 | bromo(2-thienyl)magnesium | 5713-61-1 | C4H3BrMgS | 详情 | 详情 |
| (III) | 37630 | methyl 2-hydroxy-2,2-di(2-thienyl)acetate | 26447-85-8 | C11H10O3S2 | 详情 | 详情 |
| (IV) | 37631 | (1R,2S,4R,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.0(2,4)]nonan-7-ol；Scopine | 498-45-3 | C8H13NO2 | 详情 | 详情 |
| (V) | 37632 | (1R,2S,4R,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.0(2,4)]non-7-yl 2-hydroxy-2,2-di(2-thienyl)acetate；Scopine 2,2-dithienylglycolate | 136310-64-0 | C18H19NO4S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：The reaction of labeled 2-hydroxyacetophenone (I) with dimethyl oxalate and NaOMe gives 4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester (II), which is hydrogenated with H2 over Pd/C to yield 3,4-dihydro-2H-1-benzopyran-2(R)-carboxylic acid methyl ester (III). The optical resolution of (III) by chiral chromatography affords the labeled (R)-enantiomer (IV), which is condensed with benzylamine (V) to provide the corresponding amide (VI). The reduction of (VI) by means of NaAlH2(OC2H4OMe)2 gives the labeled chiral amine (VII), which is condensed with the butyl bromide derivative (VIII) to yield the tertiary amine (IX). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C to afford the target labeled Repinotan.
| 【1】 Seidel, D.; et al.; Synthesis of [14C]-labelled repinotan hydrochloride and its major metabolite M-6. J Label Compd Radiopharm 2002, 45, 13, 1115. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 | |
| (I) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 62016 | methyl 4-oxo-4H-chromene-2-carboxylate | C11H8O4 | 详情 | 详情 | |
| (III) | 62017 | methyl 2-chromanecarboxylate | C11H12O3 | 详情 | 详情 | |
| (IV) | 62018 | methyl (2R)-3,4-dihydro-2H-chromene-2-carboxylate | C11H12O3 | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 62019 | (2R)-N-benzyl-3,4-dihydro-2H-chromene-2-carboxamide | C17H17NO2 | 详情 | 详情 | |
| (VII) | 62020 | N-benzyl-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]amine; N-benzyl[(2R)-3,4-dihydro-2H-chromen-2-yl]methanamine | C17H19NO | 详情 | 详情 | |
| (VIII) | 17043 | 2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C11H12BrNO3S | 详情 | 详情 | |
| (IX) | 62021 | 2-(4-{benzyl[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]amino}butyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C28H30N2O4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)By condensation of 3-chloroacetophenone (I) with dimethyl oxalate (II) by means of NaOMe in methanol.
| 【1】 Hind, S.L.; Janssen, M.; Reinhard, J.F. Jr.; Drysdale, M.J.; Synthesis and SAR of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids esters and 2-amino-4-aryl-4-oxobut-2-enoic acids and esters: Potent inhibitors of kynurenine-3-hydroxylase as potential neuroprotective agents. J Med Chem 2000, 43, 1, 123. |
合成路线5
该中间体在本合成路线中的序号：(II)By condensation of 3-fluoroacetophenone (I) with dimethyl oxalate (II) by means of NaOMe in methanol.
| 【1】 Hind, S.L.; Janssen, M.; Reinhard, J.F. Jr.; Drysdale, M.J.; Synthesis and SAR of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids esters and 2-amino-4-aryl-4-oxobut-2-enoic acids and esters: Potent inhibitors of kynurenine-3-hydroxylase as potential neuroprotective agents. J Med Chem 2000, 43, 1, 123. |
合成路线6
该中间体在本合成路线中的序号：(A)Synthesis of intermediate (3S)-(XI): Iodination of 4-chloro-2-nitrotoluene (I) with NaI, I2 and H2SO4 yields (II), which is then treated with dimethyl oxalate (A) in toluene in presence of KOMe or alternatively NaOMe, in MeOH to afford (III). Cyclization of (III) is performed by a first treatment with SnCl2 in dimethoxyethane followed by TiCl3/H2O to provide indole (IV), which is converted into (VI) by reaction with alcohol (V) in presence of NaHCO3, benzyltriethyl ammonium chloride and Pd(OAc)2, followed by a treatment with sodium thiosulfate. The reaction of aldehyde (VI) with KOtBu and triethyl phosphonoacetate (B) in THF yields ethyl ester (VIIa-b), which is then converted into iodo derivative (VIIIa-b) by means of NaI and NCS in DMF. Cyclization of (VIIIa-b) by treatment with Pd(PPh3)4 in DMF and Ag3PO4/H2O affords tetrahydrobenzindole (IX), which is reduced by means of Sm, and I2 in MeOH/THF to give (X). Alternatively (X) is obtained by simultaneous cyclization and reduction of (VIIIa-b) by treatment with SnBu3H and AIBN in chlorobenzene. Finally ethyl ester (X) is selectively hydrolyzed with HCl in HOAc to provide (XI) in its racemic form. Enantiomer (3S)-(XI) can be isolated by separation of the corresponding diasteromers obtained by reaction of (XI) with L-(-) norphedrine in isopropanol followed by hydrolysis with HCl in EtOAc and THF.
| 【1】 Katayama, S.; Kishimoto, H.; Ae, N.; Nagata, R. (Sumitomo Pharmaceuticals Co., Ltd.); Tricyclic indole-2-carboxylic acid cpd. used as NMDA receptor antagonist. WO 0056711 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (A) | 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 |
| (VIIa) | 41490 | methyl 6-chloro-4-[(E)-5-ethoxy-5-oxo-3-pentenyl]-1H-indole-2-carboxylate | C17H18ClNO4 | 详情 | 详情 | |
| (VIIb) | 41491 | methyl 6-chloro-4-[(Z)-5-ethoxy-5-oxo-3-pentenyl]-1H-indole-2-carboxylate | n/a | C17H18ClNO4 | 详情 | 详情 |
| (VIIIa) | 41492 | methyl 6-chloro-4-[(E)-5-ethoxy-5-oxo-3-pentenyl]-3-iodo-1H-indole-2-carboxylate | n/a | C17H17ClINO4 | 详情 | 详情 |
| (VIIIb) | 41493 | methyl 6-chloro-4-[(Z)-5-ethoxy-5-oxo-3-pentenyl]-3-iodo-1H-indole-2-carboxylate | n/a | C17H17ClINO4 | 详情 | 详情 |
| (3S)-(XI) | 41497 | 2-[(3S)-7-chloro-2-(methoxycarbonyl)-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl]acetic acid | C15H14ClNO4 | 详情 | 详情 | |
| (I) | 41485 | 4-chloro-1-methyl-2-nitrobenzene；4-chloro-2-nitrotoluene;4-chloro-1-methyl-2-nitro-benzene | 89-59-8 | C7H6ClNO2 | 详情 | 详情 |
| (II) | 41486 | 5-chloro-1-iodo-2-methyl-3-nitrobenzene | n/a | C7H5ClINO2 | 详情 | 详情 |
| (III) | 41487 | methyl 3-(4-chloro-2-iodo-6-nitrophenyl)-2-oxopropanoate | C10H7ClINO5 | 详情 | 详情 | |
| (IV) | 41488 | methyl 6-chloro-4-iodo-1H-indole-2-carboxylate | C10H7ClINO2 | 详情 | 详情 | |
| (V) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (VI) | 41489 | methyl 6-chloro-4-(3-oxopropyl)-1H-indole-2-carboxylate | C13H12ClNO3 | 详情 | 详情 | |
| (IX) | 41494 | methyl 7-chloro-3-[(Z)-2-ethoxy-2-oxoethylidene]-4,5-dihydrobenzo[cd]indole-2(1H)-carboxylate | C17H16ClNO4 | 详情 | 详情 | |
| (X) | 41495 | methyl 7-chloro-3-(2-ethoxy-2-oxoethyl)-1,3,4,5-tetrahydrobenzo[cd]indole-2-carboxylate | C17H18ClNO4 | 详情 | 详情 | |
| (XI) | 41496 | 2-[7-chloro-2-(methoxycarbonyl)-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl]acetic acid | C15H14ClNO4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XXIII)Addition of 4-fluorophenylmagnesium bromide (XXII) to dimethyl oxalate (XXIII) leads to methyl 4-fluorobenzoylformate (XXIV). Subsequent fluorination of (XXIV) employing diethylaminosulfur trifluoride affords the gem-difluoro ester (XXV). Reduction of ester (XXV) with NaBH4 in cold MeOH gives rise to the aldehyde hemiacetal (XXVI). Then, Wittig condensation of hemiacetal (XXVI) with the ylide generated from phosphonium salt (XXI) provides olefin (XXVII). This is partly reduced to the saturated compound (XXVIII) by treatment with in situ generated diimide, and completely reduced to (XXVIII) by catalytic hydrogenation over iridium black. Cleavage of the N-Boc protecting group of (XXVIII) to furnish piperidine (XXIX) is accomplished by means of iodotrimethylsilane in CHCl3.
| 【1】 Mills, S.G.; Kim, D.; Hale, J.; MacCoss, M.; Berk, S.; Chapman, K.; Lynch, C.; Caldwell, C.; Willoughby, C.; Rosauer, K. (Merck & Co., Inc.); Pyrrolidine modulators of chemokine receptor activity. US 6265434; WO 0059503 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 65138 | {[1-(tert-butoxycarbonyl)-4-piperidinyl]methyl}(triphenyl)phosphonium iodide | C29H35INO2P | 详情 | 详情 | |
| (XXII) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XXIII) | 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 |
| (XXIV) | 65143 | methyl 2-(4-fluorophenyl)-2-oxoacetate | C9H7FO3 | 详情 | 详情 | |
| (XXV) | 65141 | methyl 2,2-difluoro-2-(4-fluorophenyl)acetate | C9H7F3O2 | 详情 | 详情 | |
| (XXVI) | 65142 | 2,2-difluoro-2-(4-fluorophenyl)-1-methoxy-1-ethanol | C9H9F3O2 | 详情 | 详情 | |
| (XXVII) | 65140 | tert-butyl 4-[(E)-3,3-difluoro-3-(4-fluorophenyl)-1-propenyl]-1-piperidinecarboxylate | C19H24F3NO2 | 详情 | 详情 | |
| (XXVIII) | 65139 | tert-butyl 4-[3,3-difluoro-3-(4-fluorophenyl)propyl]-1-piperidinecarboxylate | C19H26F3NO2 | 详情 | 详情 | |
| (XXIX) | 65144 | 4-[3,3-difluoro-3-(4-fluorophenyl)propyl]piperidine | C14H18F3N | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XXXVI)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9
该中间体在本合成路线中的序号：(XXXVI)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 |