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【结 构 式】 
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【分子编号】11043 【品名】Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 【CA登记号】4755-77-5 |
【 分 子 式 】C4H5ClO3 【 分 子 量 】136.5346 【元素组成】C 35.19% H 3.69% Cl 25.97% O 35.15% |
合成路线1
该中间体在本合成路线中的序号：(IV)The cyclization of p-methoxyacetophenone (I) with thiourea (II) by means of SO2Cl2 gives 4-(p-methoxyphenyl)-2-aminothiazole (III), which is then reacted with ethoxalyl chloride (IV) in presence of a base to afford F-1865.
| 【1】 Casadio, S.; Cousse, H.; Tarayre, J.P.; Mouzin, G. (Pierre Fabre SA.); 4-Phenyl-2-thiazolyloxamate derivs., method for their preparation and their application in the treatment of asthma. EP 0006368; ES 481633; FR 2429210; JP 55002684; US 4246271 . |
| 【2】 Tarayre, J.P.; Bonnaud, B.; TIOXAMAST. Drugs Fut 1990, 15, 5, 469. |
| 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) | 11041 | 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone | 100-06-1 | C9H10O2 | 详情 | 详情 |
| (II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (III) | 11042 | 4-(4-Methoxy-phenyl)-thiazol-2-ylamine; 4-(4-methoxyphenyl)-1,3-thiazol-2-ylamine; 4-(4-methoxyphenyl)-1,3-thiazol-2-amine | 2104-04-3 | C10H10N2OS | 详情 | 详情 |
| (IV) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)A new synthesis of racemic TA-3090 has been reported: The condensation of 5-chloro-2-nitrothiophenol (I) with 4-methoxybenzyl chloride (II) by means of sodium ethoxide in ethanol gives the thioether (III), which is reduced with SnCl2 in hot ethanol to afford 4-chloro-2-(4-methoxybenzylthio)aniline (IV). The acylation of (IV) with ethoxalyl chloride (V) by means of NaHCO3 in dichloromethane - water yields the oxamate (VI), which is condensed with 2-(dimethylamino)ethyl chloride (VII) by means of K2CO3 and 18-crown-6 in hot acetonitrile to afford the alkylated oxamate compound (VIII). The cyclization of (VIII) by means of lithium diisopropylamide in THF gives 8-chloro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiaze pine-3,4(2H,5H)-dione (IX), which is reduced with NaBH4 in aqueous ethanol to cis-8-chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzothiazepin-4-one (X). Finally, this compound is acetylated in the usual manner.
| 【1】 Takeda, M.; Takamura, N.; Oh-ishi, T.; Harada, T.; Morimoto, M.; Inoue, H.; Nagasawa, M.; A new synthetic route to 1,5-benzothiazepines. Synthesis of derivatives of diltiazem. Chem Pharm Bull 1992, 40, 8, 1986. |
| 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) | 11909 | 5-Chloro-2-nitrophenylhydrosulfide; 5-Chloro-2-nitrobenzenethiol | C6H4ClNO2S | 详情 | 详情 | |
| (II) | 11910 | 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether | 824-94-2 | C8H9ClO | 详情 | 详情 |
| (III) | 11911 | 4-[[(5-Chloro-2-nitrophenyl)sulfanyl]methyl]phenyl methyl ether; 4-Chloro-2-[(4-methoxybenzyl)sulfanyl]-1-nitrobenzene | C14H12ClNO3S | 详情 | 详情 | |
| (IV) | 11912 | 4-Chloro-2-[(4-methoxybenzyl)sulfanyl]phenylamine; 4-Chloro-2-[(4-methoxybenzyl)sulfanyl]aniline | C14H14ClNOS | 详情 | 详情 | |
| (V) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (VI) | 11914 | ethyl 2-[4-chloro-2-[(4-methoxybenzyl)sulfanyl]anilino]-2-oxoacetate | C18H18ClNO4S | 详情 | 详情 | |
| (VII) | 11907 | Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine | 107-99-3 | C4H10ClN | 详情 | 详情 |
| (VIII) | 11916 | ethyl 2-[4-chloro[2-(dimethylamino)ethyl]-2-[(4-methoxybenzyl)sulfanyl]anilino]-2-oxoacetate | C22H27ClN2O4S | 详情 | 详情 | |
| (IX) | 11917 | (2S)-8-Chloro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione | C20H21ClN2O3S | 详情 | 详情 | |
| (X) | 11908 | (2S,3S)-8-Chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C20H23ClN2O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Acitazanolast can be obtained by two related procedures: 1) By condensation of 3-(1H-tetrazol-5-yl)aniline (I) with oxalyl chloride (II) in dimethoxyethane. 2) By condensation of the aniline (I) with ethyl oxalyl chloride (III) by means of triethylamine in DMF to the corresponding ethyl ester (IV), which is then hydrolyzed with base (KOH or NaOH) in ethanol.
| 【1】 Rabasseda, X.; Mealy, N.; Castaner, J.; Acitazanolast. Drugs Fut 1995, 20, 9, 873. |
| 【2】 Sawaki, S.; Ootake, Y.; Hashimoto, T.; Abe, T.; Horio, Y. (Wakamoto Pharmaceutical Co., Ltd.); 3-(1H-Tetrazol-5-yl)oxanilic acid and salts thereof, method for preparing the same and pharmacological compsns. Containing the cpd. EP 0256507; JP 1988044570; US 4795756 . |
| 【3】 Sawaki, M.; Ohtake, Y.; Hashimoto, M.; Abe, T.; Horio, Y. (Wakamoto Pharmaceutical Co., Ltd.); Antiallergic agents. JP 1989029312 . |
| 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) | 12511 | 3-(1H-1,2,3,4-Tetraazol-5-yl)aniline; 3-(1H-1,2,3,4-Tetraazol-5-yl)phenylamine | C7H7N5 | 详情 | 详情 | |
| (III) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (IV) | 12513 | ethyl 2-oxo-2-[3-(1H-1,2,3,4-tetraazol-5-yl)anilino]acetate | C11H11N5O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)The reaction of 2,4-dichloro-5-(trifluoromethyl)nitrobenzene (I) with aminomethanephosphonic acid (II) by means of NaOH in ethanol/water gives the anilinomethanephosphonic acid (III), which is condensed first with morpholine (IV) by heating at 120 C and esterified with triethyl orthoformate at 150 C yielding 5-(4-morpholinyl)-2-nitro-4-(trifluoromethyl)phenylaminomethyl phosphonic acid diethyl ester (V). The reduction of the nitro group of (V) with H2 over Pd/C in ethanol affords the corresponding amino-derivative (VI), which is cyclized with oxalic acid monoethyl ester monochloride (VII) by means of triethylamine in THF providing the quinoxaline (VIII). Finally, this compound is hydrolyzed to the free phosphonic acid with trimethylbromo silane in acetonitrile.
| 【1】 Huth, A.; Turski, L. (Schering AG); Quinoxalindione derivs., their preparation and their use in drugs. DE 4314591; DE 4344486; EP 0696288; EP 1002796; JP 1996508037; US 5750525; WO 9425469 . |
| 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) | 28301 | 1,5-dichloro-2-nitro-4-(trifluoromethyl)benzene | 400-70-4 | C7H2Cl2F3NO2 | 详情 | 详情 |
| (II) | 28302 | aminomethylphosphonic acid | 1066-51-9 | CH6NO3P | 详情 | 详情 |
| (III) | 28303 | [5-chloro-2-nitro-4-(trifluoromethyl)anilino]methylphosphonic acid | C8H7ClF3N2O5P | 详情 | 详情 | |
| (IV) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (V) | 28304 | diethyl [5-(4-morpholinyl)-2-nitro-4-(trifluoromethyl)anilino]methylphosphonate | C16H23F3N3O6P | 详情 | 详情 | |
| (VI) | 28305 | diethyl [2-amino-5-(4-morpholinyl)-4-(trifluoromethyl)anilino]methylphosphonate | C16H25F3N3O4P | 详情 | 详情 | |
| (VII) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (VIII) | 28306 | diethyl [7-(4-morpholinyl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydro-1(2H)-quinoxalinyl]methylphosphonate | C18H23F3N3O6P | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Addition of benzylmagnesium chloride to O-(trimethylsilyl)cyanohydrin (II) (obtained from phenylacetaldehyde (I) and Me3SiCN), led to benzylacyloin (III). Esterification with ethyl oxalyl chloride (IV) in the presence of Et3N afforded oxalate (V), which was cyclized with DBU in cold DMF to provide dihydrogrevillin (VI). This was methylated with ethereal diazomethane to give ether (VII), and then brominated in AcOH. Elimination of the resulting bromide (VIII) by treatment with DBU produced (IX), which was demethylated with BBr3 to afford grevillin (X). This compound was isomerized with NaOEt in EtOH to produce terphenyl quinone (XI). Finally, Perkin reaction with phenylacetic acid (XII), followed by treatment with HBr furnished the title compound.
| 【1】 Pattenden, G.; et al.; Synthesis of grevillins and their biogenetic interrelationship with terphenylquinones, xylerythrins and pulvinic acids. Tetrahedron Lett 1987, 28, 4, 4749. |
| 【2】 Pattenden, G.; et al.; Synthesis of grevillins, novel pyrandione pigments of fungi. Biogenetic ibnterrelationships between grevillins, pulvinic acids, terphenylquinones and xylerythrins. J Chem Soc - Perkins Trans I 1991, 2363. |
| 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) | 18456 | 2-phenylacetaldehyde | 122-78-1 | C8H8O | 详情 | 详情 |
| (II) | 18457 | 3-phenyl-2-[(trimethylsilyl)oxy]propanenitrile | C12H17NOSi | 详情 | 详情 | |
| (III) | 18458 | 3-hydroxy-1,4-diphenyl-2-butanone | C16H16O2 | 详情 | 详情 | |
| (IV) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (V) | 18460 | 1-benzyl-2-oxo-3-phenylpropyl 2-ethoxy-2-oxoacetate | C20H20O5 | 详情 | 详情 | |
| (VI) | 18461 | 6-benzyl-3-hydroxy-4-phenyl-2H-pyran-2,5(6H)-dione | C18H14O4 | 详情 | 详情 | |
| (VII) | 18462 | 6-benzyl-3-methoxy-4-phenyl-2H-pyran-2,5(6H)-dione | C19H16O4 | 详情 | 详情 | |
| (VIII) | 18463 | 6-benzyl-6-bromo-3-methoxy-4-phenyl-2H-pyran-2,5(6H)-dione | C19H15BrO4 | 详情 | 详情 | |
| (IX) | 18464 | 3-methoxy-4-phenyl-6-[(Z)-benzylidene]-2H-pyran-2,5-dione | C19H14O4 | 详情 | 详情 | |
| (X) | 18465 | 3-hydroxy-4-phenyl-6-[(Z)-benzylidene]-2H-pyran-2,5-dione | C18H12O4 | 详情 | 详情 | |
| (XI) | 18466 | 2,5-dihydroxy-3,6-diphenylbenzo-1,4-quinone | 548-59-4 | C18H12O4 | 详情 | 详情 |
| (XII) | 16143 | 3-(4-iodobutyl)-1-[[(E)-benzylidene]amino]-1H-imidazole-2,4(3H,5H)-dione | C14H16IN3O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：Benzothiazin (III) was prepared by condensation of 2-aminothiophenol (I) with ethyl 4-bromoacetoacetate (II). Subsequent reduction of (III) with NaBH3CN provided (IV), which was brominated using N-bromosuccinimide to afford (V). This was coupled with ethyl oxalyl chloride to give amide (VI). Nitration of (VI) was then performed with HNO3 in H2SO4 at -10 C. Further reduction of the nitro group of (VII) with concomitant cyclization produced the tricyclic compound (VIII). After resolution by chiral preparative HPLC, the required (R)-enantiomer was hydrolyzed with NaOH to afford carboxylic acid (IX). This compound was finally isolated as the sodium salt upon treatment with aqueous NaHCO3, followed by lyophilization.
| 【1】 Moretti, R.; Zimmermann, K. (Novartis AG); Quinoxaline-2,3-diones with an oxa or thiaheterocyclic fused ring. CA 2157231; EP 0705835; JP 1996109185 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 | |
| (I) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (III) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (IV) | 25184 | ethyl 2-[2H-1,4-benzothiazin-3(4H)-ylidene]acetate | C12H13NO2S | 详情 | 详情 | |
| (IV) | 25185 | ethyl 2-(3,4-dihydro-2H-1,4-benzothiazin-3-yl)acetate | C12H15NO2S | 详情 | 详情 | |
| (V) | 25186 | ethyl 2-(7-bromo-3,4-dihydro-2H-1,4-benzothiazin-3-yl)acetate | C12H14BrNO2S | 详情 | 详情 | |
| (VI) | 25187 | ethyl 2-[7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-2-oxoacetate | C16H18BrNO5S | 详情 | 详情 | |
| (VII) | 25188 | ethyl 2-[7-bromo-3-(2-ethoxy-2-oxoethyl)-5-nitro-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-2-oxoacetate | C16H17BrN2O7S | 详情 | 详情 | |
| (VIII) | 25189 | ethyl 2-(9-bromo-5,6-dioxo-2,3,6,7-tetrahydro-5H-[1,4]thiazino[4,3,2-de]quinoxalin-3-yl)acetate | C14H13BrN2O4S | 详情 | 详情 | |
| (IX) | 25190 | 2-[(3R)-9-bromo-5,6-dioxo-2,3,6,7-tetrahydro-5H-[1,4]thiazino[4,3,2-de]quinoxalin-3-yl]acetic acid | C12H9BrN2O4S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The reaction of 2-methyl-4-(trifluoromethyl)aniline (I) with ethoxalyl chloride (II) by means of triethylamine in ethyl acetate gives the oxamic ester (III), which is nitrated at the aromatic ring with KNO3 and H2SO4 yielding the intermediate (IV). The reductocyclization of (IV) by means of TiCl3 in acetone affords the quinoxalinedione (V), which is treated with PCl5 in refluxing POCl3 affording the dichloroquinoxaline (VI). The reaction of (VI) with sodium methoxide in refluxing methanol gives the dimethoxyquinoxaline (VII), which is brominated with NBS and AIBN in refluxing benzene yielding the bromomethyl quinoxaline (VIII). The condensation of (VIII) with dimethyl 1(S)-aminoethylphosphonate (IX) by means of NaHCO3 in DMF affords the phosphonate derivative (X), which is finally submitted to acid hydrolysis to provide the target compound.
| 【1】 Auberson, Y.P.; et al.; N-Phosphonoalkyl-5-aminomethylquinoxaline-2,3-diones: In vivo active AMPA and NMDA(glycine) antagonists. Bioorg Med Chem Lett 1999, 9, 2, 249. |
| 【2】 Acklin, P.; Allgeier, H.; Auberson, Y.; Ofner, S.; Veenstra, S.J. (Novartis AG); Substd. aminoalkane phosphonic acids. EP 0934326; US 6117873; WO 9817672 . |
| 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) | 27132 | 2-methyl-4-(trifluoromethyl)aniline | C8H8F3N | 详情 | 详情 | |
| (II) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (III) | 27133 | ethyl 2-[2-methyl-4-(trifluoromethyl)anilino]-2-oxoacetate | C12H12F3NO3 | 详情 | 详情 | |
| (IV) | 27134 | ethyl 2-[2-methyl-6-nitro-4-(trifluoromethyl)anilino]-2-oxoacetate | C12H11F3N2O5 | 详情 | 详情 | |
| (V) | 27135 | 5-methyl-7-(trifluoromethyl)-1,4-dihydro-2,3-quinoxalinedione | C10H7F3N2O2 | 详情 | 详情 | |
| (VI) | 27136 | 2,3-dichloro-5-methyl-7-(trifluoromethyl)quinoxaline | C10H5Cl2F3N2 | 详情 | 详情 | |
| (VII) | 27137 | 2,3-dimethoxy-5-methyl-7-(trifluoromethyl)quinoxaline | C12H11F3N2O2 | 详情 | 详情 | |
| (VIII) | 27138 | 5-(bromomethyl)-2,3-dimethoxy-7-(trifluoromethyl)quinoxaline | C12H10BrF3N2O2 | 详情 | 详情 | |
| (IX) | 27139 | dimethyl (1S)-1-aminoethylphosphonate | C4H12NO3P | 详情 | 详情 | |
| (X) | 27140 | dimethyl (1S)-1-([[2,3-dimethoxy-7-(trifluoromethyl)-5-quinoxalinyl]methyl]amino)ethylphosphonate | C16H21F3N3O5P | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)Cyclization of 2-ethoxybenzamidine (I) with 2-butyramidopropionic acid (II) and ethoxalyl chloride (III) by means of DMAP in refluxing pyridine gives 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-4-one (IV), which is sulfonated with chlorosulfonic acid to provide the sulfonyl chloride (V). Finally, this compound is condensed with 1-ethylpiperazine (VI) in dichloromethane.
| 【1】 Niewohner, U.; Bischoff, E.; Es-Sayed, M.; Schenke, T.; Schmidt, G.; Lampe, T.; Haning, H.; Imidazo[5,1-f][1,2,4]triazin-4(3H)-ones, a new class of potent PDE 5 inhibitors. Bioorg Med Chem Lett 2002, 12, 6, 865. |
| 【2】 Castaner, J.; Martin, L.; Rabasseda, X.; Sorbera, L.A.; Vardenafil. Drugs Fut 2001, 26, 2, 141. |
| 【3】 Perzborn, E.; Keldenich, J.; Schlemmer, K.-H.; Haning, H.; Serno, P.; Bischoff, E.; El-Sayed, M.; Niewöhner, U.; Nowakowski, M.; Schenke, T.; Dembowsky, K. (Bayer AG); 2-Phenyl substd. imidazotriazinones as phosphodiesterase inhibitors. DE 19750085; DE 19812462; EP 1049695; WO 9924433 . |
| 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) | 44352 | 2-ethoxybenzenecarboximidamide | 53623-81-7 | C9H12N2O | 详情 | 详情 |
| (II) | 44353 | N-butyrylalanine | C7H13NO3 | 详情 | 详情 | |
| (III) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (IV) | 44354 | 2-(2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one | C17H20N4O2 | 详情 | 详情 | |
| (V) | 44355 | 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride | C17H19ClN4O4S | 详情 | 详情 | |
| (VI) | 14213 | N-Ethylpiperazine; 1-Ethylpiperazine | 5308-25-8 | C6H14N2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(A)Knoevenagel condensation of ketone (I) with ethyl cyanoacetate followed by Michael addition of cyanoacetamide to the resulting alpha-cyanocinnamate (IIa-b) yields cyclic imide (III). Hydrolysis and decarboxylation of (III) with H2SO4 gives diacid (IV), which is cyclized by means of hot H2SO4 to provide indanone (V). Treatment of (V) with oxalyl chloride in CH2Cl2 and catalytic DMF followed by addition of EtOH affords ethyl ester (VI), which is then converted into oxime (VII) by means of t-BuONO in Et2O and HCl. Hydrogenolysis of (VII) with H2 over Pd/C in HOAc/HCl provides alpha-amino derivative (VIII). By reacting (VIII) with ethyl oxalyl chloride (A), in CH2Cl2 in presence of Et3N, (IX) was obtained and then cyclized in presence of NH4OAc in refluxing HOAc to yield pyrazino derivative (X). Finally (X) is hydrolyzed with HCl in dioxane.
| 【1】 Jimonet, P.; Ribeill, Y.; Bohme, A.; et al.; Indeno[1,2-b]pyrazin-2,3-diones: A new class of antagonists at the glycine site of the NMDA receptor with potent in vivo activity. J Med Chem 2000, 43, 12, 2371. |
| 【2】 Jimonet, P.; Ribeill, Y.; Audiau, F.; Aloup, J.-C.; Barreau, M.; Mignani, S.; Genevois-Borella, A.; Damour, D. (Aventis Pharma SA); 5H-Indeno[1,2-b]pyrazine-2,3-dione derivs., their preparation and medicinal products containing them. US 5922716; WO 9526342 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 | |
| 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 | |
| (A) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (IIa) | 41464 | ethyl (Z)-3-(4-chlorophenyl)-2-cyano-2-butenoate | C13H12ClNO2 | 详情 | 详情 | |
| (IIb) | 41465 | ethyl (E)-3-(4-chlorophenyl)-2-cyano-2-butenoate | C13H12ClNO2 | 详情 | 详情 | |
| (I) | 12685 | 4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone | 99-91-2 | C8H7ClO | 详情 | 详情 |
| (III) | 41466 | 4-(4-chlorophenyl)-4-methyl-2,6-dioxo-3,5-piperidinedicarbonitrile | C14H10ClN3O2 | 详情 | 详情 | |
| (IV) | 41467 | 3-(4-chlorophenyl)-3-methylpentanedioic acid | C12H13ClO4 | 详情 | 详情 | |
| (V) | 41468 | 2-(5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetic acid | C12H11ClO3 | 详情 | 详情 | |
| (VI) | 41469 | ethyl 2-(5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate | C14H15ClO3 | 详情 | 详情 | |
| (VII) | 41470 | ethyl 2-[5-chloro-2-(hydroxyimino)-1-methyl-3-oxo-1,3-dihydro-2H-inden-1-yl]acetate | C14H14ClNO4 | 详情 | 详情 | |
| (VIII) | 41471 | ethyl 2-(2-amino-5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate | C14H16ClNO3 | 详情 | 详情 | |
| (IX) | 41472 | ethyl 2-[[5-chloro-1-(2-ethoxy-2-oxoethyl)-1-methyl-3-oxo-2,3-dihydro-1H-inden-2-yl]amino]-2-oxoacetate | C18H20ClNO6 | 详情 | 详情 | |
| (X) | 41473 | ethyl 2-(6-chloro-9-methyl-2,3-dioxo-2,3,4,9-tetrahydro-1H-indeno[1,2-b]pyrazin-9-yl)acetate | C16H15ClN2O4 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VIII)Condensation of o-nitroacetophenone (I) with aldehyde (II) in the presence of piperidine acetate afforded the chalcone (III). Both the double bond and the nitro group of (III) were reduced by catalytic hydrogenation over PtO2 to give (IV). 5-Bromopiperonal (VI) was prepared by treatment of 5-bromo-3,4-dihydroxybenzaldehyde (V) with dibromomethane. Reductive condensation of aldehyde (V) with amine (IV) by means of sodium cyanoborohydride produced the secondary amine (VII), which was condensed with ethyl oxalyl chloride (VIII) to produce amide (IX). Cyclization of (IX) to the corresponding quinolone (X) was achieved by treatment with K2CO3 in EtOH. The ethyl group of the target compound was introduced by Stille coupling of bromide (X) with vinyl tributyltin, followed by catalytic hydrogenation of the resulting ethylene derivative (XI) to give (XII). Finally, saponification of diester (XII) with KOH furnished the title dipotassium salt.
| 【1】 Haesslein, J.-L. (Aventis Pharma SA); Quinoline derivs., process for their preparation, the resultant intermediates, their use as medicaments and the pharmaceutical compsns. containing them. FR 2733233; WO 9633190 . |
| 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) | 46369 | 1-(2-nitrophenyl)-1-ethanone | C8H7NO3 | 详情 | 详情 | |
| (II) | 46370 | ethyl 3-formylbenzoate | C10H10O3 | 详情 | 详情 | |
| (III) | 46371 | ethyl 3-[(E)-3-(2-nitrophenyl)-3-oxo-1-propenyl]benzoate | C18H15NO5 | 详情 | 详情 | |
| (IV) | 46372 | ethyl 3-[3-(2-aminophenyl)-3-oxopropyl]benzoate | C18H19NO3 | 详情 | 详情 | |
| (V) | 46374 | 2-bromo-4,5-dihydroxybenzaldehyde | C7H5BrO3 | 详情 | 详情 | |
| (VI) | 46373 | 6-bromo-1,3-benzodioxole-5-carbaldehyde | C8H5BrO3 | 详情 | 详情 | |
| (VII) | 46375 | ethyl 3-[3-(2-[[(6-bromo-1,3-benzodioxol-5-yl)methyl]amino]phenyl)-3-oxopropyl]benzoate | C26H24BrNO5 | 详情 | 详情 | |
| (VIII) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (IX) | 46376 | ethyl 3-(3-[2-[[(6-bromo-1,3-benzodioxol-5-yl)methyl](2-ethoxy-2-oxoacetyl)amino]phenyl]-3-oxopropyl)benzoate | C30H28BrNO8 | 详情 | 详情 | |
| (X) | 46377 | ethyl 1-[(6-bromo-1,3-benzodioxol-5-yl)methyl]-3-[3-(ethoxycarbonyl)benzyl]-4-oxo-1,4-dihydro-2-quinolinecarboxylate | C30H26BrNO7 | 详情 | 详情 | |
| (XI) | 46378 | ethyl 3-[3-(ethoxycarbonyl)benzyl]-4-oxo-1-[(6-vinyl-1,3-benzodioxol-5-yl)methyl]-1,4-dihydro-2-quinolinecarboxylate | C32H29NO7 | 详情 | 详情 | |
| (XII) | 46379 | ethyl 3-[3-(ethoxycarbonyl)benzyl]-1-[(6-ethyl-1,3-benzodioxol-5-yl)methyl]-4-oxo-1,4-dihydro-2-quinolinecarboxylate | C32H31NO7 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(III)Treatment of phenylacetyl chloride (I) with tris(trimethylsilyloxy)ethylene (A) in the presence of SnCl4 affords 1-hydroxy-3-phenylpropan-2-one (II), which is then condensed with ethyl oxalyl chloride (III) in THF in the presence of Et3N to yield (IV). Phenylhexanoate derivative (IV) is cyclized by means of DBU in DMF to provide valerolactone derivative (V), which is then condensed with 1-methylindole-3-carboxaldehyde (VI) in HOAc to furnish derivative (VII). Finally, the target compound is obtained by treatment of (VII) with NaOMe in MeOH.
| 【1】 Liu, K.; Szalkowski, D.; Xu, L.; et al.; Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor. J Med Chem 2000, 43, 19, 3487. |
| 【2】 Wood, H.B.; Jones, A.B.; Zhang, B.; Liu, K. (Merck & Co., Inc.); Antidiabetic agents. EP 1067925; US 6077849; WO 9951225 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 14534 | 2,2,7,7-tetramethyl-4-[(trimethylsilyl)oxy]-3,6-dioxa-2,7-disila-4-octene; 1,2-bis[(trimethylsilyl)oxy]vinyl trimethylsilyl ether; TRIS(TRIMETHYLSILYLOXY)ETHYLENE | 69097-20-7 | C11H28O3Si3 | 详情 | 详情 |
| (I) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (II) | 45469 | 2-phenylethaneperoxoic acid | C8H8O3 | 详情 | 详情 | |
| (III) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (IV) | 45470 | ethyl 2-oxo-2-[(2-phenylacetyl)peroxy]acetate | C12H12O6 | 详情 | 详情 | |
| (V) | 45471 | 3-hydroxy-4-phenyl-2H-pyran-2,5(6H)-dione | C11H8O4 | 详情 | 详情 | |
| (VI) | 45472 | 1-Methylindole-3-carboxaldehyde; 1-Methyl-1H-indole-3-carbaldehyde; 1-Methylindole-3-carbaldehyde | 19012-03-4 | C10H9NO | 详情 | 详情 |
| (VII) | 45473 | 3-hydroxy-6-[(Z)-(3-methyl-3H-benzimidazol-1-yl)methylidene]-4-phenyl-2H-pyran-2,5-dione | 455-15-2 | C20H16N2O4 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(V)Diazotization of substituted aniline (I) followed by reaction with ethyl 2-chloro-3-oxobutanoate (II) in MeOH yields hydrazono chloroacetate derivative (III), which is converted into oxamidrazonate (IV) by means of NH3 (gas). Treatment of derivative (IV) with ethyloxalyl chloride (V) affords ethoxalyl derivative (VI), which is then heated until cyclization occurs, providing derivative (VII). Reduction of triazole dicarboxylate (VII) with iron in HOAc gives tricyclic compound (VIII), which is nitrated by means of HNO3 to afford nitro derivative (IX). Reduction of the nitro group of (IX) by means of iron in HOAc provides the corresponding 8-amino derivative (X), which is treated with diformylhydrazine and trimethylsilyl chloride (TMSCl) in pyridine to furnish ethyl carboxylate (XI). Finally, saponification of (XI) with NaOH in EtOH gives the desired compound.
| 【1】 Catarzi, D.; et al.; 4,5-Dihydro-1,2,4-triazolo[1,5-a]quinoxalin-4-ones: Excitatory amino acid antagonists with combined glycine/NMDA and AMPA receptor affinity. J Med Chem 1999, 42, 13, 2478. |
| 【2】 Colotta, V.; Carlà, V.; Costagli, C.; Filacchioni, G.; Varano, F.; Cecchi, L.; Galli, A.; Catarzi, D.; 7-Chloro-4,5-dihydro-8-(1,2,4-triazol-4-yl)-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates as novel highly selective AMPA receptor antagonists. J Med Chem 2000, 43, 21, 3824. |
| 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) | 47585 | 1-Amino-4-chloro-2-nitrobenzene; 2-Nitro-4-chloroaniline; p-chloro-o-nitroaniline; 4-chloro-2-nitroaniline; 4-chloro-2-nitrophenylamine | 89-63-4 | C6H5ClN2O2 | 详情 | 详情 |
| (II) | 21337 | ethyl 2-chloro-3-oxobutanoate | 609-15-4 | C6H9ClO3 | 详情 | 详情 |
| (III) | 47586 | N-(4-chloro-2-nitrophenyl)-2-ethoxy-2-oxoethanehydrazonoyl chloride | C10H9Cl2N3O4 | 详情 | 详情 | |
| (IV) | 47587 | N'-(4-chloro-2-nitrophenyl)-2-ethoxy-2-oxoethanehydrazonamide | C10H11ClN4O4 | 详情 | 详情 | |
| (V) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (VI) | 47588 | ethyl 2-([1-[(E)-2-(4-chloro-2-nitrophenyl)hydrazono]-2-ethoxy-2-oxoethyl]amino)-2-oxoacetate | C14H15ClN4O7 | 详情 | 详情 | |
| (VII) | 47589 | diethyl 1-(4-chloro-2-nitrophenyl)-1H-1,2,4-triazole-3,5-dicarboxylate | C14H13ClN4O6 | 详情 | 详情 | |
| (VIII) | 47590 | ethyl 7-chloro-4-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylate | C12H9ClN4O3 | 详情 | 详情 | |
| (IX) | 47591 | ethyl 7-chloro-8-nitro-4-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylate | C12H8ClN5O5 | 详情 | 详情 | |
| (X) | 47592 | ethyl 8-amino-7-chloro-4-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylate | C12H10ClN5O3 | 详情 | 详情 | |
| (XI) | 47593 | ethyl 7-chloro-4-oxo-8-(4H-1,2,4-triazol-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylate | C14H10ClN7O3 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(III)The methylation of 6-chloro-1H-indole-2-carboxylic acid ethyl ester (I) with NaH and Me-I in DMF gives the 1-methylindole derivative (II), which is condensed with 2-chloro-2-oxoacetic acid ethyl ester (III) by means of TiCl4 in dichloroethane to yield 6-chloro-2-[2-(ethoxycarbonyl)-1-methyl-1H-indol-3-yl]-2-oxoacetic acid ethyl ester (IV). The cyclization of (IV) with phenylhydrazine (V) in refluxing acetic acid affords the 7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylic acid ethyl ester (VI). The reduction of the ester group of (VI) by means of NaBH4 in refluxing THF/methanol affords the hydroxymethyl derivative (VII), which is oxidized with MnO2 in refluxing dichloromethane to provide the corresponding carbaldehyde (VIII). The reaction of (VIII) with p-Toluenesulfonylmethyl isocyanide (TosMIC) and potassium tert-butoxide in dimethoxyethane gives the acetonitrile derivative (IX), which is hydrolyzed with HCl in refluxing methanol to yield the acetate ester derivative (X). Finally, this compound is treated with dimethylamine and trimethylaluminum in toluene to afford the target dimethylacetamide derivative.
| 【1】 Bartsch, R.; Sevrin, M.; Froissant, J.; Evanno, Y.; Dubois, L.; Marguet, F.; Gille, C. (Sanofi-Synthélabo); 4-Oxo-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-acetamide derivs., their preparation and their application in therapy. EP 1000063; FR 2766823; JP 2001512122; US 6262045; WO 9906406 . |
| 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) | 55771 | ethyl 6-chloro-1H-indole-2-carboxylate | C11H10ClNO2 | 详情 | 详情 | |
| (II) | 55772 | ethyl 6-chloro-1-methyl-1H-indole-2-carboxylate | C12H12ClNO2 | 详情 | 详情 | |
| (III) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (IV) | 55773 | ethyl 6-chloro-3-(2-ethoxy-2-oxoacetyl)-1-methyl-1H-indole-2-carboxylate | C16H16ClNO5 | 详情 | 详情 | |
| (V) | 11818 | Phenyl hydrazine; 1-Phenylhydrazine | 100-63-0 | C6H8N2 | 详情 | 详情 |
| (VI) | 55774 | ethyl 7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate | C20H16ClN3O3 | 详情 | 详情 | |
| (VII) | 55775 | 7-chloro-1-(hydroxymethyl)-5-methyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one | C18H14ClN3O2 | 详情 | 详情 | |
| (VIII) | 55776 | 7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carbaldehyde | C18H12ClN3O2 | 详情 | 详情 | |
| (IX) | 55777 | 2-(7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indol-1-yl)acetonitrile | C19H13ClN4O | 详情 | 详情 | |
| (X) | 55778 | methyl 2-(7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indol-1-yl)acetate | C20H16ClN3O3 | 详情 | 详情 | |
| (XI) | 19443 | N-methylmethanamine; N,N-dimethylamine | 124-40-3 | C2H7N | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(II)The Friedel-Kraft's reaction of 2-isopropylindan (I) with ethyloxalyl chloride (II) by means of AlCl3 in methylene chloride gives ethyl 2-(2-isopropyl-5-indanyl)-2-oxoacetate (III), which is hydrolyzed with NaOH in refluxing ethanol to the corresponding free acid (IV). The reaction of (IV) with methylmagnesium iodide in ether yields 2-(2-isopropyl-5-indanyl)-2-hydroxypropionic acid (V), which is dehydrated with H2SO4 in refluxing dioxane affording 2-(2-isopropyl-5-indanyl)acrylic acid (VI) (1,2,4). Finally this compound is reduced with H2 over Raney-Ni or Pd/C in methanol or dioxane
| 【1】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Arrigoni, Martelli, E.; Isoprofen. Drugs Fut 1981, 6, 8, 471. |
| 【2】 Payne, T.G. (Hexachimie SA); CH 605564 . |
| 【3】 Teulon, J,M,; et al. (Hexachimie SA); BE 824522; CA 1063618; CH 603533; CH 605567; DD 117209; DD 118271; DD 123319; DE 2504689; FR 2260334; GB 1492175; JP 76125367; JP 76125368; NL 7501518; NL 7501519; US 4069326; US 4088787; US 4182896; ZA 7500707 . |
| 【4】 Teulon, J.M.; et al.; Antiinflammatory and analgesic diastereoisomeric derivatives of indan-5-acetic acid. J Med Chem 1978, 21, 4, 901. |
| 【5】 Payne, T.G. (Hexachimie SA); CH 605565 . |
| 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) | 60960 | 2-isopropylindane | C12H16 | 详情 | 详情 | |
| (II) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (III) | 60961 | ethyl 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-2-oxoacetate | C16H20O3 | 详情 | 详情 | |
| (IV) | 60962 | 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-2-oxoacetic acid | C14H16O3 | 详情 | 详情 | |
| (V) | 60963 | 2-hydroxy-2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)propanoic acid | C15H20O3 | 详情 | 详情 | |
| (VI) | 60964 | 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)acrylic acid | C15H18O2 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(V)Knoevenagel condensation between N-Boc-4-piperidinone (I) and ethyl cyanoacetate (II) produced the piperidinylidene cyanoacetate (III), which was further converted to the thienopyridine derivative (IV) upon treatment with sulfur and morpholine. Acylation of amine (IV) with ethyl oxalyl chloride (V) furnished the oxalamide (VI). Subsequent hydrolysis of the ester groups of (VI) under basic conditions led to diacid (VII). The title compound was finally obtained by trifluoroacetic acid-promoted Boc group cleavage.
| 【1】 Modulators of protein tyrosine phosphatases. WO 9946237 . |
| 【2】 Jones, T.K.; Ripka, W.C.; Andersen, H.S.; Olsen, O.H.; Bakir, F.; Branner, S.; Iversen, L.F.; Holsworth, D.D.; Axe, F.U.; Ge, Y.; Uyeda, R.T.; Judge, L.M.; Moeller, N.P.H. (Novo Nordisk A/S; Ontogen Corp.); Modulators of protein tyrosine phosphatases (PTPases). JP 2002506072; US 6410586; WO 9946267 . |
| 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) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (III) | 58781 | tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethylidene)-1-piperidinecarboxylate | C15H22N2O4 | 详情 | 详情 | |
| (IV) | 58782 | 6-(tert-butyl) 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate | C15H22N2O4S | 详情 | 详情 | |
| (V) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (VI) | 58783 | 6-(tert-butyl) 3-ethyl 2-[(2-ethoxy-2-oxoacetyl)amino]-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate | C19H26N2O7S | 详情 | 详情 | |
| (VII) | 58784 | 6-(tert-butoxycarbonyl)-2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid | C15H18N2O7S | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(V)Friedel-Crafts acylation of diphenyl ether (IV) with ethyl chloroglyoxylate (V) affords the (4-phenoxyphenyl)glyoxylate (VI). This is then treated with hydroxylamine to produce a mixture of Z- and E-oximes (VII) and (VIII), which can be separated by recrystallization, followed by column chromatography. The desired Z-oxime (VII) is alkylated by the benzyl chloride derivative (III) to furnish the O-benzyl oxime (IX). Finally, saponification of the ethyl ester group of (IX) with NaOH in MeOH gives rise to the target carboxylic acid
| 【1】 Imoto, H.; Imamiya, E.; Momose, Y.; Sugiyama, Y.; Kimura, H.; Sohda, T.; Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives. Chem Pharm Bull 2002, 50, 10, 1349. |
| 【2】 Kimura, H.; Momose, Y.; Odaka, H.; Sakamoto, J.; Imoto, H. (Takeda Chemical Industries, Ltd.); Oxyiminoalkanoic acid derivs. with hypoglycemic and hypolipidemic activity. EP 1077957; JP 2000034266; JP 2000198772; US 6251926; US 6495581; WO 9958510 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 60074 | 4-(chloromethyl)phenyl (5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl ether; 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-oxazole | C18H16ClNO2 | 详情 | 详情 | |
| (IV) | 60075 | 1-phenoxybenzene; diphenyl ether | C12H10O | 详情 | 详情 | |
| (V) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (VI) | 60076 | ethyl 2-oxo-2-(4-phenoxyphenyl)acetate | C16H14O4 | 详情 | 详情 | |
| (VII) | 60080 | ethyl 2-(hydroxyimino)-2-(4-phenoxyphenyl)acetate | C16H15NO4 | 详情 | 详情 | |
| (VIII) | 60077 | ethyl 2-(hydroxyimino)-2-(4-phenoxyphenyl)acetate | C16H15NO4 | 详情 | 详情 | |
| (IX) | 60078 | ethyl 2-[({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)imino]-2-(4-phenoxyphenyl)acetate | C34H30N2O6 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(I)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).
| 【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18
该中间体在本合成路线中的序号：(XI)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
| 【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19
该中间体在本合成路线中的序号：(II)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.
| 【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20
该中间体在本合成路线中的序号：(XXI)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21
该中间体在本合成路线中的序号：(XXI)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22
该中间体在本合成路线中的序号：(XXI)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 |