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【结 构 式】

【分子编号】17571

【品名】Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate

【CA登记号】95-92-1

【 分 子 式 】C6H10O4

【 分 子 量 】146.143

【元素组成】C 49.31% H 6.9% O 43.79%
与该中间体有关的原料药合成路线共 26 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16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24合成路线25合成路线26

合成路线1

该中间体在本合成路线中的序号：(III)

This compound can be obtained by two related ways: 1) The hydrolysis of 3-hydroxy-3-phenyl-1-butyne (I) with aqueous H2SO4 catalyzed by mercuric sulfate gives 3-hydroxy-3-phenyl-2-butanone (II), which is cyclized and decarboxylated by reaction with diethyl oxalate (III) and NaH in hot THF. 2) When the reaction of (II) with (III) is carried out under milder conditions 6-methyl-6-phenyltetrahydropyran-2,3,5-trione (IV) is obtained. This compound is then treated with aqueous NaOH at pH 11.

参考文献 中间体
合成目标
【1】 Jirkovsky, J.L.; Dvornik, D.; Cayen, M.N.; Process for preparing 4,5-dihydro-4-oxofuran-2-carboxylic acid derivatives. EP 0006305; ES 8100283; US 4169202; WO 8000025 .
【2】 Serradell, M.N.; Blancafort, P.; Grau, M.; Castaner, J.; AY-25,712. Drugs Fut 1983, 8, 3, 184.
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) 35961 2-phenyl-3-butyn-2-ol 127-66-2 C10H10O 详情 详情
(II) 35962 3-hydroxy-3-phenyl-2-butanone C10H12O2 详情 详情
(III) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(IV) 35963 6-methyl-6-phenyl-2H-pyran-2,3,5(4H,6H)-trione C12H10O4 详情 详情

合成路线2

该中间体在本合成路线中的序号：(III)

The hydrogenation of 2-hydroxy-3-allyl-6-(2-hydroxypropoxy)acetophenone (I) with H2 over Pd/C in ethanol gives 2-hydroxy-3-propyl-6-(2-hydroxypropoxy)acetophenone (II), which is then cyclized with diethyl oxalate (III) by means of sodium ethoxide in refluxing ethanol. The sodium salt is prepared by treatment of the acid with NaHCO3 in water.

参考文献 中间体
合成目标
【1】 Cairns, H.; Hazard, R.; King, J.; Lee, T.B.; DE 2530289 .
【2】 Sneddon, J.M.; Serradell, M.N.; Castaner, J.; Blancafort, P.; FPL-52,694. Drugs Fut 1982, 7, 6, 388.
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) 37073 1-[3-allyl-2-hydroxy-6-(2-hydroxypropoxy)phenyl]-1-ethanone C14H18O4 详情 详情
(II) 37074 1-[2-hydroxy-6-(2-hydroxypropoxy)-3-propylphenyl]-1-ethanone C14H20O4 详情 详情
(III) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情

合成路线3

该中间体在本合成路线中的序号：(A)

The alkylation of 4-(N-acetyl-N-ethylamino)-2-hydroxyacetophenone (I) with allyl bromide (II) by means of K2CO3 in DMF gives the allyl ether (III), which is isomerized by refluxing in diethylaniline to 4-(N-acetyl-N-ethylamino)-3-allyl-2-hydroxyacetophenone (IV) The reduction of (IV) with H2 over Pd/C in ethanol affords the corresponding propyl derivative (V), which is deacetylated with HBr in refluxing acetic acid water to 4-(ethylamino)-3-propyl-2-hydroxyacetophenone (VI). The addition of (VI) dimethyl acetylenedicarboxylate (VII) in refluxing ethanol affords the aminomaleate (VIII), which by cyclization witn polyphosphoric acid at 100 C gives methyl 1-ethyl-6-acetyl-7-hydroxy-4 oxo-8-propyl-4H-quinoline-2-carboxylate (IX). The condensation of (IX) with diethyl oxalate in DMF by means of NaH results in the ester of the final product (X), which is then hydrolyzed with NaHCO3 iin refluxing ethanol.

参考文献 中间体
合成目标
【1】 Wilkinson, D.J.; Lockley, W.J.S.; Synthesis of nedocromil sodium labelled with tritium, deuterium and carbon-14. J Label Compd Radiopharm 1985, 22, 9, 883.
【2】 Caims, H.; Cox, D. (Rhone-Poulenc Rorer Ltd.); Nouvelles pyranoquinoleinones et leurs compositions pharmaceutiques. DE 2819215; ES 469391; JP 1199909; JP 53137969 .
【3】 Cairns, H.; Cox, D. (Rhone-Poulenc Rorer Ltd.); 4,6-Dioxo-4H,6H-pyrano[3,2-g]quinoline-2,8-dicarbocyclic acids. GB 2022078 .
【4】 Prous, J.; Castaner, J.; Nedocromil sodium. Drugs Fut 1986, 11, 9, 756.
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) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(I) 24545 N-(4-acetyl-3-hydroxyphenyl)-N-ethylacetamide C12H15NO3 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 24547 3-[4-acetyl-3-(allyloxy)phenyl]-2-pentanone C16H20O3 详情 详情
(IV) 24548 N-(4-acetyl-2-allyl-3-hydroxyphenyl)-N-ethylacetamide 69049-64-5 C15H19NO3 详情 详情
(V) 24549 N-(4-acetyl-3-hydroxy-2-propylphenyl)-N-ethylacetamide C15H21NO3 详情 详情
(VI) 24550 1-[4-(ethylamino)-2-hydroxy-3-propylphenyl]-1-ethanone 69049-68-9 C13H19NO2 详情 详情
(VII) 24551 Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester 762-42-5 C6H6O4 详情 详情
(VIII) 24552 dimethyl (Z)-2-[4-acetyl(ethyl)-3-hydroxy-2-propylanilino]-2-butenedioate 77941-04-9 C19H25NO6 详情 详情
(IX) 24553 methyl 6-acetyl-1-ethyl-7-hydroxy-4-oxo-8-propyl-1,4-dihydro-2-quinolinecarboxylate 69049-70-3 C18H21NO5 详情 详情
(X) 24554 diethyl 9-ethyl-4,6-dioxo-10-propyl-6,9-dihydro-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate 69049-72-5 C23H25NO7 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

Treatment of alanine (I) with phosgene in THF provides N-carboxyanhydride derivative (II), which is then coupled to proline (III) by means of KOH and K2CO3 in THF/H2O or acetonitrile to provide dipeptide (IV). Coupling of (IV) to ethyl 2-oxo-4-phenylbutyrate (V) by means of H2 over Raney-Ni in EtOH (or EtOH/HOAc), followed by the corresponding work-up for isomer separation, yields derivative (VI). (In turn, ketoester (V) can be obtained by treatment of 2-phenylethyl bromide (VII) with Mg turnings in refluxing THF, followed by reaction of the resulting Grignard reagent with diethyl oxalate (VIII) in THF). Finally, the desired product is obtained by saponification of the ethyl ester group of (VI) with NaOH.

参考文献 中间体
合成目标
【1】 Blacklock, T.J.; et al.; Synthesis of semisynthetic dipeptides using N-carboxyanhydrides and chiral induction on Raney nickel. A method practical for large scale. J Org Chem 1988, 53, 4, 836.
【2】 Reider, P.J.; Huffman, M.A.; Leblond, C.; Sun, Y. (Merck & Co., Inc.); Improved stereoselective process for enalapril. WO 0017228 .
【3】 Blacklock, T.J.; Shuman, R.F. (Merck & Co., Inc.); Process for preparing polypeptides. US 4510083 .
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) 50831 L-Alanine; L-2-Aminopropionic acid; (S)-(+)-2-Aminopropionic acid; L-2-Aminopropionic acid; (S)-2-Aminopropionic acid; (S)-(+)-Alanine 56-41-7 C3H7NO2 详情 详情
(II) 50829 (4S)-4-methyl-1,3-oxazolidine-2,5-dione; S-Alanine-N-carboxylic acid anhydride 2224-52-4 C4H5NO3 详情 详情
(III) 16731 L-proline 147-85-3 C5H9NO2 详情 详情
(IV) 32151 (2S)-1-[(2S)-2-aminopropanoyl]-2-pyrrolidinecarboxylic acid 13485-59-1 C8H14N2O3 详情 详情
(V) 50832 ethyl 2-oxo-4-phenylbutanoate C12H14O3 详情 详情
(VI) 50830 (2S)-1-((2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-2-pyrrolidinecarboxylic acid C20H28N2O5 详情 详情
(VII) 20730 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide 103-63-9 C8H9Br 详情 详情
(VIII) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

1) The cyclization of 2,3-dimethylaniline (I) with diethyl acetylmalonate (II) in 1-chloronaphthalene at 240 C gives 3-acetyl-4-hydroxy-7,8-dimethylquinolin-2(1H)-one (III), which by reaction with diethyl oxalate (IV) by means of sodium ethoxide in refluxing benzene yields ethyl-4-(4-hydroxy-7,8-dimethyl-2-oxo-1,2-dihydroquinolin-3yl)-2,4-dioxo-butanoate (V). The cyclization of (V) in acetic acid concentrated HCl at 100 C affords 5,6-dihydro-7,8 dimethyl-4,5-dioxo-4H-pyrano[3,2-c]quinoline-2-carboxylic acid (VI), which is converted into the corresponding acyl chloride (VII) by reaction with refluxing SOCl2. Finally, this compound is treated with hot 3-methylbutanol (VIII).

参考文献 中间体
合成目标
【1】 Takahashi, K.; Hata, S.; Morinaka, Y.; Yamada, S.; Antiallergic agents I. Pyranoquinoline derivatives. Eur J Med Chem - Chim Ther 1981, 16, 3, 251.
【2】 Castaner, J.; Prous, J.; Repirinast. Drugs Fut 1987, 12, 1, 37.
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) 23025 2,3-Dimethylphenylamine; 2,3-Dimethylaniline; 2,3-Xylidine 87-59-2 C8H11N 详情 详情
(II) 23026 diethyl 2-acetylmalonate 570-08-1 C9H14O5 详情 详情
(III) 23027 3-acetyl-4-hydroxy-7,8-dimethyl-2(1H)-quinolinone C13H13NO3 详情 详情
(IV) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(V) 23029 ethyl 4-(4-hydroxy-7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)-2,4-dioxobutanoate C17H17NO6 详情 详情
(VI) 24014 Phenyllithium 591-51-5 C6H5Li 详情 详情
(VII) 23031 7,8-dimethyl-4,5-dioxo-5,6-dihydro-4H-pyrano[3,2-c]quinoline-2-carbonyl chloride C15H10ClNO4 详情 详情
(VIII) 23032 3-methyl-1-butanol 123-51-3 C5H12O 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 intermediate (racemic)-2-(methoxycarbonylmethyl)-6,6-dimethyltetrahydropyran-2-carboxylic acid (VIII) has been obtained by several related methods: 1. The Grignard condensation of 4-methyl-3-pentenyl bromide (I) with diethyl oxalate (II) in HF gives the 2-oxoheptenoate (III), which is condensed with methyl acetate (IV) by means of LiHMDS in THF to yield 3-(ethoxycarbonyl)-3-hydroxy-7-methyl-6-octenoic acid methyl ester (V). The cyclization of (V) by means of Ts-OH in hot toluene or by means of hot aqueous formic acid affords 2-(methoxycarbonylmethyl)-6,6-dimethyltetrahydropyran-2-carboxylic acid ethyl ester (VI), which is hydrolyzed with KOH in boiling water to provide the corresponding dicarboxylic acid (VII). Finally, this compound is regioselectively monoesterified by means of BF3/MeOH in methanol to furnish the intermediate (racemic)-2-(methoxycarbonylmethyl)-6,6-dimethyltetrahydropyran-2-carboxylic acid (VIII). 2. The reaction of 3-(ethoxycarbonyl)-3-hydroxy-7-methyl-6-octenoic acid methyl ester (V) with HCl in hot methanol gives 3-(ethoxycarbonyl)-3,7-dihydroxy-7-methyloctanoic acid methyl ester (IX), which is then cyclized by means of ZnCl2 in hot dichloroethane to yield the previously described intermediate (VIII). 3. The hydrolysis of 3-(ethoxycarbonyl)-3-hydroxy-7-methyl-6-octenoic acid methyl ester (V) with KOH in refluxing methanol/water gives the corresponding diacid (X), which is regioselectively monoesterified by means of BF3/MeOH in methanol to yield 3-carboxy-3-hydroxy-7-methyl-6-octenoic acid methyl ester (XI). Finally, this compound is cyclized by means of Ts-OH in hot toluene to afford the previously described carboxylic intermediate (VIII). The racemic acid (VIII) is submitted to optical resolution by esterification with quinine (XII) by means of 2,4,6-trichlorobenzoyl chloride and TEA or DCC to give a diastereomeric mixture of esters (XIII) that is separated by preparative HPLC to obtain the desired diastereomer (XIV). The hydrolysis of (XIV) with KOH in refluxing ethanol/water gives the corresponding chiral dicarboxylic acid (XV), which is regioselectively monoesterified with BF3/MeOH in methanol to yield the chiral (R)-2-(methoxycarbonylmethyl)-6,6-dimethyltetrahydropyran-2-carboxylic acid (XVI). The esterification of (XVI) with cephalotaxine (XVII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in toluene affords the corresponding ester (XVIII), which is treated with HBr in dichloromethane/HOAc, providing the bromoester (XIX). Finally, this compound is treated with NaHCO3, CaCO3 or BaCO3 in acetone/water to give the target hydroxyester.

参考文献 中间体
合成目标
【1】 Robin, J.-P.; et al.; The first semi-synthesis of enantiopure homoharringtonine via anhydrohomoharringtonine from a preformed chiral acyl moiety. Tetrahedron Lett 1999, 40, 2931.
【2】 Robin, J.; Robin, J.-P.; Cavoleau, S.; Chauviat, L.; Charbonnel, S.; Dhal, R.; Dujardin, G.; Fournier, F.; Gilet, C.; Girodier, L.; Mevelec, L.; Poutot, S.; Rouaud, S. (OncoPharm Corp.); Novel cephalotaxane derivs. and process for their preparation. EP 1064285; FR 2776292; WO 9948894 .
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) 31462 5-bromo-2-methyl-2-pentene C6H11Br 详情 详情
(II) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(III) 52779 ethyl 3,6-dimethyl-2-oxo-5-heptenoate C11H18O3 详情 详情
(IV) 44566 methyl acetate 79-20-9 C3H6O2 详情 详情
(V) 52780 1-ethyl 4-methyl 2-hydroxy-2-(4-methyl-3-pentenyl)succinate C13H22O5 详情 详情
(VI) 52781 ethyl 2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylate C13H22O5 详情 详情
(VII) 52782 2-(carboxymethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid C10H16O5 详情 详情
(VIII) 52783 2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid C11H18O5 详情 详情
(IX) 52784 1-ethyl 4-methyl 2-hydroxy-2-(4-hydroxy-4-methylpentyl)succinate C13H24O6 详情 详情
(X) 52785 2-hydroxy-2-(4-methyl-3-pentenyl)succinic acid C10H16O5 详情 详情
(XI) 52786 2-hydroxy-2-(2-methoxy-2-oxoethyl)-6-methyl-5-heptenoic acid C11H18O5 详情 详情
(XII) 52787 (R)-(6-methoxy-4-quinolinyl)[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methanol C20H24N2O2 详情 详情
(XIII) 52788 (R)-(6-methoxy-4-quinolinyl)[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methyl 2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylate C31H40N2O6 详情 详情
(XIV) 52789 (R)-(6-methoxy-4-quinolinyl)[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methyl (2R)-2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylate C31H40N2O6 详情 详情
(XV) 52790 (2R)-2-(carboxymethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid C10H16O5 详情 详情
(XVI) 52791 (2R)-2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid C11H18O5 详情 详情
(XVII) 52792 (1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-ol C18H21NO4 详情 详情
(XVIII) 52793 (1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-yl (2R)-2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylate C29H37NO8 详情 详情
(XIX) 52794 1-[(1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-yl] 4-methyl (2R)-2-(4-bromo-4-methylpentyl)-2-hydroxybutanedioate C29H38BrNO8 详情 详情

合成路线7

该中间体在本合成路线中的序号：(V)

The condensation of 2-(2-methyl-3-nitrophenyl)acetic acid (I) with dipropylamine (II) by means of refluxing SOCl2 gives the corresponding amide (III), which is reduced with borane/THF yielding the tertiary amine (IV). The condensation of (IV) with diethyl oxalate by means of sodium ethoxide in refluxing ethanol affords the pyruvate ester (V), which is treated with NaOH and H2O2 yielding the acetic acid derivative (VI). Finally, this compound is cyclyzed by hydrogenation with H2 over Pd/C in ethanol.

参考文献 中间体
合成目标
【1】 Gallagher, G. Jr. (SmithKline Beecham Corp.); 4-Aminoalkyl-2(3H)-indolones. EP 0113964; ES 8600239; ES 8604143; US 4452808 .
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) 34861 2-(2-methyl-3-nitrophenyl)acetic acid C9H9NO4 详情 详情
(II) 21856 N,N-dipropylamine; N-propyl-1-propanamine 142-84-7 C6H15N 详情 详情
(III) 34862 2-(2-methyl-3-nitrophenyl)-N,N-dipropylacetamide C15H22N2O3 详情 详情
(IV) 34863 N-(2-methyl-3-nitrophenethyl)-N,N-dipropylamine; N-(2-methyl-3-nitrophenethyl)-N-propyl-1-propanamine C15H24N2O2 详情 详情
(V) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(VI) 34864 ethyl 3-[2-[2-(dipropylamino)ethyl]-6-nitrophenyl]-2-oxopropanoate C19H28N2O5 详情 详情
(VII) 34865 2-[2-[2-(dipropylamino)ethyl]-6-nitrophenyl]acetic acid C16H24N2O4 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IV)

By condensation of ethyl 8-propyl-7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate (I) with 4-(2,3-epoxypropoxy)-3-propyl-2-hydroxyacetophenone (II) by means of benzyltrimethylammonium hydroxide in refluxing DMF, followed by hydrolysis with NaHCO3 in refluxing ethanol - water. The starting compounds (I) and (II) are prepared as follows: 1) The condensation of 3-propyl-2,4-dihydroxyacetophenone (III) with diethyl oxalate (IV) by means of sodium ethoxide in refluxing ethanol gives (I). 2) The condensation of acetophenone (III) with 1-chloro-2,3-epoxypropane (V) by means of KOH in refluxing ethanol - water gives (II).

参考文献 中间体
合成目标
【1】 Pratt, A.D.; Bantick, J..; Lee, T.B.; Chamberlain, T.R.; Hardern, D.N.; Appleton, R.A.; Antagonits of slow reacting substance od anaphylaxis. Synthesis of a series of chromone-2-carboxylic acids. J Med Chem 1979, 20, 3, 371.
【2】 Augstein, J.; Lee, T.B.; Carter, D. (AstraZeneca plc); Chromone derivs.. FR 2147287 .
【3】 Augstein, J.; Carter, D.; Lee, T.B. (AstraZeneca plc); Chrome cpds. having SRS-A properties. US 3882148 .
【4】 Blancafort, P.; Castaner, J.; Sneddon, J.M.; Serradell, M.N.; FPL-55,712. Drugs Fut 1982, 7, 7, 472.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
37126 　 C10H18NO 详情 详情
(I) 37124 ethyl 7-hydroxy-4-oxo-8-propyl-4H-chromene-2-carboxylate C15H16O5 详情 详情
(II) 37125 1-[2-hydroxy-4-(2-oxiranylmethoxy)-3-propylphenyl]-1-ethanone C14H18O4 详情 详情
(III) 13137 2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone 40786-69-4 C11H14O3 详情 详情
(IV) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(V) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情

合成路线9

该中间体在本合成路线中的序号：(VI)

Condensation of 2-bromo-p-toluidine (I) with cyclohexane-1,3-dione (II) gives bromo enaminone (III), which is N-methylated with iodomethane and NaH, affording tertiary enaminone (IV). Treatment of (IV) with triphenylphosphine-palladium acetate complex/NHCO3 or palladium acetate in acetonitrile provides carbazolone (V). Treatment of carbazolone (V) with sodium metal in EtOH/dioxane (or sodium methoxide in 1,2-dimethoxyethane) and diethyl oxalate (VI) provides ethoxallyl derivative (VII), which is then converted into glyoxylic acid lactone (VIII). Coupling of (VIII) with 2-methylimidazol (IX) by means of benzyltriethylammonium chloride in CHCl3/H2O furnishes glyoxylate (X), which is converted into the target product by reaction again with 2-methylimidazol (IX) in dioxane and final treatment with HCl. Alternatively, glyoxylate (X) can be directly obtained from (VIII) by reaction with formaldehyde and 2-methylimidazol (IX) in dioxane.

参考文献 中间体
合成目标
【1】 Iida, H.; et al.; Intramolecular cyclization of enaminones involving arylpalladium complexes. Synthesis of carbazoles. J Org Chem 1980, 45, 15, 2938.
【2】 Harsanyi, K.; Bod, P.; Trischler, F.; Fekecs, E.; Horvath, E.; Csehl, A.; Hegedus, B.; Mersich, E.; Szabo, G. (Gedeon Richter Ltd.); Carbazolone derivs. and process for preparing the same. EP 0595111 .
【3】 Dobay, L.; Czibula, L.; Szantay, C.; Gazdag, M.; Greiner, I.; Werkne Papp, E.; Tarkanyi, G.; Zsoldosne Babjak, M.; Mihalyfi, K. (Gedeon Richter Ltd.); An intermediate and process for its synthesis. WO 0172716 .
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) 27739 2-bromoaniline 615-36-1 C6H6BrN 详情 详情
(II) 11244 1,3-Cyclohexanedione 504-02-9 C6H8O2 详情 详情
(III) 53887 3-(2-bromoanilino)-2-cyclohexen-1-one n/a C12H12BrNO 详情 详情
(IV) 53888 3-[2-bromo(methyl)anilino]-2-cyclohexen-1-one n/a C13H14BrNO 详情 详情
(V) 53889 9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one 27387-31-1 C13H13NO 详情 详情
(VI) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(VII) 53890 ethyl 2-hydroxy-2-(9-methyl-4-oxo-1,2,4,9-tetrahydro-3H-carbazol-3-ylidene)acetate n/a C17H17NO4 详情 详情
(VIII) 53891 　 n/a C16H13NO4 详情 详情
(IX) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(X) 53892 2-methyl-1H-imidazol-3-ium 2-[3-(hydroxymethyl)-9-methyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-2-oxoacetate n/a C20H21N3O5 详情 详情

合成路线10

该中间体在本合成路线中的序号：(II)

The condensation of 2',6'-dimethoxyacetophenone (I) with diethyl oxalate (II) by means of sodium methoxide in refluxing methanol gives the dioxobutyrate (III), which is cyclized with 7-chloroquinoline-4-hydrazine (IV) in refluxing acetic acid yielding the pyrazole derivative (V). The hydrolysis of the ester group of (V) with KOH in refluxing methanol/water affords the corresponding carboxylic acid (VI), which is finally treated with SOCl2 in refluxing toluene and condensed with 2-aminoadamantane-2-carboxylic acid.

参考文献 中间体
合成目标
【1】 Boigegrain, R.; Gully, D.; Jeanjean, F.; Molimard, J.-C. (Sanofi-Synthélabo ); Amido-3-pyrazole derivs., process for their preparation and pharmaceutical compsns. containing them. EP 0477049; FR 2665898; JP 1992244065; US 5420141; US 5607958; US 5616592; US 5635526; US 5744491; US 5744493 .
【2】 Maffrand, J.P.; Gully, D.; Boigegrain, R.; Soubrie, P.; Kitabgi, P.; Rostene, W.; Le Fur, G.; Neurotensin receptor agonists and antagonists. Drugs Fut 1993, 18, 12, 1137.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
41280 2-amino-2-adamantanecarboxylic acid C11H17NO2 详情 详情
(I) 41275 1-(2,6-dimethoxyphenyl)-1-ethanone 2040-04-2 C10H12O3 详情 详情
(II) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(III) 41276 sodium (Z)-4-(2,6-dimethoxyphenyl)-1-methoxy-1,4-dioxo-2-buten-2-olate C13H13NaO6 详情 详情
(IV) 41277 7-chloro-4-hydrazinoquinoline 23834-14-2 C9H8ClN3 详情 详情
(V) 41278 methyl 1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxylate C22H18ClN3O4 详情 详情
(VI) 41279 1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxylic acid C21H16ClN3O4 详情 详情

合成路线11

该中间体在本合成路线中的序号：(III)

Reaction of tetrabutylammonium [11C]cyanide (I) with methyl chloroformate in a two phase system afforded labeled methyl cyanoformate (II), which was refluxed in ethanolic HCl to yield diethyl [1-11C]oxalate (III).

参考文献 中间体
合成目标
【1】 Thorell, J.O.; et al.; Synthesis of a C-11-labelled nitrated 1,4-dihydroquinoxaline-2,3-dione, the NMDA glycine receptor antagonist ACEA 1021 (Licostinel). J Label Compd Radiopharm 1998, 41, 4, 345-353.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(II) 18001 methyl 2-nitriloacetate; carbonocyanic acid, methyl ester 17640-15-2 C3H3NO2 详情 详情
(II) 45300 methyl 2-nitriloacetate C3H3NO2 详情 详情
(III) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(III) 45301 ethyl 2-ethoxy-2-oxoacetate C6H10O4 详情 详情

合成路线12

该中间体在本合成路线中的序号：(III)

Phenylenediamine (IV) was protected as the benzoselenadiazole (V) on treatment with selenium dioxide in 1 N HCl. The subsequent nitration with nitric and sulfuric acid provided (VI), which on stirring with a mixture of concentrated HCl and HI gave the nitrodiamine (VII). Cyclization of (VII) with labeled diethyl oxalate (III) in sulfuric acid at 175 C yielded labeled quinoxalinedione.

参考文献 中间体
合成目标
【1】 Thorell, J.O.; et al.; Synthesis of a C-11-labelled nitrated 1,4-dihydroquinoxaline-2,3-dione, the NMDA glycine receptor antagonist ACEA 1021 (Licostinel). J Label Compd Radiopharm 1998, 41, 4, 345-353.
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) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(III) 45301 ethyl 2-ethoxy-2-oxoacetate C6H10O4 详情 详情
(IV) 18003 4,5-dichloro-1,2-benzenediamine; 4,5-Dichloro-o-phenylenediamine; 2-amino-4,5-dichlorophenylamine 5348-42-5 C6H6Cl2N2 详情 详情
(V) 18004 5,6-dichloro-2,1,3-benzoselenadiazole C6H2Cl2N2Se 详情 详情
(VI) 18005 5,6-dichloro-4-nitro-2,1,3-benzoselenadiazole C6HCl2N3O2Se 详情 详情
(VII) 18006 2-amino-4,5-dichloro-3-nitrophenylamine; 4,5-dichloro-3-nitro-1,2-benzenediamine C6H5Cl2N3O2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(III)

Alternatively, condensation of phenylenediamine (IV) with oxalate (III) in hot sulfuric acid afforded labeled quinoxalinedione (VIII), to which was added acetic acid or diethyl oxalate in order to protect amino groups, and was then nitrated with fuming nitric acid and sulfuric acid.

参考文献 中间体
合成目标
【1】 Thorell, J.O.; et al.; Synthesis of a C-11-labelled nitrated 1,4-dihydroquinoxaline-2,3-dione, the NMDA glycine receptor antagonist ACEA 1021 (Licostinel). J Label Compd Radiopharm 1998, 41, 4, 345-353.
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) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(III) 45301 ethyl 2-ethoxy-2-oxoacetate C6H10O4 详情 详情
(IV) 18003 4,5-dichloro-1,2-benzenediamine; 4,5-Dichloro-o-phenylenediamine; 2-amino-4,5-dichlorophenylamine 5348-42-5 C6H6Cl2N2 详情 详情
(VIII) 18007 6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione 25983-13-5 C8H4Cl2N2O2 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VII)

A new synthesis of ML-3000 has been published: The reaction of 3-phenyl-2-propynyl chloride (I) with isobutyraldehyde (II) by means of tetrabutylammonium iodide/NaI/NaOH in toluene/water gives 2,2-dimethyl-5-phenyl-4-pentynal (III), which is condensed with glycine methyl ester by means of NaBH(OAc)3 and triethylamine in dichloromethane yielding the N-alkyl-glycine (V). The cyclization of (V) by means of pivalic acid at 150 C affords the bicyclic ketone (VI), which is condensed with diethyl oxalate (VII) by means of sodium ethoxide in ethanol giving the ethoxalyl derivative (VIII). The esterification of (VIII) with the triflic amide (IX) yields the triflate (X), which is condensed with 4-chlorophenylboronic acid (XI) by means of palladium tetrakis(triphenylphosphine) as catalyst in refluxing THF affording the compound (XII). The reduction of the oxoacetic group with tosyl hydrazide (XIII) in refluxing ethanol gives the expected acetate derivative (XIV), which is finally hydrolyzed with NaOH in hot ethanol/water.

参考文献 中间体
合成目标
【1】 Cossy, J.; Belotti, D.; Synthesis of ML-3000, an inhibitor of cyclooxygenase and 5-lipoxygenase. J Org Chem 1997, 62, 23, 7900.
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) 17565 1-(3-chloro-1-propynyl)benzene C9H7Cl 详情 详情
(II) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(III) 17567 2,2-dimethyl-5-phenyl-4-pentynal C13H14O 详情 详情
(IV) 17568 methyl 2-aminoacetate C3H7NO2 详情 详情
(V) 17569 methyl 2-[(2,2-dimethyl-5-phenyl-4-pentynyl)amino]acetate C16H21NO2 详情 详情
(VI) 17570 2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-6(5H)-one C15H17NO 详情 详情
(VII) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(VIII) 17572 ethyl 2-(6-hydroxy-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate C19H21NO4 详情 详情
(IX) 17573 N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide 37595-74-7 C8H5F6NO4S2 详情 详情
(X) 17574 ethyl 2-(2,2-dimethyl-7-phenyl-6-[[(trifluoromethyl)sulfonyl]oxy]-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate C20H20F3NO6S 详情 详情
(XI) 17575 4-chlorophenylboronic acid 1679-18-1 C6H6BClO2 详情 详情
(XII) 17576 ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetate C25H24ClNO3 详情 详情
(XIII) 17577 p-Toluenesulfonyl Hydrazide; 4-methylbenzenesulfonohydrazide 1576-35-8 C7H10N2O2S 详情 详情
(XIV) 16723 ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetate C25H26ClNO2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(IV)

The reaction of ethyl 2-sulfanylacetate (I) with 2-bromoacetonitrile (II) by means of NaOEt in ethanol gives ethyl 2-(cyanomethylsulfanyl)acetate (III), which is cyclized with diethyl oxalate (IV) by means of NaOEt in ethanol yielding 5-cyano-3,4-dihydroxythiophene-2-carboxylic acid ethyl ester (V). The protection of the hydroxyl groups of (V) with 2-methoxyethoxymethyl chloride (Mem-Cl) and DIEA in dichloromethane affords the protected thiophene (VI), which is reduced with (t-BuO)2AlH in THF providing the carbinol (VII). The oxidation of (VII) with MnO2 in dichloromethane yields the carbaldehyde (VIII), which is condensed with malonodinitrile (IX) by means of piperidine in dioxane giving the alkylidenemalonodinitrile (X). The epoxidation of (X) with tert-butyl hydroperoxide and TEA in dioxane yields the epoxide (XI), which is treated with HCl in THF to afford 2-chloro-2-[5-cyano-3,4-bis(2-methoxyethoxymethoxy) thiophen-2-yl]acetic acid (XII). The esterification of (XII) with diphenyldiazomethane affords the corresponding diphenylmethyl ester (XIII), which is condensed with N-hydroxyphthalimide (XIV) and NaHCO3 in dichloromethane providing the adduct (XV). The cleavage of the phthalimido group of (XV) with hydrazine in methanol gives 2-(aminooxy)-2-[5-cyano-3,4-bis(2-methoxyethoxymethoxy)thiophen-2-yl]acetic acid diphenylmethyl ester (XVI), which is condensed with 2-oxo-2-[2-(tritylamino)thiazol-4-yl]acetic acid (XVII) yielding the corresponding alcoxyimino derivative (XVIII).

参考文献 中间体
合成目标
【1】 Aszodi, J.; Dini, C.; Fauveau, P. (Aventis Pharma SA); Cephalosporins having in position 7 as substd. axymino radical, intermediates, processes for their preparation and their use as medicaments. CA 2111164; EP 0628562; JP 1994345776 .
【2】 Dini, C.; Aszodi, J.; Synthesis of a dihydroxythiophene analogue of catechosporines. Bioorg Med Chem Lett 2000, 10, 4, 349.
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) 23995 ethyl 2-sulfanylacetate 2713-34-0 C4H8O2S 详情 详情
(II) 31883 2-bromoacetonitrile 590-17-0 C2H2BrN 详情 详情
(III) 35506 ethyl 2-[(cyanomethyl)sulfanyl]acetate C6H9NO2S 详情 详情
(IV) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(V) 35507 ethyl 5-cyano-3,4-dihydroxy-2-thiophenecarboxylate C8H7NO4S 详情 详情
(VI) 35508 ethyl 5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarboxylate C16H23NO8S 详情 详情
(VII) 35509 5-(hydroxymethyl)-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarbonitrile C14H21NO7S 详情 详情
(VIII) 35510 5-formyl-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarbonitrile C14H19NO7S 详情 详情
(X) 35511 2-([5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]methylene)malononitrile C17H19N3O6S 详情 详情
(XI) 35512 3-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2,2-oxiranedicarbonitrile C17H19N3O7S 详情 详情
(XII) 35513 2-chloro-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetic acid C15H20ClNO8S 详情 详情
(XIII) 35514 benzhydryl 2-chloro-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetate C28H30ClNO8S 详情 详情
(XIV) 13505 N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione 524-38-9 C8H5NO3 详情 详情
(XV) 35515 benzhydryl 2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetate C36H34N2O11S 详情 详情
(XVI) 35516 benzhydryl 2-(aminooxy)-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetate C28H32N2O9S 详情 详情
(XVII) 23008 2-oxo-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid C24H18N2O3S 详情 详情
(XVIII) 35517 2-[(2-(benzhydryloxy)-1-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2-oxoethoxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid C52H48N4O11S2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(V)

The reaction of tetrahydrofuran (I) with HBr gives 4-bromobutanol (II), which is oxidized with NaOCl and TEMPO to yield the aldehyde (III). The reaction of (III) with ethyleneglycol and Ts-OH provides the cyclic ketal (IV), which is submitted to a Grignard condensation with diethyl oxalate (V) and Mg to give the alpha-ketoester (VI). The hydrolysis of (VI) with LiOH yields the corresponding alpha-ketoacid (VII), which is submitted to a stereoselective amination with ammonia and phenylalanine dehydrogenase to afford 2(S)-amino-5-(1,3-dioxol-2-yl)pentanoic acid (VIII). The reaction of (VIII) with SOCl2 and Me-OH provides 2(S)-amino-5,5-dimethoxypentanoic acid methyl ester (IX). The reaction of L- homocystine (X) with Boc2O gives the N-protected-L-homocystine (XI), which is condensed with pentanoic ester (IX) to yield the dimeric adduct (XII). The cleavage of (XII) with dithiothreitol (DTT) affords the monomeric intermediate (XIII), which is finally cyclized by means of Ms-OH to provide the target pyrido[2,1-b][1,3]thiazepine intermediate (XIV).

参考文献 中间体
合成目标
【1】 Patel, R.N.; Enzymatic synthesis of chiral intermediates for omapatrilat, an antihypertensive drug. Biomol Eng 2001, 17, 6, 167.
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) 41419 tetrahydrofuran 109-99-9 C4H8O 详情 详情
(II) 50608 Tetramethylene Bromohydrin; 4-Bromo-1-butanol;4-bromobutan-1-ol 33036-62-3 C4H9BrO 详情 详情
(III) 50609 4-bromobutanal C4H7BrO 详情 详情
(IV) 50610 2-(3-bromopropyl)-1,3-dioxolane C6H11BrO2 详情 详情
(V) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(VI) 50611 ethyl 5-(1,3-dioxolan-2-yl)-2-oxopentanoate C10H16O5 详情 详情
(VII) 50612 5-(1,3-dioxolan-2-yl)-2-oxopentanoic acid C8H12O5 详情 详情
(VIII) 50613 (2S)-2-amino-5-(1,3-dioxolan-2-yl)pentanoic acid C8H15NO4 详情 详情
(IX) 22504 methyl (2S)-2-amino-6,6-dimethoxyhexanoate C9H19NO4 详情 详情
(X) 42169 (2S)-2-amino-4-[[(3S)-3-amino-3-carboxypropyl]disulfanyl]butyric acid C8H16N2O4S2 详情 详情
(XI) 50614 (2S)-2-[[(benzyloxy)carbonyl]amino]-4-[((3S)-3-[[(benzyloxy)carbonyl]amino]-3-carboxypropyl)disulfanyl]butyric acid C24H28N2O8S2 详情 详情
(XII) 50615 dimethyl (7S,10S,17S,20S)-10,17-bis[[(benzyloxy)carbonyl]amino]-3,24-dimethoxy-9,18-dioxo-2,25-dioxa-13,14-dithia-8,19-diazahexacosane-7,20-dicarboxylate C42H62N4O14S2 详情 详情
(XIII) 50616 methyl (2S)-2-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-sulfanylbutanoyl)amino]-6,6-dimethoxyhexanoate C21H32N2O7S 详情 详情
(XIV) 50617 (4S,7S,10aS)-4-[[(benzyloxy)carbonyl]amino]-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid C18H22N2O5S 详情 详情

合成路线17

该中间体在本合成路线中的序号：(A)

Treatment of carboxylic acid (I) with MeOH and H2SO4 yields methyl ester (II), which is then converted into cyano derivative (III) by reaction with LiCN in DMF and AcOH. Hydrolysis of (III) with aqueous KOH in EtOH provides dicarboxylic acid (IV), which is cyclized by means of Ac2O to give the dicarboxylic anhydride (V). Alternatively, (V) can be obtained by condensation of ester (VI) with diethyl oxalate (A) in Et2O in the presence of t-BuOK to afford (VII), which is cyclized with H2SO4 and submitted to catalytic hydrogenation over Pd/C. Condensation of anhydride (V) with (S)-alpha-methylbenzylamine yields a mixture of imides, from which (3aR,9bR)-(IX) is obtained by crystallization. Reduction of (3aR,9bR)-(IX) with BH3·THF followed by hydrogenation over Pd/C affords isoindole derivative (X), which is then alkylated with chloroacetonitrile (XI) in acetonitrile in the presence of DIEA and reduced with LiAlH4 to give the primary amine (XII). Treatment of (XIII) with POCl3 and Et3N yields 2-chloro-3-cyanopyrazine (XIV), which is oxidized to provide (XV) by means of K2S2O8 in H2SO4. Treatment of N-oxide (XV) with ethyl thioglycolate (XVI) and NaOEt in DMF affords pyrazinothiophene (XVII), which is then chlorinated with POCl3 to give (XVIII). Finally, reaction of amine (XII) with (XVIII) and triphosgene in toluene and Et3N affords the desired product.

参考文献 中间体
合成目标
【1】 Meyer, M.D.; Altenbach, R.J.; Basha, F.Z.; Carroll, W.A.; Drizin, I.; Kerwin, J.F. Jr.; Lebold, S.A.; Lee, E.L.; Elmore, S.W.; Sippy, K.B.; Tietje, K.R.; Wendt, M.D.; Yamamoto, D.M. (Abbott Laboratories Inc.); Tricyclic substd. hexahydrobenz[e]isoindole alpha-1 adrenergic antagonists. EP 0808318; US 5597823; WO 9622992 .
【2】 Basha, F.Z.; Meyer, M.D.; Altenbach, R.J.; et al.; Structure-activity studies for a novel series of tricycic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of bening prostatic hyperplasia (BPH). J Med Chem 2000, 43, 8, 1586.
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) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(I) 42524 5-methoxy-3,4-dihydro-1-naphthalenecarboxylic acid C12H12O3 详情 详情
(II) 42525 methyl 5-methoxy-3,4-dihydro-1-naphthalenecarboxylate C13H14O3 详情 详情
(III) 42526 methyl 2-cyano-5-methoxy-1,2,3,4-tetrahydro-1-naphthalenecarboxylate C14H15NO3 详情 详情
(IV) 42527 5-methoxy-1,2,3,4-tetrahydro-1,2-naphthalenedicarboxylic acid C13H14O5 详情 详情
(V) 42528 (3aR,9bR)-6-methoxy-3a,4,5,9b-tetrahydronaphtho[1,2-c]furan-1,3-dione C13H12O4 详情 详情
(VI) 42529 ethyl 4-(2-methoxyphenyl)butanoate C13H18O3 详情 详情
(VII) 42530 diethyl 2-(2-methoxyphenethyl)-3-oxosuccinate C17H22O6 详情 详情
(VIII) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(IX) 42531 (3aR,9bR)-6-methoxy-2-[(1S)-1-phenylethyl]-3a,4,5,9b-tetrahydro-1H-benzo[e]isoindole-1,3(2H)-dione C21H21NO3 详情 详情
(X) 42532 (3aR,9bR)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-6-yl methyl ether; (3aR,9bR)-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole C13H17NO 详情 详情
(XI) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(XII) 42533 (3aR,9bR)-2-(2-aminoethyl)-6-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]isoindole-1,3(2H)-dione C15H18N2O3 详情 详情
(XIII) 42534 3-hydroxy-2-pyrazinecarboxamide 55321-99-8 C5H5N3O2 详情 详情
(XIV) 42535 3-chloro-2-pyrazinecarbonitrile 55557-52-3 C5H2ClN3 详情 详情
(XV) 42536 3-chloro-2-cyanopyrazin-1-ium-1-olate C5H2ClN3O 详情 详情
(XVI) 23995 ethyl 2-sulfanylacetate 2713-34-0 C4H8O2S 详情 详情
(XVII) 42537 7-amino-6-(ethoxycarbonyl)thieno[2,3-b]pyrazin-1-ium-1-olate C9H9N3O3S 详情 详情
(XVIII) 42538 ethyl 7-amino-2-chlorothieno[2,3-b]pyrazine-6-carboxylate C9H8ClN3O2S 详情 详情

合成路线18

该中间体在本合成路线中的序号：(III)

The reaction of 3-(trifluoromethyl)aniline (I) with Boc2O gives the carbamate (II), which is condensed with 14C labeled diethyl oxalate (III) by means of BuLi to yield the ketoester (IV). The cyclization of (IV) by means of refluxing aq. HCl affords the labeled 6-(trifluoromethyl)isatin (V), which is condensed with 5-chloro-2-methoxyphenylmagnesium bromide (VI) to provide the hydroxyketone (VII). The fluorination of (VII) with DAST gives the target compound as a racemic mixture (VIII), which is finally submitted to optical resolution by chiral HPLC.

参考文献 中间体
合成目标
【1】 Dischino, D.D.; Gribkoff, V.K.; Hewawasam, P.; Luke, G.M.; Rinehart, J.K.; Spears, T.L.; Starrett, J.E. Jr.; Synthesis of 3H and 14C labeled (S)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one, MaxiPost(TM). An agent for post-stroke neuroprotection. J Label Compd Radiopharm 2003, 46, 2, 139.
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) 26347 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride 98-16-8 C7H6F3N 详情 详情
(II) 39335 tert-butyl 3-(trifluoromethyl)phenylcarbamate C12H14F3NO2 详情 详情
(III) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(III) 64193 allyl (2R,3S,4R,5R)-2-[({(2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-[(Z)-11-octadecenoylamino]tetrahydro-2H-pyran-2-yl}oxy)methyl]-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-3-yl carbonate C82H151N2O18PSi 详情 详情
(IV) 39336 ethyl 2-[2-[(tert-butoxycarbonyl)amino]-4-(trifluoromethyl)phenyl]-2-oxoacetate C16H18F3NO5 详情 详情
(IV) 64197 ethyl 2-[2-[(tert-butoxycarbonyl)amino]-4-(trifluoromethyl)phenyl]-2-oxoacetate C16H18F3NO5 详情 详情
(V) 39337 6-(trifluoromethyl)-1H-indole-2,3-dione C9H4F3NO2 详情 详情
(V) 64198 6-(trifluoromethyl)-1H-indole-2,3-dione C9H4F3NO2 详情 详情
(VI) 39338 bromo(5-chloro-2-methoxyphenyl)magnesium C7H6BrClMgO 详情 详情
(VII) 39339 3-(5-chloro-2-methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one C16H11ClF3NO3 详情 详情
(VII) 64199 3-(5-chloro-2-methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one C16H11ClF3NO3 详情 详情
(VIII) 43889 3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one C16H10ClF4NO2 详情 详情
(VIII) 64200 3-(5-Chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-2,3-dihydro-1H-indol-2-one C16H10ClF4NO2 详情 详情

合成路线19

该中间体在本合成路线中的序号：(B)

The condensation of 6-acetyl-7-hydroxy-1,2,3,4-tetrahydronaphthalene (I) with allyl bromide (A) by means of K2CO3 in DMF gives 6-acetyl-7-allyloxy-1,2,3,4-tetrahydronaphthalene (II), which is isomerized to 5-allyl-7-acetyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene (III) by heating at 200 C. Hydrogenation of (III) with H2 over Pd/C in ethanol affords 5-propyl-7-acetyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene (IV), which is then cyclized with diethyl oxalate (B) by means of sodium ethoxide in refluxing etha-nol to yield ethyl 10-propyl-4-oxo-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxylate (V) [an alternative way to prepare (V) is the cyclization of (III) with diethyl oxalate (B) by means of sodium ethoxide to give ethyl 10-allyl-4-oxo-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxylate (VI), which is then reduced to (V) with H2 over Pd/C in ethanol]. The nitration of (V) with nitric acid in sulfuric acid gives ethyl 10-propyl-4-oxo-5-nitro-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxylate (VII), which is reduced with H2 over Pd/C in ethanol-acetic acid to afford the corresponding amino derivative (VIII). Finally, this compound is diazotated with NaNO2 and H2SO4 and then treated with 50% H2SO4 at 120 C.

参考文献 中间体
合成目标
【1】 Brown, R.C.; et al.; DE 2553688 .
【2】 BE 0836121 .
【3】 Castañer, J.; Blancafort, P.; Hillier, K.; Serradell, M.N.; Proxicromil. Drugs Fut 1979, 4, 12, 889.
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) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(B) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(I) 39625 1-(3-hydroxy-5,6,7,8-tetrahydro-2-naphthalenyl)-1-ethanone C12H14O2 详情 详情
(II) 39626 1-[3-(allyloxy)-5,6,7,8-tetrahydro-2-naphthalenyl]-1-ethanone C15H18O2 详情 详情
(III) 39627 1-(4-allyl-3-hydroxy-5,6,7,8-tetrahydro-2-naphthalenyl)-1-ethanone C15H18O2 详情 详情
(IV) 39628 1-(3-hydroxy-4-propyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-ethanone C15H20O2 详情 详情
(V) 39629 ethyl 4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-benzo[g]chromene-2-carboxylate C19H22O4 详情 详情
(VI) 39630 ethyl 10-allyl-4-oxo-6,7,8,9-tetrahydro-4H-benzo[g]chromene-2-carboxylate C19H20O4 详情 详情
(VII) 39631 ethyl 5-nitro-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-benzo[g]chromene-2-carboxylate C19H21NO6 详情 详情
(VIII) 39632 ethyl 5-amino-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-benzo[g]chromene-2-carboxylate C19H23NO4 详情 详情

合成路线20

该中间体在本合成路线中的序号：(II)

The condensation of 4,5-dichloro-1,2-phenylenediamine (I) with diethyl oxalate (II) produced quinoxalinedione (III), which was brominated with PBr5 at 155 C to afford the dibromo derivative (IV). Displacement of one bromine group of (IV) with 4-(diethylamino)butylamine (V) furnished (VI). The remaining bromine of (VI) was then displaced with 5-(tributylstannyl)-2,2'-bithienyl (VII) to produce the title compound, isolated as the corresponding hydrochloride salt.

参考文献 中间体
合成目标
【1】 Li, J.J.; Yue, W.-S.; Trivedi, B.K.; et al.; Structure-activity relationship of 2-amino-3-heteroaryl-quinoxalines as potent, non-peptide interleukine-8-receptor antagonists. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 144.
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) 18003 4,5-dichloro-1,2-benzenediamine; 4,5-Dichloro-o-phenylenediamine; 2-amino-4,5-dichlorophenylamine 5348-42-5 C6H6Cl2N2 详情 详情
(II) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(III) 18007 6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione 25983-13-5 C8H4Cl2N2O2 详情 详情
(IV) 44243 2,3-dibromo-6,7-dichloroquinoxaline C8H2Br2Cl2N2 详情 详情
(V) 44244 N-(4-aminobutyl)-N,N-diethylamine; N(1),N(1)-diethyl-1,4-butanediamine C8H20N2 详情 详情
(VI) 44245 N-(3-bromo-6,7-dichloro-2-quinoxalinyl)-N-[4-(diethylamino)butyl]amine; N(1)-(3-bromo-6,7-dichloro-2-quinoxalinyl)-N(4),N(4)-diethyl-1,4-butanediamine C16H21BrCl2N4 详情 详情
(VII) 44246 　 C20H32S2Sn 详情 详情

合成路线21

该中间体在本合成路线中的序号：(I)

The cyclization of diethyl oxalate (I) with N-ethylethylenediamine (II) in ethanol gives ethyl-2,3-dioxopiperazine (III), which by reaction first with trimethylsilyl chloride and triethytamine and then with phosgene in THF is converted into 4-ethyl-2,3-dioxopiperazine-1-carboxylic acid chloride (IV). Finally, this compound is condensed with 6-D-(-)-alpha-aminophenylacetamidopenicillanic acid (V) by means of triethylamine in THF - water.

参考文献 中间体
合成目标
【1】 Saikawa, I.; et al.; Penicillins and cephalosporins and process for producing the same. DE 2519400; FR 2269937; FR 2320295; GB 1508062 .
【2】 Loren, J.G.; Castañer, J.; Piperacillin. Drugs Fut 1978, 3, 11, 829.
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) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(II) 39928 N(1)-ethyl-1,2-ethanediamine; N-(2-aminoethyl)-N-ethylamine 110-72-5 C4H12N2 详情 详情
(III) 39929 1-ethyl-2,3-piperazinedione 59702-31-7 C6H10N2O2 详情 详情
(IV) 24305 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride 59703-00-3 C7H9ClN2O3 详情 详情
(V) 31107 (2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 69-53-4 C16H19N3O4S 详情 详情

合成路线22

该中间体在本合成路线中的序号：(B)

Reduction of 3-(4-fluorobenzoyl)propionic acid (I) by means of AlCl3 in CH2Cl2 and borane/tert-butylamine complex yields alcohol (II), which is then converted into aldehyde (IV) by reaction with 4-hydroxybenzaldehyde (III) in presence of PPh3 in THF and diethyl azodicarboxylate. Treatment of (IV) with a solution of methyltriphenylphosphonium bromide in THF and a solution of n-BuLi in hexane affords styrene derivative (V), which couples with 2’-hydroxy-3’-iodoacetophenone (VI) in presence of Et3N and Pd(OAc)2 in CH3CN to provide (VII). Cyclization of (VII) by means of a first treatment with NaOEt in EtOH followed by reaction with diethyl oxalate in Et2O/EtOH yields benzopyrane derivative (VIII) which is then hydrolyzed with NaOH in THF/MeOH to give (IX). Carboxylic acid (IX) is first converted into carboxamide (X) by treatment with a saturated NH3 solution in MeOH and then into carbonitrile (XI) by means of POCl3 in DMF. Finally, treatment of (XI) with a solution of NaN3, NH4Cl and DMF leads to the formation of the desired product.

参考文献 中间体
合成目标
【1】 Carganico, G.; Mauleon Casellas, D.; Pascual Avellana, J.; Garcia Perez, M.L.; Palomer Benet, A. (Menarini Industrie Farma Riunite srl); Benzopyran derivs. having leukotriene-antagonistic action. EP 0888327; ES 2127106; JP 2000506878; US 5990142; WO 9734885 .
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) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(A) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(I) 39863 4-(4-fluorophenyl)-4-oxobutyric acid 366-77-8 C10H9FO3 详情 详情
(II) 41474 4-(4-fluorophenyl)-1-butanol C10H13FO 详情 详情
(III) 13433 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde 123-08-0 C7H6O2 详情 详情
(IV) 41475 4-[4-(4-fluorophenyl)butoxy]benzaldehyde C17H17FO2 详情 详情
(V) 41476 1-fluoro-4-[4-(4-vinylphenoxy)butyl]benzene; 4-(4-fluorophenyl)butyl 4-vinylphenyl ether C18H19FO 详情 详情
(VI) 27290 1-(2-hydroxy-3-iodophenyl)-1-ethanone C8H7IO2 详情 详情
(VII) 41477 1-[3-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-2-hydroxyphenyl]-1-ethanone C26H25FO3 详情 详情
(VIII) 41478 ethyl 8-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-4-oxo-4H-chromene-2-carboxylate C30H27FO5 详情 详情
(IX) 41479 8-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-4-oxo-4H-chromene-2-carboxylic acid C28H23FO5 详情 详情
(X) 41480 8-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-4-oxo-4H-chromene-2-carboxamide C28H24FNO4 详情 详情
(XI) 41481 8-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-4-oxo-4H-chromene-2-carbonitrile C28H22FNO3 详情 详情

合成路线23

该中间体在本合成路线中的序号：(II)

The condensation of 4,5-dichloro-1,2-phenylenediamine (I) with diethyl oxalate (II) produced quinoxalinedione (III), which was brominated with PBr5 at 155 C to afford the dibromo derivative (IV). Displacement of one bromine group of (IV) with 4-(diethylamino)butylamine (V) furnished (VI). The remaining bromine of (VI) was then displaced with 2-(tributylstannyl)benzofuran (VII) to produce the title compound.

参考文献 中间体
合成目标
【1】 Li, J.J.; Yue, W.-S.; Trivedi, B.K.; et al.; Structure-activity relationship of 2-amino-3-heteroaryl-quinoxalines as potent, non-peptide interleukine-8-receptor antagonists. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 144.
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) 18003 4,5-dichloro-1,2-benzenediamine; 4,5-Dichloro-o-phenylenediamine; 2-amino-4,5-dichlorophenylamine 5348-42-5 C6H6Cl2N2 详情 详情
(II) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(III) 18007 6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione 25983-13-5 C8H4Cl2N2O2 详情 详情
(IV) 44243 2,3-dibromo-6,7-dichloroquinoxaline C8H2Br2Cl2N2 详情 详情
(V) 44244 N-(4-aminobutyl)-N,N-diethylamine; N(1),N(1)-diethyl-1,4-butanediamine C8H20N2 详情 详情
(VI) 44245 N-(3-bromo-6,7-dichloro-2-quinoxalinyl)-N-[4-(diethylamino)butyl]amine; N(1)-(3-bromo-6,7-dichloro-2-quinoxalinyl)-N(4),N(4)-diethyl-1,4-butanediamine C16H21BrCl2N4 详情 详情
(VII) 44247 1-benzofuran-2-yl(tributyl)stannane C20H32OSn 详情 详情

合成路线24

该中间体在本合成路线中的序号：(X)

Claisen condensation between diethyl oxalate (X) and 2-butanone (XI) leads to the diketo ester (XII), which is subsequently cyclized with hydrazine hydrate to furnish the pyrazolecarboxylate (XIII). After alkaline hydrolysis of ester (XIII), the resultant pyrazolecarboxylic acid (XIV) is nitrated by fuming HNO3 in hot H2SO4 to provide (XV). Chlorination of acid (XV) with SOCl2, followed by treatment with ammonia in THF yields the pyrazolecarboxamide (XVI). The alkylation of pyrazole (XVI) with iodomethane and Cs2CO3 leads to a mixture of N-methylated regioisomers (XVII) and (XVIII), which are separated by crystallization, followed by column chromatography. The desired isomer (XVII) is further reduced by catalytic hydrogenation to the aminopyrazole (XIX)

参考文献 中间体
合成目标
【1】 Street, S.D.A.; Wood, A.; Bunnage, M.E.; Mathias, J.P. (Pfizer Inc.; Pfizer Ltd.); Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction. WO 9954333 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(XI) 33891 Methyl ethyl ketone; 2-Butanone 78-93-3 C4H8O 详情 详情
(XII) 62099 ethyl 2,4-dioxohexanoate C8H12O4 详情 详情
(XIII) 62100 ethyl 3-ethyl-1H-pyrazole-5-carboxylate C8H12N2O2 详情 详情
(XIV) 62101 3-ethyl-1H-pyrazole-5-carboxylic acid C6H8N2O2 详情 详情
(XV) 62102 3-ethyl-4-nitro-1H-pyrazole-5-carboxylic acid C6H7N3O4 详情 详情
(XVI) 62103 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide C6H8N4O3 详情 详情
(XVII) 62105 5-ethyl-1-methyl-4-nitro-1H-pyrazole-3-carboxamide C7H10N4O3 详情 详情
(XVIII) 62104 3-ethyl-1-methyl-4-nitro-1H-pyrazole-5-carboxamide C7H10N4O3 详情 详情
(XIX) 62106 4-amino-5-ethyl-1-methyl-1H-pyrazole-3-carboxamide C7H12N4O 详情 详情

合成路线25

该中间体在本合成路线中的序号：(II)

2-Bromopyridine (I) is metalated by means of butyllithium and subsequently condensed with diethyl oxalate (II) to produce the keto ester adduct (III). Reaction of (III) with hot diethylaminosulfur trifluoride gives rise to the difluoro ester (IV), which is further reduced to alcohol (V) employing NaBH4 in EtOH. Treatment of (V) with triflic anhydride and 2,6-di-t-butyl-4-methylpyridine in CH2Cl2 yields the corresponding triflate (VI), which is then converted into azide (VII) by reaction with NaN3 in DMF. The pyridine ring of (VII) is oxidized by means of m-chloroperbenzoic acid to produce the N-oxide (VIII). Then, azido group reduction with PPh3 in moist THF leads to the primary amine (IX)

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
(I) 29052 2-Bromopyridine；α-bromopyridine;α-bromoazine 109-04-6 C5H4BrN 详情 详情
(II) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(III) 29952 ethyl 2-oxo-2-(2-pyridinyl)acetate C9H9NO3 详情 详情
(IV) 63213 ethyl 2,2-difluoro-2-(2-pyridinyl)acetate C9H9F2NO2 详情 详情
(V) 63214 2,2-difluoro-2-(2-pyridinyl)-1-ethanol C7H7F2NO 详情 详情
(VI) 63215 2,2-difluoro-2-(2-pyridinyl)ethyl trifluoromethanesulfonate C8H6F5NO3S 详情 详情
(VII) 63216 2,2-difluoro-2-(2-pyridinyl)ethyl azide; 2-(2-azido-1,1-difluoroethyl)pyridine C7H6F2N4 详情 详情
(VIII) 63217 2-(2-azido-1,1-difluoroethyl)-1-pyridiniumolate C7H6F2N4O 详情 详情
(IX) 63218 2-(2-amino-1,1-difluoroethyl)-1-pyridiniumolate C7H8F2N2O 详情 详情

合成路线26

该中间体在本合成路线中的序号：(IV)

Treatment of 2-fluorobenzyl bromide (I) with hydrazine hydrate in refluxing EtOH gives 2-fluorobenzyl hydrazine (II) (1), which by cyclocondensation with the sodium salt of ethyl cyanopyruvate (III) — prepared by reaction of diethyl oxalate (IV) with acetonitrile mediated by NaOEt (2) — by means of TFA in refluxing dioxane yields the 5-aminopyrazole derivative (V). Condensation of intermediate (V) with 3-dimethylaminoacrolein (VI) in the presence of TFA in refluxing dioxane provides the pyrazolo[3,4-b]pyridine derivative (VII), which is amidated with methanolic ammonia, affording amide (VIII). Treatment of amide (VIII) with pyridine and trifluoroacetic anhydride in THF followed by methanolysis of the resulting nitrile (IX) by means of NaOMe in MeOH generates the methyl imidoate (X), which, without isolation, undergoes amination with NH4Cl in the presence of glacial acetic acid in refluxing MeOH to give the carboxamidine (XI). Coupling of amidine (XI) with phenylazomalononitrile (XII) by means of NaOMe in DMF at 110 °C affords diamine (XIII), which upon reduction with H2 over Raney-Ni in H2O/DMF at 62 °C provides triamine (XIV). Acylation of amine (XIV) with methyl chloroformate (XV) in pyridine affords carbamate (XVI), which is finally N-methylated by means of MeI and NaH in DMF (3) or LiHMDS in THF (4). Scheme 1.

参考文献 中间体
合成目标
【1】 Kelley, J.L., Davis, R.G., McLean, E.W., Glen, R.C., Soroko, F.E., Cooper, B.R. Synthesis and anticonvulsant activity of N-benzylpyrrolo[2,3-d]-, -pyrazolo[3,4-d]-, and -triazolo[4,5-d]pyrimidines: Imidazole ring-modified analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine. J Med Chem 1995, 38(19): 3884-8.
【2】 Von Borsche, W., Manteuffel, R. Substituted pyrazole derivatives condensed with six-membered heterocyclic rings. Justus Liebigs Ann Chem 1934, 512: 97.
【3】 Alonso-Alija, C., Bischoff, E., Muenter, K., Feurer, A., Stahl, E., Weigand, S., Stasch, J.-P. (Bayer Healthcare AG). Carbamate-substituted pyrazolopyridines. CA 2485143, DE 10220570, EP 1506193, JP 2005531553, US 2006052397, US 7173037, WO 2003095451.
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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) 38775 1-(bromomethyl)-2-fluorobenzene 446-48-0 C7H6BrF 详情 详情
(II) 50471 1-(2-fluorobenzyl)hydrazine 51859-98-4 C7H9FN2 详情 详情
(III) 52079 sodium (Z)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate 627076-29-3 C6H6NNaO3 详情 详情
(IV) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(V) 50472 ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate 256504-39-9 C13H14FN3O2 详情 详情
(VI) 11789 (E)-3-(Dimethylamino)-2-propenal 692-32-0 C5H9NO 详情 详情
(VII) 50473 ethyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate 256376-59-7 C16H14FN3O2 详情 详情
(VIII) 50474 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide 256376-62-2 C14H11FN4O 详情 详情
(IX) 50475 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile 256376-65-5 C14H9FN4 详情 详情
(X) 50476 methyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidoate 304874-06-4 C15H13FN4O 详情 详情
(XI) 50477 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide 256376-68-8 C14H12FN5 详情 详情
(XII) 63162 2-[(E)-2-phenyldiazenyl]malononitrile 6017-21-6 C9H6N4 详情 详情
(XIII) 63163 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4,6-pyrimidinediamine; 6-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4-pyrimidinylamine 428854-23-3 C23H18FN9 详情 详情
(XIV) 63164 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylamine; 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine 428854-24-4 C17H15FN8 详情 详情
(XV) 16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(XVI) 65980 Methyl (4,6-diamino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)carbamate 625115-52-8 C19H17FN8O2 详情 详情
Extended Information