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【结 构 式】

【分子编号】16829

【品名】Diethyl malonate

【CA登记号】105-53-3

【 分 子 式 】C7H12O4

【 分 子 量 】160.16988

【元素组成】C 52.49% H 7.55% O 39.96%
与该中间体有关的原料药合成路线共 55 条
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合成路线1

该中间体在本合成路线中的序号：(II)

The condensation of 2,4-dichloro-5-fluorobenzoyl chloride (I) with diethyl malonate (II) by means of magnesium ethoxide in ether gives diethyl 2,4-dichloro-5-fluorobenzoylmalonate (III), which is partially hydrolyzed and decarboxylated with p-toluenesulfonic acid water yielding ethyl 2,4-dichloro-5-fluorobenzoylacetate (IV). The condensation of (IV) with triethyl orthoformate (V) in refluxing acetic anhydride affords ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyacrylate (VI), which is treated with cyclopropylamine (VII) in ethanol to give ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-cyclopropylaminoacrylate (VIII). The cyclization of (VIII) with NaH in refluxing dioxane yields 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IX), which is finally condensed with piperazine (X) in hot DMSO.

参考文献 中间体
合成目标
【1】 Reddy, P.G.; Baskaran, S.; Microwave assisted amination of quinolone carboxylic acids: An expeditious synthesis of fluoroquinolone antibacterials. Tetrahedron Lett 2001, 42, 38, 6775.
【2】 Grohe, K.; Zeiler, H. J.; Metzger, K.G. (Bayer AG); 1-Cyclopropyl-6-fluoro-1,4-dihidro-4-oxo-7-piperazino-quinoline-3-carboxilic acids, process for their preparation and antibacterial agents containing them. EP 0078362; JP 4253963; JP 58074667 .
【3】 Serradell, M.N.; Castaner, J.; Ciprofloxacin. Drugs Fut 1984, 9, 3, 179.
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) 22093 2,4-dichloro-5-fluorobenzoyl chloride 86393-34-2 C7H2Cl3FO 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 22095 diethyl 2-(2,4-dichloro-5-fluorobenzoyl)malonate C14H13Cl2FO5 详情 详情
(IV) 22096 ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate C11H9Cl2FO3 详情 详情
(V) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(VI) 22098 ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate C14H13Cl2FO4 详情 详情
(VII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(VIII) 22100 ethyl (E)-3-(cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl)-2-propenoate C15H14Cl2FNO3 详情 详情
(IX) 30340 ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate 86483-54-7 C15H13ClFNO3 详情 详情
(X) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

This compound can be prepared in two different ways: 1) The reaction of 1,4-dichloro-2-butene (I) with diethyl malonate (II) by means of sodium ethoxide in refluxing ethanol gives 1,1-bis(ethoxycarbonyl)-2-vinylcyclopropane (III), which by reaction with ammonia gas in DMF at 120 C is converted into 3-carboxamido-5-vinyl-2-pyrrolidone (IV). Finally, this compound is treated with concentrated HCl in refluxing acetic acid. 2) The treatment of (IV) with sodium ethoxide in refluxing ethanol gives 3-carboxy-5-vinyl-2-pyrrolidone (V), which is decarboxylated by treatment with refluxing acetic acid to afford 5-vinyl-2-pyrrolidone (VI). The bromination of (VI) with Br2 in CCl4 yields 5-(1,2-dibromoethyl)-2-pyrrolidone (VII), which by treatment with Na in liquid NH3 in a pressure vessel at 25 C is converted into 4-aminohex-5-inoic acid (VIII). Finally, this compound is partially reduced with H2 over a suitable catalyst.

参考文献 中间体
合成目标
【1】 Gittos, M.W.; Leterre, G.J.; Process for making 4-aminohex-5-enoic acid. FR 2415630; GB 2013205; JP 54112860; US 4178463 .
【2】 Metcalf, B.W.; Jung, M.; Olefinic derivatives of amino acids. US 4039549 .
【3】 Metcalf, B.W.; Jung, M.; Olefinic derivatives of amino acids. CA 1077487; FR 2304329; GB 1472525; JP 76125320; US 3960927 .
【4】 Blancafort, P.; Paton, D.M.; Serradell, M.N.; Castaner, J.; RMI-71,754. Drugs Fut 1981, 6, 6, 363.
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) 32186 (E)-1,4-dichloro-2-butene 110-57-6 C4H6Cl2 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 32187 Diethyl 2-vinyl-1,1-cyclopropanedicarboxylate C11H16O4 详情 详情
(IV) 32188 2-Oxo-5-vinyl-3-pyrrolidinecarboxamide; 3-Carboxamido-5-vinyl-2-pyrrolidone 71107-19-2 C7H10N2O2 详情 详情
(V) 32189 2-oxo-5-vinyl-3-pyrrolidinecarboxylic acid C7H9NO3 详情 详情
(VI) 32190 5-Vinyl-2-pyrrolidinone C6H9NO 详情 详情
(VII) 32191 5-(1,2-dibromoethyl)-2-pyrrolidinone C6H9Br2NO 详情 详情
(VIII) 32192 4-amino-5-hexynoic acid C6H9NO2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(A)

Chlorination of 4-amino-3-trifluoromethylbenzoic acid (I) gives 4-amino-3-chloro-5-trifluoromethylbenzoic acid (II), which is transformed in two steps to 4'-amino-3'-chloro-5'-trifluoromethylacetophenone (IV) by means of its acid chloride (III) and diethyl malonate. UV-catalyzed bromination with bromine in glacial acetic acid at 60-65 C gives the corresponding alpha-bromoketone (V). Reaction of (V) with tert-butylamine in isopropanol at 20 C leads to 4'-amino-2-tert-butylamino-3'-chloro-5'-trifluoromethylacetophenone (VI), which, without isolation, is reduced with sodium borohydride to the base (VII) of the title compound. The latter is obtained by treatment of (VII) with hydrochloric acid in diethyl ether. The optical isomers of mabuterol have been separated via the diastereomeric esters obtained by treating the racemate with (-)-methoxvcarbonyl chloride.

参考文献 中间体
合成目标
【1】 Kruger, G.; Keck, J.; Noll, K.; Pieper, H.; Synthesis of futher amino-halogen substituted phenylaminoethanols. Arzneim-Forsch Drug Res 1984, 34, 11a, 1612.
【2】 Kruger, G.; Engelhardt, G.; Mabuterol Hydrochloride. Drugs Fut 1985, 10, 11, 913.
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) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(I) 29777 4-amino-3-(trifluoromethyl)benzoic acid C8H6F3NO2 详情 详情
(II) 29778 4-amino-3-chloro-5-(trifluoromethyl)benzoic acid C8H5ClF3NO2 详情 详情
(III) 29779 4-amino-3-chloro-5-(trifluoromethyl)benzoyl chloride C8H4Cl2F3NO 详情 详情
(IV) 29780 1-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-1-ethanone C9H7ClF3NO 详情 详情
(V) 29781 1-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-2-bromo-1-ethanone C9H6BrClF3NO 详情 详情
(VI) 29782 1-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-2-(tert-butylamino)-1-ethanone C13H16ClF3N2O 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

Alkylation of diethyl malonate (II) with 5-(4-chlorophenyl)pentyl bromide (I) gives diethyl 5-(4-chlorophenyl)pentyl malonate (III). Intermediate (III) is hydrolyzed to the monoester (IV), followed by condensation with paraformaldehyde in pyridine/piperidine to yield ethyl 7-(4-chlorophenyl)-2-methyleneheptanoate (V), which is oxidized with m-chloroperbenzoic acid. Alternatively, intermediate (IV) can be prepared by condensation of 4-chlorocinnamaldehyde (VI) with diethyl ethylidenemalonate (VII) to yield intermediate (VIII) and subsequent hydrogenation.

参考文献 中间体
合成目标
【1】 Eistetter, K.; Wolf, H.P.O.; Synthesis and hypoglycaemic activity of phenylalkyloxirane carboxylic acid derivatives. J Med Chem 1982, 25, 22, 109-113.
【2】 Eistetter, K.; Rapp, E. (Byk Gulden Lomberg Chemische Fabrik GmbH); Substd. oxiranecarboxylic acids, their use and medicaments containing them. US 4324796 .
【3】 Kohl, B.; Eistetter, K.; Amschler, H.; Ludwig, G.; Wolf, H.P.O. (Byk Gulden Lomberg Chemische Fabrik GmbH); Phenylalkyloxirane carboxylic acids, preparation and therapeutical use. EP 0071175 .
【4】 Wolf, H.P.O.; Eistetter, K.; POCA. Drugs Fut 1983, 8, 5, 428.
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) 36082 1-(5-bromopentyl)-4-chlorobenzene C11H14BrCl 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 36083 diethyl 2-[5-(4-chlorophenyl)pentyl]malonate C18H25ClO4 详情 详情
(IV) 36085 7-(4-chlorophenyl)-2-(ethoxycarbonyl)heptanoic acid C16H21ClO4 详情 详情
(V) 35086 1-benzyl 4-(tert-butyl) (2R,3S)-2-isobutyl-3-(3-[[(4-nitrophenoxy)carbonyl]oxy]propyl)butanedioate C29H37NO9 详情 详情
(VI) 36087 (E)-3-(4-chlorophenyl)-2-propenal C9H7ClO 详情 详情
(VII) 36088 (E)-2-(ethoxycarbonyl)-2-butenoic acid C7H10O4 详情 详情
(VIII) 36084 (2E,4E,6E)-7-(4-chlorophenyl)-2-(ethoxycarbonyl)-2,4,6-heptatrienoic acid C16H15ClO4 详情 详情

合成路线5

该中间体在本合成路线中的序号：(II)

1) Alkylation of diethyl malonate (II) with 1 6-dibromohexane (I) results in diethyl 6-bromohexylmaionate (III). Compound (II) is hydrolyzed to the monoester (IV), followed by condensation with paraformaldehyde in ethanol/piperidine/2-methylquinoline to yield ethyl 8-bromo-2-methyleneoctanoate (V), which is oxidized with permaleic acid to (VI). Subsequent reaction with 4-chlorophenolate produces etomoxir.

参考文献 中间体
合成目标
【1】 Eistetter, K.; Ludwig, G.; Rapp, E.; Wolf, H. (Byk Gulden Lomberg Chemische Fabrik GmbH); Phenoxyalkoxyalkyl- and phenoxyalkyl-substd. oxiranecarboxylic acids, their use and medicaments containing them. EP 0046590; US 4337267 .
【2】 Eistetter, K.; Wolf, H.P.O.; ETOMOXIR. Drugs Fut 1986, 11, 12, 1034.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
62997 4-chlorobenzenolate C6H4ClO 详情 详情
(I) 24786 1,6-dibromohexane 629-03-8 C6H12Br2 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 24864 diethyl 2-(6-bromohexyl)malonate C13H23BrO4 详情 详情
(IV) 24865 8-bromo-2-(ethoxycarbonyl)octanoic acid C11H19BrO4 详情 详情
(V) 24866 ethyl 2-(6-bromohexyl)acrylate C11H19BrO2 详情 详情
(VI) 24867 ethyl 2-(6-bromohexyl)-2-oxiranecarboxylate C11H19BrO3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

2) Alternatively, etomoxir can be prepared as follows: Alkylation of 4-chlorophenol with 1,6-dibromohexane (I) yields 1 bromo-6-(4-chlorophenoxy)hexane (VII). Diethyl malonate (II) is alkylated by (VII), yielding (VIII), followed by hydrolysis to the monoester (IX), which is condensed with para formaldehyde/pyridine/piperidine to give ethyl 8-(4-chlorophenoxy)-2-methyleneoctanoate (IX). Oxidation with m-chloroperbenzoic acid produces etomoxir.

参考文献 中间体
合成目标
【1】 Eistetter, K.; Ludwig, G.; Rapp, E.; Wolf, H. (Byk Gulden Lomberg Chemische Fabrik GmbH); Phenoxyalkoxyalkyl- and phenoxyalkyl-substd. oxiranecarboxylic acids, their use and medicaments containing them. EP 0046590; US 4337267 .
【2】 Eistetter, K.; Wolf, H.P.O.; ETOMOXIR. Drugs Fut 1986, 11, 12, 1034.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
35543 4-chlorophenol 106-48-9 C6H5ClO 详情 详情
(I) 24786 1,6-dibromohexane 629-03-8 C6H12Br2 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(VII) 24870 6-bromohexyl 4-chlorophenyl ether C12H16BrClO 详情 详情
(VIII) 24871 diethyl 2-[6-(4-chlorophenoxy)hexyl]malonate C19H27ClO5 详情 详情
(IX) 24872 8-(4-chlorophenoxy)-2-(ethoxycarbonyl)octanoic acid C17H23ClO5 详情 详情
(X) 24873 ethyl 2-[6-(4-chlorophenoxy)hexyl]acrylate C17H23ClO3 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 condensation of 3-bromo-5-isoxazolylcarbonyl chloride (I) with diethyl malonate (II) gives the corresponding malonyl derivative (III), which is submitted to a decarboxylative hydrolysis yielding 5-acetyl-3-bromoisoxazole (IV). Bromination of (IV) affords 5-(bromoacetyl)-3-bromoisoxazole (V), which is reduced to 2-bromo-1-(3-bromo-5-isoxazolyl)ethanol (VI). Title compound is obtained by reaction of (VI) with tert-butylamine directly or via oxirane (VII), which is obtained by reaction of (VI) with sodium hydride, and finally by reaction of (VII) with tert-butylamine.

参考文献 中间体
合成目标
【1】 Fantucci, M.; Sala, R.; Chiarino, D.; Frigeni, V.; Della Bella, D.; Carenzi, A.; New isoxazole derivatives with a potent and select. Farm Sci Ed 1986, 41, 6, 440.
【2】 Chiarino, D.; Della Bella, D. (Zambon Group SpA); 1-(3-Bromo-isoxazol-5-yl)-2-tert-butylaminoethanol. JP 1980108862; US 4276299 .
【3】 Castaner, J.; Prous, J.; Broxaterol. Drugs Fut 1987, 12, 2, 107.
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) 22864 3-bromo-5-isoxazolecarbonyl chloride C4HBrClNO2 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 22866 diethyl 2-[(3-bromo-5-isoxazolyl)carbonyl]malonate C11H12BrNO6 详情 详情
(IV) 22867 1-(3-bromo-5-isoxazolyl)-1-ethanone C5H4BrNO2 详情 详情
(V) 22868 2-bromo-1-(3-bromo-5-isoxazolyl)-1-ethanone C5H3Br2NO2 详情 详情
(VI) 22869 2-bromo-1-(3-bromo-5-isoxazolyl)-1-ethanol C5H5Br2NO2 详情 详情
(VII) 22870 3-bromo-5-(2-oxiranyl)isoxazole C5H4BrNO2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

This compound can be obtained by three related ways: 1) The condensation of 3-cyclopentyloxy-4-methoxybenzaldehyde (I) with diethyl malonate (II) by means of piperidine in refluxing acetic acid gives diethyl 3-cyclopentyloxy-4-methoxybenzylidenemalonate (III), which is treated with nitromethane and tetramethylguanidine (TMG) yielding diethyl 2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-nitroethyl]malonate (IV). The reductocyclization of (IV) with H2 over Raney Ni in hot methanol gives ethyl 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylat (V). Finally, this compound is hydrolyzed and decarboxylated. 2) The reaction of malonate (III) with KCN in ethanol at 60 C gives ethyl 3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)propionate (VI), which is reduced with H2 over PtO2 in acetic acid yielding ethyl 4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)butanoate (VII). Finally, this compound is hydrolyzed and cyclized. 3) The reaction of malonate (III) with KNC in refluxing ethanol gives 3-cyano-3-(3-cyclopentyloxy-4-methoxy)propanoic acid (VIII), which is reduced with H2 over PtO2 as before yielding 4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)butanoic acid (IX). Finally, this compound is cyclized.

参考文献 中间体
合成目标
【1】 Huth, A.; Schmiechen, R.; Kehr, W.; Palenschat, D.; Paschelke, G.; Wachtel, H. (Schering AG); 4-(Polyalkoxyphenyl)-2-pyrrolidones (II).. BE 846335; ES 451518; FR 2324299; GB 1563398; US 4153713 .
【2】 Crossland, J.; Prous, J.; Castaner, J.; ROLIPRAM < Rec INN; USAN >. Drugs Fut 1988, 13, 1, 38.
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) 16510 3-(cyclopentyloxy)-4-methoxybenzaldehyde C13H16O3 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 21586 diethyl 2-[3-(cyclopentyloxy)-4-methoxybenzylidene]malonate C20H26O6 详情 详情
(IV) 21587 diethyl 2-[1-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-nitroethyl]malonate C21H29NO8 详情 详情
(V) 21588 ethyl 4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxo-3-pyrrolidinecarboxylate C19H25NO5 详情 详情
(VI) 21589 ethyl 3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]propanoate C18H23NO4 详情 详情
(VII) 21590 ethyl 4-amino-3-[3-(cyclopentyloxy)-4-methoxyphenyl]butanoate C18H27NO4 详情 详情
(VIII) 21591 3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]propionic acid C16H19NO4 详情 详情
(IX) 21592 4-amino-3-[3-(cyclopentyloxy)-4-methoxyphenyl]butyric acid C16H23NO4 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

The condensation of cinnamic nitrile (I) with diethyl malonate (II) by means of K2CO3 and tetrabutylammonium bromide in refluxing acetone or NaOEt in refluxing ethyl acetate gives 2-[2-cyano-1-(4-fluorophenyl)ethyl]malonic acid diethyl ester (III), which is cyclized by reduction of its cyano group with H2 over PtO2 in ethanol/conc. HCl or over Ru/C in ethanol to yield (rac)-(trans)-4-(4-fluorophenyl)-2-oxopiperidine-3-carboxylic acid ethyl ester (IV). Finally, this compound is reduced with NaBH4 in THF to afford (rac)-(trans)-4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine (V), the target intermediate.

参考文献 中间体
合成目标
【1】 Dalmases Barjoan, P.; Carulla Oliver, J.M.; Moreno Manas, M.; Perez, M. (Laboratorios Vita, SA); Piperidinone deriv., process for obtaining it and process for using it. ES 2137131 .
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) 56466 (E)-3-(4-fluorophenyl)-2-propenenitrile C9H6FN 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 56467 1-ethyl 3-methyl 2-[2-cyano-1-(4-fluorophenyl)ethyl]malonate C15H16FNO4 详情 详情
(IV) 56468 ethyl (3S,4R)-4-(4-fluorophenyl)-2-oxo-3-piperidinecarboxylate C14H16FNO3 详情 详情
(V) 43487 [(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol; trans-(3S)-4-(4-fluorophenyl)-1-methyl-3-piperidine methanol 105812-81-5 C13H18FNO 详情 详情

合成路线10

该中间体在本合成路线中的序号：(II)

1) The condensation of 2,4-dichloro-5-fluoro-benzoyl chloride (I) with diethyl malonate (II) by means of magnesium ethoxide gives diethyl 2,4-dichloro-5-fluorobenzoylmalonate (III), which is partially decarboxylated with p-toluenesulfonic acid yielding ethyl 2,4-dichloro-5-fluorobenzoylacetate (IV). The condensation of (IV) with triethyl orthoformate (V) by means of refluxing acetic anhydride affords ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyacrylate (VI), which is treated with cyclopropylamine (VII) in ethanol giving ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(cyclopropylamino)acrylate (VII). The cyclization of (VII) by means of NaH in refluxing dioxane yields 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX), which is finally condensed with N-ethylpiperazine (X) by heating at 140 C in DMSO.

参考文献 中间体
合成目标
【1】 Grohe, K.; Klimetzek, V.; Metzger, K.G.; Stunkel, K.G.; Zeiler, H.-J. (Bayer AG); Immunostimulant agent. AU 8542762; DE 3420116; EP 0165474; ES 8607020; JP 1985258163; US 4659603 .
【2】 Grohe, K.; Petersen, U.; Kuck, K.-H. (Bayer AG); Antimicrobial agent of quinolone-carboxylic acid b. DE 3248507; US 4563459 .
【3】 Castaner, J.; Prous, J.; Enrofloxacin. Drugs Fut 1988, 13, 4, 305.
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) 22093 2,4-dichloro-5-fluorobenzoyl chloride 86393-34-2 C7H2Cl3FO 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 22095 diethyl 2-(2,4-dichloro-5-fluorobenzoyl)malonate C14H13Cl2FO5 详情 详情
(IV) 22096 ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate C11H9Cl2FO3 详情 详情
(V) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(VI) 22098 ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate C14H13Cl2FO4 详情 详情
(VII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(VIII) 22100 ethyl (E)-3-(cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl)-2-propenoate C15H14Cl2FNO3 详情 详情
(IX) 22101 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 86393-33-1 C13H9ClFNO3 详情 详情
(X) 14213 N-Ethylpiperazine; 1-Ethylpiperazine 5308-25-8 C6H14N2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(VIII)

The reduction of 2,3,4-trichloro-5-fluoronitrobenzene (I) with Fe - HCl in hot water gives 2,3,4-trichloro-5-fluoroaniline (II), which by diazotation with NaNO2 - HCl and reaction with sodium tetrafluoroborate and cuprous cyanide is converted to 2,3,4-trichloro-5-fluorobenzonitrile (III). The reaction of (III) with KF in DMSO at 140 C affords 3-chloro-2,4,5-trifluorobenzonitrile (IV), which by hydrolysis with 30% HBr in refluxing acetic acid gives 3-chloro-2,4,5-trifluorobenzamide (V). The hydrolysis of (V) with 18N H2SO4 at 135 C yields the corresponding benzoic acid (VI), which is treated with refluxing SOCl2 to afford the acyl chloride (VII). The condensation of (VII) with diethyl malonate (VIII) by means of Mg - ethanol in hot toluene gives diethyl 3-chloro-2,4,5-trifluorobenzoylmalonate (IX), which is partially decarboxylated with p-toluenesulfonic acid in refluxing water to give ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (X). The condensation of (X) with triethyl orthoformate (XI) in refluxing acetic anhydride yields ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate (XII), which is treated with cyclopropylamine (XIII) in ethanol to afford ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)acrylate (XIV). The cyclization of (XIV) by means of NaF in DMF at 150 C gives ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (XV), which is hydrolyzed with H2SO4 in refluxing water - acetic acid to the corresponding carboxylic acid (XVI). The condensation of (XVI) with 3-(tert-butoxycarbonylamino)pyrrolidine (XVII) by means of 1,8-diazabicyclo [5.4.0]undecane (DBU) in refluxing acetonitrile yields 7-[3-(tert-butoxycarbonylamino)-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XVIII), which is finally deprotected by a treatment with concentrated HCl in methanol.

参考文献 中间体
合成目标
【1】 Irikura, T.; Suzue, S.; Murayama, S.; Hirai, K.; Ishizaki, T. (Kyorin Pharmaceutical Co., Ltd.); 7-(1-Pyrrolidinyl)-3-quinolinecarboxylic acid derivs.. AU 8542829; AU 8654272; EP 0195316; EP 0195841; ES 8606330; ES 8704932; JP 1986205235; JP 1986205237; JP 1986205238; JP 1986205239; JP 1986205258; JP 1986205259 .
【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Saito, H.; Tomioka, H.; Sato, K.; Hirai, K.; Suzue, S.; AM-1091. Drugs Fut 1989, 14, 10, 931.
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) 21294 2,3,4-trichloro-1-fluoro-5-nitrobenzene C6HCl3FNO2 详情 详情
(II) 21295 2,3,4-trichloro-5-fluorophenylamine; 2,3,4-trichloro-5-fluoroaniline C6H3Cl3FN 详情 详情
(III) 21296 2,3,4-trichloro-5-fluorobenzonitrile C7HCl3FN 详情 详情
(IV) 21297 3-chloro-2,4,5-trifluorobenzonitrile C7HClF3N 详情 详情
(V) 21298 3-chloro-2,4,5-trifluorobenzamide C7H3ClF3NO 详情 详情
(VI) 11678 3-Chloro-2,4,5-trifluorobenzoic acid C7H2ClF3O2 详情 详情
(VII) 11679 3-Chloro-2,4,5-trifluorobenzoyl chloride C7HCl2F3O 详情 详情
(VIII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(IX) 21302 diethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)malonate C14H12ClF3O5 详情 详情
(X) 11681 ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate 101987-86-4 C11H8ClF3O3 详情 详情
(XI) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(XII) 11682 ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate C14H12ClF3O4 详情 详情
(XIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XIV) 11683 ethyl (E)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)-2-propenoate C15H13ClF3NO3 详情 详情
(XV) 21308 ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C15H12ClF2NO3 详情 详情
(XVI) 11684 8-Chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 101987-89-7 C13H8ClF2NO3 详情 详情
(XVII) 21310 tert-butyl 3-pyrrolidinylcarbamate 99724-19-3 C9H18N2O2 详情 详情
(XVIII) 21311 7-[3-[(tert-butoxycarbonyl)amino]-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C22H25ClFN3O5 详情 详情

合成路线12

该中间体在本合成路线中的序号：(VIII)

A new synthesis for KB-5246 has been described: The reaction of 2,3,4-trifluoroaniline (I) with carbon disulfide (II) and triethylamine gives the corresponding dithiocarbamate (III), which by cyclization with 1-acetoxy-3-chloro-2-propanone (IV) in ethyl acetate yields 4-(acetoxymethyl)-3-(2,3,4-trifluorophenyl)thiazole-2(3H)-thione (V). The cyclization of (V) with potassium hydroxide in refluxing ethanol-water affords 6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazine-1-thione (VI), which is treated with trichloromethyl chloroformate in hot toluene to give the thiazolium chloride (VII), which is not isolated. The in situ reaction of (VII) with diethyl malonate by means of triethylamine in toluene gives (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonic acid diethyl ester (IX), which is cyclized again with polyphosphoric acid (PPA) at 115 C to afford 7,8-difluoro-5-oxo-9,1-(epoxymethano)-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester (X). The hydrolysis of (X) with oleum gives the corresponding acid (XI), which is finally condensed with N-methylpiperazine (XII) in hot DMSO.

参考文献 中间体
合成目标
【1】 Kondo, H.; Tsukamoto, G.; Taguchi, M.; Jinbo, Y.; Kawahata, Y.; Sakamoto, F.; Inoue, Y.; Synthesis and antibacterial activity of new tetracyclic quinolone antibacterials. J Med Chem 1992, 35, 1, 94.
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) 13059 2,3,4-Trifluorophenylamine; 2,3,4-Trifluoroaniline 3862-73-5 C6H4F3N 详情 详情
(III) 13060 2,3,4-trifluorophenylcarbamodithioate C7H3F3NS2 详情 详情
(IV) 13061 2-(chlorooxy)-2-oxoethyl acetate C4H5ClO4 详情 详情
(V) 13062 [2-thioxo-3-(2,3,4-trifluorophenyl)-2,3-dihydro-1,3-thiazol-4-yl]methyl acetate C12H8F3NO2S2 详情 详情
(VI) 13063 6,7-Difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazine-1-thione C10H5F2NOS2 详情 详情
(VII) 13064 1-Chloro-6,7-difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazin-10-ium chloride C10H5Cl2F2NOS 详情 详情
(VIII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(IX) 13066 diethyl 2-(6,7-difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate C17H15F2NO5S 详情 详情
(X) 13067 ethyl 5,6-difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylate C15H9F2NO4S 详情 详情
(XI) 13068 5,6-Difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylic acid C13H5F2NO4S 详情 详情
(XII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(IV)

The reaction of 2,3,4-trifluoroaniline (I) with carbon disulfide and triethylamine gives triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (II), which by reaction with ethyl chlorocarbonate in chloroform yields the corresponding isothiocyanate (III). The condensation of (III) with diethyl malonate (IV) by means of NaH in THF affords the sodium salt of diethyl [(2,3,4-trifluoroanilino)(mercapto)methylene]malonate (V), which is condensed with 1-acetoxy-3-chloroacetone in DMF to give the substituted thioester (VII). The cyclization of (VII) by means of sulfuric acid yields the thiazoline derivative (VIII), which is cyclized again by means of NaH in refluxing dioxane to afford diethyl (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate (IX). A final, new cyclization of (IX) by means of ethyl polyphosphate (PPE) at 138 C, followed by hydrolysis of the intermediate ester with sulfuric acid gives 7,8-difluoro-9,1-epoxymethano-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid (X). This compound is then condensed with 1-methylpiperazine (XI) in hot DMSO and treated with aqueous HCl.

参考文献 中间体
合成目标
【1】 Taguchi, M.; Kondo, H.; Inoue, Y.; Kawahata, Y.; Tsukamoto, G. (Kanebo Pharmaceuticals, Ltd.); Quinolinecarboxylic acid derivs., a compsns. comprising the same, process for preparing the same, and the use of the same for the manufacture of medicaments. EP 0286089; JP 1989199979; US 4808584 .
【2】 Prous, J.; Castaner, J.; KB-5246. Drugs Fut 1989, 14, 6, 519.
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) 13059 2,3,4-Trifluorophenylamine; 2,3,4-Trifluoroaniline 3862-73-5 C6H4F3N 详情 详情
(II) 20905 N,N-dipropyl-1-propanaminium 2,3,4-trifluorophenylcarbamodithioate C16H25F3N2S2 详情 详情
(III) 20906 1,2,3-trifluoro-4-isothiocyanatobenzene; 2,3,4-trifluorophenyl isothiocyanate 119474-40-7 C7H2F3NS 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 20908 sodium 3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-(2,3,4-trifluoroanilino)-1-propene-1-thiolate C14H13F3NNaO4S 详情 详情
(VI) 20909 4-chloro-3-oxobutyl acetate C6H9ClO3 详情 详情
(VII) 20910 diethyl 2-[[[2-(acetoxy)acetyl]sulfanyl](2,3,4-trifluoroanilino)methylene]malonate C18H18F3NO7S 详情 详情
(VIII) 20911 diethyl 2-[4-(hydroxymethyl)-3-(2,3,4-trifluorophenyl)-1,3-thiazol-2(3H)-ylidene]malonate C17H16F3NO5S 详情 详情
(IX) 13066 diethyl 2-(6,7-difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate C17H15F2NO5S 详情 详情
(X) 13068 5,6-Difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylic acid C13H5F2NO4S 详情 详情
(XI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线14

该中间体在本合成路线中的序号：(I)

The cyclization of diethyl malonate (I) with cis-1,4-dichloro-2-butene (II) by means of LiH in DMF gives 3-cyclopentene-1,1-dicarboxylic acid diethyl ester (III), which is monodecarboxylated by hydrolysis with NaOH in ethanol, followed by heating at 170-180 C to yield 3-cyclopentene-1-carboxylic acid (IV). The reaction of (IV) with SOCl2 affords the acyl chloride (V), which by reaction with ethanol provides the ethyl ester (VI). The oxidation of (VI) with OsO4 and N-methylmorpholine N-oxide (NMMO) in acetone/water gives the dihydroxy compound (VII), which is further oxidized with NaIO4 in THF to yield the dialdehyde (VIII). The cyclization of (VIII) by means of glycine ethyl ester and acetonedicarboxylic acid affords the 9-azabicyclo[3,3,1]nonan-3-one derivative (IX), which is reduced with NaBH4 in ethanol to provide the corresponding alcohol (X). The protection of the OH group of (X) with dihydropyran and methanesulfonic acid gives the tetrahydropyranyl ether (XI), which is cyclized by means of tBuO-K in hot toluene, yielding the tricyclic ketone (XII). The deprotection of (XII) with 5N HCl affords the alcohol (XIII), which is finally esterified with 1H-indole-3-carbonyl chloride (XIV) by means of tetrafluoroboric acid and silver tetrafluoroborate in nitroethane. Alternatively, 1H-indole (XV) is condensed with oxalyl chloride (XVI) to give 3-indolylglyoxylyl chloride (XVII), which is used to acylate the alcohol (XIII) by means of tetrafluoroboric acid and silver tetrafluoroborate as before. Simultaneous decarbonylation takes place in this acylation reaction.

参考文献 中间体
合成目标
【1】 Gittos, M.W. (Merrell Pharmaceuticals, Inc.); Esters of hexahydro-8-hydroxy-2, 6-methano-2H-quinolizin-3(4H)-one and related compds.. AU 8780596; EP 0266730; JP 1988258476 .
【2】 Gittos, M.W.; Fatmi, M.; Potent 5-HT3 antagonists incorporating a novel bridged pseudopelletierine ring system. Actual Chim Ther 1989, 16, 187.
【3】 Gittos, M.W.; Fatmi, M.; Galvan, M.; Dolasetron Mesylate. Drugs Fut 1993, 18, 6, 506.
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) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(II) 50004 cis-1,4-Dichloro-2-butene;(Z)-1,4-Dichlorobutene;(Z)-1,4-Dichloro-2-butene;(2Z)-1,4-Dichloro-2-butene;cis-1,2-Bis(chloromethyl)ethene 1476-11-5 C4H6Cl2 详情 详情
(III) 50000 diethyl 3-cyclopentene-1,1-dicarboxylate C11H16O4 详情 详情
(IV) 50001 3-cyclopentene-1-carboxylic acid C6H8O2 详情 详情
(V) 50002 3-Cyclopentenecarboxylic acid 7686-77-3 C6H7ClO 详情 详情
(VI) 13469 ethyl 3-cyclopentene-1-carboxylate C8H12O2 详情 详情
(VII) 13470 ethyl 3,4-dihydroxycyclopentanecarboxylate C8H14O4 详情 详情
(VIII) 13471 ethyl 4-oxo-2-(2-oxoethyl)butanoate C8H12O4 详情 详情
(IX) 13472 ethyl 9-(2-ethoxy-2-oxoethyl)-7-oxo-9-azabicyclo[3.3.1]nonane-3-carboxylate C15H23NO5 详情 详情
(X) 13473 ethyl 9-(2-ethoxy-2-oxoethyl)-7-hydroxy-9-azabicyclo[3.3.1]nonane-3-carboxylate C15H25NO5 详情 详情
(XI) 13474 ethyl 9-(2-ethoxy-2-oxoethyl)-7-(tetrahydro-2H-pyran-2-yloxy)-9-azabicyclo[3.3.1]nonane-3-carboxylate C20H33NO6 详情 详情
(XII) 50003 5-(tetrahydro-2H-pyran-2-yloxy)-8-azatricyclo[5.3.1.0(3,8)]undecan-10-one C15H23NO3 详情 详情
(XIII) 13475 5-Hydroxy-8-azatricyclo[5.3.1.0(3,8)]undecan-10-one C10H15NO2 详情 详情
(XIV) 17153 1H-indole-3-carbonyl chloride C9H6ClNO 详情 详情
(XV) 15292 Indole; 1H-indole 120-72-9 C8H7N 详情 详情
(XVI) 29841 Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride 79-37-8 C2Cl2O2 详情 详情
(XVII) 13476 Indole-3-glyoxylyl chloride; 2-(1H-Indol-3-yl)-2-oxoacetyl chloride 22980-09-2 C10H6ClNO2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(XI)

Alternatively, the condensation of dimethyl malonate (VI) with benzaldehyde (VII) by means of piperidine in refluxing toluene gives dimethyl benzylidenemalonate (VIII), which is reduced with H2 over Pd/C in toluene to yield the corresponding benzyl derivative (IX). The hydrolysis of (IX) with NaOH in water affords the benzylmalonic acid (X). Alternatively, intermediate (X) can also be obtained starting from diethyl malonate (XI), which is condensed with with benzaldehyde (VII) by means of piperidine in refluxing toluene to give diethyl benzylidenemalonate (XII). Reduction of (XII) with H2 over Pd/C in toluene yields the corresponding benzyl derivative (XIII), which is then hydrolized with NaOH in water. The monodecarboxylation of (X) and its condensation with paraformaldehyde and diethylamine in refluxing ethyl acetate provides 2-benzylacrylic acid (XIV), which is condensed with thioacetic acid (V) by heating at 70 C to afford 2-(acetylsulfanylmethyl)-3-phenylpropionic acid (XV). Finally, this compound is condensed with N-tosylglycine benzyl ester (XVI) by means of HOBt, DCC and TEA in THF.

参考文献 中间体
合成目标
【1】 Roques, B.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs. and their therapeutic application. EP 0038758 .
【2】 Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 12893 Ethanethioic S-acid C2H4OS 详情 详情
(VI) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(VII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VIII) 49460 Dimethyl benzylidenemalonate C12H12O4 详情 详情
(IX) 49461 dimethyl 2-benzylmalonate C12H14O4 详情 详情
(X) 37280 2-benzylmalonic acid 616-75-1 C10H10O4 详情 详情
(XI) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XII) 37482 diethyl 2-benzylidenemalonate 5292-53-5 C14H16O4 详情 详情
(XIII) 20208 diethyl 2-benzylmalonate 607-81-8 C14H18O4 详情 详情
(XIV) 37279 2-benzylacrylic acid C10H10O2 详情 详情
(XV) 55230 3-(acetylsulfanyl)-2-benzylpropanoic acid C12H14O3S 详情 详情
(XVI) 55228 N-p-Tosylglycine benzyl ester C16H17NO4S 详情 详情

合成路线16

该中间体在本合成路线中的序号：(IV)

The reduction of 4-bromophenylacetic acid (I) with boron hydride gives 2-(4-bromophenyl)ethanol (II), which is mesylated with methanesulfonyl chloride to the sulfonate (III). The condensation of (III) with diethyl malonate (IV) by means of NaH yields 2-[2-(4-bromophenyl)ethyl]malonic acid diethyl ester (V), which is reduced with LiAlH4 to the diol (VI). The enantioselective transesterification of (VI) with methyl acetate by means of porcine pancreatic lipase (PPL, Sigma type II, no. 3126) affords the (R)-enantiomer of monoester (VII), which is treated with tert-butyldimethylsilyl chloride in dichloromethane, giving the (S)-enantiomer of the silylated acetoxy derivative (VIII). The hydrolysis of (VIII) with methanolic NaOH yields the silylated alcohol (IX), which is mesylated with methanesulfonyl chloride as before affording the sulfonate (X). The reaction of (X) with sodium azide in hot DMF gives 1-azido-4-(4-bromophenyl)-2(S)-(tert-butyldimethylsilyloxymethyl)butane (XIII), which is deprotected with acetic acid in THF yielding 2(S)-(azidomethyl)-4-(4-bromophenyl)butanol (XII). Mesylation of (XII) as before affords sulfonate (XIII), which is condensed with diethyl malonate (IV) by means of NaH as before, giving the chiral malonate derivative (XIV). The cyclization of (XIV) by means of tributyl phosphine in THF yields (3RS,5R)-5-[2-(4-bromophenyl)ethyl]-2-oxopiperidine-3-carboxylic acid ethyl ester (XV), which is treated with trimethyloxonium tetrafluoroborate in CHCl3 to afford the methoxy derivative (XVI). Cyclization of (XVI) with guanidine hydrochloride (XXII) by means of sodium ethoxide in hot ethanol gives 2-amino-6(R)-[2-(4-bromophenyl)ethyl]-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (XVII), which is treated with copper cyanide in refluxing 1-methyl-2-pyrrolidone, yielding the nitrile (XVIII). Hydrolysis of (XVIII) with refluxing 6N HCl affords the corresponding benzoic acid (XIX), which is condensed with L-glutamic acid diethyl ester (XX) by means of N-methylmorpholine and 2-chloro-4,6-dimethoxy-1,3,5-triazine in DMF, affording the diethyl ester of the desired product (XXI). Finally, this compound is hydrolyzed with 1N NaOH.

参考文献 中间体
合成目标
【1】 Barnett, C.J.; Wilson, T.M. (Eli Lilly and Company); Enantioselective synthesis of antifolates. EP 0417212 .
【2】 Barnett, C.J.; Wilson, T.M.; Asymmetric synthesis and absolute configuration of 5,10-dideaza-5,6,7,8-tetrahydropteroic acid and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). Tetrahedron Lett 1989, 30, 46, 6291.
【3】 Castaner, J.; Prous, J.; Lometrexol. Drugs Fut 1993, 18, 2, 121.
【4】 Wilson, T.M.; Barnett, C.J.; Asymmetric synthesis and absolute configuration of 5,10-dideaza-5,6,7,8-tetrahydropteroic acid and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). Chemistry and Biology of Pteridines (1989): Pteridines and Folic Acid Derivatives. H.-C. Curtius, S. Ghisla and N. Blau (Eds.). de Gruyter, New York 1990, 102.
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) 14247 2-(4-Bromophenyl)acetic acid; p-Bromophenylacetic acid; 4-Bromophenylacetic acid 1878-68-8 C8H7BrO2 详情 详情
(II) 14248 2-(4-Bromophenyl)-1-ethanol; 4-Bromophenethyl alcohol；2-(4-bromophenyl)ethanol；2-(4-Bromophenyl)ethan-1-ol 4654-39-1 C8H9BrO 详情 详情
(III) 14249 4-Bromophenethyl methanesulfonate C9H11BrO3S 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 14251 diethyl 2-(4-bromophenethyl)malonate C15H19BrO4 详情 详情
(VI) 14252 2-(4-Bromophenethyl)-1,3-propanediol C11H15BrO2 详情 详情
(VII) 14253 (2R)-4-(4-bromophenyl)-2-(hydroxymethyl)butyl acetate C13H17BrO3 详情 详情
(VIII) 14254 (2S)-4-(4-bromophenyl)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)butyl acetate C19H31BrO3Si 详情 详情
(IX) 14255 (2S)-4-(4-Bromophenyl)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-butanol C17H29BrO2Si 详情 详情
(X) 14256 (2R)-4-(4-bromophenyl)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)butyl methanesulfonate C18H31BrO4SSi 详情 详情
(XI) 14257 [[(2S)-2-(Azidomethyl)-4-(4-bromophenyl)butyl]oxy](tert-butyl)dimethylsilane; (2S)-2-(Azidomethyl)-4-(4-bromophenyl)butyl tert-butyl(dimethyl)silyl ether C17H28BrN3OSi 详情 详情
(XII) 14258 (2S)-2-(Azidomethyl)-4-(4-bromophenyl)-1-butanol C11H14BrN3O 详情 详情
(XIII) 14259 (2S)-2-(azidomethyl)-4-(4-bromophenyl)butyl methanesulfonate C12H16BrN3O3S 详情 详情
(XIV) 14260 diethyl 2-[(2R)-2-(azidomethyl)-4-(4-bromophenyl)butyl]malonate C18H24BrN3O4 详情 详情
(XV) 14261 ethyl (5R)-5-(4-bromophenethyl)-2-oxohexahydro-3-pyridinecarboxylate C16H20BrNO3 详情 详情
(XVI) 14268 ethyl (5R)-5-(4-bromophenethyl)-2-methoxy-3,4,5,6-tetrahydro-3-pyridinecarboxylate C17H22BrNO3 详情 详情
(XVII) 14263 (6R)-2-Amino-6-(4-bromophenethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one C15H17BrN4O 详情 详情
(XVIII) 14264 4-[2-[(6R)-2-Amino-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzonitrile C16H17N5O 详情 详情
(XIX) 14265 4-[2-[(6R)-2-Amino-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoic acid C16H18N4O3 详情 详情
(XX) 11013 diethyl (2S)-2-aminopentanedioate C9H17NO4 详情 详情
(XXI) 14267 diethyl (2S)-2-[(4-[2-[(6R)-2-amino-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl)amino]pentanedioate C25H33N5O6 详情 详情
(XXII) 14262 Guanidine hydrochloride 50-01-1 CH5N3.HCl 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

Condensation of piperonyl chloride (I) with diethyl malonate (II) by means of Na in anhydrous refluxing EtOH (NaOEt) provides 2-[3,4-(methylenedioxy)benzyl]malonic acid diethyl ester (III), which is converted into the monoethyl ester (IV) by saponification with KOH in EtOH. Treatment of (IV) with diethylamine in paraformaldehyde/H2O affords acrylic ester (V), which is then subjected to saponification with NaOH in acetone/H2O to provide [3,4-(methylenedioxy)benzyl]-2-propenoic acid (VI). Alternatively, derivative (VI) can also be obtained by following this route: treatment of piperonal (VII) with diethyl malonate (II) in refluxing toluene in the presence of piperidine and acetic acid provides diethyl piperonylidene malonate (VIII), which is then hydrogenated over Pd/C to furnish diethyl piperonylmalonate (IX). Saponification of the ethyl ester moiety of (IX) by refluxing with NaOH in H2O affords piperonylmalonic acid (X), which is finally converted into intermediate (VI) by decarboxylation by treatment with diethylamine in refluxing paraformaldehyde. Reaction of (VI) with thioacetic acid at 70 C affords a racemic mixture of propionic acid derivatives (XI), which is resolved by first formation of a chiral salt (either by reaction with (R)-alpha-methylbenzylamine or by reaction with (+)-ephedrine in ether), recrystallization of the corresponding diastereomer and finally liberation of the 2-(S)-(acetylthiomethyl)-3-[3,4-(methylenedioxy)benzyl]propionic acid [(S)-(XII)] by hydrolysis with HCl in H2O/CH2Cl2. Finally, fasidotril is obtained by condensation of (S)-(XII) with benzyl alaninate (XIII) by means of HOBt and DCC in THF/CHCl3 in the presence of Et3N.

参考文献 中间体
合成目标
【1】 Plaquevent, J.-C.; Danvy, D.; Monteil, T.; Greciet, H.; Duhamel, L.; Duhamel, P.; Gros, C.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs., method for their preparation and their therapeutic application. EP 0419327; FR 2652087; WO 9104246 .
【2】 Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 .
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),(IX) 49496 diethyl 2-(1,3-benzodioxol-5-ylmethyl)malonate C15H18O6 详情 详情
(S)-(XII) 49501 (2S)-3-(acetylsulfanyl)-2-(1,3-benzodioxol-5-ylmethyl)propionic acid C13H14O5S 详情 详情
(I) 28617 5-(chloromethyl)-1,3-benzodioxole C8H7ClO2 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(IV) 49497 2-(1,3-benzodioxol-5-ylmethyl)-3-ethoxy-3-oxopropionic acid C13H14O6 详情 详情
(V) 38469 ethyl (E)-3-(1,3-benzodioxol-5-yl)-2-propenoate C12H12O4 详情 详情
(VI) 11634 (E)-3-(1,3-Benzodioxol-5-yl)-2-propenoic acid; 3,4-(Methylenedioxy)cinnamic acid 2373-80-0 C10H8O4 详情 详情
(VII) 10127 1,3-Benzodioxole-5-carbaldehyde; Heliotropine 120-57-0 C8H6O3 详情 详情
(VIII) 49499 diethyl 2-(1,3-benzodioxol-5-ylmethylene)malonate C15H16O6 详情 详情
(X) 49500 2-(1,3-benzodioxol-5-ylmethyl)malonic acid C11H10O6 详情 详情
(XI) 49498 3-(acetylsulfanyl)-2-(1,3-benzodioxol-5-ylmethyl)propionic acid C13H14O5S 详情 详情
(XIII) 10143 benzyl (2S)-2-aminopropanoate C10H13NO2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(IV)

The reaction of 3-chloropropanol (I) with 2-methoxypropene (II) by means of PPTS gives the mixed ketal (III), which is condensed with diethyl malonate (IV) by means of sodium ethoxide in hot ethanol, affording the adduct (V). The reduction of (V) with NaH and Red-Al in refluxing toluene provides the allyl alcohol derivative (VI), which is submitted to an asymmetric epoxidation to give the epoxide (VII). The reaction of (VII) with octadecyl bromide (VIII) by means of NaH and tetrabutylammonium iodide (TBAI) yields the corresponding ether (IX), which by reaction with PPTS in HOAc is converted to the tetrahydrofuran-2-methanol derivative (X). Finally, this compound is condensed with POCl3, TEA, choline mesylate (XI) and DMAP in dichloromethane/pyridine to afford the target compound.

参考文献 中间体
合成目标
【1】 Lohmeyer, M.; Bittman, R.; Antitumor ether lipids and alkylphosphocholines. Drugs Fut 1994, 19, 11, 1021.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
41308 2-hydroxy-N,N,N-trimethyl-1-ethanaminium methanesulfonate C6H17NO4S 详情 详情
(I) 19490 3-chloro-1-propanol 627-30-5 C3H7ClO 详情 详情
(II) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(III) 41304 1-(3-chloropropoxy)-1-methylethyl methyl ether; 1-chloro-3-(1-methoxy-1-methylethoxy)propane C7H15ClO2 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 41309 diethyl 2-[3-(1-methoxy-1-methylethoxy)propyl]malonate C14H26O6 详情 详情
(VI) 41305 2-[3-(1-methoxy-1-methylethoxy)propyl]-2-propen-1-ol C10H20O3 详情 详情
(VII) 28797 1-bromooctadecane 112-89-0 C18H37Br 详情 详情
(VIII) 41306 [(2S)-2-[3-(1-methoxy-1-methylethoxy)propyl]oxiranyl]methyl octadecyl ether; (2S)-2-[3-(1-methoxy-1-methylethoxy)propyl]-2-[(octadecyloxy)methyl]oxirane C28H56O4 详情 详情
(IX) 41307 [(2S)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methanol C24H48O3 详情 详情

合成路线19

该中间体在本合成路线中的序号：(IV)

The reaction of tetrahydrofuran-2,2-dimethanol (I) with butyryl chloride (II) and Na2CO3 in dichloromethane gives the dibutyrate (III), which is asymmetrized by means of pancreas lipase type II (PPL) or microbial lipase Mucor javanicus (LMJ) yielding the (R)-monobutyrate (IV). The protection of the OH group of (IV) with Tr-Cl and pyridine in dichloromethane affords the trityl ether (V), which is treated with K2CO3 in methanol to provide the chiral carbinol (VI). The reaction of (VI) with benzyl bromide by means of NaH and tetrabutylammonium iodide (TBAI) in refluxing THF gives the corresponding benzyl ether (VII), which is deprotected with TFA in dichloromethane/water to yield the chiral carbinol (VIII). The reaction of (VIII) with octadecyl bromide (IX) by means of NaH and tetrabutylammonium iodide (TBAI) in refluxing THF gives the corresponding octadecyl ether (X), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to yield the chiral carbinol (XI). Finally, this carbinol is condensed with POCl3, choline tosylate (XII), TEA and pyridine in THF to afford the target compound.

参考文献 中间体
合成目标
【1】 Prasad, K.; et al.; Asymmetrization of tetrahydrofuran-2,2-dimethanol: Synthesis of the enantiomers of SRI 62-834. J Org Chem 1995, 60, 23, 7693.
【2】 Estermann, H.; Houlihan, W.J.; Kapa, P.K.; Underwood, R.L. (Novartis AG; Novartis Deutschland GmbH); Enantiomers of 2-tetrahydrofuran derivs., intermediates therefor and their preparation. EP 0462935; JP 1992270276 .
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) 19490 3-chloro-1-propanol 627-30-5 C3H7ClO 详情 详情
(II) 10792 Butanoyl chloride; Butyryl chloride 141-75-3 C4H7ClO 详情 详情
(III) 47575 [2-[(butyryloxy)methyl]tetrahydro-2-furanyl]methyl butyrate C14H24O5 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 47577 [(2S)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methyl butyrate C29H32O4 详情 详情
(VI) 47578 [(2R)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methanol C25H26O3 详情 详情
(VII) 47579 benzyl [(2R)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methyl ether; (2R)-2-[(benzyloxy)methyl]-2-[(trityloxy)methyl]tetrahydrofuran C32H32O3 详情 详情
(VIII) 47580 [(2S)-2-[(benzyloxy)methyl]tetrahydro-2-furanyl]methanol C13H18O3 详情 详情
(IX) 28797 1-bromooctadecane 112-89-0 C18H37Br 详情 详情
(X) 47581 (2R)-2-[(benzyloxy)methyl]-2-[(octadecyloxy)methyl]tetrahydrofuran; benzyl [(2R)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methyl ether C31H54O3 详情 详情
(XI) 41307 [(2S)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methanol C24H48O3 详情 详情
(XII) 41265 2-hydroxy-N,N,N-trimethyl-1-ethanaminium 4-methylbenzenesulfonate C12H21NO4S 详情 详情

合成路线20

该中间体在本合成路线中的序号：(XXXII)

Alkylation of potassium phthalimide (XXVII) with epichlorohydrin (XXVIII) provided N-glycidyl phthalimide (XXIX). Epoxide ring opening in (XXIX) with aqueous HBr led to bromohydrin (XXX), which was further oxidized to bromo ketone (XXXI) by means of CrO3. Coupling of bromo ketone (XXXI) with diethyl malonate (XXXII) to afford (XXXIII) was accomplished in the presence of NaOEt in EtOH/DMF as the solvent. Acid hydrolysis of the malonate ester (XXXIII), followed by thermal decarboxylation, gave rise to phthalimido levulinic acid (XI). The phthaloyl group of (XI) was finally hydrolyzed under acidic conditions to furnish delta-aminolevulinic acid.

参考文献 中间体
合成目标
【1】 Collins, A.; Tschudy, D.P.; Malonic ester synthesis of delta-aminolevulinic acid. The reaction of N-3-bromoacetonylphthalimide with malonic ester. J Org Chem 1959, 24, 556.
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) 59147 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoic acid C13H11NO5 详情 详情
(XXVII) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(XXVIII) 10246 N-Phenyl-2-[(triphenylstannyl)selanyl]benzamide C31H25NOSeSn 详情 详情
(XXIX) 12335 2-(2-Oxiranylmethyl)-1H-isoindole-1,3(2H)-dione; N-(2,3-Epoxypropyl)phtalimide 5455-98-1 C11H9NO3 详情 详情
(XXX) 59158 2-(3-bromo-2-hydroxypropyl)-1H-isoindole-1,3(2H)-dione C11H10BrNO3 详情 详情
(XXXI) 59159 2-(3-Bromo-2-oxopropyl)isoindole-1,3-dione C11H8BrNO3 详情 详情
(XXXII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XXXIII) 59160 diethyl 2-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-oxopropyl]malonate C18H19NO7 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 condensation of diethyl malonate (I) with (R)-(-)-epichlorohydrin (II) by means of NaOEt in ethanol gives (3aS,4aR)-3-oxo-3,3a,4,4a-tetrahydro-1H-cyclopropa[c]furan-3a-carboxylic acid ethyl ester (III), which is selectively reduced at the lactone group by means of sodium borohydride in ethanol to yield (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester (IV). The protection of (IV) with 2,2-dimethoxypropane (V) and Ts-OH in DMF affords the cyclic acetonide (VI), which is reduced with LiBH4 in THF to provide the hydroxymethyl acetonide (VII). The protection of the OH group of (VII) with benzyl bromide and NaH in DMF gives the benzyl ether (VIII), which is treated with HCl in THF/water to cleave the acetonide ring and yield the bis hydroxymethyl compound (IX). The acylation of (IX) with benzoyl chloride and pyridine affords the dibenzoate (X), which is debenzylated with H2 over Pd/C in ethanol/acetic acid to provide (1S,2R)-1,2-bis(benzoyloxymethyl)cyclopropanemethanol (XI). The reaction of (XI) with Ts-OH and DMAP in dichloromethane gives the corresponding tosylate (XII), which is condensed with 6-O-benzylguanine (XIII) by means of K2CO3 in DMF to yield the fully protected nucleoside (XIV). The hydrolysis of the benzoyl group of (XIV) by means of NaOMe in methanol affords the dihydroxy compound (XV), which is finally debenzylated by means of HCl in ethanol/water to provide the target guanine cyclopropyl nucleoside.

参考文献 中间体
合成目标
【1】 Sekiyama, T.; et al.; Synthesis and antiviral activity of novel acyclic nucleosides: Discovery of a cyclopropyl nucleoside with potent inhibitory activity against herpesviruses. J Med Chem 1998, 41, 8, 1284.
【2】 Hatsuya, S.; Sekiyama, T.; Tsuji, T.; Iwayama, S.; Okunishi, M. (Ajinomoto Co., Inc.); Cyclopropane deriv.. EP 0502690; JP 1993194421; US 5342840; US 5449840 .
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) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(II) 38067 (2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin 51594-55-9 C3H5ClO 详情 详情
(III) 38068 ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate C8H10O4 详情 详情
(IV) 38069 ethyl (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylate C8H14O4 详情 详情
(V) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(VI) 53924 ethyl (1R,7R)-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylate C11H18O4 详情 详情
(VII) 53925 [(7R)-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methanol C9H16O3 详情 详情
(VIII) 53926 benzyl [(7R)-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methyl ether; (1S,7R)-1-[(benzyloxy)methyl]-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]octane C16H22O3 详情 详情
(IX) 53927 [(1R,2R)-2-[(benzyloxy)methyl]-2-(hydroxymethyl)cyclopropyl]methanol C13H18O3 详情 详情
(X) 53928 {(1R,2S)-2-[(benzoyloxy)methyl]-2-[(benzyloxy)methyl]cyclopropyl}methyl benzoate C27H26O5 详情 详情
(XI) 53929 [(1R,2S)-2-[(benzoyloxy)methyl]-2-(hydroxymethyl)cyclopropyl]methyl benzoate C20H20O5 详情 详情
(XII) 53930 [(1R,2R)-2-[(benzoyloxy)methyl]-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)cyclopropyl]methyl benzoate C27H26O7S 详情 详情
(XIII) 14383 6-(benzyloxy)-9H-purin-2-ylamine; 6-(benzyloxy)-9H-purin-2-amine 19916-73-5 C12H11N5O 详情 详情
(XIV) 53931 {(1R,2S)-2-{[2-amino-6-(benzyloxy)-9H-purin-9-yl]methyl}-2-[(benzoyloxy)methyl]cyclopropyl}methyl benzoate C32H29N5O5 详情 详情
(XV) 53932 [(1S,2R)-1-{[2-amino-6-(benzyloxy)-9H-purin-9-yl]methyl}-2-(hydroxymethyl)cyclopropyl]methanol n/a C18H21N5O3 详情 详情

合成路线22

该中间体在本合成路线中的序号：(XVIII)

3) The reaction of diethyl malonate (XVIII) with 3-methylbutanal (XIX) by means of dipropylamine in acetic acid gives the corresponding 2-(3-methylbutylidene)malonate derivative (XX), which is treated with KCN to yield the corresponding addition compound (XXI). The decarboxylative hydrolysis of (XXI) with KOH affords 3-cyano-5-methylhexanoic acid (XXII), which is reduced with H2 over Ni to yield racemic pregabalin (XXIII). Finally, this racemate is submitted to optical resolution with (S)-(+)-mandelic acid.

参考文献 中间体
合成目标
【1】 Bryans, J.S.; Wustrow, D.J.; 3-Substituted GABA analogs with central nervous system activity: A review. Med Res Rev 1999, 19, 2, 149.
【2】 Newhouse, B.J.; Ibrahim, P.; Burgess, L.E.; et al.; Potent selective nonpeptidic inhibitors of human lung tryptase. Proc Natl Acad Sci USA 1999, 96, 15, 8348.
【3】 Mulhern, T.; Sobieray, D.M.; Huckabee, B.K.; Grote, T.M.; Titus, R.D. (Pfizer Inc.); Method of making (S)-3-(aminomethyl)-5-methylhexanoic acid. WO 9640617 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XIX) 26052 3-methylbutanal 590-86-3 C5H10O 详情 详情
(XX) 26053 diethyl 2-(3-methylbutylidene)malonate C12H20O4 详情 详情
(XXI) 26054 diethyl 2-(1-cyano-3-methylbutyl)malonate C13H21NO4 详情 详情
(XXII) 26055 3-cyano-5-methylhexanoic acid C8H13NO2 详情 详情
(XXIII) 26056 3-(aminomethyl)-5-methylhexanoic acid 130912-52-6 C8H17NO2 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 title compound has been obtained by several related ways: The reaction of 2-chloro-3-nitropyridine (I) with methylboronic acid by means of Pd(PPh3)4 and K2CO3 in hot dioxane gives 2-methyl-3-nitropyridine (III), which is condensed with dimethylformamide dimethylacetal (IV) to yield 2-[2-(dimethylamino)vinyl]-3-nitropyridine (V). The oxidation of (V) by means of NaIO4 affords 3-nitropyridine-2-carbaldehyde (VI), which is condensed with semicarbazide (VII) to provide the corresponding semicarbazone (VIII). Finally, the nitro group of (VIII) is reduced with SnCl2 or Na2S to furnish the target 3-aminopyridine-2-carbaldehyde semicarbazone. 2-Methyl-3-nitropyridine (III) can also be obtained by condensation of 2-chloro-3-nitropyridine (I) with diethyl malonate (II) by means of Na, followed by decarboxylative hydrolysis with H2SO4 at 125 C. The direct oxidation of 2-methyl-3-nitropyridine (III) with SeO2 in dioxane gives carbaldehyde (VI), which is treated with ethyleneglycol (IX) and Ts-OH to yield the cyclic acetal (X). The reduction of (X) with H2 over Pd/C in ethanol affords 3-aminopyridine-2-carbaldehyde ethylene ketal (XI), which is treated with semicarbazide (VI) and HCl to afford the target 3-aminopyridine-2-carbaldehyde semicarbazone. The condensation of 2-chloro-3-nitropyridine (I) with tributyl vinyl tin (XII) Pd(PPh3)4 and PPH3 in refluxing toluene gives 3-nitro-2-vinylpyridine (XIII), which is oxidized with O3 and Me2S in methanol to yield 3-nitropyridine-2-carbaldehyde (VI). This compound is condensed with semicarbazide (VII) and reduced to the target compound as already described.

参考文献 中间体
合成目标
【1】 Li, J.; et al.; Syntheses and antitumor activities of potent inhibitors of ribonucleotide reductase: 3-Amino-4-methylpyridine-2-carboxaldehyde-thiosemicarbazone (3-AMP), 3-amino-pyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) and its water-soluble prodrugs. Curr Med Chem 2001, 8, 2, 121.
【2】 Niu, C.; et al.; Synthesis of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP). Tetrahedron 1998, 54, 23, 6311.
【3】 Liu, M-C.; et al.; Synthesis and antitumor activity of amino derivatives of pyridine-2-carboxaldehyde thiosemicarbazone. J Med Chem 1992, 35, 20, 3672.
【4】 Sartorelli, A.C.; Lin, T.-S. (Yale University); 2-Formylpyridine thiosemicarbazone derivs., their preparation and their use as antitumor agents. EP 0570294; JP 1994128230; US 5281715; US 5721259 .
【5】 Doyle, T.W.; Li, J.; Chen, S.-H.; Li, X.; Niu, C.-S. (Vion Pharmaceuticals, Inc.); Process for the synthesis of ribonucleotide reductase inhibitors 3-AP and 3-AMP. US 5869676; WO 9851670 .
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) 10321 2-Chloro-3-nitropyridine 5470-18-8 C5H3ClN2O2 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 54410 2-methyl-3-nitropyridine 18699-87-1 C6H6N2O2 详情 详情
(IV) 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
(V) 54411 (E)-N,N-dimethyl-2-(3-nitro-2-pyridinyl)-1-ethenamine; N,N-dimethyl-N-[(E)-2-(3-nitro-2-pyridinyl)ethenyl]amine C9H11N3O2 详情 详情
(VI) 54414 3-nitro-2-pyridinecarbaldehyde 10261-94-6 C6H4N2O3 详情 详情
(VII) 12954 1-Hydrazinecarbothioamide; Thiosemicarbazide 79-19-6 CH5N3S 详情 详情
(VIII) 54415 2-[(E)-(3-nitro-2-pyridinyl)methylidene]-1-hydrazinecarbothioamide C7H7N5O2S 详情 详情
(IX) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(X) 54413 2-(1,3-dioxolan-2-yl)-3-nitropyridine C8H8N2O4 详情 详情
(XI) 54412 2-(1,3-dioxolan-2-yl)-3-pyridinylamine; 2-(1,3-dioxolan-2-yl)-3-pyridinamine C8H10N2O2 详情 详情
(XII) 54417 3,3-dibutyl-1-heptene C15H30 详情 详情
(XIII) 54416 3-nitro-2-vinylpyridine C7H6N2O2 详情 详情

合成路线24

该中间体在本合成路线中的序号：(XI)

The reaction of 3-chlorotetrafluoropyridine (I) with sodium tert-butoxide in THF gives 4-tert-butoxy-3-chloro-2,5,6-trifluoropyridine (II), which is dechlorinated with H2 over Pd/C in methanol yielding 4-tert-butoxy-2,3,6-trifluoropyridine (III). The methylation of (III) with methyl iodide and lithium diethylamide (LDA) in THF affords 4-tert-butoxy-2,3,6-trifluoro-5-methylpyridine (IV), which is selectively defluorinated with hydrazine in refluxing propanol to give 4-tert-butoxy-2,5-difluoro-3-methylpyridine (V). The condensation of (V) with cyclopropylacetonitrile (VI) by means of LDA in THF yields 2-(4-tert-butoxy-5-fluoro-3-methyl-2-pyridyl)-2-cyclopropylacetonitrile (VII), which is treated first with trifluoroacetic acid and then with POCl3 to afford 2-(4-chloro-5-fluoro-3-methyl-2-pyridyl)-2-cyclopropylacetonitrile (VIII). The alcoholysis of (VIII) with ethanol/HCl gives the corresponding ethyl ester (IX), which is partially reduced with LiAlH4 in THF to afford the corresponding aldehyde (X). The condensation of (X) with diethyl malonate (XI) by means of piperidine in refluxing ethanol yields the ethylidenemalonate (XII), which, without isolation, is cyclized by heating at 235 C in Dowtherm to afford 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (XIII). The reaction of (XIII) with 3(S)-(tert-butoxycarbonylamino)pyrrolidine (XIV) by means of NaHCO3 in acetonitrile gives the corresponding condensation product (XV), which is hydrolyzed ith LiOH in THF/water to the corresponding free acid (XVI). Finally, this compound is deprotected with 4N HCl in dioxandichloromethane.

参考文献 中间体
合成目标
【1】 Fromtling, R.A.; Castañer, J.; ABT-719. Drugs Fut 1995, 20, 11, 1103.
【2】 Chu, D.T.W.; Li, Q.; Claiborne, A.; et al.; Synthesis and antibacterial activity of A-86719.1 and related 2-pyridones: A novel series of potent DNA gyrase inhibitors. 34th Intersci Conf Antimicrob Agents Chemother (Oct 4-7, Orlando) 1994, Abst F41.
【3】 Chu, D.T.; Li, Q.; Cooper, C.S.; Fung, A.K.L.; Lee, C.M.; Plattner, J.J. (Abbott Laboratories Inc.); Quinolizinone type cpds. JP 1997503783; WO 9510519 .
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) 16819 3-chloro-2,4,5,6-tetrafluoropyridine; Pyridine, 3-chloro-2,4,5,6-tetrafluoro- 1735-84-8 C5ClF4N 详情 详情
(II) 16820 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine; tert-butyl 3-chloro-2,5,6-trifluoro-4-pyridinyl ether C9H9ClF3NO 详情 详情
(III) 16821 4-(tert-butoxy)-2,3,6-trifluoropyridine; tert-butyl 2,3,6-trifluoro-4-pyridinyl ether C9H10F3NO 详情 详情
(IV) 16822 tert-butyl 2,3,6-trifluoro-5-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine C10H12F3NO 详情 详情
(V) 16823 tert-butyl 2,5-difluoro-3-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine C10H13F2NO 详情 详情
(VI) 16824 2-cyclopropylacetonitrile; Cyclopropylacetonitrile 6542-60-5 C5H7N 详情 详情
(VII) 16825 2-[4-(tert-butoxy)-5-fluoro-3-methyl-2-pyridinyl]-2-cyclopropylacetonitrile C15H19FN2O 详情 详情
(VIII) 16826 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile C11H10ClFN2 详情 详情
(IX) 16827 ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetate C13H15ClFNO2 详情 详情
(X) 16828 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde C11H11ClFNO 详情 详情
(XI) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XII) 16830 diethyl 2-[2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylethylidene]malonate C18H21ClFNO4 详情 详情
(XIII) 16831 ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate C16H15ClFNO3 详情 详情
(XIV) 11685 tert-butyl N-[(3S)tetrahydro-1H-pyrrol-3-yl]carbamate C9H18N2O2 详情 详情
(XV) 16833 ethyl 8-[(3S)-3-[(tert-butoxycarbonyl)amino]tetrahydro-1H-pyrrol-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate C25H32FN3O5 详情 详情
(XVI) 16834 8-[(3S)-3-[(tert-butoxycarbonyl)amino]tetrahydro-1H-pyrrol-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid C23H28FN3O5 详情 详情

合成路线25

该中间体在本合成路线中的序号：(I)

The reaction of diethyl malonate (I) with (R)-(-)-epichlorohydrin (II) by means of sodium ethoxide in refluxing ethanol gives the 3-oxa-2-oxobicyclic compound (III), which by reduction with NaBH4 in ethanol yields (1S,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester (IV). The reaction of (IV) with diphenyldiazomethane by means of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in dichloroethane affords (1R,7R)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylic acid ethyl ester (V), which is reduced with LiBH4 in THF giving the carbinol (VI). The reaction of (VI) with CBr4 and triphenylphosphine in dichloromethane yields the bromomethyl derivative (VII), which is condensed with 5-(2-(E)-bromovinyluracil (VIII) by means of K2CO3 and 18-crown-6 in hot DMF affording the expected addition compound (IX). Finally, this compound is deprotected with HCl in methanol.

参考文献 中间体
合成目标
【1】 Onishi, T.; Mukai, C.; Sekiyama, T.; Tsuji, T.; Iwayama, S.; Okunishi, M. (Ajinomoto Co., Inc.); Bis(hydroxymethyl)cyclopropylmethyl pyrimidine derivs.,their preparation and their use as anti-viral agents. EP 0649840; JP 1995165731; US 5496824 .
【2】 Onishi, T.; Mukai, C.; Nakagawa, R.; et al.; Synthesis and antiviral activity of novel anti-VZV 5-substituted uracil nucleosides with a cyclopropane sugar moiety. J Med Chem 2000, 43, 2, 278.
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) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(II) 38067 (2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin 51594-55-9 C3H5ClO 详情 详情
(III) 38068 ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate C8H10O4 详情 详情
(IV) 38069 ethyl (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylate C8H14O4 详情 详情
(V) 38070 ethyl (1R,7S)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylate C21H22O4 详情 详情
(VI) 38071 [(7S)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methanol C19H20O3 详情 详情
(VII) 38072 (1R,7S)-1-(bromomethyl)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane C19H19BrO2 详情 详情
(VIII) 38073 5-[(E)-2-bromoethenyl]-2,4(1H,3H)-pyrimidinedione 69304-49-0 C6H5BrN2O2 详情 详情
(IX) 38074 5-[(E)-2-bromoethenyl]-1-[[(7S)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methyl]-2,4(1H,3H)-pyrimidinedione C25H23BrN2O4 详情 详情

合成路线26

该中间体在本合成路线中的序号：(XVI)

Intermediate (VII) can be obtained by following two different pathways: 1. Hydrogenation of 4-pyridine acetic acid (IX) over PtO2 in AcOH affords piperidinyl derivative (X), which is then protected with Boc2O and NaOH in THF to yield (XI). Reduction of the CO2H group of (XI) with BH3.THF in THF gives alcohol (XII), which is then subjected to Swern oxidation with oxalyl chloride and DMSO in CH2Cl2, followed by reaction with Wittig reagent (XIII) and N-methyl morpholine (NMM), to provide crotonate (XIV). Hydrogenation of (XIV) over Pd/C in MeOH furnishes methyl butyrate (XV), which is finally hydrolyzed with NaOH in MeOH. 2. Alternatively, intermediate (VII) can be obtained by reaction of diethyl malonate (XVI) with 4-vinylpyridine and NaH in EtOH to afford derivative (XVIII), which is hydrolyzed and decarboxylated with HCl/H2O and then hydrogenated over PtO2 to provide piperidine derivative (XIX). Finally, (XIX) is protected by reaction with Boc2O and NaOH in THF.

参考文献 中间体
合成目标
【1】 Molino, B.F.; Klein, S.I.; Czekaj, M.; et al.; Design of a new class of orally active fibrinogen receptor antagonists. J Med Chem 1998, 41, 14, 2492.
【2】 Klein, S.I.; Molino, B.F. (Aventis Pharma SA); Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides. EP 0812205; JP 1997507213; US 5866685; WO 9510295 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 45852 4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butyric acid C14H25NO4 详情 详情
(IX) 17883 2-(4-pyridinyl)acetic acid 28356-58-3 C7H7NO2 详情 详情
(X) 45854 2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid 51052-78-9 C7H13NO2 详情 详情
(XI) 19346 1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid 157688-46-5 C12H21NO4 详情 详情
(XII) 43453 tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate C12H23NO3 详情 详情
(XIII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XIV) 45855 tert-butyl 4-[(E)-4-methoxy-4-oxo-2-butenyl]-1-piperidinecarboxylate C15H25NO4 详情 详情
(XV) 45856 tert-butyl 4-(4-methoxy-4-oxobutyl)-1-piperidinecarboxylate C15H27NO4 详情 详情
(XVI) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XVII) 45857 4-vinylpyridine C7H7N 详情 详情
(XVIII) 45858 diethyl 2-[2-(4-pyridinyl)ethyl]malonate C14H19NO4 详情 详情
(XIX) 45859 4-(4-piperidinyl)butyric acid C9H17NO2 详情 详情

合成路线27

该中间体在本合成路线中的序号：(X)

Synthesis of intermediate (XX): The reaction of 2-chloro-2',4'-difluoroacetophenone (I) with sodium acetate and NaI in DMF gives 2-acetoxy-2',4'-difluoroacetophenone (II), which by methylenation with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide in THF yields 2-(2,4-difluorophenyl)-2-propen-1-ol acetate ester (III). The hydrolysis of (III) with KOH in dioxane/water affords the corresponding alcohol (IV), which is regioselectively epoxidized with titanium tetraisopropoxide and L-(+)-diethyl tartrate in dichloromethane to (S)-(-)-2-(2,4-difluorophenyl)oxirane-2-methanol (V). The reaction of (V) with 1,2,4-triazole (VI) in DMF affords (R)-2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)propane-1,2-diol (VII), which is selectively mesylated with methanesulfonyl chloride and triethylamine to the monomesylate (VIII). The cyclization of (VIII) with NaH in DMF gives the oxirane (IX), which is condensed with diethyl malonate (X) by means of NaH in DMSO to yield a mixture of (5R-cis)- and (5R-trans)-5-(2,4-difluorophenyl)-2-oxo-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-carboxylic acid ethyl ester (XI). The reduction of (XI) with NaBH4 and LiCl in ethanol affords (R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1,2,4-triazol-1-yl) pentane-1,4-diol (XII), which is selectively tosylated with tosyl chloride and triethylamine in THF to the bistosylate (XIII). The cyclization of (XIII) by means of NaH in refluxing toluene gives (5R-cis)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol tosylate ester (XIV). The reaction of (XIV) with 1-(4-hydroxyphenyl)-4-(4-nitrophenyl)piperazine (XV) to obtain compound (XVI), and the following reaction sequence (XVI) to (XVII) to (XVIII) to (XIX) to (5R-cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin-1-yl]phenyl-3,4-dihydro-2H-1,2,4-triazol-3-one (XX) has been performed according to J Med Chem 1984, 27: 894-900.

参考文献 中间体
合成目标
【1】 Fromtling, R.A.; Castañer, J.; SCH-56592. Drugs Fut 1996, 21, 2, 160.
【2】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0736030; JP 1997500658; US 5661151; US 5703079; WO 9517407 .
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) 16321 2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone 51336-94-8 C8H5ClF2O 详情 详情
(II) 16322 2-(2,4-Difluorophenyl)-2-oxoethyl acetate C10H8F2O3 详情 详情
(III) 16323 2-(2,4-difluorophenyl)-2-propenyl acetate C11H10F2O2 详情 详情
(IV) 15491 2-(2,4-difluorophenyl)-2-propen-1-ol C9H8F2O 详情 详情
(V) 17058 [(2S)-2-(2,4-difluorophenyl)oxiranyl]methanol C9H8F2O2 详情 详情
(VI) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(VII) 16327 (2R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol C11H11F2N3O2 详情 详情
(VIII) 17061 (2R)-2-(2,4-difluorophenyl)-1-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-3-(1H-1,2,4-triazol-1-yl)-2-propanol C14H17F2N3O2S 详情 详情
(IX) 15477 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole C11H9F2N3O 详情 详情
(X) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XI) 16331 ethyl (5R)-5-(2,4-difluorophenyl)-2-oxo-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furancarboxylate C16H15F2N3O4 详情 详情
(XII) 16332 (4R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1H-1,2,4-triazol-1-yl)-1,4-pentanediol C14H17F2N3O3 详情 详情
(XIII) 17066 (4R)-4-(2,4-difluorophenyl)-4-hydroxy-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-5-(1H-1,2,4-triazol-1-yl)pentyl 4-methylbenzenesulfonate C28H29F2N3O7S2 详情 详情
(XIV) 16311 [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate C21H21F2N3O4S 详情 详情
(XV) 16345 4-[4-(4-nitrophenyl)piperazino]phenol C16H17N3O3 详情 详情
(XVI) 16347 [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether C30H30F2N6O4 详情 详情
(XVII) 17070 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylamine C30H32F2N6O2 详情 详情
(XVIII) 17071 N-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-N-(1-phenoxyvinyl)amine C38H38F2N6O3 详情 详情
(XIX) 16350 N-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-1-hydrazinecarboxamide C31H34F2N8O3 详情 详情
(XX) 16351 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C32H32F2N8O3 详情 详情

合成路线28

该中间体在本合成路线中的序号：(X)

2) The 2-(2,4-difluorophenyl)-2-propen-1-ol (IV) is converted into the corresponding propenyl bromide (XXVI), which is condensed with diethyl malonate (X) to afford the malonyl derivative (XXVII). The reduction of (XXVII) with NaBH4 and LiCl yields the 1,3-propanediol derivative (XXVIII), which is enantioselectively acetylated with vinyl acetate and Novozyme 435 in acetonitrile yielding the isomeric (S)-monoacetate (XXIX). The cyclization of (XXIX) with iodine and NaHCO3 in acetonitrile affords (5R-cis)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-methanol acetate ester (XXX), which is condensed with sodium 1,2,4-triazole (XXXI) to give (5R-cis)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol acetate ester (XXXII). The hydrolysis of (XXXII) with NaOH yields the corresponding methanol (XXXIII), which is finally tosylated to the tosyl ester (XIV), already obtained previously.

参考文献 中间体
合成目标
【1】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Bennett, F.; Pike, R.E.; Wang, H.; Pinto, P.; Liu, Y.T.; Patel, N.; Ganguly, A.K.; Novel analogs of SCH 51048: Synthesis and preliminary structure activity relationships. 35th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, San Francisco) 1995, Abst F83..
【2】 Fromtling, R.A.; Castañer, J.; SCH-56592. Drugs Fut 1996, 21, 2, 160.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
24543 vinyl acetate 108-05-4 C4H6O2 详情 详情
(IV) 15491 2-(2,4-difluorophenyl)-2-propen-1-ol C9H8F2O 详情 详情
(X) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XXVI) 16335 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene C9H7BrF2 详情 详情
(XXVII) 16337 diethyl 2-[2-(2,4-difluorophenyl)-2-propenyl]malonate C16H18F2O4 详情 详情
(XXVIII) 16338 2-[2-(2,4-difluorophenyl)-2-propenyl]-1,3-propanediol C12H14F2O2 详情 详情
(XXIX) 16339 (2S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-pentenyl acetate C14H16F2O3 详情 详情
(XXX) 16340 [(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methyl acetate C14H15F2IO3 详情 详情
(XXXI) 13104 1,2,4-Triazole, sodium derivative 41253-21-8 C2H2N3Na 详情 详情
(XXXII) 16342 [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl acetate C16H17F2N3O3 详情 详情
(XXXIII) 16343 [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol C14H15F2N3O2 详情 详情

合成路线29

该中间体在本合成路线中的序号：(IV)

Nitration of 2,4,5-trifluoro-3-methylbenzoic acid (I) with H2SO4 and HNO3 provides nitrobenzoic acid derivative (II), which is then converted into the nitrobenzoyl chloride derivative (III) by reaction with oxalyl chloride in CH2Cl2 in the presence of DMF. Condensation of (III) with diethyl malonate (IV) by means of Mg in EtOH in the presence of CCl4 yields diethyl (2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate (V), which is then treated with p-toluene sulfonic acid in refluxing H2O to furnish ethyl acetate derivative (VI). Reaction of (VI) with ethyl orthoformate and acetic anhydride at reflux affords ethyl acrylate derivative (VII), which is then treated with cyclopropylamine (VIII) in EtOH to give compound (IX). Cyclization of (IX) is then induced either by treatment with NaH in 1,4-dioxane or with 18-crown-6-ether and K2CO3 in THF to provide quinolone derivative (X), whose nitro group is reduced by hydrogenation over Ni Raney in HOAc to give amino derivative (XI). Hydrolysis of the ethyl ester moiety of (XI) is performed by refluxing with HCl/HOAc to furnish carboxylic acid (XII), which is then treated with boron trifluoride etherate to give boron chelate (XIII). Finally, condensation of (XIII) with (S)-7-trifluoroacetylamino-5-azaspiro[2.4]heptane hydrochloride (XIV) by means of Et3N in DMSO, followed by deprotection with KOH in H2O and treatment with MeSO3H affords the desired compound. Alternatively, the target product can also be synthesized from the Boc protected derivative (XVI) obtained either by coupling of boron chelate (XIII) with (S)-7-Boc-amino-5-azaspiro[2.4]heptane hydrochloride (XIV) by means of DIEA in DMSO (or Et3N in MeOH) or by reaction between carboxylic acid (XII) and compound (XV) by heating in DMSO. Finally, the Boc protecting group of (XVI) is removed with HCl and the corresponding methanesulfonate salt formed by treatment with MeSO3H.

参考文献 中间体
合成目标
【1】 Yoshida, T.; et al.; Studies on quinolone antibacterials.V. Synthesis and antibacterial activity of chiral 5-amino-7-(4-substituted-3-amino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acids and derivatives. Chem Pharm Bull 1996, 44, 7, 1376.
【2】 Ito, Y.; Kato, H.; Yasuda, S.; Kado, N.; Yoshida, T.; Yamamoto, Y. (Hokuriku Seiyaku Co., Ltd.); 5-Amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid deriv.. CA 2126118; EP 0641793; JP 1995309864; US 5547962 .
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) 51094 2,4,5-trifluoro-3-methylbenzoic acid C8H5F3O2 详情 详情
(II) 51095 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid C8H4F3NO4 详情 详情
(III) 51096 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride C8H3ClF3NO3 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 51097 diethyl 2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate C15H14F3NO7 详情 详情
(VI) 51098 ethyl 3-oxo-3-(2,4,5-trifluoro-3-methyl-6-nitrophenyl)propanoate C12H10F3NO5 详情 详情
(VII) 51099 ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)-2-propenoate C15H14F3NO6 详情 详情
(VIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(IX) 51100 ethyl (Z)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)-2-propenoate C16H15F3N2O5 详情 详情
(X) 51101 ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-5-nitro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H14F2N2O5 详情 详情
(XI) 51102 ethyl 5-amino-1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H16F2N2O3 详情 详情
(XII) 51103 5-amino-1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C14H12F2N2O3 详情 详情
(XIII) 51104 　 C14H11BF4N2O3 详情 详情
(XIV) 51105 N-[(7S)-5-azaspiro[2.4]hept-7-yl]-2,2,2-trifluoroacetamide C8H11F3N2O 详情 详情
(XV) 15193 tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate C11H20N2O2 详情 详情
(XVI) 51106 5-amino-7-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C25H31FN4O5 详情 详情

合成路线30

该中间体在本合成路线中的序号：

Reductive ring closure of diethyl 2-nitrobenzylidenemalonate (I) afforded quinolone (II). Subsequent N-alkylation of (II) with isopropyl iodide gave (III). Carboxylic acid (IV) was then obtained by basic hydrolysis of the ethyl ester (III). In a related procedure, reductive alkylation of 2-aminobenzyl alcohol (V) with acetone in the presence of NaBH4 gave the N-isopropyl derivative (VI). Oxidation of (VI) using activated MnO2 in toluene yielded aldehyde (VII). Further Knoevenagel condensation of (VII) with diethyl malonate in the presence of piperidine and AcOH produced the previously described quinolone ester (III). Alternatively, condensation of (VII) with malonic acid directly produced the previously described quinolonecarboxylic acid (IV). Acid chloride (VIII) was then prepared by treatment of (IV) with thionyl chloride in hot toluene.

参考文献 中间体
合成目标
【1】 Yokomori, S.; Muramatsu, M.; Suzuki, M.; Ito, C.; Asanuma, H.; Isobe, Y.; Ohuchi, Y.; Kaneko, T.; Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists. Chem Pharm Bull 2001, 49, 1, 29.
【2】 Ohuchi, Y.; Suzuki, M.; Asanuma, H.; Yokomori, S.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Quinolinecarboxylic acid deriv.. EP 0710662; JP 1996034784; US 5753673; WO 9531455 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(I) 36330 diethyl 2-(2-nitrobenzylidene)malonate C14H15NO6 详情 详情
(II) 36331 ethyl 2-oxo-1,2-dihydro-3-quinolinecarboxylate C12H11NO3 详情 详情
(III) 36332 ethyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate C15H17NO3 详情 详情
(IV) 36333 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid C13H13NO3 详情 详情
(V) 18619 (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol 5344-90-1 C7H9NO 详情 详情
(VI) 36334 [2-(isopropylamino)phenyl]methanol；2-(isopropylamino)benzyl alcohol;(2-(isopropylamino)phenyl)methanol C10H15NO 详情 详情
(VII) 36335 2-(isopropylamino)benzaldehyde C10H13NO 详情 详情
(VIII) 36336 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride C13H12ClNO2 详情 详情

合成路线31

该中间体在本合成路线中的序号：

The reaction of 2,6-dichloropyridine (I) with BuLi and CO2 in THF gives 2,6-dichloropyridine-3-carboxylic acid (II) (1), which by reaction with refluxing SOCl2 yields the acyl chloride (III). The reaction of (III) with malonic ester by means of magnesium ethoxide in ethyl ether affords the nicotinoylacetic ester (IV), which is condensed with thiazol-2-amine (V) and triethylorthoformate by means of acetic anhydride providing the nicotinoyl acrylate (VI). The cyclization of (VI) by means of K2CO3 in hot dioxane gives the 7-chloro-4-oxo-1-(2-thiazolyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (VII), which is condensed with the chiral pyrrolidine (VIII) by means of triethylamine yielding the proteted intermediate (IX). Finally, this compound is deprotected and hydrolyzed with hot aqueous HCl.

参考文献 中间体
合成目标
【1】 Tomita, K.; et al.; Synthesis and antitumor activity of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 249.
【2】 Tomita, K.; Chiba, K.; Kashimoto, S.; Shibamori, K.; Tsuzuki, Y. (Dainippon Pharmaceutical Co., Ltd.); Novel cpd., process for producing the same, and antitumor agent. EP 0787726; US 5817669; WO 9534559 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(I) 13573 2,6-Dichloropyridine 2402-78-0 C5H3Cl2N 详情 详情
(II) 26644 2,6-dichloronicotinic acid 38496-18-3 C6H3Cl2NO2 详情 详情
(III) 26645 2,6-dichloronicotinoyl chloride C6H2Cl3NO 详情 详情
(IV) 26646 ethyl 3-(2,6-dichloro-3-pyridinyl)-3-oxopropanoate C10H9Cl2NO3 详情 详情
(V) 19795 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine 96-50-4 C3H4N2S 详情 详情
(VI) 26647 ethyl (Z)-2-[(2,6-dichloro-3-pyridinyl)carbonyl]-3-(1,3-thiazol-2-ylamino)-2-propenoate C14H11Cl2N3O3S 详情 详情
(VII) 26648 ethyl 7-chloro-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate C14H10ClN3O3S 详情 详情
(VIII) 26649 tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate C11H22N2O3 详情 详情
(IX) 26650 ethyl 7-[(3S,4S)-3-[(tert-butoxycarbonyl)(methyl)amino]-4-methoxypyrrolidinyl]-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate C25H31N5O6S 详情 详情

合成路线32

该中间体在本合成路线中的序号：(II)

The condensation of 2,4,5-trifluoro-3-methoxybenzoyl chloride (I) with 14C-labeled diethyl malonate (II) by means of MgCl2 and TEA gives the benzoylmalonate (III), which is monodecarboxylated with TsOH in refluxing water, yielding the benzoylacetate (IV). The reaction of (IV) with triethyl orthoformate and Ac2O at 140 C affords the benzoylacrylate (V), which is treated with cyclopropylamine (VI) in cyclohexane to provide ethyl 3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylate (VII). The cyclization of (VII) by means of K2CO3 in hot N-methylpyrrolidone gives the quinolone carboxylate (VIII), which is hydrolyzed with NaOH in hot methanol, affording the carboxylic acid (IX). Finally, this compound is condensed with (S,S)-2,8-diazabicyclo[4.3.0]octane (X) by means of 1,4-diazabicyclo[2.2.2]octane (DABCO) in refluxing acetonitrile.

参考文献 中间体
合成目标
【1】 Seidel, D.; Conrad, M.; Brehmer, P.; Mohrs, K.; Petersen, U.; Synthesis of carbon-14 labelled moxifloxacin hydrochloride. J Label Compd Radiopharm 2000, 43, 8, 795.
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) 12259 2,4,5-Trifluoro-3-methoxybenzoyl chloride C8H4ClF3O2 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(II) 45330 diethyl malonate C7H12O4 详情 详情
(III) 12260 diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate C15H15F3O6 详情 详情
(III) 45331 diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate C15H15F3O6 详情 详情
(IV) 12261 ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate C12H11F3O4 详情 详情
(IV) 45332 ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate C12H11F3O4 详情 详情
(V) 12262 ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C15H15F3O5 详情 详情
(V) 45333 ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C15H15F3O5 详情 详情
(VI) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(VII) 12264 ethyl (E)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C16H16F3NO4 详情 详情
(VII) 45334 ethyl (Z)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C16H16F3NO4 详情 详情
(VIII) 12265 ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H15F2NO4 详情 详情
(VIII) 45335 ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H15F2NO4 详情 详情
(IX) 12266 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 112811-72-0 C14H11F2NO4 详情 详情
(IX) 45336 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C14H11F2NO4 详情 详情
(X) 17253 (4aS,7aS)octahydro-1H-pyrrolo[3,4-b]pyridine C7H14N2 详情 详情

合成路线33

该中间体在本合成路线中的序号：(IX)

2-Methoxynaphthalene (I) was condensed with bis(N-phenyl-chloromethylimine) (II) using AlCl3 to give 3-methoxyacenaphthene-quinone (III), which was oxidized with H2O2 to afford the naphthalic anhydride (IV). After acid hydrolysis of (IV) and methylation with dimethyl sulfate, the resulting diester (V) was reduced with LiAlH4 to yield diol (VI), which was transformed into dibromide (VII) by means of PBr3. Condensation of (VII) with diethyl malonate (VIII) provided the phenalene dicarboxylate ester (IX). Then, basic hydrolysis of (IX) followed by decarboxylation of the diacid furnished the phenalene-2-carboxylic acid (X). Amine (XIV) was obtained from acid (X) by formation of the acyl azide (XII) through the mixed anhydride (XI), followed by Curtius rearrangement to the corresponding isocyanate (XIII) and acid hydrolysis. Finally, amine (XIV) was acetylated with acetic anhydride to provide the target acetamide.

参考文献 中间体
合成目标
【1】 Jellimann, C.; et al.; Melatonergic properties of the (+)- and (-)-enanti. J Med Chem 1999, 42, 6, 1100.
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) 23645 methyl 2-naphthyl ether; 2-methoxynaphthalene 93-04-9 C11H10O 详情 详情
(II) 23646 2-chloro-N-phenyl-2-(phenylimino)ethanimidoyl chloride C14H10Cl2N2 详情 详情
(III) 23647 3-methoxyacenaphthoquinone C13H8O3 详情 详情
(IV) 23648 4-methoxy-1H,3H-benzo[de]isochromene-1,3-dione C13H8O4 详情 详情
(V) 23649 dimethyl 2-methoxy-1,8-naphthalenedicarboxylate C15H14O5 详情 详情
(VI) 23650 [8-(hydroxymethyl)-2-methoxy-1-naphthyl]methanol C13H14O3 详情 详情
(VII) 23651 1,8-bis(bromomethyl)-2-naphthyl methyl ether; 1,8-bis(bromomethyl)-2-methoxynaphthalene C13H12Br2O 详情 详情
(IX) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(IX) 23653 diethyl 4-methoxy-1H-phenalene-2,2(3H)-dicarboxylate C20H22O5 详情 详情
(X) 23654 4-methoxy-2,3-dihydro-1H-phenalene-2-carboxylic acid C15H14O3 详情 详情
(XI) 23655 4-Methoxy-2,3-dihydro-1H-phenalene-2-carboxylic acid ethoxycarbonyl anhydride C18H18O5 详情 详情
(XII) 23656 4-methoxy-2,3-dihydro-1H-phenalene-2-carbonyl azide C15H13N3O2 详情 详情
(XIII) 23657 4-methoxy-2,3-dihydro-1H-phenalen-2-yl isocyanate; 2-isocyanato-4-methoxy-2,3-dihydro-1H-phenalene C15H13NO2 详情 详情
(XIV) 23658 4-methoxy-2,3-dihydro-1H-phenalen-2-amine; 4-methoxy-2,3-dihydro-1H-phenalen-2-ylamine C14H15NO 详情 详情

合成路线34

该中间体在本合成路线中的序号：(II)

The condensation of 3,4-dimethylbenzyl chloride (I) with diethyl malonate (II) by means of sodium ethoxide ethanol gives the diethyl 2-(3,4-dimethylbenzyl)malonate (III), which by treatment with aqueous refluxing NaOH and the with refluxing aqueous sulfuric acid yields 3-(3,4-dimethylphenyl)propionic acid (IV). The reaction of (IV) with refluxing SOCl2 affords the corresponding acyl chloride (V), which is treated with ammonia providing the amide (VI). The reduction of (VI) with LiAlH4 in refluxing THF gives 3-(3,4-dimethylphenyl)propylamine (VII), which by condensation with 2-(4-hydroxy-3-methoxyphenyl)acetic acid (VIII) by heating at 150 C yields the corresponding amide (IX). The alkylation of the phenolic group of (IX) with 1,2-dibromoethane (X) and NaH in refluxing THF affords the 2-bromoethoxy derivative (XI), which by treatment with NaN3 and Bu4NBr in refluxing benzene gives the 2-azidoethoxy derivative (XII). Finally, this compound is reduced with H2 over Pd/C in ethyl acetate to afford the target compound.

参考文献 中间体
合成目标
【1】 Lee, J.-C.; Lee, K.-S.; Han, M.-S.; Jung, Y.S.; Choi, J.; Park, N.-S.; Ha, D.-C.; Seong, C.-M.; Lim, H.-J.; Choi, S.W.; Synthesis of homovanillic amide derivatives and their analgesic activity. Arch Pharmacal Res 1996, 19, 3, 246.
【2】 Lim, H.-J.; Park, N.-S.; Choi, J.-K.; Ha, D.-C.; Kim, H.-S.; Lee, B.-Y.; N-Aralkylated 4-(2-aminoethoxy)phenylacetamide derivatives as potent analgesic and antiinflammatory agents. Korean Journal of Medicinal Chemistry 1991, 1, 1, 36.
【3】 Lee, K.S.; Choi, J.K.; Hong, M.S.; Kim, H.S.; Lim, H.J.; Ha, D.C.; Park, N.S. (Korea Research Institute of Chemical Technology); Novel phenylacetamide derivs. and processes for the preparation thereof. EP 0525360; US 5242944 .
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) 40283 4-(chloromethyl)-1,2-dimethylbenzene 102-46-5 C9H11Cl 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 40284 diethyl 2-(3,4-dimethylbenzyl)malonate C16H22O4 详情 详情
(IV) 40285 3-(3,4-dimethylphenyl)propionic acid C11H14O2 详情 详情
(V) 40286 3-(3,4-dimethylphenyl)propanoyl chloride C11H13ClO 详情 详情
(VI) 40287 3-(3,4-dimethylphenyl)propanamide C11H15NO 详情 详情
(VII) 40288 3-(3,4-dimethylphenyl)-1-propanamine; 3-(3,4-dimethylphenyl)propylamine C11H17N 详情 详情
(VIII) 40289 4-Hydroxy-3-methoxyphenylacetic acid; Homovanillic acid; 2-(4-hydroxy-3-methoxyphenyl)acetic acid 306-08-1 C9H10O4 详情 详情
(IX) 40290 N-[3-(3,4-dimethylphenyl)propyl]-2-(4-hydroxy-3-methoxyphenyl)acetamide C20H25NO3 详情 详情
(X) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(XI) 40291 2-[4-(2-bromoethoxy)-3-methoxyphenyl]-N-[3-(3,4-dimethylphenyl)propyl]acetamide C22H28BrNO3 详情 详情
(XII) 40292 2-[4-(2-azidoethoxy)-3-methoxyphenyl]-N-[3-(3,4-dimethylphenyl)propyl]acetamide C22H28N4O3 详情 详情

合成路线35

该中间体在本合成路线中的序号：(XVII)

In a different protection strategy, (diethoxyethyl)malonate (XIX) was obtained by alkylation of diethyl malonate (XVII) with bromoacetaldehyde diethyl acetal (XVIII). Reduction of the ester groups of (XIX) with LiBH4 provided diol (XX). The asymmetric mono-acetate ester (XXI) was generated by enantioselective acylation of the prochiral diol (XX) with vinyl acetate in the presence of lipase PS 30. Reaction of the free hydroxyl of (XXI) with p-toluenesulfonyl chloride afforded tosylate (XXII), which was subsequently condensed with 2-amino-6-chloropurine (I), yielding adduct (XXIII). Conversion of the chloropurine ring of (XXIII) to the target guanine derivative (XXV) was achieved by displacement of the chloro group with benzyl alcohol, with concomitant acetate ester hydrolysis, followed by hydrogenolytic cleavage of the resultant benzyl ether (XXIV). Alternatively, initial acetate ester hydrolysis in (XXIII) gave alcohol (XXVI), which was further subjected to chloro group hydrolysis in the presence of either KOH or tertiary amines to yield (XXV). Conversion of alcohol (XXV) to the target stearate ester (XXVIII) was achieved by treatment with stearoyl chloride (IX) or with the mixed anhydride of stearic acid (XXVII) with pivaloyl chloride or with tosyl chloride.

参考文献 中间体
合成目标
【1】 Engelhardt, P.; Hoberg, M.; Zhou, X.-X.; Lindborg, B.; Johansson, N.G. (Medivir AB); Acyclic nucleoside derivs.. EP 0888348; JP 2000504720; JP 2000504721; US 5869493; WO 9730051; WO 9730052 .
【2】 Synthesis of acyclic nucleoside derivs.. WO 9834917 .
【3】 Synthesis of acyclic nucleoside derivs.. WO 0008025 .
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) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(IX) 52961 n-Octadecanoyl chloride; Octadecanoyl Chloride; Stearic acid chloride; Stearoyl chloride 112-76-5 C18H35ClO 详情 详情
(XVII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XVIII) 12113 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal 2032-35-1 C6H13BrO2 详情 详情
(XIX) 52968 3,3-Diethoxypropane-1,1-dicarboxylic acid diethyl ester; Diethyl 3,3-Diethoxypropane-1,1-dicarboxylate 21339-47-9 C13H24O6 详情 详情
(XX) 52969 2-(2,2-Diethoxyethyl)-1,3-propanediol; 2-Hydroxymethyl-4,4-diethoxybutanol 55387-85-4 C9H20O4 详情 详情
(XXI) 52970 (2R)-4,4-diethoxy-2-(hydroxymethyl)butyl acetate C11H22O5 详情 详情
(XXII) 52971 (2S)-4,4-diethoxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)butyl acetate C18H28O7S 详情 详情
(XXIII) 52972 (2R)-2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-4,4-diethoxybutyl acetate C16H24ClN5O4 详情 详情
(XXIV) 52973 (2R)-2-{[2-amino-6-(benzyloxy)-9H-purin-9-yl]methyl}-4,4-diethoxy-1-butanol C21H29N5O4 详情 详情
(XXV) 52974 2-amino-9-[(2R)-4,4-diethoxy-2-(hydroxymethyl)butyl]-1,9-dihydro-6H-purin-6-one C14H23N5O4 详情 详情
(XXVI) 52975 (2R)-2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-4,4-diethoxy-1-butanol C14H22ClN5O3 详情 详情
(XXVII) 27095 stearic acid 57-11-4 C18H36O2 详情 详情
(XXVIII) 52976 (2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4,4-diethoxybutyl stearate C32H57N5O5 详情 详情

合成路线36

该中间体在本合成路线中的序号：(X)

The sulfonation of 4-chlorodiphenyl ether (I) with chlorosulfonic acid in dichloromethane gives the 4-(4-chlorophenoxy)benzenesulfonic acid (II), which is treated with oxalyl chloride and DMF in the same solvent yielding the sulfonyl chloride (III). The reduction of (III) with trimethyl phosphite and KOH in toluene affords the methylsulfanyl derivative (IV), which is chlorinated with SO2Cl2 in dichloromethane to give the chloromethylsulfanyl derivative (V). The condensation of (V) with the silylated enol ether (VI) by means of ZnCl2 and KOH in refluxing dichloromethane yields 4-[4-(4-chlorophenoxy)phenylsulfanylmethyl]tetrahydropyran-4-carboxylic acid (VII), which is treated with oxalyl chloride affording the corresponding acyl chloride (VIII). The reaction of (VIII) with NH2OH in dichloromethane provides the carbohydroxamic acid (IX), which is finally oxidized with oxone (potassium peroxymonosulfate) in N-methyl-2-pyrrolidone/H2O to furnish the target sulfone.

参考文献 中间体
合成目标
【1】 Zook, S.E.; Dagnino, R. Jr.; Deason, M.E.; Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation. EP 0874830; JP 2000502330; WO 9720824 .
【2】 Campbell, J.A.; Dvorak, C.A.; Fisher, L.E.; McGrane, P.L. (F. Hoffmann-La Roche AG); Process for preparing 3-arylsulfur hydroxamic acids. EP 0965592 .
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) 39894 1-chloro-4-phenoxybenzene; 4-chlorophenyl phenyl ether 7005-72-3 C12H9ClO 详情 详情
(II) 39895 4-(4-chlorophenoxy)benzenesulfonic acid C12H9ClO4S 详情 详情
(III) 39896 4-(4-chlorophenoxy)benzenesulfonyl chloride C12H8Cl2O3S 详情 详情
(IV) 39897 4-chlorophenyl 4-(methylsulfanyl)phenyl ether; 1-(4-chlorophenoxy)-4-(methylsulfanyl)benzene 225652-11-9 C13H11ClOS 详情 详情
(V) 39898 1-[(chloromethyl)sulfanyl]-4-(4-chlorophenoxy)benzene; 4-[(chloromethyl)sulfanyl]phenyl 4-chlorophenyl ether C13H10Cl2OS 详情 详情
(VI) 39899 ethoxy(tetrahydro-4H-pyran-4-ylidene)methyl trimethylsilyl ether; [ethoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane C11H22O3Si 详情 详情
(VII) 39900 4-([[4-(4-chlorophenoxy)phenyl]sulfanyl]methyl)tetrahydro-2H-pyran-4-carboxylic acid C19H19ClO4S 详情 详情
(VIII) 39901 4-([[4-(4-chlorophenoxy)phenyl]sulfanyl]methyl)tetrahydro-2H-pyran-4-carbonyl chloride C19H18Cl2O3S 详情 详情
(IX) 39902 4-([[4-(4-chlorophenoxy)phenyl]sulfanyl]methyl)-N-hydroxytetrahydro-2H-pyran-4-carboxamide C19H20ClNO4S 详情 详情
(X) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XI) 12060 Bis(2-chloroethyl) ether; 1-Chloro-2-(2-chloroethoxy)ethane; 2,2'-Dichlorodiethyl ether 111-44-4 C4H8Cl2O 详情 详情
(XII) 18726 diethyl tetrahydro-4H-pyran-4,4-dicarboxylate C11H18O5 详情 详情
(XIII) 39003 N-butyl-2-cyclohexylacetamide C12H23NO 详情 详情

合成路线37

该中间体在本合成路线中的序号：(I)

Alkylation of diethyl malonate (I) with chloroethyl ether (II) in the presence of NaOEt in refluxing EtOH provided tetrahydropyran dicarboxylate (III). Hydrolysis of diester (III) with ethanolic KOH, and decarboxylation of the resulting diacid (IV) at 180 C gave tetrahydropyran-4-carboxylic acid (V). This was reduced to the alcohol (VI) on treatment with LiAlH4 in refluxing THF, and then converted into mesylate (VII) by reaction with metanesulfonyl chloride and triethylamine in THF. 3-(Aminomethyl)pyridine (VIII) was protected as the imine (X) by reaction with benzophenone (IX) in refluxing benzene with a Dean-Stark trap. Alkylation of imine (X) with mesylate (VII) in the presence of LDA in cold THF gave intermediate (XI) which, on acidic hydrolysis provided amine (XII). Reaction of (XII) with saturated aqueous HBr at 100 C in a pressure tube formed dibromide (XIII), which was basified with K2CO3 and heated to 80 C to provide the target quinuclidine.

参考文献 中间体
合成目标
【1】 Bencherif, M.; Lippiello, P.M.; Caldwell, W.S. (R.J. Reynolds Tobacco Co.); Depolarizing skeletal muscle relaxants. WO 9607410 .
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) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(II) 12060 Bis(2-chloroethyl) ether; 1-Chloro-2-(2-chloroethoxy)ethane; 2,2'-Dichlorodiethyl ether 111-44-4 C4H8Cl2O 详情 详情
(III) 18726 diethyl tetrahydro-4H-pyran-4,4-dicarboxylate C11H18O5 详情 详情
(IV) 18727 tetrahydro-4H-pyran-4,4-dicarboxylic acid C7H10O5 详情 详情
(V) 18728 tetrahydro-2H-pyran-4-carboxylic acid C6H10O3 详情 详情
(VI) 18729 tetrahydro-2H-pyran-4-ylmethanol C6H12O2 详情 详情
(VII) 18730 tetrahydro-2H-pyran-4-ylmethyl methanesulfonate C7H14O4S 详情 详情
(VIII) 18731 3-pyridinylmethanamine; 3-pyridinylmethylamine 3731-52-0 C6H8N2 详情 详情
(IX) 18732 benzophenone 119-61-9 C13H10O 详情 详情
(X) 18733 N-(dibenzylene)(3-pyridinyl)methanamine; N-(dibenzylene)-N-(3-pyridinylmethyl)amine C19H16N2 详情 详情
(XI) 18734 N-(dibenzylene)-N-[1-(3-pyridinyl)-2-tetrahydro-2H-pyran-4-ylethyl]amine; N-(dibenzylene)-1-(3-pyridinyl)-2-tetrahydro-2H-pyran-4-yl-1-ethanamine C25H26N2O 详情 详情
(XII) 18735 1-(3-pyridinyl)-2-tetrahydro-2H-pyran-4-ylethylamine; 1-(3-pyridinyl)-2-tetrahydro-2H-pyran-4-yl-1-ethanamine C12H18N2O 详情 详情
(XIII) 18736 5-bromo-3-(2-bromoethyl)-1-(3-pyridinyl)-1-pentanamine; 5-bromo-3-(2-bromoethyl)-1-(3-pyridinyl)pentylamine C12H18Br2N2 详情 详情

合成路线38

该中间体在本合成路线中的序号：(IV)

The reduction of diethyl 2-phenylmalonate (I) with LiAlH4 in ethyl ether gives the expected diol (II), which is tosylated with tosyl chloride and pyridine yielding the ditosylate (III). The cyclization of (III) with diethyl malonate (IV) by means of NaH in dioxane affords the diethyl 3-phenylcyclobutane-1,1-dicarboxylate (V), which is saponified with KOH to the diacid (VI). The partial decarboxylation of (VI) by heating at 200 C provides 3-phenylcyclobutane-1-carboxylic acid (VII), which is esterified with phenacyl bromide to the corresponding phenacyl ester (VIII). The oxidation of (VIII) with ruthenium chloride and periodic acid gives cyclobutane-1,3-dicarboxylic acid monophenacyl ester (IX) as a 1:1 mixture of the cis and trans isomers. The condensation of (IX) with malonic acid monoethyl ester (X) by means of oxalyl chloride and BuLi in THF yields tyhe intermediate diester (XI), which is condensed with thioxanthen (XII) in acetic acid to provide the thioxanthenyl acetic ester (XIII). The decarboxylative hydrolysis of (XIII) with NaOH in ethanol gives the ketoacid (XIV), which is cyclized with KCN and ammonium carbonate in ethanol/water yielding the imidazolidinedione (XV). The hydrolysis of (XV) with NaOH affords the 3-[1-amino-1-carboxy-2-(9-thioxanthenyl)ethyl]cyclobutane-1-carboxylic acid (XVI) as a 2:1 mixture of the cis and trans racemates. Finally, this mixture is treated with L-lysine and crystallized to afford the pure target compound.

参考文献 中间体
合成目标
【1】 Clark, B.P.; et al.; alpha-Substituted-cyclobutylglycine LY393675 potently antagonises group 1 metabotropic glutamate receptors. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.125.
【2】 Clark, B.P.; Harris, J.R. (Eli Lilly and Company); Pharmaceutical acidic cpds.. EP 0837061; JP 1998120635; US 6054448 .
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) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(I) 26952 diethyl 2-phenylmalonate 83-13-6 C13H16O4 详情 详情
(II) 24198 2-phenyl-1,3-propanediol C9H12O2 详情 详情
(III) 26953 3-[[(4-methylphenyl)sulfonyl]oxy]-2-phenylpropyl 4-methylbenzenesulfonate C23H24O6S2 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 26954 diethyl 3-phenyl-1,1-cyclobutanedicarboxylate C16H20O4 详情 详情
(VI) 26955 3-phenyl-1,1-cyclobutanedicarboxylic acid C12H12O4 详情 详情
(VII) 26956 3-phenylcyclobutanecarboxylic acid C11H12O2 详情 详情
(VIII) 26957 2-oxo-2-phenylethyl 3-phenylcyclobutanecarboxylate C19H18O3 详情 详情
(IX) 26958 3-[(2-oxo-2-phenylethoxy)carbonyl]cyclobutanecarboxylic acid C14H14O5 详情 详情
(X) 15086 3-ethoxy-3-oxopropionic acid 1071-46-1 C5H8O4 详情 详情
(XI) 26959 2-oxo-2-phenylethyl 3-(3-ethoxy-3-oxopropanoyl)cyclobutanecarboxylate C18H20O6 详情 详情
(XII) 26071 9H-thioxanthen-9-ol C13H10OS 详情 详情
(XIII) 26960 2-oxo-2-phenylethyl 3-[3-ethoxy-3-oxo-2-(9H-thioxanthen-9-yl)propanoyl]cyclobutanecarboxylate C31H28O6S 详情 详情
(XIV) 26961 3-[2-(9H-thioxanthen-9-yl)acetyl]cyclobutanecarboxylic acid C20H18O3S 详情 详情
(XV) 26962 3-[2,5-dioxo-4-(9H-thioxanthen-9-ylmethyl)-4-imidazolidinyl]cyclobutanecarboxylic acid C22H20N2O4S 详情 详情
(XVI) 26963 3-[1-amino-1-carboxy-2-(9H-thioxanthen-9-yl)ethyl]cyclobutanecarboxylic acid C21H21NO4S 详情 详情

合成路线39

该中间体在本合成路线中的序号：(I)

The reaction of monolabeled diethyl malonate (I) with 2-benzyloxyethyl bromide (II) by means of NaH in refluxing THF gives the corresponding benzyloxyethyl derivative (III), which is reduced with LiAlH4 in ethyl ether yielding the diol (IV). The protection of (IV) by reaction with 2,2-dimethoxypropane (V) and p-toluenesulfonic acid affords the 1,3-dioxane (VI), which is debenzylated with H2 over Pd/C in THF giving the alcohol (VII). The reaction of (VII) with CBr4 and PPh3 in DMF yields the bromide (VIII), which is condensed with the purine (IX) by means of K2CO3 in DMF affording the expected purin-9-yl derivative (X). The hydrolysis of the 1,3-dioxane group with AcOH /water gives the diol (XI), which is monoacylated with isopropyl chloroformate (XII) by means of cool pyridine yielding the mixture of regioisomers (XIII), (XIV). Finally, this mixture is dechlorinated with ammonium formate over Pd/C in refluxing methanol afffording the target compound also as a mixture of regioisomers.

参考文献 中间体
合成目标
【1】 Kim, D.K.; et al.; Synthesis of carbon-14 labelled 2-amino-9-(3-hydroxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine (SK 1875), a potential prodrug of penciclovir. J Label Compd Radiopharm 1999, 42, 6, 597.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII),(VIII) 10916 2-(2,2-Dimethyl-1,3-dioxan-5-yl)-1-ethanol C8H16O3 详情 详情
(XIII),(XIV) 35533 4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)butyl isopropyl carbonate C14H20ClN5O4 详情 详情
(I) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(I) 45348 diethyl malonate C7H12O4 详情 详情
(II) 35528 1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether 1462-37-9 C9H11BrO 详情 详情
(III) 35529 diethyl 2-[2-(benzyloxy)ethyl]malonate C16H22O5 详情 详情
(III) 45349 diethyl 2-[2-(benzyloxy)ethyl]malonate C16H22O5 详情 详情
(IV) 35523 2-[2-(benzyloxy)ethyl]-1,3-propanediol C12H18O3 详情 详情
(IV) 45350 2-[2-(benzyloxy)ethyl]-1,3-propanediol C12H18O3 详情 详情
(V) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(VI) 35530 5-[2-(benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxane; benzyl 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl ether C15H22O3 详情 详情
(VI) 45351 5-[2-(benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxane; benzyl 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl ether C15H22O3 详情 详情
(VII) 45352 2-(2,2-dimethyl-1,3-dioxan-5-yl)-1-ethanol C8H16O3 详情 详情
(VIII) 45353 2-(2,2-dimethyl-1,3-dioxan-5-yl)-1-ethanol C8H16O3 详情 详情
(IX) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(X) 35531 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-ylamine; 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-amine C13H18ClN5O2 详情 详情
(X) 45354 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-amine; 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-ylamine C13H18ClN5O2 详情 详情
(XI) 35532 2-[2-(2-amino-6-chloro-9H-purin-9-yl)ethyl]-1,3-propanediol C10H14ClN5O2 详情 详情
(XI) 45355 2-[2-(2-amino-6-chloro-9H-purin-9-yl)ethyl]-1,3-propanediol C10H14ClN5O2 详情 详情
(XII) 26492 2-[(chlorocarbonyl)oxy]propane 108-23-6 C4H7ClO2 详情 详情
(XIII) 45356 4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)butyl isopropyl carbonate C14H20ClN5O4 详情 详情
(XIV) 45357 4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)butyl isopropyl carbonate C14H20ClN5O4 详情 详情

合成路线40

该中间体在本合成路线中的序号：(XII)

The reaction of 3-chlorotetrafluoropyridine (I) with sodium tert-butoxide in THF gives 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine (II), which is dechlorinated with H2 over Pearlman's catalyst in methanol yielding 4-(tert-butoxy)-2,3,6-trifluoropyridine (III). The methylation of (III) with methyl iodide and lithium diethylamide (LDA) in THF affords 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine (IV), which is treated with hydrazine in refluxing propanol to give 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine (V). The condensation of (V) with 2-bromo-2-cyclopropylacetopnitrile (VI) by means of LDA in THF yields the expected condensation product (VII), which is treated with TFA to eliminate the tert-butyl protecting group and with POCl3 in DMF to afford the 4-chloropyridyl derivative (VIII). The hydrolysis of the nitrile group of (VIII) with HCl in ethanol gives the corresponding acetate ester (IX), which is reduced with LiAlH4 in THF to the alcohol (X). The oxidation of (X) with oxalyl chloride in DMSO/dichloromethane yields the aldehyde (XI), which is cyclized with diethyl malonate (XII) by means of piperidine in refluxing acetic acid, followed by heating at 220 C C in Dowtherm to afford 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (XIII). The condensation of (XIII) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XIV) by means of triethylamine in DMF gives the expected condensation product (XV), which is methylated with methyl iodide and sodium hexamethyldisylazane (Na-HMDS) in THF yielding the N-methyl derivative (XVI). The hydrolysis of the ester group of (XVI) with LiOH in THF/water provides the corresponding free acid (XVII), which is finally deprotected with HCl in acetic acid. The synthesis of the intermediate 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XIV) has already been described in the first synthesis of compound no. 268134 (see scheme 26813401a).

参考文献 中间体
合成目标
【1】 Or, Y.S.; Armiger, Y.-L.; Fung, A. (Abbott Laboratories Inc.); Pyridone antibiotic with improved safety profile. US 5977133; WO 0010998 .
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) 16189 (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoic acid C10H8O3S 详情 详情
(II) 16820 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine; tert-butyl 3-chloro-2,5,6-trifluoro-4-pyridinyl ether C9H9ClF3NO 详情 详情
(III) 16821 4-(tert-butoxy)-2,3,6-trifluoropyridine; tert-butyl 2,3,6-trifluoro-4-pyridinyl ether C9H10F3NO 详情 详情
(IV) 16822 tert-butyl 2,3,6-trifluoro-5-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine C10H12F3NO 详情 详情
(V) 16823 tert-butyl 2,5-difluoro-3-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine C10H13F2NO 详情 详情
(VI) 31629 2-bromo-2-cyclopropylacetonitrile C5H6BrN 详情 详情
(VII) 16825 2-[4-(tert-butoxy)-5-fluoro-3-methyl-2-pyridinyl]-2-cyclopropylacetonitrile C15H19FN2O 详情 详情
(VIII) 16826 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile C11H10ClFN2 详情 详情
(IX) 16827 ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetate C13H15ClFNO2 详情 详情
(X) 31627 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropyl-1-ethanol C11H13ClFNO 详情 详情
(XI) 16828 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde C11H11ClFNO 详情 详情
(XII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XIII) 16831 ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate C16H15ClFNO3 详情 详情
(XIV) 15193 tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate C11H20N2O2 详情 详情
(XV) 26950 ethyl 8-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate C27H34FN3O5 详情 详情
(XVI) 16951 (1R)-1-[(4S,5R)-2,2-dimethyl-5-[(E)-1-tetradecenyl]-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanol C40H54O4 详情 详情
(XVII) 31628 8-[(7S)-7-[(tert-butoxycarbonyl)(methyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid C26H32FN3O5 详情 详情

合成路线41

该中间体在本合成路线中的序号：(XII)

The reaction of 3-chlorotetrafluoropyridine (I) with potassium tert-butoxide in THF gives the 4-tert-butoxypyridine (II), which is dechlorinated with H2 over Pearlman's catalyst in methanol yielding 4-tert-butoxy-2,3,6-trifluoropyridine (III). The methylation of (III) with methyl iodide and LDA in THF affords the 5-methyl derivative (IV), which is partially defluorinated with hydrazine in refluxing propanol to provide 4-tert-butoxy-2,5-difluoro-3-methylpyridine (V). The condensation of (V) with cyclopropylacetonitrile (VI) by means of LDA in THF gives the alpha substituted acetonitrile (VII), which is treated with trifluoroacetic acid yielding the phenol (VIII). The reaction of (VIII) with POCl3 in dichloromethane/DMF affords the corresponding chloro derivative (IX), which is treated with dry HCl in ethanol giving the carboxylic ester (X). The reduction of (X) with LiAlH4 in THF affords the expected aldehyde (XI), which is cyclized with diethyl malonate, piperidine and acetic acid in refluxing ethanol giving the quinolizine carboxylate (XIII). The reaction of (XIII) with (1S,6S)-2-(tert-butoxycarbonyl)-2,8-diazabicyclo[4.3.0]nonane (XIV) by means of NaHCO3 in refluxing acetonitrile yields the condensation product (XV), which is saponified with LiOH in THF/wter providing the protcted target compound (XVI). Finally, this compound is deprotected with HCl in dioxane/methylene chloride.

参考文献 中间体
合成目标
【1】 Chu, D.T.; Li, Q.; Cooper, C.S.; Fung, A.K.L.; Lee, C.M.; Plattner, J.J.; Ma, Z.; Wang, W.-B. (Abbott Laboratories Inc.); Quinolizinone type cpds.. EP 0871628; JP 1999510478; WO 9639407 .
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) 16819 3-chloro-2,4,5,6-tetrafluoropyridine; Pyridine, 3-chloro-2,4,5,6-tetrafluoro- 1735-84-8 C5ClF4N 详情 详情
(II) 16820 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine; tert-butyl 3-chloro-2,5,6-trifluoro-4-pyridinyl ether C9H9ClF3NO 详情 详情
(III) 16821 4-(tert-butoxy)-2,3,6-trifluoropyridine; tert-butyl 2,3,6-trifluoro-4-pyridinyl ether C9H10F3NO 详情 详情
(IV) 16822 tert-butyl 2,3,6-trifluoro-5-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine C10H12F3NO 详情 详情
(V) 16823 tert-butyl 2,5-difluoro-3-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine C10H13F2NO 详情 详情
(VI) 16824 2-cyclopropylacetonitrile; Cyclopropylacetonitrile 6542-60-5 C5H7N 详情 详情
(VII) 16825 2-[4-(tert-butoxy)-5-fluoro-3-methyl-2-pyridinyl]-2-cyclopropylacetonitrile C15H19FN2O 详情 详情
(VIII) 27200 2-cyclopropyl-2-(5-fluoro-4-hydroxy-3-methyl-2-pyridinyl)acetonitrile C11H11FN2O 详情 详情
(IX) 16826 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile C11H10ClFN2 详情 详情
(X) 16827 ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetate C13H15ClFNO2 详情 详情
(XI) 16828 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde C11H11ClFNO 详情 详情
(XII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XIII) 16831 ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate C16H15ClFNO3 详情 详情
(XIV) 27201 tert-butyl (4aS,7aS)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate C12H22N2O2 详情 详情
(XV) 27202 ethyl 8-[(4aS,7aS)-1-(tert-butoxycarbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate C28H36FN3O5 详情 详情
(XVI) 27203 8-[(4aS,7aS)-1-(tert-butoxycarbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid C26H32FN3O5 详情 详情

合成路线42

该中间体在本合成路线中的序号：(IV)

Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III). Condensation of (III) with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with benzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.

参考文献 中间体
合成目标
【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203.
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) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(II) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(III) 24605 4-methyl-1-penten-3-ol C6H12O 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 24607 diethyl 2-[(E)-4-methyl-2-pentenyl]malonate C13H22O4 详情 详情
(VI) 24608 (E)-6-methyl-4-heptenoic acid C8H14O2 详情 详情
(VII) 24609 (1R,2R)-2-(methylamino)-1-phenyl-1-propanol C10H15NO 详情 详情
(VIII) 24610 (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide C18H27NO2 详情 详情
(IX) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(X) 24634 (2S,4E)-2-benzyl-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide C25H33NO2 详情 详情
(XI) 24635 (3R,5S)-3-benzyl-5-[(1R)-1-bromo-2-methylpropyl]dihydro-2(3H)-furanone C15H19BrO2 详情 详情
(XII) 24636 (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-benzyldihydro-2(3H)-furanone C15H19N3O2 详情 详情
(XIII) 24637 tert-butyl (1S)-1-[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate C20H29NO4 详情 详情
(XIV) 24638 (2R,4S,5S)-2-benzyl-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-6-methylheptanoic acid C20H31NO5 详情 详情
(XV) 24639 (2R,5S)-2-benzyl-5-[(tert-butoxycarbonyl)amino]-6-methyl-4-oxoheptanoic acid C20H29NO5 详情 详情

合成路线43

该中间体在本合成路线中的序号：(IV)

Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III).Transesterification with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with 4-methylbenzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XIII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.

参考文献 中间体
合成目标
【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203.
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) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(II) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(III) 24605 4-methyl-1-penten-3-ol C6H12O 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(VI) 24608 (E)-6-methyl-4-heptenoic acid C8H14O2 详情 详情
(VII) 24609 (1R,2R)-2-(methylamino)-1-phenyl-1-propanol C10H15NO 详情 详情
(VIII) 24610 (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide C18H27NO2 详情 详情
(IX) 24623 1-(bromomethyl)-4-methylbenzene 104-81-4 C8H9Br 详情 详情
(X) 24624 (2S,4E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-2-(4-methylbenzyl)-4-heptenamide C26H35NO2 详情 详情
(XI) 24625 (3R,5S)-5-[(1R)-1-bromo-2-methylpropyl]-3-(4-methylbenzyl)dihydro-2(3H)-furanone C16H21BrO2 详情 详情
(XII) 24626 (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-(4-methylbenzyl)dihydro-2(3H)-furanone C16H21N3O2 详情 详情
(XIII) 24627 tert-butyl (1S)-2-methyl-1-[(2S,4R)-4-(4-methylbenzyl)-5-oxotetrahydro-2-furanyl]propylcarbamate C21H31NO4 详情 详情
(XIV) 24628 (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-6-methyl-2-(4-methylbenzyl)heptanoic acid C21H33NO5 详情 详情
(XV) 24629 (2R,5S)-5-[(tert-butoxycarbonyl)amino]-6-methyl-2-(4-methylbenzyl)-4-oxoheptanoic acid C21H31NO5 详情 详情

合成路线44

该中间体在本合成路线中的序号：(IV)

Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III).Transesterification with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with 4-flourobenzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XIII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.

参考文献 中间体
合成目标
【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203.
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) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(II) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(III) 24605 4-methyl-1-penten-3-ol C6H12O 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 24607 diethyl 2-[(E)-4-methyl-2-pentenyl]malonate C13H22O4 详情 详情
(VI) 24608 (E)-6-methyl-4-heptenoic acid C8H14O2 详情 详情
(VII) 24609 (1R,2R)-2-(methylamino)-1-phenyl-1-propanol C10H15NO 详情 详情
(VIII) 24610 (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide C18H27NO2 详情 详情
(IX) 24611 1-(bromomethyl)-4-fluorobenzene 459-46-1 C7H6BrF 详情 详情
(X) 24612 (2S,4E)-2-(4-fluorobenzyl)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide C25H32FNO2 详情 详情
(XI) 24613 (3R,5S)-5-[(1R)-1-bromo-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone C15H18BrFO2 详情 详情
(XII) 24614 (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone C15H18FN3O2 详情 详情
(XIII) 24615 tert-butyl (1S)-1-[(2S,4R)-4-(4-fluorobenzyl)-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate C20H28FNO4 详情 详情
(XIV) 24616 (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-4-hydroxy-6-methylheptanoic acid C20H30FNO5 详情 详情
(XV) 24617 (2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoic acid C20H28FNO5 详情 详情

合成路线45

该中间体在本合成路线中的序号：(I)

Diethyl malonate (I) was alkylated with 2-bromoethyl ethyl ether (II) in the presence of NaOEt to provide diethyl 2-(ethoxyethyl)malonate (III). Treatment of 2-chloronitrobenzene (IV) with 2,2,2-trifluoroethanol (V) afforded the trifluoroethyl ether (VI). Subsequent reduction of the nitro group of (VI) by means of iron in acetic acid gave aniline (VII), which was condensed with malonate (III) in refluxing diphenyl ether, yielding furoquinoline (VIII). Further reaction of (VIII) with o-toluidine (IX) in boiling diethylene glycol produced the tetrahydropyrroloquinoline (X). Aromatization of the pyrrole ring of (X) to give (XI) was achieved by dehydrogenation in diphenyl ether in the presence of Pd/C. Chloroquinoline (XII) was then obtained by chlorination of (XI) with POCl3. Finally, displacement of the chlorine atom of (XII) by means of ethanolamine at 180 C furnished the title compound.

参考文献 中间体
合成目标
【1】 Kim, H.-J.; Kim, S.-S.; Yoo, Y.-K.; Kang, S.-K.; Cheon, H.-G.; Choi, J.-K.; Yum, E.-K. (Korea Research Institute of Chemical Technology); Pyrrolo[3,2-c]quinoline derivs. containing haloalkoxy group and pharmaceutically acceptable salts thereof. CA 2268166; EP 0966466; JP 2000504352; US 6011044; WO 9909029 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(I) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(II) 34659 2-bromoethyl ethyl ether; 1-bromo-2-ethoxyethane 592-55-2 C4H9BrO 详情 详情
(III) 34660 diethyl 2-(2-ethoxyethyl)malonate C11H20O5 详情 详情
(IV) 15248 1-chloro-2-nitrobenzene 88-73-3 C6H4ClNO2 详情 详情
(V) 19483 2,2,2-trifluoro-1-ethanol 75-89-8 C2H3F3O 详情 详情
(VI) 29562 2-nitrophenyl 2,2,2-trifluoroethyl ether; 1-nitro-2-(2,2,2-trifluoroethoxy)benzene C8H6F3NO3 详情 详情
(VII) 29563 2-(2,2,2-trifluoroethoxy)aniline; 2-(2,2,2-trifluoroethoxy)phenylamine C8H8F3NO 详情 详情
(VIII) 34661 6-(2,2,2-trifluoroethoxy)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one C13H10F3NO3 详情 详情
(IX) 15511 o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine 95-53-4 C7H9N 详情 详情
(X) 34662 1-(2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-c]quinolin-4-one C20H17F3N2O2 详情 详情
(XI) 34663 1-(2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one C20H15F3N2O2 详情 详情
(XII) 34664 4-chloro-1-(2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]quinoline; 4-chloro-1-(2-methylphenyl)-1H-pyrrolo[3,2-c]quinolin-6-yl 2,2,2-trifluoroethyl ether C20H14ClF3N2O 详情 详情

合成路线46

该中间体在本合成路线中的序号：

2-Chloro-2',4'-difluoroacetophenone (I) was converted to acetate ester (II) by displacement of the chlorine with sodium acetate in the presence of NaI. Subsequent Wittig reaction of (II) with methylenetriphenylphosphorane produced the allyl ester (III), which was hydrolyzed to alcohol (IV) with KOH in aqueous dioxan. Asymmeytric Sharpless epoxidation of (IV) with tert-butyl hydroperoxide in the presence of L-(+)-diethyl tartrate and titanium tetraisopropoxide furnished the (S)-epoxide (V). Ring opening of (V) with the sodium salt of 1,2,4-triazole (VI) gave the triazolyl diol (VII). After conversion of the primary hydroxyl group to tosylate (VIII), ring closure in the presence of NaH generated epoxide (IX). Condensation of (IX) with diethyl malonate afforded a mixture of diastereomeric butyrolactones (Xa, Xb), which was converted to triol (XI) by reduction with lithium borohydride. Treatment of (XI) with p-toluenesulfonyl chloride produced ditosylate (XII). Ring closure of (XII) employing NaH in boiling toluene gave rise to a diastereomeric mixture of tetrahydrofurans, from which the required cis isomer (XIII) was isolated by column chromatography.

参考文献 中间体
合成目标
【1】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0773941; WO 9638443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(Xa) 34838 ethyl (3S,5R)-5-(2,4-difluorophenyl)-2-oxo-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furancarboxylate C16H15F2N3O4 详情 详情
(Xb) 34839 ethyl (3R,5R)-5-(2,4-difluorophenyl)-2-oxo-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furancarboxylate C16H15F2N3O4 详情 详情
(I) 16321 2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone 51336-94-8 C8H5ClF2O 详情 详情
(II) 16322 2-(2,4-Difluorophenyl)-2-oxoethyl acetate C10H8F2O3 详情 详情
(III) 16323 2-(2,4-difluorophenyl)-2-propenyl acetate C11H10F2O2 详情 详情
(IV) 15491 2-(2,4-difluorophenyl)-2-propen-1-ol C9H8F2O 详情 详情
(V) 17058 [(2S)-2-(2,4-difluorophenyl)oxiranyl]methanol C9H8F2O2 详情 详情
(VI) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(VII) 16327 (2R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol C11H11F2N3O2 详情 详情
(VIII) 16328 (2R)-2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl methanesulfonate C12H13F2N3O4S 详情 详情
(IX) 15477 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole C11H9F2N3O 详情 详情
(XI) 16332 (4R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1H-1,2,4-triazol-1-yl)-1,4-pentanediol C14H17F2N3O3 详情 详情
(XII) 17066 (4R)-4-(2,4-difluorophenyl)-4-hydroxy-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-5-(1H-1,2,4-triazol-1-yl)pentyl 4-methylbenzenesulfonate C28H29F2N3O7S2 详情 详情
(XIII) 16311 [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate C21H21F2N3O4S 详情 详情

合成路线47

该中间体在本合成路线中的序号：(I)

Diethyl diazomalonate (III) was prepared by reaction of diethyl malonate (I) with p-tosyl azide (II) in the presence of Et3N. Subsequent coupling of (II) with 4-hydroxytetrahydropyran (IV) using dirhodium tetraacetate as the catalyst afforded ether (V). Alkylation of (V) with 3-(tert-butoxycarbonylamino)propyl bromide (VI) yielded adduct (VII). Finally, hydrolysis of ester groups of (VII) employing LiOH furnished the title dicarboxylic acid lithium salt.

参考文献 中间体
合成目标
【1】 Fiorentino, S.; Allegretti, M.; Mantovanini, M.; Clavenna, G.; Caselli, G.; Gandolfi, C.A. (Dompé Farmaceutici SpA); Geminal carboxylic acids and esters thereof pharmaceutical formulations containing them useful in the treatment of bone dysmetabolism. EP 0792878; US 5908863 .
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) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(II) 37748 4-methylbenzenesulfonyl azide 941-55-9 C7H7N3O2S 详情 详情
(III) 37749 diethyl 2-diazomalonate C7H10N2O4 详情 详情
(IV) 37750 tetrahydro-2H-pyran-4-ol; 4-Hydroxytetrahydropyran 2081-44-9 C5H10O2 详情 详情
(V) 37751 diethyl 2-(tetrahydro-2H-pyran-4-yloxy)malonate C12H20O6 详情 详情
(VI) 37752 tert-butyl 3-bromopropylcarbamate C8H16BrNO2 详情 详情
(VII) 37753 diethyl 2-[3-[(tert-butoxycarbonyl)amino]propyl]-2-(tetrahydro-2H-pyran-4-yloxy)malonate C20H35NO8 详情 详情

合成路线48

该中间体在本合成路线中的序号：(A)

Treatment of a commercial mixture of 4-chloro-tetrafluropyridine (I) and 3-chlorotetrafluoropyridine (II) with sodium tert-butoxide, followed by chromatographic separation, afforded 4-tert-butoxy-3-chloro-2,5,6-trifluoropyridine (III). Subsequent hydrogenolysis of the chlorine atom of (III) provided (IV), which was methylated with iodomethane in the presence of LDA yielding methylpyridine (V). Selective removal of the 6-fluorine of (V) to give (VI) was achieved by treatment with hydrazine hydrate in boiling n-propanol, followed by air oxidation of the intermediate pyridyl hydrazine. Alkylation of cyclopropaneacetonitrile (VII) with (VI) furnished the pyridinyl cyclopropaneacetonitrile (VIII). After acid cleavage of the tert-butyl group of (VIII), treatment with phosphoryl chloride in DMF gave rise to 4-chloropyridine derivative (IX). Then, alcoholysis of the cyano group of (IX) produced ethyl ester (X). Ester reduction by means of LiAlH4 and subsequent Swern oxidation of the resulting alcohol (XI) provided aldehyde (XII). The required quinolizinone system (XIII) was prepared by Knoevenagel condensation of pyridine aldehyde (XII) with diethyl malonate (1). The chiral piperidine (XV) was obtained by chiral HPLC resolution of racemic cis-N-carbobenzoxy-3-(tert-butoxycarbonylamino)-4-methylpiperidine (XIV), followed by hydrogenolytic cleavage of the carbobenzoxy group. Aromatic substitution of chloroquinolizinone (XIII) with piperidine (XV) yielded adduct (XVI). Hydrolysis of the ethyl ester of (XVI) with LiOH and further acid deprotection of the Boc group furnished the title compound.

参考文献 中间体
合成目标
【1】 Wang, S.; Ma, Z.; Flamm, R.K.; Cooper, C.S.; Li, Q.; Nilius, J.D.; Chu, D.T.W.; Sun OR, Y.; Meulbroek, J.A.; Shen, L.L.; Fung, A.K.L.; Synthesis and antimicrobial activity of 4H-4-oxoquinolizine derivatives: Consequences of structural modification at the C-8 position. J Med Chem 1999, 42, 20, 4202.
【2】 Chu, D.T.; Li, Q.; Cooper, C.S.; Fung, A.K.L.; Lee, C.M.; Plattner, J.J.; Ma, Z.; Wang, W.-B. (Abbott Laboratories Inc.); Quinolizinone type cpds.. EP 0871628; JP 1999510478; WO 9639407 .
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) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(I) 40621 4-chloro-2,3,5,6-tetrafluoropyridine C5ClF4N 详情 详情
(II) 16819 3-chloro-2,4,5,6-tetrafluoropyridine; Pyridine, 3-chloro-2,4,5,6-tetrafluoro- 1735-84-8 C5ClF4N 详情 详情
(III) 16820 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine; tert-butyl 3-chloro-2,5,6-trifluoro-4-pyridinyl ether C9H9ClF3NO 详情 详情
(IV) 16821 4-(tert-butoxy)-2,3,6-trifluoropyridine; tert-butyl 2,3,6-trifluoro-4-pyridinyl ether C9H10F3NO 详情 详情
(V) 16822 tert-butyl 2,3,6-trifluoro-5-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine C10H12F3NO 详情 详情
(VI) 16823 tert-butyl 2,5-difluoro-3-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine C10H13F2NO 详情 详情
(VII) 16824 2-cyclopropylacetonitrile; Cyclopropylacetonitrile 6542-60-5 C5H7N 详情 详情
(VIII) 16825 2-[4-(tert-butoxy)-5-fluoro-3-methyl-2-pyridinyl]-2-cyclopropylacetonitrile C15H19FN2O 详情 详情
(IX) 16826 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile C11H10ClFN2 详情 详情
(X) 16827 ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetate C13H15ClFNO2 详情 详情
(XI) 31627 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropyl-1-ethanol C11H13ClFNO 详情 详情
(XII) 16828 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde C11H11ClFNO 详情 详情
(XIII) 16831 ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate C16H15ClFNO3 详情 详情
(XIV) 40623 benzyl (3S,4S)-3-[(tert-butoxycarbonyl)amino]-4-methyl-1-piperidinecarboxylate C19H28N2O4 详情 详情
(XV) 40622 tert-butyl (3S,4S)-4-methylpiperidinylcarbamate C11H22N2O2 详情 详情
(XVI) 40624 ethyl 8-[(3S,4S)-3-[(tert-butoxycarbonyl)amino]-4-methylpiperidinyl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate C27H36FN3O5 详情 详情

合成路线49

该中间体在本合成路线中的序号：(XVIII)

An alternative procedure for the preparation of the carbapenem system was based on the desulfurative ring contraction of a 1-aza-3-thiabicyclo[4.2.0]octane. The required diethyl (mercaptomethyl)malonate (XXI) was prepared by condensation of diethyl malonate (XVIII) with paraformaldehyde to give methylene malonate (XIX). Conjugate addition of thioacetic acid to (XIX) afforded thioester (XX) and subsequent acid hydrolysis yielded the desired mercaptomethyl derivative (XXI). Coupling of (XXI) with azetidinonepropionic acid (XXII) via activation with CDI generated thioester (XXIII). Oxalic acid chloride isobutyryloxymethyl ester (XXV) was obtained from isobutyryl chloride (XXIV) by condensation with paraformaldehyde, followed by reaction of the resulting chloromethylbutyrate with monobenzyl oxalate tetrabutylammonium salt, hydrogenolysis of the benzyl group and chlorination with oxalyl chloride. Coupling of this acid chloride (XXV) with azetidinone (XXIII) gave imide (XXVI), which was reduced to the hydroxy derivative (XXVII) with Zn and AcOH. After chlorination of (XXVII) with SOCl2 and pyridine, cleavage of the methylenemalonate group, followed by cyclization in the presence of Et3N gave rise to the bicyclic system (XXIX).

参考文献 中间体
合成目标
【1】 Horikawa, H.; Iwasaki, T.; Kondo, K. (Tanabe Seiyaku Co., Ltd.); Process for preparing beta-lactam deriv. and synthetic intermediate thereof. EP 0559533 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XIX) 37725 diethyl 2-methylenemalonate C8H12O4 详情 详情
(XX) 37726 diethyl 2-[(acetylsulfanyl)methyl]malonate C10H16O5S 详情 详情
(XXI) 37727 diethyl 2-(sulfanylmethyl)malonate C8H14O4S 详情 详情
(XXII) 30029 (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid C14H27NO4Si 详情 详情
(XXIII) 37728 diethyl 2-[([(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanoyl]sulfanyl)methyl]malonate C22H39NO7SSi 详情 详情
(XXIV) 14932 isobutyryl chloride; 2-methylpropanoyl chloride 79-30-1 C4H7ClO 详情 详情
(XXV) 37729 [(2-chloro-2-oxoacetyl)oxy]methyl 2-methylpropanoate C7H9ClO5 详情 详情
(XXVI) 37730 diethyl 2-[([(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1-(2-[[(3-methylbutanoyl)oxy]methoxy]-2-oxoacetyl)-4-oxoazetidinyl]propanoyl]sulfanyl)methyl]malonate C30H49NO12SSi 详情 详情
(XXVII) 37731 diethyl 2-[([(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1-(1-hydroxy-2-[[(3-methylbutanoyl)oxy]methoxy]-2-oxoethyl)-4-oxoazetidinyl]propanoyl]sulfanyl)methyl]malonate C30H51NO12SSi 详情 详情
(XXVIII) 37732 diethyl 2-[([(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1-(1-chloro-2-[[(3-methylbutanoyl)oxy]methoxy]-2-oxoethyl)-4-oxoazetidinyl]propanoyl]sulfanyl)methyl]malonate C30H50ClNO11SSi 详情 详情
(XXIX) 37733 (isobutyryloxy)methyl (5R,6S,7S)-7-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methyl-4,8-dioxo-3-thia-1-azabicyclo[4.2.0]octane-2-carboxylate C21H35NO7SSi 详情 详情

合成路线50

该中间体在本合成路线中的序号：(II)

The cyclization of 4-guanidinobenzonitrile (I) with diethyl malonate (II) by means of NaOEt in ethanol gives 4-(4,6-dihydroxypyrimidin-2-ylamino)benzonitrile (III), which is treated with POCl3 to yield the corresponding dichloro derivative (IV). The bromination of (IV) with Br2 and NaHCO3 in methanol/water affords 4-(5-bromo-4,6-dichloropyrimidin-2-ylamino)benzonitrile (V), which is condensed with sodium 4-cyano-2,6-dimethylphenolate (VI) and N-methylpyrrolidone in dioxane to provide the chloro precursor (VII). Finally, this compound is treated with ammonia in isopropanol to yield the target dinitrile derivative.

参考文献 中间体
合成目标
【1】 Ludovici, D.W.; De Corte, B.L.; Kukla, M.J.; et al.; Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues. Bioorg Med Chem Lett 2001, 11, 17, 2235.
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) 55735 N-(4-cyanophenyl)guanidine C8H8N4 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 55736 4-[(4,6-dihydroxy-2-pyrimidinyl)amino]benzonitrile C11H8N4O2 详情 详情
(IV) 55737 4-[(4,6-dichloro-2-pyrimidinyl)amino]benzonitrile C11H6Cl2N4 详情 详情
(V) 46617 4-[(5-bromo-4,6-dichloro-2-pyrimidinyl)amino]benzonitrile C11H5BrCl2N4 详情 详情
(VI) 55738 sodium 4-cyano-2,6-dimethylbenzenolate C9H8NNaO 详情 详情
(VII) 55739 ethyl 1-(2-{[(1S)-1-phenylethyl]amino}acetyl)cyclopropanecarboxylate C16H21NO3 详情 详情

合成路线51

该中间体在本合成路线中的序号：(II)

Condensation of 4-vinylpyridine (I) with diethyl malonate (II) affords the bis(pyridylethyl)malonate (III) which, upon acidic hydrolysis and decarboxylation leads to mono-acid (IV). Catalytic hydrogenation of the pyridine rings of (IV) in the presence of Pd/C furnishes the corresponding piperidinyl compound (V), which is further protected as the N-Boc derivative (VI) employing di-t-butyl dicarbonate. Acid (VI) is coupled to glycine methyl ester (VII) via activation with cyanuric fluoride to yield amide (VIII). Then, alkaline hydrolysis of the methyl ester group provides carboxylic acid (IX).

参考文献 中间体
合成目标
【1】 Lesur, B.; Henry, M.; Yue, C.; Giboulot, T. (Laboratoires L. Lafon); Bispiperidines as antithrombotic agents. EP 1098878; FR 2781223; JP 2002520393; US 6333338; WO 0003986 .
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) 45857 4-vinylpyridine C7H7N 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 63020 diethyl 2,2-bis[2-(4-pyridinyl)ethyl]malonate C21H26N2O4 详情 详情
(IV) 63022 4-(4-pyridinyl)-2-[2-(4-pyridinyl)ethyl]butanoic acid C16H18N2O2 详情 详情
(V) 63023 4-(4-piperidinyl)-2-[2-(4-piperidinyl)ethyl]butanoic acid C16H30N2O2 详情 详情
(VI) 63024 4-[1-(tert-butoxycarbonyl)-4-piperidinyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}butanoic acid C26H46N2O6 详情 详情
(VII) 17568 methyl 2-aminoacetate C3H7NO2 详情 详情
(VIII) 63025 tert-butyl 4-(5-[1-(tert-butoxycarbonyl)-4-piperidinyl]-3-{[(2-methoxy-2-oxoethyl)amino]carbonyl}pentyl)-1-piperidinecarboxylate C29H51N3O7 详情 详情
(IX) 63026 2-[(4-[1-(tert-butoxycarbonyl)-4-piperidinyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}butanoyl)amino]acetic acid C28H49N3O7 详情 详情

合成路线52

该中间体在本合成路线中的序号：(II)

The condensation of 3-pyridincarboxaldehyde (I) with diethyl malonate (II) by means of piperidine in refluxing benzene gives diethyl (3-pyridyl)methylenemalonate (III), which by reaction with dimethylamine (A) in ether is converted into diethyl alpha-dimethylamino-(3-pyridyl)methylmalonate (IV). The reduction of (IV) with LiAlH4 in THF affords 2-[alpha-dimethylamino-(3-pyridyl)methyl]-1,3-propanediol (V), which is finally cyclized with paraformaldehyde by means of boron trifluoride ethearate in acetonitrile. (1-3)

参考文献 中间体
合成目标
【1】 Booher, R.N. (Eli Lilly and Company); US 3905987 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Doxpicomine hydrochloride. Drugs Fut 1981, 6, 9, 548.
【3】 Booher, R.N.; et al.; Various 5-substituted and 2,5-disubstituted 1,3-dioxanes, a new class of analgesic agents. J Med Chem 1977, 20, 7, 885.
【4】 Booher, R.N. (Eli Lilly and Company); US 3962269 .
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) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(I) 12849 Nicotinaldehyde; 3-Pyridinecarboxaldehyde 500-22-1 C6H5NO 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 60974 diethyl 2-(3-pyridinylmethylene)malonate C13H15NO4 详情 详情
(IV) 60975 diethyl 2-[(dimethylamino)(3-pyridinyl)methyl]malonate C15H22N2O4 详情 详情
(V) 60976 2-[(dimethylamino)(3-pyridinyl)methyl]-1,3-propanediol C11H18N2O2 详情 详情

合成路线53

该中间体在本合成路线中的序号：(I)

Diethyl malonate (I) was alkylated with 2-bromoethyl ethyl ether (II) to provide diethyl (2-ethoxyethyl)malonate (III). Subsequent condensation of malonate (III) with 2-(trifluoromethoxy)aniline (IV) in boiling diphenyl ether generated the furoquinoline derivative (V). This was then condensed with 2-methyl-4-methoxyaniline (VI) in refluxing diethylene glycol to furnish adduct (VII). Chlorination of pyrroloquinolone (VII) with phosphoryl chloride gave rise to the chloro pyrroloquinoline (VIII). The chloro group of (VIII) was finally displaced with ethanolamine (IX) at 190 C, yielding the title compound.

参考文献 中间体
合成目标
【1】 Kim, H.-J.; Kim, S.-S.; Yoo, Y.-K.; Kang, S.-K.; Cheon, H.-G.; Choi, J.-K.; Yum, E.-K. (Korea Research Institute of Chemical Technology); Pyrrolo[3,2-c]quinoline derivs. containing haloalkoxy group and pharmaceutically acceptable salts thereof. CA 2268166; EP 0966466; JP 2000504352; US 6011044; WO 9909029 .
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) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(II) 34659 2-bromoethyl ethyl ether; 1-bromo-2-ethoxyethane 592-55-2 C4H9BrO 详情 详情
(III) 34660 diethyl 2-(2-ethoxyethyl)malonate C11H20O5 详情 详情
(IV) 51625 2-trifluoromethoxyaniline; alpha,alpha,alpha-trifluoro-o-anisidine; o-trifluoromethoxyaniline 1535-75-7 C7H6F3NO 详情 详情
(V) 51626 6-(trifluoromethoxy)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one C12H8F3NO3 详情 详情
(VI) 40006 4-methoxy-2-methylphenylamine; 4-methoxy-2-methylaniline 102-50-1 C8H11NO 详情 详情
(VII) 51627 1-(4-methoxy-2-methylphenyl)-6-(trifluoromethoxy)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-c]quinolin-4-one C20H17F3N2O3 详情 详情
(VIII) 51628 4-chloro-1-(4-methoxy-2-methylphenyl)-6-(trifluoromethoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline; 4-chloro-1-(4-methoxy-2-methylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolin-6-yl trifluoromethyl ether C20H16ClF3N2O2 详情 详情
(IX) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情

合成路线54

该中间体在本合成路线中的序号：(VI)

The condensation of 5-chloro-2-nitroanisole (V) with diethyl malonate (VI) by means of NaH in hot DMF gives 2-(3-methoxy-4-nitrophenyl)malonic acid diethyl ester (VII), which is reduced with H2 over Pd/C in ethyl acetate, yielding the corresponding amino derivative (VIII). The condensation of (VIII) with 2-methylphenyl isocyanate (IX) by means of TEA in dichloromethane affords the expected urea (X), which is submitted to a decarboxylative hydrolysis with NaOH in refluxing tert-butanol to provide the phenylacetic acid (XI). The condensation of acetic acid (XI) with the amino group of the isoxazole intermediate (IV) by means of HOBt, DIEA and EDC in DMF gives the amide (XII), which is treated with NaOH in tert-butanol to afford the target propionic acid.

参考文献 中间体
合成目标
【1】 Duplantier, A.J.; et al.; Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent alpha4beta1 integrin antagonists. Bioorg Med Chem Lett 2001, 11, 19, 2593.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 51635 methyl 3-[3-[(1S)-1-amino-3-methylbutyl]-5-isoxazolyl]propanoate C12H20N2O3 详情 详情
(V) 51636 4-Chloro-2-methoxy-1-nitrobenzene; 4-Chloro-2-methoxynitrobenzene; 5-Chloro-2-nitroanisole 6627-53-8 C7H6ClNO3 详情 详情
(VI) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(VII) 51637 diethyl 2-(3-methoxy-4-nitrophenyl)malonate C14H17NO7 详情 详情
(VIII) 51638 diethyl 2-(4-amino-3-methoxyphenyl)malonate C14H19NO5 详情 详情
(IX) 27106 1-isocyanato-2-methylbenzene 614-68-6 C8H7NO 详情 详情
(X) 51639 diethyl 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]malonate C22H26N2O6 详情 详情
(XI) 39718 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid C17H18N2O4 详情 详情
(XII) 51640 methyl 3-(3-[(1S)-1-[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]-3-methylbutyl]-5-isoxazolyl)propanoate C29H36N4O6 详情 详情

合成路线55

该中间体在本合成路线中的序号：(II)

Cyclization of morpholine-4-carboximidamide hydrobromide (I) with diethyl malonate (II) by means of naoEt in refluxing EtoH gives 2-(morpholin-4-yl)pyrimidine-4,6-diol (III), which by chlorination with PoCl3 at 120 °C affords 4,6-dichloro-2-(morpholin-4-yl)pyrimidine (IV). nucleophilic substitution of the dichloropyrimidine (IV) with morpholine (V) in the presence of Et3n in refluxing N-methyl-2-pyrrolidone provides 2,4-di(morpholin-4-yl)-6-chloropyrimidine (VI) . Alternatively, dimorpholinopyrimidine (VI) is prepared by reaction of 2,4,6-trichloropyrimidine (VII) with morpholine (V) in THF, followed by chromatographic separation . Finally, chloropyrimidine derivative (VI) is submitted to a Suzuki cross-coupling reaction with boronate ester (VIII) in the presence of Pd(dppf)2Cl2·CH2Cl2 or Pd(dppf)2Cl2 and na2Co3 in 1,2-dimethoxyethane at 90-95 °C .
Alternatively, iodination of chloride (VI) with HI and naI yields the corresponding iodide (IX) , which is also coupled with boronate (VIII) in the presence of Pd(dppf)Cl2·CH2Cl2 and K2Co3 in 1,4-dioxane/H2o at 100 °C .
Boronate ester (VIII) is obtained by bromination of 4-(trifluoromethyl) pyridin-2-amine (X) with nBS in CHCl3 or CH2Cl2 to afford 5-bromo-4-(trifluoromethyl)pyrimidin-2-amine (XI), which is finally condensed with bis(pinacolato)diboron (XII) in the presence of Pd(dppf)2Cl2·CH2Cl2 and KoAc in refluxing dioxane or DMSO .

参考文献 中间体
合成目标
【1】 Pick, T., Barsanti, P., Iwanowicz, E. et al. (novartis AG). Pyrimidine derivatives used as PI-3 kinase inhibitors. EP 1984350, EP 2261223, JP 200952764, US 2010249126, US 8217035, US 2012225859, Wo 2007084786.
【2】 Burger, M.T., Pecchi, S., Wagman, A. et al. Discovery of BKM120, a pan class I PI3 kinase inhibitor in phase I/II clinical trials. 240th ACS natl Meet (Aug 22-26, Boston) 2010, Abst MEDI 489.
【3】 Vu, A.T., Morris, J. Malhotra, S.V. Efficient and improved synthesis of a PI3K inhibitor anticancer agent. 241st ACS natl Meet (March 27-31, Anaheim) 2011, Abst oRGn 115.
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) 67957 morpholine-4-carboximidamide hydrobromide 　 C5H11N3O.HBr 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 67958 2-morpholinopyrimidine-4,6-diol 　 C8H11N3O3 详情 详情
(IV) 67959 4,6-dichloro-2-(morpholin-4-yl)pyrimidine 10397-13-4 C8H9Cl2N3O 详情 详情
(V) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(VI) 67960 4,4'-(6-chloropyrimidine-2,4-diyl)dimorpholine 　 C12H17ClN4O2 详情 详情
(VII) 43734 2,4,6-trichloropyrimidine 3764-01-0 C4HCl3N2 详情 详情
(VIII) 67961 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine 　 C12H16BF3N2O2 详情 详情
(IX) 67962 4,4'-(6-iodopyrimidine-2,4-diyl)dimorpholine 　 C12H17IN4O2 详情 详情
(X) 67963 4-(trifluoromethyl)pyridin-2-amine 106447-97-6 C6H5F3N2 详情 详情
(XI) 67964 5-bromo-4-(trifluoromethyl)pyridin-2-amine 　 C6H4BrF3N2 详情 详情
(XII) 53342 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester 73183-34-3 C12H24B2O4 详情 详情
Extended Information