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【结 构 式】

【分子编号】26958

【品名】3-[(2-oxo-2-phenylethoxy)carbonyl]cyclobutanecarboxylic acid

【CA登记号】

【 分 子 式 】C14H14O5

【 分 子 量 】262.26216

【元素组成】C 64.12% H 5.38% O 30.5%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(IX)

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.

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
Extended Information