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【结 构 式】

【分子编号】14268

【品名】ethyl (5R)-5-(4-bromophenethyl)-2-methoxy-3,4,5,6-tetrahydro-3-pyridinecarboxylate

【CA登记号】

【 分 子 式 】C17H22BrNO3

【 分 子 量 】368.27062

【元素组成】C 55.44% H 6.02% Br 21.7% N 3.8% O 13.03%

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:(XVI)

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.

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
Extended Information