【结 构 式】 |
【分子编号】14248 【品名】2-(4-Bromophenyl)-1-ethanol; 4-Bromophenethyl alcohol;2-(4-bromophenyl)ethanol;2-(4-Bromophenyl)ethan-1-ol 【CA登记号】4654-39-1 |
【 分 子 式 】C8H9BrO 【 分 子 量 】201.06286 【元素组成】C 47.79% H 4.51% Br 39.74% O 7.96% |
合成路线1
该中间体在本合成路线中的序号:(II)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 |
合成路线2
该中间体在本合成路线中的序号:(XVII)Coupling of 2-(4-bromophenyl)ethanol (XVII) with dimethylketene ethyl trimethylsilyl acetal (XVIIIa) in the presence of Pd(dba)2, (t-Bu)3P and ZnF2 in DMF at 80 °C gives the 2-arylisobutyrate ester (XIXa). Subsequent hydroxyl group sulfonylation in (XIXa) with MsCl and Et3N in CH2Cl2 yields the mesylate ester (XIV).
Similarly, 2-(4-bromophenyl)ethanol (XVII) (optionally pretreated with HMDS and NH4Cl in MeCN) is coupled with dimethylketene methyl trimethylsilyl acetal (XVIIIb) in the presence of Pd(dba)2, (t-Bu)3P and ZnF2 in DMF at 80 °C, giving 2-arylisobutyrate ester (XIXb), which is then sulfonylated with MsCl in the presence of Et3N in CH2Cl2, affording synthon (XV) .
【1】 Lee, C.-H., Khoo, J.-H., Kwon, K.-C., Ju, H. (Yuhan Corp.). Process for preparation of 2-methyl-2’-phenylpropionic acid derivatives and novel intermediate compounds. WO 2009102155. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XVIIIa) | 44478 | 1-Ethoxy-2-methyl-1-trimethylsiloxypropene;1-Ethoxy-2-methyl-1-(trimethylsilyloxy)propene;1-Ethoxy-2-methyl-1-(trimethylsilyl)oxy-1-propene;1-ethoxy-2-methyl-1-propenyl trimethylsilyl ether; [(1-ethoxy-2-methyl-1-propenyl)oxy](trimethyl)silane ;dimethylketene ethyl trimethylsilyl acetal | 31469-16-6 | C9H20O2Si | 详情 | 详情 |
(XVIIIb) | 42016 | 1-Methoxy-2-methyl-1-(trimethylsiloxy)propene;1-Methoxy-2,2-dimethyl-1-(trimethylsiloxy)ethene;1-Methoxy-1-(trimethylsilyloxy)-2-methylpropene;[(1-methoxy-2-methyl-1-propenyl)oxy](trimethyl)silane; 1-methoxy-2-methyl-1-propenyl trimethylsilyl ether ;dimethylketene methyl trimethylsilyl acetal | 31469-15-5 | C8H18O2Si | 详情 | 详情 |
(XIXa) | 69019 | ethyl 2-(4-(2-hydroxyethyl)phenyl)-2-methylpropanoate | C14H20O3 | 详情 | 详情 | |
(XIXb) | 69020 | methyl 2-(4-(2-hydroxyethyl)phenyl)-2-methylpropanoate | C13H18O3 | 详情 | 详情 | |
(XIV) | 69016 | ethyl 2-methyl-2-(4-(2-((methylsulfonyl)oxy)ethyl)phenyl)propanoate | C15H22O5S | 详情 | 详情 | |
(XV) | 69018 | methyl 2-methyl-2-(4-(2-((methylsulfonyl)oxy)ethyl)phenyl)propanoate | C14H20O5S | 详情 | 详情 | |
(XVII) | 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 |