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【结 构 式】 
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【分子编号】14247 【品名】2-(4-Bromophenyl)acetic acid; p-Bromophenylacetic acid; 4-Bromophenylacetic acid 【CA登记号】1878-68-8 |
【 分 子 式 】C8H7BrO2 【 分 子 量 】215.04638 【元素组成】C 44.68% H 3.28% Br 37.16% O 14.88% |
合成路线1
该中间体在本合成路线中的序号：(I)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：(I)Acid chloride (II) (prepared from 4-bromophenylacetic acid (I) and SOCl2), was condensed with ethyl isobutyrylacetate (III) in the presence of NaH in toluene to yield diketoester (IV). Further reaction of (IV) with hydrazine monohydrate in AcOH gave pyrazole (V). The subsequent N-alkylation of (V) with propyl iodide and NaH provided a 3:1 mixture of regioisomers (VI) and (VII), which were separated by silica gel chromatography. The major isomer (VI) was coupled with arylboronic acid (VIII) in the presence of CsF and Pd(PPh3)4 to provide biphenyl compound (IX). The title compound was then obtained by simultaneous cleavage of the ethyl ester and the N-trityl group on heating with hydroethanolic KOH.
| 【1】 Almansa, C.; Gonzales, C.; Torres, M.C.; Carceller, E.; Bartroli, J. (J. Uriach & Cia., SA); New pyrazole derivs. as angiotensin II antagonists. EP 0721454; ES 2105939; JP 1997504804; WO 9604273 . |
| 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) | 19407 | 2-(4-bromophenyl)acetyl chloride | C8H6BrClO | 详情 | 详情 | |
| (III) | 19408 | ethyl 4-methyl-3-oxopentanoate | 7152-15-0 | C8H14O3 | 详情 | 详情 |
| (IV) | 19409 | ethyl 2-[2-(4-bromophenyl)acetyl]-4-methyl-3-oxopentanoate | C16H19BrO4 | 详情 | 详情 | |
| (V) | 19410 | ethyl 5-(4-bromobenzyl)-3-isopropyl-1H-pyrazole-4-carboxylate | C16H19BrN2O2 | 详情 | 详情 | |
| (VI) | 19411 | ethyl 5-(4-bromobenzyl)-3-isopropyl-1-propyl-1H-pyrazole-4-carboxylate | C19H25BrN2O2 | 详情 | 详情 | |
| (VII) | 19412 | ethyl 3-(4-bromobenzyl)-5-isopropyl-1-propyl-1H-pyrazole-4-carboxylate | C19H25BrN2O2 | 详情 | 详情 | |
| (VIII) | 19413 | 2-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)phenylboronic acid | C26H21BN4O2 | 详情 | 详情 | |
| (IX) | 19414 | ethyl 3-isopropyl-1-propyl-5-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-pyrazole-4-carboxylate | C45H44N6O2 | 详情 | 详情 |