【结 构 式】 |
【分子编号】24623 【品名】1-(bromomethyl)-4-methylbenzene 【CA登记号】104-81-4 |
【 分 子 式 】C8H9Br 【 分 子 量 】185.06346 【元素组成】C 51.92% H 4.9% Br 43.18% |
合成路线1
该中间体在本合成路线中的序号:(IV)Title compound was prepared by two synthetic ways. Friedel-Crafts acylation of N-(phenylsulfonyl)indole (II) with acid chloride (I) with concomitant O-debenzylation in the presence of AlCl3 yielded ketone (III). Then, hydroxyl group alkylation of (III) with alpha-bromo-p-xylene (IV) provided p-methylbenzyl ether (V). Subsequent displacement of the chloro group in (IV) by 1-(2-ethoxyphenyl)piperazine (VI) furnished (VII). After hydrolysis of sulfonyl group of (VII) with KOH, the resulting deprotected indole (VIII) was alkylated with ethyl 4-bromobutyrate to give (IX). Finally, hydrolysis of the ethyl ester of (IX) by means of ethanolic KOH provided the title carboxylic acid potassium salt.
【1】 Sato, H.; et al.; Dual-acting agents with alpha1-adrenoceptor antagonistic and steroid 5 alpha-reductase inhibitory activities. Synthesis and evaluation of arylpiperazine derivatives. Bioorg Med Chem Lett 1999, 9, 11, 1553. |
【2】 Yoshida, K.; Kurimoto, T.; Takei, M.; Sato, H. (Zeria Pharmaceutical Co., Ltd.); Indole deriv. and medicine containing the same. EP 0753511; US 5760040; WO 9526955 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 | |
(I) | 26120 | 4-(benzyloxy)-3-(3-chloropropoxy)benzoyl chloride | C17H16Cl2O3 | 详情 | 详情 | |
(II) | 26121 | 1-(phenylsulfonyl)-1H-indole | 40899-71-6 | C14H11NO2S | 详情 | 详情 |
(III) | 26122 | [3-(3-chloropropoxy)-4-hydroxyphenyl][1-(phenylsulfonyl)-1H-indol-3-yl]methanone | C24H20ClNO5S | 详情 | 详情 | |
(IV) | 24623 | 1-(bromomethyl)-4-methylbenzene | 104-81-4 | C8H9Br | 详情 | 详情 |
(V) | 26123 | [3-(3-chloropropoxy)-4-[(4-methylbenzyl)oxy]phenyl][1-(phenylsulfonyl)-1H-indol-3-yl]methanone | C32H28ClNO5S | 详情 | 详情 | |
(VI) | 23055 | ethyl 2-(1-piperazinyl)phenyl ether; 1-(2-ethoxyphenyl)piperazine | C12H18N2O | 详情 | 详情 | |
(VII) | 26124 | [3-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy]-4-[(4-methylbenzyl)oxy]phenyl][1-(phenylsulfonyl)-1H-indol-3-yl]methanone | C44H45N3O6S | 详情 | 详情 | |
(VIII) | 26125 | [3-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy]-4-[(4-methylbenzyl)oxy]phenyl](1H-indol-3-yl)methanone | C38H41N3O4 | 详情 | 详情 | |
(IX) | 26126 | ethyl 4-(3-[3-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy]-4-[(4-methylbenzyl)oxy]benzoyl]-1H-indol-1-yl)butanoate | C44H51N3O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(IV)In a related procedure, dihydroxybenzoyl indole (X) was selectively alkylated at 4-hydroxyl group with alpha-bromo-p-xylene (IV) to provide ether (XI). Further alkylation of (XI) with 1-bromo-3-chloropropane gave (XII). Then, halogen displacement in (XII) by piperazine (VI) furnished the precursor ethyl ester (IX), which was finally hydrolyzed to the target carboxylic acid as above.
【1】 Sato, H.; et al.; Dual-acting agents with alpha1-adrenoceptor antagonistic and steroid 5 alpha-reductase inhibitory activities. Synthesis and evaluation of arylpiperazine derivatives. Bioorg Med Chem Lett 1999, 9, 11, 1553. |
【2】 Yoshida, K.; Kurimoto, T.; Takei, M.; Sato, H. (Zeria Pharmaceutical Co., Ltd.); Indole deriv. and medicine containing the same. EP 0753511; US 5760040; WO 9526955 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 | |
(IV) | 24623 | 1-(bromomethyl)-4-methylbenzene | 104-81-4 | C8H9Br | 详情 | 详情 |
(VI) | 23055 | ethyl 2-(1-piperazinyl)phenyl ether; 1-(2-ethoxyphenyl)piperazine | C12H18N2O | 详情 | 详情 | |
(IX) | 26126 | ethyl 4-(3-[3-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy]-4-[(4-methylbenzyl)oxy]benzoyl]-1H-indol-1-yl)butanoate | C44H51N3O6 | 详情 | 详情 | |
(X) | 26127 | ethyl 4-[3-(3,4-dihydroxybenzoyl)-1H-indol-1-yl]butanoate | C21H21NO5 | 详情 | 详情 | |
(XI) | 26128 | ethyl 4-(3-[3-hydroxy-4-[(4-methylbenzyl)oxy]benzoyl]-1H-indol-1-yl)butanoate | C29H29NO5 | 详情 | 详情 | |
(XII) | 26129 | ethyl 4-(3-[3-(3-chloropropoxy)-4-[(4-methylbenzyl)oxy]benzoyl]-1H-indol-1-yl)butanoate | C32H34ClNO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(IX)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.
【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4
该中间体在本合成路线中的序号:(II)5-Fluoroisatin (I) is alkylated with 4-methylbenzyl bromide (II) in the presence of NaH to afford the N-benzyl isatin derivative (III). Then, Knoevenagel condensation of isatin (III) with cyanoacetic acid (IV) by means of triethylamine in dioxane gives the indolinylidene adduct (V) as a mixture of E and Z isomers. Subsequent catalytic hydrogenation of (V) over Pd/C then furnishes the target compound
【1】 Da Settimo, F.; Primofiore, G.; Da Settimo, A.; La Motta, C.; Simorini, F.; Novellino, E.; Greco, G.; Lavecchia, A.; Boldrini, E.; Novel, highly potent aldose reductase inhibitors: Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives. J Med Chem 2003, 46, 8, 1419. |
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) | 21552 | 5-fluoro-1H-indole-2,3-dione | 443-69-6 | C8H4FNO2 | 详情 | 详情 |
(II) | 24623 | 1-(bromomethyl)-4-methylbenzene | 104-81-4 | C8H9Br | 详情 | 详情 |
(III) | 63451 | thieno[3,2-b]pyridin-7(4H)-one | C7H5NOS | 详情 | 详情 | |
(IV) | 12591 | Cyanoacetic Acid; 2-Cyanoacetic acid | 372-09-8 | C3H3NO2 | 详情 | 详情 |
(V) | 63542 | 2-cyano-2-[5-fluoro-1-(4-methylbenzyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]acetic acid | C19H13FN2O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(II)5-Fluoroisatin (I) is alkylated with 4-methylbenzyl bromide (II) in the presence of NaH to afford the N-benzyl isatin derivative (III). Then, Knoevenagel condensation of isatin (III) with isopropyl cyanoacetate (IV) by means of piperidine in isopropanol gives the indolinylidene adduct (V) as a mixture of E and Z isomers. Subsequent catalytic hydrogenation of (V) over Pd/C then furnishes the target compound
【1】 Da Settimo, F.; Primofiore, G.; Da Settimo, A.; La Motta, C.; Simorini, F.; Novellino, E.; Greco, G.; Lavecchia, A.; Boldrini, E.; Novel, highly potent aldose reductase inhibitors: Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives. J Med Chem 2003, 46, 8, 1419. |
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) | 21552 | 5-fluoro-1H-indole-2,3-dione | 443-69-6 | C8H4FNO2 | 详情 | 详情 |
(II) | 24623 | 1-(bromomethyl)-4-methylbenzene | 104-81-4 | C8H9Br | 详情 | 详情 |
(III) | 63541 | 5-fluoro-1-(4-methylbenzyl)-1H-indole-2,3-dione | C16H12FNO2 | 详情 | 详情 | |
(IV) | 63543 | isopropyl 2-cyanoacetate | C6H9NO2 | 详情 | 详情 | |
(V) | 63544 | isopropyl 2-cyano-2-[5-fluoro-1-(4-methylbenzyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]acetate | C22H19FN2O3 | 详情 | 详情 |