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【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%

与该中间体有关的原料药合成路线共 5 条

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
Extended Information