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【结 构 式】

【分子编号】22930

【品名】2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid

【CA登记号】

【 分 子 式 】C19H16ClNO4

【 分 子 量 】357.79308

【元素组成】C 63.78% H 4.51% Cl 9.91% N 3.91% O 17.89%
与该中间体有关的原料药合成路线共 10 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10

合成路线1

该中间体在本合成路线中的序号：(I)

This compound can be obtained by three different ways: 1) The reaction of 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid (indomethacin) (I) with SOCl2 gives the corresponding acetyl chloride (II), which is treated with hydroxylamine hydrochloride and NaOH in water to afford 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetohydroxamic acid (III). Finally, this compound is hydrolyzed with 0.5 N NaOH in water. 2) The reaction of 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetal-dehyde (IV) with N-hydroxybenzenesulfonamide (V) in DMSO by means of NaOH yields compound (III) already obtained. 3) By reaction of tert-butyl-5-methoxy-2-methyl-3-indolylacetate (VI) with hydroxylamine in methanol.

参考文献 中间体
合成目标
【1】 Tamietto, T.; Franzone, J.S.; De Martiis, F.; Sintesi e proprieta ntiflogistiche di alcuni acidi acetoidrossamici. Boll Chim Farm 1975, 114, 309-318.
【2】 De Martiis, F.; Arrigoni-Martelli, E.; Tamietto, T.; US 3624103 .
【3】 Tamietto, T.; US 4186133 .
【4】 Serradell, M.N.; de Angelis, L.; Blancafort, P.; Castaner, J.; ABC-8/5. Drugs Fut 1982, 7, 6, 371.
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) 22930 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid C19H16ClNO4 详情 详情
(II) 24047 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetyl chloride C19H15Cl2NO3 详情 详情
(III) 37034 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]-N-hydroxyacetamide C19H17ClN2O4 详情 详情
(IV) 37035 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetaldehyde C19H16ClNO3 详情 详情
(V) 37036 N-hydroxybenzenesulfonamide 599-71-3 C6H7NO3S 详情 详情
(VI) 37038 N-phenyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]aniline C16H24N2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reacion of 1-(4-chlorobenzoyl)-2-methyl-5-methoxyindolyl-3-acetic acid (I) with SOCl2 in refluxing benzene gives the corresponding acyl chloride (II), which is condensed with farnesol (III) by means of triethylamine in THF.

参考文献 中间体
合成目标
【1】 Yamatsu, I.; Abe, S.; Inai, Y.; Suzuki, T.; Kinoshita, K.; Mishima, M.; Katoh, Y.; Kobayashi, S.; Murakami, M.; Yamada, K. (Eisai Co., Ltd.); Polyprenyl esters of acemethacins and anti-inflammatory method of use thereof. DE 3226687; FR 2510107; GB 2104513; JP 8315940 .
【2】 Serradell, M.N.; Castaner, J.; E-0710. Drugs Fut 1984, 9, 7, 506.
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) 22930 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid C19H16ClNO4 详情 详情
(II) 24047 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetyl chloride C19H15Cl2NO3 详情 详情
(III) 21965 (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-ol 4602-84-0 C15H26O 详情 详情

合成路线3

该中间体在本合成路线中的序号：(III)

2) The reaction of indomethacin (III) with thionyl chloride in hot toluene gives the corresponding acyl chloride (IV), which is then condensed with tropic acid (V) in refluxing toluene containing pyridine to afford title compound.

参考文献 中间体
合成目标
【1】 Nemecek, O.; Fisnerova, L.; Grimova, J.; Roubal, Z. (SPOFA - United Pharmaceutical Works); 2-Phenyl-2-carboxyethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetate and process for preparation thereof. US 4136194 .
【2】 Fisnerova, L.; Tropesin. Drugs Fut 1986, 11, 9, 779.
【3】 Fisnerova, L.; et al.; Pharmacologically interesting indomethacin derivatives. Cesk Farm 1977, 26, 6, 227-31.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 22930 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid C19H16ClNO4 详情 详情
(IV) 24074 2-[(3,4-dihydro-2H-thiochromen-8-yloxy)methyl]oxirane C12H14O2S 详情 详情
(V) 24320 3-[(4-oxopentanoyl)oxy]-2-phenylpropionic acid C14H16O5 详情 详情

合成路线4

该中间体在本合成路线中的序号：(III)

3) The treatment of indomethacin (III) with 1,1'-carbonyldiimidazole (A) at room temperature in dichloromethane affords the imidazolide (IVa), which is reacted with tropic acid (V) under the same mild conditions to afford title compound.

参考文献 中间体
合成目标
【1】 Nemecek, O.; Fisnerova, L.; Grimova, J.; Roubal, Z. (SPOFA - United Pharmaceutical Works); 2-Phenyl-2-carboxyethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetate and process for preparation thereof. US 4136194 .
【2】 Fisnerova, L.; Tropesin. Drugs Fut 1986, 11, 9, 779.
【3】 Fisnerova, L.; et al.; Pharmacologically interesting indomethacin derivatives. Cesk Farm 1977, 26, 6, 227-31.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 11353 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) 530-62-1 C7H6N4O 详情 详情
(IVa) 24326 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]-1-(1H-imidazol-1-yl)-1-ethanone C22H18ClN3O3 详情 详情
(III) 22930 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid C19H16ClNO4 详情 详情
(V) 24327 tropic acid 529-64-6 C9H10O3 详情 详情

合成路线5

该中间体在本合成路线中的序号：(III)

This compound can be obtained in tvvo different ways: 1) The reaction of 3-bromophthalide (A) with 5-methoxy-2-methyl-1H-indole-3-acetic acid (I) previously salified with triethylamine in refluxing acetone gives (±)-1,3-dihydro-3-oxo-1-isobenzofuranyl-5-methoxy-2-methyl-1H-indole-3-acetate (II). Compound (II) is salified with sodium hydride and then acylated with p-chlorobenzoyl chloride (B). 2) By condensation of the organic salt of 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (III) with 3-bromophthalide (A).

参考文献 中间体
合成目标
【1】 AR 282717 .
【2】 Torriani, H.; Talmetacin. Drugs Fut 1982, 7, 11, 825.
【3】 Los, M.A.; BE 0858897 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(A) 24560 3-Bromophthalide; 3-Bromo-2-benzofuran-1(3H)-one 6940-49-4 C8H5BrO2 详情 详情
(I) 37079 5-Methoxy-2-methyl-1H-indole-3-acetic acid; 2-(5-Methoxy-2-methyl-1H-indol-3-yl)acetic acid 2882-15-7 C12H13NO3 详情 详情
(II) 37080 3-oxo-1,3-dihydro-2-benzofuran-1-yl 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetate C20H17NO5 详情 详情
(III) 22930 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid C19H16ClNO4 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

1) By condensation of 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (II) with benzyl bromoacetate (A) by means of K2CO3 in DMF. 2) By cyclocondensation of a mixture of N-(p-methoxyphenyl)-N-(p-chlorobenzoyl)hydrazine (III) and benzyl levulinate (IV) at 80 C in acetic acid.

参考文献 中间体
合成目标
【1】 Boltze, K.; Brendler, O.; Dell, H.-D.; Jacobi, H.; Novel substituted indole compound, process for the preparation and therapeutic compositions containing it.. DE 2234651; ES 416877; FR 2192828; JP 49043970; US 3910952 .
【2】 Leeson, P.A.; Castaner, J.; Acemetacin. Drugs Fut 1977, 2, 7, 423.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 12869 benzyl 2-bromoacetate 5437-45-6 C9H9BrO2 详情 详情
(I) 33962 2-(benzyloxy)-2-oxoethyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate C28H24ClNO6 详情 详情
(II) 22930 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid C19H16ClNO4 详情 详情
(III) 24319 4-chloro-N-(4-methoxyphenyl)benzohydrazide C14H13ClN2O2 详情 详情
(IV) 33963 2-(benzyloxy)-2-oxoethyl 4-oxopentanoate C14H16O5 详情 详情

合成路线7

该中间体在本合成路线中的序号：(I)

The reaction of indomethacin (I) with SOCl2 in hot benzene gives the corresponding acyl chloride (II), which is then condensed with 2,3-butanediol (III) by means of pyridine in THF.

参考文献 中间体
合成目标
【1】 Isomae, K.; Kuwamura, T.; Mogi, K.; Ogawa, Y.; Sato, S. (SSP Co., Ltd.); Esters of indomethacin. DE 3235850; GB 2125786 .
【2】 Prous, J.; Castaner, J.; SY-6001. Drugs Fut 1986, 11, 3, 194.
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) 22930 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid C19H16ClNO4 详情 详情
(II) 24047 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetyl chloride C19H15Cl2NO3 详情 详情
(III) 24048 2,3-butanediol 513-85-9 C4H10O2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(I)

The esterification of indomethacin (I) with paracetamol (II) in the presence of DCC is performed in pyridine to afford apyramide, which is recrystallized in isopropanol.

参考文献 中间体
合成目标
【1】 Serrano, J.J.; Richard, M.; Sauvaire, D.; Michel, A.; Apyramide. Drugs Fut 1987, 12, 3, 203.
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) 22930 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid C19H16ClNO4 详情 详情
(II) 21611 4'-Hydroxyacetanilide;4-Acetamidophenol;N-Acetyl-4-aminophenol;Paracetamol;Acetaminophen;p-Hydroxyacetanilide; Paracetamol; N-(4-hydroxyphenyl)acetamide 103-90-2 C8H9NO2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(I)

The title compound was synthesized by two procedures. Indomethacin (I) was coupled with 3-hydroxybenzyl nitrate (II) using DCC to yield the title ester.

参考文献 中间体
合成目标
【1】 Del Soldato, P.; Sannicolo', F. (NicOx SA); Nitric ester derivs. and their use in urinary incontinence and other diseases. JP 2000517332; WO 9809948 .
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) 22930 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid C19H16ClNO4 详情 详情
(II) 17298 3-[(nitrooxy)methyl]phenol C7H7NO4 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IV)

The reaction of N-benzoyl-N',N'-di-n-propyl-DL-isoglutamine (I) with N-3-chloropropyl-N'-2-hydroxyethylpiperazine (II) by means of sodium methoxide in DMSO at 105 C gives N-[3-(N-benzoyl-N',N'-di-n-propyl-DL-isoglutaminyl)oxypropyl]-N'-(2-hydroxyethyl)piperazine (III), which is then condensed with 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (IV) by means of dicyclohexylcarbodiimide and NaHCO3 in ethyl acetate, and treated finally with maleic acid (V)

参考文献 中间体
合成目标
【1】 Blancafort, P.; Serradell, M.N.; Castaner, J.; de Angelis, L.; Proglumetacin maleate. Drugs Fut 1980, 5, 3, 142.
【2】 Makovec, F.; et al. (Rotta Research Laboratorium SpA); BE 830880; CA 1053663; DE 2535799; FR 2281755; GB 1467568; JP 7643773; JP 7643774; JP 7916511; JP 7916512; NL 7509091; SA 7509091; US 3985878 .
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) 60631 4-(benzoylamino)-5-(dipropylamino)-5-oxopentanoic acid C18H26N2O4 详情 详情
(II) 60632 2-[4-(3-chloropropyl)-1-piperazinyl]-1-ethanol C9H19ClN2O 详情 详情
(III) 60633 3-[4-(2-hydroxyethyl)-1-piperazinyl]propyl 4-(benzoylamino)-5-(dipropylamino)-5-oxopentanoate C27H44N4O5 详情 详情
(IV) 22930 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid C19H16ClNO4 详情 详情
(V) 37495 Maleic acid; (Z)-2-Butenedioic acid 110-16-7 C4H4O4 详情 详情
Extended Information