Tropesin, VUFB-12018, Repanidal, -Drug Synthesis Database

【结构式】

【药物名称】Tropesin, VUFB-12018, Repanidal

【化学名称】d,l-2-Phenyl-3-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-ylacetoxy]propionic acid
　　　　　　(±)-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid 2-carboxy-2-phenylethyl ester

【CA登记号】65189-78-8, 65828-79-7 (undefined stereoch.)

【分子式】C₂₈H₂₄ClNO₆

【分子量】505.95958

【开发单位】Res. Inst. Pharmacy Biochemistry (VUFB) (Originator), SPOFA (Originator)

【药理作用】Non-Steroidal Antiinflammatory Drugs

合成路线1 合成路线2 合成路线3

合成路线1

1) The reaction of N1-(4-chlorobenzoyl)-N1-(4-methoxyphenyl)hydrazine (I) [the starting material for the synthesis of indomethacin], with d,l-(2-carboxyethyl-2-phenyl)-4-oxopentanoate (II) under the conditions of Fischer indole synthesis by means of 100% phosphoric acid in toluene at 100 C. d,l-(2-Carboxyethyl-2-phenyl)-4-oxopentanoate (II) is obtained hy treatment of d,l-tropic acid with levulinic acid chloride.

参考文献中间体

【1】 Grimova, J.; Rabek, V.; Roubal, Z.; Fisnerova, L.; Pharmacologically interesting derivatives of indomethacin. Cesk Farm 1977, 26, 277.
【2】 Fisnerova, L.; Nemecek, O.; Method of producing 2-phenyl-2-carboxyethyl ester of 1-p-chlorobenzoyl-5-methoxy-2-methyl-3-indolyl acetic acid. CS 194284 .
【3】 Sletzinger, M.; Chemerda, J.M.; Summit, G.G. (Merck & Co., Inc.); N-acyl-phenylhydrazine sulfamic acids and salts thereof. DE 1643462; DE 1643463; DE 1768016; DE 1770022; FR 1540724; FR 1540725; GB 1161270; GB 1173986 .
【4】 Fisnerova, L.; Nemecek, O.; Method of producing 2-phenyl-2-carboxyethyl ester of levulinic acid. CS 194283 .
【5】 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 .
【6】 Fisnerova, L.; Tropesin. Drugs Fut 1986, 11, 9, 779.

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)	24319	4-chloro-N-(4-methoxyphenyl)benzohydrazide		C₁₄H₁₃ClN₂O₂	详情	详情
(II)	24320	3-[(4-oxopentanoyl)oxy]-2-phenylpropionic acid		C₁₄H₁₆O₅	详情	详情

合成路线2

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

【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	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3

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

【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

Extended Information