NO126864B

NO126864B -

Info

Publication number: NO126864B
Application number: NO00594/71A
Authority: NO
Inventors: Hisao Yamamoto; Masaru Nukao
Original assignee: Sumitomo Chemical Co
Priority date: 1966-01-12
Filing date: 1971-02-18
Publication date: 1973-04-02
Also published as: NL6700300A; CS155157B2; DE1620441B2; SE314985B; BR6786134D0; DE1618933A1; NL146804B; FI49162C; SU375847A3; CS155158B2; DK134715B; DE1620441A1; BE692456A; DE1643506B2; AT283349B; NO126865B; DE1620441C3; FR7844M; CS155156B2; AT277995B

Description

Fremgangsmåte til fremstilling av l-acyl-3-indolylalifatiske syreestere. Process for the preparation of l-acyl-3-indolyl aliphatic acid esters.

Foreliggende oppfinnelse vedrører en ny fremgangsmåte til fremstilling av l-acyl-3-indolylalifatiske syreestere med den generelle formel: The present invention relates to a new process for the production of l-acyl-3-indolylaliphatic acid esters with the general formula:

hvor R^ er en alkylgruppe, halogensubstituert alkylgruppe eller alke- where R^ is an alkyl group, halogen-substituted alkyl group or alken-

nylgruppe med opptil. 10 karbonatorner. R- og R er like eller forskjel-5 •' new group with up to. 10 Carbon Thorns. R- and R are equal or different-5 •'

lige og er et hydrogenatom eller en lavere alkylgruppe, Br er. en lavere alkoksygruppe med opptil 4 karbonatomer, en benzyloksy- eller tetrahydropyranyloksygruppe, R^ er en laverealkyl-, laverealkoksy-eller laverealkyltiogruppe, et halogenatom eller et hydrogenatom, m er 0 eller 1, og n er 0 eller et helt tall fra 1 til 3, men m og n kan.ikke samtidig være 0. • equal and is a hydrogen atom or a lower alkyl group, Br is. a lower alkoxy group of up to 4 carbon atoms, a benzyloxy or tetrahydropyranyloxy group, R^ is a lower alkyl, lower alkoxy or lower alkylthio group, a halogen atom or a hydrogen atom, m is 0 or 1, and n is 0 or an integer from 1 to 3 , but m and n cannot simultaneously be 0. •

Syntesen av indolkomponenter med N-stilliriger substituert med acylgrupper, er f.eks. beskrevet i Elderfield: "Heterocyclic Compounds", Vol. 3 (1952), kapittel 1, sidene 1 - 247, og i W.C. Sampter og F.M Miller: "Chemistry of Heterocyclic Compounds with Indole and Carbazole Systems" (1954), sidene 1 - 69. Syntesen av N-acylindol-forbindelser ifølge foreliggende fremgangsmåte er imidlertid ikke tidligere beskrevet. The synthesis of indole components with N-still ligands substituted with acyl groups is e.g. described in Elderfield: "Heterocyclic Compounds", Vol. 3 (1952), Chapter 1, pages 1 - 247, and in W.C. Sampter and F.M Miller: "Chemistry of Heterocyclic Compounds with Indole and Carbazole Systems" (1954), pages 1 - 69. However, the synthesis of N-acylindole compounds according to the present process has not previously been described.

Ifølge foreliggende oppfinnelse er det tilveiebragt en ny fremgangsmåte og denne er kjennetegnet ved at et fenylhydrazonderivat med den generelle formel: hvor R^, R^, R^, R^, m og n er som angitt ovenfor, omsettes med en acylforbindelse med den generelle formel: According to the present invention, a new method has been provided and this is characterized by the fact that a phenylhydrazone derivative with the general formula: where R^, R^, R^, R^, m and n are as stated above, is reacted with an acyl compound with the general formula formula:

hvor B?~ har den samme betydning som angitt ovenfor, og Y er et halogenatom eller gruppen -O.CO.R''', hvor R"*" har den ovenfor angitte betydning. where B?~ has the same meaning as stated above, and Y is a halogen atom or the group -O.CO.R''', where R"*" has the meaning stated above.

Egnede oppløsningsmidler som kan anvendes i ovennevnte fremgangsmåte er inerte oppløsningsmidler, organiske syrer og organiske syreestere. Som inerte oppløsningsmidler kan manfieks. anvende benzen, toluen, xylen, cykloheksan, tetrahydrofuran og heksan, som organiske syrer, f.eks. eddiksyre, kloreddiksyre, propionsyre, smørsyre, kapro-insyre og heptanoinsyre, og som organiske syreestere f.eks. etylklor-acetat, metylbutyrat, metylakrylat, metylvalerat og metylsorbat. Suitable solvents that can be used in the above-mentioned method are inert solvents, organic acids and organic acid esters. As inert solvents can manfieks. use benzene, toluene, xylene, cyclohexane, tetrahydrofuran and hexane, as organic acids, e.g. acetic acid, chloroacetic acid, propionic acid, butyric acid, caproic acid and heptanoic acid, and as organic acid esters, e.g. ethyl chloroacetate, methyl butyrate, methyl acrylate, methyl valerate and methyl sorbate.

Claims

As the acyl compound of the formula'-III, it is most common to use acyl chloride. You can also use acyl bromide or the acid anhydride. The reaction temperature varies from 30° to 150°C, preferably from 80° to 120°C. The reaction will usually be complete within a couple of hours. If, after complete reaction, one either concentrates the solvent or adds acetic acid, water or petroleum ether, the desired product will precipitate, after which this can be purified by concentration after extraction with ether, benzene or chloroform. All l-acyl-3-indolyl aliphatic acid esters produced are new compounds and have analgesic and antipyretic effects. Some of these esters, such as e.g. t-butyl ester, benzyl ester and tetrahydro-pyranyl ester can further be hydrolysed by suitable treatment to 1-acyl-3-indolyl aliphatic acids. The free acids have a higher therapeutic activity than the esters. The present procedure shall be illustrated by the following examples.

Example 1 2.5 g of the p-methoxyphenylhydrazone of methyl levulinate was added to 50 ml of glacial acetic acid. The solution was then added dropwise to 0.9 g of acetyl chloride and was then kept heated at 80°C for 3 hours. The mixture was then added with stirring to 50 ml of cold water, whereby an oily substance was formed. This was extracted with ether, and methyl-1-acetyl-2-methyl-5-methoxy-3-indolyl acetate was obtained. Infrared absorption spectrum of this product was in full agreement with the spectrum from a standard product prepared by acetylation of methyl-2-methyl-5-methoxy-3-indolyl acetate.

Example 2 By using 1.2 g of acetic anhydride instead of 0.9 g of acetyl chloride in the method in example 1. methyl-1-acetyl-2-methyl-5-methoxy-3-indolyl acetate was produced. Process for the preparation of 1-acyl-3-indolylaliphatic acid esters with the general formula:

where R is an alkyl group, halogen-substituted alkyl group or alke- . nyl group with up to 10 carbon atoms, R and R are the same or different and are a hydrogen atom or a lower alkyl group, R 5 is a lower alkoxy group with up to 4 carbon atoms, a benzyloxy or tetrahydropyranyloxy group, R 5 is a lower alkyl, lower alkoxy or lower alkylthio group, a halogen atom or a hydrogen atom, m is 0 or 1, and n is 0 or an integer from 1 to 3, but m and n cannot simultaneously be 0, characterized in that a phenylhydrazone derivative with the general formula: 2 ~Z C £

where R , R , R , R , m and n are as indicated above, is reacted with an acyl compound of the general formula:

where R<1> has the same meaning as stated above, and Y is a halogen atom or the group -O.CO.R<1>, where R<1> has the above meaning,