IL25997A - Process for preparing n-unsubstituted-3-indolyl alkanoic acids - Google Patents

Description

Process for preparing 24781 1 This invention relates to processes for the 2 preparation of 3 acetate and to alkyl substituted derivatives More it relates to processes for the preparation of these valuable compounds in high yields 6 out the necessity of isolating 7 The valuable compounds prepared by the novel 8 process of this invention may be illustrated by the formula 2 wherein is lower alkyl containing for example up to carbon atoms and is lower suitably me hoxy or 7 These compounds are useful intermediates in preparation of known antiflammatory compounds 0 of the class represented by 1 acetic 2 acid and amide 3 and anhydride derivatives of such Compounds of this class have a high degree of activity and are known to be effective in the prevention and inhibition of granuloma tissue They are of in 7 ment of arthritic and dermatological disorders and in 8 conditions which are responsive to treatment with flammatpry agen s tically useful and heteroaroyl substituted Indoles may be illustrated by the following reaction sequence which illustrates the preparation of acetic acid starting with a compound prepared 1 derivative thereof in to an intermediate 2 which cyclizes under the conditions of the 3 reaction to form the desired indole The hydrazine in is prepared by treatment of an alkali metal phenylhydrazine 6 preferably the sodium salt by hydrolysis with hydrochloric 7 acid in ethanol or other primary or secondary 8 lower The phenylhydrazine hydrochloride 9 tates out of solution together with monosodium ethyl sulfate 10 or analogous half ester and further contaminated with the 11 alcohol The phenylhydrazine must be purified 12 especially to remove any traces of solvent so as to avoid 13 transesterification during the reaction with the It has been observed that in the preferred 15 acylation toluene or even 16 trace as low as by weight of transesterified 17 product seriously interferes with the reaction and as much 18 as weight may completely stop the 19 serious shortcoming of this as 20 cated is that the intermediate ydr 21 zine hydrochloride must be isolated before reaction with the 22 This results in less than yields 23 not only because of the extra step but also because isolated compound is unstable and occasionally decomposes 2 spontaneously with burning and with generation of noxious 26 In accordance with the process of this invention 27 formation of the indole is effected in situ without isolation 28 of the thus affording higher yields than have 29 heretofore been obtained and avoiding the danger 1 the reaction since the yield of the final product may be 2 seriously It generally preferred 3 to operate under conditions such that the amount of water present from any source is between 3 and 20 moles of water 5 per mole of alkali metal phenylhydrazine 6 In the first step of the process of this 7 the selected sulfonate salt is reacted in tertiary butanol 8 with at least two moles of hydrogen chloride per mole of 9 sulfonate at a temperature of from about to about 0 during a period of from about 10 to about The 1 preferred for ease of is to effect 2 reaction at room about to for 3 from 16 to Excess hydrogen chloride can be but there is little advantage in doing since it is neutralized in the next step of the This 6 and in fact the entire process is carried out in an inert 7 such as argon or helium since both 8 the intermediate and the final product are susceptible to 9 oxidation by It is in fact although not 0 absolutely that the initial reaction mixture be 1 purged alternately with nitrogen and vacuum several times to 2 insure removal of substantially all of the 3 It is most convenient to use concentrated chloric for example 8 to 10 normal hydrochloric acid as the source of hydrogen if 6 hydrogen chloride a mixture 7 the sulfonate salt in butanol containing the calculated 8 of 9 At the end of the reaction the acidity of 1 preferably by adjusting the pH to about to about 2 by the addition of concentrated Ammonium 3 hydroxide is but any organic inorganic base sufficiently soluble in the reaction medium to react the hydrogen chloride can be Alkali metal and alkaline 6 earth metal hydroxides are It is preferred to operate 7 at a pH of from to since if the formation of the 8 indole is attempted in the presence of excess some 9 cleavage of the tertiary butyl group may take place so that 0 the yield of pure product may be adversely If 1 not enough acid is the intermediate 2 does not 3 The preferably up to about 10 molar excess to insure as complete reaction as is 5 then added and the indole is formed by heating the mixture at from about to about for from to about 7 7 It is most convenient to simply reflux the mixture 8 for from about to 6 9 While it is preferred to use freshly distilled 0 levulinate which is normally about a less 1 pure product from to purity can be employed with 2 suitable quantity adjustments to correct for the 3 At the end of the reaction period the product normally in from about 70 to yield or 5 One convenient method of more specifically 6 trated in the examples is to allow the mixture to 7 not to a low enough temperature for the product to 8 crystallize out of solution to add about by volume 9 of inorganics dissolve in the water and two 1 containing the desired product is separated and about 2 by volume of water is Initially the two layers are 3 but as the product separates out they become Crystallization may be completed by cooling and 5 aging for several 6 The following examples are given by 7 way of illustration 8 EXAMPLE 1 9 acetate 10 sulfonate 11 hydrate is slurried in 10 parts of 12 The slurry is cooled below under nitrogen and of 13 hydrochloric acid added dropwise with good The reaction mixture warmed up to room temperature and stirring continued for Concentrated ammonium 16 hydroxide is then added to adjust the pH to 17 levulinate is added to the reaction mixture 18 under nitrogen and it is heated with good stirring at reflux 19 for 5 20 The total amount of water in this reaction is about 21 moles per mole of phenylhydrazine 22 The reaction mixture is allowed to cool to and 23 3 of water The water layer is separated and the organic phase diluted with an additional of 25 The mixture is aged in the refrigerator for 26 9 hours and The is washed with cold 29 is established by analysis and by comparison with an authentic of with t levullnate to prepare EXAMPLES 2 6 The following table illustrates varying process conditions which are used in accordance with the process of this invention to prepare the compound 3 10 Salt1 HC1 T e6 PH7 Base T9 2 H EtO Na 20 20 50 NaOH 70 7 3 Me MeO Na 5 55 10 4 4 Et EtO Na 3 25 16 R 5 5 Pr MeO N2 16 25 20 K OH R 6 Bu EtO K2 5 25 2 R 6 Alkali metal salt of phenyl ydrazine Used in anhydrous In either concentrated 10 or anhydrous Total moles of water in reaction mixture per mole of sulfonate 5 Temperature in decrees Centigrade for formation of Time of reaction in pH of reaction medium for reaction with Concentrated aqueous 1 Examples 2 through were carried out on initial 2 reaction mixtures which were purged by alternate nitrogen and 3 vacuum in accordance with the procedure of Example 1 In Examples 3 and 6 the vacuum step is EXAMPLE 7 6 acetate 7 Sodium sulfonate 8 is slurried in 10 parts of anhydrous 9 slurry is cooled to about and two moles of anhydrous 0 hydrogen chloride is bubbled into the mixture with 1 The stirring is continued for 25 hours and anhydrous ammonia 2 is bubbled in to adjust the pH to 3 by testing aliquots in The levulinate is added to the reaction mixture under nitrogen and the mixture is heated under reflux for 6 6 The product is isolated as described in Example 7 EXAMPLE 8 8 Preparation of indolyl acetic acid 9 To a stirred suspension of of sodium hydride 0 oil in of dry benzene is added under 1 a solution of l 2 indolyl acetate in 200 of dry The mixture is 3 then heated to reflux until the theoretical amount of hydrogen The mixture is cooled to and 15 of chloride is added dropwise with good 6 After the mixture is poured into one liter 7 of acetic The organic layer is washed 8 thoroughly with saturated dried 9 over magnesium sulfate treated with charcoal and evaporated 1 being re The crude product is boiled 2 with 300 milliliters of Skellysolve cooled to room 3 treated with concentrated to 100 milliliters and to 5 A mixture of 1 gram of the acetate prepared as described and powdered porous is 7 heated in an oil bath at with magnetic stirring under 8 a blanket of nitrogen for about 2 After cooling 9 under the product is dissolved in benzene and 10 and extracted The aqueous solution 11 is filtered with suction to remove neutralized with 12 acetic and then acidified weakly with dilute hydrochloric 13 The crude product is recrystallized from aqueous ethanol and dried in vacuo at 6 151 insufficientOCRQuality

Claims (1)

1. p rocese for the preparation of alkox and derivatives thereof having the general in which hydrogen or lower alkyl containing up to 4 carbon atoms and is lower wherein in a first stage an alkali metal salt of a alkox drazine sulfonate is reacted in an inert atmosphere with at least 2 moles of hydrogen chloride at a temperature of from about to about optionally in the presence of water and in a second stage hydrochloride of the alkox phenylhydrazlne thus formed is without being with at least one preferably an excess of up of a levulinate of the general in which has the same meaning at a pH of from about to about preferably to and at a temperature between about and the reflux temperature of the A proceas according to Claim which carried out in the presence of from 3 to 20 moles of water per mole of sulfonate A process according to Claim 1 or wherein the alkali metal salt is a sodium or potassium A process according to any of Claims 1 to wherein the first reaction stage is out at a temperature between and process according to any of Claims 1 to wherein the first reaction stage is carried out course of 10 to 50 preferably 16 to 24 A process according to any of Claims 1 to wherein the second reaction stage is carried out the course of 4 to 7 preferably 5 to process according to any of Claims 1 to 6 for the preparation of wherein an alkali metal salt of sulfonate and levulinate of the formula II in Claim 1 in which is are used as starting A process for the preparation of compounds of formula I in Claim 1 according to any one of the preceding claims substantially as hereinbefore described with reference to the tor insufficientOCRQuality