IL27173A - 1-carboxylic acyl-3-indolyl alkanoic acid derivatives and method for their preparation - Google Patents

Description

J NOVEL METHOD FOH ACID DERIVATIVES This invention relates to a method preparing acid derivatives represented by the an alky alkadienyl group or alkenyl group having up to carbon and a or lower is R is an alkoxy group having up to carbon group or a hydroxy is a alkyl or halogen 0 or and n is 0 or an integer of from 1 excluding o The alkanolo derivatives represented fey the general ormula 1 Obtained in high yields reacting at an elevated temperature a hydrazine a salt represented by the general wherein and the same signifcances as de ined with an acid derivative represented by the general an organic solvent in the presence or absence of a suitable condensing reaction of the present invention proceeds smoothly even no solvent is used in some the use of suitable solvents is For in the condensation of free it is able to use organic acids such as lactic and butyric solvents as benzene or organic solvents such as and while in condensation of aoid it desirable to suitable in addition to said The reaction progresses at ature within the range of from to about but the adoption of a temperature range of from to is the most The condensin agent is not bat the of inorganic acids such as sulfuric and phosphoric acids gives favorable in The reaction reaction temperatures and condensing agents raised as and invention is not limited The method of the present invention extremely not only the synthesis is entirely unknown hut of the starting hydrazine derivatives salts are novel That the synthesis of compounds having ions by groups is described for Chapter pages and and Compounds with Indole and pages the synthesis compounds in accordance with the method of the present invention has never been reported nor described in any Japanese or foreign literature of new the method of the present invention is entirely earboxyllc aoyl groups of compounds are so by acid or alkali that it has been considered impossible to obtain derivatives from corresponding hydrazine derivatives by Suvorov et e 1762 9β have recently reported about this problem as They have explained that does not proceeed without of a hydrazine compound because freedom of pair is necessary for formation of new present were able to find that compounds can directly synthesized frost phenyihydrazines according to the novel The process of the present invention be explained by the reaction wherein and and have the same meanings as identi ied acids have synthesized according t a process carried out said if hydrolyzing the ester to free the al has been markedly complicated low in accordance with the method of the present acids can he synthesized in extremely high yields and no such complicated operations ae in the conventional process are present greatly advantageous not only for scale production for scale The indolyl alkanoic acid derivatives obtained according to the method of the present invention have prominent actions as analgesic and and are markedly useful acid derivatives easily obtainable in accordance with the method of the present invention are for indolylpropionic and ethyl The resulting indole derivative represented by the single In the method of the present when the alfcanoie acid compound of which in the formula ie group reacts with a hydrazine or a salt thereof of the formula the resulting acid compound is in some cases so that becomes in its formula as shown reaction temperature adopted this is from preferably from to As the there are used organic acids such as propionic and lactic acids inert organic solvents such as benzene and or other various organic solvents such as acetonitrile As the condensing there are employed inorganic such as hydrochloric and sulfuric metal halides such as zinc chloride or boron The above method of the present invention requires no complex or procedures and is extremely high in yield as compared with the conven ional The above method there ore markedly advantageous not only laboratory scale production but also for commercial scale One example of the this method is as In accordance with method the following compounds are Indolylacetio indolylacetio ic acetic io io the 1 alkanoio aoid represented by the oan be obtained by reacting an derivatives represented by the general wherein and as defined and B is a ketone or an aldehyde with a ketone represented by the formula As solvents there used organic acids such as lactic and butyric organic such benzene and or The reaction proceeds at a temperature within the range of from to but a temperature of f to is Condensin agents employed are inorganic such as hydrochloric and sulfuric metal halides as zinc chloride and copper heavy metal heron fluorides or polyphosphoric The is starting material employed in the above synthesized in the following That a phenylhydrazine derivative is reacted in a suitable with a ketone or aldehyde compound to yield a corresponding compound which is then acylated with in a pyridine whereby the derivative represented by the formula As a group which itself takes no or that in a solvent the presence of there been established the following According to this following compounds l Methyl Ethyl propionic l 1 o f The derivatives and salts thereof shown which are starting materials employed in the present are also novel Hydraaone derivatives represented by the general wherein and 6 are as defined and hydrazine salts represented by the general wherein and are as defined compounds are prepared in the following manners derivatives represented by the general formula wherein and B are as defined are reacted under suitable conditions with compounds represented general C II wherein is defined and 7 is a halogen atom or ester to obtain the novel derivatives represented by the formula or the novel derivatives represented by the formula The above reaction proceeds through the course of and in order to obtain the compounds of the formula or the derivatives represented by the should be 2 used as starting In ease has been acylated without having been covered with suitable ketones or symmetrical hydrazine compounds also are That in above the reaction progresses according to the equations v Ketones aldehydes to he used to cover are not particularly limited and any of these may he In it is desirable to use those which about no side reactions and which are inexpensive and are practical for commercial Suitable of these for chloral and According to the above the following hyd derivatives San be hyd hyd In reacting the hydrazone derivatives represented by the formula with the compounds represented by the the bonds been weakened by means of there are general the derivatives represented by formula fo example the ease of such compounds of aee or the has been effected under relatively severe the bonds are easily broken after aeylation directly give hydrazine of the in place of derivatives of the ormul For and are directly Obtained from hydrazines corresponding As the ac l ting carboxyllc aoyl halides are most the reaction well by use carboxyllc acid anhydrides to sometimes give th the novel hydrazine derivatives represented by the formula and salts thereof are obtained in high yields by the acid decomposition of the hydrazone derivatives represented by the formula AJ the phenylhydrazone derivatives represented by the formula are used various ketone compounds or aldehyde compounds such fo met methyl levulinate above desirable to use compound which oan be readily decomposed completion of reaction and no reaetlon that lowers the yield and which is easily In view of these it may he said that is As the solvents to be used in the decomposition of said alcohols are in ease more than an equivalent of alcohol is used in it is also possible to us an ordinary inert solvent eueh for benzene or For an acid is used in tout an organic may alee be used in some However the use of an organic acid is not preferable in most becaus not only the reaction yield is but side reactions are liable to be brought inorganic are and phosphoric In this more yields can be attained in a dry state than in wet The reaction terminates in a short period even at a low temperature and is markedly high in the desired hydrazine derivatives are obtained in the form of and therefore crystals thereof can be easily obtained either by ooncentrating the solvents or by cooling the reaction when these salts are added to an alkali even hydrazine derivatives can quantitatively be According to the above there are for and and sulfates and phosphates of said The new compounds according to the present invention have and static and are markedly In additio the are also important as intermediates for arious medicines such or and atherosclerosis the alkanoic acid derivatives represented the formula can also obtained according to the following That phenylhydrazone derivatives represented by the general formula wherein and are the same as in the case of formula are reacted in a suitable solvent with the oarboxylie represented by the formula to prepare the alkanoic acid represented by the formula Suitable solvents employed in the above method are inert acids and organic aoid As the inert there are tetrahydrofuran and as the organic and heptanoic and as the organie acid ethyl methyl methyl methyl valeriate and methyl As the aoyl compound represented by the aeyl chloride is most frequently In addition oarboxylie aeyl bromide or oarboxylie acid anhydride may also The reaction temperature is from to preferably from to the reaction is complete in about several after completion of the the solvent is concentrated acetic water or petroleum ether is a desired product is and when the product concentrated after extraction with benzene or a purified product can be According to the above the following compounds are Methyl Ethyl Methyl Benzyl Tetrahydropyranyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl All these l acid esters are novel compounds and analgesic and antipyretic Furthe some of these such as for benzyl ester and tetrahydropyranyl are by suitable treatment to become aliphatic The free type are higher in pharmacological activity than the ester type The aeld can also be prepared according to the following That oompounds represented by the general formula n are as defined 7 is an amino or are decomposed to obtain on scale novel acid derivatives represented by the general formula wherein and n as defined For a benzyl ester of a acid derivative is hydrogenated in the presence of a suitable metal whereby the ester is decomposed to give a free indolyl alkanoio acid The reaction for as when a tertiary butyl ester of said acid treated in the presence of an sulfonlc sulfonic is hydrolyzed to give the desired There are some cases where the desired product sometimes ia obtained by mere heating and melting the tertiary butyl The reaction for as 3 when a acid is treated in inert solvent in the presence of a suitable amount of nitrous a free indolyl alkanoic sometimes Aceording to the above the following compounds be indolylacetic indolylacetic indolylaoetio indolylacetio indolylaoetio indolylacetio indolylacetic Indolylaoetio io Aa another method for preparing acid compounds represented by the general foriaula there is the following That acid derivatives represented by the formula can he obtained by dehydrating or simultaneously acid derivatives represented by the general wherein R R R and R are as This reaction in by heating the compounds in an inert solvent with The reaotlon progresses so far as the heating temperature is in the range of to in case the reaotlon does not proceed the compound either azeotropically refluxed as toluene or xylene which bolls togethe with or heated In the presenoe of a suitable dehydrating proper amount of anhydrous sodium whereby a dehydration reaotlon takes In case is such group as the compound treated in the presence of an sulfonio whereby the compound is hydrolyaed without effecting the acid amide bond to give the desired free The the starting material of the above process is obtained by adding a ester to derivative corresponding thereto heating the mixture with stirring in organic solvent in the presence of sine grains if a small piece of One example of above reaction is when the dehydration reaction and lace tic According to the aoove the following novel compounds are l ic i l ic 3 ic the desired alkanoic acid can also be obtained according to the following That the alkanoio aoid derivatives represented by the formula can be obtained by dehydrogenating l alkanoic aoid derivatives ed by the general wherein and are as defined In this dehydrogenation solvent such as xylene and toluene and other various organic solvents as acetic ethanol and can be As selenium halogen and the like oxidizing agents are According to the above the ollowing compounds can be easily propionic indolylaoetlo The starting material acid derivative is obtained in high yield by reacting a aeid derivative corresponding thereto with chloride in the presence of an alkali he aeid derivatives obtained in accordance with the present invention are useful compounds which have markedly excellent analgesic and actions as as and For is a novel compound has never been reported in any According to pharmacological the above compound markedly low toxicity is excellent in pharmacological activity and its therapeutic ratio is extremely as will understood from the following Of developed indomethacin is greatest in the activity hut is accordingly high in The present inventors also observed that even when of said medicine was orally a rat showed an occult In addition all the conventional drugs tend to promote the bleeding of digestive organs and not few examples been reported that pe folations of the stomach and intestines brought to phenylbutazone which is most widely used as antiphlogis ic at has low activity in comparison to its high acute toxicity and hence has a considerably small therapeutic In contrast to the above the acid is markedly low in and even when of said aeid is orally administrated to each of rat and they scarcely show and occult bleeding negative in excrements the of the is higher than those of phenylbutazone and the therapeutic ratio thereof is far greater than any other the aeid a compound markedly high in practical In addition indoly aeid and aeid show substantially similar pharmacological Most of these have higher and antipyretic activity tha and these compounds have preventive on experimental atherosclerosis and significant blood cholesterol lowering e method of the present invention will he illustrated further in detail but the examples are only for illustrative and are no to be construed as the scope of the Example 1 hydrochloride and of levulinic were heated with stirring at for 1 hour After the reaction liquid charged with wate and deposited precipitate recovered by filtration and was whereby of crude crystals of aeid were crystals were from ethanol to obtain a pure product having a melting point of According to the process of Example a corresponding hydrazine derivative hydrochloride and an derivative were heated with stirring at for hours to obtain in high yields the compounds as enumerated Example 2 Example 3 indolylacetic ion solvents Example hydrochloride and of were to 20 of acetic and the mixture was heated with stirring at for 2 To the reaction liquid was added 60 of and deposited precipitate was and was dried to obtain of This product was with acetone to obtain a pure produot having a melting point of Even when the above reaction was effected using as in place of propionic lactic butyric or desired products were obtained in high Example 5 The prooess of Example was repeated using methanol instead of acetic acid as solvent to obtain methyl as a light yellow oily Example 6 of hydrazine and 1 of levullnle were added to 30 of glaeial acetie To the mixture was farther added about 2 of concentrated hydrochloric and the resulting mixture was heated with stirring at for 2 After completion of the the deposited precipitate filtered and was whereby of acid was This was to obtain a pure product having a melting point of 7 20 of hydrazlne hydrochloride was added to of and the mixture was with stirring at for After completion of the the reaction liquid was charged in 200 of cold and the resulting substance was and extracted with and then ether was whereby crude crystals of aeld were The crude crystals were with a mixed solvent of ether and alcohol to obtain of a pure yield According to the process of the following compounds were Example 8 acetone Example 9 Ethyl an oily Example 10 Ethyl an oily 1 20 o hydrazine hydrochloride was added of levulinic the mixture was heated with stirring for 2 Thereafter the reaction liquid was charged in of cold the resulting precipitate was filtrated and was of oryetale of indolylaeetio acid were crystals were with to Obtain of a Example of hydrochloride and 10 of valeric were added to o and the mixture was heated with stirring at for 2 the reaction liquid was charged in 150 of cold and the resulting precipitate was filtered and was whereby 10 of crude crystals of acid were The crude crystals recrystallized with obtain of a pure According to process of Example the following compounds Example Example indolylacetle Example indolylaeetio Example iO of hydrazine and 9 of benzyl levulinate were heated and stirred in 30 of and the resulting crystals were removed by The filtrate was concentrated under reduced pressure and the concentrate was washed with cold whereby an oily substance was The oily substance was treated with to obtain According to process of Example the following compounds were Example Benzyl an oily JT 19 20 of drazone and of pyridine were dissolved in of anhydrous the ohloroaoetyl chloride was added dropwise over a period of about minutes at while cooling with the solution was stirred while further cooling with to deposit a The precipitate was filtered and was then washed with 50 of cold filtrate and the washings were and the resulting liquid was concentrated to about the original To the 60 of anhydrous ethanol was and a dry hydrogen chloride gas was duced the while cooling with After stirring the liquid with the deposited crystals were collected by were washed with ether and were then dried to Obtain of This hydrochloride was treated with a aqueous sodium carbonate solution to obtain substantially quantitatively free which was then ethanol to obtain a pure product having a melting point of Example 20 21 of aoetaldehyde methosyphenylhydrasone was dissolved 60 of To the 21 of was added while strongly cooling with the the temperature was maintained at to time required fo the addition was about 20 The reaction liquid was allowed to stand overnight with and was then treated with 300 of cold water to deposit The crystals collected by filtration and were then dried to obtain of crude crystals of acetaldehyde Example 2i According to the process of Example acetaldehyde gave dehyde yield Example 22 of acetaldehyde was dissolved in of anhydrous To the ehloroacetyl chloride was added dropwlse at over a period of about After allowing the solution to cool the resulting tate was iltered The iltrate was concentrated under reduced pressure and the concentrate was charged petroleum ether to deposit a The precipitate was filtered and was then dried to obtain of crude crystals of acetaldehyde Example 23 o phenylhydrazone of methyl luvulinate chloroacetyl ehloride was added with cooling and the solution was allowed to stand at room temperature for several The reaotlon liquid was then charged in oold water obtain an This oily substance was treated and puri with aqueous ethanol to obtain 2k According to the process of Example was treated with acetyl chloride to obtain substantially a ively crude crystals of aeetaldehyde Example 25 Aocording to the process of Example aeetaldehyde was treated with ehloride to obtain aeetaldehyde N Example 26 According to the process of Example aoetaldehyde was treated with chloride to obtain substantially aeetaldehyde Example According to the process of Example was treated with chloroacetyl chloride to obtain benzaldehyde S According to the prooeee of Example aeetaldehyde treated with chloride to Obtain in a yield of According to the process of aeetaldehyde was treated with acryloyl chloride to obtain in a yield of aeetaldehyde According to the proceae of aeetaldehyde was treated with orotonyl chloride to Obtain in a yield of aeetaldehyde According to the process of aeetaldehyde was treated with acetyl chloride to ohtaln substantially quantitatively aeetaldehyde According to the process of aeetaldehyde was treated with acetyl chloride aeetaldehyde Example According to the process of Example acetaldehyde was treated vith chloride to Obtain in a yield of about acetaldehyde Example 3 Example 9k of acetaldehyde was added to 60 of pyridine and of To the 03 o chloride was added dropwise over a period of while cooling with The mixture was stirred at ature for 3 hours to deposit a The was separated by and concentrated to a small To the iOO of ethanol was and a dry hydrogen chloride gas was introduced into the resulting liquid with whereby a large amount of crystals were The liquid was stored in a refrigerator for one and the crystals were collected by f ltration and were then washed with ether to obtain of Example 36 According to the process Example benzaldehyde was treated with acetyl chloride to Obtain 37 According to the process of Example Z of acetaldehyde was treated with chloride obtain of hydrazine yield Example According to the process of Example of acetaldehyde was treated with chloride to obtain 67 of op Example 39 of aeetaildehyde azone was dissolved in 200 of Into the solution a dry hydrogen chloride gas was with excess hydrogen chloride was removed under reduced pressure whereby a large of crystals were crystals yield to the process of hydrasone treated to obtain According to the process of hydrazonerepresented by the following was treated to obtain Quantitatively Example 2 According to the process of Example treated to obtain substantially quantitatively This hydrochloride was added to a sodium carbonate whereby free was quantitatively The thus produced was with ethanol obtain product having a melting point of Example Accordin to the of Example seetaldehyde was treated 1 to obtain According to the process of Example acetaldehyde was to hydrazine e 5 According to the process of Example acetaldehyde 1 hydrazone treated to obtain according to the process of Example d hydrochloride was treated obtain free US According to the process of 3 aeetaldehyde th was treated to 21 of p yield Example hi Aeoording to the process of Example 3 20 of aeetaldehyde treated to obtain of yield Example Aeoording o the process of Example 5 of aeetaldehyde was treated to obtain 80 of ine Example of aeetaldehyde ylhydrazone was suspended in 300 of Into a dry hydrogen chloride gas was introduced to After allowing the suspension to stand for several ether was added until precipitate was and the reaction liquid was stored with cooling overnight to deposit a large amount of crystals were According to the process of Example 13 of was treated to obtain 10 hydrazine yield to the process of 105 of acetaldehyde was treated to obtain of yield According to process of Example acetaldehyde treated to to the of aldehyde was treated to obtain Example According to the process of Example wee treated to obtain Example 55 According to the process of Example aeetaldehyde was 1 treated to obtain N Example Acoordlng to the process of Example acetaldehyde was treated to Obtain Example 57 to the process of Example acetaldehyde was treated to obtain 58 According to the process of Example acetaldehyde hydrszone treated to obtain of was added to 45 To the mixture was further added slfonic and the mixture was After the reaction mixture was washed with 30 of a aqueous sodium bicarbonate was successively washed several times with water and was benzene was removed by distillation unde reduced and the ion mixture was purified by recrystalllzation with acetone to obtai Elementary analysis H Calculated According to the above the following compounds were Example 60 Elementary analysis it Calculated Found 7b Example Elementary analysis C H Calculated Found Example 62 indolylaoetio Elementary C Calculated Found 7 5 Example 63 of hydrochloride and of were heated at with stirring in 10 of aeetie aeld for After the mixture was charged in oold water to deposit The were recovered iltration and were whereby of crude cryatale of 2 aeld were were zed to obtain light yellow According to the same process as the following compounds were obtained soldi Example 65 Example 66 of ldehyde was added to 50 of levulinic and of dry hydrogen chloride was introduced into the mixture with Thereafte the temperature was gradually elevated and the mixture heated at for 3 After allowing to stand whereby a resinous substance The resinous substance was alcohol and acetone with active carbon to Obtain beautiful crystals of According to the same process as the following were t Example lace Example of of 300 of toluene and 3 of aeid wee heated at for 3 hours with After completion of the the reaction mixture washed with water three and the toluene layer was dried over anhydrous sodium Thereafter the toluene solution was concentrated and allowed to stand in a refrigerator to give erode crystals of from gave pure analysis ι Found Example According to the process of Example the following compound was obtained Example 72 of of methyl was to of glacia To the of acetyl chloride was added the mixture was heated at for 3 the mixture was charged with stirring in 50 of cold whereby an oily substance was The oily substance was extracted with ether to obtain methyl Infrared absorption spectrum of this product entirely coincided with that of a standard product prepared by the of methyl In the reaction of Example of anhydride was used in place of of acetyl whereby methyl indolylaeetate was obtained as Example 7k of aeid was added to of and of chloranil was further added The reaction mixture was heated and refluxed 4 with acetone and insolublee were the acetone solution was dried crude of indolylacetic acid were The crystals were recryatallized from to obtain a light yellow pure According to the of Example the following compound was produced Example 75 insufficientOCRQuality

Claims (1)

1. A compound of the CO wherein is an alkyl alkyl alkadienyl group or alkenyl group having up to carbon R2 and are a hydrogen or lower alkyl is an alkoxy group having up to carbon group or a hydroxy is a lower alkyl alkoxy group or halogen is is 0 or and n is 0 or an integer of from 1 to acid A process producing acid compounds of the formula given in claim which i comprises reacting an N acid phenylhydrazine compound of the wherein R R have the same meanings as in claim with an alkanoic acid compound of the wherein Λ the meaning as in 1 to A producing alkanoic according to claim wherein the phenyl compound is prepared lbayy compound the 1 and have the meanings aa and la a or an aldehyde with a decomposing A process for producing aold aeeording to claim 3 wherein the aeyl compound is prepared reacting a compound of the has the same meaning as in claim 1 and B la a ketone or an aldehyde with a compound having the CO i wherein has the same meaning as in claim i and ie a atom or an ester Λ process for producing acid according to claim wherein the phenyl hydrazine compound is prepared by reacting a compound of the formulas wherein has the seme meaning as in claim 1 and B a ketone or an aldehyde the bonding of the compound being comparatively with a compound having the formulat CO wherein R has the same meanings as in and represents halogen or an ester Λ method for preparing aeid represented by the general CO wherein end n have the same meaning as in claim 1 end is a lower group or a group which comprises reacting a phenylhydrasone derivative represented by the general wherein and n are defined a acyl compound represented the general τ CO wherein as defined and Y is a halogen atom or ester residue to yield the aeld A process for producing acid compounds of the formula given in which comprises reacting an acyl phenylhydraizone compound of the wherein have the same meanings as claim 1 and B is a ketone or an aldehyde with an aeld oompound of the n and have the same meaning as in claim 1 to yield the acid process producing aeld compounds according to claim the phenylnydraizone is prepared by reacting a phenylhydrazone compound of the wherein the meaning as in claim and B is a ketone or an aldehyde with a compound having the Y t CO f wherein the meanings as in claim 1 and Y a halogen atom or an ester process for producing ac t wherein and n have the meaning as in claim 1 and is an or which comprises hydrolyzing a compound represented by the general wherein and are as defined and is an or group to yield the acid process for producing acetic acid derivatives represented by the general R and the meaning as in claim 1 which comprises dehydrating or simultaneously l a indolylacetic acid derivative represented by the general formulas CO t 1 6 wherein R R end R are as defined and is a A process for producing indolyl alkanoic derivatives represented by the general formulas wherein and have the same meaning as in which comprises alkanoic aeid derivative represented by the general wherein and are as above to the acid 1 A process for producing indolylalkanoic acid derivatives represented by the general m wherein have same meaning as in claim 1 and is hydrogen halogen group or which comprises reacting an aoylated a represented by the general wherein and are as de with acid derivative represented by the general wherein and are as de ined above to yield the acid A proeees the preparation of aeid compounds of the formula given in claim substantially as hereinbefore described with reference to the aeid compounds of formula given in claim whenever prepared by process according to any claims 2 to A pharmaceutical composition as compound as claimed in claims 1 or and an inert pharmaceutical diluent or Attorney for App cants insufficientOCRQuality