NO122423B

NO122423B -

Info

Publication number: NO122423B
Application number: NO427869A
Authority: NO
Inventors: G Gal; M Sletzinger
Original assignee: Merck & Co Inc
Priority date: 1964-04-13
Filing date: 1969-10-29
Publication date: 1971-06-28

Description

Fremgangsmåte ved fremstilling av sub- Procedure for the production of sub-

stituerte 3- indolyl- eddiksyreforbindelser substituted 3-indolyl-acetic acid compounds

Foreliggende oppfinnelse angår en ny fremgangsmåte ved fremstilling av 3-indolyl-eddiksyreforbindelser med en halogenbenzoylgruppe bundet til nitrogenatomet i indolringen. The present invention relates to a new method for the production of 3-indolyl-acetic acid compounds with a halobenzoyl group bound to the nitrogen atom in the indole ring.

3-indolyl-eddiksyrer acylert i N-l-stillingen i indolringen med en halogenbenzoylgruppe har vist seg å være sterke anti-inflammatoriske midler. Fremstillingen av disse materialer innbefatter i alminnelighet acylering av en 3-indolyl-eddiksyreester som er usubstituert i N-l-stillingen under dannelse av en N-halogen-benzoyl-3-indolyl-eddiksyreester, fra hvilken den frie syre kan er-holdes. Det har imidlertid vist seg at N-acylgruppen lett hydro-lyseres og derfor under de vanligvis anvendte betingelser ved for-såpningen av esteren til den frie syre, går tapt. Av denne grunn må forsiktighet utvises ved overføringen av de N-acylerte indolyl- 3-Indolyl-acetic acids acylated at the N-1 position of the indole ring with a halobenzoyl group have been shown to be potent anti-inflammatory agents. The preparation of these materials generally involves acylation of a 3-indolyl-acetic acid ester which is unsubstituted in the N-1 position to form an N-halo-benzoyl-3-indolyl-acetic acid ester, from which the free acid can be derived. However, it has been shown that the N-acyl group is easily hydrolysed and is therefore lost under the usually used conditions during the saponification of the ester to the free acid. For this reason, care must be taken when transferring the N-acylated indolyl-

eddiksyreestere til de tilsvarende frie syrer. En bekvem metode for å utføre denne overføring innbefatter acylering av de tertiære estere av N-usubstituerte indolyl-eddiksyrer, da de således dannede tertiære N-acylerte indolyl-eddiksyreestere kan overføres til de frie N-acylerte indolyl-eddiksyrer ved pyrolyse uten i særlig grad å bevirke fjerning av N-acylgruppen. acetic acid esters to the corresponding free acids. A convenient method of carrying out this transfer involves acylation of the tertiary esters of N-unsubstituted indolyl acetic acids, since the tertiary N-acylated indolyl acetic acid esters thus formed can be transferred to the free N-acylated indolyl acetic acids by pyrolysis without particularly to effect removal of the N-acyl group.

N-halogenbenzoyl-3-indolyl-eddiksyreforbindelsene som fremstilles ved foreliggende fremgangsmåte, har den generelle formel: The N-halobenzoyl-3-indolyl-acetic acid compounds produced by the present method have the general formula:

hvor R^ er halogenfenyl, where R^ is halophenyl,

Rr, er lavere alkyl, og Rr, is lower alkyl, and

er lavere alkoxy, og salter og estere derav. is lower alkoxy, and salts and esters thereof.

Den mest foretrukne forbindelse som fremstilles ifølge oppfinnelsen , er l-p-klorbenzoyl-2-methyl-5-methoxy-3-indolyl-eddiksyre. The most preferred compound produced according to the invention is 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl-acetic acid.

Ifølge oppfinnelsen fremstilles forbindelsene av formel I ved at (a) en forbindelse av formelen: According to the invention, the compounds of formula I are prepared by (a) a compound of the formula:

hvor R og R^ er som ovenfor angitt, tilsettes til en oppløsning av eddiksyre og vandig dialkylamin og t-butylglyoxylat ved ca. 10°C, og at reaksjonsblandingen eldes i ca. 3 timer for å danne den tertiære butylester av den tilsvarende 3-indolyl-eddiksyre med en di-laverealkylaminogruppe i a-stillingen i eddiksyre-sidekjeden, (b) at en suspensjon av den erholdte forbindelse og natriumhydrid i et inert oppløsningsmiddel oppvarmes ved ca. 8o°C inntil den teoretiske mengde hydrogen er avspaltet, (c) at reaksjonsblandingeri fra det foregående trinn avkjøles til ca. 10°C og tilsettes en forbindelse av formelen R^COX, hvor X er halogen eller p-nitrofenoxy, og hvor R^ er som ovenfor angitt, idet where R and R^ are as indicated above, is added to a solution of acetic acid and aqueous dialkylamine and t-butylglyoxylate at approx. 10°C, and that the reaction mixture is aged for approx. 3 hours to form the tertiary butyl ester of the corresponding 3-indolyl-acetic acid with a di-lower alkylamino group in the a-position of the acetic acid side chain, (b) that a suspension of the compound obtained and sodium hydride in an inert solvent is heated at approx. 8o°C until the theoretical amount of hydrogen is split off, (c) that the reaction mixture from the previous step is cooled to approx. 10°C and a compound of the formula R^COX is added, where X is halogen or p-nitrophenoxy, and where R^ is as indicated above, as

temperaturen holdes ved IO - 15°C i ca. 1 time, the temperature is kept at 10 - 15°C for approx. 1 hour,

og at a-di-laverealkylaminogruppen i sidekjeden fjernes ved katalytisk hydrogenering i et surt medium enten efter trinn a) eller and that the α-di-lower alkylamino group in the side chain is removed by catalytic hydrogenation in an acidic medium either after step a) or

c) , og c) , and

(d) at den erholdte aroylerte ester pyrolyseres i et inert organisk (d) that the aroylated ester obtained is pyrolyzed in an inert organic

oppløsningsmiddel, solvent,

og at den erholdte forbindelse, om ønskes, overføres til et salt eller en ester derav på i og for seg kjent vis. and that the obtained compound, if desired, is transferred to a salt or an ester thereof in a manner known per se.

Foreliggende fremgangsmåte kan videre illustreres ved følgende prosessdiagram: The present method can be further illustrated by the following process diagram:

Trinn 1: Sidekjededannelse: Kondensasjon av en indol med dialkylamin og t-butylglyoxylat for å danne en a-aminoindol-3-carboxylatester. Step 1: Side chain formation: Condensation of an indole with dialkylamine and t-butylglyoxylate to form an α-aminoindole-3-carboxylate ester.

Trinn 2: Acylering: Se nedenfor. Step 2: Acylation: See below.

Trinn 3= Hydrogener ing: Fjernelse av a-aminogruppen ved omsetning Step 3 = Hydrogenation: Removal of the α-amino group by reaction

med hydrogen for å danne en pyrolyserbar ester. with hydrogen to form a pyrolyzable ester.

Trinn 4: Pyrolyse: Se nedenfor. Step 4: Pyrolysis: See below.

Ved foreliggende fremgangsmåte kondenseres en indol (II) som er usubstituert ved 3_stillingen, i en Mannich-reaksjon med et dialkylamin og t-butylesteren av glyoxylsyre for å danne en side-kjede med en dialkylaminogruppe i a-stillingen på indol-sidekjeden (trinn 1). Dialkylaminogruppen fjernes så ved direkte hydrogenering ifølge trinn 3 for å danne t-butylester-mellomproduktet (IV), som så acyleres og pyrolyseres som beskrevet nedenfor for å få den ønskede syre (I) . In the present method, an indole (II) which is unsubstituted at the 3-position is condensed in a Mannich reaction with a dialkylamine and the t-butyl ester of glyoxylic acid to form a side chain with a dialkylamino group in the a-position of the indole side chain (step 1 ). The dialkylamino group is then removed by direct hydrogenation according to step 3 to form the t-butyl ester intermediate (IV), which is then acylated and pyrolyzed as described below to give the desired acid (I).

Acyleringsreaksjonen (trinn 2) utføres fortrinnsvis ved å be-handle 3-indolyl-eddiksyreestermaterialet med et alkalimetallhydrid, som natriumhydrid, for å danne f.eks. et natriumsalt, og derpå straks bringe dette salt i kontakt med et halogenbenzoylhalogenid i et vannfritt oppløsningsmedium. Det foretrekkes å anvende oppløs - ningsmidler som dimethylformamid, dimethylformamid-benzen, benzen, toluen eller xylen. Det foretrekkes også å utføre acyleringen ved omtrent vaerelsetemperatur, skjønt lavere temperaturer kan anvendes hvis de spesielle reaktanter er særlig tilbøyelige til spaltning. The acylation reaction (step 2) is preferably carried out by treating the 3-indolyl acetic acid ester material with an alkali metal hydride, such as sodium hydride, to form e.g. a sodium salt, and then immediately bringing this salt into contact with a halobenzoyl halide in an anhydrous dissolution medium. It is preferred to use solvents such as dimethylformamide, dimethylformamide-benzene, benzene, toluene or xylene. It is also preferred to carry out the acylation at approximately room temperature, although lower temperatures can be used if the particular reactants are particularly prone to cleavage.

En alternativ metode ved acylering av 1-stillingen er å anvende p-nitrofenylesteren av halogenbenzoesyren. Sistnevnte fremstilles ved å blande halogenbenzoesyren og p-nitrofenol i tetra-hydrofuran og sakte tilsette dicyclohexyl-carbodiimid i tetrahydro-furan. Dicyclohexylureaet som dannes, fjernes ved filtrering, og nitrofenylesteren utvinnes fra filtratet. Acyleringen av 3-indolyl-eddiksyreestermaterialet fåes ved å danne et natriumsalt av dette materiale med natriumhydrid i et vannfritt oppløsningsmiddel og tilsette nitrofenylesteren. An alternative method for acylation of the 1-position is to use the p-nitrophenyl ester of the halobenzoic acid. The latter is prepared by mixing the halobenzoic acid and p-nitrophenol in tetrahydrofuran and slowly adding dicyclohexylcarbodiimide in tetrahydrofuran. The dicyclohexylurea that is formed is removed by filtration, and the nitrophenyl ester is recovered from the filtrate. The acylation of the 3-indolyl acetic acid ester material is obtained by forming a sodium salt of this material with sodium hydride in an anhydrous solvent and adding the nitrophenyl ester.

Det neste trinn i fremgangsmåten (trinn 4) innbefatter om-dannelse av den aroylerte ester til den aroylerte syre (I). Denne overføring utføres ved pyrolyse av 'esteren. Denne metode muliggjør en selektiv fjernelse av estergruppen uten å påvirke 1-aroylsubsti-tuenten. i alminnelighet oppvarmes esteren til ca. 210°C i fravær av en katalysator. Fortrinnsvis overføres den imidlertid ved oppvarm-ning til mellom 25 - 110°C i nærvær av en katalytisk mengde av en arylsulfonsyre, som toluensulfonsyre, eller en annen sterk syre. The next step in the process (step 4) involves conversion of the aroylated ester to the aroylated acid (I). This transfer is carried out by pyrolysis of the ester. This method enables a selective removal of the ester group without affecting the 1-aroyl substituent. in general, the ester is heated to approx. 210°C in the absence of a catalyst. Preferably, however, it is transferred by heating to between 25 - 110°C in the presence of a catalytic amount of an arylsulfonic acid, such as toluenesulfonic acid, or another strong acid.

Som det fremgår av reaksjonsskjemaet, kan acyleringsreaksjonen (trinn 2) utføres på a-dimethylamino-a-(3-indolyl)-eddiksyreestermaterialet fra trinn 1 og dialkylaminogruppen så fjernes ved hydrogenering (trinn 3), og den erholdte acylester overføres til den frie syre ved pyrolyse (trinn 4)• As can be seen from the reaction scheme, the acylation reaction (step 2) can be carried out on the α-dimethylamino-α-(3-indolyl)-acetic acid ester material from step 1 and the dialkylamino group is then removed by hydrogenation (step 3), and the acyl ester obtained is transferred to the free acid by pyrolysis (step 4)•

Eksempel Example

l- p- klorbenzoyl- 2- methyl- 5- methoxy- 3- indolyl- eddiksyre Trinn 1: t-butyl-2-methyl-5-methoxy-3-indolyl-(a-dimethylamino)-acetat 15 ml eddiksyre ble tilsatt til 9 9 av en vandig 50%-ig opp-løsning av dimethylamin. Blandingen ble avkjølt til 10°C, og 13,0 g t-butylglyoxylat og 16,1 g 2-methyl-5-methoxy-indol ble tilsatt. Reaksjonen var eksoterm, og indolen gikk i oppløsning. Efter 3 timers eldning ble 4 N natriumhydroxydoppløsning tilsatt for å l-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl-acetic acid Step 1: t-butyl-2-methyl-5-methoxy-3-indolyl-(a-dimethylamino)-acetate 15 ml of acetic acid was added to 9 9 of an aqueous 50% solution of dimethylamine. The mixture was cooled to 10°C, and 13.0 g of t-butylglyoxylate and 16.1 g of 2-methyl-5-methoxy-indole were added. The reaction was exothermic, and the indole dissolved. After 3 hours of aging, 4 N sodium hydroxide solution was added to

nøytralisere syren. Det krystalliserte produkt ble frafiltrert, vasket med vann og tørret i vakuum. neutralize the acid. The crystallized product was filtered off, washed with water and dried in vacuo.

Trinn 2: Til en suspensjon av 6,0 g 50%-ig natriumhydrid i 100 ml benzen ble tilsatt en oppløsning av 31,8 g t-butyl-2-methyl-5-methoxy-3-indolyl-(a-dimethylamino)-acetat i 120 ml benzen ved 8o°C. Reaksjonsblandingen ble oppvarmet ved 8o°C inntil den teoretiske mengde hydrogen var dannet og ble derpå avkjølt ved 10°C. Step 2: To a suspension of 6.0 g of 50% sodium hydride in 100 ml of benzene was added a solution of 31.8 g of t-butyl-2-methyl-5-methoxy-3-indolyl-(a-dimethylamino) -acetate in 120 ml of benzene at 8o°C. The reaction mixture was heated at 80°C until the theoretical amount of hydrogen was formed and was then cooled at 10°C.

18,1 g p-klorbenzoylklorid i 20 ml benzen ble så tilsatt drapevis ved 10 C til 15 C. Efter en times eldning, ble 10 ml eddiksyre tilsatt forsiktig for å spalte overskuddet av natriumhydrid. De uorganiske salter ble frafiltrert, og filtratet ble konsentrert til 50 ml. Det oljeaktige residuum ble oppløst i 200 ml varm cyclohexan, og oppløsningen ble avkjølt til 10°C. Det krystallinske produkt ble frafiltrert, vasket med kold cyclohexan og tørret i vakuum. 18.1 g of p-chlorobenzoyl chloride in 20 ml of benzene was then added dropwise at 10°C to 15°C. After an hour's aging, 10 ml of acetic acid was carefully added to decompose the excess sodium hydride. The inorganic salts were filtered off, and the filtrate was concentrated to 50 ml. The oily residue was dissolved in 200 ml of hot cyclohexane, and the solution was cooled to 10°C. The crystalline product was filtered off, washed with cold cyclohexane and dried in vacuo.

Trinn 3: 4,56 g t-butyl-1-p-klorbenzoyl-2-methyl-5-methoxy-3-indolyl-(a-dimethylamino)-acetat i 25 ml dioxan ble hydrogenert i nærvær av 1,0 g palladium på trekullkatalysator. Efter at den teoretiske mengde hydrogen var absorbert, ble katalysatoren frafiltrert og oppløsningsmidlet fjernet i vakuum. Det oljeaktige residuum ble omkrystallisert fra cyclohexan. Man fikk således 3,1 g t-butyl-1-p-klorbenzoyl-2-methyl-5-methoxy-3-indolyl-acetat (smeltepunkt 105°C). Step 3: 4.56 g of t-butyl-1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl-(α-dimethylamino)-acetate in 25 ml of dioxane was hydrogenated in the presence of 1.0 g of palladium on charcoal catalyst. After the theoretical amount of hydrogen had been absorbed, the catalyst was filtered off and the solvent removed in vacuo. The oily residue was recrystallized from cyclohexane. 3.1 g of t-butyl-1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl-acetate were thus obtained (melting point 105°C).

Trinn 4'- Til en oppløsning av 500 mg p-toluensulfonsyre i 8o ml benzen ble tilsatt 10 g av den ovenfor fremstilte acylerte ester. Blandingen ble oppvarmet under tilbakeløp i en time (i løpet av denne tid ble 600 ml isobutylen dannet). Step 4'- To a solution of 500 mg of p-toluenesulfonic acid in 80 ml of benzene was added 10 g of the acylated ester prepared above. The mixture was heated under reflux for one hour (during which time 600 ml of isobutylene was formed).

Reaksjonsblandingen ble så avkjølt til 6o - 65°C og vasket en gang med 25 ml vann inneholdende 1,0 g natriumacetat og to ganger med 25 ml vann. Den varme benzenoppløsning ble så tørret over natriumsulf at, avfarvet ved tilsetning av 1,0 g trekull, filtrert varm og konsentrert til et volum på 30 ml. Den gulfarvede oppløs-ning ble avkjølt til 10 oC og eldet i 2 timer. Det ra produkt ble filtrert og omkrystallisert fra t-butanol og tørret i vakuum ved 8o°C, hvorved man fikk 7,0 g (8l%) med smeltepunkt 153 - 154°C. The reaction mixture was then cooled to 60-65°C and washed once with 25 ml of water containing 1.0 g of sodium acetate and twice with 25 ml of water. The hot benzene solution was then dried over sodium sulfate, decolorized by the addition of 1.0 g of charcoal, filtered hot and concentrated to a volume of 30 ml. The yellow colored solution was cooled to 10°C and aged for 2 hours. The crude product was filtered and recrystallized from t-butanol and dried in vacuum at 80°C, whereby 7.0 g (81%) with melting point 153 - 154°C were obtained.

Claims

Procedure for the preparation of substituted 3-indolyl-acetic acid compounds with the formula:

where R is halophenyl, R2 is lower alkyl, and R^_ is lower alkoxy, and salts and esters thereof, characterized in that (a) a compound of the formula: where R„ and ^ are as indicated above, is added to a solution of acetic acid and aqueous dialkylamine and t-butylglyoxylate at approx. 10 C, and that the reaction mixture is aged for approx. 3 hours to form the tertiary butyl ester of. the corresponding 3-indolyl-acetic acid with a di-lower alkylamino group in the a-position of the acetic acid side chain, (b) that a suspension of the obtained compound and sodium hydride in an inert solvent is heated at approx. 8o°C until the theoretical amount of hydrogen is split off, (c) that the reaction mixture from the previous step is cooled to approx. l0°C and a compound of the formula R^COX is added, where X is halogen or p-nitrophenoxy, and where R^ is as stated above, the temperature being kept at 10 - 15°C for approx. 1 hour, and that the α-di-lower alkylamino group in the side chain is removed by catalytic hydrogenation in an acidic medium either after step a) or c), and (d) that the aroylated ester obtained is pyrolysed in an inert organic solvent, and that the obtained compound, if desired, is transferred to a salt or an ester thereof in a manner known per se.