MXPA99010191A - Method of manufacturing sertindole - Google Patents

Abstract

A process of manufacturing sertindole comprising preparation of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine, by reacting an alkalimetal salt of 2,5-dichlorobenzoic acid with an alkalimetal salt of N-(4-fluorophenyl)glycine in an aqueous, alkaline environment in the presence of a copper catalyst;cyclisation of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine to the corresponding 3-acetoxy-indole;reduction of the 3-acetoxy-indole and subsequent elimination of H2O thereby obtaining 5-chloro-1-(4-fluorophenyl)indole which is reacted with 4-piperidone in a mixture of an acetic acid and concentrated HC1;reduction of the resulting 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole and reaction of this compound with 1-(2-chloroethyl)-2-imidazolidinon in order to obtain sertindole. Alternatively, 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole is first reacted with 1-(2-chloroethyl)-2-imidazolidinon followed by reduction thereby obtaining sertindole. This process uses reactants and solvents that are suitable and allowed in large scale manufacture. Furthermore good total yields are obtained.

Description

METHOD TO MANUFACTURE SERTINDOL Field of the Invention The present invention relates to a novel method of making the compound l- [2- [4- [5-chloro-l- (4-f luorphenyl) -lH-indol-3-yl] -l- piperidinyl] ethyl] -2- imidazolidinone, which is referred to as the recommended sertindole INN and a novel method for manufacturing the intermediates N- (4-f luo rf eni 1) -N- (2-ca rboxi-4-c 1 orof eni 1) glycol and 5-chloro-1- (4-f luorphenyl) -3- (1, 2, 3, 6-tetrahydropyridin-4-yl) indole used in the method.

BACKGROUND OF THE INVENTION Sertindole is a well-known antipsychotic drug having the following formula: The compound was disclosed in the patent No. 4,710,500 and the antipsychotic activity thereof was disclosed in US Pat. No. 5,112,838. Sertindole is a potent 5-HT2 receptor antagonist that acts centrally in vivo and has also been revealed to be active in models indicative of effects in the treatment of anxiety, hypertension, drug abuse and cognitive disorders. . Recently, it has been shown to have an antipsychotic effect in clinical studies, P sy c oph a rm a c o 1 o gy (P s i co f a r a co o g a) (1996) 124: 168-175. U.S. Patent No. 4,710,500 covered a class of l-aryl-3- (piperazinyl-, tetrahydropyridi 1_- or piperidyl) indole compounds including sertindole. A number of methods for preparing the compounds were revealed generically, some of which could be used in the preparation of sertindole The methods were: a) reaction of 1-arylindole suitably substituted with 4-piperidone 1-substituted and subsequent reduction of the compound tetr ah i dr op iridi 1 or resultant, b) arylation of the corresponding 1-unsubstituted indole compound, c) reduction of the corresponding compound having an oxo group in the 2-position of the indole ring.

The "sertindole was specifically exemplified, however, no experimental procedure was given for its preparation .. Perregaard et al., J. Me d. Ch em., 1992, 35, 1092-1101, revealed a new method for preparing sertmdol. The method comprises the reaction of the intermediate 5-chloro-l- (4-f 1 uo rfeni 1) i ndo 1 with 4-piperidone in a mixture of trifluoroacetic acid and acetic acid, reduction of 5-chloro-l- (4-f luorphenyl) -3- (1, 2, 3, 6-tetrahydropyri-di n - 4 - i 1) indo 1 in order to obtain 5 - c 1 gold - 1 - (4 -f 1 u or rf in i 1) - 3 - (p ipe r idin- 4 - i 1) indole, which in turn reacts with 1 - (2 - c 1 oroeti 1) - 2 - imi da zo 1 i di nona, in the presence of K2C03 and Kl in methyl isobutyl ketone (IBK). 5 - c 1 gold - 1 - (4 - f 1 u or rfeni 1) i 1 was obtained from 3 - acetyl oxy - nite 1 corresponding by reduction of NaBH in methanol and consequent elimination of H20, under acidic conditions The 3-acet ox i - indo 1 was prepared from N- (4-f luorphenyl) -N- (2-carboxy-4-chlorophenyl) glycine following literary procedures. In Perregaard et al., D a ns k Kem i, 95, 3 p.6-9, a process for preparing N- (4-fluorfenyl) - - (2-carboxy-4-chlorophenyl) glycine is described. By this method, glycine is obtained by catalyzed copper reaction of 2,5-dichlorobenzoic acid with N- (4-f luo r f eni) g 1 i c ina. The potassium salts of the two acids are used in the presence of K2C03 in the N-met lpyrrolidone (NMP) solvent. However, it has been found that the foregoing processes are not useful on a technical scale. Total yields are too slow and processes include the use of reagents or solvents that are not adequate and in some cases not allowed on a large scale for environmental or safety reasons. In addition, due to "the aqueous functionality of NMP, the production of the reaction is tedious, and the regeneration of NMP is expensive and takes a long time." "Accordingly, the present invention relates to a new process., useful in the production on a technical scale of sertindole. It has been found that the main process steps are the preparation of N- (4-f luo rf in 1) -N- (2 - ca rboxi - 4 - c 1 orof eni 1) gl ici na and the reaction of 5-cyclo r o- 1 - (4-f luo rf eni 1) i ndo 1 with 4-piperidone. Accordingly, the present invention provides a process for the preparation of N- (4-fluoro-phenyl-1) -N- (2-carboxy-4-chloro-phenyl) glyphide comprising the reaction of an alkali metal salt of 2,5-dichlorobenzoic acid with an alkali metal salt of N- (4-f 1 u or rf in i 1) g 1 in an aqueous alkaline environment in the presence of a copper catalyst followed by treatment with an aqueous acid according to It is illustrated in the following reaction scheme: where Mi, and M; they are alkali metal ions. According to Perregaard et al., D a n s k Kem i, 95, a reaction using the potassium salts of the reactants, is carried out in NMP. However, the use of NMP required a removable production of time consumption and the reaction supported substantial amounts of tar derivatives. The reaction temperature was 120-130 ° C. By carrying out the reaction in an aqueous environment in place of NMP, a higher yield __ and only a negligible amount of tar derivatives are obtained. In addition, the absorption process is simple and the use of an aqueous medium causes substantial environmental benefits. Finally, the reaction temperature drops to the reflux temperature of the aqueous medium or due to j o. In another aspect, the invention provides a novel process for preparing 5-chloro-l- (4-f luorphenyl) -3- (1, 2, 3, 6, -tetrah? Dropiridin-4-yl) indole comprising reaction of 5-chloro-l- (4-f 1 uo rf eni 1) i ndol with 4-piperidone in a mixture of a mineral acid and acetic acid according to is illustrated in the following reaction scheme: By using a mixture of acetic acid and a mineral acid instead of a mixture of acetic acid and trifluoroacetic acid, substantial environmental advantages are obtained. In addition, trifluoroacetic acid is very volatile and aggressive, therefore it is not undesirable for large scale production. In addition, the formation of unwanted piperidine b i s - s u s t i t u i t undesired can be avoided: Formula I In another aspect, the invention provides a novel process for manufacturing sertindole comprising the preparation of N- (4-f 1 or f 1) -N- (2-carboxy-4-c 1 oropheni 1) g 1 by a reaction comprising a catalyzed copper reaction of an alkali metal salt of 2,5-di c 1 or oben zoi co with an alkali metal salt of N- (4-f 1 u or rf in i 1) gl i ciña in an aqueous alkaline environment in the presence of a copper catalyst and / or where 5 - c 1 gold - 1 - (4 - f luor f eni 1) - 3 - (1, 2, 3, 6 - tetrahy op op i iri din- - i 1) indole, by a reaction comprising the reaction of 5-chloro-l- (4-f 1 uo rf eni 1) i ndo 1 with 4-piperidone in a mixture of a mineral acid and acetic acid. The reaction of the alkali metal salt of 2,5-dichlorobenzoic acid with alkali metal salt of N- (4-flu-phenyl) glycine is carried out at an elevated temperature, conveniently at a temperature between 80 ° C and the temperature of reflux of the medium, preferably at about reflux temperature. By the specifications and the claims, the aqueous medium is intended to include water and water to which a cosolvent is added, such as stylet glycol as the reaction medium. Preferably, water is used, such as demineralized, deionized or distilled water. The alkaline metal salts of the reactants are lithium, sodium or potassium salts and the same salts of the reactants are conveniently used. More preferably, potassium salts are used. It is important that the HCl formed during the reaction be neutralized in order to avoid unwanted collagenous reactions. The reaction medium is rendered alkaline by the addition of a base, such as an alkali metal hydroxide, an alkali metal acetate, an alkali metal carbonate, an alkali metal hydrogen carbonate, an alkali metal phosphate or an alkali metal citrate. Preferably, alkali metal carbonate, such as Li 2 CO 3, Na 2 CO 3 or K 2 CO 3, is used. Conveniently, the same alkali metal is used as that which is included in the reagents; Preferably, the base is potassium carbonate. The amount of base is preferably greater than the amount equiometrically of 2,5-dichlorobenzoic acid. On the other hand, [0H-] can cause hydrolysis of acid 2, 5 -di cl or r obe z o i co, thus decreasing the yield. Thus, the base can be conveniently added gradually during the process. The catalyst can be any Cu (O) catalyst, preferably c ob r e -b ronce. It is added in catalytic quantities. The specific amount is not critical and can be easily determined by a person skilled in the art. The ratio between the amounts of the alkali metal salt of N- (4-f 1 or rfei 1) g 1 icine and the alkali metal salt of acid 2, 5 -di cl or oben z oi co is then 0.5 to 3. , Preferably from 1.0 to 2.5, and more preferably from 2.0 to 2.3 mol / 1. The excess of N- (4-f iuo rf eni 1) gl ic ina can be regenerated. The reaction is conveniently carried out in a minimum amount of aqueous solvent still technically feasible. Thus, the performance is reduced by decreasing the amount of solvent. The amount of water is preferably less than 10 ml./g. of 2,5-dichlorobenzoic acid, more preferably less than 5 ml./g. , in particular less than 3.5 ml./g., more preferably less than 2.5 ml./g. The reaction rate is not very critical and can be readily determined by any person skilled in the art. The absorption of the product by aqueous acid can be carried out simply by addition of the filtered reaction mixture to the diluted acid, thereby precipitating the product.The product can further be purified with hot toluene or by recrystallization of ethanol. The dilute aqueous acid is preferably hydrochloric acid.In the reaction of 5-chloro-l- (4-f-1-f-1) -indo-1 with 4-p-ideo, the mineral acid used is preferably phosphoric acid. , nitric acid, sulfuric acid or hydrochloric acid, >; -30% w / w aqueous HCl, in particular concentrated hydrochloric acid. By concentrated HCl is meant approximately 37% w / w aqueous HCl. The 4-piperidone is preferably used as the hydrochloride of 4-p i p e r i dona-h i dr a t o. Preferably, the reaction should be carried out in excess of 4-p i p e r i donation hydrochloride. Preferably, more than 1.5 equivalents of 4-piperidone are used per equivalent of 5-c 1 or r o-1 - (4-f luo r t or ni) 1, more preferably more than 1.75. Conveniently, 2.0 equivalents are used. It is important that sufficient acid be present to prevent the formation of the pyridine bi s -s u s t i t uida of formula I and to allow a sufficient yield. When hydrochloric acid is used as the mineral acid, an amount of at least 2.5 ml is preferably used. of concentrated HCl per g. of 5-c 1 or r o - 1 - (4-f 1 uo r f i 1) i nd 1. More preferably, the ratio is 3.5 to 5 ml. of concentrated HCl per g. "of 5-chloro-1- (4-f luorphenyl) indole The amount of acetic acid should be sufficient to make the reaction technically feasible.At least, at least 8 ml are used. of acetic acid per g of 5-c 1 gold-1 - (4-f 1 u or rf eni 1) n 1. Preferably, the amount of acetic acid is more than 10 ml of acetic acid per g of 5-cl or o- 1 - (4-f 1 uo rfe ni 1) idol, more preferably 10-14 ml The ratio between acetic acid and concentrated HCl is preferably from 2: 1 to 4: 1 v / v. The reaction is conveniently carried out by the addition, by dripping, of a solution of 5-chloro- 1- (4-f luo rfeni 1) indo 1 in hot acetic acid for hydrochloride, ideally -hydrous by mixing the two. reagents in a mixture of acetic acid and mineral acid followed by reflux. "The reaction time is easily determined by a person skilled in the art. The intermediary can be absorbed in a conventional manner. The additional process leading to sertindole comprises cyclization of N- (4-f luorphenyl) -N- (2-caboxbox i-4-c 1 or of en 1) glycol to the corresponding 3-acetoxy-indole, using example 'acetic anhydride in the presence of alkali metal acetate, such as sodium acetate. The 5 - c lo r o - 1 - (4 -f 1 u or r f e n i 1) i nde 1 is then obtained from 3-a c e t i i n i 1 by reduction and subsequent elimination of H20. The resulting 5-cyclo r o- 1 - (4-f 1 uo rf 1) i) reaction 1 reacts with 4-piperidone according to the aforementioned procedure, 5-chlor or-1 - (4 -f luorphenyl) -3 - (1,2,3,6-tetrahydropyridin-4-yl) indole is reduced in order to obtain 5-c 1 gold - 1 - (4 -f 1 uo rf eni 1) - 3 - (p ip er idin - 4 - i 1) indole which in turn reacts with 1 - (2 - c 1 oroeti 1) - 2 - imi da zo 1 i di nona to obtain sertindole. Alternatively, 5-chloro-1- (4-fluorophenyl) -3- (1, 2, 3, 6-tetrahydropyridin-4-yl) -indole can first be reacted with l- (2-c 1 or oe ti 1) -2- imida zo 1 i dinone, followed by reduction, thereby obtaining sertindole, which can be isolated as an acid addition salt, for example, the tartrate, or as the free base. The . alkali metal salt of 2,5-di c 1 or oben zoi co acid and the alkali metal salt of N- (4-f luorphenyl) glycine, used as starting materials are easily prepared from 2,5-di c 1 acid or ob in zoi co commercially available and N- (4-f 1 uo rf eni 1) gl ic ina, respectively, by standard procedures. The sertindole, as obtained by the process, can conveniently be formulated, as described in US Patent No. 5,112,838. Experimental Section Preparation of N- (4-fluoro-phenyl) -N- (2-carboxyphenyl) glycine A suspension comprising potassium 2,5-dichlorobenzoate (100 g, 0.44 mol, 1 eq.) Was heated. , N- (4-fluorophenyl) potassium glycinate (190 g., 0.92 mol., 2 ~ 1 eq.), Potassium carbonate (36.2 g., 0.26 mol., 0.6 eq., CO 3) "), copper bronze (2.8 g., 0.04 mol.Cu, 0.1 eq.) and 250 ml. of 1% strength water was heated to reflux under N2 atmosphere for 20.5 hours. and then cooled to 50 ° C. 2.5 ml were added to the reaction mixture. of a g u a _ and 5 g. activated carbon; said mixture was homogeneous, except for Cu-bronze. The mixture was cooled under stirring for one hour and filtered. The filter cake was washed with 2 x 125 ml. of water. The filtrate was poured into a mixture of ice (2 1) and 37% aqueous HCl (3-400 ml.) Under vigorous stirring, thereby crystallizing the crude product as a fine crystalline material. do ama ri 11 en to. The suspension was stirred at 75-80 ° C for 30 minutes, cooled to 15-20 ° C and filtered and the filter cake was washed with 500 ml. of water and dried under a stream of air overnight at 50 ° C. The filtrate was collected by regeneration of N- (4-f luor f1) 1 g 1 i c i na t o. Yield of the raw product: 113 g. (80.3%); p.f. 170-86 ° C. HPLC analysis: 84.2% w / w of the product, 10.5% w / w of acid 3-cl or r o s a 1 i cí 1 i co. 20 g of the above anhydrous crude product was then purified by suspension in 200 ml. of toluene and reflux for 30 minutes. The suspension could be cooled to room temperature under stirring and then filtered. The filter cake was washed with toluene (20 ml.) And dried overnight in a vacuum atmosphere at 50 ° C.

Yield 17.0 g., M.p. 190-92 ° C. Purity > 98% as determined by NMR analysis.

Example 2 Preparation of N- (4-fluoro-phenyl) -N- (2-carboxyphenyl) glycine. 21.0 kg were added. from 2.5-d i c 1 or potassium oxide to a 180-liter reactor, and then 36.0 liter of water were added. This mixture was heated under stirring until all the solids were substantially dissolved (temperature 60-70 ° C) and slowly 25.0 kg was added. of N- (4-f 1 or r f in i 1) g 1 i c potassium. The mixture was heated until all the materials were dissolved, ie at about 80 ° C and added to a mixture of 7.67 kg. of K2C03 582 g. of Cu-bronze and 7 1. of water. The combined mixture refluxed overnight (approximately 15 hours) and cooled to 50 ° C. 1 kg added of activated carbon suspended in 5 1. of water followed by 40 1. of water. The mixture was stirred under cooling for 1 hour and filtered over a filter notch. The filter cake was washed with 10 1 of water and the green filtrate was carried out slowly for about two hours poured on a mixture of 22.5 1. to 37% of HCl and 30 1. of water under gentle heating (45- 50 ° C) and stirring. The mixture was heated to 72 ° C, cooled to 25 ° C and filtered. The filter cake was washed with water (2 x 10 1.) and dried on trays overnight at 60 ° C. The yield was 26.7 kg of a pale yellow crystalline crude product. , 26.7 kg was transferred to a 200 1 reactor and 150 1. of toluene was added and the mixture was heated to reflux temperature (90 ° _C) under N2 cover, then the mixture was distilled until To reach a temperature of 110 ° C (5 1 of distillate), 5 liters of toluene was added and the mixture was refluxed at 110 ° C for two hours "at approximately 60 ° C and left overnight. 27 ° C. The mixture was filtered and the filter cake was washed, with toluene (3 x 15 1.) and dried to obtain 21.0 kg. of the pure product titled.

E emplo 3 1- (4-fluorophenyl) -3-ace oxy-5-chloroindole N- (4-f luor of eni 1) -N- (2 -ca rbox i feni 1) glycine (717.1 g, 2.22 g. moles), sodium acetate (36.4 g, 0.44 moles, 0.2 eq.) and acetic anhydride in a 4 L three neck flask equipped with a reflux condenser and mechanical stirrer.

The suspension is heated under stirring to reflux. The reaction mixture is refluxed for 1 hour and cooled to room temperature in an ice water bath. The homogeneous suspension under stirring is emptied on ice (2 * L) and neutralized with concentrated NaOH (ca. 6L) to a pH of 6-7. During neutralization, the temperature remains below approx. 30 ° C, which requires the addition of an additional 5-6 L of ice. Therefore, the product is precipitated and isolated by filtration. The product is completely washed with 3L of water and 2L of n-Heptane and dried overnight in vacuo at 60 ° C. Yield: 600.5 g (89.1%), mp 109-12 ° C.

Example 4 1- (4-fluorophenyl) -5-chloroindole 1 - (4-f luor of eni 1) - 3 -acetyloxy-5-chloroindole (100.0 g, 0.33 mol) was dissolved in 100 L of EtOH . During the next hour the tablets of sodium borohydride (18.7 g, 1.5 eq.) Are added in discontinuous form to reflux. The reaction mixture is stirred overnight at reflux and cooled to room temperature. Concentrated HCl (about 50 L to pH 1) is added and the reaction mixture is stirred at room temperature for 1 hour. It is add 200 mL of demineralized water, and the resulting suspension is filtered. The filtered cake is washed with 50 ml of additional water and 10 ml of EtOH. The product is dried overnight in vacuo at 50 ° C. Yield: 68.4 g (84.7%), mp 91-93 ° C.

Example 5 Preparation of 5-chloro-1- (4-fluorophenyl) -3- (1, 2, 3, 6-te-ahydropyr idin-4-yl) indole. 5-chloro- or 1- (4-chloro) were transferred. -f luor or feni 1) indole (6.70 kg) and 4-pipe ri dona -mono-hydrate, hydrochloride (8.38 kg) to a 200 L reactor under N2 cover. The acetic acid (67L) was added and the reaction mixture was heated to 60 ° C. The concentrated HCl (37%, 33.5 L) was added for 1/2 hour and then the mixture was heated to reflux temperature (85 ° C) and refluxed for 1 hour (final temperature 95 ° C). After cooling to 30 ° C, 33.5 L of acetone was added "followed by further cooling to 25 ° C. The filtration was washed (20 L acetone) and dried in vacuo at 60 ° C to give the title product as a white powder, yield 8.94 kg.

Example 6 l- [2- [4- [5-chloro-l- (4-fluorophenyl) -lH-indol-3-yl] -1,2,3,6-tetrahydro-l-pyridyl] ethyl] -2 -imidazolidinone 5-chloro- 1 - (4-f luor of eni 1) - 3 - (1, 2, 3, 6 - tetr ah i dr opi r idin- 4 - i 1) indo 1 (6.0 kg) was mixed. , 16.5 moles), l- (2-chloroethyl) imidazolone (3.19 kg, 1.3 eq.), Sodium carbonate (anhydrous) and me ti 1 is obu 111 cetone (60 L). The reaction mixture was heated under N 2 cover and stirred to 90-95 ° C, and stirred overnight at this temperature. The next day the reaction mixture was filtered while still hot. The apparatus and filter cake were washed with the addition of 2.5 L of methyl isobutyl ketone. The combined filtrates are left overnight for crystallization. The product is isolated in a "nutch" (notched), washed with 7.5"L of n-Heptane and dried overnight in vacuo at 60 ° C. Yield: 5.39 kg (74.3%), mp 146.4 ° C. E n g lis 7 1- [2- [4- [5-chloro-l- (4-f luorophenyl) -1-H-indo 1-3-yl] -l-piperidinyl] ethyl] -2-imidazolidinone, tartrate It dissolves 1 - [2 - [4 - [5 - c 1 oro - 1 - (4-fluorophenyl) -lH-indol-3-yl] - 1, 2, 3, 6-tetrahidro-l-piri di 1 ] e 111] -2-imidaz or 1-idonene (3.5 kg) in acetic acid (98-100%, 29 L) while being heated to 40 ° C. The activated carbon was added and the suspension was stirred for 1 hour, it was left overnight and filtered.The filter cake was washed with 6 L acetic acid.The combined filtrates were added to 50 L of the hydrogenation reactor which was covered by N2.70 g of Pt02 was added, the apparatus Closed and blown N2 to the end for 5 minutes.The hydrogenation is carried out in a flow of H2 (2.5 L per minute) for 8.25 h The reaction mixture was blown thoroughly with nitrogen, the activated carbon was added and the mixture was filtered in a closed nutch. The filtrate was combined with corresponding filters from three additional rogenations (a total of 14.53 kg of starting material and evaporated in vacuo at approximately 50 ° C. The filtrate was ignited with 3x10 L of toluene at 50-60 ° C. The remainder is dissolved in 146 L of ethanol and in this suspension a suspension of 40 ° C of tartaric acid 5.22 kg L - (+) in 16 L of demineralized water was added under agitation .The suspension was left overnight without cooling or stirring The crystallized tartrate was filtered in a nutch and washed with 15 L of ethanol.

The crude tartrate was recrystallized from 190 L of ethanol and 30 L of demineralized water by heating to boiling (about 78 ° C). The suspension is left overnight for crystallization without cooling or stirring. The next day the suspension is cooled to approx. 18CC and the tartrate is filtered, washed with 60 L of ethanol and dried overnight under 60 ° C air stream.

Example 8 1- [2- [4- [5-chloro-l- (4-fluorophenyl) -iH-indo-1-3-yl] -1-piperidinyl] ethyl] -2-imidazolidinone 7.96 kg 1 - [ 2 - [4 - [5-chloro- 1 - (4-fluoro-phenyl) -lH-indol-3-yl] -1,2,3,6-tetrahydro-lp iridi 1] eti 1] - 2 - The mixture is placed in an oven, tartrate, in 25 L of demineralised water and 30 L of dichloromethane are added. A total of NaOH 3 L 27% solution, pH = 9, is added to the suspension under stirring. The mixture is stirred for 1 hour (pH still = 9), where after the dichloromethane phase is separated. The water phase is extracted with 15 L of additional dichloromethane. The combined dichloromethane phases are dried with NaS04 and evaporated. The product is ignited with 5 L of acetone, 35 L of acetone are added and the suspension is heated to reflux. The crystallized product does not dissolve completely. The heating was discontinued and the mixture was left overnight with gentle cooling. The crystallized product is isolated in a nutch, washed with 5 1 of additional acetone * and dried overnight under a current of air at 60 ° C. Yield: 4.90 kg (83.2%), mp 154.7 ° C.

Claims (29)

1. A process for the preparation of N- (4-fluorophenyl) -N- (2-carboxy-4-chlorophenyl) glycine comprising a copper-catalyzed arylation of 2, 5-di c 1 or n-octazole with N- ( 4-f 1 uo rf eni 1) g 1 ic where the alkaline metal salts of 2, 5-di or ob ozoic acid and N- (4-f 1 uo rf eni 1) gl i ci na are used in an environment aqueous alkali in the presence of a copper catalyst according to the reaction scheme: where Mi, and M2 are ai cali metal ions.

2. The process according to claim 1, characterized in that the reaction is carried out at a high temperature, preferably at a temperature between 80 ° C and the reflux temperature of the medium, in particular at about the reflux temperature.

3. The process according to claim 1 or 2, characterized in that the reaction medium is water or water to which a cosolvent is added.

4. The process according to claim 3, characterized in that the water is used as a solvent.

5. The process according to the rei indication 3 or 4, characterized in that the amount of water is less than 10 ml./g. of 2,5-di c 1 or r oben z or i co acid, preferably less than 5 ml./g.

6. The process according to claim 5, characterized in that the amount of water is less than 3.5 ml./g, preferably less than 2.5 ml./g. of acid 2, 5 - di c 1 or r ob e n z o i co.

7. The process according to any one of claims 1 to 6, characterized in that the alkali metal salts used are lithium, sodium or potassium salts.

8. The process according to claim 7, characterized in that the same salt of the reactants is used, preferably potassium salts.

9. The process d according to any of claims 1 to 8, characterized in that the base is an alkali metal carbonate, preferably Li 2 CO 3, Na 2 CO 3 or K 2 CO 3.

10. The process according to claim 9, characterized in that the alkali metal of the alkali metal carbonate is the same as the alkali metal of the reactants.

11. The process according to any of claims 1 to 8, characterized in that the base is potassium carbonate.

12. The process according to any of claims 1 to 11, characterized in that the amount of base is greater than the stoichiometric amount of acid 2, 5 -di cl or oben z or i co.

13. The process according to any of claims 1 to 12, characterized in that the catalyst is cobr e -b ronce.

14. The process according to any one of claims 1 to 13, characterized in that the ratio between the amount of the alkali metal salt of N- (4-f 1 uo rf eni 1) g 1 ici and the alkali metal salt of acid 2, 5 -di c 1 or ob in zoi co is from 0.5 to 3.0, preferably from 1.0 to 2.5, in particular from 2.0 to 2.3 mol / mol.

15. A process for preparing 5-chloro-l- (4-fluorophenyl) -3- (1,2,3,6-tetrahydropyridin-4-yl) indole comprising the reaction of 5-c 1 oro-1 - (4 - f 1 uo rfeni 1) - step 1 with 4-piperidone in a mixture of mineral acid with acetic acid.

16. The process according to claim 15, characterized in that the 4-pipepdone is used in the form of 4-piperidone hydrate hydrochloride.

17. The process according to claim 15 or 16, characterized in that the mineral acid used is phosphoric acid, nitric acid, sulfuric acid or hydrochloric acid.

18. The process according to claim 17, characterized in that the mineral acid used is concentrated hydrochloric acid.

19. The process according to the rei indication 15 or 16, characterized in that at least 1.5 equivalents of 4-piperidone is used per equivalent of 5-c 1 or r o-1 - (4-f 1 uo r f e n i 1) indole.

20. The process according to the rei indication 19, characterized in that at least 1.75 equivalents of 4-piperidone is used for the equivalent of 5-c 1 or r or -1- (4-f luorphenyl) indole.

21. The process according to the rei indication 20, characterized in that at least 2.0 equivalents of 4-piperidone is used per equivalent of 5-chlor o- 1 - (4-f luo r f eni 1) indo 1.

22. The process according to claim 18, characterized in that hydrochloric acid is used in an amount of at least 2.5 ml. of concentrated HCl per g. of 5-chloro-l- (4-f luorphenyl) indole.

23. The process according to claim 15 or 16, characterized in that at least 8 ml is used. of acetic acid per g. of 5-chloro-l- (4-f luorphenyl) indole.

24. The process according to claim 23, characterized in that at least 10 ml is used. of acetic acid per g. of 5-chloro-1- (4-fluorophenyl) indole.

25. The process according to claim 24, characterized in that it is used 10-14 ml. of acetic acid per g. of 5-c 1 or r o-1 - (4-f luorphenyl) indole.

26. The process according to claim 22, characterized in that the ratio is 3.5 to 5 ml. of concentrated HCl per g. of 5-chloro-l- (4-f luorphenyl) indole.

27. The process according to claim 18, characterized in that the ratio between acetic acid and concentrated HCl is from 2: 1 to 4: 1 (v / v).

28. A process for manufacturing sertindole comprising the preparation of N- (4-f luorphenyl) -N- (2-carb ox i-4-c 1 orop nor 1) glycine by a process of any of claims 1 to 14 , and / or the preparation of 5-chloro- 1 - (4-f luor f eni 1) - 3 - (1, 2, 3, 6-tetrahi dr op iridin-4-i 1) indo 1 according to any of the rei indications 15-27.

29. A process for manufacturing sertindole which comports: a) the preparation according to any of claims 1 to 14 of N- (4-f luorphenyl) -N- (2-ca rboxi-4-c 1 orof eni 1) Gluci na, by reacting an alkali metal salt of 2,5-di c 1 or obe zoi co with an alkali metal salt of N- (4-f luo rfe ni 1) - gl i ciña in an alkaline environment aqueous in the presence of a copper catalyst; b) the cyclization of N- (4-f 1 uo rfeni 1) -N- (2 -ca r boxi - 4 - cl orof eni 1) gl ic ina for the corresponding 3 - acet ox i - i ndo 1 using anhydride alkali metal acetate / alkali metal acetate, preferably sodium acetate; c) reduction of 3-ace toxin-1 and subsequent d) elimination of H20 whereby 5-chloro-l- (4-fluorophenyl) indole is obtained; e) reaction of 5-c 1 gold-1 - (4-f 1 uo rfe ni 1) indole with 4-piperidone according to any of claims 15-27 in a mixture of an acetic acid and concentrated HCl f) reduction of the - c lor o - 1 - (4 - f luo rf eni 1) -3- (1, 2, 3, 6-tetrahydropyridin-4-yl) indole resulting, in order to obtain 5-chloro-l- (4- f luorphenyl) -3- (piperidin-4-yl) indole g) reaction of the product of f) with l- (2-c 1 oroeti 1) -2-imi da zo 1 i di nona, o-h) reaction of 5-chloro-l- (4-fluorfenyl) -3- (1, 2, 3, 6-tetr ahydropyr idin-4-i 1) indole with l- (2-c 1 or oe ti 1) - 2 - imi da z ol idi nona, followed by reduction of the product, by which sertindol is obtained.