CA2486883C - 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 HCI; 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 OF MANUFACTURING SERTINDOLE
The present application is a division of application n° 2,288,334 filed on May 7, 1998.
Field of invention The present invention relates to a new method of manufacturing the compound 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1-H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinone having the recommended INN name sertindole and a new method of manufacturing the intermediates, N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophznyl)glycine and 5-chloro-1-(4-fluoropl:o~~yl1-3-(1,2,3,6-tetrahydropyridin-4-yl)indole used in the method.
Background of the invention Sertindole is a well I:nown antipsychotic drug having the formula CI~~ N-(CH.2)TN NH
/~
N
I
F
The compound was disclosed in US patent No 4,710,500 and the antipsychotic activity thereof was described in US patent No 5,112,838. Sertindole is a potent centrally acting 5-HTZ receptor antagonist in vivo and has further been disclosed to be active in models indicative of effects in the treatment of anxiety, hypertension, drug abuse and cognitive disorders. Recently, it has been reported to show antipsychotic effect in clinical studies, PSychopharmacology (1996) 124:168-175.
US patent No 4,710,500 covered a class of 1-aryl-3-(piperazinyl-, tetrahydropyridyl or piperidyl)indole compounds including sertindole. A number of methods of preparing the compounds were generically disclosed, some of which could be used in the preparation of sertindole. The methods were:

a) reaction of a properly substituted 1-arylindole with a proper 1-substituted 4-piperidone and subsequent reduction of the resulting tetrahydropyridyl compound;
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.
Sertindole was specifically exemplified, however, no experimental procedure for its preparation was given.
Perregaard et al., J. A~ecl. Che»t, 1992, 35, 1092-1101, disclosed a new method of preparing sertindole. This method comprises reaction of the intermediate 5-chloro-1-(4-fluorophenyl)indole ~.vith 4-piperidone in a mixture of trifluoroacetic acid and acetic acid, reduction of the resulting S-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole in order to obtain S-chloro-1-(4-fluorophenyl)-3-(piperidin-4-yl)indole which in turn is reacted with 1-(2-chloroethyl)-2-imidazolidinon in the presence of K,CO~ and KI in methyl isobutyl ketone (MIBK). The 5-chloro-I-(4-fluorophenyl)indole was obtained from the corresponding 3-acetoxy-indole by NaBH~ reduction in methanol and subsequent elimination of HBO under acidic conditions. The 3-acetoxy-indole was prepared from the N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine following literature procedures.
A procedure for preparing the N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine is described in Perregaard et al.,Dansk lierni, 95, 3. p. 6-9. By this method the glycine is obtained by a copper catalyzed reaction of 2,5-dichlorobenzoic acid with N-(4-fluorophenyl)glycine. The potassium salts of the two acids are used in the presence of K,CO, in the solvent N-methylpyrrolidone (NMP).
However, it has been found that the above processes are not useful in technical scale. The total yields are too low and the processes involve the use of reactants or solvents that are not suitable and in some cases not allowed in large scale for environmental or safety reasons.
Furthermore, due to the aqueous solubility of NMP, the work-up of the reaction is tedious, and regeneration of NMP is costly and time consuming.

. CA 02486883 1998-05-07 Summary of the invention Consequently, the present invention as disclosed and claimed in the parent application n° 2,288,334 relates to a new process useful in technical scale production of sertindole.
It has now been found that the main limiting steps of the process are the preparation of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine and the reaction of 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone.
Accordingly, the invention provides a process for the preparation of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorphenyl)glycine comprising reaction of 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 followed by treatment with an aqueous acid, as illustrated in the following reaction scheme:
NHCH2COOM2 CI~~COOH
CI~~COOM~ ~ 1 )BaseICuIH20 CI I 2) Aq. dilute Acid F
F
wherein M, and M: are alkali metal ions.
According to Perregaard et al.,Dansk Kemi, 95, a reaction using the potassium salts of the reactants is carried out in NMP. However, the use of NMP necessitated a time consuming extractive work-up, and the reaction afforded substantial amounts of tarry by-products. The reaction temperature was 120-130 °C.
By carrying out the reaction in aqueous environment instead of NMP, a higher yield and only a negligible amount of tarry by-products are obtained. Furthermore, the work-up procedure is simple and the use of an aqueous medium causes substantial environmental advantages.

Finally, the reaction temperature is lowered to the reflux temperature of the aqueous medium or below.
In another aspect the invention claimed hereinafter, there is provided a novel process for preparing 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-yl)indole comprising reaction of the 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone in a mixture of a mineral acid and acetic acid, wherein at least 1.5 equivalents of 4-piperidone is used per equivalent 5-chloro-1-(4-fluorophenyl) indole. This process is illustrated in the following reaction scheme:
CI~~ ~ NH,HCI
~~ Ho ' ~
~1 v _N
'~' ,' NH,HCI
HO~~J Acetic Acid i-HCl I
F
F
By using a mixture of acetic acid and a mineral acid instead of a trifluoroacetic acid - acetic acid mixture, substantial environmental advantages are obtained. Furthermore, trifluoro acetic acid is very volatile and aggressive, accordingly being undesirable far large scale production.
Also, the formation of the undesired bis-substituted piperidine may be avoided:
H;HCI
ni CI
Formula I
In yet another aspect, the invention as claimed hereinafter provides a novel process of manufacturing sertindole comprising preparation of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine by a reaction comprising a copper catalysed I I
F F

~

4a reaction of an alkalimetal salt of 2,5-dichlorobenzoic acid with an alkali metal salt of N-(4-fluorophenyl)glycine in an aqueous, alkaline environment in the presence of a copper catalyst and/or in which 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole is obtained by a reaction comprising reaction of the 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone in a mixture of a mineral acid and acetic acid.
The reaction of the alkalimetal salt of 2,5-dichlorobenzoic acid with the alkalimetal salt of N-(4-fluorophenyl)glycine is carried out at an elevated temperature, conveniently at a temperature bet~veen 80 °C and the reflux temperature of the medium, preferably at about the reflux temperature.
Throughout the specification and claims the term aqueous medium is intended to include water and water to which a cosolvent such as ethyleneglycol is added as reaction medium.
s Preferably water such as demineralised, deionised or destilled water is used.
Preferred alkali metal salts of the reactants are the lithium, sodium or potassium salts and conveniently the same salts of the reactants are used. Most preferably the potassium salts are used.
~o It is important that the HC1 formed during the reaction is neutralised in order to avoid undesired side reactions. The reaction medium is made alkaline by addition of a base such as an alkali metal hydroxide, alkali metal acetate, alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal phosphate or alkali metal citrate. Preferably an alkali metal carbonate, ~5 such as Li_CO,, Na=CO, or K,CO,, is used. Conveniently, the same alkali metal as included in the reactants is used. Preferably the base is potassium carbonate. The amount of base is preferably larger than the stoechiometric amount of 2,5-dichlorobenzoic acid.
On the other hand, increased [OH'.] may cause hydrolysis of 2,S-dichlorobenzoic acid, thereby decreasing the yield. Thus, the base may conveniently be added gradually during the process.
Zo The catalyst may be any Cu(0)-catalyst, preferably copper-bronze_It is added in catalytic amounts. The specific amount is not critical and may easily be determined by a person skilled in the art.
as The ratio between the amounts of the alkali metal salt of N-(4-fluorophenyl)glycine and the alkali metal salt of 2,5-dichlorobenzoic acid is conveniently from O.S to 3.0, preferably 1.0 to 2.S and most preferably 2.O fo 2.3 mol/mol. Excess N-(4-fluorophenyl)glycine may be regenerated.
3o The reaction is conveniently carried out in a minimal amount of aqueous solvent still technically feasible. Thus, the yield is improved by decreasing the amount of solvent. The ' CA 02486883 1998-05-07 amount of water is preferably less than 10 mL/g 2,5-diehlorobenzoic acid, more preferably less than 5 mL/g in particular less than 3.5 mLlg, most preferably less than 2.5 mL/g.
The reaction time is not very critical and may easily be determined by a person skilled in the s a~ t.
The work-up of the product by dilute aqueous acid may be carried out simply by adding the filtered reaction mixture to the dilute acid, thereby precipitating the product. The product may be further purified with hot toluene or by recrystallisation from aqueous ethanol. The dilute io aqueous acid is preferably hydrochloric acid.
In the reaction of the ~-chloro-1-(4-fluorvphenyl)indole with 4-piperidone, the mineral acid used is preferably phosphoric acid, nitric acid, sulfuric acid or hydrochloric acid, such as larger than 30% w/w aqueous HCI, in particular concentrated hydrochloric acid.
By ~s concentrated HCl is meant about 37% w/w aqueous HCI.
The 4-piperidone is preferably used as the ~-piperidone-hydrate, hydrochloride.
The reaction should preferably be carried out in excess of piperidone-hydrate hydrochloride.
~o Preferably more than 1.5 equivalents of 4-piperidone pr equivalent 5-chloro-1-(4-fluorophenyl)indole, more preferably more than 1.75, are used. Conveniently, 2.0 equivalents are used.
It is important that sufficient acid is.present to allow a sufficient yield.
When hydrochloric is acid is used as mineral acid, it is preferably used in an amount of at Least 2.5 mL concentrated HCl pr. g 5-chloro-1-(4-fluorophenyl)indole. Most preferably the ratio is 3.5 to 5 mL
concentrated HCl pr. g 5-chloro-1-(4-fluorophenyl)indole.
The amount of acetic acid has to be sufficient to make the reaction teclu~ically feasible.
so Conveniently, at least 8 mL acetic acid pr. g 5-chloro-1-(4-lluorophenyl)indole is used.
Preferably, the amount of acetic acid is more than 10 mL acetic acid pr. g 5-chloro-1-(4-fluorophenyl)indole, most preferably 10 - 14 mL. The ratio between acetic acid and concentrated HCl is preferably ~:1 to 4:1 vol/vol, The reaction is conveniently can;ied out by adding, drop-wise, a solution of the 5-chloro-1-(4-fluorophenyl)indole in hot acetic acid ~to the piperidone-hydrate, hydrochloride or by mixing s the t<vo reactants in a mixture of acetic acid and mineral acid followed by r~flux. The reaction time is easily determined by a person skilled in the art.
The intermediate may be worked up in a conventional manner.
The further process leading to sertindole comprises cyclization of N-(4-fluorophenyl)-N-(2-io carboxy-4-chlorophenyl)glycine to the corresponding 3-acetoxy-indole using eg. acetic anhydride in the presence of alkalimetal acetate such as sodium acetate. 5-chloro-1-(4-fluoro)indole is then obtained from the 3-acetoxy-indole by reduction and subsequent elimination of HZO. The resulting 5-chloro-1-(4-fluorophenyl)indole is reacted with 4-piperidone according to the above procedure, the resulting 5-chloro-1-(4-fluorophenyl)-3-~s (1,2,3,6-tetrahydropyridin-4-yI)indole is reduced in order to obtain 5-chloro-1-(4-fluorophenyl)-3-(piperidin-4-yl)indole which in turn is reacted with 1-(2-chloroethyl)-2-imidazolidinon to obtain sertindole. Alternatively, the S-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole may first be reacted with 1-(2-chloroethyl)-2-imidazolidinon followed by reduction, thereby obtaining sertindole, which may be isolated as an acid zo addition salt, e.g. the tartrate, or as the free base, The alkalimetal salt of 2,5-dichlorobenzoie acid and the alkalimetal salt of N-(4-fluorophenyl)glycine used as starting materials are easily prepared from commercially available 2,5-dichlorobenzoic acid and N-(4-fluorophenyl)glycine, respectively, by standard zs procedures.
Sertindole, as obtained by the process, may conveniently be formulated as described in US
patent No 5,112,838.

Experimental Section Example 1 Preparation of N-(4-fluorophenyl)-N-(2-carboxyphenynglycin A suspension comprising,potassium 2,S-dichlorobenzoate (100 g, 0.44 mot, 1 eq.), potassium N-(4-fluorophenyl)glycinate (190 g, 0.92 mot, 2.1 eq.), potassium carbonate (36.2 g, 0.26 mot, 0.6 eq. C03 '), copper bronze (2.8 g, 0.04 mot Cu, 0.1 eq.) and 250 mL
demineralised water was heated at reflux under NZ atmosphere for 20.5 hours and then cooled to SO °C.
io 2.5 mL water and S g activated carbon were added to the reaction mixture which, except for the Cu-bronze, was homogeneous. The mixture was allowed to cool under stirring for 1 hour and filtered. The filter cake was washed with ? x 12S mI, water. The filtrate was poured on a mixture of ice (2 L) and 37% aq. HCl (3-400 mL) under vigorous stirring, thereby crystallising the crude product as a fine, crystalline, yellow-brown material.
The suspension ~s was stirred at 7S-80 °C for 30 min, cooled to 1S-20 °C, and fltered, and the filter cake was washed with S00 mL water and dried under air stream over night at SO
°C. The filtrate was collected for regeneration of N-(4-fluorophenyl)glycinate.
Yield of crude product: 113 g (80.3%), mp. 170-8G °C.
HPLC-analysis: 84.2% w/w product, 10.5% w/w 3-chlomsalicylic acid.
IO
20 g of the above dry crude product was further purified by suspension in 200 mL toluene and reflux for 30 min. The suspension was allowed to cool to room temperature under stirring and was then filtered. The filter cake was washed with toluene (20 mL) and dried overnight in vacuum at SO °C.
is Yield: 17.0 g, mp. 190-92 °C. Purity > 98% as determined by NMR-analysis.
Example 2 Preparation of N-(4-flnorophenyl)-N-(2-c~rboxyphenyl)glycin 21.0 kg potassium 2,S-dichlorobenzoate was added to a 180 L reactor and 36.0 L
water was added. This mixture was heated under stirring until substantially all solids were dissolved (temp 60 - 70 °C) and 25.0 kg potassium N-(4-fluorophenyl)glycinate was added slowly. The mixture was heated until all materials were dissolved, i.e. at about 80 °C and added to a mixture of 7.67 kg K=C03 , 582 g Cu-bronze and 7 L water. The combined mixture was refluxed overnight (about 15 h) and cooled to SO °C. 1 kg activated carbon suspended in 5 L
s water was added followed by 40 L water. The mixture was stirred under cooling for 1 hour, and filtered o:? a notch covered with filter aid. The filter cake was washed with 10 L water and the green filtrate was slowly during about 2 hours poured on a mixture of 22.5 L 37%
HCl and 30 L 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 L) and io dried on trays overnight at 60 °C. Yield 26.7 kg of a pale yellow crystalline crude product.
The crude product, 26.7 kg,.was transfer-ed to a 200 L reactor and 150 L
toluene added and the mixture was heated to the reflux temperature (90 °C) under NZ
cover. Then the mixture was destilled until a temperature of 110 °C was reached (5 L
distillate). 5 L toluene was ~s added, and the mixture was refluxed at I 10 °C for 2 hours, cooled to about 60 °C and left overnight at 27 °C. The mixture was filtered and the filter cake was washed with toluene (3 x 15 L) and dried, thereby obtaining 21.0 kg of the pure title product.
zo Example 3 1-(4-nourophenyi)-3-acetoxy-S-chloroindole N-(4-flourophenyl)-N-(2-carboxyphenyl)glycin (717.1 g, 2,22 mol), sodium acetate (3G.4 g, 0.44 mot, 0.2 eq.) and acetic anhydride were placed in a 4 L three necked flash equipped with zs mechanical stirrer and reflux condenser.
The suspension was heated under stirring until reflux. The reaction mixture was refluxed for 1 hour and was cooled to room temperature on icelwater bath. The homogenous suspension was under stirring poured onto ice (2 L) and was neutralised with concentrated NaOH (appr.
30 6 L) until a pH of G-7. During the neutralisation the temperature was kept under appr. 30 °C, which required the adding of a further 5-G L of ice. Thereby the product precipitated and was IO
isolated by filtration. The product was washed thoroughly with 3 L of water and 2 L of n-Heptane and dried over night in vacuum at 60 °C.
Yield: 600.5 g (89.1 %), mp 109-12 °C.
Example 4 1-(4-iluorophenyl)-5-chloroindole 1-(4-llourophenyl)-3-acetoxy-5-chloroindole (I00.0 g, 0.33 mol) was dissolved in 1000 mL
~ o EtOH. During the next hour sodium borohydride pellets ( 18.7 g, 1.5 eq.) were added batehwise at reflux. The reaction mixture was stirred over night at reflux and cooled to room temperature. Concentrated HCl (appr. 50 mL until pH 1) was added and the reaction mixture was stirred at room temperature for 1 hour. 200 mL demineralized water was added, and the resulting suspension was filtrated. The filter cake was washed with further 50 mL water and is 10 mL EtOH. The product was dried over night in vacuum at SO °C.
'Yield: 68.4 g (84.7%), mp 91-93 °C.
Example 5 ao Preparation of 5-chloro-1-(4-fluorophenyl}-3-(1,2,3,6-tetrahydropyridin-4-yl)indole 5-chloro-1-(4-Iluorophenyl)indole (6.70 kg) and 4-piperidone-mono-hydrate,hydrochloride (8.38 kg) were transferred to a 200 L reactor under NZ cover. Acetic acid (67 L) was added and the reaction mixture was heated to 60°C. Concentrated HCl (37%, 33.5 L) was added is during 112 hour and then the mixture was heated to the reflux temperature (85°C) and refluxed for 1 hour (final temperature 95°C). After cooling to 30°C, 33.5 L acetone was added followed by further cooling to 25°C. Filtration, wash (acetone 20 L) and drying in vacuum at 60°C gave the title product as a white powder, yield 8.94 kg.

lI
Example 6 I-[2-(4-[5-chloro-1-(4-flourophenyl)-1H indol-3-y1J-1,2,3,6-tetrahydro-l-pyridyi]ethylJ-2-irnidazolidinone s 5-chloro-I-(4-flaorophenyl)-3-(1,2,3,b-tetrahydropyridin-4-yl)indole (6.0 kg. 16.5 mall, I (2-chloroethyl)imidazolon (3.19 kg, 1.3 eq.), sodium carbonate (anhydrous) and methyl isobutyl ketone X60 L) were mixed. The reaction mixture was Jzoated under Nz-cover and stin-ing until 90-95 °C, and was stirred over night at this temperature. The next day the reaction mixture was filtered while still hot. The apparatus and filter cake were washed with father 2.5 L of ~o methyl isobutyl ketone. The combined filtrates were left over night for crystallisation. The product was isolated on a hutch, washed with ?.5 L n-Heptane and dried over night in vacuum at 60 °C.
'i'ield: 5.39 kg (74.3%), mp 146.4 °C.
is Example 7 1-(2-(4-(5-cliloro-1-(4-fluorophenyl)-I-H indoI-3-yl]-I-piperidinyljethylj-2-imidazolidiaone, tartrate zo 1-[2-[4-[5-chloro-1-(4-flourophenyl)-liEi-indol-3-yl]-1,2,3,6-tetrahydro-1-pyridyl]ethyl]-2-inudazolidinone (3.5 kg) was dissolved in acetic acid (98-100%, 29 L) while being heated until 40 °C. Activated carbon was added and the suspension was stir-ed for 1 hour, left over night and filtered. The filter cake was washed with 6 L acetic acid. The combined filtrates were added to a 50 L hydmgeneration reactor which was covered by N~. 70 g PtOz was zs added, the apparatus was closed and N2 blown through for 5 min.
Hydrogeneration was carried out in an Hi -flow (2.5 L per min) for 8.25 H.
The reaction mixture was blovun through with nitrogen, activated carbon was added and the mixture was filtered on a closed hutch. The filtrate was combined with corresponding filtrates of three other hydrogenerations (a total of 14.53 kg starting material) and evaporated in 3o vacuum at appr. SO °C. The filtrate was flushed off with 3 x I O L
toluene at 50-60 °C. The remanence was dissolved in 146 L ethanol and to this suspension a 40 °C
suspension of 5 ~2 kg L -(+) tartaric acid in 16 L demineralised water was added under stirring.
The suspension was left over night with no cooling or stirring. The crystallised tartrate was filtered on a notch and washed with 15 L ethanol.
The prude tartrate was recrystallised from 190 L ethanol and 30 L
demineralised water by heating until boiling (appr. 78 °C). The suspension was left over night for crystallasation with no cooling or stirring. The next day the suspension was cooled to appr. 18 °C and the tartrate was filtered off, washed with 60 L ethanol and dried over night under air stream at 60 °C.
io Example 8 1-[Z-[4-[5-chloro-1-(4-floarophenyl)-1H indol-3-yi]-1-piperidinyl]ethyl]-2-imidazolidinone 7.96 kg 1-[2-[4-[5-chloro-1-(4-flourophenyl~lH indol-3-yl]-1,2,3,6-tetrahydro-~s pyridyl]ethyl]-2-imidazolodione, tartrate was suspended in 25 L
demineralised water and 30 -L dichloromethane was added. A total of 3 L 27% NaOH-solution, pH=9, was added to the suspension under stirring. The mixture was stirred for 1 hour (pH still =9), whereafter the dichloromethane phase was separated.
The water phase was extracted with further 15 L dichloromethane. The combined 2o dichloromethane phases were dried with NaS04 and were evaporated.The product was flushed off with 5 L acetone, 35 L acetone was added and the suspension was heated until rellux. The crystallised product did not dissolve completely. Heating was discontinued and the mixture was left over night with gentle cooling. The crystallised product was isolated on a notch, washed with further 5 L acetone and dried over night under air stream at 60 °C.
Yield: 4.90 kg (83.2%), mp 154.7 °C.

Claims (15)

1. A process for preparing 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydro-pyridin-4-yl)indole comprising reaction of 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone in a mixture of a mineral acid and acetic acid, wherein at least 1,5 equivalents of 4-piperidone is used per equivalent of 5-chloro-1-(4-fluorophenyl) indole.

2. Process according to claim 1, characterised in that the 4-piperidone is used in the form of 4-piperidone-hydrate hydrochloride.

3. Process according to claim 1 or 2, characterised in that the mineral acid used is phosphoric acid, nitric acid, sulphuric acid or hydrochloric acid.

4. Process according to claim 3, characterised in that the mineral acid used is concentrated hydrochloric acid.

5. Process according to claim 1, characterised in that at least 1.75 equivalent of 4-piperidone is used per equivalent of 5-chloro-1-(4-fluorophenyl)indole.

6. Process according to claim 5, characterised in that at least 2.0 equivalent of 4-piperidone is used per equivalent of 5-chloro-1-(4-fluorophenyl)indole.

7. Process according to claim 4, characterised in that hydrochloric acid is used in an amount of at least 2.5 mL concentrated HCl per g of 5-chloro-1-(4-fluorophenyl)indole.

8. Process according to claim 1 or 2, characterised in that at least 8 mL
acetic acid is used per g of 5-chloro-1-(4-fluorophenyl)indole.

9. Process according to claim 8, characterised in that at least 10 mL acetic acid is used per g of 5-chloro-1-(4-fluorophenyl)indole.

10. Process according to claim 9, characterised in that 10-14 mL acetic acid is used per g of 5-chloro-1-(4-fluorophenyl)indole.

11. Process according to claim 7, characterised in that the ratio is 3.5 to 5 mL
concentrated HCl per g of 5-chloro-1-(4-fluorophenyl)indole.

12. Process according to claim 4, characterised in that the ratio between acetic acid and concentrated HCl is 2:1 to 4:1 (vol/vol).

13. A process of manufacturing sertindole comprising preparation of 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole according to any one of claims 1 to 12.

14. A process of manufacturing sertindole comprising:
a) 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;
b) cyclisation of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine to the corresponding 3-acetoxy-indole using acetic anhydride/alkalimetal acetate;

c) reduction of the 3-acetoxy-indole and subsequent;
d) elimination of H20 thereby obtaining 5-chloro-1-(4-fluorophenyl)indole;

e) reaction of 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone according to any one of claims 1 to 12 in a mixture of an acetic acid and concentrated HCl;
f) reduction of the resulting 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydro-pyridin-4-yl)indole in order to obtain 5-chloro-1-(4-fluorophenyl)-(piperidin-4-yl)indole;
g) reaction of the product of f) with 1-(2-chloroethyl)-2-imidazolidinon, or h) reaction of 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydro-pyridin-4-yl)indole with 1-(2-chloroethyl)-2-imidazolidinon followed by reduction of the product, thereby obtaining sertindole.

15. Process according to claim 14, characterized in step b), the alkalimetal acetate is sodium acetate.