HK1063182B - A process for the preparation of 5-ht2a receptor antagonists and salts thereof - Google Patents

Description

5-HT2AReceptor antagonists and salts thereof

The present invention relates to a process for the preparation of 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile of formula I and salts thereof, and intermediates in the synthesis.

The compound 7- {4- [2- (4-fluorophenyl) -ethyl]-piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile and corresponding physiologically acceptable salts thereof surprisingly against 5-HT_2AThe receptor has selective affinity. In particular, they are selective 5-HT_2AAn antagonist.

5-HT_2AThe antagonists exhibit clinically neuroleptic activity with no or minimal side effects and are accordingly considered neuroleptic with few side effects. Furthermore, they are useful for the treatment of neurological disorders which are attributed to disturbances of serotonin-activated transmission, such as depression, anxiety states, panic disorders, obsessive-compulsive disorders, pain, sleep disorders, insomnia, eating disorders, such as anorexia nervosa, bulimia, addictive behaviour, dependence on certain addictive substances, such as LSD and MDMA, cardiovascular disorders, such as various angina, raynaud's syndrome, intermittent claudication, cardiac or peripheral vasospasm, fibromyalgia, cardiac arrhythmias and thrombotic disorders, as the substance inhibits platelet aggregation. Can be combined with conventional or atypical neuroleptic to inhibit side effects caused by neuroleptic. The substance can also be used for the treatment of glaucoma due to decreased intraocular pressure. The substance can be used for inhibiting toxic symptoms caused by ergovalin poisoning.

The compounds are therefore useful as pharmaceutically active ingredients in human and veterinary medicine. They are also useful as intermediates for the preparation of other pharmaceutically active ingredients.

The preparation of 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile and its salts has received great attention because of its promise as a drug.

It is therefore an object of the present invention to find said 5-HT_2ANovel efficient synthesis of receptor antagonists.

The invention therefore relates to a process for the preparation of 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile of formula I and salts thereof,

is characterized in that:

(1) formylating an indole ester of formula II,

wherein R is an alkyl or aralkyl group having 1 to 6 carbon atoms,

(2) reacting the formyl ester of the formula III formed from (1)

Wherein R is as defined above, and wherein,

reaction with hydroxylamine to give the oxime derivative of formula IV,

wherein R is as defined above, and wherein,

(3) converting an oxime of formula IV to a cyanoindole ester of formula V

Wherein R has one of the meanings indicated above,

(4) saponification of the ester of formula V to give 3-cyano-1H-indole-7-carboxylic acid,

(5) reacting 3-cyano-1H-indole-7-carboxylic acid with 1- [2- (4-fluorophenyl) ethyl ] piperazine or a salt thereof to give a compound of formula I, and

(6) the resulting base of formula I is converted to one of its salts by treatment with an acid.

The substituent R in the formulae II to VI is an alkyl or aralkyl group having 1 to 6 carbon atoms.

The alkyl radical preferably has 1, 2, 3 or 4 carbon atoms and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1-, 1, 2-, 1, 3-, 2, 2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 2-or 1, 2, 2-trimethylpropyl, trifluoromethyl or pentafluoroethyl.

Aralkyl is- (CH)₂)_oAr, where Ar is preferably phenyl or naphthyl, o can be 0, 1 or 2. In particular, aralkylbenzyl, phenethyl or naphthylmethyl, with benzyl being particularly preferred.

R is preferably methyl or ethyl, particularly preferably ethyl.

The indole esters of formula II are commercially available or can be prepared by known synthetic methods. For example, the preparation can be carried out starting from 3-methyl-2-nitrobenzoic acid (commercially available) by the following reaction:

(1) esterifying 3-methyl-2-nitrobenzoic acid,

(2) reaction with N, N-dimethylformamide acetal to give 3- (2-dimethylaminoethyl) -2-nitrobenzoate, and

(3) subsequent palladium catalyzed ring closure affords the indole esters of formula II.

Particularly suitable indoles of the formula II are methyl 1H-indole-7-carboxylate, ethyl 1H-indole-7-carboxylate, tert-butyl 1H-indole-7-carboxylate and benzyl 1H-indole-7-carboxylate. The synthesis according to the invention is particularly preferably carried out with ethyl 1H-indole-7-carboxylate.

Suitable N, N-dimethylformamide acetals are, for example, N-dimethylformamide bis [2- (trimethylsilyl) ethyl ] acetal, N-dimethylformamide dibenzylacetal, N-dimethylformamide dibutylacetal, N-dimethylformamide di-tert-butylacetal, N-dimethylformamide diethylacetal, N-dimethylformamide diisopropylacetal, N-dimethylformamide dimethylacetal, N-dimethylformamide dineopentylacetal, N-dimethylformamide dipropylacetal and N, N-dimethylformamide ethylideneacetal. Particularly preferred are N, N-dimethylformamide diethylacetal and N, N-dimethylformamide dimethylacetal.

The palladium-catalyzed cyclization reaction is carried out analogously to the method of Leimgruber-Batco [ Clark R.D.et al, Heterocycles, 1984, 22, 195-.

The reaction conditions chosen are known from this document. However, it is also possible to prepare the compounds of the formula II by other methods known from the literature and will not be explained in detail here (literature: Houben-Weyl, Methoden der Organ. Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart).

The formylation of the compound of formula II to give the formylester of formula III is carried out analogously to the procedure of Vilsmeyer-Haack [ Jutz C.et al, Iminium Salts in organic Chemistry Part I, New York, John Wiley & Sons Inc., 1976, pp.234ff, pp.237ff ], where R has one of the meanings specified above. The reaction is preferably carried out in an aprotic polar solvent at a reaction temperature between 0 and 50 ℃ and with heating to 100 to 130 ℃. Particularly preferred solvents are Dimethylformamide (DMF) and mixtures of DMF with aromatic hydrocarbons such as benzene, toluene or xylene, or with other amides such as N-methylpyrrolidone (NMP).

The formylation is particularly preferably carried out in DMF in POCl₃In the presence of oxygen.

Particularly suitable formylindoles of the formula III are 7-methoxycarbonyl-3-indolylal, 7-ethoxycarbonyl-3-indolylal, 7-tert-butoxycarbonyl-3-indolylal and 7-benzyloxycarbonyl-3-indolylal. The synthesis according to the invention is particularly preferably carried out with 7-ethoxycarbonyl-3-indolecarboxaldehyde.

Oximation of the compounds of the formula III (as described above) is carried out under standard conditions (literature: Kurtz P., Houben-Weyl, Methoden der Organ. Chemie [ methods of organic chemistry ], Vol.VIII, Georg-Thieme-Verlag, Stuttgart).

The oximation is particularly preferably carried out in a polar aprotic solvent such as DMF, benzene, toluene, xylene or NMP at a temperature between 0 and 50 ℃ and in particular at room temperature.

The preparation of cyanoindole esters of formula V as described above is carried out by treatment with an acid. Suitable acids are, for example, inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids such as formic acid, acetic acid, p-toluenesulfonic acid or methanesulfonic acid. The reaction is particularly preferably carried out in a high-boiling aprotic solvent, such as DMF or NMP, or a mixture thereof with an aprotic solvent at between 20 and 100 ℃, in particular at 50 ℃.

In one embodiment of the process, steps (1) to (3) are carried out in situ, i.e.in a one-step process, analogous to Liebscher J.et al, Z.Chem.1983, 23, 214-215, without isolation of the intermediate products. The one-step process gives better yields than the step-by-step synthesis.

Saponification of the compound of formula V under standard conditions gives 3-cyano-1H-indole-7-carboxylic acid (literature: Houben-Weyl, Methoden der Organ. Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart).

The saponification is particularly preferably carried out with KOH in methanol at room temperature.

As an alternative to chemical saponification, ester cleavage by means of esterases is also possible. Suitable esterases are, for example, Bacillus esterases, Bacillus stearothermophilus esterases, Candida lipolytica esterases, Mucor miehei esterase, horse liver esterase, Saccharomyces cerevisiae esterase, pig liver esterase, Thermoanaerobacter brucei esterase and pig liver esterase isozyme 1. These esterases may be used in immobilized form. Commercially available immobilized esterases are for example Porcine Liver Esterase (PLE) immobilized on Eupergit  C or on ethylene oxide-acrylic acid particles. The enzymatic reaction is preferably carried out in an aqueous buffer system, but other solvents, in particular alcohols such as ethanol, may also be present.

The reaction of 3-cyano-1H-indole-7-carboxylic acid with 1- [2- (4-fluorophenyl) ethyl ] piperazine or one of its salts, in particular with 1- [2- (4-fluorophenyl) ethyl ] piperazine dihydrochloride, is carried out by methods known in the literature for acylating amines [ Houben-Weyl, I.c., Volume 15/II, p1-806(1974) ]. However, it is also possible to react the compounds in the presence of an inert solvent. Examples of suitable solvents are hydrocarbons such as benzene, toluene and xylene; ketones such as acetone and butanone; alcohols such as methanol, ethanol, isopropanol, and n-butanol; ethers such as Tetrahydrofuran (THF) and dioxane; amides such as Dimethylformamide (DMF) or N-methylpyrrolidone; nitriles such as acetonitrile, mixtures of these solvents or mixtures with water, if desired, may also be used. It may be advantageous to add an acid binder, for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or a weak acid salt of an alkali or alkaline earth metal, preferably potassium, sodium or calcium, or an organic base, such as triethylamine, dimethylaniline, pyridine or quinoline, or an excess of a piperazine derivative. Depending on the conditions employed, the reaction temperature is between about 0 and 150 ℃, usually between 20 and 130 ℃.

Instead of 3-cyano-1H-indole-7-carboxylic acid, it is also possible to use derivatives of this acid, preferably preactivated carboxylic acids, or the corresponding carboxylic acid halides, symmetrical or mixed anhydrides or active esters of 3-cyano-1H-indole-7-carboxylic acid. Such radicals for carboxyl group activation in typical acylation reactions are described in the literature (for example in standard procedures, such as Houben-Weyl, Methoden der Organischen Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart). The activated ester is advantageously formed in situ, for example by the addition of HOBt or N-hydroxysuccinamide.

The compound 1- [2- (4-fluorophenyl) ethyl ] piperazine and salts thereof are known and can be prepared by conventional methods known to those skilled in the art. A description of this preparation is disclosed, for example, in DE 2855703.

The resulting base of formula I can be converted to the associated acid addition salt with an acid. Acids suitable for this reaction are those which yield physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, nitric acid or sulfamic acid, and also organic acids, in particular aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic mono-or polycarboxylic acids, sulfonic acids or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane-or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid and laurylsulfuric acid.

In a preferred embodiment, the salt formation is carried out by precipitation with hydrochloric acid (37%) in an acetone/water solvent mixture of between 5: 1 and 4: 1. Form 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile hydrochloride.

In another embodiment of the process of the present invention, the cyanoindole esters of formula V can be reacted directly (without prior saponification to 3-cyano-1H-indole-7-carboxylic acid) by chemical or biochemical ammonolysis with 1- [2- (4-fluorophenyl) ethyl ] piperazine or the corresponding salt.

The chemical ammonolysis can be carried out by methods such as Menger f.m.et al, j.am.chem.soc.1969, 91, 5346-9. The biochemical ammonolysis can be carried out, for example, by reacting a compound of formula V with 1- [2- (4-fluorophenyl) ethyl ] piperazine or one of the corresponding salts in the presence of a lipase or an antibody. The biochemical ammonolysis can be carried out by methods such as Gotor V.et al, bioorg.Med.chem.1999, 7, 2189-2197.

The invention accordingly relates analogously to processes for the preparation of 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile of the formula I,

is characterized in that:

(1) formylating an indole ester of formula II,

wherein R is an alkyl or aralkyl group having 1 to 6 carbon atoms,

(2) reacting the formyl ester of the formula III formed from (1)

Wherein R is as defined above, and wherein,

reaction with hydroxylamine to give the oxime derivative of formula IV,

wherein R is as defined above, and wherein,

(3) converting an oxime of formula IV to a cyanoindole ester of formula V

Wherein R has one of the meanings indicated above,

(4) (ii) conversion of the ester of formula V to the compound of formula I by aminolysis with 1- [2- (4-fluorophenyl) ethyl ] piperazine or one of the salts, and

(5) the resulting base of formula I is converted to one of its salts by treatment with an acid.

In another embodiment of the process of the present invention, the compound 3-cyano-1H-indole-7-carboxylic acid can be prepared by: halogenating indole esters of formula II as described above

To give a compound of the formula VI

Wherein R is an alkyl or aralkyl group having 1 to 6 carbon atoms, and

hal is Cl, Br or I,

and then cyaniding.

Halogenation of compounds of formula II as described above is carried out using standard conditions (literature: Houben-Weyl, Methoden der Organ. Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart) or with Heterocycles, 1986, 24, 2879-85, ibid.1989, 29, 1663-7; J.am.chem.Soc.1985, 107, 2943-5; chem.1993, 58, 2058-60 or chem.soc, Perkin trans.1, 1989, 2009-15.

Bromination or iodination at the 3-position of the indole can also be carried out analogously to Bocchi et al Synthesis 1982, 1096-.

Examples of solvents suitable for the halogenation are hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ketones such as acetone and butanone; alcohols such as methanol, ethanol, isopropanol, and n-butanol; ethers such as Tetrahydrofuran (THF) and dioxane; amides such as Dimethylformamide (DMF) and N-methylpyrrolidone; nitriles such as acetonitrile, and, if desired, mixtures of these solvents.

Compounds which can be prepared by halogenation according to the invention are, for example, methyl 3-chloro-1H-indole-7-carboxylate, methyl 3-bromo-1H-indole-7-carboxylate, methyl 3-iodo-1H-indole-7-carboxylate, ethyl 3-chloro-1H-indole-7-carboxylate, ethyl 3-bromo-1H-indole-7-carboxylate, ethyl 3-iodo-1H-indole-7-carboxylate, tert-butyl 3-chloro-1H-indole-7-carboxylate, tert-butyl 3-bromo-1H-indole-7-carboxylate, tert-butyl 3-iodo-1H-indole-7-carboxylate, tert-butyl 3-bromo-1H-indole-7-carboxylate, tert-butyl 3-1H-indole-7-carboxylate, methyl 3-bromo-1H-indole-7-, Benzyl 3-chloro-1H-indole-7-carboxylate, benzyl 3-bromo-1H-indole-7-carboxylate, and benzyl 3-iodo-1H-indole-7-carboxylate. The use of ethyl 3-bromo-1H-indole-7-carboxylate or ethyl 3-iodo-1H-indole-7-carboxylate is particularly suitable according to the invention.

Substitution of the halo group of the compound of formula VI with a cyano group is carried out with nickel catalysis analogously to the method of Cassar L.et al, adv. chem.Ser.1974, 132, 252-73 or with palladium catalysis analogously to the method of Sakamoto T.et al, J.chem.Soc., Perkin Trans.1, 1999, 16, 2323-2326 or Chatani N.et al, J.org. chem.1986, 51, 4714-16.

Particular preference is given to introducing cyano groups under palladium catalysis.

The invention accordingly relates analogously to processes for the preparation of 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile of the formula I,

is characterized in that:

(1) halogenating the indole ester of formula II,

wherein R is an alkyl or aralkyl group having 1 to 6 carbon atoms,

(2) converting the halo group of the ester of formula VI from (1) to a cyano group,

wherein R and Hal are as defined above,

simultaneously saponifying the ester to 3-cyano-1H-indole-7-carboxylic acid,

(3) reacting 3-cyano-1H-indole-7-carboxylic acid with 1- [2- (4-fluorophenyl) ethyl ] piperazine or a salt thereof to give a compound of formula I, and

(4) the resulting base of formula I is converted to one of its salts by treatment with an acid.

Another aspect of the invention relates to compounds of formula IV and salts thereof,

wherein R is an alkyl or aralkyl group having 1 to 6 carbon atoms.

Alkyl and arylalkyl have one of the above meanings.

The compound of formula IV may occur in two isomeric forms, i.e. compounds of formulae IVa and IVb. Formula IV includes the individual isomers of formulae IVa and IVb and mixtures thereof.

Wherein R has one of the meanings indicated above.

Preferred compounds of the formula IV are

3-hydroxyimino-1H-indole-7-carboxylic acid methyl ester,

3-hydroxyimino-1H-indole-7-carboxylic acid ethyl ester,

3-hydroxyimino-1H-indole-7-carboxylic acid tert-butyl ester and

3-hydroxyimino-1H-indole-7-carboxylic acid benzyl ester, including Z-and E-forms and mixtures thereof.

Particularly preferred compounds of the formula IV are

(Z) -3-hydroxyimino-1H-indole-7-carboxylic acid ethyl ester,

(E) -3-hydroxyimino-1H-indole-7-carboxylic acid ethyl ester and E/Z mixture.

Salts of the compounds of formula IV may be prepared by the methods described above for the compounds of formula I.

The compound of formula IV is a valuable intermediate in the synthesis of 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile and salts thereof as described above.

Another aspect of the invention relates to compounds of formula V and salts thereof,

wherein R is an alkyl or aralkyl group having 1 to 6 carbon atoms.

Alkyl and aralkyl have one of the meanings indicated above.

Preferred compounds of the formula V are

3-cyano-1H-indole-7-carboxylic acid methyl ester,

3-cyano-1H-indole-7-carboxylic acid ethyl ester,

3-cyano-1H-indole-7-carboxylic acid tert-butyl ester and

benzyl 3-cyano-1H-indole-7-carboxylate, and salts thereof.

The process of the invention is particularly preferably carried out with ethyl 3-cyano-1H-indole-7-carboxylate.

Salts of the compounds of formula V may be prepared by the methods described above for the compounds of formula I.

The compound of formula V is a valuable intermediate in the synthesis of 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile and salts thereof as described above.

The invention similarly relates to the compound 3-cyano-1H-indole-7-carboxylic acid and salts thereof.

Another aspect of the invention relates to compounds of formula VI and salts thereof,

wherein R is an alkyl or aralkyl group having 1 to 6 carbon atoms, and

hal is Cl, Br or I.

Alkyl and aralkyl have one of the meanings indicated above.

Preferred compounds of the formula VI are

3-bromo-1H-indole-7-carboxylic acid methyl ester,

3-bromo-1H-indole-7-carboxylic acid ethyl ester,

3-bromo-1H-indole-7-carboxylic acid tert-butyl ester,

3-bromo-1H-indole-7-carboxylic acid benzyl ester,

3-iodo-1H-indole-7-carboxylic acid methyl ester,

3-iodo-1H-indole-7-carboxylic acid ethyl ester,

3-iodo-1H-indole-7-carboxylic acid tert-butyl ester and

benzyl 3-iodo-1H-indole-7-carboxylate, and salts thereof.

The process of the invention is particularly preferably carried out with ethyl 3-bromo-1H-indole-7-carboxylate or ethyl 3-iodo-1H-indole-7-carboxylate.

Salts of the compounds of formula VI may be prepared by the methods previously described for the compounds of formula I.

The compound of formula VI is a valuable intermediate in the synthesis of 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile and salts thereof as described above.

It is envisaged that the person skilled in the art will be able to utilise the above description to its fullest extent, even if not with other details. The preferred embodiments are therefore to be considered in all respects as illustrative and not restrictive.

All temperature data above and below are given in c. In the following examples, "conventional procedure" means that water is added if necessary, the mixture is adjusted to a pH of between 2 and 10 if necessary, the mixture is extracted with ethyl acetate or dichloromethane, depending on the composition of the final product, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel and/or crystallization.

Example 1:

1.13-Formylindole-7-carboxylic acid methyl ester

2.9ml of phosphorus oxychloride was slowly added to 7ml of N, N-dimethylformamide (formylation solvent) under a nitrogen atmosphere. 5g (0.029mol) of methyl indole-7-carboxylate are dissolved in 7ml of DMF and slowly added to the formylation solution, during which the temperature does not rise above 30 ℃. The mixture was then heated at 100 ℃ for 1 hour. After cooling, the mixture is poured into water, neutralized with sodium hydroxide solution and the crystals deposited are filtered off with suction. m.p.154 ℃. Yield 5.3g (89.9% of theory).

1.23- (Hydroxyiminomethyl) indole-7-carboxylic acid methyl ester

5g of methyl 3-formylindole-7-carboxylate (0.024mol) were added to a solution of 0.03mol of hydroxylammonium hydrochloride in dimethylformamide. The reaction mixture was heated at 125 ℃ for 1 hour to obtain 5.1g of methyl 3- (hydroxyiminomethyl) indole-7-carboxylate by a conventional procedure.

1.33-cyanoindole-7-carboxylic acid methyl ester

5g of methyl 3- (hydroxyiminomethyl) indole-7-carboxylate are suspended in 20ml of toluene, 1ml of sulfonyl chloride are added and the mixture is refluxed for 1 hour. Evaporation and extraction with ethyl acetate gave 4.5g of cyanoindole-7-carboxylic acid methyl ester, m.p.212 ℃.

1.43-cyanoindole-7-carboxylic acid

4.5g (0.022mol) of methyl cyanoindole-7-carboxylate are suspended in 100ml of methanol and a solution of 30ml of sodium hydroxide solution (w ═ 32%) in 30ml of water is added at room temperature. Stirring overnight gave a virtually clear solution which was filtered and evaporated. Water was added to the residue until a clear solution was formed, and the mixture was adjusted to pH 2 with concentrated hydrochloric acid under ice cooling. The white crystals are filtered off with suction and dried under reduced pressure for 2 hours to give 4g of 3-cyanoindole-7-carboxylic acid (97.7% of theory); m.p. 317.5-318.5.

1.57- {4- [2- (4-fluorophenyl) ethyl ] piperazine-1-carbonyl } -1H-indole-3-carbonitrile

5g (0.027mol) of 3-cyanoindole-7-carboxylic acid are dissolved in 40ml of hot N-methylpyrrolidone, the solution is cooled to 40 ℃ and 7.6g (0.027mol) of N, N-carbonyldiimidazole are added. The mixture was stirred at room temperature for a further 1 hour. A suspension of 1- (2- (4-fluorophenyl) ethyl) piperazine dihydrochloride in 40ml of N-methylpyrrolidone is then poured in. After 5 minutes, a clear solution formed, followed by the deposition of white crystals. The mixture was stirred at room temperature overnight. The crystals were filtered off with suction, washed and dried to give 5g of 7- {4- [2- (4-fluorophenyl) ethyl ] piperazine-1-carbonyl } -1H-indole-3-carbonitrile as the free base having a melting point (m.p.) of 192.0-193.5 ℃.

The chemical names 7- {4- [2- (4-fluorophenyl) ethyl ] piperazine-1-carbonyl } -1H-indole-3-carbonitrile and 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile are synonymous.

1.67- {4- [2- (4-fluorophenyl) ethyl ] piperazine-1-carbonyl } -1H-indole-3-carbonitrile hydrochloride

2.1g of the free base obtained according to 1.5 are heated in 50ml of acetone and water is added until a clear solution is formed. Then a mixture of 0.6ml hydrochloric acid (w ═ 37%) and 1.2ml acetone was stirred in. The mixture was then evaporated to half of its original volume in a rotary evaporator. The precipitated hydrochloride is filtered off with suction, washed with acetone and diethyl ether and dried to give 1.6g of 7- {4- [2- (4-fluorophenyl) ethyl ] piperazine-1-carbonyl } -1H-indole-3-carbonitrile hydrochloride (69% of theory) in the decomposition range 314 ℃ 319 ℃.

Example 2:

2.13-cyanoindole-7-carboxylic acid methyl ester

9.1g of phosphorus oxychloride was added to 30ml of dimethylformamide at a reaction temperature of 20 to 30 ℃ with ice cooling. A solution of 8g of methyl indole-7-carboxylate in dimethylformamide is added dropwise, during which the temperature rises to 40 ℃. After heating at 125 ℃ for 1 hour, the solution is added dropwise, while still hot, to a solution of 6.3g hydroxylammonium chloride in dimethylformamide (40ml), and the mixture is stirred at 120 ℃ for a further 15 minutes. The mixture was poured into water, extracted with ethyl acetate, filtered through neutral alumina and evaporated to give 4.5g of methyl 3-cyanoindole-7-carboxylate (48.9% of theory) with a melting range of 212-213.5 ℃.

Other reactions were carried out similarly to examples 1.4 to 1.6.

Example 3:

3.13-Bromoindole-7-carboxylic acid ethyl ester

12g of perbrominated pyridine hydrobromide were added to a solution of 5g of indole-7-carboxylic acid ethyl ester in pyridine (50 g). The reaction mixture was warmed to 30-50 ℃ and stirred until the conversion was complete (about 3 to 10 hours).

Obtaining the 3-bromoindole-7-carboxylic acid ethyl ester through conventional operation.

3.23-cyanoindole-7-carboxylic acid

7g of ethyl 3-bromoindole-7-carboxylate were dissolved in 70g of NMP, and 4g of CuCN was added. The mixture was heated to 100-140 ℃ with stirring. After 3 hours, the mixture was subjected to the conventional procedure to give 3-cyanoindole-7-carboxylic acid.

Further reactions of 3-cyanoindole-7-carboxylic acid were carried out analogously to examples 1.5 to 1.6.

Claims (7)

1. A process for the preparation of 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile of formula I or a salt thereof,

is characterized in that:

(1) formylating an indole ester of formula II,

wherein R is a methyl group or an ethyl group,

(2) reacting the formyl ester of the formula III formed from (1)

Wherein R is as defined above, and wherein,

reaction with hydroxylamine to give the oxime derivative of formula IV,

wherein R is as defined above, and wherein,

(3) converting an oxime of formula IV to a cyanoindole ester of formula V

Wherein R is as defined above, and wherein,

(4) saponification of the ester of formula V to give 3-cyano-1H-indole-7-carboxylic acid,

(5) reacting 3-cyano-1H-indole-7-carboxylic acid with 1- [2- (4-fluorophenyl) ethyl ] piperazine or a salt thereof to give a compound of formula I, and optionally

(6) The resulting base form of formula I is converted to one of its salts by treatment with an acid.

2. The process according to claim 1, characterized in that steps (1) to (3) are carried out as a one-pot synthesis.

3. A process for the preparation of 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile of formula I as defined in claim 1, or a salt thereof, characterized in that steps (1) to (3) are carried out according to the process described in claim 1,

(4) converting cyanoindole ester of formula V as defined in claim 1 to a compound of formula I by aminolysis with 1- [2- (4-fluorophenyl) ethyl ] piperazine or one of its salts, and optionally

(5) The resulting base form of formula I is converted to one of its salts by treatment with an acid.

4. A process for the preparation of 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile of formula I as defined in claim 1, or a salt thereof, characterized in that

(1) Reacting an indole ester of formula II

Wherein

R is a methyl group or an ethyl group,

halogenation to compounds of formula VI

Wherein

Hal is Cl, Br or I,

(2) cyanation of a compound of formula VI to give a cyanoindole ester of formula V

And steps (4), (5) and optionally step (6) as described in claim 1.

5. A process according to claim 1, 3 or 4, characterised in that 1- [2- (4-fluorophenyl) ethyl ] piperazine is used in the form of the dihydrochloride.

6. A process according to claim 1, 3 or 4, characterized in that the base form 7- {4- [2- (4-fluorophenyl) -ethyl ] -piperazin-1-ylcarbonyl } -1H-indole-3-carbonitrile of formula I is converted into its hydrochloride salt.

3-cyano-1H-indole-7-carboxylic acid or a salt thereof.