HK1081527B

HK1081527B - Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile

Info

Publication number: HK1081527B
Application number: HK06101734.3A
Authority: HK
Inventors: Jerome Emile Georges Guillemont; Didier Philippe Robert Schils; Joannes Josephus Maria Willems; Bart Petrus Anna Maria Jozef Medaer; Elisabeth Therese Jeanne Pasquier; Paul Adriaan Jan Janssen; Jan Heeres; Ruben Gerardus George Leenders
Original assignee: Janssen Pharmaceutica N. V.
Priority date: 2002-08-09
Filing date: 2003-08-07
Publication date: 2010-05-28

Description

Process for the preparation of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile

The present invention relates to 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] -amino ] -2-pyrimidinyl ] amino ] benzonitrile, to N-oxides, to pharmaceutically acceptable addition salts, to quaternary ammonium or stereochemically isomeric forms thereof and to the preparation of the same and to key intermediates in said preparation.

WO 99/50250 discloses substituted diaminopyrimidine compounds having HIV (human immunodeficiency virus) inhibitory activity and their preparation. WO 03/16306 discloses the preparation of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile from a melt of [4- [ (4-chloro-2-pyrimidinyl) amino ] benzonitrile and 3- (4-amino-3, 5-dimethylphenyl) -2-acrylonitrile.

4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] -benzonitrile, an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof are novel, highly effective HIV, especially HIV-1 replication inhibiting compounds. They have a high ability to inhibit wild-type human immunodeficiency virus and resistant mutants thereof.

Thus, 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] -amino ] benzonitrile, an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, is useful as a medicament. They are useful in the prevention or treatment of HIV infection, including the prevention or treatment of HIV infection by mutant strains, i.e., strains that become drug resistant to drugs known in the art (drug-resistant or multidrug-resistant HIV strains); they are useful in the treatment of warm-blooded animals including humans infected with HIV or infected with viruses whose presence is mediated by or dependent on reverse transcriptase, or in the prevention of viral infections in these warm-blooded animals. Accordingly, the present invention relates to the use of 4- [ [4- [ [4- (2-cyano-vinyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile, an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, or a stereochemically isomeric form thereof, for the manufacture of a medicament for the prevention or treatment of HIV infection. The invention also relates to a method of treating warm-blooded animals including humans suffering from a viral infection, especially an HIV infection, or a method of preventing warm-blooded animals including humans from suffering from a viral infection, especially an HIV infection. Said method comprising the administration, preferably oral administration, of an effective amount of a compound of formula (I), a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a possible stereochemically isomeric form thereof, to warm-blooded animals, including humans.

The present invention also provides a composition for treating viral infections comprising a therapeutically effective amount of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile, an N-oxide, a pharmaceutically acceptable addition salt, a quaternary ammonium or stereochemically isomeric form thereof, and a pharmaceutically acceptable carrier or diluent.

The compounds of the present invention, or any subgroup thereof, may be formulated into various pharmaceutical forms for administration. Suitable compositions which may be mentioned are all compositions for the systemic administration of drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unit dosage form particularly suitable for oral, rectal, transdermal or parenteral administration. For example, in preparing the compositions in oral dosage form, any of the conventional pharmaceutical media may be employed, such as water, glycols, oils, alcohols, and the like for oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or for powders, pills, capsules and tablets, the pharmaceutical media are solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form in which case solid pharmaceutical carriers are obviously employed. For compositions for parenteral administration, the carrier will usually comprise at least a major proportion of sterile water, and may also include other components, for example to facilitate dissolution. For example, injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are converted into liquid form preparations immediately prior to use. In compositions suitable for transdermal administration, the carrier optionally includes a penetration enhancer and/or a suitable wetting agent, optionally in combination with suitable additives of any nature in minor proportions, which additives do not produce a significant deleterious effect on the skin. The additives may be conveniently administered to the skin and/or may aid in the preparation of the desired composition. These compositions may be administered in various ways, for example as transdermal patches, as drops (spot-on), as ointments. The compounds of the present invention may also be administered by inhalation or insufflation using methods and formulations used in the art for administration by this means. Thus, the compounds of the invention may generally be administered to the lungs in solution, suspension or dry powder. Any system developed for the delivery of solutions, suspensions or dry powders by oral or nasal inhalation or insufflation is suitable for the administration of the compounds of the invention.

The HIV replication inhibitory activity of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethyl-phenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile, an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, can be determined using the following assay.

Determination of anti-HIV Activity

In vitro evaluation of anti-HIV drugs was performed using rapid, sensitive and automated assay methods. The present invention is described in the prior art (Koyanagi et al, int.j. cancer,36445-451, 1985) show a high susceptibility to HIV infection and an easy-to-infect HIV-1 transformationThe T4-cell line MT-4 as a target cell line. The inhibition of HIV-induced cytopathic effects was used as the end point. Viability of HIV-infected and pseudo-infected cells was assessed spectrophotometrically by reducing 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) in situ. Cytotoxic Concentration (CC) of 50%₅₀In M) is defined as the concentration of compound that reduces the absorbance of the mock-infected control sample by 50%. The percent protection achieved by the compound in HIV-infected cells was calculated by the following formula:

expressed in% by weight, the total amount of the active ingredient,

wherein (OD)_T)_HIV(ii) the optical density determined for a given concentration of test compound in HIV-infected cells; (OD)_C)_HIVOptical density determined for untreated HIV-infected cell control; (OD)_C)_MOCKOptical density determined for the untreated pseudo-infected cell control; all optical density values were determined at 540 nm. Will achieve 50% protection according to the above formulaDose was defined as 50% Inhibitory Concentration (IC)₅₀In units of M). Will CC₅₀And IC₅₀The ratio of (a) to (b) is defined as the Selectivity Index (SI).

The compound X obtained, i.e.

(E-isomer) of a compound represented by the formula,

the results are as follows:

IC₅₀＝10^-9.4M；

CC₅₀＝10^-5M；

SI＝10^-5M/10^-9.4M＝25,119。

compound X was also tested for replication inhibitory activity against HIV-1 resistant mutants (single or double mutants). So that the results indicate that compound X has high activity against drug strains.

For development purposes and commercial availability, in order to ensure an economical supply of the compounds of the invention, efficient synthetic methods which can be carried out on a large industrial scale are required for the preparation of these compounds.

It is an object of the present invention to provide a process for the preparation of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile, an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, in high yield and under conditions which afford the economic advantage of being practiced on a large industrial scale.

Accordingly, the present invention provides a process for the preparation of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile of formula (I), an N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof,

said process comprising reacting an intermediate of formula (II), a suitable acid addition salt or a stereochemically isomeric form thereof

With an intermediate of formula (III), a suitable acid addition salt or N-oxide thereof in the presence of a suitable solvent

Wherein W₁Represents a suitable leaving group.

W₁Suitable leaving groups represented are, for example, halogen, triflate, tosylate, methylsulfonyl and the like. W₁Preferably represents halogen, more particularly chlorine.

In the above reaction, suitable solvents are, for example, acetonitrile; alcohols such as ethanol, 2-propanol-HCl; n, N-dimethylformamide; n, N-dimethylacetamide; 1-methyl-2-pyrrolidone; 1, 4-dioxane; propylene glycol monomethyl ether. The solvent is preferably acetonitrile; alcohols such as ethanol, 2-propanol-HCl; n, N-dimethylformamide; n, N-dimethylacetamide; propylene glycol monomethyl ether. More preferably the solvent is 2-propanol, a solution of 6N HCl in 2-propanol or acetonitrile, especially acetonitrile.

The intermediates of formula (II) are preferably used in the form of acid addition salts, especially hydrochloric acid addition salts, and the intermediates of formula (III) are preferably used in the form of the free base.

The product obtained from the above reaction can be conveniently isolated in the form of a base or an acid addition salt and can be further converted to an acid addition salt by treatment with an acid, or conversely, an acid addition salt can be converted to the free base form by treatment with a base and, if desired, a stereochemically isomeric form, an N-oxide form or a quaternary amine of the product can be formed. The reaction product may be isolated from the reaction medium and, if desired, further purified according to methods generally known in the art, such as extraction, crystallization, distillation, trituration and chromatography.

According to another aspect of the present invention there is provided a process for the preparation of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile of formula (I), an N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof,

said process comprising reacting an intermediate of formula (IV), a suitable acid addition salt or N-oxide thereof

Wherein W₂Represents a suitable leaving group which is, for example,

with acrylonitrile in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent.

W₂Suitable leaving groups represented are, for example, halogen, triflate, tosylate, mesylate and the like. W₂Preferred is halogen, more particularly iodine or bromine.

The palladium (Pd) catalyst may be a homogeneous Pd catalyst such as Pd (OAc)₂、PdCl₂、Pd(PPh₃)₄、Pd(PPh₃)₂Cl₂、Pd₂(dba)₃(tris (dibenzylideneacetone) dipalladium), palladium sulfomethylphenyl glutaramide metallocycle, and the like, or a heterogeneous Pd catalyst such as palladium on carbon, palladium on metal oxide, palladium on zeolite.

Preferably, the palladium catalyst is a heterogeneous Pd catalyst, more preferably palladium on carbon (Pd/C). Pd/C is a recyclable catalyst that is stable and relatively inexpensive. It can be easily separated (filtered) from the reaction mixture, thus reducing the risk of Pd remaining in the final product. The use of Pd/C also avoids the need for expensive, toxic and product-contaminating ligands, such as phosphine ligands.

Suitable bases are, for example, sodium acetate, potassium acetate, N-diethylethylamine, sodium bicarbonate, sodium hydroxide and the like.

Suitable solvents are, for example, acetonitrile, N-dimethylacetamide, ionic liquids such as [ bmim [ ]]PF₆N, N-dimethylformamide, water, tetrahydrofuran, dimethylsulfoxide, 1-methyl-2-pyrrolidone and the like.

The product obtained by the above reaction can be converted into an acid addition salt by treatment with an acid, if necessary, and a stereochemically isomeric form, an N-oxide form or a quaternary amine of the product can be formed, if necessary. The reaction product may be isolated from the reaction medium and, if desired, further purified according to methods generally known in the art, such as extraction, crystallization, distillation, trituration and chromatography.

Alternatively, the compounds of formula (I) may be prepared by dehydrating the corresponding amide derivative.

Accordingly, the present invention also provides a process for the preparation of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile of formula (I), an N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof,

said process comprising reacting an intermediate of formula (VI), a suitable acid addition salt or a stereochemically isomeric form thereof

Wherein W₁Represents a suitable leaving group which is, for example,

the intermediate of formula (VII) thus obtained, a pharmaceutically acceptable acid addition salt, a stereochemically isomeric form or an N-oxide thereof is then dehydrated

In the above reaction, suitable solvents are, for example, acetonitrile; alcohols such as ethanol, 2-propanol-HCl; n, N-dimethylformamide; n, N-dimethylacetamide; 1-methyl-2-pyrrolidone; 1, 4-dioxane; propylene glycol monomethyl ether. The solvent is preferably acetonitrile; alcohols such as ethanol, 2-propanol-HCl; n, N-dimethylformamide; n, N-dimethylacetamide; propylene glycol monomethyl ether. More preferably, the solvent is 2-propanol, a solution of 6N HCl in 2-propanol or acetonitrile.

The conversion of the intermediate of formula (VII) into the compound of formula (I), i.e. the dehydration step, may be carried out according to methods well known to those skilled in the art, for example in a "synthetic organic conversion reaction. The functional group preparation guide "(" Comprehensive Organic transformations. A guide to functional group precursors "), Richard C.Larock, John Wiley and Sons, Inc, 1999, P1983-1985, which is incorporated herein by reference. Various suitable reagents are listed in this reference, such as SOCl₂、HOSO₂NH₂、ClSO₂NCO、MeO₂CNSO₂NEt₃、PhSO₂Cl、TsCl、P₂O₅、(Ph₃PO₃SCF₃)O₃SCF₃Polyphosphate esters, (EtO)₂POP(OEt)₂、(EtO)₃PI₂2-chloro-1, 3, 2-dioxaphospholane, 2, 2, 2-trichloro-2, 2-dihydro-1, 3, 2-dioxaphospholane, POCl₃、PPh₃、P(NCl₂)₃、P(NEt₂)₃、COCl₂、NaCl.AlCl₃、ClCOCOCl、ClCO₂Me、Cl₃CCOCl、(CF₃CO)₂O、Cl₃CN＝CCl₂2, 4, 6-trichloro-1, 3, 5-triazine, NaCl₃、HN(SiMe₂)₃、N(SiMe₂)₄Methanesulfonyl chloride and the like. All reagents listed in this publication are incorporated herein by reference.

In addition, the present invention provides a process for the preparation of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile of formula (I), an N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof,

Wherein W₂Represents a suitable leaving group which is, for example,

with acrylamide in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent,

In order to achieve a highly efficient synthesis process, it is not sufficient to optimize only the final reaction steps, i.e. the reaction steps that form the desired product, but also the synthesis of the intermediates.

Thus, another aspect of the present invention relates to a process for the preparation of key intermediates, i.e. intermediates of formula (II) in the synthesis of compounds of formula (I), N-oxides, pharmaceutically acceptable acid addition salts, quaternary amines or stereochemically isomeric forms thereof.

Thus, the present invention also provides a process for the preparation of intermediates of formula (II), suitable acid addition salts, quaternary amines or stereochemically isomeric forms thereof

Said process comprising reacting an intermediate of formula (V), a suitable acid addition salt or a quaternary ammonium thereof

Wherein W₃Represents a suitable leaving group which is, for example,

W₃Suitable leaving groups represented are, for example, halogen, triflate, tosylate, mesylate and the like. W₃Preferred is halogen, more particularly iodine or bromine. Most preferred is iodine.

Alternatively, intermediates of formula (II) can be prepared by dehydration of the corresponding amide derivative.

The present invention therefore also provides a process for the preparation of intermediates of formula (II), suitable acid addition salts, quaternary amines or stereochemically isomeric forms thereof,

Wherein W₃Represents a suitable leaving group which is, for example,

the intermediate of formula (VI) thus obtained, a suitable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof is then dehydrated

W₃Suitable leaving groups represented are, for example, halogen, triflate, tosylate, mesylate and the like. W₃Preferred is halogen, more particularly iodine or bromine.

The conversion of the intermediate of formula (VI) into the intermediate of formula (II), i.e. the dehydration step, may be carried out according to methods well known to those skilled in the art, for example in a "synthetic organic conversion reaction. The functional group preparation guide "(" Comprehensive Organic transformations. A guide to functional group precursors "), Richard C.Larock, John Wiley and Sons, Inc, 1999, P1983-1985, which is incorporated herein by reference. Various suitable reagents are listed in this reference, such as SOCl₂、HOSO₂NH₂、ClSO₂NCO、MeO₂CNSO₂NEt₃、PhSO₂Cl、TsCl、P₂O₅、(Ph₃PO₃SCF₃)O₃SCF₃Polyphosphate esters, (EtO)₂POP(OEt)₂、(EtO)₃PI₂2-chloro-1, 3, 2-dioxaphospholane, 2, 2, 2-trichloro-2, 2-dihydro-1, 3, 2-dioxaphospholane, POCl₃、PPh₃、P(NCl₂)₃、P(NEt₂)₃、COCl₂、NaCl.AlCl₃、ClCOCOCl、ClCO₂Me、Cl₃CCOCl、(CF₃CO)₂O、Cl₃CN＝CCl₂2, 4, 6-trichloro-1, 3, 5-triazine, NaCl₃、HN(SiMe₂)₃、N(SiMe₂)₄Methanesulfonyl chloride and the like. All reagents listed in this publication are incorporated herein by reference.

The term halogen as used in this context is typically fluorine, chlorine, bromine and iodine.

For therapeutic use, salts of the compounds of formula (I) are those in which the counterion is pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases can also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention.

The pharmaceutically acceptable addition salts mentioned above and below include the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) can form. The latter can be conveniently obtained by treating the base form with a suitable acid, for example, an inorganic acid, e.g., hydrohalic acids such as hydrochloric acid, hydrobromic acid, and the like; sulfuric acid; nitric acid; phosphoric acid, and the like; or an organic acid such as acetic acid, propionic acid, hydroxyacetic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1, 2, 3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and the like. The salt form can in turn be converted to the free base form by treatment with a base.

The term addition salt also includes the hydrates and solvent adducts which the compounds of formula (I) can form. Examples of these forms are hydrates, alcoholates and the like.

The term "quaternary ammonium" as used in this context refers to quaternary ammonium salts which may be formed by reaction of the basic nitrogen of the compound of formula (I) with a suitable quaternising agent, for example an optionally substituted alkyl halide, aryl halide or aralkyl halide such as methyl iodide or benzyl iodide. Other reactants having good leaving groups may also be used, such as alkyl triflates, alkyl mesylates and alkyl p-toluenesulfonates. Quaternary amines have a positively charged nitrogen. Pharmaceutically acceptable counterions include chloride, bromide, iodide, trifluoroacetate and acetate. The selected counter ion may be introduced using an ion exchange resin.

The N-oxide forms of the compounds of the invention include compounds of formula (I) in which one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide. The compounds of formula (I) may be converted to the corresponding N-oxide form according to methods known in the art for converting a trivalent nitrogen into its N-oxide form. The N-oxidation reaction can generally be carried out by reacting the starting materials of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids, such as benzoxybenzoic acid (benzacarboperoxoic acid) or haloperoxybenzoic acids such as 3-chloro-peroxybenzoic acid, peroxy alkanoic acids such as peroxyacetic acid, alkyl hydroperoxides such as t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of these solvents.

It will be appreciated that the compounds of formula (I) and the N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof may contain one or more chiral centres and exist in stereochemically isomeric forms.

The term "stereochemically isomeric forms" as used hereinbefore and hereinafter refers to all the possible stereoisomeric forms which the compounds of formula (I), and the N-oxides, addition salts, quaternary amines or physiologically functional derivatives thereof, may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds refers to the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as the individual isomers of each formula (I) and the N-oxides, salts, solvates or quats thereof being substantially free of, i.e. mixed with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. In particular, the stereocenter may have the R-or S-configuration or the cis-or trans-configuration; for example, the substituents on the divalent cyclic (partially) saturated group may have a cis-or trans-configuration. The compounds of the formula (I) can have E (hetero) or Z (homo) -stereochemistry at the double bond. When a compound of formula (I) is designated as (E), this means that the compound is substantially free of the (Z) isomer. The terms cis, trans, R, S, E and Z are well known to those skilled in the art. Stereochemically isomeric forms of the compounds of formula (I) are also intended to be encompassed within the scope of this invention.

The term "compound of formula (I)" is meant to include also the N-oxide forms, addition salts, quaternary amines and stereochemically isomeric forms thereof, wherever the context may be. Of most interest are those compounds of formula (I) which are stereochemically pure. A preferred compound is compound X.

The Z-isomer of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile can also be prepared by the reaction of the invention and can be isolated according to techniques known in the art. Thus, 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (Z) is also included in the scope of the present invention.

The following examples illustrate the invention.

Experimental part

A. Preparation of intermediate compounds

Example A1

Preparation of intermediate (II)

a) To a solution of 159g of 4-iodo-2, 6-dimethyl-aniline in 650ml of N, N-dimethylacetamide was added 63.8g of sodium acetate. The reaction mixture was kept under nitrogen. 7g of wet palladium on charcoal (Pd/C10%) and 64.4ml of acrylonitrile are added. The reaction mixture was heated to 130 ℃ and stirred overnight. After cooling to room temperature, 0.5 l of toluene and 0.5 l of N, N-dimethylacetamide were added. The reaction mixture was filtered through Dicalite and the residue was washed with 0.5 l of toluene. Water (6 l) was added to the mixture and stirred for 30 min. The layers were separated. To the aqueous layer was added 1 liter of toluene and the mixture was stirred for 30 minutes. The layers were separated again. The separated organic layer was collected and the solvent was evaporated. Yield: 123g of intermediate (II).

Retention time of intermediate (II) on CPSILgCB (25m × 0.32mm × 0.5 μm) (which was flushed with He, initial temperature 40 ℃, increasing at a rate of 10 ℃/min until a temperature of 300 ℃) was reached: the (Z) isomer was 17.50 minutes and the (R) isomer was 18.77 minutes.

Example A2

Preparation of the hydrochloride salt of intermediate (II) (1: 1)

a) To a mixture of 123g of intermediate (II) in 630ml of ethanol was added 1.25 l of diisopropyl ether. The reaction mixture was placed under a nitrogen atmosphere. The mixture was heated to 60 ℃ and stirred for 30 minutes. 120ml of 6N HCl in 2-propanol were added and the mixture was stirred for 30 minutes. After cooling to room temperature, the reaction mixture was filtered and the residue was washed with 100ml of 2-propanol. The residue was dried at 50 ℃ under reduced pressure. Yield: 103g (77%) of the hydrochloride salt of intermediate (II) (1: 1).

b) 1.012kg of wet palladium on charcoal (Pd/C10%), 9.361kg of sodium acetate and 34.41kg of N, N-dimethylacetamide were added to the reactor and placed under a nitrogen atmosphere. The mixture was stirred and heated at 140 ℃. 23.497kg of 4-iodo-2, 6-dimethyl-aniline, 7.569kg of acrylonitrile and 54.98kg of N, N-dimethylacetamide were charged into a second reactor and placed under a nitrogen atmosphere. The mixture was stirred at room temperature for 30 minutes. The solution in the second reactor was transferred to the first reactor over 1 hour and the temperature of the first reactor was maintained at 140 ℃. The reaction mixture was stirred at 140 ℃ overnight and then cooled to room temperature. The reaction mixture was filtered (1) and the filter was washed with 95.1 l of toluene (2). To the organic phase thus obtained, i.e. (1) + (2), 380.4 l of water were added and the mixture was stirred vigorously. Then, the stirring was stopped and the phases (3) were separated. The aqueous layer was washed with 95.1 l of toluene and the phases (4) were separated again. The combined organic phases, i.e. (3) + (4), were transferred into a second reactor and distilled under reduced pressure. 190.2 l of EtOH were added and the mixture was stirred at room temperature. A solution of HCl (6N) in 2-propanol (18.13 l) was added at room temperature and the reaction mixture was stirred at room temperature overnight and then filtered (. +). The solid obtained was washed with 14.74 l 2-propanol and dried at 50 ℃ under reduced pressure. Yield: 50-60% of the hydrochloride salt of intermediate (II) (1: 1). Additional product (10-15%) was recovered by distilling the filtrate (. star.) and wash (. star.), followed by filtration at room temperature.

Example A3

Preparation of wherein W₁An intermediate of formula (III) representing chlorine, said intermediate being represented by formula (III-a)

The intermediates of formula (III-a) were prepared according to the procedure described in WO 99/50250.

In particular, POCl₃4- [ (1, 4-dihydro-4-oxo-2-pyrimidinyl) amino group in (90ml)]The benzonitrile (0.12mol) mixture is stirred at reflux for 20 minutes under argon atmosphere. The reaction mixture was poured slowly into 750ml of ice/water and the solid isolated by filtration. The solid was suspended in 500ml of water and the pH of the suspension was adjusted to neutrality by addition of 20% NaOH solution. The solid is separated off again by filtration, suspended in 200ml of 2-propanone and 1000ml of CH are added₂Cl₂. The mixture was heated until all solids dissolved. After cooling to room temperature, the aqueous layer was separated and the organic layer was dried. During the removal of the drying agent by filtration, a white solid was formed in the filtrate. The filtrate was further cooled in a freezer and then filtered to obtain 21.38g (77.2%) [4- [ (4-chloro-2-pyrimidinyl) amino group]Benzonitrile, i.e. intermediates of formula (III-a).

Retention time of intermediate (III-a) on Hypersil BDS (10 cm. times.4 mm. times.3 μm) (0 min with 0.5% NH)₄Ac/CH₃CN 90/10 elution, 0/100 elution at 15 min): 8.33 minutes.

Example A4

Preparation of wherein W₂An intermediate of formula (IV) representing bromine, said intermediate being represented by formula (IV-a)

A mixture of 4-bromo-2, 6-dimethylaniline (0.013mol) and intermediate (III-a) (0.013mol) was stirred at 150 ℃ for 1 hour. The mixture was poured into 10% K₂CO₃By using CH in combination with the aqueous solution of₂Cl₂MeOH (95/5) extraction. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was crystallized from diisopropyl ether. The precipitate was filtered and dried. Yield: 2.3g (45%). The mother liquor layer was chromatographed over silica gel column (eluent: CH)₂Cl₂/CH₃OH-NH₄OH 98.5/1.5; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.90g (17%). The total yield of intermediate (IV-a) was: 3.2g (62%).

Retention time of intermediate (IV-a) on Hypersil BDS (10 cm. times.4 mm. times.3 μm) (0 min with 0.5% NH)₄Ac/CH₃CN 90/10 elution, 0/100 elution at 15 min): 10.31 minutes.

Wherein W₂Intermediates of formula (IV) representing iodine, which are represented by formula (IV-b), can be prepared in an analogous manner

Retention time of intermediate (IV-b) on Hypersil BDS (10 cm. times.4 mm. times.3 μm) (0 min with 0.5% NH)₄Ac/CH₃CN 90/10 elution, 0/100 elution at 15 min): 10.54 minutes.

Example A5

a) Preparation of intermediates of formula (VI) (E)

In 10ml of dry acetonitrile, 2.00g (10.0mol) of 4-bromo-2, 6-dimethylaniline and 1.07g (1.5eq) of propylene were dissolvedAmide, 224mg (0.1eq) Pd (OAc)₂609mg (0.2eq) of tris (2-methylphenyl) phosphine and 1.52g N, N-diethylethylamine. With N₂The mixture was purged for 20 minutes and stirred at 70 ℃ overnight. The mixture was diluted with 150ml dichloromethane and saturated NaHCO₃The solution was washed and dried (saturated NaCl, Na)₂SO₄) And filtered. The solvent was evaporated and the residue was stirred in diisopropyl ether and then filtered. Yield: 1.51g (79.5%) of intermediate (VI) (E)

b) Preparation of intermediates of formula (II) (E)

Adding POCl₃(3ml) cooled to 0 ℃ and 500mg (2.63mmol) of intermediate (VI) (E) added. After 30 minutes, the cooling bath was removed and the mixture was stirred at 20 ℃ overnight. The mixture was added dropwise to 150ml of diisopropyl ether with vigorous stirring. The precipitate was filtered and washed with diisopropyl ether. The residue was added to 100ml ethyl acetate/100 ml saturated NaHCO₃The solution was stirred. The ethyl acetate layer was separated and dried (saturated NaCl, Na)₂SO₄) And filtered. The solvent was evaporated. Yield: 380mg (84%) of intermediate (II) (E).

c) Preparation of intermediates of formula (VII) (E)

In N₂Next, 0.8g (4.33 mmol; 1 equivalent) of intermediate (VI) (E), 1g (4.33 mmol; 1 equivalent) of intermediate (III-a) and 16ml of 2-propanol were added to a 100ml flask. To this mixture was added 0.72ml of 6N HCl in 2-propanol. The mixture was stirred at reflux for 72 hours and then cooled to afford intermediate (VII) (E) HCl.

Intermediate (VII) (E) HCl can be converted to the free base form according to methods known in the art (see also example B1). The intermediate of formula (VII) (E) may be converted to compound X following the procedure described above in example A5 b.

Example A6

Preparation of intermediates of formula (VII) (E)

2.53ml of acetonitrile, 0.056g (0.253mmol) of Pd (OAc)₂And 0.154g (0.506mmol) of tris (2-methylphenyl) phosphine were placed in a 100ml flask, and the mixture was stirred for 10 minutes. To the mixture were added 1g (2.53mmol) of intermediate (IV-a), 0.51ml (3.8mmol) of N, N-diethylethylamine and 0.36g (5.06mmol) of acrylamide. The mixture was heated to reflux (80 ℃) for 5 days to give 28% of intermediate (VII) (E).

Retention time of intermediate (VII) (E) on Hypersil BDS (10 cm. times.4 mm. times.3 μm) (0 min with 0.5% NH)₄Ac/CH₃CN 90/10 elution, 0/100 elution at 15 min): 6.59 minutes.

The intermediate of formula (VII) (E) may be converted to compound X following the procedure described above in example A5 b.

B. Preparation of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E) (Compound X) (melting point 245 ℃)

Example B1

a) A mixture of 93.9g (0.45mol) of the hydrochloride of intermediate (II) (prepared according to example A2) and 109g (0.4725mol) of intermediate (III-a) is prepared under nitrogen in 1.8 l of acetonitrile. The mixture was stirred and refluxed for 69 hours, then allowed to standIt was cooled to 55 ℃. The mixture was filtered and the residue was washed with 200ml acetonitrile and then dried under reduced pressure at 50 ℃ overnight. 144.6g (0.3666mol) of the resulting solid are placed in 1 l of K₂CO₃10% aqueous solution. The mixture was stirred at room temperature and then filtered. The residue was washed with water 2 times and then dried at 50 ℃ under reduced pressure. The residue was taken up in 6.55 l of isopropanol and the mixture was refluxed, then stirred overnight and filtered at room temperature. The residue was dried under reduced pressure at 50 ℃. Yield: 113.2g (68.6%) 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] ethyl ester]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E) (compound X).

b) A mixture of 93.9g (0.45mol) of the hydrochloride of intermediate (II) (prepared according to example side A2) and 103.8g (0.45mol) of intermediate (III-a) was prepared in 0.9 l of acetonitrile under nitrogen. The mixture was stirred and refluxed for 24 hours, then allowed to cool to 50 ℃. Adding K at 40-50 deg.C for 15-20 min₂CO₃(124.4g, 0.9mol) in H₂A solution in O (0.45 l) was then stirred at 50 ℃ for 1 hour. The precipitate was separated, washed 2 times with 0.045 l of acetonitrile and then dried at 50 ℃ under reduced pressure. 73.3g of the resulting solid was mixed with 400ml of EtOH and refluxed for 2 hours, then cooled to room temperature. The precipitate was filtered off and the residue was washed with 50ml of etoh. The resulting residue was dried under reduced pressure at 50 ℃ overnight. Yield: 65.7g (89.6%) 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] ethyl ester]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E) (compound X).

Example B2

Intermediate (IV-a) (0.00021mol) obtained according to example A4, acrylonitrile (CH)₂＝CH-CN)(0.00213mol)、Pd(OAc)₂(0.000043mol), N-diethylethylamine (0.000043mol) and tris (2-methylphenyl) phosphine (0.00021mol) in CH₃The mixture in CN (7ml) was stirred in a sealed vessel at 150 ℃ overnight. Addition of H₂And O. Subjecting the mixture to CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.15g) was subjected to silica gel column chromatography (eluent: CH)₂Cl₂Ethyl acetate 80/20; 15-40 mum) purifying. Fraction 1 was collected and the solvent was evaporated to yield 0.045g of 4- [ [4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl group]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E/Z ═ 80/20). The solid was crystallized from diethyl ether. Yield: 0.035g 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl)]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E) (compound X) (55%).

Example B3

4.41g (10mmol) of intermediate (IV-b) and 15ml of N, N-dimethylacetamide were placed in a 100ml flask under nitrogen. To the mixture was added 0.98g sodium acetate (12mmol), 107mg (0.1mmol Pd) 10% Pd/C (wet) and 1ml (15 mmol) acrylonitrile. The mixture was stirred at 140 ℃ and the progress of the reaction was followed by liquid chromatography. The reaction yielded 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E/Z ═ 80/20) which can be treated as described in example B2 to yield 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E).

Claims

1. A process for the preparation of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile of formula (I), an N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine, or a stereochemically isomeric form thereof,

Wherein W₁Represents a leaving group selected from halogen, triflate, tosylate and methylsulfonyl,

then optionally, if desired, converting the free base into an acid addition salt by treatment with an acid or, conversely, converting the acid addition salt into the free base by treatment with a base; and then optionally, if desired, preparing a stereochemically isomeric form, an N-oxide form or a quaternary ammonium thereof.

2. The process of claim 1, wherein the solvent is acetonitrile.

3. The process of claim 1, wherein the solvent is 1-methyl-2-pyrrolidone.

4. A process according to any one of claims 1 to 3, wherein the 4- [ [4- [ [4- (2-cyanovinyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile of formula (I), an N-oxide thereof, a pharmaceutically acceptable acid addition salt thereof, a quaternary amine or a stereochemically isomeric form thereof is 4- [ [4- [ [4- (2-cyanovinyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E).

5. The method of any one of claims 1-3, wherein W₁Is a halogen.

6. The method of claim 5, whichMiddle W₁Is ammonia.

7. A process according to any one of claims 1 to 3, wherein the 4- [ [4- [ [4- (2-cyanovinyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile of formula (I), the N-oxide, the pharmaceutically acceptable acid addition salt, the quaternary amine or the stereochemically isomeric form thereof is 4- [ [4- [ [4- (2-cyanovinyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E) or a pharmaceutically acceptable acid addition salt thereof, and wherein

Reacting a compound of formula (II)

With compounds of the formula (III)

The stereochemically isomeric form (E) is then prepared and the free base is then optionally converted, if necessary, to an acid addition salt by treatment with an acid.

8. A process according to any one of claims 1 to 3, wherein the 4- [ [4- [ [4- (2-cyanovinyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile of formula (I), an N-oxide thereof, a pharmaceutically acceptable acid addition salt thereof, a quaternary amine or a stereochemically isomeric form thereof is 4- [ [4- [ [4- (2-cyanovinyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E) or a pharmaceutically acceptable acid addition salt thereof, and wherein

Suitable acid addition salts of the compounds of formula (II)

With compounds of the formula (III)

The stereochemically isomeric form (E) is then prepared and the acid addition salt is then optionally converted to the free base by treatment with a base, if necessary.