RU2329260C1 - Method of obtaining 2-anilinopyrimidines or their salts (options) - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention pertains to a new method of obtaining derivatives of N-phenyl-2-pyrimidineamine (2-anilinopyrimidine) with general formula (I), which have a wide spectrum of biological effects and can be used mainly, for treating various types of tumours, leucaemia, cerebral ischemia, vascular stenosis and other diseases. In general formula (I)

, R₁ represents a pyridyl or its oxide bonded to a carbon atom, which can be substituted with a low alkyl or alkoxy, each of R₂ and R₃ independently represents hydrogen, branched of unbranched low alkyl, phenyl, unsubstituted of substituted with a haloid, R₄ represents hydrogen, unbranched or branched low alkyl, R₅ represents hydrogen, low alkyl, possibly substituted with halogen atoms. Other representations of radical are given in the formula of invention. The method involves the following stages: A) reaction of urea, mainly in a basic medium with N,N-dialkyamino-1-(3-pyridyl)-2-propene-1-ono with general formula II:

with obtaining of the corresponding dihydropyrimidinone with general formula (III)

B) oxidation of compound (III) by proton oxidation, with obtaining of the corresponding hydroxypyrimidine with formula IV

, C) activation of the hydroxy group in the obtained compound IV , for example, treatment using sulphohalide R'SC₂Hal or anhydride R'(SO₂)₂O, with obtaining of a compound with general formula V

, where R' represents aryl of low alkyl, D) reaction of the obtained compound V with the corresponding aromatic amino compound with formula VI

, with obtaining of compound with formula (I) and subsequent possible conversion of the obtained compounds to other compounds with general formula (I).

EFFECT: method allows for excluding use of toxic compounds and simplifies the process.

13 cl, 13 ex

Description

The invention relates to a new method for producing 2-anilinopyrimidines of the general formula (I)

where R ₁ means pyridyl bonded by a carbon atom or its oxide, which may be substituted by lower alkyl or alkoxy, each of R ₂ and R ₃ independently means hydrogen, branched or unbranched lower alkyl, phenyl, unsubstituted or substituted by halogen, R ₄ is hydrogen, unbranched or branched lower alkyl, R ₅ is hydrogen, lower alkyl, possibly substituted by halogen atoms, R ₆ and R ₈ is hydrogen, lower alkoxy, branched or unbranched lower alkyl, R ₇ is lower alkyl, lower alkoxy, halogen lower alkyl, lower alkoxy halide, nit o, carboxy, amino or a radical of formula II -N (R ₉₎ -C (= O) -R _10, -C (= O) -NR ₉ R _10, -CH ₂ -NR ₉ R _10, -OCH ₂ - NR ₉ R ₁₀ -, NR ₉ SO ₂ -R ₁₀ , where R _{9 is} hydrogen or R ₉ and R ₁₀ together with the nitrogen atom form a piperidino group, a piperazino group having a substituent on the second nitrogen atom selected from lower alkyl or lower acyl, or R ₁₀ is carbon-bonded pyridyl, thienyl, cyclohexyl, naphthyl or phenyl, optionally substituted with halogen, cyano, lower alkoxy, lower alkyl, carboxy or 4-methylpiperazinylmethyl, R is hydrogen, lower alkyl,

or their pharmaceutically acceptable salt or their isomers.

Part of the compounds of this group, the method of their preparation and use are known both in the technical and in the patent literature (see, for example, Zoltan Szakacs, Szabocs Beni et al. J. Med. Chem. 2005, 48, p. 249-255, RF patents 2125992, 2208012, RF applications 2003103848, 2005129100, US patents 6096753, 4438117, US 2003/0069425, US 2004/0102453, US 2006/0223818, WO 2002/022597, WO 2004/029038, WO 2005/095379, WO 2005/0108358, WO 2005/095379, WO 2006/069525, WO 2006/117185, WO 2006/223817, WO 2006/071130, CA 2443092, DE 1271116, PL 370264).

Derivatives of anilinopyrimidines have a wide range of biological effects, but are mainly substances with antitumor activity. Some of them are known agents, for example, imatinib, which can be used to treat leukemia, cerebral ischemia, vascular stenosis, etc.

To obtain derivatives of anilinopyrimidines in previously known methods, mainly reactions of pyrimidine-substituted compounds with derivatives of aniline or the conversion of anilinopyrimidines to other derivatives are used (for example, see WO 2004/029038, WO 2006/071130, US 20060149061, RF application 2005129100). Methods are also known which include the preparation of a starting pyrimidine derivative comprising the formation of a pyrimidine ring (see, for example, US 2004/0102453, US 2003/0069425, RF 2125992). In addition, it is known to obtain various crystalline forms of pyrimidoaniline derivatives and salts.

The most complete method for the synthesis of derivatives of 2-anilinopyrimidines of the formula I

or their pyridyl oxides, is the method described in the patent of the Russian Federation No. 2125992.

According to the specified method, N, N-dialkylamino-1- (3-pyridyl) -2-propen-1-one of the formula III

enter into interaction with the corresponding nitrophenylguanidine obtained from cyanamide and the corresponding derivative of nitroaniline, followed by reduction of the nitro group in the presence of palladium.

The resulting derivative of anilinopyrimidine of formula I, where R ₁ = pyridyl, if necessary, is oxidized with perchlorobenzoic acid to obtain compound I, where R ₁ = N-oxidopyridyl, to obtain compound I, where R ₇ is the residue of formula N (R ₉ ) —C (= O) —R ₁₀ , anilino-pyrimidine of the formula V, where R ₁₆ = an amino group, is reacted with a compound of the formula VI HO — C (= O) —R ₁₀ .

Considered a known method also provides for the preparation of N, N-dialkylamino-1- (3-pyridyl) -2-propen-1-one (III) by the interaction of methyl ketone VII of the formula R ₁ -CO-CH ₂ -R ₂ and dimethyl acetal N, N- dimethylformamide or acetamide dimethyl acetal, or N, N-dialkylamino-1- (3-pyridyl) -2-propen-1-one (III) can be obtained by converting compound VII with an ester of the formula R ₃ -C (= O) OCH ₂ CH ₃ and reaction of the obtained product with the corresponding amine.

The described known method has a number of disadvantages that complicate its use in industrial production. First of all, its implementation requires the use of toxic substances, for example cyanamide, volatile solvents (for example, diethyl ether, acetone, hexane), the presence of palladium to restore the nitro group to the amino group, and the use of aggressive liquids.

Difficulties in technological design lead to insufficiently high yield of products both at intermediate stages and to the overall yield of the target product. In addition, the quality of the products obtained, including the target product, is also not high enough, as evidenced by the spread in the melting temperature of 4-5 degrees.

The objective of the invention is to develop a new and improved method for producing anilinopyrimidines, devoid of these disadvantages. The method according to the invention eliminates toxic substances and allows to obtain derivatives of anilinopyrimidines with a good yield and the required quality.

The method for producing compounds of general formula I according to the invention comprises the following steps:

A) the interaction of urea in a basic medium, for example in an alkaline metal alcohol solution, with N, N-dialkylamino-1- (3-pyridyl) -2-propen-1-one of the formula II

wherein R ₁ is pyridyl bonded with a carbon atom which may be substituted with lower alkyl or alkoxy, each of R ₂ and R ₃ independently is hydrogen, branched or unbranched lower alkyl, phenyl unsubstituted or substituted with halogen, to give the corresponding dihydropyrimidinone of general formula (III )

where R ₁ -R ₃ have the above meanings,

B) oxidizing compound (III) with a proton oxidizing agent to give the corresponding hydroxypyrimidine of formula IV

where R ₁ -R ₃ have the above meanings,

C) activation of the hydroxy group in the obtained compound IV, for example, by treating with a sulfohalide R′SO ₂ Hal or anhydride R ′ (SO ₂ ) ₂ O to obtain a compound of formula V

where R ′ means aryl or lower alkyl,

D) the interaction of the obtained compound V with the corresponding aromatic amino compound of the formula VI

wherein R ₄ -R ₈ have the meanings indicated for formula I above,

and, if necessary, functional groups that are not involved in the reaction are protected, with the removal of the protective groups, if any, and the preparation of anilinopyrimidine of the formula (I).

Compounds where R is hydrogen can be alkylated, for example, with dimethyl sulfate.

The resulting compounds can be isolated in free form or in the form of salts, including pharmaceutically acceptable salts.

If necessary, in the resulting compound, you can turn one group into another.

The obtained compound (I), where R ₁ is pyridyl, can be treated with an oxidizing agent, for example, perchlorobenzoic acid, to obtain a compound in which R ₁ is N-oxidopyridyl.

The compound of formula (I), where R ₇ is a halogen-lower alkyl, a halogen-lower alkoxy, carboxy group, when reacted with an amine HNR ₉ R ₁₀ can be converted to the corresponding aminoalkyl, aminoalkoxy or amide compound.

Or, free amino groups can be acylated or sulfonylated.

The compound of formula (I), where R ₇ is phenyl substituted with an amino group, can be acylated, for example, with an acid of the formula HOC (= O) -R ₁₀ or an activated derivative thereof, where R ₁₀ has the above meanings.

Imatinib can be prepared according to the invention: 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl] benzamide or its salt selected from mesylate, hydrochloride, dihydrochloride, tosylate or besylate, etc.

New compounds corresponding to the general formulas may also be prepared.

where the values of the radicals R means hydrogen, lower alkyl, R ₁ , R ₂ are indicated above, L means N (R ₉ ) -C (= O) -, -C (= O) -NR ₉ -, -CH ₂ -NR ₉ -, -OCH ₂ -NR ₉ -, -NR ₉ SO ₂ -.

Also provided according to the invention are new starting compounds of formula V.

The salts obtained according to the invention are known acid addition salts such as mono-, di- or trihydrochlorides, mesylates, tosylates, besylates, maleates, fumarates, succinates, pamoates, formates, malonates, salts with benzoic acid, 1.5 - dinaphthalindisulfonates, salicylates, lactates, mandelates, ascorbates, vanillates, sulfates, picrates and other salts.

Salts may also be formed with alkali or alkaline earth metals. Salts can also be used to purify the resulting compounds.

Stage A) is carried out in the presence of a proton compound and a metal salt, possibly in the presence of a solvent. An organic or inorganic acid, such as acetic, hydrochloric, sulfuric, nitric, or phosphoric acid, can be used as a proton compound. As the metal salt, copper (II) chloride and iron (II) chloride can be used. The proton compound can be used in an amount of from 0.01-1 mol per ketone taken, a metal salt from 0.001 to 0.1 mol per initial ketone.

Step A) can be carried out in the absence or presence of a solvent, for example a lower alcohol such as methanol, ethanol, isobutyl alcohol, isopropyl alcohol, acetonitrile, dichloroethane, ethers such as tetrahydrofuran.

Inorganic acids such as sulfuric, nitric or phosphoric can be used as the protic acid in step B). Oxidation can be carried out both in a solvent and without it.

The amount of acid used may be from 1 to 5 moles per 1 mol of the dihydropyrimidinone compound of the formula III.

As a solvent, carboxylic acids, such as acetic, propionic, butyric, can be used individually or in combination in an amount of from 0.1 to 5 ml per 1 g of dihydropyrimidinone compound depending on the homogeneity and dispersion of the reaction mass. The oxidation can be carried out in an inert gas atmosphere, possibly in the presence of a reaction initiator, such as sodium nitrite, at a temperature of from 0 to 50 ° C. It is possible to carry out the process at room temperature.

Stage B) is preferably carried out in the presence of a base, for example an alkali metal carbonate, bicarbonate, sodium or potassium tert-butoxide or methoxide, or a tertiary amine such as triethylamine or pyridine, possibly in an inert gas medium at a temperature of from 0 to 50 ° C, preferably at room.

As the hydroxy group activating agent in step B), an alkanesulfonyl halide such as methanesulfonyl chloride, methanesulfonyl fluoride, trifluoromethanesulfonyl fluoride, or chloride, propanesulfonyl chloride, benzenesulfonyl chloride, and naphthalenesulfonyl chloride, p-dr.

As sulfonic anhydrides, methanesulfonic, benzenesulfonic, p-toluenesulfonic, trifluoromethanesulfonic anhydrides can be used. These agents can be used in an amount of from 1 to 8 moles per 1 mol of hydroxypyrimidine compounds.

The reaction can be carried out in the presence or absence of solvents such as water, acetone, tetrahydrofuran, ethyl or butyl acetate, in an amount depending on the homogeneity and dispersion of the reaction medium.

It is possible to activate the hydroxy group of the pyrimidine compound by replacing the hydroxy group with a halogen using, for example, phosphorus oxychloride.

The reaction in step D) can be carried out in a solvent medium, optionally in the presence of bases, such as those described above, at a temperature of from 15 to 150 ° C. It is also possible to carry out this stage in a two-phase system in the presence of an interphase catalyst in an amount of from 0.01 to 0.05 moles per 1 mol of a 2-substituted pyrimidine compound. Quaternary ammonium compounds such as tetraethylammonium bromide or chloride, benzyltriethylammonium chloride, dodecyl trimethylammonium chloride or hexadecyl trimethylammonium chloride can be used as a phase transfer catalyst.

Below are examples that confirm, but not limit the present invention. The structure and quality of the resulting products are confirmed by chromatography, IR and NMR spectroscopy.

Example 1

A. Preparation of 4- (3-pyridinyl) -3,4-2 (1H) -dihydropyrimidin-2-one

350 ml of ethanol are placed in a three-necked 2-liter flask equipped with a stirrer, thermometer and reflux condenser, 1.0 mol of 3-dimethylamino (3-pyridyl) -2-propen-1-one, 1.3 mol of urea, 0, 01 mol of copper chloride and sulfuric acid, heated under reflux for one hour at a temperature of 65-68 ° C, cooled to room temperature. The pH of the solution was adjusted to 5. The precipitate formed was filtered on a Buchner funnel. The resulting wet solid was dissolved in methanol-dichloroethane, the solution was added to a silica gel column, and the product was eluted with chloroform: methanol: water 65: 25: 4. The eluate is evaporated on a rotary evaporator to obtain the title compound, a yield of about 68% based on the initial urea.

B. Preparation of 6- (3-pyridinyl) -2-dihydropyrimidinone.

In a three-necked 2-liter flask equipped with a stirrer, a condenser and a calcium chloride tube, 500 ml of absolute ethanol are placed, 23 g (1.0 mol) of granular metal sodium are added, and at the end of the reaction, 60.0 g ( 1 mol) of urea, stirred for 10 minutes, 150 g (1.0 mol) of 3-dimethylamino (3-pyridyl) -2-propen-1-one were added, heated under reflux overnight, cooled to room temperature. Glacial acetic acid is added to the resulting clear solution to pH 5. The precipitate formed is filtered off on a Buchner funnel. The resulting wet solid was dissolved in methanol-dichloroethane, the solution was added to a silica gel column, and the product was eluted with chloroform: methanol: water 65: 25: 4. The eluate is evaporated on a rotary evaporator to obtain the title compound, a yield of about 68% based on urea.

Example 2. Obtaining 4- (3-pyridinyl) -2-hydroxypyrimidine.

In a three-necked glass flask with a capacity of 100 ml, equipped with a stirrer and a thermometer, 22 ml (0.03 mol) of nitric acid (60-61%, specific gravity 1.38) are placed. 5.1 g (0.03 mol) of 4- (3-pyridinyl) -3,4-2 (1H) -dihydropyrimidin-2-one is slowly added to nitric acid at room temperature, the mixture is stirred at room temperature for 30 minutes . After completion of the reaction, the reaction mixture was neutralized by placing it in 280 ml of a saturated aqueous solution of sodium bicarbonate. The product is extracted with ethyl acetate. The organic liquid was separated, concentrated under reduced pressure, and the residue was crystallized from toluene. Get the target product with a yield of about 92% in terms of the original 4- (3-pyridinyl) -3,4-2 (1H) -dihydropyrimidin-2-one. 4- (6-Methoxypyridin-3-yl) -3,4-2 (1H) -dihydropyrimidin-2-one is similarly obtained.

Example 3. Obtaining 2-chloro-4- (3-pyridinyl) pyrimidine.

10 g (0.343 mol) of 4- (3-pyridinyl) -2-hydroxypyrimidine and 34 ml (0.37 mol) of phosphorus oxychloride are placed in a 250 ml three-necked glass flask equipped with a stirrer, thermometer and reflux condenser. The mixture is heated to 100-106 ° C for one and a half hours under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into a mixture of water and ice. The resulting aqueous mixture was neutralized with saturated aqueous sodium bicarbonate. The product is extracted with ethyl acetate. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried ethyl acetate layer was filtered off and concentrated under reduced pressure to give 2% chloro-4- (3-pyridinyl) pyrimidine as a yellow foam in 90% yield.

Can similarly be obtained

2-chloro-5-methyl-4- (3-pyridinyl) pyrimidine,

2-chloro-4- (4-methoxy-3-pyridinyl) pyrimidine,

2-chloro-6- (4-fluorophenyl) -4- (3-pyridinyl) pyrimidine.

Example 4. Obtaining 4- (3-pyridinyl) -2- (napa-toluenesulfonyloxy) pyrimidine.

3.4 g (0.02 mol) of 4- (3-pyridyl-2-hydroxypyrimidine, 2.9 g (0.026 mol) of triethylamine and 40 ml of acetonitrile are placed in a 250 ml glass three-necked flask equipped with a stirrer, thermometer and reflux condenser. The process is carried out under nitrogen. The mixture is cooled to 0-5 ° C and slowly, dropwise, with stirring, add 40 g (0.022 mol) of napa-toluenesulfonyl chloride, the reaction is carried out at 20-25 ° C, without stopping stirring, for one After completion of the reaction, 25 ml of water was added to the mixture and the product was extracted with toluene, the organic layer was separated, and the aqueous m solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried mixture is filtered, concentrated under reduced pressure. The residue is crystallized from ethanol. 6- (3-Pyridinyl) -2- (napa-toluenesulfonyloxy) -pyrimidine is obtained in the form of a colorless product with a yield of 88 % based on 4- (3-pyridyl) -2-hydroxypyrimidine.

Example 5. Obtaining 4- (6-methoxypyridin-3-yl) -2-methanesulfonyloxypyrimidine.

5.6 g (0.03 mol) 6- (6-methoxypyridin-3-yl) -2-hydroxypyrimidine, 3.0 g (0.03 mol) are placed in a 250 ml glass flask equipped with a stirrer, thermometer and reflux condenser. ) triethylamine and 50 ml of toluene. The mixture in the flask is cooled to 0-5 ° C in an ice bath. 5.4 g (0.03 mol) of methanesulfonic anhydride are slowly added to the cooled mixture, and the resulting mixture is continued to stir for 3 hours at the same temperature. After completion of the reaction, 90 ml of water are added to the reaction mixture. The liquid organic part is separated from the aqueous reaction mixture, which is then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-2QO; eluent: hexane / ethyl acetate (8: 2 volume ratio)).

4- (6-methoxypyridin-3-yl) -2-methanesulfonyloxypyrimidine is obtained in 78% yield (based on 4- (6-methoxypyridin-3-yl) -2-hydroxypyrimidine).

In similar conditions receive

5-methyl-4- (3-pyridinyl) -2-methanesulfonyloxypyrimidine,

4- (6-methoxy-3-pyridinyl) -2-methanesulfonyloxypyrimidine,

6- (4-fluorophenyl) -4- (6-methoxypyridin-3-yl) -2-methanesulfonyloxypyrimidine.

Example 6. Preparation of 4- (N-oxide-3-pyridinyl) -5-methyl-2- (napa-toluenesulfonyloxy) pyrimidine.

0.068 moles of 4- (3-pyridinyl) -5-methyl-2- (napa-toluenesulfonyloxy) pyrimidine are suspended in 5 ml of methylene chloride and mixed with 0.071 moles of 3-chloroperbenzoic acid. The mixture was kept under stirring at room temperature for 3 hours. After filtration and thin-layer chromatography (methylene chloride: methanol: 25% aqueous ammonia solution = 90: 10: 1) of the residue, 4- (N-oxide-3-pyridinyl) -5-methyl-2- (napa-toluenesulfonyloxy) pyrimidine is obtained with a yield of about 90%.

Example 7. Obtaining 4- (6-methoxypyridin-3-yl) -2- (3-aminophenyl) pyrimidinamine.

In a 50 ml glass flask equipped with a stirrer, thermometer and dropping funnel, (0,0163 mol) of 6- (4-methoxypyridin-3-yl) -2-methanesulfonyloxypyrimidine is placed. To the flask slowly add (0.0652 mol) m-phenylenediamine in an aqueous solution of sodium bicarbonate. While cooling, the resulting mixture was stirred for one hour at the same temperature. The product, 6- (6-methoxypyridin-3-yl) -2- (3-aminophenyl) pyrimidinamine, was isolated. The yield was 77% (counting on the starting 6- (6-methoxypyridin-3-yl) -2-methanesulfonyloxypyrimidine).

Similarly, choosing the appropriate starting reagents, protective groups, solvents and ratios, get

4- (3-pyridinyl) -2- (5-amino-2-methylphenyl) pyrimidinamine,

4- (4-methoxypyridin-3-yl) -2- (5-carboxyphenyl) pyrimidinamine,

4- (3-pyridinyl) -2- (5-carboxyphenyl) pyrimidinamine,

4- (3-pyridinyl) -2- (5-carboxy-4-methylphenyl) pyrimidinamine,

4- (3-pyridinyl) -2- (5-amino-2-methylphenyl) pyrimidinamine,

4- (3-pyridinyl) -2- (5-amino-2-isopropylphenyl) pyrimidinamine,

4- (6-methoxypyridin-3-yl) -2- (5-amino-2-isopropylphenyl) pyrimidinamine.

Example 8. Obtaining 4- (4-methoxypyridin-3-yl) -2- (4-fluoromethylphenylsulfonylaminophenyl) pyrimidinamine.

0.019 moles of 4- (4-methoxypyridin-3-yl) -2- (3-aminophenyl) pyrimidinamine is dissolved in 2.5 ml of pyridine and 0.023 mmol of 4-fluoromethylphenylsulfonyl fluoride is added. The mixture is stirred for one day at ambient temperature. Add 5 ml of water, cool to -5 ° C and filter. After washing with water and drying, the desired product is obtained, which is subjected to silica gel chromatography with a mixture of chloroform-methanol in a volume ratio of 9: 1, which gives one spot.

Similarly, using appropriate reagents and conditions, receive

4- (pyridin-3-yl) -2- (4-fluoromethylphenylsulfonylaminophenyl) pyrimidinamine,

4- (pyridin-3-yl) -2- (4-chloromethylphenylcarbonylaminophenyl) pyrimidinamine,

2- (3-chloromethylphenylcarbonylaminophenyl) pyrimidinamine.

Example 9. Obtaining 6- (4-fluorophenyl) -4- (6-isopropylpyridin-3-yl) -2-trifluoromethanesulfonyloxypyrimidine.

0.03 mmol of 6- (4-fluorophenyl) -2-hydroxy-4- (6-isopropylpyridin-3-yl) pyrimidine, 0.03 mol of triethylamine and placed in a 300 ml glass flask equipped with a stirrer, thermometer and reflux condenser 150 ml of toluene. The mixture in the flask is cooled to 0 ° C in an ice bath. 0.03 mmol of trifluoromethanesulfonic anhydride is slowly added to the cooled mixture and the resulting mixture is reacted for 3 hours at the same temperature. After completion of the reaction, 90 ml of water are added to the reaction mixture, stirred and the organic liquid portion is separated. The latter is dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-2QO; eluent: hexane / ethyl acetate (8: 2 volume ratio)). 6- (4-fluorophenyl) -4- (6-isopropylpyridin-3-yl) -2-trifluoromethanesulfonyloxypyrimidine is obtained. The yield was 74% (in terms of the starting 6- (4-fluorophenyl) -2-hydroxy-4- (6-isopropylpyridin-3-yl) pyrimidine).

Example 10. Obtaining 6- (4-fluorophenyl) -2-hydroxy-4- (6-isopropylpyridin-3-yl) -pyrimidine.

In a 50 ml glass flask equipped with a stirrer and a thermometer, 0.01 mol of 6- (4-fluorophenyl) -4- (6-isopropylpyridin-3-yl) -3,4-2 (1H) -dihydropyrimidinone obtained as such in the same manner as in example 1, and 5 ml of acetic acid. To this mixture, 0.05 mol of nitric acid was slowly added (60-61%, specific weight 1.38). 0.01 mol of sodium nitrite is then added to this mixture and the reaction is carried out for one hour at room temperature. After completion of the reaction, the reaction mixture was neutralized by pouring it into 50 ml of a saturated aqueous solution of sodium bicarbonate. The reaction mixture was then extracted with ethyl acetate. The organic liquid was separated and concentrated under reduced pressure. The residue is crystallized from toluene. The crystalline product was collected on a filter and washed with toluene to give 6- (4-fluorophenyl) -2-hydroxy-4- (6-isopropylpyridin-3-yl) pyrimidine as a crystalline product. The yield was 90% (based on the amount of 6- (4-fluorophenyl) -4- (6-isopropylpyridin-3-yl) -3,4-2 (1H) -dihydropyrimidinone).

Example 11. Benzamidophenyl-4- (4-methoxypyridin-3-yl) pyrimidin-2-ylamine.

0.05 mol of 4- (4-methoxypyridin-3-yl) -2- (3-aminophenyl) pyrimidinamine is reacted in an aqueous medium with 0.06 mol of benzoic acid chloride using dicyclohexylcarbodiimide as a condensing agent. Chromatographically pure benzamidophenyl 4- (4-methoxypyridin-3-yl) pyrimidin-2-ylamine is obtained in 69% yield.

Example 12 Preparation of 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) phenyl] benzamide

    To 0.025 mol of 4- (3-pyridinyl) -2- (5-amino-2-methylphenyl) pyrimidinamine obtained under the conditions of Example 7, add 0.03 mol of 4- (4-methylpiperazinomethyl) benzoyl chloride in a solution of pyridine in a stream of argon at temperature of 45 ° C for 5 hours. The solvent is distilled off, 250 ml of water are added to the residue and basified to pH 10. The product is extracted with dichloromethane (2 × 200 ml). The extract was dried over sodium sulfate, filtered off, the solvent was distilled off. 50 ml of ethyl acetate was added to the residue and filtered, the residue was washed with ethyl acetate. Dried and get the target product with a yield of 65%. Mp 212-213 ° C.

Example 13 Preparation of 4 - [(piperidin-1-ylmethyl) -N- [4-methyl-3 - [(4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide.

To 0.1 mol of (4-chloromethyl) -N- [4-methyl-3 - [(4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide in a dichloromethane solution, 0.12 mol 4 is added with stirring -methylpiperidine. The process is carried out at room temperature, continuously stirring, in the presence of triethylamine. At the end of the reaction, the mixture is washed with water, the organic layer is separated, dried over sodium sulfate and evaporated on a rotary evaporator under reduced pressure. An almost pure product is obtained (according to IR and NMR spectroscopy.) The yield of the target product is 67%.

Claims (13)

1. The method of obtaining derivatives of N-phenyl-2-pyrimidinamine of the general formula (I)

where R ₁ means pyridyl bonded by a carbon atom or its oxide, which may be substituted by lower alkyl or alkoxy, each of R ₂ and R ₃ independently mean hydrogen, branched or unbranched lower alkyl, phenyl, unsubstituted or substituted by halogen, R ₄ is hydrogen, unbranched or branched lower alkyl, R ₅ is hydrogen, lower alkyl, possibly substituted by halogen atoms, R ₆ and R ₈ is hydrogen, lower alkoxy, branched or unbranched lower alkyl, R ₇ is lower alkyl, lower alkoxy, halogen lower alkyl, lower alkoxy halide, nit o, carboxy, amino, or the radical of formula II -N (R ₉₎ -C (= O) -R _10, -C (= O) -NR ₉ R _10, -CH ₂ -NR ₉ R _10, -OCH ₂ -NR ₉ R ₁₀ -, NR ₉ SO ₂ -R ₁₀ , where R ₉ hydrogen or R ₉ and R ₁₀ together with the nitrogen atom form a piperidino group, a piperazino group having a substituent on the second nitrogen atom selected from lower alkyl or lower acyl, or R ₁₀ is carbon attached pyridyl, thienyl, cyclohexyl, naphthyl or phenyl, optionally substituted with halogen, cyano, lower alkoxy, lower alkyl, carboxy or 4-methylpiperazinylmethyl, R is hydrogen or lower alkyl, or their pharmaceutically acceptable salt or their isomers, comprising the following stages: A) the interaction of urea in the main environment with N, N-dialkylamino-1- (3-pyridyl) -2-propen-1-one of the formula II

where R ₁ means pyridyl bonded by a carbon atom, which may be substituted by lower alkyl or alkoxy, each of R ₂ and R ₃ independently means hydrogen, branched or unbranched lower alkyl, phenyl, unsubstituted or substituted by halogen, with the receipt of the corresponding dihydropyrimidinone of General formula (III)

where R ₁ -R ₂ have the above meanings, B) oxidizing compound (III) with a proton oxidizing agent to give the corresponding hydroxypyrimidine of formula IV

where R ₁ -R ₃ have the above meanings, C) activation of the hydroxy group in the obtained compound IV, for example, by treating with a sulfohalide R′SO ₂ Hal or anhydride R ′ (SO ₂ ) ₂ O to obtain a compound of formula V

where R ′ means aryl or lower alkyl, G) the interaction of the obtained compounds V with the corresponding aromatic amino compound of formula VI

wherein R ₄ -R ₈ have the meanings indicated for formula I, in which, if necessary, the functional groups not participating in the reaction are protected, followed by removal of the protective groups, if any, to give anilinopyrimidine of the formula (I), while if necessary, the obtained compound of formula (I), where R _{1 is} pyridyl, can be treated with an oxidizing agent, such as perchlorobenzoic acid, to obtain a compound in which R ₁ is N-oxidopyridyl, or compound I, where R is hydrogen, is subjected to alkylation with obtaining compounds where R - lower alkyl, or a compound of formula (I), wherein R ₇ - halo-lower alkyl, halo-lower alkoxy, carboxy, by reaction with an amine HNR ₉ R ₁₀ can be converted into the corresponding aminoalkyl, aminoalkoxy or amide compound, or a compound of formula ( I), where R ₇ is a primary or secondary amino group, acylate or sulfonylate to give the corresponding amides or sulfamides and isolate the products in free form or in the form of salts, including pharmaceutically active salts. 2. The method according to claim 1, characterized in that the compound of formula (I), where R ₇ is phenyl substituted with an amino group, is treated with an acid of the formula HOC (= O) -R ₁₀ or its activated derivative, where R ₁₀ has the above meanings . 3. The method according to claim 1 or 2, according to which the compound of formula (I), where R ₇ is halogen-lower alkyl, is reacted with a secondary amine HNR ₉ R ₁₀ . 4. The method according to claim 1 or 2, according to which receive a compound in which R ₃ or R ₄ or R ₈ mean isopropyl. 5. The method according to claim 1 or 2, according to which 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3 - [[(4-pyridin-3-yl) pyrimidin-2-yl is obtained ] amino] phenyl] benzamide or a salt thereof. 6. The method according to claim 5, according to which receive a salt selected from mesylate, hydrochloride, dihydrochloride, tosylate or besylate. 7. The method according to claim 1, characterized in that receive the compound of General formula

8. The method according to any one of claims 1 and 7, characterized in that the compound of the general formula

9. The method according to claim 1, characterized in that receive the compound of General formula

10. The method according to claim 1, characterized in that the activation of the hydroxy group in compound IV is carried out by treatment with a sulfon halide R′SO ₂ Hal or anhydride R ′ (SO ₂ ) ₂ O to obtain a compound of formula V

where R ′ means aryl or lower alkyl, followed by the interaction of the obtained compound V with the corresponding aromatic amino compound of the formula VI

wherein R ₄ -R ₈ have the meanings indicated for formula I, in which, if necessary, the functional groups not participating in the reaction are protected, followed by removal of the protective groups, if any, to give anilinopyrimidine of the formula (I), while if necessary, the obtained compound of formula (I), where R ₁ is pyridyl, can be treated with an oxidizing agent, such as perchlorobenzoic acid, to obtain a compound in which R ₁ is N-oxidopyridyl, or a compound of formula (I), where R ₇ is primary or secondary amino group, subject to acy ation or sulfonylation to give the corresponding amides or sulfonamides and product isolation in free form or in salt form, including a pharmaceutically active salts. 11. Method for the preparation of 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3 - [[(4-pyridin-3-yl) pyrimidin-2-yl] amino] phenyl] benzamide or its salts consisting in the fact that the compound of formula V

where R ₁ means 3-pyridyl, each of R ₂ and R ₃ means hydrogen, R ′ means aryl or lower alkyl, react with 2-methyl-1,3-phenylenediamine of formula VI ′

where R ₇ means amino, R ₄ means methyl, R ₅ , R ₆ , R ₈ is hydrogen, R is hydrogen, to obtain the compounds of formula VII

where R ₁ is pyridyl, R ₇ is amino, R ₄ is methyl, R, R ₂ , R ₃ , R ₅ , R ₆ , R ₈ is hydrogen, which is reacted with an acid or its activated derivative of the general formula: XC (= O) -R ₁₀ , where R ₁₀ means phenyl substituted with 4-methylpiperazinylmethyl, X is OH or halogen, and isolation of the desired product in free form or as a pharmaceutically acceptable salt. 12. The method according to claim 10, characterized in that 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3 - [[(4-pyridin-3-yl) pyrimidin-2-yl are obtained ] amino] phenyl] benzamide in the form of a hydrochloride, dihydrochloride, besylate or mesylate. 13. The method according to claim 10, characterized in that as the starting compound use the compound of formula V, obtained according to claim 1.