RU2301801C2 - Method for preparing sulfonulaminopyrimidine compounds (variants), intermediate substances and methods for their preparing - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel methods (variants) for synthesis of 2-(N-methyl-N-methanesulfonylamino)-pyrimidine of the formula (3)

and aminopyrimidine compound of the formula (8)

that can be used in synthesis of the known medicinal preparation - rosuvastatin. In compounds of formulae (3) and (8) R represents lower alkyl; each of R¹ and R² represents independently hydrogen atom, alkyl group, alkylsulfonyl group or arylsulfonyl group. Method for synthesis of compound of the formula (3) involves the following steps: (I) isobutyrylacetate ester of compound of the formula (5):

wherein R represents lower alkyl is subjected for interaction with 4-fluorobenzaldehyde and urea in the presence of proton compound and metal salt; (II) compound synthesized in reaction at step (I) is oxidized; (III) obtained product after oxidation from stage (II) is subjected for interaction with organic sulfonyl halide of the formula (2): R'-SO₂-X wherein R' represents lower alkyl substituted possibly with halogen atoms, phenyl substituted possibly with 1-3 groups chosen from nitro-group, halogen atoms, branched or direct lower alkyl, lower alkoxy-group; X represents halogen atom or organic sulfonic anhydride of the formula (2a): (R'-SO₂)-O wherein R' has a value given above in the presence of a base; (IV) product of reaction at step (III) is subjected for interaction with N-methyl-N-methanesulfonamide in the presence of a base. Method for synthesis of compound of the formula (8) involves a step for interaction of corresponding 2-halide- or 2-substituted sulfonylpyrimidine with corresponding amino-compound. Also, invention relates to novel intermediate compounds and methods for their synthesis. Proposed methods provide avoiding toxic compounds and to obtain compounds of high purity and with the high yield.

EFFECT: improved methods of synthesis.

35 cl, 27 ex

Description

Field of Invention

The present invention relates to the production of aminopyrimidine compounds having the following formula (8):

[in formula (8), R is lower alkyl and each of R ¹ and R ² independently represents a hydrogen atom, an alkyl group, an alkylsulfonyl group or an arylsulfonyl group], more specifically, to obtain 2- (N-methyl-N-methanesulfonylamino ) pyrimidine having the following formula (3):

where R represents lower alkyl.

State of the art

Bioorg. Med. Chem., 5, 437 (1997), discloses that a compound representing 2- (N-methyl-N-methanesulfonylamino) pyrimidine is used as an intermediate to produce a cholesterol lowering agent (hydroxymethylglutaryl CoA reductase inhibitor: S -4522) having the following formula:

which is now commonly known as the calcium salt of rosuvastatin or rosuvastatin calcium.

WO 01/04100 discloses a process for the preparation of a compound comprising 2- (N-methyl-N-methanesulfonylamino) pyrimidine, the process comprising the steps of reacting methyl isobutyryl acetate with 4-fluorobenzonitrile to give methyl 2- [1- amino-1- (4-fluorophenyl) methylene] -4-methyl-3-oxopentanate and 2- [1-amino-1- (4-fluorophenyl) methylene-4-methyl-3-oxopentanate is reacted with N-cyano- N-methylmethanesulfonamide, which is obtained by the reaction between N-methylmethanesulfonamide and cyanochloride, to give 4- (4-fluorophenyl) -6-isoprop l-5-methoxycarbonyl-2- (N-methanesulphonyl-N-methylamino) pyrimidine.

It is disclosed that the total yield (by the amount of methyl isobutyryl acetate) is 45.5%.

The method disclosed in WO 01/04100, is disadvantageous for industrial production due to the low yield and the need to use toxic cyanochloride as one of the starting compounds.

Accordingly, it is an object of the present invention to provide a new process for the preparation of 2- (N-methyl-N-methanesulfonylamino) pyrimidine or an analogous aminopyrimidine compound, more specifically, to provide a new process that allows the preparation of this compound in a more convenient manner and / or without the use of a toxic compound and / or allows to obtain this compound with high yield and / or high purity.

Another objective of this invention is to propose a new method for producing a compound representing 2- (N-methyl-N-methanesulfonylamino) pyrimidine, or an analogous aminopyrimidine compound, which is advantageously used in industrial production.

Summary of the invention

The present invention relates to a method for producing 2- (N-methyl-N-methanesulfonylamino) pyrimidine having the formula (3)

[R is lower alkyl],

including stages in which

hydroxypyrimidine compound having the formula (1)

where R is as described above

reacted with an organic sulfonyl halide having the formula (2)

where R 'represents lower alkyl, possibly substituted by halogen atoms, phenyl, possibly substituted by 1-3 groups selected from nitro, halogen atoms, branched or unbranched lower alkyl, lower alkoxy groups,

X represents a halogen atom,

or with an organic sulfonic anhydride having the formula (2a)

where R 'is as described above, in the presence of a base,

and the resulting reaction product is reacted with N-methyl-N-methanesulfonamide in the presence of a base.

Preferably, a compound of formula (1) is reacted with a compound of formula (2) and the resulting reaction product is reacted with N-methyl-N-methanesulfonamide.

Preferably, a hydroxypyrimidine compound obtained by oxidizing a dihydropyrimidinone compound having the formula (4) is used

where R is as defined above.

The oxidation of the dihydropyrimidinone compound can be carried out using nitric acid.

A dihydropyrimidinone compound obtained by reacting an isobutyryl acetate ester of the formula (5) is preferably used.

where R is as defined above,

with 4-fluorobenzaldehyde and urea in the presence of a proton compound and a metal salt.

The proton compound may be protic acid.

Preferably, the protic acid is sulfuric acid.

Preferably, the metal salt is copper (I) chloride.

This invention also relates to a hydroxypyrimidine compound having the above formula (1).

Preferably, R in the hydroxypyrimidine compound of formula (1) is methyl.

This invention further relates to a method for producing a hydroxypyrimidine compound of the formula (1), in which the dihydropyrimidinone compound of the formula (4) is oxidized

where R represents lower alkyl.

The oxidation of the dihydropyrimidinone compound can be carried out using nitric acid.

A dihydropyrimidinone compound obtained by reacting an isobutyryl acetate ester of the formula (5) is preferably used.

where R is as defined above,

with 4-fluorobenzaldehyde and urea in the presence of a proton compound and a metal salt.

The proton compound may be protic acid.

Preferably, the protic acid is sulfuric acid.

Preferably, the metal salt is copper (I) chloride.

This invention further relates to a dihydropyrimidinone compound having the formula (4).

Preferably, R in the dihydropyrimidinone compound of formula (4) is methyl.

This invention further relates to a method for producing a dihydropyrimidinone compound of the formula (4), wherein the isobutyryl acetate ester having the formula (5)

where R represents lower alkyl,

react with 4-fluorobenzaldehyde and urea in the presence of a proton compound and a metal salt.

The proton compound may be protic acid. Preferably, the protic acid is sulfuric acid.

Preferably, the metal salt is copper (I) chloride.

This invention further relates to a method for producing an aminopyrimidine compound having the formula (8)

where R is lower alkyl and each of R ¹ and R ² independently represents a hydrogen atom, an alkyl group, an alkylsulfonyl group or an arylsulfonyl group in which a 2-substituted pyrimidine compound having the formula (6)

where R is as described above, and X represents a halogen atom or an R'-substituted sulfonyloxy group, where R 'is as described above,

subjected to interaction with an amine compound having the formula (7)

where each of R ¹ and R ² is as described above.

Preferably, R ¹ is methyl and R ² is methanesulfonyl.

The reaction of the 2-substituted pyrimidine compound with an amine compound can be carried out in the presence of a base.

This invention further relates to a halogenopyrimidine compound having the formula (9)

where R represents lower alkyl and Hal represents a halogen atom.

Preferably R is methyl and Hal is a chlorine atom.

This invention further relates to a method for producing a halogenopyrimidine compound of the formula (9), wherein the hydroxypyrimidine compound of the above formula (1) is reacted with a halogenating agent.

Preferably, the halogenating agent is phosphorus oxychloride or thionyl chloride.

This invention further relates to an organic sulfonyloxypyrimidine compound having the formula (10)

where R represents lower alkyl and R 'represents lower alkyl, possibly substituted by halogen atoms, phenyl, possibly substituted by 1-3 groups selected from nitro, halogen atoms, branched or unbranched lower alkyl, lower alkoxy groups.

Preferably, in the organic sulfonyloxypyrimidine compound, each of R and R ′ is independently methyl.

This invention further relates to a method for producing an organic sulfonyloxypyrimidine compound of the formula (10), wherein the hydroxypyrimidine compound of the above formula (1) is reacted with an organic sulfonyl halide having the formula (2)

where R 'represents lower alkyl, possibly substituted by halogen atoms, phenyl, possibly substituted by 1-3 groups selected from nitro, halogen atoms, branched or unbranched lower alkyl, lower alkoxy groups, and X represents a halogen atom,

or organic sulfonic anhydride having the formula (2a):

where R 'is as described above

in the presence of a base.

This invention further relates to a process for the preparation of 2- (N-methyl-N-methanesulfonylamino) pyrimidine of the above formula (3), the process comprising the steps of

(I) the isobutyryl acetate ester of the above formula (5) is reacted with 4-fluorobenzaldehyde and urea in the presence of a proton compound and a metal salt;

(Ii) oxidizing the reaction product of step (I);

(III) the oxidation product of step (II) is reacted with an organic sulfonyl halide of the above formula (2) or an organic sulfonic anhydride of the above formula (2a) in the presence of a base and

(IV) the reaction product of step (III) is reacted with N-methyl-N-methanesulfonamide in the presence of a base.

This invention also relates to a method for producing rosuvastatin or a pharmaceutically acceptable salt thereof, comprising preparing a compound of the above formula (3) by the above methods or a compound of the above formula (8) by the above method and subsequently converting the resulting compound to rosuvastatin or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

A representative method for producing 2- (N-methyl-N-methanesulfonylamino) pyrimidine of formula (3) of the present invention is schematically illustrated as follows:

Each step in the reaction scheme illustrated above is disclosed in more detail below.

Stage (I)

In step (I), isobutyryl acetate ether of the following formula (5):

[R is lower alkyl]

react with 4-fluorobenzaldehyde and urea in the presence of a proton compound and a metal salt.

The group R in the formulas of the compounds involved in the reactions of this invention may be an alkyl group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl, more specifically, an alkyl group having 1- 6 carbon atoms, and especially an alkyl group having 1-4 carbon atoms. Group R can take any isomeric configurations, such as normal, iso and tertiary.

The proton compound may be an inorganic acid or a salt thereof, such as hydrochloric acid, sulfuric acid, potassium bisulfate, sodium bisulfate, nitric acid or phosphoric acid; organic sulfonic acid, such as methanesulfonic acid, ethanesulfonic acid, benzosulfonic acid, para-toluenesulfonic acid or para-bromobenzosulfonic acid; organic carboxylic acid such as acetic acid, propionic acid, butyric acid or benzoic acid; an alcohol such as methanol, ethanol or propanol. Protonic acids such as hydrochloric acid, sulfuric acid, para-toluenesulfonic acid and acetic acid are preferred. Sulfuric acid is most preferred. Proton compounds can be used individually or in combination.

Proton compounds can be used in an amount of preferably from 0.01 to 3 mol, more preferably from 0.1 to 1 mol, per mole of isobutyryl acetate.

The metal salt used in the reaction may be copper (I) chloride, copper (II) chloride, copper (II) acetate, iron (II) chloride, iron (III) chloride, aluminum chloride, nickel (II) bromide, tin chloride (IV) titanium tetrachloride or magnesium bromide. Copper (I) chloride, copper (II) chloride, iron (III) chloride and nickel (II) bromide are preferred. Most preferred is copper (I) chloride. Metal salts may contain crystallization water. Metal salts can be used individually or in combination.

The metal salt can be used in an amount of preferably from 0.001 to 5 mol, more preferably from 0.01 to 0.1 mol, per mol of isobutyryl acetate.

4-Fluorobenzaldehyde can be used in an amount of preferably from 0.5 to 10 mol, more preferably from 0.9 to 1.1 mol, per mol of isobutyryl acetate.

Urea can be used in an amount of preferably from 0.5 to 10 mol, more preferably from 1.5 to 2 mol, per mole of isobutyryl acetate.

The reaction can be carried out in the presence or absence of a solvent. There are no particular restrictions on the solvents used, since the solvent does not interfere with the desired reaction. Examples of suitable solvents include alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol and tert-butyl alcohol; esters such as diethyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated aromatic hydrocarbons, such as chlorobenzene, and nitrated aromatic hydrocarbons, such as nitrobenzene. Preferred are methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, diisopropyl ether, tetrahydrofuran, dimethoxyethane, acetonitrile, butyronitrile, isobutylitrile, dichloromethane, dichloroethane, chloroform, toluene, xylene and Methanol, ethanol and isopropyl alcohol are particularly preferred. Solvents can be used individually or in combination.

The solvent can be used in an amount of preferably from 0.1 to 10 liters, more preferably from 0.3 to 2 liters, per mole of isobutyryl acetate. This amount may vary depending on the homogeneity and dispersibility of the reaction mixture.

The reaction can be carried out by reacting isobutyryl acetate, 4-fluorobenzaldehyde and urea in a solvent in the presence of a proton compound and a metal salt in an inert gas atmosphere. The reaction can be carried out at a temperature of preferably from -10 to 200 ° C, more preferably from 30 to 100 ° C. There are no special restrictions regarding ambient pressure.

The resulting reaction product, namely the dihydropyrimidinone compound of formula (4), can be isolated and purified in accordance with conventional procedures, such as distillation, crystallization, recrystallization and column chromatography.

Stage (II)

In step (II), the dihydropyrimidinone compound of formula (4), i.e. the reaction product of step (I), is oxidized to form a hydroxypyrimidine compound of formula (1).

Oxidation (or dehydrogenation oxidation) can be carried out in various conventional ways. Oxidation using nitric acid is preferred because this oxidation procedure is easy to carry out and subsequent processing of the reaction product is simple.

Nitric acid can be used in an amount of preferably from 1 to 20 mol, more preferably from 3 to 15 mol, per mol of the dihydropyrimidinone compound of the formula (4). Nitric acid is preferably used in a concentration of from 40 to 80%, more preferably from 50 to 70%.

The oxidation can be carried out in the presence or absence of a solvent. There are no particular restrictions on the solvent used, since this solvent does not interfere with the desired reaction. Examples of preferred solvents include carboxylic acids, such as acetic acid, propionic acid and butyric acid. Solvents can be used individually or in combination.

The solvent can be used in an amount of preferably 0.1 to 7 ml, more preferably 0.5 to 3 ml, per 1 g of the dihydropyrimidinone compound. This amount may vary depending on the homogeneity and dispersibility of the reaction mixture.

The oxidation can be carried out by reacting the dihydropyrimidinone compound and nitric acid in a solvent in an inert gas atmosphere. The oxidation can be carried out at a temperature of preferably from -10 to 100 ° C, more preferably from 0 to 50 ° C. There are no special restrictions regarding ambient pressure. To accelerate oxidation, a reaction initiator, such as sodium nitrite, may be included in the reaction system.

The resulting reaction product, namely the gyroxypyrimidine compound of formula (1), can be isolated and purified in accordance with generally accepted procedures, such as distillation, crystallization, recrystallization, and column chromatography.

Stage (III) and (IV)

In steps (III) and (IV), the hydroxypyrimidine compound of formula (1), i.e. the reaction product of step (II), is reacted with an organic sulfonyl halide of formula (2)

or organic sulfonic anhydride of the formula (2a)

in the presence of a base, and the resulting reaction product is reacted with N-methyl-N-methanesulfonamide in the presence of a base.

In formulas (2) and (2a), R 'represents lower alkyl, possibly substituted by halogen atoms, phenyl, possibly substituted by 1-3 groups selected from nitro, halogen atoms, branched or unbranched lower alkyl, lower alkoxy groups. Examples include alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, heptyl, octyl, nonyl and decyl, more specifically, alkyl groups having 1-6 carbon atoms, and especially alkyl groups having 1-4 atoms carbon; fluorinated alkyl groups such as trifluoromethyl, nonafluorobutyl, tridecafluorohexyl, heptadecafluorooctyl and uncozafluorodecyl; an unsubstituted or substituted phenyl group such as phenyl, tolyl, xylyl, mesityl, triisopropylphenyl, methoxyphenyl, chlorophenyl and nitrophenyl. Thus, the group R 'may have one or more than one substituent, provided that these substituents do not interfere with the ongoing reaction. This group can take any isomeric configurations, such as normal, iso and tertiary. A particularly suitable R ′ value is a phenyl group which is unsubstituted or carries 1, 2 or 3 substituents. These substituents can be independently selected from, for example, alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, halogen and nitro.

In the formula (2), X represents a halogen atom such as fluorine, chlorine, bromine or iodine.

Examples of the sulfonyl halides include methanesulfonyl fluoride, methanesulfonyl chloride, ethanesulfonyl chloride, 1-propanesulfonyl, 2-propanesulfonyl chloride, trifluoromethanesulfonyl fluoride, trifluoromethanesulfonyl chloride, nonaftorbutansulfonilftorid, tridekaftorgeksansulfonilftorid, geptadekaftoroktansulfonilftorid, unkozaftordekansulfonilftorid, benzosulfonilhlorid, p-toluenesulfonyl, p-toluenesulfonyl chloride, 2,4,6-trimetilbenzosulfonilhlorid 2 , 4,6-triisopropylbenzosulfonyl chloride, para-methoxybenzenesulfonium lchloride, para-chlorobenzosulfonyl chloride and 2-nitrobenzosulfonyl chloride. Preferred are trifluoromethanesulfonyl fluoride, benzosulfonyl chloride, para-toluenesulfonyl chloride, 2,4,6-trimethylbenzosulfonyl chloride, 2,4,6-triisopropylbenzosulfonyl chloride, para-methoxybenzenesulfonyl chloride and para-chlorobenzenesulfonyl chloride. Particularly preferred are para-toluenesulfonyl chloride, 2,4,6-trimethylbenzosulfonyl chloride, 2,4,6-triisopropylbenzosulfonyl chloride and para-methoxybenosulfonyl chloride.

Examples of sulfonic anhydrides include methanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride, para-toluenesulfonic anhydride. Trifluoromethanesulfonic anhydride, benzenesulfonic anhydride and para-toluenesulfonic anhydride are preferred. Trifluoromethanesulfonic anhydride and para-toluenesulfonic anhydride are particularly preferred.

The sulfonyl halide or sulfonic anhydride can be used in an amount of preferably 0.1 to 20 mol, more preferably 0.5 to 5 mol, most preferably 1 to 2 mol, per mol of the hydroxypyrimidine compound.

In the next step, N-methylmethanesulfonamide can be used in an amount of preferably from 0.1 to 30 mol, more preferably from 1 to 5 mol, per mole of hydroxypyrimidine compound.

The reactions of steps (III) and (IV) can preferably be carried out in the presence of a base. Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium tert-butoxide, potassium tert-butoxide and sodium tert-pentoxide, and tertiary amines such as triethylamine, triisopropylamine, diisopropylethylamine and pyridine. Sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-pentoxide, triethylamine and pyridine are preferred. Potassium carbonate, sodium tert-pentoxide and triethylamine are particularly preferred. Most preferred are potassium carbonate and sodium tert-pentoxide. The bases can be used individually or in combination.

The base can be used in an amount of preferably from 0.1 to 30 mol, more preferably from 1 to 5 mol, per mol of the hydroxypyrimidine compound. The entire amount of the base can be included in the reaction system before the start of the reaction, or the base can be added in portions after the start of the reaction.

The reaction can be carried out in the presence or absence of a solvent. There are no particular restrictions on the solvent, since the solvent does not affect the reaction. Examples of solvents include water; ketones such as acetone, methyl ethyl ketone and diethyl ketone; ethers such as diethyl ether and tetrahydrofuran; esters such as ethyl acetate, propyl acetate and butyl acetate; nitriles, such as acetonitrile and propionitrile; amides such as N, N-dimethylformamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; urea, such as N, N'-dimethylimidazolinone. Acetone, tetrahydrofuran, ethyl acetate, butyl acetate, acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide are preferred. Ethyl acetate, butyl acetate and acetonitrile are particularly preferred. Most preferred are butyl acetate and acetonitrile. Solvents can be used individually or in combination.

The solvent can be used in an amount of preferably from 0.01 to 100 liters, more preferably from 0.5 to 5 liters, per mole of hydroxypyrimidine compound. This amount may vary depending on the homogeneity and dispersibility of the reaction mixture.

The reaction can be carried out by reacting a hydroxypyrimidine compound and an organic sulfonyl halide or sulfonic anhydride in a solvent in the presence of a base with stirring in an inert gas atmosphere. The base can be added in portions. The reaction can be carried out at a temperature of preferably from -30 to 250 ° C, more preferably from 0 to 150 ° C. There are no special restrictions regarding ambient pressure.

The resulting reaction product, namely the compound of formula (3), which is 2- (N-methyl-N-methanecarbosulfonylamino) pyrimidine, can be isolated and purified in accordance with conventional procedures, such as distillation, crystallization, recrystallization and column chromatography.

A compound of formula (3), which is 2- (N-methyl-N-methanesulfonylamino) pyrimidine, and other pyrimidine compounds of formula (8) can be prepared from a hydroxypyrimidine compound of formula (1) via a 2-substituted pyrimidine compound of formula (6) on the following stages (V) and (VI):

In formula (8), R is as defined above, and each of R ¹ and R ² independently represents a hydrogen atom, an alkyl group, an alkylsulfonyl group or an arylsulfonyl group.

Stage (V)

In step (V), the hydroxypyrimidine compound of the formula (1) is reacted with a halogenating agent such as a chlorinating agent, an organic sulfonyl halide of the formula (2)

where R 'has the meaning as indicated above, and X represents a halogen atom,

or organic sulfonic anhydride of the formula (2a)

where R 'is as defined above.

Examples of halogenating agents include phosphorus oxychloride and thionyl chloride. Halogenating agents can be used individually or in combination.

The halogenating agent can be used in an amount of preferably 0.1 to 50 mol, more preferably 1 to 20 mol, most preferably 1.5 to 10 mol, per mol of the hydroxypyrimidine compound.

Examples of organic sulfonyl halides and sulfonic anhydrides are the same as previously described herein.

Organic sulfonyl halide or sulfonic anhydride can be used in an amount of preferably 0.1 to 20 mol, more preferably 0.5 to 5 mol, most preferably 1 to 2 mol, per mole of hydroxypyrimidine compound.

The reaction can be carried out in the presence or absence of a solvent. There are no particular solvent restrictions since the solvent does not interfere with the reaction. Examples of solvents include aromatic hydrocarbons such as toluene; halogenated aromatic hydrocarbons such as chlorobenzene; nitrated hydrocarbons such as nitrobenzene; halogenated aliphatic hydrocarbons such as methylene chloride and 1,2-dichloroethane; amides, such as N, N-dimethylformamide; water (not for halogenating agent); nitriles such as acetonitrile and propionitrile; carboxylic acid esters such as ethyl acetate, propyl acetate, butyl acetate; ketones, such as acetone, methyl ethyl ketone, diethyl ketone, and ethers, such as diethyl ether and tetrahydrofuran. Butyl acetate, toluene, methylene chloride, acetonitrile, chlorobenzene, nitrobenzene and N, N-dimethylformamide are preferred. Solvents can be used individually or in combination.

In the reaction using a halogenating agent, the solvent can be used in an amount of preferably from 0.01 to 10 liters, more preferably from 0.1 to 2 liters, per mole of hydroxypyrimidine compound. The amount may vary depending on the homogeneity and dispersibility of the reaction mixture.

In the reaction using sulfonyl chloride or sulfonic anhydride, the solvent can be used in an amount of preferably from 0.1 to 50 liters, more preferably from 0.5 to 2 liters, per mole of hydroxypyrimidine compound. The amount may vary depending on the homogeneity and dispersibility of the reaction mixture.

The reaction can be carried out by reacting a hydroxypyrimidine compound and a halogenating agent in a solvent while stirring under an inert gas atmosphere. The reaction can be carried out at a temperature of preferably from 0 to 200 ° C, more preferably from 50 to 120 ° C. There are no special restrictions regarding ambient pressure.

The reaction can be carried out by reacting a hydroxypyrimidine compound and a sulfonyl halide or sulfonyl anhydride in a solvent with stirring under an inert gas atmosphere. The reaction can be carried out at a temperature of preferably from -30 to 200 ° C, more preferably from 0 to 50 ° C. There are no special restrictions regarding ambient pressure.

The resulting reaction product, namely a 2-substituted pyrimidine compound, such as a chloropyrimidine compound or a sulfonyloxypyrimidine compound, can be isolated and purified in accordance with conventional procedures such as distillation, crystallization, recrystallization and column chromatography.

Stage (VI)

In step (VI), a 2-substituted pyrimidine compound, such as a chloropyrimidine compound or a sulfonyloxypyrimidine compound obtained in step (V), is reacted with an amine compound having the formula (7)

where each of R ¹ and R ² is as described above.

Examples of the groups R ¹ and R ² include a hydrogen atom, alkyl groups such as methyl, ethyl, propyl, butyl, pentyl and hexyl; alkylsulfonyl groups such as methanesulfonyl; and arylsulfonyl groups such as benzosulfonyl and para-toluenesulfonyl.

The amine compound can be used in an amount of preferably from 0.1 to 30 mol, more preferably from 1 to 5 mol, per mol of the 2-substituted pyrimidine compound.

The reaction is preferably carried out in the presence of a base. Examples of the bases are as previously indicated.

The base can preferably be used in an amount of preferably from 0.1 to 30 mol, more preferably from 1 to 5 mol, per mol of the 2-substituted pyrimidine compound.

The reaction can be carried out in the presence or absence of a solvent. There are no particular solvent restrictions since the solvent does not affect the reaction. Examples of solvents include water; ketones such as acetone, methyl ethyl ketone and diethyl ketone; ethers such as diethyl ether and tetrahydrofuran; esters such as ethyl acetate, propyl acetate and butyl acetate; nitriles such as acetonitrile and propionitrile; amides such as N, N-dimethylformamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; urea, such as N, N'-dimethylimidazolidone. Acetone, tetrahydrofuran, ethyl acetate, butyl acetate, acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide are preferred. Ethyl acetate, butyl acetate and acetonitrile are particularly preferred. The solvent can be used individually or in combination.

The solvent can be used in an amount of preferably from 0.01 to 100 liters, more preferably from 0.5 to 5 liters, per mole of a 2-substituted pyrimidine compound. This amount may vary depending on the homogeneity and dispersibility of the reaction mixture.

The reaction can be carried out by reacting a 2-substituted pyrimidine compound and an amine compound in a solvent in the presence of a base while stirring in an inert gas atmosphere. The reaction can be carried out at a temperature of preferably from −20 to 250 ° C., more preferably from 25 to 150 ° C. There are no special restrictions regarding ambient pressure.

The reaction can be carried out in two separate liquid phases in the presence of a phase transition catalyst. Examples of catalysts of phase transition include chloride, tetramethylammonium bromide, tetramethylammonium, tetraethylammonium fluoride, tetraethylammonium chloride, bromide, tetraethylammonium bromide, tetrapropylammonium iodide, tetrapropylammonium, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, bromide tetrapentilammoniya bromide, tetrahexylammonium bromide tetrageptilammoniya bromide tetraoctylammonium, benzyldimethyltetradecylammonium chloride, benzyltriethylammonium chloride, phenyltri chloride etilammoniya, phenyltrimethylammonium iodide, and hexadecyltrimethylammonium chloride. Tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltriethylammonium chloride and hexadecyltrimethylammonium chloride are preferred. Most preferred are tetrabutylammonium bromide, benzyltriethylammonium chloride and hexadecyltrimethylammonium chloride.

The phase transition catalyst can be used in an amount of from 0.01 to 0.5 mol, preferably from 0.05 to 0.2 mol, per mol of a 2-substituted pyrimidine compound.

The resulting reaction product, namely the compound of formula (3), which is 2- (N-methyl-N-methanesulfonylamino) pyrimidine, or other aminopyrimidine compounds of formula (8), can be isolated and purified in accordance with generally accepted procedures, such as distillation, crystallization, recrystallization or column chromatography.

The present invention is further disclosed by the following non-limiting examples.

Example 1. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2 (1H) -dihydropyrimidinone.

In a 500-ml glass flask equipped with a stirrer, thermometer and reflux condenser, 28.8 g (0.2 mol) of methyl isobutyryl acetate, 24.8 g (0.2 mol) of 4-fluorobenzaldehyde, 21.0 g (0.35 mol) were placed ) urea, 200 mg (2 mmol) of copper (I) chloride, 2 ml of sulfuric acid and 200 ml of methanol. The contents of the flask were heated to 64-65 ° C for 24 hours under reflux and stirring to carry out the reaction. The result is a precipitated crystalline product. This crystalline product was collected on filter paper and washed with methanol to obtain 49.7 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2 (1H) -dihydropyrimidinone as a colorless crystalline product having the following characteristics. The yield was 85% (based on the amount of methyl isobutyryl acetate).

Melting point 223-225 ° C.

UV _λmax (CH ₃ CN, nm): 194.3; 278.6.

IR (KBr, cm ^-1 ): 3296, 3229, 3137, 2963, 1685, 1629, 1504, 1225, 1097.

¹ H-NMR (DMSO-d ₆ , δ (ppm)): 1.14 (6H, dd, J = 6.8, 6.9 Hz), 3.52 (3H, s), 4.0-4.2 (1H, m), 5.15 (1H, d, J = 3.4 Hz), 7.1-7.2 (2H, m), 7.2-7.3 (2H, m), 7.76 (1H, d, J = 3.2 Hz), 8.91 (1H, s).

HRMS (high resolution mass spectrometry): 292, 1247 (theoretical value (C ₁₅ H ₁₇ FN ₂ O ₃ (M +)) 292, 1223).

Example 2. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3, 4-2 (1H) -dihydropyrimidinone.

The procedures of Example 1 were repeated except that 200 mg (2 mmol) of copper (I) chloride was replaced with 5.41 g (20 mmol) of iron (III) chloride hexahydrate. 35.6 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2 (1H) -dihydropyrimidinone are obtained. The yield was 61% (based on the amount of methyl isobutyryl acetate).

Example 3. Obtaining 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine.

In a 50 ml glass flask equipped with a stirrer and a thermometer, 11 ml (144 mmol) of nitric acid (60-61%, specific gravity 1.38) were placed. 4.00 g (13.7 mmol) of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2 (1H) -dihydropyrimidinone obtained in the same way were slowly added to nitric acid at room temperature. as in Example 1, and this mixture was reacted for 30 minutes at room temperature. After completion of the reaction, the reaction mixture was neutralized by placing this mixture in 140 ml of a saturated aqueous solution of sodium bicarbonate. Then the reaction mixture was extracted with ethyl acetate. The organic liquid was separated and concentrated under reduced pressure. The residue was crystallized from toluene. The crystalline product was collected on a filter and washed with toluene to obtain 3.64 g of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product having the following characteristics. The yield was 92% (based on the amount of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2 (1H) -dihydropyrimidinone).

Melting point 193 ° C (with decomposition).

UV _λmax (CH ₃ CN, nm): 196.6; 243.2; 317.9.

IR (KBr, cm ^-1 ): 2991, 2887, 1717, 1653, 1589, 1433, 1280, 1223.

¹ H-NMR (DMSO-d ₆ , δ (ppm)): 1.23 (6H, d, J = 6.8H4), 3.0-3.2 (1H, m), 3.56 (3H, s), 7.3-7.4 (2H, m), 7.5-7.6 (2H, m), 12.25 (1H, brs).

MCBP: 290.1054 (theoretical value (C ₁₅ H ₁₅ FN ₂ O ₃ (M +)) 290.1067).

Example 4. Obtaining 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine.

2.92 g (10 mmol) of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2 (1H) -dihydropyrimidinone obtained in this way was placed in a 50 ml glass flask equipped with a stirrer and a thermometer. in the same manner as in Example 1, and 5 ml of acetic acid. 3.74 ml (50 mmol) of nitric acid (60-61%, specific gravity 1.38) were slowly added to this mixture. To this mixture was further added 0.07 g (1 mmol) of sodium nitrite and the reaction was carried out for one hour at room temperature. After completion of the reaction, the reaction mixture was neutralized by placing this mixture in 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 was crystallized from toluene. The crystalline product was collected on a filter and washed with toluene to obtain 2.61 g of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product. The yield was 90% (based on the amount of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2 (1H) -dihydropyrimidinone).

Example 5. Obtaining 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine.

54.0 g (735 mmol) of nitric acid (60-61%, specific gravity 1.38) were placed in a 200 ml glass flask equipped with a stirrer and a thermometer. To nitric acid, 30.6 g (105 mmol) of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2 (1H) -dihydropyrimidinone obtained in the same manner as in Example 1, and this mixture was reacted for 30 minutes at room temperature. After completion of the reaction, the reaction mixture was poured into 162 ml of water. The aqueous mixture was neutralized by adding 61 g of an aqueous solution of sodium hydroxide (48 wt.%) To precipitate a crystalline product. The crystalline product was collected by filtration and dried to obtain 27.6 g of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product.

The yield was 91% (based on the amount of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2 (1H) -dihydropyrimidinone).

Example 6. Obtaining 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine.

323.3 g (3.09 mol) of nitric acid (60-61%, density 1.38) were placed in a 2 L glass flask equipped with a stirrer and a thermometer. Then, concentrated nitric acid was cooled to 10 ° C. 2.36 g (34.2 mmol) of sodium nitrite was added to nitric acid, and then 100 g (342 mmol) of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3.4-2 (1H) was slowly added. -dihydropyrimidinone obtained in the same manner as in Example 1. This mixture was subjected to reaction for 2 hours at a temperature of 10-12 ° C. After completion of the reaction, 970 ml of water was poured into the reaction mixture. The aqueous mixture was then neutralized by adding 257 g of an aqueous sodium hydroxide solution (48 wt.%) To precipitate a crystalline product. The crystalline product was collected by filtration and dried to obtain 93.3 g of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product. The yield was 94% (based on the amount of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2 (1H) -dihydropyrimidinone).

Example 7. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine.

5.81 g (20 mmol) of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 3.59 g (26 mmol) was placed in a 200 ml glass flask equipped with a stirrer, thermometer and reflux condenser. ) potassium carbonate (available from Asahi Glass Works, Co., Ltd., Lot No. 1111632; particle size distribution: 75-250 μm 14%; passage through 75 μm 86%) and 40 ml of butyl acetate. 4.19 g (22 mmol) of p-toluenesulfonyl chloride was slowly added to this mixture with stirring, and the reaction was carried out at 40 ° C. for 4 hours. After that, the reaction mixture was cooled to room temperature. 2.84 g (26 mmol) of N-methylmethanesulfonamide and 4.15 g (30 mmol) of potassium carbonate (the same as above) were added to the cooled reaction mixture. The mixture was heated to 110-125 ° C for 2 hours under reflux for the reaction. After completion of the reaction, the mixture was cooled to room temperature. 25 ml of water and 20 ml of acetone were added to the cooled mixture, and the organic liquid was separated. The organic liquid was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dry organic liquid was filtered and concentrated under reduced pressure. The residue was crystallized from heptane to give 6.58 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine as a pale yellow crystalline product. The yield was 86% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

Example 8. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine.

50.0 g (172 mmol) of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 20.8 g (189 mmol) were placed in a 1000 ml glass flask equipped with a stirrer, thermometer and reflux condenser. ) sodium tert-pentoxide and 344 ml of acetonitrile and the resulting mixture was stirred at 0-10 ° C for 30 minutes. To this mixture 36.1 g (189 mmol) of p-toluenesulfonyl chloride were slowly added and the reaction was carried out for 5 hours at room temperature. After that, the reaction mixture was cooled to a temperature of 0-10 ° C. To the cooled reaction mixture was added 28.2 g (258 mmol) of N-methylmethanesulfonamide and 26.5 g (241 mmol) of sodium tert-pentoxide. The mixture was kept at 0-10 ° C for one hour and then heated to 75-82 ° C for 2 hours under reflux for the reaction. After completion of the reaction, the mixture was cooled to room temperature. To the cooled mixture was added 344 ml of water. The aqueous mixture was cooled to 0-10 ° C and stirred for one hour, while a crystalline product precipitated. The crystalline product was collected by filtration and dried to give 45.3 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine as a pale yellow crystalline product. The yield was 68% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

Example 9. Preparation of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine from methyl isobutyryl acetate, 4-fluorobenzaldehyde and urea.

1) 24.4 kg (169 mol) of methyl isobutyryl acetate, 20.0 kg (161 mol) of 4-fluorobenzaldehyde, 16.9 kg (282 mol) of urea were placed in a 200 liter enameled reaction vessel equipped with a stirrer, thermometer and reflux condenser, 0.2 kg (2 mol) of copper (I) chloride, 3.0 kg of sulfuric acid and 80.4 kg of methanol. The mixture was heated to 64-66 ° C for 20 hours under reflux for the reaction. After completion of the reaction, the reaction mixture was cooled to room temperature to precipitate a crystalline product. The crystalline product was collected on filter paper and washed with methanol to obtain 43.4 kg of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2 (1H) -dihydropyrimidinone as a colorless crystalline product.

2) 62.5 kg (615.6 mol) of diluted nitric acid and 0.5 kg (6.8 mol) of sodium nitrite were placed in an enameled reaction vessel with a volume of 200, equipped with a stirrer and a thermometer. To this mixture, 20.0 kg (68.4 mmol) of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2 (1H) -dihydropyrimidinone obtained as above was slowly added with cooling. The resulting mixture was reacted at a low temperature (10 ° C). After completion of the reaction, the reaction mixture was neutralized by the addition of a solution of sodium hydroxide in aqueous methanol. Then, an aqueous solution of sodium hydroxide was added to this mixture. The resulting mixture was placed under reduced pressure to distill off methanol. 96.5 kg of acetone and 96.5 kg of water were added to the residue. The aqueous residue was then neutralized by the addition of acetic acid to precipitate a crystalline product. The crystalline product was collected on filter paper and washed with a mixture of acetone and water to obtain 17.9 kg of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine.

3) 17.9 kg (62.0 mol) of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine obtained, were placed in a 200 L enameled reaction vessel equipped with a stirrer, thermometer and reflux condenser. as indicated above, 107.7 kg of butyl acetate, 11.1 kg (80.3 mol) of potassium carbonate (available from Asahi Glass Works, Co., Ltd., Lot No. 1111632, particle size distribution: 75-250 μm 14 %; passage through 75 μm 86%) and 12.9 kg (67.7 mol) of para-toluenesulfonyl chloride. The mixture was heated at 60 ° C for 2 hours to carry out the reaction. After that, the reaction mixture was cooled to room temperature. To the cooled mixture was added 8.8 kg (80.6 mol) of N-methylmethanesulfonamide and 12.9 kg (93.3 mol) of potassium carbonate and the resulting mixture was heated at 122-125 ° C for 3 hours to carry out the reaction. After completion of the reaction, the reaction mixture was cooled to room temperature. Acetone and water were added to the cooled mixture and the organic liquid portion was separated. The organic liquid was then washed successively with an aqueous solution of sodium hydroxide (3 wt.%) And a saturated aqueous solution of sodium chloride. The washed organic liquid was concentrated under reduced pressure. Isopropyl alcohol and water were added to the residue, resulting in precipitation of the crystalline product. The crystalline product was filtered on filter paper and washed with isopropyl alcohol. The washed crystalline product and 85.7 kg of acetone were placed in a 200 L enameled reaction vessel equipped with a stirrer, thermometer and reflux condenser. The mixture was stirred at 50-55 ° C to dissolve the crystalline product in acetone. The insoluble portion was removed by a linear filter. Thereafter, 58.3 kg of water was added to the solution to precipitate a crystalline product. The crystalline product was collected on filter paper and washed with a mixture of acetone and water to give 19.5 kg of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine.

Example 10. Obtaining 2-chloro-4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonylpyrimidine.

1.00 g (3.43 mmol) of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine and 3.4 ml (25 ml) were placed in a 25 ml glass flask equipped with a stirrer, thermometer and reflux condenser. 3.7 mmol) phosphorus oxychloride. The mixture was heated to 100-106 ° C for one and a half hours under reflux for the reaction. 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 neutralized aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure to obtain 1.03 g of 2-chloro-4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product having the following characteristics. The yield was 97% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

Melting point 99-101 ° C.

UV _λmax (CH ₃ CN, nm): 194.7; 276.5.

IR (KBr, cm ^-1 ): 2980, 1728, 1542, 1508, 1227, 1086.

¹ H-NMR (DMSO-d ₆ , δ (ppm)): 1.33 (6H, d, J = 6.8 Hz), 3.1-3.2 (1H, m), 3.76 (3H, s), 7.15 (2H , t, J = 8.5 Hz), 7.6-7.7 (2H, m).

HRMS: 308.0695 (theoretical value (C ₁₅ H ₁₄ CIFN ₂ O ₂ (M +)) 308.0728).

Example 11. Obtaining 2-chloro-4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonylpyrimidine.

1.00 g (3.43 mmol) of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 0.5 ml, were placed in a 25 ml glass flask equipped with a stirrer, thermometer, and reflux condenser. 3.9 mmol) of thionyl chloride, 3.44 ml of toluene and 0.11 ml of N, N-dimethylformamide. The mixture was heated to 80 ° C for 3 hours to carry out the reaction. 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 neutralized aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure to obtain 0.80 g of 2-chloro-4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product. The yield was 76% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

Example 12. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine.

546 mg (5 mmol) of N-methylmethanesulfonamide, 551 mg (5 mmol) of sodium tert-pentoxide, 10 ml of acetonitrile and 309 mg (1 mmol) of 2-chloro- were placed in a 25-ml glass flask equipped with a stirrer, thermometer and reflux condenser. 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonylpyrimidine. The mixture was heated to 81-82 ° C for 3 hours under reflux for the reaction. After completion of the reaction, the reaction mixture was cooled to room temperature. 10 ml of water was added to the cooled mixture, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200 column, eluent: hexane / ethyl acetate, 2: 1 volume ratio). 339 mg of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine was obtained. The yield was 89% (based on the amount of 2-chloro-4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonylpyrimidine).

Example 13 Preparation of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine

10.0 g (34.4 mmol) of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 5.22 g (58.5 mmol) of triethylamine and 34 were placed in a 100 ml glass flask. ml of acetonitrile. The mixture in the flask was cooled to 0-5 ° C in an ice bath. 5.12 g (44.7 mmol) of methanesulfonyl chloride was slowly added to the cooled mixture, and the resulting mixture was reacted at 20-25 ° C. for 2 hours. After completion of the reaction, 60 ml of water was added to the reaction mixture. The aqueous reaction mixture was extracted with toluene and the toluene portion was separated. The toluene portion was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried mixture was filtered and concentrated under reduced pressure. The residue was crystallized from methanol to give 11.3 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine as a colorless crystalline product having the following characteristics. The yield was 89% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

Melting point 110-111 ° C.

UV _λmax (CH ₃ CN, nm): 193.7; 276.8.

IR (KBr, cm ^-1 ): 2980, 1724, 1562, 1391, 1250, 1175, 1079, 971.

¹ H-NMR (CDCI ₂ , δ (ppm)): 1.33 (6H, d, J = 6.6 Hz), 3.20 (1H, m), 3.60 (3H, s), 7.1-7.2 (2H, s ), 7.6-7.8 (2H, m).

HRMS: 368.0842 (theoretical value (C ₁₅ H ₁₇ FN ₂ O ₅ S (M +)) 368.0892).

Example 14. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (para-toluenesulfonyloxy) pyrimidine.

27.6 g (95.1 mmol) of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 12.5 g (123 mmol) of triethylamine and 95 ml of acetonitrile were placed in a 200 ml glass flask. . The mixture in the flask was cooled to 0-5 ° C in an ice bath. 20.0 g (105 mmol) of p-toluenesulfonyl chloride were slowly added to the cooled mixture, and the resulting mixture was reacted at 20-25 ° C. for one hour. After completion of the reaction, 95 ml of water was added to the reaction mixture. The aqueous reaction mixture was extracted with toluene and the toluene portion was separated. The toluene portion was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried mixture was filtered and concentrated under reduced pressure. The residue was crystallized from methanol to obtain 35.9 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (para-toluenesulfonyloxy) pyrimidine as a colorless crystalline product having the following characteristics. The yield was 85% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

Melting point 94-96 ° C.

UV _λmax (CH ₃ CN, nm): 194.9; 275.2.

IR (KBr, cm ^-1 ): 2961, 1734, 1539, 1389, 1352, 1247, 1090, 980.

¹ H-NMR (CDCI ₃ , δ (ppm)): 1.23 (6H, d, J = 6.8 Hz), 2.45 (3H, s), 3.0-3.2 (1H, m), 3.74 J = 8.5 Hz )

HRMS: 444.1155 (theoretical value (C ₃₂ H ₂₁ FN ₂ O ₅ S (M +)) 444.1194).

Example 15. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-benzosulfonyloxypyrimidine.

The procedures of Example 13 were repeated except that 18.5 g (105 mmol) of benzosulfonyl chloride was replaced with para-toluenesulfonyl chloride.

39.3 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-benzosulfonyloxypyrimidine were obtained as a pale yellow crystalline product having the following characteristics. The yield was 96% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

¹ H-NMR (CDCI ₃ , δ (ppm)): 1.21 (6H, d, J = 6.4 Hz), 3.0-3.1 (1H, m), 3.73 (3H, s), 7.1-7.2 (2H , m), 7.5-7.7 (5H, m), 8.1-8.2 (2H, m).

Example 16. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (2,4,6-trimethylbenzosulfonyloxy) pyrimidine.

The procedures of Example 13 were repeated, except that para-toluenesulfonyl chloride was replaced with 23.0 g (105 mmol) of 2,4,6-trimethylbenzosulfonyl chloride.

37.7 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (2,4,6-trimethylbenzosulfonyloxy) pyrimidine were obtained as a pale yellow crystalline product having the following characteristics. The yield was 84% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

¹ H-NMR (CDCI ₃ , δ (ppm)): 1.17 (6H, d, J = 6.8 Hz), 2.34 (3H, s), 2.67 (6H, s), 3.0-3.1 (1H, m ), 3.73 (3Н, s), 7.00 (2Н, s), 7.0-7.2 (2Н, m), 7.4-7.5 (2Н, m).

Example 17. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (2,4,6-triisopropylbenzenesulfonyloxy) pyrimidine.

The procedures of Example 13 were repeated, except that para-toluenesulfonyl chloride was replaced with 31.8 g (105 mmol) of 2,4,6-triisopropylbenzene sulfonyl chloride.

47.1 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (2,4,6-triisopropylbenzosulfonyloxy) pyrimidine was obtained as a pale yellow crystalline product having the following characteristics. The yield was 89% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

¹ H-NMR (CDCl ₃ , δ (ppm)): 1.12 (6H, d, J = 6.6 Hz), 1.19 (12H, d, J = 6.8 Hz), 1.27 (6H, d, J = 7.1 Hz), 2.8-2.95 (1H, m), 2.95-3.1 (1Н, m), 3.73 (3Н, s), 4.1-4.3 (2Н, m), 7.0-7.1 (2Н, m), 7.20 (2Н, s) 7.4-7.5 (2H, m).

Example 18. Preparation of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (para-methoxybenzosulfonyloxy) pyrimidine.

The procedures of Example 13 were repeated with the exception that p-toluenesulfonyl chloride was replaced with 21.7 g (105 mmol) of p-methoxybenzenesulfonyl chloride.

39.9 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (lara-methoxybenzosulfonyloxy) pyrimidine were obtained as a colorless crystalline product having the following characteristics. The yield was 91% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

¹ H-NMR (CDCI ₃ , δ (ppm)): 1.25 (6H, d, J = 6.8 Hz), 3.0-3.2 (1H, m), 3.74 (3H, s), 3.88 (3H, s ), 6.99 (2Н, dd, J = 2.0, 9.0 Hz), 7.0-7.2 (2Н, m), 7.5-7.7 (2Н, m), 8.07 (2Н, dd, J = 2.2, 9.0 Hz).

Example 19. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (para-chlorobenzosulfonyloxy) pyrimidine.

The procedures of Example 13 were repeated, except that para-toluenesulfonyl chloride was replaced with 22.2 g (105 mmol) of para-chlorobenzosulfonyl chloride.

39.9 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (para-chlorobenzosulfonyloxy) pyrimidine were obtained as a colorless crystalline product having the following characteristics. The yield was 89% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

¹ H-NMR (CDCI ₃ , δ (ppm)): 1.23 (6H, d, J = 6.6 Hz), 3.0-3.2 (1H, m), 3.74 (3H, s), 7.1-7.2 (2H , m) 7.5-7.7 (4H, m), 8.0-8.1 (2H, m).

Example 20. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (2-nitrobenzosulfonyloxy) pyrimidine.

The procedures of Example 13 were repeated with the exception that p-toluenesulfonyl chloride was replaced with 23.3 g (105 mmol) of 2-nitrobenzenesulfonyl chloride.

28.0 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (2-nitrobenzosulfonyloxy) pyrimidine are obtained in the form of an opaque crystalline product having the following characteristics. The yield was 62% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

¹ H-NMR (CDCI ₃ , δ (ppm)): 1.17 (6H, d, J = 6.8 Hz), 3.0-3.2 (1H, m), 3.75 (3H, s), 7.1-7.2 (2H , m), 7.5-7.6 (2Н, m), 7.7-8.0 (3Н, m), 8.33 (1Н, dd, J = 1.7, 8.1 Hz).

Example 21. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine.

196 mg (1.8 mmol) of N-methylmethanesulfonamide, 198 mg (1.8 mmol) of sodium tert-pentoxide, 7.5 ml of acetonitrile and 667 mg (1) were placed in a 25 ml glass flask equipped with a stirrer, thermometer and reflux condenser. , 5 mmol) of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (p-toluenesulfoxy) pyrimidine. The mixture was heated to 81-82 ° C for one and a half hours under reflux for the reaction. After completion of the reaction, the reaction mixture was cooled to room temperature. 10 ml of water was added to the cooled mixture, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200 column; eluent: hexane / ethyl acetate (2: 1 volume ratio)). 428 mg of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine was obtained. The yield was 75% (based on the amount of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (p-toluenesulfonyloxy) pyrimidine).

Example 22. Obtaining 2-amino-4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonylpyrimidine.

In a 25 ml glass flask equipped with a stirrer, thermometer and gas inlet, 1.00 g (2.71 mmol) of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine was placed under ice cooling and 8.1 ml of tetrahydrofuran. The mixture was stirred at room temperature for 12 hours in an atmosphere of gaseous ammonia to carry out the reaction. After completion of the reaction, 10 ml of water was added to the reaction mixture. Then the aqueous mixture was subjected to extraction with toluene. The toluene portion was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried toluene portion was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200 column; eluent: hexane / ethyl acetate (2: 1 volume ratio)). 0.63 g of 2-amino-4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonylpyrimidine was obtained. The yield was 80% (based on the amount of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine).

6-isopropyl-5-methoxycarbonylpyrimidine

Example 23. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-N-methylaminopyrimidine.

In a 50 ml glass flask equipped with a stirrer, thermometer and dropping funnel, 6.00 g (16.3 mmol) of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine was placed. 5.06 g (65.2 mmol) of an aqueous 40% (w / w) methylamine solution was slowly added dropwise to the flask under ice cooling. The resulting mixture was stirred for one hour at the same temperature to carry out the reaction. After completion of the reaction, 16 ml of water was added to the reaction mixture. Then the aqueous mixture was subjected to extraction with toluene. The toluene portion was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried toluene portion was filtered and concentrated under reduced pressure to obtain 4.81 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-N-methylaminopyrimidine. The yield was 97% (based on the amount of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine).

Example 24. Obtaining 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine.

In a 300 ml glass flask equipped with a stirrer, thermometer and reflux condenser, 8.7 g (30.0 mmol) of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 3.0 g ( 30.0 mmol) of triethylamine and 150 ml of toluene. The mixture in the flask was cooled to 0 ° C in an ice bath. 8.46 g (30.0 mmol) of trifluoromethanesulfonic anhydride were slowly added to the cooled mixture, and the resulting mixture was reacted for 3 hours at the same temperature. After completion of the reaction, 90 ml of water was added to the reaction mixture. The organic liquid was separated from the aqueous reaction mixture. The organic liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200 column; eluent: hexane / ethyl acetate (8: 2 volume ratio)). 8.46 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine having the following characteristics was obtained as a colorless oil. The yield was 74% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

IR (KBr, cm ^-1 ): 3421, 2978, 1737, 1570, 1429, 1222, 1136, 973, 851.

¹ H-NMR (CDCI ₃ , δ (ppm)): 1.33 (6H, d, J = 6.6 Hz), 3.1-3.2 (1H, m), 3.80 (3H, s), 7.1-7.2 (2H , m), 7.7-7.8 (2H, m).

HRMS: 422.0585 (theoretical value (C ₁₆ H ₁₄ F ₄ N ₂ O ₅ S (M +)) 422.0560).

Example 25. Preparation of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine.

2.9 g (10.0 mmol) of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 1.7 g, were placed in a 300 ml glass flask equipped with a stirrer, thermometer and reflux condenser. 16.8 mmol) of triethylamine and 50 ml of toluene. The mixture in the flask was cooled to 0 ° C in a water bath. 2.4 g (14.1 mmol) of trifluoromethanesulfonyl chloride were slowly added to the cooled mixture, and the resulting mixture was reacted for 3 hours at the same temperature. After completion of the reaction, 30 ml of water was added to the reaction mixture. The organic liquid was separated from the aqueous reaction mixture. The organic liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200 column; eluent: hexane / ethyl acetate (8: 2 volume ratio)). 2.8 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine, having the following characteristics, were obtained as a colorless oil. The yield was 66% (based on the amount of 4- (4-fluorophenyl) -2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

Example 26. Preparation of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine.

3.0 g (7 mmol) of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine, 0.99 g, were placed in a 50 ml glass flask equipped with a stirrer, thermometer and reflux condenser (9, 1 mmol) N-methyl-N-methanesulfonamide, 1.45 g (10.5 mmol) of potassium carbonate (available from Wako Junyaku Co., Ltd., specialty) and 14 ml of butyl acetate. The mixture was heated to 122-125 ° C for 3 hours under reflux for the reaction. After completion of the reaction, the reaction mixture was cooled to room temperature. 10 ml of water and 7 ml of acetone were added to the reaction mixture, and the organic liquid portion was separated. The organic liquid was washed with saturated aqueous sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200 column; eluent: hexane / ethyl acetate (5: 1 volume ratio)). 2.1 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine were obtained as a white crystalline product. The yield was 78% (based on the amount of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine).

Example 27. Preparation of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine.

1.1 g (2.5 mmol) of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (para-toluenesulfonyloxy) pyrimidine was placed in a 50 ml glass flask equipped with a stirrer, thermometer and reflux condenser, 0.55 g (5.0 mmol) of N-methylmethanesulfonamide, 0.69 g (5.0 mmol) of potassium carbonate (available from Wako Junyaku Co., Ltd., specialty), 0.32 g (1.0 mmol) tetrabutylammonium bromide, 20 ml of toluene and 5 ml of water. The mixture was heated to 85 ° C for 28 hours under reflux for the reaction. After completion of the reaction, the reaction mixture was cooled to room temperature. 10 ml of water and 7 ml of acetone were added to the reaction mixture, and the organic liquid portion was separated. The organic liquid portion was analyzed by high performance liquid chromatography. It was confirmed that 0.6 g of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine was obtained. The yield was 63% (based on the amount of 4- (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-2- (p-toluenesulfonyloxy) pyrimidine).

Industrial application

The pyrimidine compound, especially the 2- (N-methyl-N-methanesulfonylamino) pyrimidine compound that is prepared according to this invention, is useful as an intermediate to produce a cholesterol lowering agent (hydroxymethylglutaryl-CoA reductase agent ) The compound of formula (3) can be converted into a hydroxymethylglutaryl-CoA reductase inhibitor by the method disclosed in European Patent Application Publication No. 05214171 to Bioorg. Med. Chem., 5, 437 (1997), and International Patent Application No. WO 0049014. Descriptions of these sources are incorporated herein by reference to demonstrate how a compound of formula (3) or formula (8) can be converted into a hydroxymethylglutaryl-CoA- inhibitor reductases, in particular rosuvastatin or a pharmaceutically acceptable salt thereof, such as calcium rosuvastatin.

Claims (41)

1. The method of obtaining 2- (N-methyl-N-methanesulfonylamino) -pyrimidine having the formula (3)

where R represents lower alkyl, including stages at which hydroxypyrimidine compound having the formula (1)

where R is as described above reacted with an organic sulfonyl halide having the formula (2)

where R 'represents lower alkyl, possibly substituted by halogen atoms, phenyl, possibly substituted by 1-3 groups selected from nitro, halogen atoms, branched or unbranched lower alkyl, lower alkoxy groups, and X represents a halogen atom, or with organic sulfonic anhydride, having the formula (2a)

where R 'is as defined above in the presence of a base, and the resulting reaction product is reacted with N-methyl-N-methanesulfonamide in the presence of a base. 2. The method according to claim 1, wherein the compound of formula (1) is reacted with a compound of formula (2) and the resulting reaction product is reacted with N-methyl-N-methanesulfonamide. 3. The method according to claim 1, wherein a hydroxypyrimidine compound obtained by oxidizing a dihydropyrimidinone compound having the formula (4) is used

where R is as defined in claim 1. 4. The method according to claim 3, wherein the dihydropyrimidinone compound is oxidized using nitric acid. 5. The method according to claim 3, wherein a dihydropyrimidinone compound obtained by reacting an isobutyryl acetate ester having the formula (5) is used

where R is as defined in claim 1, with 4-fluorobenzaldehyde and urea in the presence of a proton compound and a metal salt. 6. The method according to claim 5, where the proton compound is a protic acid. 7. The method according to claim 6, where the protic acid is sulfuric acid. 8. The method according to claim 5, where the metal salt is copper chloride (I). 9. Hydroxypyrimidine compound having the formula (1)

where R represents lower alkyl. 10. The hydroxypyrimidine compound of claim 9, wherein R is methyl. 11. The method of producing hydroxypyrimidine compounds according to claim 9

in which the dihydropyrimidinone compound of the formula (4) is oxidized

where R represents lower alkyl. 12. The method according to claim 11, wherein the dihydropyrimidinone compound is oxidized using nitric acid. 13. The method according to claim 11, in which a dihydropyrimidinone compound obtained by reacting an isobutyryl acetate ester having the formula (5) is used

where R is the same as defined in clause 10, with 4-fluorobenzaldehyde and urea in the presence of a proton compound and a metal salt. 14. The method according to item 13, where the proton compound is a protic acid. 15. The method according to 14, where the protic acid is sulfuric acid. 16. The method according to item 13, where the metal salt is a copper chloride (I). 17. The dihydropyrimidinone compound having the formula (4)

where R represents lower alkyl. 18. The dihydropyrimidinone compound of claim 17, wherein R is methyl. 19. A method of producing a dihydropyrimidinone compound according to 17, wherein

where R is as specified in paragraph 17, react with 4-fluorobenzaldehyde and urea in the presence of a proton compound and a metal salt. 20. The method according to claim 19, where the proton compound is a protic acid. 21. The method according to claim 20, where the protic acid is sulfuric acid. 22. The method according to claim 19, where the metal salt is copper (I) chloride. 23. A method of obtaining an aminopyrimidine compound having the formula (8)

where R represents lower alkyl, and each of R ¹ and R ² independently represents a hydrogen atom, an alkyl group, an alkylsulfonyl group or an arylsulfonyl group, wherein the 2-substituted pyrimidine compound having the formula (6)

where R is as described above, and X is a halogen atom or an R'-substituted sulfonyloxy group, where R 'is as described above, subjected to interaction with an amino compound having the formula (7)

where each of R ¹ and R ² is as described above. 24. The method according to item 23, where R ¹ represents methyl and R ² represents methanesulfonyl. 25. The method according to item 23, where the interaction of a 2-substituted pyrimidine compound with an amino compound is carried out in the presence of a base. 26. Halogenopyrimidine compound having the formula (9)

where R represents lower alkyl and Hal represents a halogen atom. 27. The halo pyrimidine compound of claim 26, wherein R is methyl. 28. The halo pyrimidine compound of claim 26, wherein Hal represents a chlorine atom. 29. A method of producing a halogenopyrimidine compound according to claim 26, wherein the hydroxypyrimidine compound having the formula (1)

where R represents lower alkyl, subjected to interaction with a halogenating agent. 30. The method according to clause 29, where the halogenating agent is phosphorus oxychloride or thionyl chloride. 31. Organic sulfonyloxypyrimidine compound having the formula (10)

where R is lower alkyl and R ¹ is lower alkyl, possibly substituted by halogen atoms, phenyl, possibly substituted by 1-3 groups selected from nitro, halogen atoms, branched or unbranched lower alkyl, lower alkoxy groups. 32. The organic sulfonyloxypyrimidine compound of claim 31, wherein R and R 'each independently is methyl. 33. A method for producing an organic sulfonyloxypyrimidine compound according to claim 31, wherein the hydroxypyrimidine compound having the formula (1)

where R represents lower alkyl, reacted with an organic sulfonyl halide having the formula (2)

where R 'represents lower alkyl, possibly substituted by halogen atoms, phenyl, possibly substituted by 1-3 groups selected from nitro, halogen atoms, branched or unbranched lower alkyl, lower alkoxy groups, and X represents a halogen atom, or organic sulfonic anhydride, having the formula (2a)

where R 'has the meaning, as indicated above, in the presence of a base. 34. A method of obtaining 2- (N-methyl-N-methanesulfonylamino) -pyrimidine having the formula (3)

where R represents lower alkyl, moreover, this method includes the stages at which (I) isobutyryl acetate ether of the formula (5)

where R is lower alkyl, is reacted with 4-fluorobenzaldehyde and urea in the presence of a proton compound and a metal salt; (Ii) oxidizing the reaction product of step (I); (III) the oxidation product of step (II) is reacted with an organic sulfonyl halide having the formula (2)

where R 'represents lower alkyl, possibly substituted by halogen atoms, phenyl, possibly substituted by 1-3 groups selected from nitro, halogen atoms, branched or unbranched lower alkyl, lower alkoxy groups, and X represents a halogen atom, or organic sulfonic anhydride, having the formula (2a)

where R 'has the meaning, as indicated above, in the presence of a base, and (IV) the reaction product of step (III) is reacted with N-methyl-N-methanesulfonamide in the presence of a base. 35. The method according to any one of claims 1, 23 and 34, according to which the resulting compounds of formula (3) or (8), respectively, can be used to obtain rosuvastatin. Priority on points and signs: 02/19/2002 according to claims 1-8, in the case of using the compound (2) to obtain the compound (3); 07/13/2001 according to claims 9-22; 01/16/2002 according to claims 23-25; 10/09/2001 according to paragraphs 28 and 30; November 27, 2001 according to paragraphs 31-32 and 33, in the case of using the compound (2) to obtain the compound (10); 07/12/2002 according to claims 1 and 3-8, in the case of obtaining the compound (3) using the compound (2a), claim 33, in the case of using the compound (2a) to obtain the compound (10), as well as claims 26, 27, 29, 34, 35.