Method for preparing sulfonulaminopyrimidine compounds (variants), intermediate substances and methods for their preparing

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

 

The scope of the invention

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

[in the formula (8) R is a lower alkyl and each of R1and R2independently represents a hydrogen atom, alkyl group, alkylsulfonyl group or arylsulfonyl group], more specifically, to obtain 2-(N-methyl-N-methanesulfonamido)pyrimidine having the following formula (3):

where R represents lower alkyl.

Prior art

Bioorg. Med. Chem., 5, 437 (1997), reveals that the connection, which represents a 2-(N-methyl-N-methanesulfonamido)pyrimidine, used as an intermediate connection for receiving agent that reduces the level of cholesterol (inhibitor hydroxymethylglutaryl-COA reductase: S-4522), having the following formula:

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

WO 01/04100 discloses a method of obtaining a connection, which represents a 2-(N-methyl-N-methanesulfonamido)pyrimidine, and this method includes a stage on which interact methylisobutylketone 4-phthorbenzotephum obtaining methyl-2-[1-amino-1-(4-forfinal)methylene]4-methyl-3-oxopentanoate and interact 2-[1-amino-1-(4-forfinal)methylene-4-methyl-3-oxopentanoate with N-cyano-N-methylmethanesulfonamide, which is obtained by reaction between N-methylmethanesulfonamide and langarica, to obtain 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methanesulfonyl-N-methylamino)pyrimidine.

Revealed that the total yield (number of methylisobutylketone) is 45.5%.

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

Accordingly, the purpose of this invention is to provide a new method for producing 2-(N-methyl-N-methanesulfonamido)pyrimidine or an equivalent aminopyrimidine compounds, more specifically, to offer a new way to get this connection more convenient way and/or without the use of toxic compounds and/or allows you to obtain this compound in high yield and/or high purity.

Another objective of this invention is to propose a new method for obtaining compounds of representing 2-(N-methyl-N-methanesulfonamido)pyrimidine, or an equivalent aminopyrimidines connection is advantageous to use in industrial production.

Summary of the invention

The present invention relates to a method for producing 2-(N-methyl-N-methanesulfonamido)pyrimidine, have his formula (3)

[R is a lower alkyl],

including the stage at which

hydroxypyrimidine compound having the formula (1)

where R is the same as above,

subjected to interaction with organic sulphonylchloride 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, a branched or unbranched lower alkyl, lower alkoxygroup,

X represents a halogen atom,

or with organic sulfonic anhydride having the formula (2A)

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

and the resulting reaction product is subjected to interaction with N-methyl-N-methanesulfonamido in the presence of a base.

Preferably the compound of formula (1) is subjected to interaction with the compound of the formula (2) and the resulting reaction product is subjected to interaction with N-methyl-N-methanesulfonamido.

Preferably use hydroxypyrimidine compound obtained by oxidation dihydropyrimidine compounds having the formula (4)

where R is the same as op is Adelino above.

Oxidation dihydropyrimidinase connection can be performed using nitric acid.

Preferably use dihydropyrimidinase compound obtained by reacting isobutyrylacetate ether having the formula (5)

where R is as defined above,

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

Proton connection can be a proton acid.

Preferably the proton acid is a sulfuric acid.

Preferably the metal salt is a chloride of copper(I).

This invention also relates to hydroxypyrimidinone connection with the above formula (1).

Preferably R in hydroxypyrimidinone the compound of formula (1) is a methyl.

This invention further relates to a method for hydroxypyrimidinone the compounds of formula (1), which oxidizes dihydropyrimidinase compound with the formula (4)

where R represents lower alkyl.

Oxidation dihydropyrimidinase connection can be performed using nitric acid.

Preferably use dihydropyrimidinase compound obtained by reacting isobutene the acetate ester, having the formula (5)

where R is as defined above,

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

Proton connection can be a proton acid.

Preferably the proton acid is a sulfuric acid.

Preferably the metal salt is a chloride of copper(I).

This invention further relates to dihydropyrimidinase connection with formula (4).

Preferably R in dihydropyrimidinase the compound of formula (4) represents methyl.

This invention further relates to a method for dihydropyrimidinase the compounds of formula (4), in which isobutyrylacetate ether having the formula (5)

where R represents lower alkyl,

subjected to interaction with 4-vorbesuregen and urea in the presence of proton compound and a metal salt.

Proton connection can be a proton acid. Preferably the proton acid is a sulfuric acid.

Preferably the metal salt is a chloride of copper(I).

This invention further relates to a method for aminopyrimidine compounds having the formula (8)

1and R2independently represents a hydrogen atom, alkyl group, alkylsulfonyl group or arylsulfonyl group, wherein the 2-substituted pyrimidine compound having the formula (6)

where R is as indicated above and X represents a halogen atom or R'-substituted sulfonyloxy, where R' is the same as above,

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

where each of R1and R2this, as stated above.

Preferably R1represents methyl and R2represents methanesulfonyl.

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

This invention further relates to halogenopyrimidines connection with formula (9)

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

Preferably R represents methyl, and Hal represents a chlorine atom.

This invention further relates to a method for halogenopyrimidines the compounds of formula (9), which interact hydroxypyrimidinone compounds of the above formula (1) with a halogenation Agay is volume.

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

This invention further relates to organic sulphodimethylpyrimidine connection with 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, a branched or unbranched lower alkyl, lower alkoxygroup.

Preferably in organic sulphodimethylpyrimidine connecting each of R and R' independently represents methyl.

This invention further relates to a method of obtaining organic sulphodimethylpyrimidine the compounds of formula (10), which interact hydroxypyrimidinone compounds of the above formula (1) with organic sulphonylchloride 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, a branched or unbranched lower alkyl, lower alkoxygroup, and X represents a halogen atom,

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

<>

where R' is the same as above,

in the presence of a base.

This invention further relates to a method for producing 2-(N-methyl-N-methanesulfonamido)pyrimidine above formula (3), and this method includes a stage on which

(I) isobutyrylacetate ether of the above formula (5) is subjected to interaction with 4-vorbesuregen and urea in the presence of proton compound and a metal salt;

(II) oxidizing the reaction product of stage (I);

(III) the oxidation product of stage (II) is subjected to interaction with organic sulphonylchloride above formula (2) or organic sulfonic anhydride of the above formula (2A) in the presence of a base and

(IV) the reaction product of stage (III) is subjected to interaction with N-methyl-N-methanesulfonamido in the presence of a base.

This invention also relates to a process for the preparation of rosuvastatin or its pharmaceutically acceptable salts, including the production of compounds of the above formula (3) above, or compounds of the above formula (8) described above and the subsequent conversion of the obtained compound in the rosuvastatin or its pharmaceutically acceptable salt.

Detailed description of the invention

A representative method of obtaining 2-(N-methyl-N-methanesulfonamido)pyrimi is in formula (3) according to the present invention schematically illustrated in the following way:

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

Stage (I)

At stage (I) isobutyrylacetate ether of the following formula (5):

[R is a lower alkyl]

subjected to interaction with 4-vorbesuregen and urea in the presence of proton compound and a metal salt.

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

Proton compound may be an inorganic acid or its salt such as hydrochloric acid, sulfuric acid, potassium bisulfate, sodium bisulfate, nitric acid or phosphoric acid; organic sulfonic acid, such as methanesulfonate acid, econsultancy acid, benzosulfonate acid, para-toluensulfonate acid or para-bromobenzosulfonyl acid; organic carboxylic acid, such as acetic acid, propionic acid, butyric acid or entina acid; alcohol, such as methanol, ethanol or propanol. Preferred such proton acid as hydrochloric acid, sulfuric acid, para-toluensulfonate acid and acetic acid. The most preferred sulfuric acid. Proton compounds can be used individually or in combination.

Proton compounds can be used in amounts of preferably from 0.01 to 3 mol, more preferably from 0.1 to 1 mol for one mol isobutyrylacetate ether.

Salt of the metal used in the reaction may be chloride, copper(I)chloride copper(II)acetate copper(II)chloride iron(II)chloride iron(III), aluminium chloride, bromide, Nickel(II)chloride tin(IV)tetrachloride titanium or magnesium bromide. Preferred chloride copper(I)chloride copper(II)chloride iron(III) and Nickel bromide(II). The preferred chloride copper(I). Metal salts may contain water of crystallization. Metal salts can be used individually or in combination.

The metal salt can be applied in the amount of preferably from 0.001 to 5 mol, more preferably from 0.01 to 0.1 mol, per one mol isobutyrylacetate ether.

4-Forbindelse can be applied in the amount of preferably from 0.5 to 10 mol, more preferably from 0.9 to 1.1 mol, per one mol isobutyrylacetate ether.

Urea can be applied in amounts of preferably from 0.5 to 10 mol,more preferably from 1.5 to 2 mol, one mol isobutyrylacetate ether.

The reaction can be carried out in the presence or in the absence of solvent. With respect to the applicable solvents particular there is no restriction, since the solvent does not violate the desired reaction. Examples of applicable solvents include alcohols, such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol and tert-butyl alcohol; ethers 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. The preferred methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, diisopropyl ether, tetrahydrofuran, dimethoxyethane, acetonitrile, butyronitrile, isobutyronitrile, dichloromethane, dichloroethane, chloroform, toluene, xylene and chlorobenzene. Especially preferred methanol, ethanol and isopropyl alcohol. The solvents can be used individually or in combination.

The solvent can be applied in the amount of preferably from 0.1 to 10 liters, more preferably from 0.3 to 2 liters, per one mol isobutyrylacetate ether. This number may vary depending on the homogeneity and dispersive ability of the pigment of the reaction mixture.

The reaction can be performed by reacting isobutyrylacetate ether, 4-forventelige and urea in a solvent in the presence of proton compound and metal salt in the atmosphere of inert gas. The reaction can be conducted at a temperature of preferably from -10 to 200°S, more preferably from 30 to 100°C. In relation to the ambient pressure specific no restrictions.

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

Stage (II)

At stage (II) dihydropyrimidine compound of the formula (4), i.e. the reaction product of stage (I), are oxidized with the formation of hydroxypyrimidinone the compounds of formula (1).

Oxidation (or dehydrogenase oxidation may be arranged in various conventional ways. Preferably the oxidation with nitric acid, because this procedure is easy to carry out oxidation, and subsequent treatment is denied the reaction product is simple.

Nitric acid can be used in amounts of preferably from 1 to 20 mol, more preferably from 3 to 15 mol, per one mol dihydropyrimidinase the compounds of formula (4). It is preferable to use nitric acid in a concentration of from 40 to 80%, more preferably from 50 to 70%.

The oxidation can be performed in the presence or in the absence of solvent. Special restrictions apply solvent is available, since this solvent does not violate the desired reaction. Examples of preferred solvents include carboxylic acids such as acetic acid, propionic acid and butyric acid. The solvents can be used individually or in combination.

The solvent can be applied in the amount of preferably 0.1 to 7 ml, more preferably from 0.5 to 3 ml, per 1 g dihydropyrimidinase connection. This number may vary depending on the homogeneity and dispersive ability of the pigment of the reaction mixture.

The oxidation can be accomplished by interaction dihydropyrimidine compounds and nitric acid in the solvent in an atmosphere of inert gas. The oxidation can be performed at a temperature of preferably from -10 to 100°S, more preferably from 0 to 50°C. there are No particular restrictions on the ambient pressure. To accelerate the oxide what s in the reaction system can include a reaction initiator, such as sodium nitrite.

The resulting reaction product, namely peroxidative compound of formula (1), can be extracted and cleaned in accordance with conventional procedures such as distillation, crystallization, recrystallization and column chromatography.

Stage (III) and (IV)

At the stages (III) and (IV) hydroxypyrimidine compound of formula (1), i.e. the reaction product of stage (II)is subjected to interaction with organic sulphonylchloride formula (2)

or organic sulfonic anhydride of formula (2A)

in the presence of a base and the resulting reaction product is subjected to interaction with N-methyl-N-methanesulfonamido in the presence of a base.

In formulas (2) and (2a) R' is a lower alkyl, possibly substituted by halogen atoms, phenyl, possibly substituted by 1-3 groups selected from nitro, halogen atoms, a branched or unbranched lower alkyl, lower alkoxygroup. 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, especially alkyl groups having 1-4 carbon atoms; fluorinated alkyl groups such as trifluoromethyl, nonattributed, tridecafluorohexyl is, heptadecafluorooctyl and uncategorical; 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 Deputy, provided that these substituents do not violate carry out the reaction. This group may take any isomeric configuration, such as normal, ISO, and tertiary. Especially suitable value R' represents a phenyl group which is unsubstituted or carries 1, 2 or 3 substituent. 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 sulphonylchloride include methanesulfonate, methansulfonate, acanaloniidae, 1-propanesulfonate, 2-propanesulfonate, triftormetilfullerenov, triftormetilfullerenov, nonatherosclerotic, tridecafluorohexyl, heptadecafluorooctane, uncategorizedanswereye, benzoylformate, para-toluensulfonate, para-toluensulfonate, 2,4,6-trimethylbenzenesulfonyl, 2,4,6-triisopropylbenzenesulfonyl, paramethoxymethamphetamine, para-chlorobenzotrichloride and 2-nitrobenzenesulfonamide. Preferred triftormetilfullerenov, benzoylformate, para-toluensulfonate, 2,4,6-trimethylbenzenesulfonyl, 2,4,6-triisopropylbenzenesulfonyl, para-methoxybenzenesulfonamide and para-chlorobenzotrichloride. Particularly preferred para-toluensulfonate, 2,4,6-trimethylbenzenesulfonyl, 2,4,6-triisopropylbenzenesulfonyl and para-methoxybenzenesulfonamide.

Examples of sulfonic anhydrides include methanesulfonyl anhydride, triftormetilfullerenov anhydride, benzosulfimide anhydride, para-toluensulfonyl anhydride. Preferred triftormetilfullerenov anhydride, benzosulfimide anhydride and steam-toluensulfonyl anhydride. Especially preferred triftormetilfullerenov anhydride and steam-toluensulfonyl anhydride.

Sulfonylated or sulfonovy anhydride can be used in quantities of preferably 0.1 to 20 mol, more preferably from 0.5 to 5 mol, most preferably from 1 to 2 mol, per one mol hydroxypyrimidinone connection.

At the next stage, N-methylmethanesulfonamide can be applied in the amount of preferably from 0.1 to 30 mol, more preferably from 1 to 5 mol, per one mol hydroxypyrimidinone connection.

Reaction studies is (III) and (IV) is preferably carried out in the presence of a base. Examples of bases include carbonates of alkali metals such as sodium carbonate and potassium carbonate; bicarbonates of alkali metals such as sodium bicarbonate; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkoxides of alkali metals such as sodium methoxide, tert-piperonyl sodium tert-piperonyl and potassium tert-pentoxide, sodium, and tertiary amines, such as triethylamine, triisopropanolamine, diisopropylethylamine and pyridine. The preferred sodium carbonate, potassium carbonate, tert-piperonyl potassium tert-pentoxide, sodium, triethylamine and pyridine. Particularly preferred carbonate, potassium tert-pentoxide, sodium and triethylamine. The most preferred carbonate and potassium tert-pentoxide sodium. The base can be used separately or in combination.

The base can be used in amounts of preferably from 0.1 to 30 mol, more preferably from 1 to 5 mol, per one mol hydroxypyrimidinone connection. All number bases can be included in the reaction system before the reaction, or the base can be added in the reaction system portions after start of the reaction.

The reaction can be carried out in the presence or in the absence of solvent. Special restrictions no solvent, as the solvent does not affect the reaction. Examples of what rastvoritelei include water; ketones, such as acetone, methyl ethyl ketone and diethylketone; ethers, such as diethyl ether and tetrahydrofuran, esters such as ethyl acetate, propyl and butyl acetate; NITRILES, such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide and N-organic; sulfoxidov, such as dimethyl sulfoxide; and urea such as N,N'-dimethylimidazolidin. Preferred acetone, tetrahydrofuran, ethyl acetate, butyl acetate, acetonitrile, N,N-dimethylformamide and dimethylsulfoxide. Particularly preferred ethyl acetate, butyl acetate and acetonitrile. The most preferred butyl acetate and acetonitrile. The solvents can be used individually or in combination.

The solvent can be applied in the amount of preferably from 0.01 to 100 liters, more preferably from 0.5 to 5 liters per one mol hydroxypyrimidinone connection. This number may vary depending on the homogeneity and dispersive ability of the pigment of the reaction mixture.

The reaction can be performed by reacting hydroxypyrimidinone compounds and organic sulphonylchloride or sulfonic anhydride in a solvent in the presence of a base under stirring in an atmosphere of inert gas. The base can be added by portions. The reaction can be conducted at a temperature of preferably from -30 to 250°With more FAV is preferably from 0 to 150° C. there are No particular restrictions on the ambient pressure.

The resulting reaction product, namely the compound of the formula (3), a 2-(N-methyl-N-metacarpalphalangeal)pyrimidine, can be extracted and cleaned in accordance with conventional procedures such as distillation, crystallization, recrystallization and column chromatography.

The compound of the formula (3), a 2-(N-methyl-N-methanesulfonamido)-pyrimidine, and other pyrimidine compounds of the formula (8) can be obtained from hydroxypyrimidinone the compounds of formula (1) through 2-substituted pyrimidine compound of the formula (6) in the following stages (V) and (VI):

In the formula (8) R has the meaning as defined above, and each of R1and R2independently represents a hydrogen atom, alkyl group, alkylsulfonyl group or arylsulfonyl group.

Stage (V)

At stage (V) hydroxypyrimidine compound of formula (1) is subjected to interaction with a halogenation agent such as gloriously agent, organic sulphonylchloride formula (2)

where R' is as above, and X represents a halogen atom,

or organic sulfonic anhydride of formula (2A)

where R' is the meet value, as specified above.

Examples of the halogenation agent include phosphorus oxychloride and thionyl chloride. Halogenation agents can be used individually or in combination.

Halogenation agent can be applied in quantities of preferably 0.1 to 50 mol, more preferably from 1 to 20 mol, most preferably from 1.5 to 10 mol, per one mol hydroxypyrimidinone connection.

Examples of organic sulphonylchloride and sulfonic anhydrides are the same as described here previously.

Organic sulfonylated or sulfonovy anhydride can be used in quantities of preferably 0.1 to 20 mol, more preferably from 0.5 to 5 mol, most preferably from 1 to 2 mol, per one mol hydroxypyrimidinone connection.

The reaction can be carried out in the presence or in the absence of solvent. Special restrictions no solvent, because the solvent does not disturb the reaction. Examples of the 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 halogenation agent); NITRILES, such as acetonic the sludge and propionitrile; esters of carboxylic acids, such as ethyl acetate, propyl, butyl acetate; ketones, such as acetone, methyl ethyl ketone, diethylketone, and ethers, such as diethyl ether and tetrahydrofuran. Preferred butylacetate, toluene, methylene chloride, acetonitrile, chlorobenzene, nitrobenzene and N,N-dimethylformamide. The solvents can be used individually or in combination.

In the reaction using a halogenation agent, the solvent can be applied in the amount of preferably from 0.01 to 10 liters, more preferably from 0.1 to 2 liters, per one mol hydroxypyrimidinone connection. The number may vary depending on the homogeneity and dispersive ability of the pigment of the reaction mixture.

In the reaction using sulphonylchloride or sulfonic anhydride solvent can be applied in the amount of preferably from 0.1 to 50 liters, more preferably from 0.5 to 2 liters, per one mol hydroxypyrimidinone connection. The number may vary depending on the homogeneity and dispersive ability of the pigment of the reaction mixture.

The reaction can be performed by reacting hydroxypyrimidinone connection and halogenation agent in the solvent with stirring in an atmosphere of inert gas. The reaction can be conducted at a temperature of preferably from 0 to 200°S, more preferably from 50 to 120° C. there are No particular restrictions on the ambient pressure.

The reaction can be performed by reacting hydroxypyrimidinone connection and sulphonylchloride or sulfonylurea anhydride in a solvent with stirring in an atmosphere of inert gas. The reaction can be conducted at a temperature of preferably from -30 to 200°S, more preferably from 0 to 50°C. there are No particular restrictions on the ambient pressure.

The resulting reaction product, namely 2-substituted pyrimidine compound, such as chloropyrimidine connection or sulphodimethylpyrimidine connection, can be extracted and cleaned in accordance with conventional procedures such as distillation, crystallization, recrystallization and column chromatography.

Stage (VI)

On stage (VI) 2-substituted pyrimidine compound, such as chloropyrimidine connection or sulphodimethylpyrimidine the compound obtained in stage (V), is subjected to the interaction with the amine compound with the formula (7)

where each of R1and R2this, as stated above.

Examples of groups R1and R2include a hydrogen atom, alkyl groups such as methyl, ethyl, propyl, butyl, pentyl and hexyl; alkylsulfonyl groups, such as methanal who were radioactive, and arylsulfonyl groups, such as benzoylphenyl and para-toluensulfonyl.

Amine compound can be applied in the amount of preferably from 0.1 to 30 mol, more preferably from 1 to 5 mol, per one mol of 2-substituted pyrimidine compounds.

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

The base can preferably be used in amounts of preferably from 0.1 to 30 mol, more preferably from 1 to 5 mol, per one mol of 2-substituted pyrimidine compounds.

The reaction can be carried out in the presence or in the absence of solvent. Special restrictions no solvent, because the solvent does not affect the reaction. Examples of the solvents include water; ketones, such as acetone, methyl ethyl ketone and diethylketone; ethers, such as diethyl ether and tetrahydrofuran, esters such as ethyl acetate, propyl and butyl acetate; NITRILES such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide and N-organic; sulfoxidov, such as dimethyl sulfoxide; and urea such as N,N'-dimethylimidazolidin. Preferred acetone, tetrahydrofuran, ethyl acetate, butyl acetate, acetonitrile, N,N-dimethylformamide and dimethylsulfoxide. Particularly preferred ethyl acetate, butylacetate acetonitrile. The solvent can be applied individually or in combination.

The solvent can be applied in the amount of preferably from 0.01 to 100 liters, more preferably from 0.5 to 5 liters on one mole of the 2-substituted pyrimidine compounds. This number may vary depending on the homogeneity and dispersive ability of the pigment of the reaction mixture.

The reaction can be performed by reacting 2-substituted pyrimidine compounds and amine compounds in a solvent in the presence of a base under stirring in an atmosphere of inert gas. The reaction can be conducted at a temperature of preferably -20 to 250°S, more preferably from 25 to 150°C. there are No particular restrictions on the ambient pressure.

The reaction can be carried out in two separate liquid phases in the presence of a catalyst phase transition. Examples of catalysts of the phase transition include chloride Tetramethylammonium, bromide of Tetramethylammonium, fluoride of tetraethylammonium, chloride of tetraethylammonium, bromide of tetraethylammonium, bromide of tetrapropylammonium, iodide of tetrapropylammonium, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, bromide of Tetramethylammonium, bromide of tetradecylammonium, bromide of tetragammaton, bromide of tetraoctylammonium, chloride benzyldimethyl is tetradecylammonium, chloride of benzyltriethylammonium, chloride of phenyltrimethylammonium, iodide of phenyltrimethylammonium and chloride of hexadecyltrimethylammonium. Preferred tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, chloride of benzyltriethylammonium and chloride of hexadecyltrimethylammonium. The most preferred tetrabutylammonium bromide, chloride of benzyltriethylammonium and chloride of hexadecyltrimethylammonium.

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

The resulting reaction product, namely the compound of the formula (3), a 2-(N-methyl-N-methanesulfonamido)pyrimidine, or other aminopyrimidine the compounds of formula (8), can be extracted and cleaned in accordance with conventional procedures such as distillation, crystallization, recrystallization or column chromatography.

The present invention further disclose the following non-limiting examples.

Example 1. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidine.

In a glass flask of 500 ml equipped with a stirrer, thermometer and reflux condenser, was placed 28.8 g (0.2 mol) of methylisobutylketone, 24.8 g (0.2 mol) of 4-forventelige, 21,0 g (0.35 mol) of urea, 200 mg (2 mmol) of the chloride is a single(I), 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 distilled and stirring for the reaction. The result was precipitated crystalline product. This crystalline product was collected on a filter paper and washed with methanol to obtain 49,7 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidine in the form of a colorless crystalline product having the following characteristics. The yield was 85% (based on the number of methylisobutylketone).

The melting point 223-225°C.

UVλmax(CH3CN, nm): for 194.3; to 278.6.

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

1H-NMR (DMSO-d6that δ (ppm)): 1.14 (6N, 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).

Msvr (mass spectrometry high resolution): 292, 1247 (theoretical value (C15H17FN2O3(M+)) 292, 1223).

Example 2. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-3, 4-2(1H)-dihydropyrimidine.

Repeating the procedure of Example 1 except that was replaced with 200 mg (2 mmol) of copper chloride(I) 5,41 g (20 mmol) of uranyl chloride iron(III). Received of 35.6 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidine. The yield was 61% (based on the number metrizable is irratate).

Example 3. Getting 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine.

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

The melting point of 193°C (decomposition).

UVλmax(CH3CN, nm): 196,6; 243,2; 317.9.

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

1H-NMR, DMSO-d 6that δ (ppm)): 1.23 (6N, 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 (C15H15FN2O3(M+)) 290,1067).

Example 4. Getting 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine.

In a glass flask with a volume of 50 ml equipped with a stirrer and thermometer, was placed of 2.92 g (10 mmol) of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidine obtained in the same manner as in Example 1, and 5 ml of acetic acid. To this mixture was slowly added 3,74 ml (50 mmol) of nitric acid (60-61%, beats. weight of 1.38). To this mixture was then added 0.07 g (1 mmol) of sodium nitrite and reaction was performed for one hour at room temperature. After completion of the reaction, the reaction mixture was neutralized by placing the mixture in 50 ml of a saturated aqueous solution of sodium bicarbonate. The reaction mixture was then extracted with ethyl acetate. Organic liquid portion was separated and concentrated under reduced pressure. The residue was led from toluene. The crystalline product was collected on a filter and washed with toluene to obtain 2,61 g of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine in the form of a colorless crystalline product. The yield was 90% (based on the amount of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidine)./p>

Example 5. Getting 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine.

In a glass flask with a volume of 200 ml equipped with a stirrer and thermometer, were placed 54,0 g (735 mmol) of nitric acid (60-61%, beats. weight of 1.38). To the nitric acid was slowly added at room temperature of 30.6 g (105 mmol) of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidine obtained in the same manner as in Example 1, and the mixture was subjected to reaction for 30 minutes at room temperature. After completion of the reaction, the reaction mixture was poured in 162 ml of water. The aqueous mixture was neutralized by the addition of 61 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 a 27.6 g of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine in the form of a colorless crystalline product.

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

Example 6. Getting 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine.

In a glass flask of 2 l equipped with a stirrer and thermometer, were placed 323,3 g (3,09 mol) of nitric acid (60-61%, a density of 1.38). Then concentrated nitric acid was cooled to 10°S. nitric acid was added at 2.36 g (a 34.2 mmol) sodium nitrite is sodium and then slowly added 100 g (342 mmol) of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidine, 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 the mixture was poured 970 ml of water. 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 to 93.3 g of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine in the form of a colorless crystalline product. The yield was 94% (based on the amount of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidine).

Example 7. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonamido)pyrimidine.

In a glass flask with a volume of 200 ml equipped with a stirrer, thermometer and reflux condenser, was placed of 5.81 g (20 mmol) of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine and 3.59 g (26 mmol) of potassium carbonate (available from Asahi Glass Works Co., Ltd., Lot No. 1111632; the distribution of particle sizes: 75-250 μm 14%; passing through 75 micron 86%) and 40 ml of butyl acetate. To this mixture was slowly added 4,19 g (22 mmol) of p-toluensulfonate with stirring and reaction was performed at 40°C for 4 hours. Then the reaction mixture was cooled to room temperature. To the cooled reaction mixture after the Lyali 2,84 g (26 mmol) of N-methylmethanesulfonamide and 4.15 g (30 mmol) of potassium carbonate (such as, as indicated above). The mixture was heated to 110-125°C for 2 hours under reflux to the reaction. After completion of the reaction the mixture was cooled to room temperature. To the cooled mixture was added 25 ml of water and 20 ml of acetone and separated organic liquid part. Organic liquid portion was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Dry organic liquid portion was filtered and concentrated under reduced pressure. The residue was led from heptane to obtain a return of 6.58 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonamido)pyrimidine as a pale yellow crystalline product. The yield was 86% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

Example 8. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonamido)pyrimidine.

In a glass flask with a volume of 1000 ml equipped with a stirrer, thermometer and reflux condenser, were placed 50.0 g (172 mmol) of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine, 20,8 g (189 mmol) of tert-pentoxide, sodium and 344 ml of acetonitrile and stirred the mixture at 0-10°C for 30 minutes. To this mixture was slowly added at 36.1 g (189 mmol) of para-toluensulfonate and carried out the reaction for 5 hours at to matnog temperature. Then the reaction mixture was cooled to a temperature of 0-10°C. To the cooled reaction mixture was added to 28.2 g (258 mmol) of N-methylmethanesulfonamide and 26.5 g (241 mmol) of tert-pentoxide sodium. The mixture was kept at 0-10°C for one hour and then heated to 75-82°C for 2 hours under reflux to 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°and was stirred for one hour, while the deposited crystalline product. The crystalline product was collected by filtration and dried to obtain of 45.3 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonamido)pyrimidine as a pale yellow crystalline product. The yield was 68% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

Example 9. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonamido)pyrimidine from methylisobutylketone, 4-forventelige and urea.

1) In the enamel of the reaction vessel with a volume of 200 liters, equipped with a stirrer, thermometer and reflux condenser, was placed 24,4 kg (169 mol) of methylisobutylketone, 20,0 kg (161 mol) of 4-forventelige, 16,9 kg (282 mol) of urea, 0.2 kg (2 mol) of copper chloride(I), 3.0 kg of sulfuric acid and 80.4 kg m is canola. The mixture was heated to 64-66°for 20 hours at reflux distilled 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 a filter paper and washed with methanol to obtain 43,4 kg of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidine in the form of a colorless crystalline product.

2) In the enamel of the reaction vessel with a volume of 200, equipped with a stirrer and thermometer, were placed at 62.5 kg (615,6 mol) diluted nitric acid and 0.5 kg (6.8 mol) of sodium nitrite. To this mixture was slowly added while cooling 20,0 kg (68,4 mmol) of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidine obtained as described above. The resulting mixture was subjected to reaction at low temperature (10°). After completion of the reaction, the reaction mixture was neutralized by adding a solution of sodium hydroxide in aqueous methanol. Then to this mixture was added an aqueous solution of sodium hydroxide. The resulting mixture was placed under reduced pressure for distillation of methanol. To the residue was added 96,5 kg of acetone and 96.5 kg of water. The aqueous residue is then neutralized by adding acetic acid to precipitate a crystalline product. The crystalline product was collected on filter paper and p is washed with a mixture of acetone and water to obtain 17,9 kg of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine.

3) In the enamel of the reaction vessel with a volume of 200 liters, equipped with a stirrer, thermometer and reflux condenser, was placed 17,9 kg (62,0 mol) of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine obtained as described above, to 107.7 kg butyl acetate, 11,1 kg (80,3 mol) of potassium carbonate (available from Asahi Glass Works Co., Ltd., Lot # 1111632, the distribution of particle sizes: 75-250 μm 14%; passing through 75 micron 86%) and 12.9 kg (+67.7 mol) of para-toluensulfonate. The mixture was heated at 60°C for 2 hours to conduct reaction. Then the reaction mixture was cooled to room temperature. To the cooled mixture was added to 8.8 kg (80,6 mol) of N-methylmethanesulfonamide and 12.9 kg (93,3 mol) of potassium carbonate and heated the mixture at 122-125°C for 3 hours to conduct reaction. After completion of the reaction, the reaction mixture was cooled to room temperature. To the cooled mixture was added acetone and water and the separated organic liquid part. Organic liquid part is then successively washed with aqueous sodium hydroxide solution (3 wt.%) and saturated aqueous sodium chloride. The washed organic liquid portion was concentrated under reduced pressure. To the residue was added isopropyl alcohol and water, resulting in precipitation of a crystalline product. The crystalline product was filtered on filter b is the magician and washed with isopropyl alcohol. The washed crystalline product and 85.7 kg of acetone were placed in enamel reaction vessel with a volume of 200 liters, equipped with a stirrer, thermometer and reflux condenser. The mixture was stirred at 50-55°for the dissolution of the crystalline product in acetone. The insoluble part was removed by the linear filter. Then to the solution was added 58,3 kg of water to precipitate a crystalline product. The crystalline product was collected on a filter paper and washed with a mixture of acetone and water to obtain 19,5 kg of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonamido)pyrimidine.

Example 10. Getting 2-chloro-4-(4-forfinal)-6-isopropyl-5-ethoxycarbonylpyrimidine.

In a glass flask of 25 ml volume equipped with a stirrer, thermometer and reflux condenser, was placed 1,00 g (3,43 mmol) of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine and 3.4 ml (3.7 mmol) of phosphorus oxychloride. The mixture was heated to 100-106°With over one and a half hours under reflux to the reaction. After completion of the reaction, the reaction mixture was cooled to room temperature and was poured into a mixture of water and ice. The resulting aqueous mixture was neutralized with saturated aqueous sodium bicarbonate solution. The neutralized aqueous mixture was extracted with ethyl acetate. An ethyl acetate portion was separated, washed with saturated aqueous who lorida sodium and dried over anhydrous magnesium sulfate. Dried an ethyl acetate portion was filtered and concentrated under reduced pressure obtaining of 1.03 g of 2-chloro-4-(4-forfinal)-6-isopropyl-5-ethoxycarbonylpyrimidine in the form of a colorless crystalline product having the following characteristics. The yield was 97% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

The melting point 99-101°C.

UVλmax(CH3CN, nm): 194,7; 276,5.

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

1H-NMR (DMSO-d6that δ (ppm)): 1.33 (6N, 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).

Msvr: 308,0695 (theoretical value (C15H14CIFN2O2(M+)) 308,0728).

Example 11. Getting 2-chloro-4-(4-forfinal)-6-isopropyl-5-ethoxycarbonylpyrimidine.

In a glass flask of 25 ml volume equipped with a stirrer, thermometer and reflux condenser, was placed 1,00 g (3,43 mmol) of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine, 0.5 ml (3.9 mmol) of thionyl chloride, 3,44 ml of toluene and 0.11 ml of N,N-dimethylformamide. The mixture was heated up to 80°C for 3 hours to conduct reaction. After completion of the reaction, the reaction mixture was cooled to room temperature and was poured into a mixture of water and ice. The resulting aqueous mixture was neutralized with saturated aqueous sodium bicarbonate solution. The neutralized aqueous mixture extragear the Vali with ethyl acetate. An ethyl acetate portion was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Dried an ethyl acetate portion was filtered and concentrated under reduced pressure to get to 0.80 g of 2-chloro-4-(4-forfinal)-6-isopropyl-5-ethoxycarbonylpyrimidine in the form of a colorless crystalline product. The yield was 76% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

Example 12. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonamido)pyrimidine.

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

Example 13. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonylaminoethyl.

In a glass flask with a volume of 100 ml were placed 10.0 g (to 34.4 mmol) of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine, with 5.22 g (58,5 mmol) of triethylamine and 34 ml of acetonitrile. The mixture in the flask was cooled to 0-5°C in an ice bath. To the cooled mixture was slowly added 5,12 g (of 44.7 mmol) methanesulfonanilide and subjected the resulting reaction mixture at 20-25°C for 2 hours. After completion of the reaction, to the reaction mixture were added 60 ml of water. The aqueous reaction mixture was extracted with toluene and the toluene portion was separated. 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 led from methanol to obtain 11.3 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonylaminoethyl in the form of a colorless crystalline product having the following characteristics. The yield was 89% (according to the number of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

The melting point 110-111°C.

UVλmax(CH3CN, nm): 193,7; 276,8.

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

1H-NMR (CDCI2that δ (ppm)): 1.33 (6N, 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).

Msvr: 368,0842 (theoretical value (C15H17FN2O5S (M+)) 368,0892).

Example 14. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(para-toluensulfonate)pyrimidine.

In a glass flask with a volume of 200 ml was placed 27,6 g (95.1 mmol) of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine, 12.5 g (123 mmol) of triethylamine and 95 ml of acetonitrile. The mixture in the flask was cooled to 0-5°C in an ice bath. To the cooled mixture was slowly added to 20.0 g (105 mmol) of para-toluensulfonate and subjected the resulting reaction mixture at 20-25°C for one hour. After completion of the reaction, to the reaction mixture was added 95 ml of water. The aqueous reaction mixture was extracted with toluene and the toluene portion was separated. Toluene portion was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The dried mixture was filtered and concentrated under reduced pressure. The residue was led from methanol to obtain 35,9 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(para-toluensulfonate)pyrimidine as a colorless crystalline product having the th following specifications. The yield was 85% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

The melting point of 94-96°C.

UVλmax(CH3CN, nm): 194,9; 275,2.

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

1H-NMR (CDCI3that δ (ppm)): 1.23 (6N, d, J=6.8 Hz), 2.45 (3H, s), 3.0-3.2 (1H, m), 3.74 J=8.5 Hz).

Msvr: 444,1155 (theoretical value (C32H21FN2O5S (M+)) 444,1194).

Example 15. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-benzoylpiperidine.

Repeating the procedure of Example 13 except that the substituted para-toluensulfonate 18.5 g (105 mmol) of benzoylperoxide.

Got to 39.3 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-benzoylpiperidine in the form of pale yellow crystalline product having the following characteristics. The yield was 96% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

1H-NMR (CDCI3that δ (ppm)): 1.21 (6N, 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. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(2,4,6-trimethylbenzenesulfonyl)pyrimidine.

Repeating the procedure of Example 13 except that the substituted para-toluensulfonate 23.0 g (105 mmol) of 2,4,6-trimethylbenzenesulfonamide.

Received 37,7 is 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(2,4,6-trimethylbenzenesulfonyl)pyrimidine as a pale yellow crystalline product, having the following specifications. The yield was 84% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

1H-NMR (CDCI3that δ (ppm)): 1.17 (6N, d, J=6.8 Hz), 2.34 (3H, s), 2.67 (6N, s), 3.0-3.1 (1H, m), 3.73 (3H, s), 7.00 (2H, s), 7.0-7.2 (2H, m), 7.4-7.5 (2H, m).

Example 17. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(2,4,6-triisopropylbenzenesulfonyl)pyrimidine.

Repeating the procedure of Example 13 except that the substituted para-toluensulfonate 31.8 g (105 mmol) of 2,4,6-triisopropylbenzenesulfonyl.

Got to 47.1 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(2,4,6-triisopropylbenzenesulfonyl)pyrimidine as a pale yellow crystalline product having the following characteristics. The yield was 89% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

1H-NMR (CDCl3that δ (ppm)): 1.12 (6N, d, J=6.6 Hz), 1.19 (M, d, J=6.8 Hz), 1.27 (6N, d, J=7.1 Hz), 2.8-2.95 (1H, m), 2.95-3.1 (1H, m), 3.73 (3H, s), 4.1-4.3 (2H, m), 7.0-7.1 (2H, m), 7.20 (2H, s), 7.4-7.5 (2H, m).

Example 18. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(para-methoxybenzenesulfonyl)pyrimidine.

Repeating the procedure of Example 13 except that the substituted para-toluensulfonate 21.7 g (105 mmol) of para-methoxybenzenesulfonamide.

Received and 39.9 g of 4-(4-forfinal)-6-isopropyl-5-methoxy shall arbonyl-2-(Lara-methoxybenzenesulfonyl)pyrimidine as a colorless crystalline product, having the following specifications. The yield was 91% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

1H-NMR (CDCI3that δ (ppm)): 1.25 (6N, d, J=6.8 Hz), 3.0-3.2 (1H, m), 3.74 (3H, s), 3.88 (3H, s), 6.99 (2H, dd, J=2.0, 9.0 Hz), 7.0-7.2 (2H, m), 7.5-7.7 (2H, m), 8.07 (2H, dd, J=2.2, 9.0 Hz).

Example 19. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(para-chlorobenzenesulfonate)pyrimidine.

Repeating the procedure of Example 13 except that the substituted para-toluensulfonate 22.2 g (105 mmol) of para-chlorobenzotrichloride.

Received and 39.9 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(para-chlorobenzenesulfonate)pyrimidine as a colorless crystalline product having the following characteristics. The yield was 89% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

1H-NMR (CDCI3that δ (ppm)): 1.23 (6N, 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. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(2-nitrobenzenesulfonyl)pyrimidine.

Repeating the procedure of Example 13 except that the substituted para-toluensulfonate 23.3 g (105 mmol) of 2-nitrobenzenesulfonamide.

Received of 28.0 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(2-nitrobenzenesulfonyl)pyrimidine in the form of pprozac the CSOs crystalline product, having the following specifications. The yield was 62% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

1H-NMR (CDCI3that δ (ppm)): 1.17 (6N, 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 (2H, m), 7.7-8.0 (3H, m), 8.33 (1H, dd, J=1.7, 8.1 Hz).

Example 21. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonamido)pyrimidine.

In a glass flask of 25 ml volume equipped with a stirrer, thermometer and reflux condenser, was placed 196 mg (1.8 mmol) of N-methylmethanesulfonamide, 198 mg (1.8 mmol) of tert-pentoxide, sodium, 7.5 ml of acetonitrile and 667 mg (1.5 mmol) of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(para-toluensulfonate)pyrimidine. The mixture was heated up to 81-82°With over one and a half hours under reflux to the reaction. After completion of the reaction, the reaction mixture was cooled to room temperature. To the cooled mixture were added 10 ml of water and was extracted with an aqueous mixture with ethyl acetate. An ethyl acetate portion was separated and dried over anhydrous magnesium sulfate. Dried an ethyl acetate portion was filtered and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (column Wako Gel C-200; eluent: hexane/ethyl acetate (volume shootonline 2:1)). Received 428 mg of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonyl the but)pyrimidine. The yield was 75% (based on the amount of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(p-toluensulfonate)pyrimidine).

Example 22. Obtaining 2-amino-4-(4-forfinal)-6-isopropyl-5-ethoxycarbonylpyrimidine.

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

6-isopropyl-5-ethoxycarbonylpyrimidine

Example 23. Getting 4-(4-forfinal)-6-isopropyl-5-ethoxycarbonyl-2-N-methylaminopropane.

In a glass flask with a volume of 50 ml equipped with a stirrer, thermometer and addition funnel, was placed 6,00 g (16.3 mmol) of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonylaminoethyl. In the flask was slowly added dropwise under ice cooling of 5.06 g (65,2 mmol) of aqueous 40% (wt.) solution of methylamine. The resulting mixture was stirred for one hour at the same temperature for the reaction. After completion of the reaction the mixture was added 16 ml of water. Then water the mixture was subjected to extraction with toluene. Toluene portion was separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Dried toluene portion was filtered and concentrated under reduced pressure to get to 4.81 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-N-methylaminopropane. The yield was 97% (based on the amount of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonylaminoethyl).

Example 24. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-triftormetilfullerenov.

In a glass flask of 300 ml equipped with a stirrer, thermometer and reflux condenser, was placed 8.7 g (30.0 mmol) of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine, 3.0 g (30.0 mmol) of triethylamine and 150 ml of toluene. The mixture in the flask was cooled to 0°on ice BA is E. To the cooled mixture was slowly added 8,46 g (30.0 mmol) triftormetilfullerenov anhydride and subjected the resulting reaction mixture for 3 hours at the same temperature. After completion of the reaction the mixture was added 90 ml of water. From the aqueous reaction mixture was separated organic liquid part. Organic liquid portion was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (column Wako Gel C-200; eluent: hexane/ethyl acetate (volume ratio 8:2)). Received 8,46 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-triftormetilfullerenov with the following characteristics, in the form of a colorless oil. The yield was 74% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

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

1H-NMR (CDCI3that δ (ppm)): 1.33 (6N, 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).

Msvr: 422,0585 (theoretical value (C16H14F4N2O5S (M+)) 422,0560).

Example 25. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-triftormetilfullerenov.

In a glass flask of 300 ml equipped with a stirrer, thermometer and reflux condenser, was placed 2.9 g (10.0 mmol) of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine, 1.7 g (16,8 mmol) Treaty the amine and 50 ml of toluene. The mixture in the flask was cooled to 0°With water bath. To the cooled mixture was slowly added 2.4 g (14.1 mmol) of triftormetilfullerenov and subjected the resulting reaction mixture for 3 hours at the same temperature. After completion of the reaction, to the reaction mixture were added 30 ml of water. From the aqueous reaction mixture was separated organic liquid part. Organic liquid portion was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (column Wako Gel C-200; eluent: hexane/ethyl acetate (volume ratio 8:2)). Got 2.8 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-triftormetilfullerenov with the following characteristics, in the form of a colorless oil. The yield was 66% (based on the amount of 4-(4-forfinal)-2-hydroxy-6-isopropyl-5-ethoxycarbonylpyrimidine).

Example 26. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonamido)pyrimidine.

In a glass flask with a volume of 50 ml equipped with a stirrer, thermometer and reflux condenser, were placed 3.0 g (7 mmol) of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-triftormetilfullerenov, 0,99 g (9.1 mmol) of N-methyl-N-methanesulfonamide, 1.45 g (10.5 mmol) of potassium carbonate (available from Wako Junyaku Co., Ltd., special grade) and 14 ml of butyl acetate. The mixture was heated to 122-125°C for 3 hours at deflag the purpose for the reaction. After completion of the reaction, the reaction mixture was cooled to room temperature. To the reaction mixture were added 10 ml of water and 7 ml of acetone and separated organic liquid part. Organic liquid portion was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (column Wako Gel C-200; eluent: hexane/ethyl acetate (volume ratio 5:1)). Was obtained 2.1 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonamido)pyrimidine in the form of a white crystalline product. The yield was 78% (based on the amount of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-triftormetilfullerenov).

Example 27. Getting 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonamido)pyrimidine.

In a glass flask with a volume of 50 ml equipped with a stirrer, thermometer and reflux condenser, were placed 1.1 g (2.5 mmol) of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(para-toluensulfonate)pyrimidine, 0.55 g (5.0 mmol) of N-methylmethanesulfonamide, 0,69 g (5.0 mmol) of potassium carbonate (available from Wako Junyaku Co., Ltd., special grade), 0.32 g (1.0 mmol) of tetrabutylammonium bromide, 20 ml of toluene and 5 ml of water. The mixture was heated to 85°C for 28 hours under reflux to the reaction. After completion of the reaction, the reaction see what camping was cooled to room temperature. To the reaction mixture were added 10 ml of water and 7 ml of acetone and separated organic liquid part. Organic liquid part was analyzed using high-performance liquid chromatography. Confirmed that they had received 0.6 g of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonamido)pyrimidine. The yield was 63% (based on the amount of 4-(4-forfinal)-6-isopropyl-5-methoxycarbonyl-2-(para-toluensulfonate)pyrimidine).

Industrial application

Pyrimidine compound, especially a compound that represents a 2-(N-methyl-N-methanesulfonamido)pyrimidine, which is obtained according to this invention, is useful as intermediate compounds for obtaining agent, lowering cholesterol (the agent representing hydroxymethylglutaryl-COA-reductase). The compound of the formula (3) can be transformed into a protease hydroxymethylglutaryl-COA reductase method disclosed in the publication of a European patent application No. 0521471, Bioorg. Med. Chem., 5, 437 (1997), and in the application for international patent # WO 0049014. Descriptions of these sources is included here by reference to demonstrate how compound of the formula (3) or formula (8) can be transformed into a protease hydroxymethylglutaryl-COA reductase, in particular rosuvastatin or its pharmaceutically acceptable salt, such as rosuvastatin calcium

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

where R represents lower alkyl,

including the stage at which

hydroxypyrimidine compound having the formula (1)

where R is the same as above,

subjected to interaction with organic sulphonylchloride 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, a branched or unbranched lower alkyl, lower alkoxygroup, and X represents a halogen atom, or with 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 subjected to interaction with N-methyl-N-methanesulfonamido in the presence of a base.

2. The method according to claim 1, wherein the compound of formula (1) is subjected to interaction with the compound of the formula (2) and the resulting reaction product is subjected to interaction with N-methyl-N-methanesulfonamido.

3. The method according to claim 1, in which the use hydroxypyrene the new connection, obtained by oxidation dihydropyrimidine compounds having the formula (4)

where R is as defined in claim 1.

4. The method according to claim 3, wherein dihydropyrimidinase connection oxidized with nitric acid.

5. The method according to claim 3, in which the use dihydropyrimidinase compound obtained by reacting isobutyrylacetate ether having the formula (5)

where R is as defined in claim 1,

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

6. The method according to claim 5, where the proton compound is a proton acid.

7. The method according to claim 6, where the proton acid is a sulfuric acid.

8. The method according to claim 5, where the metal salt is a chloride of copper(I).

9. Hydroxypyrimidine compound having the formula (1)

where R represents lower alkyl.

10. Hydroxypyrimidinone connection according to claim 9, where R represents methyl.

11. The method of obtaining hydroxypyrimidinone connection according to claim 9

at which oxidizes dihydropyrimidinase compound with the formula (4)

/p>

where R represents lower alkyl.

12. The method according to claim 11, wherein dihydropyrimidinase connection oxidized with nitric acid.

13. The method according to claim 11, in which the use dihydropyrimidinase compound obtained by reacting isobutyrylacetate ether having the formula (5)

where R is the same as defined in claim 10,

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

14. The method according to item 13, where the proton compound is a proton acid.

15. The method according to 14, where the proton acid is a sulfuric acid.

16. The method according to item 13, where the metal salt is a chloride of copper(I).

17. Dihydropyrimidinase compound with the formula (4)

where R is lower alkyl.

18. Dihydropyrimidinase connection 17, where R represents methyl.

19. The method of obtaining dihydropyrimidinase connection 17, which isobutyrylacetate ether having the formula (5)

where R is, as shown in 17,

subjected to interaction with 4-vorbesuregen and urea in the presence of proton compound and a metal salt.

20. The method according to claim 19,where the proton compound is a proton acid.

21. The method according to claim 20, where the proton acid is a sulfuric acid.

22. The method according to claim 19, where the metal salt is a chloride of copper(I).

23. The method of obtaining aminopyrimidine compounds having the formula (8)

where R represents lower alkyl and each of R1and R2independently represents a hydrogen atom, alkyl group, alkylsulfonyl group or arylsulfonyl group,

in which the 2-substituted pyrimidine compound having the formula (6)

where R is as indicated above and X represents a halogen atom or R'-substituted sulfonyloxy, where R' is the same as above,

subjected to interaction with aminosilane having the formula (7)

where each of R1and R2this, as stated above.

24. The method according to item 23, where R1represents methyl and R2represents methanesulfonyl.

25. The method according to item 23, where the interaction of 2-substituted pyrimidine compounds with aminoguanidinium carried out in the presence of a base.

26. Halogenopyrimidines compound with the formula (9)

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

27. Halogenopyrimidines connection p, where R represents methyl.

28. Halogenopyrimidines connection p, where Hal represents a chlorine atom.

29. The method of obtaining halogenopyrimidines connection p where hydroxypyrimidine compound having the formula (1)

where R represents lower alkyl,

subjected to interaction with a halogenation agent.

30. The method according to clause 29, where the halogenation agent is phosphorus oxychloride or thionyl chloride.

31. Organic sulphodimethylpyrimidine compound with the formula (10)

where R represents lower alkyl and R1- lower alkyl, possibly substituted by halogen atoms, phenyl, possibly substituted by 1-3 groups selected from nitro, halogen atoms, a branched or unbranched lower alkyl, lower alkoxygroup.

32. Organic sulphodimethylpyrimidine connection p, in which each of R and R' independently represents methyl.

33. Method for producing organic sulphodimethylpyrimidine connection p where hydroxypyrimidine compound having the formula (1)

where R represents lower alkyl,

subjected to interaction with organic sulphonylchloride 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, a branched or unbranched lower alkyl, lower alkoxygroup, and X represents a halogen atom, or an organic sulfonic anhydride having the formula (2A)

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

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

where R represents lower alkyl,

moreover, this method includes a stage on which

(I) isobutyrylacetate ether of the formula (5)

where R represents lower alkyl, are subjected to interaction with 4-vorbesuregen and urea in the presence of proton compound and a metal salt;

(II) oxidizing the reaction product of stage (I);

(III) the oxidation product of stage (II) is subjected to interaction with organic sulphonylchloride having the formula (2)

where R' represents the t of a lower alkyl, possibly substituted by halogen atoms, phenyl, possibly substituted by 1-3 groups selected from nitro, halogen atoms, a branched or unbranched lower alkyl, lower alkoxygroup, and X represents a halogen atom, or an organic sulfonic anhydride having the formula (2a)

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

and (IV) the reaction product of stage (III) is subjected to interaction with N-methyl-N-methanesulfonamido in the presence of a base.

35. The method according to any one of claims 1, 23 and 34, whereby the resulting compounds of formula (3) or (8)respectively can be used to obtain rosuvastatin.

Priority points and features:

19.02.2002 according to claims 1-8, in the case of compounds (2) to obtain compound (3);

13.07.2001 on p-22;

16.01.2002 on p-25;

09.10.2001 on PP and 30;

27.11.2001 on p-32 and 33, in the case of compounds (2) to obtain compound (10);

12.07.2002 according to claims 1 and 3-8, in the case of obtaining the compound (3) using the compound (2A), p, in the case of compounds (2A) to obtain compound (10)and p, 27, 29, 34, 35.



 

Same patents:

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): their pharmaceutically acceptable salts or solvates, or stereoisomers possessing properties of agonists of β2-adrenoreceptors, to pharmaceutical composition based on thereof, using the claimed compounds in manufacturing a medicinal agent, and to a method for modulation of β2-adrenergic receptors. In the formula (I) each among R1-R5 is chosen independently from group comprising hydrogen atom, (C1-C4)-alkyl and Ra wherein alkyl is substituted optionally with substituted chosen from Rb; or R4 and R5 are combined to form group of the formula: -NRdC(=O)C(Rd)=C(Rd)-; R6, R7 and R8 represent hydrogen atom; R9 represents (C1-C4)-alkyl; R10 represents hydrogen atom or (C1-C4)-alkyl; each among R11, R12 and R13 is chosen independently from group including hydrogen atom, (C1-C4)-alkyl, vinyl, cyclohexyl, phenyl, halogen atom, -CO2Rd, -ORd, -S(O)mRd, -N(NRdRe)Rd or -S(O)2NRdRe, 5-6-membered monocyclic heteroaryl comprising 1 or 2 heteroatoms chosen from nitrogen (N), sulfur (S) atoms, 9-membered bicyclic heteroaryl comprising N as a heteroatom and 5-membered heterocycle comprising N as a heteroatom; or R11 and R12 in common with atoms to which they are bound form 6- or 7-membered heterocyclic ring comprising oxygen (O) atom as a heteroatom and wherein for R11-R13 each phenyl or heteroaryl is substituted optionally with 1 or 2 substitutes chosen independently from Rc, and each heterocyclyl is substituted optionally with 1 or 2 substitutes chosen from Rb and Rc; alkyl is substituted optionally with substitute chosen from Rb, and vinyl is substituted optionally with substitute chosen from Rm; w = 0, 1, 2, 3 or 4. Values Ra, Rb, Rc, Rd, Rm and m are given in the invention claim.

EFFECT: improved method for modulation, valuable medicinal properties of compounds and pharmaceutical composition.

22 cl, 225 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing inhibitory effect on activity of dipeptidyl peptidase IV (DPP IV) that can be used, for example, in treatment of diabetes mellitus type 2. In compounds of the formula (I) X means nitrogen atom (N) or -C-R5; R1 and R2 mean independently hydrogen atom, (C1-C6)-alkyl; R3 means saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, or perfluoro-(C1-C6)-alkyl; R4 means (lower)-alkyl, (lower)-alkoxy-, (lower)-alkylthio-group, saturated or aromatic 7-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-, amino-group or perfluoro-(C1-C6)-alkyl, 4-fluorophenyloxy-(C1-C6)-alkyl or (C3-C6)-cycloalkyl; R5 means hydrogen atom or (C1-C6)-alkyl. Also, invention relates to methods for synthesis of compounds of the formula (I), pharmaceutical compositions and their using for preparing medicaments used in treatment and/or prophylaxis of DPP IV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

21 cl, 93 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method that can be used in industry for synthesis of substituted aniline compound represented by the following general formula (6):

wherein in the general formula (6) each R1, R2 and R3 means independently alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group, alkylcarboxamide group, nitro-group, aryl group, arylalkyl group, aryloxy-group, halogen atom or hydrogen atom; each X and Y means independently hydrogen atom, alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group or halogen atom. Method involves oxidation of substituted indole compound represented by the following general formula (3):

(wherein values R1, R2, R, X and Y are given above) resulting to opening indole ring to yield acetanilide compound represented by the following general formula (4):

(wherein values R1, R2, R3, X and Y are given above) and Ac means acetyl group, and treatment of this compound by reduction and deacetylation. Also, invention relates to novel intermediate compounds. Proposed compound (6) can be used as intermediate substance for production of chemicals for agriculture and as medicinal agents.

EFFECT: improved method of synthesis.

20 cl, 1 sch, 3 tbl, 31 ex

FIELD: organic chemistry, chemical technology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I with PGl2 receptor agonist activity. In formula R1 and R2 represent independently optionally substituted phenyl; Y represents N, N-O or CR5; Z represents N or CR6; A represents NR7; D represents alkylene or alkenylene; or A and D may together form divalent group; E represents phenylene or direct bond, or D and E may together form divalent group; G represents O, S, SO, SO2; R3 and R4 represent hydrogen atom or alkyl; Q represents carboxyl, alkoxycarboxyl, tetrazolyl, carbamoyl or -CONH-SO-R10 group. Prostaglandin I2(PGl2) is potent inhibitor of platelet aggregation and may be effectively used in treatment of vascular diseases, arteriosclerosis, hypertension, etc.

EFFECT: new compounds and drugs for platelet aggregation inhibition and treatment of vascular and other diseases.

15 cl, 3 tbl, 109 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to R-2-aminoarylpropionic acid amides and pharmaceutical composition comprising thereof that can be used for prophylaxis and inhibition of recruiting and activation of leukocytes, and in treatment of pathologies directly dependent on indicated activation. Invention proposes compound of the general formula (1): wherein A, q, Ph and R have corresponding values, or its pharmaceutically acceptable salt. Also, invention describes a method for preparing amide of the formula (1) and pharmaceutical composition used in prophylaxis of leukocytes activation. Invention provides the development of pharmaceutical composition that can be used for prophylaxis and treatment of damaged tissues caused by enhancing activation of neutrophile granulocytes (polymorphonuclear leukocytes) in inflammation foci. Also, the invention relates to R-enantiomers 2-(aminoaryl)-propionylamides of the formula (1) that can be used for suppression of neutrophyles hemotaxis caused by IL-8. Also, compounds of this invention can be sued in treatment of psoriasis, ulcerous colitis, glomerulonephritis, acute respiratory insufficiency and rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds.

8 cl, 16 ex

FIELD: organic chemistry, biochemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(me-thylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dih-ydroxyhept-6-enoic acid crystalline salts wherein salt represents ammonium, methyl ammonium, ethyl ammonium, diethanol ammonium, tris-(hydroxymethyl)methyl ammonium, benzyl ammonium, 4-methoxybenzyl ammonium, lithium or magnesium salt possessing property of HMG CoA-reductase inhibitor. Also, invention relates to a pharmaceutical composition comprising crystalline salt in mixture with a pharmaceutically acceptable diluting agent or vehicle an to a method for preparing crystalline salt. Method involves addition of corresponding amine or a base to a solution of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(me-thylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-dihydro-xyhept-6-enoic acid in acetonitrile or ethyl acetate medium. The advantage of crystalline salts involves the possibility for enhancing purity and homogenicity of compounds, the possibility for re-crystallization and preparing the pure amorphous form and enhancing stability of the form.

EFFECT: improved preparing method.

15 cl, 9 dwg, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases and so on

The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases and so on

The invention relates to new derivatives of 2-(O-[pyrimidine-4-yl]metalinox)phenylacetic acid, their salts and N-oxides of the General formula I, means for combating harmful fungi and pests, the method of production thereof and method of combating harmful fungi and pests with the use of compounds of General formula I

The invention relates to new derivatives of pyrimidinediamine General formula I and fungicides for agriculture or horticulture on the basis of their

The invention relates to new derivatives of aryl - and heteroarylboronic General formula I, where R1denotes a substituted phenyl or pyridyl, R2denotes a substituted phenyl, R3denotes hydrogen, (lower)alkyl, cyano, carboxy, esterified carboxylate, phenyl, 1H-tetrazolyl or the group,- CONR5R6, R5denotes hydrogen or the radical R7, R6represents -(CH2)mR7or R5and R6together with the nitrogen atom to which they are attached, denote morpholino, 2,6-dimethylmorpholine, piperidino, 4-(lower)alkylpiperazine, 4-(lower)alkoxyimino, 4-(lower)alkoxycarbonylmethyl or 4 formylpiperazine,7denotes phenyl, substituted phenyl, pyridyl, 1H-tetrazolyl, (lower)alkyl, cyano(lower)alkyl, hydroxy(lower)alkyl, di(lower)alkylamino(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl or phenyl(lower)alkoxycarbonyl, Radenotes hydrogen or hydroxy, Rbrepresents hydrogen, Z represents hydroxy or the group-OR8or-OC(O)NR8, R8denotes pyridyl or pyrimidinyl, X represents nitrogen or CH, m is 0, 1 or 2, n is 0, 1 or 2, and

The invention relates to new pyrimidine derivative that exhibit pesticidal activity, in particular fungicidal and insect-acaricidal activity

The invention relates to some 2,6-disubstituted pyridinium and 2,4-disubstituted the pyrimidines, the way they are received, to herbicide compositions on their basis and to a method of combating the growth of unwanted vegetation

The invention relates to new derivatives of acrylic acid, exhibiting fungicidal activity mainly in relation to fungal infections of plants, processes for their preparation, fungicidal compositions and method of combating fungi

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a new complex compound of 6-methyluracil with succinic acid of the formula:

. This complex can be used in medicine as the preparation able to enhance viability under conditions and effects of extreme factors of environment - hypoxia. New complex compound of 6-methyluracil with succinic acid is prepared by mixing succinic acid with 6-methyluracil in organic solvent medium followed by heating the reaction mixture up to 60-80°C, cooling and filtration of precipitated crystals of the end product. The yield is 80%.

EFFECT: improved preparing method, valuable medicinal properties of complex compound.

2 cl, 1 tbl, 4 ex

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