WO2008151510A1 - Preparation of 4-(fluorophenyl)-6-isopropyl-2-(n-methyl-n-methylsulfonylamino)- 5-formyl-pyrimidine - Google Patents

Abstract

Preparation of 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl-pyrimidine,which is the intermediate of Rosuvatatin, involves reacting an isobutyry acetonitrile of formula (CH3)2CH-C(=O)-CH2-CN with 4-fluorobenzaldehyde and urea, followed by oxidation, substitution, and reduction, then the pyrimidine aldehyde intermediate of Rosuvatatin is synthesized.

Description

 Process for the preparation of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde

 The invention relates to a method for preparing a pharmaceutical compound, in particular to an intermediate of the hypolipidemic drug rosuvastatin calcium, 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonyl). A method for preparing aminopyrimidine-5-formaldehyde. Background technique

 Rosuvastatin calcium is a clinically used hypolipidemic drug with the chemical name (+) - (3R, 5S) -7-[4-(4-fluorophenyl)-6-isopropyl-2 - (N-Methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid calcium (2:1), the chemical structural formula is as follows -

美国专利 US5260440公开了瑞舒伐他汀及其合成方法。 该方法包括如下步 骤： （1 )、 (3 R) -3- (叔丁基二甲基硅氧基） -5-氧代 -6-三苯基膦亚甲基己酸甲酯 与 4一 （4一氟苯基） 一 6—异丙基一 2— （N—甲基一N—甲磺酰氨基） 嘧啶一 5 一甲醛（简称取代嘧啶 -5-甲醛）缩合； （2)、 脱去 3-羟基上的保护基得羟基酮酸 酯； （3 )、 还原 5-羰基得到手性的 3 , 5-二羟基庚烯酸酯； （4)、 水解 3， 5-二羟 基庚稀酸酯并转化为钙盐。

U.S. Patent No. 5,260,440 discloses rosuvastatin and methods for its synthesis. The method comprises the following steps: (1), (3 R) -3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphine methylene hexanoate and 4 (4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde (referred to as substituted pyrimidine-5-formaldehyde) condensation; (2), off The protecting group on the 3-hydroxy group is a hydroxy keto ester; (3) reducing the 5-carbonyl group to give a chiral 3,5-dihydroxyheptenoate; (4) hydrolyzing 3, 5-dihydroxyglycidyl The acid ester is converted to a calcium salt.

Intermediate 4 -(4-fluorophenyl)-6-isopropyl- 2_(N-methyl-N-A) The preparation of sulfonylaminopyrimidine-5-formaldehyde is difficult, the reaction step is long, the yield is low, and the raw material is highly toxic.

 The preparation is as follows:

由上式可知该方法存在下列缺陷：

It can be seen from the above formula that the method has the following drawbacks:

 (1) The synthetic route is long and requires 8 steps of reaction;

 (2) The reaction raw material DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) is highly toxic, and the raw materials are 4-methylmorphine-N-oxide and TPAP (peric acid tetra Propyl ammonium) and diisobutyl aluminum hydride are expensive;

 (3) Reducing reaction requires - 74 ° C low temperature, high energy consumption and large equipment investment, which is not conducive to industrial production;

(4) The total reaction yield is low. Summary of the invention

 The technical problem to be solved by the present invention is to overcome the above-mentioned deficiencies, and to provide a preparation of 4-(4-fluorophenyl)-6-isopropyl- 2_(N-A) which is low in cost, simple in reaction, and suitable for industrial production. A method of thio-N-methylsulfonylamino)pyrimidine-5-formaldehyde.

 The present invention provides a method of rosuvastatin intermediate 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde.

4-(4-fluorophenyl)-6-isopropyl-2-(-N-methyl-N-methylsulfonylamino)pyrimidine-5 The structural formula of a formaldehyde is:

本发明的方法如下列反应式所示:

The method of the present invention is as shown in the following reaction formula:

本发明的方法具体包括如下步骤：

The method of the present invention specifically includes the following steps:

 (1), isobutyrylacetonitrile and 4-fluorobenzaldehyde and urea are reacted in the presence of a protic compound and a metal salt to form a dihydropyrimidinone compound of formula 2;

 (2) oxidizing a dihydropyrimidinone compound of formula 2 to form a hydroxypyrimidine compound having formula 3;

(3) The hydroxypyrimidine compound of the formula 3 is reacted with an organic sulfonyl halide or an organic sulfonic acid anhydride, and the resulting reaction product is reacted with N-methylmethanesulfonamide to form 2-(N-methyl-N of the formula 4). -methanesulfonylamino)pyrimidine compound; (4) The 2-(N-methyl-N-methylsulfonylamino)pyrimidine compound of the formula 4 is reacted with a reducing agent to form 4-(4-fluorophenyl)-6-isopropyl-I having the formula 1. 2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde.

 Another object of the present invention is to provide a dihydropyrimidinone compound of the formula 2 having a melting point of from 174 ° C to 178 ° C. This compound is obtained by reacting isobutyrylacetonitrile with 4-fluorobenzaldehyde and urea in the presence of a protic compound and a metal salt.

 A further object of the present invention is to provide a hydroxypyrimidine compound of the formula 3 having a melting point of 199. rc (decomposed). This compound is obtained by oxidizing a dihydropyrimidinone compound of the formula 2.

 Still another object of the present invention is to provide a 2-(N-methyl-N-methylsulfonylamino)pyrimidine compound of the formula 4 which has a melting point of from 208 °C to 212 °C. This compound is obtained by reacting a hydroxypyrimidine compound of the formula 3 with an organic sulfonyl halide or an organic sulfonic acid anhydride, and reacting the resulting reaction product with N-methylmethanesulfonamide.

 Each of the steps is described in detail below in accordance with the synthesis method of the present invention.

 step 1 ):

 Isobutyrylacetonitrile is reacted with 4-fluorobenzaldehyde in the presence of a protic compound and a metal salt.

 The protic compound may be an inorganic acid or a salt thereof, such as sulfuric acid, hydrochloric acid, boric acid, phosphoric acid, nitric acid or sodium hydrogen sulfate; an organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid or substituted benzenesulfonic acid; and the like; Acetic acid, propionic acid or benzoic acid; etc.; alcohol, such as methanol, ethanol or butanol. Preferred are protic acids such as sulfuric acid, hydrochloric acid, boric acid, methanesulfonic acid and acetic acid. More preferred is sulfuric acid. Protic compounds can be used singly or in combination.

 The proton compound is preferably used in an amount of from 0.01 to 1 mole, more preferably from 0.1 to 1 mole, per mole of the isobutyryl acetonitrile.

 The metal salt used in the reaction may be cuprous chloride (I:), copper chloride (11), copper acetate (11), ferrous chloride (π), ferric chloride (m), aluminum chloride, Nickel bromide (ιι), tin chloride (ιν), titanium tetrachloride or magnesium bromide. Preferred are cuprous chloride (I), copper chloride (11), iron (III) chloride and nickel bromide (11). Most preferred is cuprous chloride (I), and the metal salt may contain water of crystallization, which may be used singly or in combination.

 1摩尔的量使用。 The amount of the use of the amount of 0. 001 - 5 moles, more preferably 0. 01-0.

5-1摩尔。 0. 5-1 moles, more preferably 0. 9-1. The amount of Moore is used.

 The urea may be preferably used in an amount of from 0.5 to 10 moles, more preferably from 1.5 to 3 moles, per mole of the isobutyrylacetonitrile.

 The reaction can be carried out in the presence or absence of a solvent, and solvents which can be used include alcohols such as methyl alcohol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol and tert-butanol; Ethers such as diethyl ether, isopropyl ether, tetrahydrofuran and dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane , chloroform and carbon tetrachloride; aromatics such as benzene, toluene and xylene; halogenated aromatic hydrocarbons such as chlorobenzene; and nitrated aromatic hydrocarbons such as nitrobenzene. Preferred are methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, diisopropyl ether, tetrahydrofuran, dimethoxyethane, acetonitrile, butyronitrile, isobutyronitrile, dichloromethane, dichloro Ethane, chloroform, toluene, xylene and chlorobenzene. Especially preferred is methanol, ethanol or isopropanol. The solvent can be used singly or in combination.

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

 The reaction can be carried out by reacting isobutyrylacetonitrile, 4-fluorobenzaldehyde and urea in a solvent in the presence of a protic compound and a metal salt in an inert gas atmosphere. The reaction can be preferably carried out at a temperature of from -10 Torr to 200 ° C, more preferably from 30 ° C to 100 ° C. There are no specific restrictions on environmental stress.

 The product formed by the reaction, i.e., the dihydropyrimidinone compound of the formula 2, can be isolated and purified according to a conventional method such as distillation, crystallization, recrystallization, and column chromatography.

 Step (2)

 In the step (2), the dihydropyrimidinone compound of the formula 2, i.e., the reaction product of the step (1), is oxidized to give a hydroxypyrimidine compound of the formula 3.

 The oxidation (or dehydrogenation) can be carried out by various conventional methods, and it is preferred to use an oxidation process of nitric acid because the oxidation process is easy to proceed and the post-treatment of the reaction product is easy.

 The nitric acid may be preferably used in an amount of 1 to 20 moles, more preferably .3 to 15 moles per 1 mole of the dihydropyrimidinone compound of the formula 2. Preferably, a concentration of from 40 to 80%, more preferably from 50 to 70%, of nitric acid can be used.

 The oxidation can be carried out in the presence or absence of a solvent, and there is no particular limitation with respect to the solvent to be used. Preferably, the solvent includes a carboxylic acid such as acetic acid, propionic acid and butyric acid. The solvent can be used singly or in combination.

The amount of the solvent is preferably used in an amount of from 0.1 to 7 liters, more preferably from 0.5 to 3 liters per gram of the dihydrodipyridone compound. The amount can vary depending on the uniformity and dispersibility of the reaction mixture. Oxidation can be carried out by allowing the dihydropyrimidinone compound and nitric acid to be carried out in a solvent or not in an inert gas atmosphere. The oxidation may preferably be carried out at a temperature of -10 ° C to 10 (TC, more preferably - 5 ° C - 5 (TC). There is no particular limitation on the ambient pressure. A reaction initiator such as sodium nitrite may be added to the reaction system. Accelerate the oxidation rate.

 The product formed by the reaction, i.e., the hydroxypyrimidine compound of the formula 3, can be isolated and purified according to a conventional method such as distillation, crystallization, recrystallization, and column chromatography.

 Step (3)

In step (3), Equation 3

The hydroxypyrimidine compound, that is, the reaction product of the step (2) is reacted with an organic sulfonyl halide having the formula 5:

 R, S02X

 Equation 5

 Wherein R' is a hydrocarbon group and X is a halogen atom,

 Or react with an organic sulfonic anhydride having the formula 5a:

(R, S02 ) ₂ 0

 Equation 5a

 Where R' is the same as above,

 After the reaction product of the step (2) is reacted with an organic sulfonyl halide having the formula 5, the resulting product is further reacted with N-methyl-N-methanesulfonamide.

In Formulae 5 and 5a, R' is a hydrocarbon group which may have one or more substituents. Examples of the hydrocarbon group include an alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a decyl group, a heptyl group, an octyl group, a decyl group and a fluorenyl group, and more specifically a group having 1 to 6 carbon atoms. An alkyl group, especially a fluorenyl group having 1 to 4 carbon atoms; a fluoroalkyl group such as a trifluoromethyl group, a nonafluorobutyl group, a decafluorohexyl group, a heptadecafluorooctyl group, and a hexafluoroaryl group; a cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group; and an aryl group such as a benzyl group, a phenylethyl group and a phenylpropyl group; and an aryl group including an unsubstituted and substituted phenyl group Or naphthyl, such as phenyl, naphthyl, tolyl, dimethyl Phenyl, trimethylphenyl, triisopropylphenyl, methoxyphenyl, chlorophenyl and nitrophenyl. Thus, a hydrocarbyl group may carry one or more substituents provided that the substituent does not interfere with the reaction involved, and the hydrocarbyl group may be in any isomeric configuration, such as n-, iso-, and t-. Particularly suitable meanings when R' is aryl include, for example, phenyl or naphthyl (especially phenyl) which is unsubstituted or carries 1, 2 or 3 substituents. The substituents may be independently selected, for example, a fluorenyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen, and a nitro group.

 In Formula 5, X is a halogen atom such as fluorine, chlorine, bromine and iodine.

 Examples of the sulfonyl halide include methanesulfonyl chloride, ethanesulfonyl chloride, 1-propylsulfonyl chloride, 2-propanesulfonyl chloride, trifluoromethylsulfonyl fluoride, trifluoromethylsulfonyl chloride, nonafluorobutylsulfonyl fluoride, and ten. Trifluorohexylsulfonyl fluoride, heptafluorooctylsulfonyl fluoride, diundosylfluorosulfonyl fluoride, benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p-toluenesulfonyl fluoride, Tosyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-chlorobenzenesulfonyl chloride and 2-nitrobenzene Sulfonyl chloride. Preferred are trifluoromethylsulfonyl fluoride, benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p-toluenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2, 4, 6 - Triisopropylbenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride and p-chlorobenzenesulfonyl chloride. Particularly preferred are p-toluenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride and p-methoxybenzenesulfonyl chloride.

 Examples of the sulfonic acid anhydride include methanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride, and p-toluenesulfonic anhydride. Preferred are trifluoromethanesulfonic anhydride, benzenesulfonic anhydride and p-toluenesulfonic anhydride.

 The sulfonyl halide or sulfonic acid anhydride may be preferably used in an amount of from 0.1 to 20 moles, more preferably from 0.5 to 5 moles, and most preferably from 1 to 2 moles per 1 mole of the hydroxy compound. .

 In the subsequent step, N-methylmethanesulfonamide may be preferably used in an amount of from 0.1 to 30 mol, more preferably from 1 to 5 mol, per 1 mol of the hydroxypyrimidine compound. The reaction of the step (3) is preferably 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 hydrogencarbonates such as sodium hydrogencarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alcohols Salts such as sodium methoxide, sodium t-butoxide, potassium t-butoxide and sodium t-pentoxide; and tertiary amines such as triethylamine, triisopropylamine, diisopropylethylamine and pyridine. Preference is given to sodium carbonate, potassium carbonate, potassium t-butoxide, potassium t-amylate, triethylamine and pyridine. Potassium carbonate, sodium t-butoxide and triethylamine are especially preferred. Most preferred are potassium carbonate and sodium t-butoxide. The bases can be used singly or in combination.

The base may preferably be 0.1 to 30 moles, more preferably 1 to 5 moles per 1 mole of the hydroxypyrimidine compound. The amount is used. The entire amount of the base may be added to the reaction system before the start of the reaction or the base may be added to the reaction system in portions after the start of the reaction.

 The reaction can be carried out in the presence or absence of a solvent, and there is no particular limitation with respect to the solvent to be used, as long as the solvent does not disturb the reaction. Examples of the solvent include water; ketones such as acetone, methyl ethyl ketone and diethyl ketone; ethers such as diethyl ether and tetrahydrofuran; esters such as ethyl acetate, ethyl propionate, and butyl acetate; nitriles such as acetonitrile and propionitrile; For example, N, N-dimethylformamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; ureas such as N,N-dimethylimidazolidinone. Preferred are acetone, tetrahydrofuran, ethyl acetate, butyl acetate, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide. Particularly preferred are ethyl acetate, butyl acetate and acetonitrile. Most preferred are butyl acetate and acetonitrile. The solvent can be used singly or in combination.

 The solvent is preferably used in an amount of from 0.01 to 100 liters, more preferably from 0.5 to 5 liters per 1 mole of the hydroxypyrimidine compound. The amount can vary depending on the uniformity and dispersibility of the reaction mixture.

 The reaction can be carried out by reacting a hydroxypyrimidine compound and an organic sulfonyl halide or a sulfonic acid anhydride in a solvent in an inert gas atmosphere under stirring in the presence of a base. The reaction can be preferably carried out at a temperature of from - 30 ° C to 250 ° C, more preferably from 0 ° C to 15 ° C. There is no particular limitation on the environmental pressure.

 The product formed by the reaction, i.e., the 2-(N-methyl-N-methylsulfonylamino)pyrimidine compound of the formula (4), can be isolated and purified according to a conventional method such as distillation, crystallization, recrystallization, and column chromatography.

 In the step (3), the hydroxypyrimidine compound of the formula 3 and a halogenating agent such as a chlorinating agent, an organic sulfonyl halide of the formula 5:

 R' S02X

 Equation 5

 Wherein R' is the same as defined above, X is a halogen atom, or a compound of formula (3) is reacted with an organic sulfonic anhydride of formula 5a:

(R, S02 ) ₂ 0

 Equation 5a

 Where R' has the same definition as above.

 Examples of the halogenating agent include phosphorus oxychloride and sulfuryl chloride. The halogenating agents can be used singly or in combination.

 The halogenating agent may preferably be used in an amount of from 0.1 to 50 moles, more preferably from 1 to 20 moles, and most preferably from 1. 5 to 10 moles per 1 mole of the hydroxypyrimidine compound.

Examples of the organic sulfonyl halide and the sulfonic acid anhydride are those described above. The organosulfonyl halide and the sulfonic acid anhydride are preferably used in an amount of from 0.1 to 20 moles, more preferably from 0.5 to 5 moles, and most preferably from 1 to 2 moles per 1 mole of the hydroxypyrimidine compound.

 The reaction can be carried out in the presence or absence of a solvent, and the solvent to be used is not particularly limited, and examples of the solvent include aromatic hydrocarbons such as toluene; halogenated aromatic hydrocarbons such as chlorobenzene; nitrated hydrocarbons such as nitrobenzene; Aliphatic hydrocarbons such as dichloromethane and 1,2-dichloroacetamidine; amides such as N,N-dimethylformamide; water (not suitable for chlorinating agents); nitriles such as acetonitrile and propionitrile; Carboxylic esters such as ethyl acetate, ethyl propionate and butyl acetate; ketones such as acetone, methyl ethyl ketone and diethyl ketone; and ethers such as diethyl ether and tetrahydrofuran. Preference is given to butyl acetate, toluene, dichloromethane, acetonitrile, chlorobenzene, nitrobenzene and N-dimethylformamide. The solvent can be used singly or in combination.

 The solvent may be preferably used in an amount of from 0.01 to 10 liters per 1 mole of the hydroxypyrimidine compound, more preferably in an amount of from 0.1 to 1 liter, for the reaction using a halogenating agent. The amount can vary depending on the homogeneity and dispersibility of the reaction mixture.

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

 The reaction can be carried out by reacting a hydroxypyrimidine compound and a halogenating agent in a solvent with or without stirring in an inert gas atmosphere. The reaction can be preferably carried out at a temperature of from 0 ° C to 200 ° C, more preferably from 50 ° C to 150 ° C. There are no specific restrictions on environmental stress.

 The reaction can be carried out by reacting a hydroxypyrimidine compound and a sulfonyl halide or a sulfonic acid anhydride in a solvent with or without stirring in an inert gas atmosphere. The reaction can be preferably carried out at a temperature of from - 30 ° C to 20 (TC, more preferably from 0 to 80 Torr. There is no particular limitation on the environmental pressure.

 The product formed by the reaction, i.e., a 2-substituted pyrimidine compound such as a chloropyrimidine compound or a sulfonyloxypyrimidine compound, can be isolated and purified according to a conventional method such as distillation, crystallization, recrystallization, and column chromatography.

The 2-substituted pyrimidine compound prepared in the step (3), such as a chloropyrimidine compound or a sulfonyloxypyrimidine compound, is reacted with an amine compound having the formula 6:

 Equation 6

 among them! ^ and ^ have the same definitions as above.

Group! Examples of ^ and R ₂ include a hydrogen atom, a fluorenyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group. And a fluorenyl group; a mercaptosulfonyl group such as a methylsulfonyl group; and an arylsulfonyl group such as a benzenesulfonyl group and a p-toluenesulfonyl group.

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

 The reaction is preferably carried out in the presence of a base, and examples of the base are those described above.

 The base may be preferably used in an amount of from 0.1 to 30 moles, more preferably from 1 to 5 moles per 1 mole of the 2-substituted hydroxypyrimidine compound.

 The reaction can be carried out in the presence or absence of a solvent, and the solvent to be used is not particularly limited, and examples of the solvent include water; ketones such as acetone, methyl ethyl ketone and diethyl ketone; ethers such as diethyl ether and tetrahydrofuran; Ethyl acetate, ethyl propionate and butyl acetate; nitriles such as acetonitrile and propionitrile; amides such as N, N-dimethylformamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide Sulfone; urea, such as N, N'-dimethylimidazolidinone. Preference is given to acetone, tetrahydrofuran, ethyl acetate, butyl acetate, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide. Particularly preferred are ethyl acetate, butyl acetate and acetonitrile. Most preferred are butyl acetate and acetonitrile. The solvent can be used singly or in combination.

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

 The reaction can be carried out by allowing the 2-substituted pyrimidine compound and the amine compound to be carried out in a solvent in the presence of a base with or without stirring in an inert gas atmosphere. The reaction can be preferably carried out at a temperature of from -20 ° C to 25 (TC, more preferably from 25 ° C to 150 ° C. There is no particular limitation on the environmental pressure.

 In step (3), the reaction is carried out in the presence or absence of a phase transfer catalyst, and the reaction in the presence of a phase transfer catalyst can be carried out in two branched liquid phases. Examples of the phase transfer catalyst include tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium bromide, tetrapropylamine. Ammonium iodide, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapentylammonium bromide, tetrahexylammonium bromide, tetraheptyl Ammonium bromide, tetraoctyl ammonium bromide, benzyl dimethyltetradecyl ammonium chloride, phenyl trimethyl ammonium chloride, phenyl trimethyl ammonium iodide, cetyl trimethyl chloride Ammonium. Preferred are tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltriethylammonium chloride, and hexadecanyltriethylphosphonium hinge. Most preferred are tetrabutylammonium bromide, benzyltriethylammonium chloride, and hexadecanyltrimethylammonium chloride.

0摩尔优选优选。 Each mole of 2-substituted pyrimidine compound, phase transfer catalyst may be 0. 01- 0. 5 moles, preferably 0. 05-0. The amount of 2 moles used.

 The product formed by the reaction, that is, 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine of the formula 4 can be obtained according to a conventional method, for example Separation and purification are carried out by distillation, crystallization, recrystallization and column chromatography.

 In the step (4), 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine of the formula 4, ie, the step The reaction product of (3) is reacted with a reducing agent to obtain 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde having the formula 1. .

 The reducing agent may be diisobutylaluminum hydride, red aluminum, lithium tetrahydrogenate or the like. If diisobutylaluminum hydride is used, 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine (Formula 4) The 5%~65% diisobutylaluminum hydride toluene solution was added dropwise in an organic solvent under an inert gas atmosphere, and the reaction was continued for several hours after the completion of the dropwise addition. After the completion of the reaction, the substituted pyrimidine-5-formaldehyde was obtained by separation and purification. The reaction temperature is - 20 ° C to 150 ° C, preferably - 10 ° C to 50 ° C.

 The organic solvent may be benzene, toluene, xylene, dichloromethane, chloroform, tetrahydrofuran, dioxane or other solvent which does not react with a reducing agent and a reaction raw material.

 The molar ratio of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine to diisobutylaluminum hydride is 1.0 0: 0-10. 0, Preferably 1. 0: 0. 8-4. 0.

 The method of the invention does not need to use highly toxic, expensive raw materials, has low process cost, simple reaction, high product yield, and is suitable for industrial production.

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

detailed description:

 [Example 1] Preparation method of 4-(4-fluorophenyl)-6 isopropyl 5-cyano-3,4-2(1H)-dihydropyrimidinone (Formula 2)

5g (0. 47mol ) 4 - fluorobenzaldehyde, 49. 4g (0. 0g (0. 47mol) of isobutyryl acetonitrile, 58.3g (0. 47mol) of 4-fluorobenzaldehyde, 49. 4g (0. 82 mol) urea, 0.53 g (5.3 mmol) of chlorinated ketone (I), 5. 3 ml of sulfuric acid and 600 ml of methanol. The reaction flask were refluxed under stirring and heating 22 hours, cooled to room temperature, solid generated was filtered, the filter cake was washed with methanol, the filtrate and washings were combined, concentrated under reduced pressure, to give 101. l _g 4- (4 -Fluorophenyl)-6-isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone has a solid product of the following characteristics. Yield of 83% (based on isobutyryl acetonitrile) The amount).

 m. p.: 174°C-178°C

 Belly (CH3CN, nra): 270

 Ή-NMR (CDC13, δ (ppm)): 1.17-1.25 (6Η, d, J=6.8Hz), 3.0-3.2 (1H, m), 5.15 (lH,m), 5.6 (lH,m) , 7.0 -7.3 (2H, m), 7.2-7.4 (2H, m), 8.0 (1H, m).

 [Example 2] 4-(4-Fluorophenyl)-6-isopropyl-5-cyano-3,4-2 (1H)-dihydropyrimidinone (Formula 2) Preparation Method

 In the same manner as in Example 1, except that the amount of methanol was changed from 600 ml to 200 ml to obtain 103.5 g of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3, 4-2 (1H)- The dihydropyrimidinone has the solid product of the characteristics of Example 1. The yield was 85% (based on the amount of isobutyrylacetonitrile).

 [Example 3] 4-(4-Fluorophenyl)-6-isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone (Formula 2)

 In the same manner as in Example 1, except that the amount of urea was changed from 49.4 g (0.82 raol) to 56.63 g (0.94 mol) to obtain 106.3 g of 4-(4-fluorophenyl)-6-isopropyl-5-cyano group. - 3, 4-2 (1H)-Dihydropyrimidinone has the solid product of the characteristics of Example 1. The yield was 87.2% (based on the amount of isobutyrylacetonitrile).

 [Example 4] 4-(4-Fluorophenyl)-6-isopropyl-5-cyano- 3,4-2 (1H)-dihydropyrimidinone (Formula 2)

 In the same manner as in Example 1, except that 14.33 g (53 mmol) of iron(III) chloride and hexahydrate were used instead of 530 mg (5.3 of 1) of chlorinated ketone (I), 79.2 g of 4-(4-fluorophenyl) was obtained. -6-Isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone has the solid product of the characteristics of Example 1. The yield was 65% (based on the amount of isobutyrylacetonitrile).

 [Example 5] Preparation method of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-cyanopyrimidine (Formula 3)

Into a 250 ml glass flask equipped with a stirrer and a thermometer, 120 ml (1.57 mol) of nitric acid (60-61%, sp. gr.: 1.38) was added. 33 g (0.127 mol) of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3, 4-2 (in the same manner as in Example 1) was slowly added to nitric acid below 10 Torr. 1H)-Dihydropyrimidinone, the mixture was reacted at room temperature for 50 minutes. After the reaction is completed, the mixture is neutralized by adding 1500 ml of a saturated aqueous solution of sodium hydrogencarbonate to give a white solid, which is filtered, washed with water and dried. Dry. 29.26 g of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-cyanopyrimidine as a white solid product. The yield was 89% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone).

 m. p. : 199. 1 ° C (decomposition)

 Υν λ丽 (CH3CN, nm): 244. 8, 317. 6

 [8] </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> Draw ol) nitric acid (60-61%, sp. gr.: 1. 38). 6克(118腿ol) 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3, 4-, prepared by the same method as in Example 1 was slowly added to the nitric acid at room temperature. 2 (1H)-dihydropyrimidinone, the mixture was reacted at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into 162 ml of water, and the aqueous mixture was neutralized by adding 78. lg of an aqueous sodium hydroxide solution (45 wt%), and the aqueous mixture was crystallized by precipitation. The crystalline product was collected by filtration and dried to give 28.3 g of 4-(4- fluorophenyl) - 2 - s yl -6 - isopropyl - 5-cyanopyrimidine as white crystals. The yield was 93% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone).

 6克 (1) In a 1 L glass flask equipped with a stirrer and a thermometer, 161.6 g (1) . 54mol ) Nitric acid (60 - 61%, sp. gr.: 1. 38). The concentrated nitric acid was cooled to 10 ° C, and 1. 2 g ( 17. 4 Torr 1 ) of sodium nitrite was added to the nitric acid, followed by the slow addition of 44.3 g ( 171 mmol ) of the 4 - (4) prepared in the same manner as in Example 1. -fluorophenyl)-6-isopropyl-5-cyano-3, 4 2 (1H)-dihydropyrimidinone. The mixture was reacted at a temperature of from 10 ° C to 15 ° C for 2 hours. After the completion of the reaction, 500 ml of water was poured into the reaction mixture, and the aqueous mixture was precipitated by adding 137 g of an aqueous aqueous sodium hydroxide solution (45 wt%) to precipitate crystals. The crystalline product was collected by filtration and dried to give 40. 6 g of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-cyanopyrimidine as a colorless crystal. The yield was 92% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone).

 [Example 8] 4-(4-Fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine (Formula 4)

In a 500 ml glass flask equipped with a stirrer, a thermometer and a reflux condenser, 28 _g (108 mmol) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-cyanopyrimidine, 17 _g (123 mmol) were added. Powdered potassium carbonate and 16.0 ml of butyl acetate. 22 g (115 mm ₀ l) of p-toluenesulfonyl chloride was slowly added to the mixture with stirring. The reaction was carried out at 50 ° C for 3 hours. The reaction mixture was then cooled to room temperature and 12. lg (10 mmol) of N-methylmethanesulfonamide and 18 g (130 mmol) of potassium carbonate were added to the cooled reaction mixture. The mixture was heated to 110 ° C - 125 ° C for 2 hours under reflux to carry out the reaction. After the reaction was completed, the mixture was cooled to room temperature. To the cooled mixture was added 100 ml of water, and the organic liquid fraction was separated. The organic liquid portion was washed with a saturated aqueous The residue was crystallized from acetone to give 32.6 g of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine. Light yellow crystalline product. The yield was 86% (based on the amount of 4-(4-fluorophenyl)-2-isoyl-6-isopropyl-5-cyanopyrimidine).

 m. p.: 208°C-212°C

 UVXmax (CH3CN, nm): 252.8

lH-NMR (CDC13, δ (ppm)) _: 1.37-1.40 (6H, d), 3.5-3.6 (3H, m), 3.6-3.7 (3H, m), 3.6-3.7 (1H, ra), 7.2- 7.3 (2H, m), 8.0-8.2 (2H, m).

 [Example 9] Preparation method of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine

 In a 500 ml glass flask equipped with a stirrer, a thermometer and a reflux condenser, 22.2 g (86 mraol) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-cyanopyrimidine, 10.4 g ( 94.5 mmol) sodium t-pentoxide and 165 ml acetonitrile, and the resulting mixture was stirred at 0 ° C - 10 ° C for 30 minutes. To the mixture was slowly added 18.0 g (94.5 mmol) of p-toluenesulfonyl chloride, and the reaction was carried out at room temperature for 5 hours. Subsequently, it was cooled to a temperature of 0 - 10 ° C, and 14. lg (129 leg ol) of N-methylmethanesulfonamide and 13.25 g (120.5 mmol) of sodium t-pentoxide were added to the cooled reaction mixture. The mixture was kept at 0 ° C 1 (TC 1 hour, followed by heating at 75 ° C - 82 ° C for 3 hours under reflux to carry out the reaction. After the reaction was completed, the mixture was cooled to room temperature. To the cooled mixture was added 180 ml of water. The aqueous mixture was cooled to O'C - 10 ° C and stirred for 1 hour to precipitate a crystalline product. The crystallized product was collected by filtration and dried to give 18.9 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxy. a light yellow crystalline product of carbonyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine. Yield 63% (based on 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl- The number of 5-cyanopyrimidines).

 [Example 10] Preparation method of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine (Formula 4)

In a 500 ml glass flask equipped with a stirrer, a thermometer and a reflux condenser, 28 g (108 mmol) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-cyanopyrimidine, 17 g (123 slept) were added. Ol) powdered potassium carbonate and 120 ml of acetonitrile. 22 g (115 mmol) of p-toluenesulfonyl chloride was slowly added to the mixture under stirring, and the reaction was carried out at 50 ° C for 3 hours. The reaction mixture was then cooled to room temperature, and 12. lg (l l Offlmol) of N-methylmethanesulfonamide and 18 g (130 ramol) of potassium carbonate were added to the cooled reaction mixture. The mixture was refluxed for 3 hours while heating. After the reaction was completed, the mixture was cooled to room temperature. To the cooled mixture was added 100 ml of water and 300 ml of ethyl acetate, and the organic liquid fraction was separated. The organic liquid portion was washed with a saturated aqueous The residue was crystallized from acetone to give 31.8 g of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine. Light yellow crystalline product. The yield was 83.9% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-cyanopyrimidine).

 [Example 11] Preparation method of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde (Formula 1)

 Add 2. 00g to a 250ml glass flask equipped with a stirrer, thermometer and reflux condenser

(5. 73 mmol) 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine and 20 ml of chloroform, slowly stirring Add 9 ml (10. 5ramol) of 20% diisobutylaluminum hydride in toluene solution, react at 5 ° 〇 -10 ° for 6 hours, add 2 1 ^ ethanol ₅ and then add 201 ^ ice water. The organic layer was separated, and the aqueous layer was extracted twice with chloroform. The organic layer was combined, washed with water to neutral, and concentrated to give a pale yellow solid, 1.61 g, yield 80%, mp: 175 ° C - 177 ° C.

 [Example 12] 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde (Formula 1)

 Add 8. 00g to a 1000ml glass flask equipped with a stirrer, thermometer and reflux condenser

(22.92 mmol) 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine and 60 ml of chloroform, slowly stirred 40 ml (46. 7 mmol) of 20% diisobutylaluminum hydride in toluene was added, and the reaction was carried out at 5 ° C to 10 ° C for 5 hours, 8 ml of ethanol was added, and 100 ml of ice water was added thereto. The organic layer was separated, and the aqueous layer was extracted twice with chloroform. The organic layer was combined, washed with water to neutral, and concentrated to give a pale yellow solid 7.1 g, yield 87%, mp: 175 ° C - 177 ° C.

 [Example 13] 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde (Formula 1)

 Add 2. 00g to a 250ral glass flask equipped with a stirrer, thermometer and reflux condenser

(5. 73 mmol) 4-(4-Fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino) Pyrimidine and 40 ml of toluene were slowly added with 8 ml of 40% red aluminum toluene solution under stirring, and reacted at 25 ° C to 30 ° C for 5 hours, 2 ml of ethanol was added, and 20 ml of ice water was added thereto. The organic layer was separated, and the aqueous layer was extracted twice with toluene. The organic layer was combined, washed with water to neutral, and concentrated to give a pale yellow solid 1.59 g, yield 79%, mp: I75 ° C - 177 ° C.

Claims

Rights request A method for preparing 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde, characterized in that the method comprises The following steps:

(1) isobutyrylacetonitrile is reacted with 4-fluorobenzaldehyde and urea in the presence of a protic compound and a metal salt to form a dihydropyrimidinone compound of formula 2;  (2) oxidizing a dihydropyrimidinone compound of formula 2 to form a hydroxypyrimidine compound having formula 3; (3) The hydroxypyrimidine compound of the formula 3 is reacted with an organic sulfonyl halide or an organic sulfonic acid anhydride, and the resulting reaction product halogenated or sulfonyloxypyrimidine compound is reacted with N-methylmethanesulfonamide to form 2 of the formula 4 -(N-methyl-N-methylsulfonylamino)pyrimidine compound;  (4) The 2-(N-methyl-N-methylsulfonylamino)pyrimidine compound of the formula 4 is reacted with a reducing agent to form 4-(4-fluorophenyl)-6-isopropyl- 2 having the formula 1. — (N-methyl-N-methylsulfonylamino)pyrimidine compound. 2. A method for preparing 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde according to claim 1 , characterized by protonation of step (1) The compound is an inorganic acid or a salt thereof: sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid or sulfuric acid. sodium hydrogen; or organic sulfonic acid: methanesulfonic acid. acid, benzenesulfonic acid or substituted benzenesulfonic acid; organic carboxylic acid: acetic acid, propionic acid or Benzoic acid; or alcohol: methanol, ethanol or butanol; preferred protic acid is sulfuric acid, hydrochloric acid, methanesulfonic acid or acetic acid, · 3⁄4 is preferred sulfuric acid; protic compounds can be used alone or in combination; isobutyrylacetonitrile and proton compounds The ratio is 1:0. 01-3 mol, preferably 0.11 mol; the metal salt used in the reaction is cuprous chloride (I), copper (II) chloride, copper (II) acetate, chlorination Ferrous (11), iron (111) chloride, aluminum chloride, nickel (11) bromide, tin (IV) chloride, titanium tetrachloride or magnesium bromide; preferably cuprous chloride (I:), Copper chloride (11), iron (III) chloride or nickel (II) bromide; most preferred is cuprous chloride (I); metal salt may contain water of crystallization, metal salt may be used alone or in combination; isobutyrylacetonitrile The ratio of the amount to the metal salt is 1: 0. 001 - 5 moles, preferably 1: 0. 01-0. 1 mole; the ratio of isobutyryl acetonitrile to 4-fluorobenzaldehyde is 1: 0. 5 10摩尔, preferably 1: 0. 9-1. 5 mole; isobutyrylacetonitrile and urea in an amount ratio of 1: 0. 5- 10 moles, preferably 1: 1.5-3 moles; reaction in a solvent In or without solvent, the solvent used is alcohol: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol or tert-butanol; ether: ether, isopropyl ether, tetrahydrofuran Or dimethoxyacetamidine; nitrile: acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbon: chloroform, dichloroethane, chloroform or carbon tetrachloride; aromatic solvent: benzene Methyl, ethanol, n-propanol, isopropyl alcohol , isobutyronitrile, dichloromethane, dichloroacetic acid, chloroform, toluene, xylene or chlorobenzene; more preferably methanol, ethanol or isopropyl alcohol; solvents may be used singly or in combination; per mole of isobutyryl acetonitrile , the amount of solvent used is 0. 1-10 liters, preferably 0.3 to 2 liters; the reaction is carried out with or without inert gas; Temperature is - 10 ° C-20 (TC, preferably 30 ° C- 100 ° C. 3. A method for preparing 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde according to claim 1 , characterized in that in the oxidation of step (2), the ratio of the dihydropyrimidinone compound of formula 2 to nitric acid is 1: 1-20 moles, preferably 1: 3-15 moles; the concentration of nitric acid is 40-80%, preferably 50-70%; the oxidation may be carried out in a solvent or without a solvent, preferably the solvent is a carboxylic acid: acetic acid, propionic acid or butyric acid, and the solvent may be used singly or in combination; the amount of solvent used per lg of dihydropyrimidinone compound is 0. 1-7升, preferably 0. 5-3 liters; oxidation can be carried out in or without an inert gas, the oxidation temperature is -10 ° C - 100 ° C, preferably - 5 ° C - 50 ° C _; Or do not add the initiator sodium nitrite. 4. A 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-) group according to claim 1. Process for the preparation of N-methanesulfonylamino)pyrimidine-5-formaldehyde, characterized by the step (3) of the organosulfonyl halide R'S02X of the formula 5, wherein X is a halogen atom: fluorine, chlorine, bromine or iodine; In 5 or 5a sulfonium sulfonate, R, is a hydrocarbon group or a hydrocarbon group having one or more substituents: the substituent is an alkyl group: methyl, ethyl, propyl, butyl, pentyl, decyl, heptyl Or an octyl, fluorenyl or fluorenyl group, preferably a fluorenyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms; a fluoroalkyl group: a trifluoromethyl group, a nonafluorobutyl group, Decafluorohexyl, heptafluorooctyl; cyclodecyl: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; unsubstituted or substituted phenyl, benzyl or naphthyl: phenyl, benzyl Base, naphthyl, tolyl, xylyl, trimethylphenyl, triisopropylphenyl, phenylethyl, phenylpropyl, methoxyphenyl, chlorophenyl or nitrophenyl.  The method for preparing 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde according to claim 1 , characterized in that the organic sulfonyl halide of the formula (3) is methanesulfonyl chloride, ethanesulfonyl chloride, 1-propanesulfonyl chloride, 2-propanesulfonyl chloride, trifluoromethylsulfonyl fluoride, trifluoromethylsulfonyl chloride , nonafluorobutylsulfonyl fluoride, tridecafluorohexylsulfonyl fluoride, heptadecafluorooctylsulfonyl fluoride, diundecfluorodecylsulfonyl fluoride, benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalene Sulfonyl chloride, p-toluenesulfonyl fluoride, p-toluenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2,4,6 triisopropylbenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-chloro Phenylsulfonyl chloride or 2-nitrobenzenesulfonyl chloride; preferably trifluoromethylsulfonyl fluoride, benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p-toluenesulfonyl chloride, 2, 4, 6-trimethyl Phenylsulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride or p-chlorobenzenesulfonyl chloride; more preferably p-toluenesulfonyl chloride, 2,4,6-trimethylbenzene Sulfonyl chloride 2, 4, 6-triisopropylbenzenesulfonyl chloride or p-methoxybenzenesulfonyl chloride; the sulfonic anhydride of formula 2a is methanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride or p-toluenesulfonic anhydride; preferably trifluoro The amount of the hydroxy sulfonic acid compound, the benzene sulfonic acid anhydride or the p-toluene sulfonic acid anhydride; the hydroxypyrimidine compound and the sulfonyl halide or the sulfonic acid anhydride is 1:0 to 20 moles, preferably 1:0.5 to 5 moles, more preferably 1 : 1-2 mole; reaction temperature is - 30 ° C - 200 ° C, preferably 0 ° C - 80 ° C. 6. A method for preparing 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde according to claim 1 , characterized in that the reaction of the step (3) is carried out in the presence or absence of a solvent which is water; or a ketone: acetone, methyl ethyl ketone or diethyl ketone; or an ether: diethyl ether or tetrahydrofuran; or an ester: ethyl acetate, c Acid B or butyl acetate; or nitrile: acetonitrile or propionitrile; or amide: N, N-dimethylformamide or N-methylpyrrolidone; or dimethyl sulfoxide; or N, N-dimethyl An imidazolidinone; preferably acetone, tetrahydrofuran, ethyl acetate, butyl acetate, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide; particularly preferably ethyl acetate, butyl acetate or acetonitrile; most preferred Butyl acetate or The acetonitrile; the solvent may be used alone or in combination; each 1 mole of the hydroxypyrimidine compound, the solvent is used in an amount of from 0.01 to 100 liters, preferably in an amount of from 0.5 to 5 liters; the reaction may be carried out by reacting a hydroxypyrimidine compound with an organic sulfonyl halide or The sulfonic acid anhydride is carried out in a solvent in the presence or absence of a base, or in an inert gas atmosphere; the reaction temperature is - 30 ° C - 200 ° C, preferably 0 ° C - 80 ° C c 7. A method of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde according to claim 1, It is characterized by the amine compound of the formula 6 in the step (3), wherein R and R ₂ are a hydrogen atom; an alkyl group: a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group or a hexyl group; : a methylsulfonyl group; an arylsulfonyl group: a benzenesulfonyl group or a p-toluenesulfonyl group; the ratio of the amine compound of the formula 6 to the hydroxypyrimidine compound is 1: 0.10 mole, preferably 1:1-5 mole; The base is an alkali metal carbonate: sodium carbonate or potassium carbonate; alkali metal hydrogencarbonate: sodium hydrogencarbonate; alkali metal hydroxide: lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alkoxide: methanol Sodium, sodium t-butoxide, potassium t-butoxide or sodium t-pentoxide; tertiary amine: triethylamine, triisopropylamine, diisopropylamine or pyridine; preferably sodium carbonate, potassium carbonate, potassium t-butoxide, Potassium tert-amylate, triethylamine or pyridine; potassium carbonate, sodium t-amylate or triethylamine is especially preferred; potassium carbonate or tert-amyl alcohol is most preferred Sodium; the base may be used singly or in combination, and the base is preferably used in an amount of from 0.1 to 30 mol, more preferably from 1 to 5 mol, per 1 mol of the hydroxypyrimidine compound; the entire amount of the base is added to the reaction system or in the reaction before the start of the reaction. After the start, it is added to the reaction system in portions; the reaction is carried out in the presence or absence of a solvent, which is water; ketone: acetone, methyl ethyl ketone or diethyl ketone; ether: diethyl ether or tetrahydrofuran; ester: ethyl acetate, propionic acid Ester or butyl acetate; nitrile: acetonitrile or propionitrile; amide: N, N-dimethylformamide or N-methylpyrrolidone; sulfoxide: dimethyl sulfoxide or urea: N, N' - two Methyl imidazolidinone; preferably acetone, tetrahydrofuran, ethyl acetate, butyl acetate, acetonitrile, N, N-dimethylformamide or dimethyl sulfoxide; more preferably ethyl acetate, butyl acetate or acetonitrile; The butyl acetate or the acetonitrile is preferably used alone or in combination; the solvent is from 0.01 to 100 liters, preferably from 0.5 to 5 liters per mole of the hydroxypyrimidine compound; the reaction is carried out with or without inert gas under stirring, Reaction temperature is - 20 ° C -25 (TC Preferably, the reaction of the amine compound of the formula 6 with the hydroxypyrimidine compound is carried out in the presence of a phase transfer catalyst in two divided liquid phases, or without a phase transfer catalyst; The phase transfer catalyst is tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium bromide, tetrapropylamine. Ammonium iodide, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapentylammonium bromide, tetrahexylammonium bromide, tetraheptyl Ammonium bromide, tetraoctyl ammonium bromide, benzyldimethyltetradecyl ammonium chloride, phenyl trimethyl ammonium chloride, phenyl trimethyl ammonium iodide or Cetyltrimethylammonium chloride; preferably tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltriethylammonium chloride, cetyltriethyl chloride Ammonium. The most preferred is tetrabutylammonium bromide, benzyltriethylammonium chloride or hexadecanolyltrimethyl chloride; the hydroxypyrimidine compound of formula 3 and phase transfer catalyst is used in an amount of 1:0. 01-0. Molar; preferably 1: 0. 05- 0. 2 mole.  8. The method for preparing 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde according to claim 1 And characterized in that in the reduction reaction of step (4), the reducing agent may be diisobutylaluminum hydride, red aluminum or lithium tetrahydroaluminum, preferably diisobutylaluminum hydride; the organic solvent is benzene, toluene , xylene, dichloromethane, chloroform, tetrahydrofuran or dioxane, preferably toluene, dichloromethane, chloroform or tetrahydrofuran; 4-(4-fluorophenyl)-6-isopropyl-5-cyano The molar ratio of 2-(N-methyl-N-methylsulfonylamino)pyrimidine to reducing agent is 1. 0: 0. 5-10. 0, preferably 1. 0: 0. 8 - 4. 0, reaction temperature It is -20 ° C - 150 ° C, preferably - 10 ° C - 50 ° C.  9. A dihydropyrimidinone compound having the formula 2:

 A process for producing the dihydropyrimidinone compound of claim 9, wherein the compound is obtained by reacting isobutyrylacetonitrile with 4-fluorobenzaldehyde and urea in the presence of a protic compound and a metal salt. 1 K A hydroxypyrimidine compound having the formula 3:

A process for producing a hydroxypyrimidine compound of the formula 3 according to claim 11, characterized in that the compound is obtained by oxidizing a dihydropyrimidinone compound of the formula 2.

 13. A 2-(N-methyl-N-methylsulfonylamino)pyrimidine compound having the formula 4:

 A process for producing a 2-(N-methyl-N-methylsulfonylamino)pyrimidine compound of the formula 4, which is characterized in that the compound is a hydroxypyrimidine compound of the formula 3 and an organic sulfonyl halide or an organic sulfonate. The anhydride is reacted, and the resulting reaction product is reacted with N-methylmethanesulfonamide to obtain: