KR100521980B1 - The preparation method for pyrimidinone compound and trihydrate of the salt of the pyrimidinone compound - Google Patents

Abstract

The present invention relates to a method for preparing a trihydrate of a pyrimidinone compound and a salt thereof, and more particularly, to a pyrimidinone derivative having an antagonistic action against angiotensin II receptor and useful for cardiovascular diseases caused by angiotensin II receptor. A pyrimidinone compound of formula (1) and a salt thereof, which can be prepared by a higher yield as well as a more convenient method, and a pyrimidine compound of formula (1) in a form in which the following pyrimidinone compound may be safely present in air A method for preparing trihydrates of salts of midinone compounds.

[Formula (1)]

Wherein R ¹ in Formula (1) is C ₁ -C ₄ linear or branched alkyl, cycloalkyl, C ₁ -C ₄ alkylalkoxy or C ₁ -C ₄ alkylmercapto; R ² Is hydrogen, halogen, C ₁ -C ₄ straight or branched alkyl, or arylalkyl; R ³ , R ⁴ may be the same or different from each other, hydrogen, halogen, hydroxy, C _{1 to} C ₄ alkoxy, amino, alkylamino or dialkylamino (each alkyl residue has 1 to 5 carbon atoms), C ₁ ~C ₄ alkoxycarbonyl or by carboxy which is optionally substituted C ₁ ~C ₄ branched or straight chain alkyl, cycloalkyl, aryl, arylalkyl, arylcarbonyl, C ₁ ~C ₄ alkoxycarbonyl, or aminocarbonyl, and , R ³ , R ⁴ Together with the nitrogen atom to which they are attached form a 4-8 membered cyclic ring which is cycloalkyl, aryl or arylalkyl, halogen, hydroxy, C ₁ -C ₄ alkoxy, amino, alkylamino or dialkyl 1 to 2 substituents selected from the group consisting of amino (the number of carbon atoms of each alkyl residue is 1 to 5), C _{1 to} C ₄ alkoxycarbonyl, carboxy, aminocarbonyl and C _{1 to} C ₄ linear or branched alkyl. May be substituted by, and may also contain -O-, -S-, -SO-, -SO ₂ -or> N-R ⁵ as ring member; Where R ⁵ Is hydrogen, C ₁ -C ₄ alkyl, aryl, arylalkyl, substituted alkenyl, pyridyl, pyrimidyl, C ₁ -C ₄ alkyl or arylcarbonyl, C ₁ -C ₄ alkoxycarbonyl, aminocarbonyl ; n is 1 to 6).

Description

The manufacturing method of the trihydrate of a pyrimidinone compound and its salt {THE PREPARATION METHOD FOR PYRIMIDINONE COMPOUND AND TRIHYDRATE OF THE SALT OF THE PYRIMIDINONE COMPOUND}

The present invention relates to a method for preparing a trihydrate of a pyrimidinone compound and a salt thereof, and more particularly, to a pyrimidinone derivative having an antagonistic action against angiotensin II receptor and useful for cardiovascular diseases caused by angiotensin II receptor. A pyrimidinone compound of formula (1) and a salt thereof, which can be prepared by a higher yield as well as a more convenient method, and a pyrimidine compound of formula (1) in a form in which the following pyrimidinone compound may be safely present in air A method for preparing trihydrates of salts of midinone compounds.

[Formula (1)]

Wherein R ¹ in Formula (1) is C ₁ -C ₄ linear or branched alkyl, cycloalkyl, C ₁ -C ₄ alkylalkoxy or C ₁ -C ₄ alkylmercapto; R ² Is hydrogen, halogen, C ₁ -C ₄ straight or branched alkyl, or arylalkyl; R ³ , R ⁴ may be the same or different from each other, hydrogen, halogen, hydroxy, C _{1 to} C ₄ alkoxy, amino, alkylamino or dialkylamino (each alkyl residue has 1 to 5 carbon atoms), C ₁ ~C ₄ alkoxycarbonyl or by carboxy which is optionally substituted C ₁ ~C ₄ branched or straight chain alkyl, cycloalkyl, aryl, arylalkyl, arylcarbonyl, C ₁ ~C ₄ alkoxycarbonyl, or aminocarbonyl, and , R ³ , R ⁴ Together with the nitrogen atom to which they are attached form a 4-8 membered cyclic ring which is cycloalkyl, aryl or arylalkyl, halogen, hydroxy, C ₁ -C ₄ alkoxy, amino, alkylamino or dialkyl 1 to 2 substituents selected from the group consisting of amino (the number of carbon atoms of each alkyl residue is 1 to 5), C _{1 to} C ₄ alkoxycarbonyl, carboxy, aminocarbonyl and C _{1 to} C ₄ linear or branched alkyl. May be substituted by, and may also contain -O-, -S-, -SO-, -SO ₂ -or> N-R ⁵ as ring member; Where R ⁵ Is hydrogen, C ₁ -C ₄ alkyl, aryl, arylalkyl, substituted alkenyl, pyridyl, pyrimidyl, C ₁ -C ₄ alkyl or arylcarbonyl, C ₁ -C ₄ alkoxycarbonyl, aminocarbonyl ; n is 1 to 6).

Recently, many studies on non-peptide angiotensin II antagonists have been published (US Pat. Nos. 4,207,324, 4,340,598, 4,576,958, 4,582,847 and 4,880,804; European Patent Publications 028,834, 245,310, 291,969, 323,841 and 324,377, etc.). Among them, European Patent Publication Nos. 028,834 and 253,310 have imidazole derivatives (e.g., Losartan) substituted with a biphenyl group, and European Patent Publication No. 245,637 have imidazole pyridine derivatives (e.g., L 158,809). They all exhibit strong angiotensin II antagonistic effects. In addition, pyrimidinone compounds, which are hexagonal hetero compounds containing nitrogen, which are different from the pentagonal imidazole derivatives, are disclosed in European Patent Publications 407,342, 419,048 and 445,811, etc. It shows lower activity than the imidazole derivative.

Therefore, the present inventors continued to study the pyrimidinone compound to prepare pyrimidinone compounds which are fundamentally different from the compounds of the prior art, and test the activity thereof, which is equal to or 50 times as the imidazole derivative. We have created a new compound with remarkably excellent activity [in vitro (rabbit arota), 60-70% inhibition rate at 10 ^-8 to 10 ^-9 molarity], and has filed a patent application with the Korean Intellectual Property Office. Application No. PCT KR 9500121, September 15 , 1995 & International Application No. PCT KR 9900198, April 26, 1999). Such pyrimidinone compounds of formula (1) have generally been prepared by the following scheme (1), as disclosed in both applications.

(Wherein R ¹ , R ² , R ³ , R ⁴ , n are the same as defined above).

That is, according to the manufacturing method of the prior art, as can be seen in the reaction scheme 1, by performing an esterification reaction with respect to the compound of formula (3), to prepare a compound of formula (4), and then By adding a compound of formula (5) to a compound of formula (4), a compound of formula (6) is prepared, and then hydrolyzed to prepare a compound of formula (7), wherein the compound of formula (7) A compound of formula (8) is prepared by reacting with an amine to cause an amidation reaction, and again a thioamidation reaction is carried out using Lawesson's Reagent to the compound of formula (8), The pyrimidinone compound of the formula (1) was prepared by preparing a compound of, followed by removing the solvent, and then treating the protecting group in an acidic state with an alcohol reagent.

However, the conventional method as described above is complex in the whole process, and in the preparation of the compound of formula (6), not only is it difficult to separate due to the non-selective reaction of the N, O alkylated compound, but also must be purified by column. In addition, in the process of preparing the compound of (1), first, the compound of the formula (9) is prepared, and then the reaction step is very difficult, such as treatment with alcohols in an acidic state. As it is complicated and must be in several stages, as a result, there is a problem that the final yield (1.28%) is very low, and an improvement is urgently needed.

Due to this problem of the prior art, efforts have been made to prepare pyrimidinone compounds in a simpler process and with a higher yield. Accordingly, the present inventors have found a novel method for pyrimidinone compounds represented by the formula (1). A manufacturing method was developed and filed with the Korean Patent Office in Korean Patent Application No. 2000-14875.

(Wherein R ¹ , R ² , R ³ , R ⁴ , n are the same as defined above).

Briefly looking at such a manufacturing method, as can be seen in the reaction scheme 2, first, a base such as lithium hydride to the compound of formula (3) and the compound of formula (4) in a mixed organic solvent of dimethylformamide and ethyl acetate By reacting to selectively prepare an N-alkylated compound of formula (6), and simultaneously undergo a hydrolysis and amidation reaction with respect to the compound of formula (6) to prepare a compound of formula (8) Subsequently, the pyrimidinone compound of the formula (1) is prepared by subjecting the compound of the formula (8) to a thioamidation reaction using a rosin reagent, followed by treatment with an alcohol reagent to remove the protecting group.

According to the above production method, only the N-alkylated compound of formula (6) can be selectively prepared, eliminating the need for purification through a column, and proceeding with only simple process steps as compared to the conventional production method, Since the pyrimidinone compound of (1) can be manufactured, the said pyrimidinone compound can be manufactured with a comparatively high yield (28.2%).

However, even with such a production method, in the preparation of the compound of the formula (8), since the hydrolysis and amidation must be performed at the same time, the yield may be lowered, and moreover, the N-alkylation reaction may occur. Since the pyrimidinone compound of the formula (1) can be prepared only through a substantially five-step reaction such as hydrolysis, amidation, thioamidation, and the removal of the protecting group, the reaction process is still complicated, and accordingly, There was a problem that the final yield was still low.

Due to this problem of the prior art, a method for producing the pyrimidinone compound of formula (1) in a higher yield through a simpler process has been urgently required.

On the other hand, the pyrimidinone compound of the formula (1) has a property of absorbing moisture when it is left in the air, as shown in Table 1, the pyrimidinone compound and its salts in the form of anhydride It is true that there was a problem in moisture stability in the case of using the medicament to prepare a drug. In Table 1 below, the content of the water contained in the salt of the pyrimidinone compound in the anhydride form is measured and displayed according to time.

time Condition Room temperature 60% RH 75% RH 1 hours 3.4% 6.2% 9.05% 2 hours 5.6% 9.1% 9.1% 3 hours 9.1% 9.15% 9.1% 6 hours 9.2% 9.1% 9.15% 9 hours 9.1% 9.2% 9.2% 24 hours 9.1% 9.1% 9.1%

However, as can be seen in Table 1, the pyrimidinone compound and its salts in the form of anhydride, when absorbing a certain amount of water, do not absorb any more water, it can be seen that the stable hydrate form, The results of analyzing the constituent elements of these hydrates are shown in Table 2 below.

Construction elements Theoretical value (trihydrate) Analysis C 54.61% 54.82 ± 0.70% H 6.11% 5.96 ± 0.20% N 16.51% 17.47 ± 0.26% O 10.78% 8.44 ± 0.14% S 5.40% 5.46 ± 0.39%

As can be seen from Table 2 below, the pyrimidone and the salts thereof of Formula (1), when present in the form of trihydrate, do not absorb any more moisture, and thus become stable and, accordingly, such trihydrate form Although a method for producing a pyrimidinone compound and a salt thereof in a high yield through a simple process has been required, the above-described prior art does not disclose such a production method at all.

Therefore, the object of the present invention is to solve the problems of the prior art, there is no need to proceed with hydrolysis, the reaction step can be further reduced, after all, through a simple process, in the high yield of the formula (1) The present invention provides a method for preparing the pyrimidinone compound and salts thereof, which enables the production of a midinone compound and salts thereof.

In addition, another object of the present invention is to prepare a trihydrate of a salt of the pyrimidinone compound of the form wherein the pyrimidinone compound of formula (1) can be stably present in air by a simple process, a high yield To provide.

In order to achieve the above object, the present invention provides a compound of formula (3) N-hydroxybenzotriazole, N-methylmorpholine and dicyclohexyl in an organic solvent, as can be seen in Scheme 3 below Reacting with an amine in the presence of carbodiimide to proceed with the amidation reaction, thereby presenting a compound of formula (4); Selectively preparing an N-alkylated compound of formula (6) by adding a base to a compound of formula (4) and a compound of formula (5) under a mixed organic solvent; And proceeding with thio amidation reaction using a rosin reagent to the compound of formula (6), and treating with a polar solvent in an acidic state to remove the protecting group. Provided are methods for preparing a non compound and salts thereof.

Formula (1)

Wherein R ¹ in Formula (1) is C ₁ -C ₄ linear or branched alkyl, cycloalkyl, C ₁ -C ₄ alkylalkoxy or C ₁ -C ₄ alkylmercapto; R ² Is hydrogen, halogen, C ₁ -C ₄ straight or branched alkyl, or arylalkyl; R ³ , R ⁴ may be the same or different from each other, hydrogen, halogen, hydroxy, C _{1 to} C ₄ alkoxy, amino, alkylamino or dialkylamino (each alkyl residue has 1 to 5 carbon atoms), C ₁ ~C ₄ alkoxy carbonyl, or straight-chain or a C ₁ ~C ₄ which is substituted by a carboxyl side chain alkyl, cycloalkyl, aryl, arylalkyl, arylcarbonyl, C ₁ ~C ₄ alkoxycarbonyl, or aminocarbonyl, R ³ , R ⁴ Together with the nitrogen atom to which they are attached form a 4-8 membered cyclic ring which is cycloalkyl, aryl or arylalkyl, halogen, hydroxy, C ₁ -C ₄ alkoxy, amino, alkylamino or dialkyl 1 to 2 substituents selected from the group consisting of amino (the number of carbon atoms of each alkyl residue is 1 to 5), C _{1 to} C ₄ alkoxycarbonyl, carboxy, aminocarbonyl and C _{1 to} C ₄ linear or branched alkyl. May be substituted by, and may also contain -O-, -S-, -SO-, -SO ₂ -or> N-R ⁵ as ring member; Where R ⁵ Is hydrogen, C ₁ -C ₄ alkyl, aryl, arylalkyl, alkenyl, pyridyl, pyrimidyl, C ₁ -C ₄ alkyl or arylcarbonyl, C ₁ -C ₄ alkoxycarbonyl, aminocarbonyl; n is 1 to 6).

(Wherein R ¹ , R ² , R ³ , R ⁴ , n are the same as defined above).

That is, according to the production method according to the present invention, after the amidation reaction proceeds to the compound of formula (3) to which the carboxylic acid is bonded, not the compound to which the ester is bonded, the N-alkylation reaction proceeds, It is not necessary to proceed with the hydrolysis reaction on the functional group, and thus, it is possible to substantially reduce the reaction in one step, so that, in a simpler process, a higher yield (43%, see Example) may be used. It is possible to prepare the pyrimidinone compound and salt thereof.

The present invention also provides a salt of the pyrimidinone compound of formula (1) under a mixed solvent of water and one or more solvents selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, chloroform and ethyl acetate It provides a method for preparing a trihydrate of the pyrimidinone compound salt of formula (1), characterized in that it comprises a reflux, dissolving step.

According to this preparation method, it is possible to produce a trihydrate form in which the pyrimidinone compound of the formula (1) can be stably present in the air at high yield.

Hereinafter, a manufacturing method according to the present invention will be described in detail with reference to a preferred example of the present invention.

(Wherein R ¹ , R ² , R ³ , R ⁴ , n are the same as defined above).

As described above, in the production method according to the present invention, first, by reacting the compound represented by the formula (3) with an amine and proceeding with the amidation reaction as shown in the addition scheme (4), To produce a compound. In the amidation reaction, amine, N-hydroxybenzotriazole, N-methylmorpholine, and dicyclohexylcarbodiimide are preferably used in 1.0 to 2.0 equivalents, respectively, in an organic solvent, and most preferably in 1,2 equivalents. desirable. As the organic solvent for the reaction, all common organic solvents for the amidation reaction, such as chloroform, methylene chloride, tetrahydrofuran, acetonitrile, dimethylformamide, can be used, but chloroform or tetrahydrofuran is used. This is preferable.

Under such a solvent, the yield of the amidation reaction can be most improved by using each of the reactants in the above amounts. In addition, in the production method according to the present invention, as described above, the amidation reaction proceeds with respect to the compound of the formula (3) to which carboxylic acid is bound. Unlike the conventional production method, hydrolysis of ester functional groups is performed. It is not necessary to proceed with the amidation reaction.

(Wherein R ¹ , R ² , R ³ , R ⁴ , n are the same as defined above).

Next, as in Scheme 5, an N-alkylated compound of Formula (6) can be selectively prepared by adding a base to a compound of Formula (4) and a compound of Formula (5) under a mixed organic solvent. . In this case, a mixed solvent of dimethylformamide and ethyl acetate, dimethylformamide and ethylene glycol dimethyl ether, dimethylformamide and tetrahydrofuran, dimethylformamide and methylene chloride, and dimethylformamide and isopropyl ether are used. In particular, it is preferable to use a mixed solvent of dimethylformamide and ethyl acetate, dimethylformamide and ethylene glycol dimethyl ether. In addition, the mixing ratio of the first solvent and the second solvent constituting the mixed solvent may be 1 to 10: 1 to 30, and particularly preferably 1 to 10. In addition, an organic salt of an alkali metal or alkali metal may be used as the base used in the N-alkylation reaction, and in particular, the use of lithium hydride among alkali metal hydrides is most preferable for selectively preparing an N-alkylated compound. Do.

(Wherein R ¹ , R ² , R ³ , R ⁴ , n are the same as defined above).

After preparing the compound of formula (6), for the compound of formula (6) as in Scheme 6, a Lawrence's Reagent is added to a compound of formula (6) under a solvent such as benzene, toluene, methylene chromide or tetrahydrofuran. After proceeding with the thio amidation reaction, a pyrimidinone compound of formula (1) can be prepared by directly adding a polar solvent such as alcohol or tetrahydrofuran to the resulting product to remove the protecting group in an acidic state. .

In the thio amidation reaction, the Rosin reagent is preferably used in an amount of 0.6 equivalents. As the polar solvent, all common polar organic solvents such as alcohol or tetrahydrofuran may be used, but methanol, ethanol, propanol, and tetrahydro may be used. Preference is given to using those selected from the group consisting of furan, acetonitrile and acetone.

That is, according to the production method according to the present invention, it is not necessary to proceed with the hydrolysis step for the ester group, substantially reducing the reaction step of one step, accordingly, through a simple process, the chemical formula in a higher yield The pyrimidinone compound of (1) can be manufactured.

     In addition, the salt of the pyrimidinone compound may be prepared according to a conventional method by adding a salt to the compound of formula (1) prepared above, wherein the salt is preferably a potassium salt. In addition, trihydrate preparation of the potassium salt of the pyrimidinone compound of the formula (1) is prepared by dissolution under reflux under a mixed solvent of water and an organic solvent. At this time, the mixed solvent is a mixed solvent of water and methanol, water and ethanol, water and isopropanol, water and tetrahydrofuran, water and acetonitrile, water and acetone, water and chloroform, water and ethyl acetate, preferred The mixing ratio was 1 to 2: 5 to 20, and the best mixing solvent in the method for preparing the trihydrate of the salt was water and tetrahydrofuran or water and isopropanol.

     As described above, the present invention can prepare a pyrimidinone derivative of Formula (1) and its salt in a high yield (43%) compared to the conventional method, and also, trihydrate of the salt of the pyrimidinone compound through a simple process Can be prepared.

     Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are intended to explain the present invention in more detail, and are not intended to limit the scope of the present invention in any form.

Example 1: Preparation of 2-n-butyl-5-carbonylmethyl-4-hydroxy-6-methyl-pyrimidine.

1.78 kg of valeroamidine and 1.89 kg of dimethylacetyl succinate were dissolved in 5.5 L of methanol, 1.31 kg of potassium hydroxide was added, stirred at room temperature for 15 hours, 20 L of water was added thereto, and the reaction temperature was cooled to 0 ° C. and 4N hydrochloric acid was added. The pH was acidified to 4 by addition of aqueous solution. The resulting solid was filtered and dried to yield 1.57 kg (70%) of the title compound.

     1 H NMR (CDCl 3): 0.90 (t, 3H), 1.21 to 1.35 (m, 2H), 1.54 to 1.64 (m, 2H), 2.16 (s, 3H), 2.45 to 2.53 (t, 3H), 3.38 (s, 2 H), 12.41 (brs, 1 H).

Example 2: Preparation of 2-n-butyl-5-dimethylaminocarbonylmethyl-4-hydroxy-6-methyl-pyrimidine

5 L of chloroform was injected into 1.57 kg of the compound of Example 1, and the reaction temperature was lowered to 0 ° C., 658 g of dimethylami hydrochloride, 1.135 kg of N-hydroxybenzotriazole, 1.7 kg (1.85 L) of N-methylmorpholine, and dicyclo 1.7 kg of hexylcarbodiimide was added sequentially and stirred at room temperature for 15 hours. The resulting solid was filtered and the filtrate was washed with 5 L of water and 5 L of saturated sodium bicarbonate and concentrated under reduced pressure. The residue was dissolved in 5 L of ethyl acetate, and then 10 L of hexane was added to form a solid, followed by filtration and drying to obtain 1.5 kg (85%) of the title compound.

     1 H NMR (CDCl 3): 0.93 (t, 3H), 1.33-1.45 (m, 2H), 1.65-1.81 (m, 2H), 2.34 (s, 3H), 2.58-2.64 (t, 2H), 2.97 (s, 3H), 3.17 (s, 3H), 3.56 (s, 2H).

Example 3: 2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl Preparation of Pyrimidin-4 (3H) -one

1.5 kg of the compound of Example 2 was dissolved in 10.5 L of a mixed solution mixed at a mixing ratio of dimethylformamide and ethylene glycol dimethyl ether 1: 9, cooled to 0 ° C., 56 g of lithium hydride was added thereto, and stirred for 30 minutes. 5,23 kg of 4- [2 ′-(N-triphenylmethyltetrazol-5-ylphenyl] benzyl bromide was added to the mixed solution, and the mixture was stirred at 60 ° C. for 90 hours. The resulting solid was filtered to give the title compound 3.93 kg (91%) were obtained.

     IR (KBr) cm < -1 >: 1660, 1620, 1555.

    1 H NMR (CDCl 3): 0.87 (t, 3H), 1.25-1.40 (m, 2H), 1.55-1.75 (m, 2H), 2.20 (s, 3H), 2.50 (t, 2H), 2.97 ( s, 3H), 3.11 (s, 3H), 3.56 (s, 2H), 5.10 (s, 2H), 6.85 to 6.89 (m, 8H), 7.11 (dd, 2H), 7.22 to 7.38 (m, 10H) , 7.48 (m, 2 H), 7.98 (dd, 1 H).

Example 4: 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl]- Preparation of Pyrimidin-4 (3H) -one

After dissolving 3.92 kg of the compound of Example 3 in 16 L of toluene, 1.31 kg of Lawesson's Reagent was added at room temperature, and the reaction was allowed to react at 80 ° C. for 6 hours and then cooled to room temperature. Methanol or tetrahydrofuran 16L was added to the reaction and the mixture was stirred under reflux for 3 hours and then concentrated. The concentrate was dissolved in ethyl acetate 10, and then 10 L of water was added to give a solid. The resulting solid product was filtered, washed with 3 L of ethyl acetate 1: 1 mixed solvent and 6 L of isopropyl ether and dried at 60 ° C. for 24 hours to obtain 2.17 kg (80%) of the title compound.

     Melting Point: 96.8 ~ 101.8 ℃

TLC R f : 0.28 (5% methanol in CHCl 3)

1 H NMR (CDCl 3): 0.89 (t, 3H), 1.28 to 1'.45 (m, 2H), 1.58 to 1.74 (m, 2H), 2.26 (s, 3H), 2.63 (t, 2H), 3.44 ( s, 2H), 3.47 (s, 3H), 3.77 (s, 2H), 5.10 (s, 2H), 7.07 (s, 5H), 7.33-7.58 (m, 3H), 7.98 (dd, 1H).

Example 5: 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl]- Preparation of pyrimidine-4 (3H) -one potassium salt trihydrate

2.17 kg of the compound of Example 4 was dissolved in 5.5 L of isopropanol, 6 L of 1M KEH (± 2-ethylhexanoic acid + potassium hydroxide) isopropanol solution was added, and the reaction was stirred at reflux for 4 hours, and then cooled to room temperature. Filtered and dried to obtain 2.1 kg (90%) of anhydrous salt. To prepare the trihydrate of the salt, the dry compound was added to a mixed solution of water and tetrahydrofuran 1: 10, dissolved under reflux, and cooled to room temperature to form crystals. The resulting crystals were filtered and dried for 24 hours at 60 ℃ to give 2.21 kg (96%) of the title compound.

The trihydrate of the salt of Example 5 was prepared by mixing water and an organic solvent according to the Table 3 method according to the preparation method, particle size analysis was analyzed using a Sympatec GmbH particle size analyzer.

    (Xn = μm; n = particle distribution, μm = particle density)

Solvent Blowjob sleeping distribution Yield (%) Remarks  Water: Methanol (1: 20) X10 = 1.67 μm, X50 = 3.90 μm, X90 = 12.64 μm 45  Water: Ethanol (1: 20) X10 = 2.87 μm, X50 = 9.90 μm, X90 = 19.44 μm 73  Water: Isopropanol (1:10) X10 = 1.37 μm, X50 = 4.95 μm, X90 = 12.39 μm 91  Water: Tetrahydrofuran (1:10) X10 = 1.46 μm, X50 = 5.46 μm, X90 = 14.17 μm 96  Water: Acetonitrile (1: 5) X10 = 3.64 μm, X50 = 13.5 μm, X90 = 34.24 μm 90  Water: Acetone (1:10) X10 = 1.88 μm, X50 = 7.60 μm, X90 = 16.96 μm 56  Water: chloroform (1:10) X10 = 1.97 μm, X50 = 8.42 μm, X90 = 23.06 μm 82  Water: ethyl acetate (1: 10) X10 = 2.11 μm, X50 = 9.51 μm, X90 = 33.15 μm 76

As can be seen in Table 3, in the preparation of the trihydrate of the salt of the pyrimidinone compound of the formula (1), it is preferable to use isopropanol or a mixed solvent of tetrahydrofuran and water. By refluxing and dissolving the salt of a pyrimidinone compound, the said trihydrate can be manufactured simply. For reference, the particle size distribution of the crystals prepared in water and an organic solvent was at least 90% 40 μm, and at least 50% 10 μm.

As described above, according to the present invention, a pyrimidinone compound and a salt thereof can be prepared in a higher yield through a simpler process than in the prior art, and the pyrimidinone compound is stably present in air. The hydrate of the salt of the pyrimidinone compound, which can be in a form that can be produced, can be prepared in a high yield through a simple process.

Claims (11)

The compound of formula (VII) is dissolved in an organic solvent selected from chloroform or tetrahydrofuran, and amine is present in the presence of 1.0 to 2.0 equivalents of N-hydroxybenzotriazole, N-methylmorpholine and dicyclohexylcarbodiimide, respectively. Reacting with to prepare a compound of formula A mixed solvent of dimethylformamide and ethyl acetate having a weight ratio of each mixed solvent of 1:10, a mixed solvent of dimethylformamide and ethylene glycol dimethyl ether, a mixed solvent of dimethylformamide and tetrahydrofuran, and dimethylformamide and methylene chloride Preparing a compound of formula (VII) by reacting a compound of formula (VII) with a compound of formula (VII) by adding lithium hydride to a mixed solvent selected from the group consisting of a mixed solvent of dimethylformamide and a mixed solvent of isopropyl ether ; And 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphane 2 by dissolving a compound of formula (VII) in an organic solvent selected from benzene, toluene, methylene chloride and tetrahydrofuran. , 4-disulfide (Rowesson's Reagent) is added to the reaction, and a polar solvent selected from the group consisting of methanol, ethanol, propanol, tetrahydrofuran, acetonitrile and acetone is added to remove the protecting group. Preparing a pyrimidinone compound; Method for producing a pyrimidinone compound of formula (III) and salts thereof, comprising: [Formula (1)] [Formula (3)] [Formula (4)] [Formula (5)] [Formula 6] R ¹ in the formula is C ₁ -C ₄ linear or branched alkyl, cyclo alkyl, C ₁ -C ₄ alkylalkoxy or C ₁ -C ₄ alkylmercapto; R ² Is hydrogen, halogen, C ₁ -C ₄ straight or branched alkyl, or arylalkyl; R ³ , R ⁴ may be the same or different from each other, hydrogen, halogen, hydroxy, C _{1 to} C ₄ alkoxy, amino, alkylamino or dialkylamino (each alkyl residue has 1 to 5 carbon atoms), C ₁ ~C ₄ alkoxy carbonyl, or straight-chain or a C ₁ ~C ₄ which is substituted by a carboxyl side chain alkyl, cycloalkyl, aryl, arylalkyl, arylcarbonyl, C ₁ ~C ₄ alkoxycarbonyl, or aminocarbonyl, R ³ , R ⁴ Together with the nitrogen atom to which they are attached form a 4-8 membered cyclic ring which is cycloalkyl, aryl or arylalkyl, halogen, hydroxy, C ₁ -C ₄ alkoxy, amino, alkylamino or dialkyl 1 to 2 substituents selected from the group consisting of amino (the number of carbon atoms of each alkyl residue is 1 to 5), C _{1 to} C ₄ alkoxycarbonyl, carboxy, aminocarbonyl and C _{1 to} C ₄ linear or branched alkyl. May be substituted by, and may also contain -O-, -S-, -SO-, -SO ₂ -or> N-R ⁵ as ring member; Where R ⁵ Is hydrogen, C ₁ -C ₄ alkyl, aryl, arylalkyl, alkenyl, pyridyl, pyrimidyl, C ₁ -C ₄ alkyl or arylcarbonyl, C ₁ -C ₄ alkoxycarbonyl, aminocarbonyl; n is 1-6. delete delete delete delete delete delete delete Refluxing and dissolving a salt of a pyrimidinone compound of formula (1) under a mixed solvent of water and one or more solvents selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, chloroform and ethyl acetate Method for producing a trihydrate of pyrimidinone compound salt of formula (1) characterized in that comprises a. [Formula (1)] Wherein R ¹ in Formula (1) is C ₁ -C ₄ linear or branched alkyl, cycloalkyl, C ₁ -C ₄ alkylalkoxy or C ₁ -C ₄ alkylmercapto; R ² Is hydrogen, halogen, C ₁ -C ₄ straight or branched alkyl, or arylalkyl; R ³ , R ⁴ may be the same or different from each other, hydrogen, halogen, hydroxy, C _{1 to} C ₄ alkoxy, amino, alkylamino or dialkylamino (each alkyl residue has 1 to 5 carbon atoms), C ₁ ~C ₄ alkoxy carbonyl, or straight-chain or a C ₁ ~C ₄ which is substituted by a carboxyl side chain alkyl, cycloalkyl, aryl, arylalkyl, arylcarbonyl, C ₁ ~C ₄ alkoxycarbonyl, or aminocarbonyl, R ³ , R ⁴ Together with the nitrogen atom to which they are attached form a 4-8 membered cyclic ring which is cycloalkyl, aryl or arylalkyl, halogen, hydroxy, C ₁ -C ₄ alkoxy, amino, alkylamino or dialkyl 1 to 2 substituents selected from the group consisting of amino (the number of carbon atoms of each alkyl residue is 1 to 5), C _{1 to} C ₄ alkoxycarbonyl, carboxy, aminocarbonyl and C _{1 to} C ₄ linear or branched alkyl. May be substituted by, and may also contain -O-, -S-, -SO-, -SO ₂ -or> N-R ⁵ as ring member; Where R ⁵ Is hydrogen, C ₁ -C ₄ alkyl, aryl, arylalkyl, alkenyl, pyridyl, pyrimidyl, C ₁ -C ₄ alkyl or arylcarbonyl, C ₁ -C ₄ alkoxycarbonyl, aminocarbonyl; n is 1 to 6). 10. The method of claim 9, wherein the mixing ratio of the water and the organic solvent is 1 to 2: 5 to 20. Trihydrate of a pyrimidinone compound salt prepared by the process according to claim 9 or 10.