Improved Process for Preparing 4,6-Dihydroxypyrimidine

Abstract

The present invention relates to a process for preparing 4,6-dihydroxypyrimidine by reacting a malonate of formula (II) with a formic acid derivative of formula (III) in the presence of an alkali metal alcoholate of formula (I) at elevated temperature. The condensation product thus formed is crystallized after contact with an acid. After phase separation and distillation, the alcohol of formula (V) is recovered from the two-phase filtrate resulting from this process, which alcohol can be used for the preparation of the alkali metal alcoholate of formula (I).

Description

BACKGROUND OF THE INVENTION

[0001] The subject of the present invention is an improved process for the preparation of 4,6-dihydroxypyrimidine (DHP, which in its tautomeric forms is also referred to as 1H-pyrimidine-4,6-dione) from malonic esters, formic acid derivatives (such as formamide, formamidine or formamidinium cation salts) and alcoholates. DHP is a valuable intermediate for the synthesis of active substances. 4,6-Dichloropyrimidine can then be prepared from 4,6-dihydroxypyrimidine, which itself can be processed into various highly effective fungicides (EP-A1 0382375, EP-A1 0393861, EP-A1 0468684, EP-A1 0468695, EP-A1 2809658). Most of the earlier processes for the preparation of DHP were based on the reaction of diammonium malonate with formamide in the presence of sodium alcoholate (mostly sodium methoxide or sodium ethoxide), where the corresponding alcohol served as the solvent (D.J. Brown in J.Chem.Soc. 1956, 2312-2314; A. In DE-OS-1200308; V.A. Zasonov et al. in Pharmaceutical Chemistry Journal, Vol. 8, No. 12, 741-744, 1974).

[0002] The above DHP processes have two characteristics here that can be regarded as disadvantages. On the one hand, the utilization rate of the nitrogen source (formamide or diammonium malonate) is poor, so that it is necessary to work with a significantly larger excess of reactants and thus a lot of ammonia or ammonium salts are produced as waste streams. On the other hand, the fine-crystalline DHP disodium intermediate is passed through during crystallization, so that in some cases the filtration of the product proceeds very slowly and the process cycle time becomes very long.

[0003] In contrast, two patents of Degussa AG (EP-A-0 816 345 and EP-A-1 284 261) describe improved processes. Thus, in EP-A-1 284 261, the process for DHP is presented such that only 2.25 mol of formamide are required for 1 mol of dimethyl malonate. DHP was then produced in a autoclave under pressure with a yield of 84 to 91% of the theoretical value using sodium methoxide as the base.

[0004] It is also known to synthesize DHP using formamidine and formamidinium cation salts (acetate or hydrochloride) as nitrogen sources instead of formamide in similar processes (CN 103 319 420).

[0005] According to the current state of the art, all hitherto known methods for preparing DHP have two further disadvantages that have not yet been overcome. For the preparation of pyrimidine derivatives from formamide and malonic esters, for chemical reasons, at least three equivalents of alcoholate are always required, calculated relative to the malonic ester. After the formation of the pyrimidine in the reaction, the corresponding alcohols are produced from these bases, which are contaminated by amine compounds and aqueous salt solutions from side reactions. For example, according to Example 3 of Patent EP-A-0816 345, 3.83 kg of methanol are produced per kilogram of DHP, and the methanol must be recovered by distillation from the mother liquor at high cost and applied in some other process. Alternatively, this contaminated methanol must be disposed of, for example by combustion. In contrast, the direct preparation of DHP with alcohols is almost impossible, since the preparation of methoxides, ethoxides and propoxides can only be carried out by electrolysis of alkali metal halides in methanol, ethanol or propanol, and special facilities are required for this electrochemical process. Alternatively, the alcoholates can be prepared by reaction of the alcohol with sodium metal, however hydrogen is produced therein, and thus it is contrary to safety technology in industrial preparation processes. The current methods for DHP thus have significant disadvantages in terms of economy and environmental technology.

[0006] There is thus the following task: to provide a method for preparing 4,6-dihydroxypyrimidine that provides the product in high yield and in particular does not have these two disadvantages. Summary of the Invention

[0007] Now a further improved method for preparing 4,6-dihydroxypyrimidine has been found, which method comprises at least the following steps

[0008] a) providing an alkali metal alcoholate of formula (I),

[0009] R 1 -OM (I)

[0010] wherein R 1 represents n-butyl, isobutyl and sec-butyl, and M represents sodium and potassium,

[0011] b) reacting a malonic ester of formula (II)

[0012]

[0013] wherein R 2 represents a C1 to C4 alkyl group,

[0014] with a formic acid derivative of formula (III),

[0015]

[0016] wherein the residue R 3 represents O, HN or NH+ X - , wherein X - represents an acid radical anion, preferably chloride ion or acetate ion,

[0017] react in the presence of the alkali metal alcoholate of formula (I).

[0018] Preferably, the alkali metal alcoholate of formula (I) is provided in step a), wherein the residue R 1 represents n-butyl and the residue M represents sodium or potassium.

[0019] Preferably, the malonic ester of formula (II) is used in step b), wherein the residue R 2 represents methyl, ethyl or n-butyl.

[0020] The formic acid derivative of formula (III) is particularly preferably formamide (the residue R 3 represents O), formamidine (the residue R 3 represents N), formamidine cation salt (the residue R 3 represents NH + X - ), wherein the residue X - represents an acid radical anion, for example chloride ion in the case of chloromidine or acetate ion in the case of formamidine acetate.

[0021] In step c), the mixture obtained in step b) is usually reacted at a temperature of 50 to 110 °C, preferably 60 to 80 °C. Preferably, step c) is carried out after step b) or simultaneously with step b).

[0022] During steps b) and c), the reaction of the malonic ester with the formic acid derivative to form a 4,6-dihydroxypyrimidine cation salt (DHP salt) takes place, and each DHP salt molecule has two cations M + .

[0023] The method of the present invention has a series of unexpected advantages over the methods of the prior art. Different from methanol and ethanol, the alcohol produced in the reaction can be easily recovered from the two-phase filtrate by simple phase separation, and the filtrate is obtained after separating DHP from the reaction mixture and contains water and salts in addition to the alcohol. After separating the desired product DHP, there is no longer a need for costly distillation purification of the filtrate containing alcohol and water in one phase.

[0024] In addition and also contrary to the methods according to the prior art, the sodium alcoholate base can be easily recovered from the alcohol of formula (V) and caustic soda by simple azeotropic distillation. That is, at least the material balance of DHP synthesis is simplified in such a way that the caustic soda is finally used as the base and almost no waste in the form of any organic compound (such as alcohol) is produced.

[0025] The reaction of the malonic ester of formula (II) with the formic acid derivative of formula (III) is shown below in a schematic diagram. This reaction is carried out in the presence of the alkali metal alcoholate of formula (I), and DHP is subsequently released by an acid.

[0026]

[0027] In this reaction scheme, in the formic acid derivative of formula (III), the residue R 3 represents O in the case of formamide, HN in the case of formamidine, and NH in the case of the formamidinium cation salt + X - . The residue X represents an acid anion here, for example chloride in the case of formamidine hydrochloride or acetate in the case of formamidine acetate.

[0028] Another advantage of the method of the present invention is that the reaction mixture does not generate pressure at the required reaction temperature and thus simplifies the equipment cost of the method.

[0029] Furthermore, in the method of the present invention, the product can be crystallized such that the unhydrolyzed reaction mixture can be fed onto water in parallel with aqueous hydrochloric acid. Thus, unexpectedly, the highest DHP yield described to date in the literature, which is 92.5% of the theoretical value, and the highest quality described to date in the literature (>98 wt% content, HPLC - ESTD method) are achieved in the new method.

[0030] The method of the present invention will be described in more detail below:

[0031] Sodium alcoholate and potassium alcoholate are preferably used as the alkali metal alcoholate of formula (I), especially sodium alcoholate. The residue R 1 in the alkali metal alcoholate of formula (I) R 1 -OM preferably represents n-butyl, sec-butyl, and isobutyl. For this method, alcohols with a small number of carbon atoms are not as suitable as alcohols with more than four carbon atoms. The alkali metal alcoholate of formula (I) based on tert-butanol is also not suitable for the method of the present invention. Sodium n-butoxide is particularly preferred.

[0032] Therefore, according to the present invention, a method for preparing 4,6 - dihydroxypyrimidine is preferably provided, wherein in step a), the alkali metal alcoholate of formula (I) is provided by:

[0033] reacting at least one alkali metal hydroxide of formula (IV)

[0034] M-OH (IV)

[0035] wherein M has the meaning given in formula (I),

[0036] with the alcohol of formula (V)

[0037] R 1 -OH (V)

[0038] wherein R 1 has the meaning mentioned in formula (I) and reacts in pure substance or in the form of a mixture,

[0039] while simultaneously distilling off water and the alcohol of formula (V) until the distillation residue has an alkali metal hydroxide content of formula (IV) of at most 1000 mg / kg, preferably at most 300 mg / kg, relative to the total weight of the mixture.

[0040] The alkali metal alkoxide of formula (I) can here be prepared from a mixture of the corresponding alcohol R 1 -OH and an alkali metal hydroxide M-OH. This can be achieved, for example, both by azeotropic distillation (e.g., in a batch reactor) and by continuous distillation (e.g., in a tubular reactor). What is important for the process for preparing DHP is that the alkali metal alkoxide formed contains a residual alkali metal hydroxide content of at most 1000 mg / kg, preferably at most 300 mg / kg, since higher contents adversely affect the quality of DHP. The alkali metal alkoxide of formula (I) can be provided directly after its preparation in step a), or it can also be prepared in advance in time and then stored. However, it should be noted that, for example, a solution of sodium n-butoxide in n-butanol with a sodium n-butoxide content of at least 25% by weight solidifies to a melt at temperatures below 60 °C and is unstable towards oxygen in the air. Therefore, for the reaction to form DHP, the alkali metal alkoxide of formula (I) is preferably stored under exclusion of oxygen, for example, under a protective gas or directly continued for use in the reaction to form DHP.

[0041] The quality of the alkali metal alkoxide of formula (I) with respect to the residual sodium hydroxide content is indirectly verified by determining water according to the Karl Fischer method. For this purpose, a sample of the alkali metal alkoxide of formula (I) taken out (e.g., sodium n-butoxide in its melt form) is first dissolved in an anhydrous organic acid, preferably acetic acid, where the corresponding sodium salt of the acid (e.g., sodium acetate) and water are formed, and the water is determined by the Karl Fischer method.

[0042] In the malonic ester of formula (II), the residue R 2 preferably represents a C1 to C4 alkyl group, particularly preferably a methyl or ethyl group.

[0043] All reaction reagents and reactants can be used in high-purity form and as process products.

[0044] In the process of the present invention, the reaction of the malonic ester of formula (II) with the formic acid derivative of formula (III) in the presence of the alkali metal alcoholate of formula (I) in step b) is carried out at a temperature of 50 to 110 °C, preferably 60 to 80 °C.

[0045] In step b), the alkali metal alcoholate of formula (I) is usually present in the form of a suspension, a melt or as a solution, and the solution preferably uses the corresponding alcohol of formula (V) as the solvent.

[0046] The reaction of the malonic ester of formula (II) with the formic acid derivative of formula (III) in the presence of the alkali metal alcoholate of formula (I) is preferably carried out as follows: The alkali metal alcoholate of formula (I) is placed in advance and the malonic acid of formula (II) and the formic acid derivative of formula (III) are added to the alkali metal alcoholate of formula (I).

[0047] The formic acid derivative of formula (III) can usually be added to the alkali metal alcoholate of formula (I) individually or simultaneously with all or part of the malonic ester of formula (II) in portions or continuously, and in some cases added to all or the remaining portion of the formic acid derivative of formula (III). Herein, the malonic ester of formula (II) and the formic acid derivative of formula (III) are advantageously fed continuously as a mixture. Herein, in the process of the present invention, it is preferred that in step b) the reaction of the malonic ester of formula (II) with the formic acid derivative of formula (III) in the presence of the alkali metal alcoholate of formula (I) is carried out such that at any point in time during the reaction, the molar ratio of the sum of the formic acid derivatives of formula (III) added up to that point to the sum of the malonic esters of formula (II) added up to that point is at least 2.05, preferably at least 2.5 to 3.5.

[0048] For example, in one embodiment, this molar ratio is achieved as follows: the total amount of the formic acid derivative of formula (III) is added to the alkali metal alcoholate of formula (I), and then the malonic ester of formula (II) is added to the mixture thus obtained. If, before adding any amount of the malonic ester of formula (II), for example, 2.05 Mol, or preferably 2.5 Mol, of the formic acid derivative of formula (III) is added to the alkali metal alcoholate of formula (I), then up to 1.0 mol of the malonic ester of formula (II) is subsequently allowed to be added, whereby at the end of the addition, i.e., at any time point during the addition, the molar ratio of the sum of the formic acid derivatives of formula (III) added up to that time point to the sum of the malonic esters of formula (II) added up to that time point is at least 2.05, or preferably 2.5. During the addition of the malonic ester of formula (II), at each earlier time point, this molar ratio is greater than 2.05, or preferably 2.5. In another embodiment, for example, 0.1 Mol of the formic acid derivative of formula (III) can first be added to the alkali metal alcoholate of formula (I), and then any amount of the malonic ester of formula (II) can be added. Then, the formic acid derivative of formula (III) and the malonic ester of formula (II) can be fed simultaneously into the resulting mixture in a molar ratio of 2.05 or preferably 2.5. Even in this case, at any time point during the addition, the molar ratio of the sum of the formic acid derivatives of formula (III) added up to that time point to the sum of the malonic esters of formula (II) added up to that time point is at least 2.05, preferably at least 2.5 to 3.5. Other embodiments may consist in adding these two reactants to the alkali metal alcoholate of formula (I) discontinuously or continuously, as long as the molar ratio defined above is maintained at any time point during the addition of at least one of these reactants. Herein, according to the present invention, continuous addition is defined as addition without interruption. Discontinuous addition means, according to the present invention, addition in several discrete portions, for example, with interruptions. Herein, the discontinuous addition may include both time phases of continuous addition and also time phases of discontinuous addition.

[0049] The temperature in the reaction mixture present in step b) is conveniently maintained in the range of 50 to 110 °C, in particular 60 to 80 °C. The reaction is slightly exothermic, such that in some cases cooling must be carried out once the addition of the malonate of formula (II) has commenced. Depending on the amounts of substances used, the addition of the malonate of formula (II) and, in some cases, the addition of the formic acid derivative of formula (III) generally takes about 10 to 120 minutes, preferably 20 to 30 minutes. Longer charging times can likewise be preset, but this brings no advantage to the process other than loss of time. Additionally, it is advantageously continued to mix the reaction mixture in step b) at a temperature of 50 to 110 °C, preferably 60 to 80 °C, for a period of time after the addition has ended, for example 20 to 60 minutes, preferably 30 to 40 minutes. The mixing can be carried out, for example, mechanically (preferably with a stirrer) or hydraulically (preferably by transfer (Umpumpen)).

[0050] The reaction mixture after reaction from step c) (containing the product DHP in the form of a di-alkali metal salt, where M + is the cation) is converted to the product DHP by contacting with an acid. Preferably, in step

[0051] d), an inorganic acid and water are reacted with the reaction mixture from step c) in order to bring the mixture to a pH value of 2 to 5, preferably 3 to 4.

[0052] The contact can be effected here, for example, by mixing, where the mixing is preferably mechanical, particularly preferably effected using a stirrer, or hydraulic, particularly preferably effected by transfer. The contacting of the inorganic acid and water with the mixture from step c) in step d) can be effected discontinuously or continuously here. By mixing the inorganic acid and water with the reaction mixture from step c), a uniform pH value setting is achieved within the resulting reaction mixture. The hydrolysis of the di-alkali metal salt of DHP thus achieved can be effected in the same reactor as the previous condensation reaction. Here, water can first be added to the reaction mixture and then the pH can be set to 3 to 4 using an aqueous acid. However, this mode of operation has a negative impact on the product quality and filterability in certain cases. In a preferred embodiment of step d), water is initially introduced, then the reaction mixture from step c) is first added and subsequently acid (dissolved in water in certain cases) is added until the required pH value of the mixture thus obtained has been achieved. In another preferred embodiment of step d), the reaction mixture from step c) is initially introduced, then water is first added and subsequently acid (dissolved in water in certain cases) is added until the required pH value of the mixture thus obtained has been achieved. In a particularly preferred embodiment of step d), water is initially introduced and then the reaction mixture from step c) and acid (dissolved in water in certain cases) are added in parallel with mixing, while maintaining the pH at 2 to 5, preferably pH 3 to 4. In step c), an inorganic acid, preferably hydrochloric acid, particularly preferably aqueous hydrochloric acid, is generally used as the acid.

[0053] The reaction mixture obtained in step d) contains precipitated DHP as a solid, which is suspended in two liquid phases. In step e) according to the invention, the reaction mixture obtained from step d) is separated, where 4,6-dihydroxypyrimidine is obtained as a solid and a two-phase filtrate is obtained, where one phase contains at least predominantly the alcohol of formula (V). These two liquid phases predominantly contain water.

[0054] This separation is generally effected by filtration or centrifugation. The separated DHP is generally washed with water and conveniently dried at an elevated temperature, for example 50 to 90 °C and under reduced pressure, for example 2 to 20 kPa. Using the process according to the invention, the reaction product is obtained in a purity of at least 98% by weight and in a yield which generally exceeds the theoretical value by 90%.

[0055] In addition to the high yields and high chemical purities achieved by preparing DHP by the method of the present invention, the method of the present invention also has the following substantial advantages: the two-phase filtrate remaining after separating 4,6-dihydroxypyrimidine in step e) can be separated into an aqueous phase and an organic phase, and the organic phase contains at least mainly the alcohol of formula (V). Then the organic phase is preferably distilled without fractional distillation, and salts and other solid organic impurities are left as residues. Then the fraction usually has an alcohol proportion of formula (V) of 80 to 99% by weight, which can be verified by gas chromatography. Then the fraction is preferably used as the alcohol of formula (V) to prepare the alkali metal alkoxide of formula (I), and the alkali metal alkoxide can then be used in another step b) of the method for preparing DHP according to the present invention. Thus, a very efficient method is achieved, in which most of the organic liquid phase generated during the separation of the reaction product can be recovered and used in subsequent reactions of the same type. Due to its various applications, there is a demand for thousands of tons of the product DHP. Thus, the amount of waste is significantly reduced by the method of the present invention, and otherwise the waste must be disposed of at high cost and with CO2 emissions (for example, by combustion). Surprisingly, the quality of the product DHP prepared by the method of the present invention is not adversely affected by this recycling.

[0056] Another subject of the present invention is therefore the use of the alcohol of formula (V) and / or its alkali metal alkoxide of formula (I) for the preparation of 4,6-dihydroxypyrimidine. Detailed description

[0057] Examples

[0058] Example 1 - Preparation of sodium n-butoxide (according to the present invention)

[0059] 80 g of 50% caustic soda (1.00 mol) and 800 g of n-butanol (10.79 mol) were initially placed in a 1 L flat-ground flask (Planschlifftopf) equipped with a column (with at least 10 theoretical plates) and a water separator above the column. The mixture was heated to the boiling point (about 90 °C) at 200 mbar and azeotroped until no more water was separated. Subsequently, the mixture was additionally concentrated by distillation until the temperature in the collecting tank reached 104 to 105 °C at 200 mbar. The molten sodium n-butoxide formed solidified at below 60 °C and was unstable to oxygen in the air. For the reaction to form DHP, it was stored under strict exclusion of oxygen or directly continued to react to form DHP. The sodium n-butoxide thus prepared had a sodium n-butoxide content of 33% by weight and a sodium hydroxide residual content of less than 1000 mg / kg.

[0060] Example 2 - Preparation of sodium n-butoxide (according to the present invention)

[0061] Example 1 was repeated using the organic liquid phase from a previous DHP preparation as a substitute for pure n-butanol. After the aqueous phase was separated, the organic phase was obtained after distillation without fractionation. The organic liquid phase had a n-butanol content of 85.6 wt%. The sodium butoxide melt thus prepared had a sodium butoxide content of 33 wt% and a residual sodium hydroxide content of less than 1000 mg / kg. The foreign components in the recycled n-butanol (mainly methanol from dimethyl malonate) were removed from the top of the column with the separated water in an azeotropic distillation.

[0062] Example 3 - Preparation of 4,6-dihydroxypyrimidine with formamide (according to the invention)

[0063] 450 g of sodium butoxide in butanol (33 wt% content; 1.55 mol) were initially placed in a 1 L flat-ground flask and the temperature was adjusted to 70 °C. Subsequently, 1.18 Mol of formamide and 0.40 Mol of dimethyl malonate were added continuously as a mixture for 60 minutes. After the addition was complete, the reaction mixture was stirred for an additional 30 minutes and cooled to 30 °C.

[0064] 250 g of demineralized water were initially placed in a second 1 L flat-ground flask. Then the reaction suspension from the first reactor was added to the second reactor together with (30 wt%) aqueous hydrochloric acid such that the pH was 3 - 4 and the temperature was kept below 30 °C. The aqueous product suspension was stirred for an additional 60 minutes at below 30 °C and filtered by suction. The product was washed three times subsequently with 50 g of demineralized water each time and dried at 70 °C and about 100 mbar. The yield of DHP was 41.7 g, corresponding to 92.5% of the theoretical value. The content was 99.5 wt% (absolute content determination by HPLC with an external standard).

[0065] The mother liquor from the DHP filtration was phase-separated and the organic phase was subjected to one heat transfer without a column in order to separate out salts and solid organic impurities. The butanol thus recovered was then reused for the preparation of sodium butoxide analogously to Example 1, without any disadvantages compared to commercially available n-butanol (see Example 2).

Claims

1. A method for preparing 4,6-dihydroxypyrimidine, comprising at least the following steps: a) Providing an alkali metal alcoholate of formula (I), R 1 -OM(I) wherein R 1 represents n-butyl, and M represents sodium and potassium, b) Reacting a malonic ester of formula (II) wherein R 2 represents a C1 to C4 alkyl group, with a formic acid derivative of formula (III), wherein residue R 3 represents O, HN or NH + X - , where X - represents an acid radical anion and reacts in the presence of an alkali metal alcoholate of formula (I), wherein the alkali metal alcoholate of formula (I) is provided in step a) by the following method: reacting at least one alkali metal hydroxide of formula (IV) M-OH (IV) wherein M has the meaning given in formula (I), with an alcohol of formula (V) R 1 -OH(V) wherein R 1 has the meaning mentioned in formula (I) and reacts in pure form or in the form of a mixture, Distilling off water and the alcohol of formula (V) until the distillation residue has an alkali metal hydroxide content of formula (IV) not higher than 1000 mg / kg relative to the total weight of the mixture.

2. The method according to claim 1, wherein the residue R 3 in which X - represents chloride ion or acetate ion.

3. The method according to claim 1 or 2, wherein the distillation residue has an alkali metal hydroxide content of formula (IV) not higher than 300 mg / kg relative to the total weight of the mixture.

4. The method according to claim 1 or 2, wherein the reaction of the malonic ester of formula (II) and the formic acid derivative of formula (III) in the presence of the alkali metal alcoholate of formula (I) in step b) is carried out at a temperature of 50 to 110 °C.

5. The method according to claim 4, wherein the temperature in step b) is 60 to 80 °C.

6. The method according to claim 1 or 2, wherein the alkali metal alcoholate of formula (I) in step b) is present in the form of a suspension, a melt or a solution.

7. The method according to claim 6, wherein the corresponding alcohol of formula (V) is used as a solvent.

8. The method according to claim 1 or 2, wherein the reaction of the malonic ester of formula (II) and the formic acid derivative of formula (III) in the presence of the alkali metal alcoholate of formula (I) in step b) is carried out as follows: adding the malonic ester of formula (II) and the formic acid derivative of formula (III) to the alkali metal alcoholate of formula (I), wherein during any time point of the addition, the molar ratio of the total amount of the formic acid derivative of formula (III) added up to that time point to the total amount of the malonic ester of formula (II) added up to that time point is at least 2.

05.

9. The method according to claim 8, wherein the molar ratio is at least 2.5 to 3.

5.

10. The method according to claim 1 or 2, wherein in the following step c) Reacting the mixture obtained in step b) at a temperature of 50 to 110 °C.

11. The method according to claim 10, wherein the temperature in step c) is 60 to 80 °C.

12. The method according to claim 10, comprising the following steps: d) Contacting an inorganic acid and water with the reaction mixture from step c) in an amount sufficient to bring the mixture to a pH value of 2 to 5.

13. The method according to claim 12, wherein the pH is 3 to 4.

14. The method according to claim 12, comprising the following steps: e) Separating the reaction mixture obtained from step d) to obtain 4,6-dihydroxypyrimidine in solid form and a two-phase filtrate, wherein one phase mainly contains at least the alcohol of formula (V).

15. The method according to claim 14, wherein the two-phase filtrate obtained in step e) is separated, and the phase obtained, which mainly contains the alcohol of formula (V), is distilled and reused for preparing the alkali metal alkoxide of formula (I) according to claim 3.

16. The method according to claim 1 or 2, wherein in step b), the reaction is carried out discontinuously or continuously by adding the malonic ester of formula (II) and the formic acid derivative of formula (III) to the alkali metal alkoxide of formula (I).

17. The method according to claim 1 or 2, wherein in the alkali metal alcoholate of formula (I) prepared in step a), the residue R 1 represents n-butyl and the residue M represents sodium or potassium.

18. The method according to claim 1 or 2, wherein the formic acid derivative of formula (III) is a formamidinium cation salt selected from formamidinium acetate or formamidinium hydrochloride.

19. The method according to claim 12, wherein in step d), the contacting of the inorganic acid and water with the mixture from step c) is carried out discontinuously or continuously.

20. The method according to claim 1 or 2, characterized in that, The malonic ester of formula (II) used is dimethyl malonate, diethyl malonate or di-n-butyl malonate.

21. Use of the alcohol of formula (V) and / or its alkali metal alkoxide of formula (I) in the method according to any one of claims 1-20 for preparing 4,6-dihydroxypyrimidine: R 1 -OH(V), R 1 -OM(I); wherein R 1 represents n-butyl, and M represents sodium and potassium.

Images