Preparation method of 4, 6-dihydroxypyrimidine

Abstract

The invention belongs to the technical field of organic chemistry, and relates to a preparation method of 4, 6-dihydroxypyrimidine. Specifically, the preparation method of the 4, 6-dihydroxypyrimidine disclosed by the invention comprises the following steps: 1) carbonylation reaction; 2) amination reaction; 3) cyclization reaction; and 4) post-treatment process. The 4, 6-dihydroxypyrimidine is directly synthesized by adopting a one-pot method, the purification process of formamide is avoided, the atom economy is high, the raw materials are cheap and easy to obtain, the product purity and yield are high, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a method for preparing 4,6-dihydroxypyrimidine, and belongs to the technical field of organic chemistry. Background Art

[0002] 4,6-dihydroxypyrimidine (DHP for short) is a pyrimidine derivative, and its tautomer is called 1H-pyrimidine-4,6-dione. It is widely used in medicine, pesticides (such as fungicides) and fine chemical products. In medicine, DHP is an important intermediate for the synthesis of sulfonamide drug sulfamoxifen, and is also an intermediate for the synthesis of vitamin B4, anti-tumor drugs and auxiliary drugs. In pesticides, DHP is one of the important raw materials for the preparation of fungicide azoxystrobin.

[0003] At present, the method for industrial production of 4,6-dihydroxypyrimidine generally uses malonic acid ester (mainly dimethyl malonate or diethyl malonate) and formamide as raw materials, reacts in a sodium alcoholate (such as sodium methoxide or sodium ethoxide) solution to generate 4,6-dihydroxypyrimidine sodium salt, and the sodium salt is acidified to obtain 4,6-dihydroxypyrimidine product (for example, CN 102115463 A, CN106883186 A, CN 106397337 A, CN 105585192A, CN 113527214 A, etc.).

[0004] The raw material formamide in the existing process is purchased directly. Formamide is generally synthesized in two steps. In the first step, carbon monoxide and methanol are reacted under the action of sodium methoxide to generate methyl formate, and in the second step, methyl formate is ammonolyzed to generate formamide. The difficulty of this process lies in the separation of different materials, such as the separation of sodium methoxide, methanol, methyl formate, formamide, etc., especially the catalyst sodium methoxide is easily hydrolyzed in water to generate insoluble sodium formate, thereby causing pollution and blockage. Moreover, in the process of separating these substances, negative pressure operation will lead to the generation of a large amount of waste water containing ammonia, methanol, methyl formate, and formamide. CN 114853570 A explains the amount and composition of the waste water, and provides a method for treating waste water in a formamide production device.

[0005] In addition, CN 113444050 A mentions that ammonia is generated during the synthesis of 4,6-dihydroxypyrimidine. To avoid the adverse factors caused by the generation of ammonia, a solution is to add methyl formate during the reaction stage to react with ammonia to generate the raw material formamide.

[0006] From the above content, we can know that the current synthesis of 4,6-dihydroxypyrimidine uses formamide as raw material, but the production process of raw material formamide involves problems such as difficulty in material separation and wastewater treatment, which increases time and equipment costs. In addition, ammonia will be generated during the synthesis of 4,6-dihydroxypyrimidine, which is not conducive to the reaction. Summary of the invention

[0007] Problem that the invention aims to solve

[0008] The synthesis process of formamide involves the catalyst sodium methoxide and the raw material methanol, etc., and sodium methoxide happens to be one of the raw materials for the synthesis of 4,6-dihydroxypyrimidine, and methanol is the reaction solvent for the synthesis of 4,6-dihydroxypyrimidine. Therefore, in order to solve the existing problems, the present invention directly uses ammonia (liquid ammonia), carbon monoxide, sodium methoxide methanol solution, and malonate as raw materials, reacts in the same reactor, and does not need to separate the catalyst sodium methoxide, and directly synthesizes 4,6-dihydroxypyrimidine.

[0009] Solutions for solving problems

[0010] [1] A method for preparing a compound of formula (V), comprising the following steps:

[0011] 1) Take fatty alcohol alkali metal salt R 1 OM fatty alcohol R 1 OH solution, so that carbon monoxide reacts with the fatty alcohol R 1 OH undergoes carbonylation reaction to obtain a reaction solution 1 containing a compound of formula (I);

[0012]

[0013] 2) the reaction solution 1 containing the compound of formula (I) undergoes an amination reaction with liquid ammonia or ammonia gas to obtain a reaction solution 2 containing the compound of formula (II);

[0014]

[0015] 3) the reaction solution 2 containing the compound of formula (II) undergoes a cyclization reaction with the compound of formula (III) to obtain a reaction solution 3 containing the compound of formula (IV);

[0016]

[0017] 4) post-treating the reaction solution 3 containing the compound of formula (IV) to obtain the compound of formula (V);

[0018]

[0019] in,

[0020] R 1 , R 2 and R 3 Each independently selected from C 1-4 alkyl;

[0021] M is sodium or potassium.

[0022] [2] The preparation method according to [1], characterized in that

[0023] R 1 , R 2 and R 3 are each independently methyl or ethyl, preferably methyl; and / or,

[0024] M is sodium.

[0025] [3] The preparation method according to [1] or [2], characterized in that

[0026] In step 1),

[0027] The reaction temperature is 80-120°C, preferably 80-100°C, more preferably 80-85°C; and / or,

[0028] The carbon monoxide atmosphere pressure of the reaction is 3.0-5.0 MPa, preferably 3.0-4.2 MPa, more preferably 3.0-3.2 MPa or 3.8-4.2 MPa; and / or,

[0029] The reaction time is at least 5 hours.

[0030] [4] The preparation method according to any one of [1] to [3], characterized in that

[0031] In step 2),

[0032] The reaction temperature is 35-60°C, preferably 45-55°C, more preferably 45-50°C or 50-55°C; and / or,

[0033] The ammonia atmosphere pressure of the reaction is 0.10-1.0Mpa, preferably 0.10-0.20Mpa, more preferably 0.10-0.12Mpa; and / or,

[0034] The completion condition of the reaction is that the ammonia atmosphere pressure is below 0.02 MPa.

[0035] [5] The preparation method according to any one of [1] to [4], characterized in that

[0036] In step 3),

[0037] The compound of formula (III) and the fatty alcohol alkali metal salt R in step 1) 1 The molar ratio of OM is 1:3 to 1:5, preferably 1:3.5 to 1:4; and / or,

[0038] The reaction temperature is 60-70°C, preferably 60-65°C; and / or,

[0039] The reaction time is 1-3 hours, preferably 2-3 hours.

[0040] [6] The preparation method according to any one of [1] to [5], characterized in that

[0041] In step 4), the post-processing comprises the following steps:

[0042] a) alcohol removal: cooling the reaction solution 3 containing the compound of formula (IV) to a target temperature of 1, adding water, and heating the reaction solution 3 to a target temperature of 2, and performing reduced pressure distillation to obtain a mother liquor and a water-containing fatty alcohol;

[0043] b) acidification and separation: acidifying the mother liquor with an acid to a target pH value, and performing solid-liquid separation to obtain a crude compound of formula (V);

[0044] c) Washing and drying: The crude compound of formula (V) is washed with water and dried to obtain the compound of formula (V).

[0045] [7] The preparation method according to [6], characterized in that

[0046] In step a),

[0047] The target temperature 1 is 10-15°C; and / or,

[0048] The target temperature 2 is 40-60° C.; and / or,

[0049] The amount of water added is the same as the amount of fatty alcohol R 1 The mass ratio of OH is 1:0.8 to 1:1.5, preferably 1:1.1 to 1:1.3; and / or,

[0050] The reduced pressure distillation is carried out under a negative pressure condition of -0.07-0.10 MPa.

[0051] [8] The preparation method according to [6] or [7], characterized in that

[0052] In step a),

[0053] The aqueous fatty alcohol is distilled to obtain anhydrous fatty alcohol for resource utilization;

[0054] Preferably, the anhydrous fatty alcohol is used in the next round of synthesis of the compound of formula (V).

[0055] [9] The preparation method according to any one of [6] to [8], characterized in that

[0056] In step b),

[0057] The acid is an inorganic acid or an organic acid, preferably formic acid, hydrochloric acid or sulfuric acid, more preferably sulfuric acid; and / or,

[0058] The molar ratio of the dissociable hydrogen ions in the acid to the compound of formula (III) is 2:1 to 6:1, preferably 2:1 to 4:1; and / or,

[0059] The acidification temperature is 25-30°C; and / or,

[0060] The target pH value is 3.0-4.0; and / or,

[0061] The solid-liquid separation is centrifugal separation.

[0062] Effects of the Invention

[0063] 1. The present invention adopts a one-pot method to directly synthesize 4,6-dihydroxypyrimidine, which not only reduces the operation steps, but also avoids the cumbersome procedures and separation steps required for the synthesis of formamide, and also avoids the wastewater generated by negative pressure operation, saving time and equipment costs.

[0064] 2. The intermediate product methyl formate can react with ammonia, a by-product of the synthesis of 4,6-dihydroxypyrimidine, to generate formamide, a raw material for its synthesis, which is beneficial to the forward progress of the reaction.

[0065] 3. The whole process has high atomic economy, the raw materials are cheap and easy to obtain, the product purity and yield are high, and it is suitable for industrial production. DETAILED DESCRIPTION

[0066] Various exemplary embodiments, features and aspects of the present invention will be described in detail below. The word "exemplary" used here means "used as an example, embodiment or illustrative". Any embodiment described here as "exemplary" is not necessarily interpreted as being superior or better than other embodiments.

[0067] In addition, in order to better illustrate the present invention, numerous specific details are provided in the following specific embodiments. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In other examples, methods, means, equipment and steps well known to those skilled in the art are not described in detail in order to highlight the subject matter of the present invention.

[0068] Unless otherwise stated, the units used in this specification are all international standard units, and the numerical values ​​and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0069] In this specification, the word "may" means both performing a certain process and not performing a certain process.

[0070] In this specification, the references to "some specific / preferred embodiments", "other specific / preferred embodiments", "embodiments", etc., mean that the specific elements (e.g., features, structures, properties and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not exist in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any suitable manner.

[0071] In this specification, the numerical range expressed using "a numerical value A to a numerical value B" means a range including the endpoints numerical values ​​A and B.

[0072] Example

[0073] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0074] Embodiment 1:

[0075] S1: 777g of 30wt% sodium methoxide methanol solution was put into an autoclave, the temperature was raised to 80-85°C, and then carbon monoxide was introduced until the pressure reached 3.0-3.2Mpa, and the mixture was stirred and reacted for 2h. During the insulation process, the pressure dropped, and after the pressure dropped to 1.0Mpa, carbon monoxide was introduced again until the pressure reached 3.0-3.2Mpa, and the mixture was stirred and reacted for 3h at 80-85°C.

[0076] Step 1:

[0077] S2: After the reaction is completed, the temperature is lowered to 50-55°C, ammonia gas is introduced into the autoclave, the system pressure is 0.10-0.12Mpa, and the mixture is stirred at this temperature for 2-3h until the pressure drops to 0.02Mpa to obtain formamide.

[0078] Step2:

[0079] S3: Raise the temperature to 60-65°C, pump in 150 g of dimethyl malonate within 30 min, and keep at this temperature for 2-3 h to obtain a solid-liquid mixture containing 4,6-dihydroxypyrimidine disodium salt.

[0080] Step 3:

[0081] S4: After the reaction is completed, the temperature is lowered to 10-15°C, and 620g of water is added. Methanol is distilled off under negative pressure conditions of -0.07 to -0.10MPa to obtain a mother liquor of 4,6-dihydroxypyrimidine disodium salt. The aqueous methanol is further distilled to obtain anhydrous methanol, which can be used for the synthesis of sodium methoxide methanol solution.

[0082] S5: Acidify the 4,6-dihydroxypyrimidine disodium salt mother liquor with 534.1 g of 25 wt % sulfuric acid at a temperature of 25-30° C. to a pH value of 3.0-3.5, and centrifuge to obtain a crude 4,6-dihydroxypyrimidine product and waste water.

[0083] Step5:

[0084] S6: The crude 4,6-dihydroxypyrimidine was washed with 100 g of water and dried to obtain 108.2 g of 4,6-dihydroxypyrimidine with a content of 99.1% and a yield of 85.0%.

[0085] The yield of 4,6-dihydroxypyrimidine is calculated based on dimethyl malonate, yield = actual weight of 4,6-dihydroxypyrimidine product / theoretical weight of 4,6-dihydroxypyrimidine × 100%.

[0086] Embodiment 2:

[0087] S1: 716g of 30wt% sodium methoxide methanol solution was put into an autoclave, the temperature was raised to 95-100°C, and then carbon monoxide was introduced until the pressure was 3.0-3.2Mpa, and the mixture was stirred and reacted for 2h. During the insulation process, the pressure dropped, and after the pressure dropped to 1.0Mpa, carbon monoxide was introduced again until the pressure was 3.0-3.2Mpa, and the mixture was stirred and reacted for 3h at 95-100°C.

[0088] S2: After the reaction is completed, the temperature is lowered to 50-55°C, ammonia is introduced into the autoclave, the system pressure is 0.10-0.12Mpa, and the mixture is stirred at this temperature for 2-3 hours until the pressure drops to 0.02Mpa to obtain formamide. The temperature is then raised to 60-65°C, 150g of dimethyl malonate is pumped in within 30 minutes, and after the pumping is completed, the mixture is kept at this temperature for 2-3 hours to obtain a solid-liquid mixture containing 4,6-dihydroxypyrimidine disodium salt.

[0089] The other steps were the same as those in Example 1, and 102.4 g of the product 4,6-dihydroxypyrimidine was obtained with a content of 99.0% and a yield of 80.5%.

[0090] Embodiment 3:

[0091] S1: 716g of 30wt% sodium methoxide methanol solution was put into an autoclave, the temperature was raised to 80-85°C, and then carbon monoxide was introduced until the pressure reached 3.0-3.2Mpa, and the mixture was stirred and reacted for 2h. During the insulation process, the pressure dropped, and after the pressure dropped to 1.0Mpa, carbon monoxide was introduced again until the pressure reached 3.0-3.2Mpa, and the mixture was stirred and reacted for 3h at 80-85°C.

[0092] S2: After the reaction is completed, the temperature is lowered to 50-55°C, ammonia is introduced into the autoclave, the system pressure is 0.10-0.12Mpa, and the mixture is stirred at this temperature for 2-3 hours until the pressure drops to 0.02Mpa to obtain formamide. The temperature is then raised to 60-65°C, 150g of dimethyl malonate is pumped in within 30 minutes, and after the pumping is completed, the mixture is kept at this temperature for 2-3 hours to obtain a solid-liquid mixture containing 4,6-dihydroxypyrimidine disodium salt.

[0093] The other steps were the same as those in Example 1, and 104.1 g of the product 4,6-dihydroxypyrimidine was obtained with a content of 99.0% and a yield of 81.8%.

[0094] Embodiment 4:

[0095] S1: 777g of 30wt% sodium methoxide methanol solution was put into an autoclave, the temperature was raised to 80-85°C, and then carbon monoxide was introduced until the pressure reached 3.8-4.2Mpa, and the mixture was stirred and reacted for 2h. During the insulation process, the pressure dropped, and after the pressure dropped to 1.0Mpa, carbon monoxide was introduced again until the pressure reached 3.8-4.2Mpa, and the mixture was stirred and reacted for 3h at 85-90°C.

[0096] S2: After the reaction is completed, the temperature is lowered to 45-50°C, ammonia is introduced into the autoclave, the system pressure is 0.10-0.12Mpa, and the mixture is stirred at this temperature for 2-3 hours until the pressure drops to 0.02Mpa to obtain formamide. The temperature is then raised to 60-65°C, 150g of dimethyl malonate is pumped in within 30 minutes, and after the pumping is completed, the mixture is kept at this temperature for 2-3 hours to obtain a solid-liquid mixture containing 4,6-dihydroxypyrimidine disodium salt.

[0097] The other steps were the same as those in Example 1, and 110.5 g of the product 4,6-dihydroxypyrimidine was obtained with a content of 98.9% and a yield of 86.8%.

[0098] Embodiment 5:

[0099] S1: 777g of 30wt% sodium methoxide methanol solution was put into an autoclave, the temperature was raised to 80-85°C, and then carbon monoxide was introduced until the pressure reached 3.0-3.2Mpa, and the mixture was stirred and reacted for 2h. During the insulation process, the pressure dropped, and after the pressure dropped to 1.0Mpa, carbon monoxide was introduced again until the pressure reached 3.0-3.2Mpa, and the mixture was stirred and reacted for 3h at 80-85°C.

[0100] S2: After the reaction is completed, the temperature is lowered to 50-55°C, ammonia is introduced into the autoclave, the system pressure is 0.15-0.20Mpa, and the mixture is stirred at this temperature for 2-3 hours to obtain formamide. The temperature is then raised to 60-65°C, 150g of dimethyl malonate is pumped in within 30 minutes, and after the pumping is completed, the mixture is kept at this temperature for 2-3 hours to obtain a solid-liquid mixture containing 4,6-dihydroxypyrimidine disodium salt.

[0101] The other steps were the same as those in Example 1, and 100.8 g of the product 4,6-dihydroxypyrimidine was obtained with a content of 99.2% and a yield of 79.2%.

[0102] The reaction materials, reaction conditions, contents and yields of some steps in the above examples are summarized and listed in the following table.

[0103]

[0104] The present invention adopts a one-pot method to directly synthesize 4,6-dihydroxypyrimidine. Through experiments, it is found that when the amount of sodium methoxide is reduced, the yield decreases; when the reaction temperature of step 1) is increased, the yield decreases; when the system pressure in step 2) is increased, the yield also decreases. The whole process of the present invention has high atomic economy, cheap and easy-to-obtain raw materials, high product purity and yield, and is suitable for industrial production.

[0105] It should be noted that, although the technical solution of the present invention is introduced with specific examples, those skilled in the art will appreciate that the present invention should not be limited thereto.

[0106] The embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles of the embodiments, practical applications, or technical improvements in the market, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein.

Claims

1. A method for preparing a compound of formula (V), comprising the following steps: 1) taking a fatty alcohol R1OH solution of a fatty alcohol alkali metal salt R1OM, and subjecting carbon monoxide to a carbonylation reaction with the fatty alcohol R1OH to obtain a reaction solution 1 containing a compound of formula (I); 2) the reaction solution 1 containing the compound of formula (I) undergoes an amination reaction with liquid ammonia or ammonia gas to obtain a reaction solution 2 containing the compound of formula (II); 3) the reaction solution 2 containing the compound of formula (II) undergoes a cyclization reaction with the compound of formula (III) to obtain a reaction solution 3 containing the compound of formula (IV); 4) post-treating the reaction solution 3 containing the compound of formula (IV) to obtain the compound of formula (V); in, R1, R2 and R3 are each independently selected from C 1-4 alkyl; M is sodium or potassium.

2. The preparation method according to claim 1, characterized in that: R1, R2 and R3 are each independently methyl or ethyl, preferably methyl; and / or, M is sodium.

3. The preparation method according to claim 1 or 2, characterized in that: In step 1), The reaction temperature is 80-120°C, preferably 80-100°C, more preferably 80-85°C; and / or, The carbon monoxide atmosphere pressure of the reaction is 3.0-5.0 MPa, preferably 3.0-4.2 MPa, more preferably 3.0-3.2 MPa or 3.8-4.2 MPa; and / or, The reaction time is at least 5 hours.

4. The preparation method according to any one of claims 1 to 3, characterized in that In step 2), The reaction temperature is 35-60°C, preferably 45-55°C, more preferably 45-50°C or 50-55°C; and / or, The ammonia atmosphere pressure of the reaction is 0.10-1.0Mpa, preferably 0.10-0.20Mpa, more preferably 0.10-0.12Mpa; and / or, The completion condition of the reaction is that the ammonia atmosphere pressure is below 0.02 MPa.

5. The preparation method according to any one of claims 1 to 4, characterized in that: In step 3), The molar ratio of the compound of formula (III) to the fatty alcohol alkali metal salt R1OM in step 1) is 1:3 to 1:5, preferably 1:3.5 to 1:4; and / or, The reaction temperature is 60-70°C, preferably 60-65°C; and / or, The reaction time is 1-3 hours, preferably 2-3 hours.

6. The preparation method according to any one of claims 1 to 5, characterized in that In step 4), the post-processing comprises the following steps: a) alcohol removal: cooling the reaction solution 3 containing the compound of formula (IV) to a target temperature of 1, adding water, and heating the reaction solution 3 to a target temperature of 2, and performing reduced pressure distillation to obtain a mother liquor and a water-containing fatty alcohol; b) acidification and separation: acidifying the mother liquor with an acid to a target pH value, and performing solid-liquid separation to obtain a crude compound of formula (V); c) Washing and drying: The crude compound of formula (V) is washed with water and dried to obtain the compound of formula (V).

7. The preparation method according to claim 6, characterized in that: In step a), The target temperature 1 is 10-15°C; and / or, The target temperature 2 is 40-60° C.; and / or, The mass ratio of the amount of water added to the amount of the fatty alcohol R1OH in step 1) is 1:0.8 to 1:1.5, preferably 1:1.1 to 1:1.3; and / or, The reduced pressure distillation is carried out under a negative pressure condition of -0.07-0.10 MPa.

8. The preparation method according to claim 6 or 7, characterized in that: In step a), The aqueous fatty alcohol is distilled to obtain anhydrous fatty alcohol for resource utilization; Preferably, the anhydrous fatty alcohol is used in the next round of synthesis of the compound of formula (V).

9. The preparation method according to any one of claims 6 to 8, characterized in that: In step b), The acid is an inorganic acid or an organic acid, preferably formic acid, hydrochloric acid or sulfuric acid, more preferably sulfuric acid; and / or, The molar ratio of the dissociable hydrogen ions in the acid to the compound of formula (III) is 2:1 to 6:1, preferably 2:1 to 4:1; and / or, The acidification temperature is 25-30°C; and / or, The target pH value is 3.0-4.0; and / or, The solid-liquid separation is centrifugal separation.

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