A continuous preparation method of 2,4-diaminopyrimidine-3-oxide

Abstract

The present invention relates to a continuous preparation method of 2,4-diaminopyrimidine-3-oxide, comprising catalytically hydrogenating 2,4-diamino-6-chloropyrimidine through a micro-filled fixed bed reactor to obtain 2,4-diaminopyrimidine and performing a continuous oxidation reaction on 2,4-diaminopyrimidine to obtain 2,4-diaminopyrimidine-3-oxide. Compared with the prior art, the present invention adopts a continuous reaction technology to transform two hazardous chemical reactions of hydrogenation and oxidation into a continuous reaction, thereby realizing the intrinsic safety of chemical production, shortening the reaction time, improving the reaction conversion rate, greatly improving the reaction efficiency, and at the same time ensuring process stability, improving product purity, and ensuring the safety and reliability of product quality.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and specifically relates to a continuous preparation method of 2,4-diaminopyrimidine-3-oxide. Background Art

[0002] 2,4-Diaminopyrimidine-3-oxide, INCI name DIAMINOPYRIMIDINEOXIDE, has been included in the "Catalogue of Used Cosmetic Raw Materials (2021 Edition)". It is an active ingredient with a similar structure to minoxidil. Its effects include: 1. Preventing hair follicle blockage and strengthening hair roots to hair tips; 2. Promoting keratin fiber production and increasing hair density; 3. Softening collagen fiber network and preventing hair loss; 4. Prolonging hair growth cycle and accelerating hair growth; 5. Making fine hair grow healthily and strengthening hair. Due to its excellent anti-hair loss ability, 2,4-diaminopyrimidine-3-oxide is now widely used in various brands of anti-hair loss products and is deeply favored by consumers.

[0003] At present, the synthesis methods of 2,4-diaminopyrimidine-3-oxide in the prior art mainly include four categories. Among them, patent CN116143706A uses 2,4-dichloropyrimidine as a raw material, first undergoes two ammoniations, and then catalytic oxidation to obtain the product. The sodium amide reagent used is highly dangerous, the reaction conditions are harsh, and the conversion rate and yield of the oxidation step are not high.

[0004] Patent CN114315738A uses cytosine, isocytosine or uracil as raw materials, chlorinates the hydroxyl group, and then oxidizes and then aminolyzes to obtain the product. The aminolysis needs to use ammonia gas under high temperature and high pressure conditions, which has low safety and produces many by-products.

[0005] Patent CN114213340A uses chemical oxidation or enzyme oxidation cyclization, which are complex to operate and difficult to separate and purify. In addition, the solution leads to residual microorganisms, which affects the quality of the product.

[0006] The literature (Aust. J. Chem., 1981, 34, 1539-43) reported that 2,4-diamino-6-chloropyrimidine-3-oxide was dechlorinated by hydrogenation under palladium catalysis. During the reaction, the nitrogen-oxygen bond at the 3-position was partially reduced to generate 2,4-diaminopyrimidine. The yield of 2,4-diaminopyrimidine after refining was low, and multiple refinings were required to control a single impurity within 0.2%. In addition, the traditional autoclave reactor used a large amount of catalyst, the cost was high, and the catalytic hydrogenation was dangerous.

[0007] The above methods all have certain limitations when applied in industry. Therefore, there is still a need to develop an efficient, stable, safe method suitable for industrial application to prepare 2,4-diaminopyrimidine-3-oxide. Summary of the invention

[0008] The purpose of the present invention is to provide a method for continuously producing 2,4-diaminopyrimidine-3-oxide in view of the shortcomings of the prior art. Compared with the traditional intermittent kettle reaction in the prior art, the method of the present invention can achieve continuous operation, short reaction time, simple operation, effectively reduce the generation of by-products, higher product purity, significantly improved safety and economy, and is suitable for industrial application.

[0009] The objective of the present invention is achieved through the following technical solutions:

[0010] The present invention provides a continuous preparation method of 2,4-diaminopyrimidine-3-oxide, comprising the following steps:

[0011] (1) dissolving 2,4-diamino-6-chloropyrimidine in a solvent as a substrate solution to be hydrogenated;

[0012] (2) mixing the 2,4-diamino-6-chloropyrimidine solution described in step (1) with hydrogen in a micromixer to form a gas-liquid mixture;

[0013] (3) subjecting the gas-liquid mixture formed in step (2) to a catalytic hydrogenation reaction in a micro-filled fixed bed reactor to produce a 2,4-diaminopyrimidine solution;

[0014] (4) The 2,4-diaminopyrimidine solution and the oxidant prepared in step (3) are respectively introduced into a microchannel reactor for continuous oxidation reaction to prepare 2,4-diaminopyrimidine-3-oxide.

[0015] Preferably, the solvent in step (1) is selected from water, methanol, ethanol or a mixture thereof.

[0016] Preferably, the mass concentration of the 2,4-diamino-6-chloropyrimidine solution in step (1) is 5% to 25%, more preferably 10% to 15%.

[0017] Preferably, the micro mixer in step (2) is selected from a membrane dispersion reactor, a micro sieve reactor, a T-type reactor micro mixer, and a micro sieve reactor is more preferred.

[0018] Preferably, the catalyst in step (3) is a palladium-carbon-silicon catalyst, and the particle size D90 of the carbon carrier of the palladium-carbon-silicon catalyst is 200-500 μm.

[0019] Further preferably, the catalyst in step (3) is a palladium-carbon-silicon catalyst, and the particle size D90 of the carbon carrier of the palladium-carbon-silicon catalyst is 300-450 μm.

[0020] Preferably, in step (3), the residence time of the gas-liquid mixture in the micro-packed bed reactor is 60 to 180 seconds; the reaction temperature is 80 to 160° C.; and the reaction pressure is 1 to 5 MPa.

[0021] Further preferably, in step (3), the residence time of the gas-liquid mixture in the micro-packed bed reactor is 90-100 seconds; the reaction temperature is 100-110° C.; and the reaction pressure is 2-2.5 MPa.

[0022] Most preferably, in step (3), the residence time of the gas-liquid mixture in the micro-packed bed reactor is 100 seconds; the reaction temperature is 100° C.; and the reaction pressure is 2-2.5 MPa.

[0023] Preferably, the oxidant in step (4) is selected from hydrogen peroxide, peracetic acid, and perbenzoic acid.

[0024] Preferably, in step (4), the molar ratio of 2,4-diaminopyrimidine to the oxidant is 1:1-6; the reaction temperature is 0-30°C; and the residence time is 20 seconds to 100 seconds.

[0025] Further preferably, in step (4), the molar ratio of 2,4-diaminopyrimidine to the oxidant is 1:2-3; the reaction temperature is 5-15° C.; and the residence time is 30 seconds to 50 seconds.

[0026] Most preferably, in step (4), the molar ratio of 2,4-diaminopyrimidine to the oxidant is 1:2-2.5; the reaction temperature is 5-15° C.; and the residence time is 40 seconds.

[0027] The reaction process of the present invention is as follows:

[0028] Compared with the prior art, the present invention has the following advantages:

[0029] 1. Compared with the prior art, the technology of the present invention unexpectedly achieves the efficient preparation of high-purity 2,4-diaminopyrimidine-3-oxide using 2,4-diamino-6-chloropyrimidine as a raw material.

[0030] Compared with the preparation method in the prior art of first subjecting 2,4-diamino-6-chloropyrimidine to an oxidation reaction and then subjecting it to a catalytic hydrogenation dechlorination atom, the present invention first subjects it to a catalytic hydrogenation dechlorination and then subjecting it to an oxidation reaction, thereby effectively avoiding the introduction of 2,4-diaminopyrimidine as a by-product into the product, and the product does not require a complex recrystallization process, and directly crystallizes after the reaction is completed, so that the product purity can reach more than 99%, while the reaction conversion rate is close to 100%, and the product yield can reach more than 90%.

[0031] 2. The catalytic hydrogenation dechlorination step of the present invention is precisely controllable, and the catalyst deactivation caused by the violent exothermic reaction can be avoided. The 100% conversion of 2,4-diamino-6-chloropyrimidine can be achieved within 60-180 seconds, and the yield is higher. The generated 2,4-diaminopyrimidine solution can be directly subjected to the next step reaction after simple gas-liquid separation, and the product does not need to be separated and purified, and no waste is discharged. That is, the present invention can complete the catalytic hydrogenation reaction of 2,4-diamino-6-chloropyrimidine safely, simply, efficiently, and environmentally friendly.

[0032] 3. Compared with the oxidation reaction carried out in a traditional reactor, the oxidation reaction of the present invention is carried out in a microchannel reactor. The heat released by the oxidation reaction can be discharged in time, the safety risk is greatly reduced, and the occurrence of side reactions can be effectively reduced. The target product is obtained with high conversion rate, high selectivity and high safety.

[0033] 4. The present invention adopts a continuous method to prepare 2,4-diaminopyrimidine-3-oxide, has no amplification effect, and can be rapidly scaled up to ton-level production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 It is a process flow chart of the present invention, wherein 1 is a micro mixer, 2 is a fixed bed reactor, 3 is a gas-liquid separator, and 4 is a microchannel reactor.

[0035] Figure 2 This is the liquid phase spectrum of 2,4-diaminopyrimidine-3-oxide obtained in Example 1 of the present invention. DETAILED DESCRIPTION

[0036] The present invention is further described below in conjunction with the accompanying drawings and specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The operating methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by equipment manufacturers. Example 1

[0037] A 2,4-diamino-6-chloropyrimidine methanol solution was prepared with a mass concentration of 10%. The solution was mixed with hydrogen in a micromixer, and the resulting gas-liquid mixture passed through a microreactor filled with a 5% palladium-carbon-silicon catalyst (catalyst size D90 of about 300 microns). The reaction temperature was set to 100° C., the reaction pressure was 2.5 MPa, the residence time was 100 seconds, and the 2,4-diaminopyrimidine solution after gas-liquid separation was collected at the outlet of the microreactor.

[0038] The 2,4-diaminopyrimidine solution obtained in the first step and the dichloromethane solution of benzoic acid peroxide are respectively injected into the microchannel reactor through two plunger pumps, and the molar ratio of diaminopyrimidine to benzoic acid peroxide is controlled to be 1:2.5, the reaction temperature is controlled to be 10-15°C, and the residence time is 40 seconds. The effluent is adjusted to pH 7-9 with a 20% sodium hydroxide aqueous solution, stirred and crystallized, filtered, dried, and refined to obtain 2,4-diaminopyrimidine-3-oxide. The product is a white solid with a conversion rate of 99.5% and a yield of 90.3% (calculated based on the consumption of 2,4-diamino-6-chloropyrimidine during the time of collecting the reaction product), a purity greater than 99.82%, and a single impurity not exceeding 0.2%. Example 2

[0039] A 70% ethanol solution of 2,4-diamino-6-chloropyrimidine was prepared with a mass concentration of 15%. The solution was mixed with hydrogen in a micromixer, and the resulting gas-liquid mixture passed through a microreactor filled with a 5% palladium-carbon-silicon catalyst (catalyst size D90 of about 450 μm). The reaction temperature was set to 100° C., the reaction pressure was 2.0 MPa, and the residence time was 100 seconds. The 2,4-diaminopyrimidine solution after gas-liquid separation was collected at the outlet of the microreactor.

[0040] The 2,4-diaminopyrimidine solution obtained in the first step and the dichloromethane peracetic acid solution were injected into the microchannel reactor through two plunger pumps, respectively, and the molar ratio of diaminopyrimidine to peracetic acid was controlled to be 1:2, the reaction temperature was controlled to be 5-10°C, and the residence time was 40 seconds. The effluent was adjusted to pH 7-9 with a 20% sodium hydroxide aqueous solution, stirred and crystallized, filtered, dried, and refined to obtain 2,4-diaminopyrimidine-3-oxide. The product was a white solid with a conversion rate of 99.8% and a yield of 89.2% (calculated based on the consumption of 2,4-diamino-6-chloropyrimidine during the time of collecting the reaction product), a purity of 99.90%, and a single impurity not exceeding 0.2%.

[0041] In addition, it should be understood that practitioners in the relevant field can easily make other different forms of changes or modifications based on the above description. Obviously, these equivalent forms also fall within the protection scope of the present invention.

Claims

1. A continuous preparation method of 2,4-diaminopyrimidine-3-oxide, characterized in that: The following steps are involved: (1) dissolving 2,4-diamino-6-chloropyrimidine in a solvent as a substrate solution to be hydrogenated; (2) mixing the 2,4-diamino-6-chloropyrimidine solution described in step (1) with hydrogen in a micromixer to form a gas-liquid mixture; (3) subjecting the gas-liquid mixture formed in step (2) to a catalytic hydrogenation reaction in a micro-filled fixed bed reactor to produce a 2,4-diaminopyrimidine solution; (4) introducing the 2,4-diaminopyrimidine solution obtained in step (3) and an oxidant into a microchannel reactor for continuous oxidation reaction to obtain 2,4-diaminopyrimidine-3-oxide; Wherein, the solvent in step (1) is selected from water, methanol, ethanol or a mixture thereof; The mass concentration of the 2,4-diamino-6-chloropyrimidine solution in step (1) is 5% to 25%; In step (3), the catalyst is a palladium-carbon-silicon catalyst, and the particle size D90 of the carbon carrier of the palladium-carbon-silicon catalyst is 200-500 microns; In step (3), the residence time of the gas-liquid mixture in the micro-packed bed reactor is 60 to 180 seconds; the reaction temperature is 80 to 160° C.; and the reaction pressure is 1 to 5 MPa; The oxidant in step (4) is selected from hydrogen peroxide, peracetic acid, and perbenzoic acid; In step (4), the molar ratio of 2,4-diaminopyrimidine to the oxidant is 1:1-6; the reaction temperature is 0-30°C; and the residence time is 20 seconds-100 seconds.

2. The method according to claim 1, characterized in that The mass concentration of the 2,4-diamino-6-chloropyrimidine solution in step (1) is 10% to 15%.

3. The method according to claim 1, characterized in that The catalyst in step (3) is a palladium-carbon-silicon catalyst, and the carbon carrier particle size D90 of the palladium-carbon-silicon catalyst is 300-450 microns.

4. The method according to claim 1, characterized in that: In step (3), the residence time of the gas-liquid mixture in the micro-packed bed reactor is 90-100 seconds; the reaction temperature is 100-110° C.; and the reaction pressure is 2-2.5 MPa.

5. The method according to claim 1, characterized in that In step (4), the molar ratio of 2,4-diaminopyrimidine to the oxidant is 1:2-3; the reaction temperature is 5-15° C.; and the residence time is 30 seconds to 50 seconds.

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