A method for preparing 3,6-diaminopyrazine-2,5-dicarboxylic acid and its synthetic intermediates

Abstract

A method for preparing 3,6-diaminopyrazine-2,5-dicarboxylic acid and its synthetic intermediates, the method comprising the step of preparing pyrimidino[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone or its disalt (pteridine) from 5-aminouracil or its monosalt.

Description

Technical Field

[0001] This disclosure relates to a method for preparing 3,6-diaminopyrazine-2,5-dicarboxylic acid and its synthetic intermediates, the method comprising the step of preparing pyrimidino[4,5-g]pterodin-2,4,7,9(1H,3H,6H,8H)-tetraone or its disalt (pterodin) from 5-aminouracil or its monosalt. Background Technology

[0002] 3,6-Diaminopyrazine-2,5-dicarboxylic acid (MB-301) is a key intermediate in the preparation of pyrazine derivatives 2,5-bis[N-(1-carboxy-2-hydroxy)]carbamoyl-3,6-diaminopyrazine (MB-102), which serves as a fluorescent tracer. Two existing synthetic routes exist for the preparation of 3,6-diaminopyrazine-2,5-dicarboxylic acid.

[0003] Synthesis Route 1 ( Dyes and Pigments (1998, 39, 49-68) involves the preparation of 2,5-diamino-3,6-dicyanopyrazine via a cyclization reaction of hydrogen cyanide and diphenyl disulfide, followed by hydrolysis to yield MB-301. The diphenyl disulfide used in this route has a foul odor, and hydrogen cyanide is a highly toxic and controlled raw material. Therefore, this route has significant drawbacks and is unsuitable for industrial production.

[0004] Synthetic route 2 (DE 10 2016 205 615 A1, 2016) uses uracil as the starting material, and prepares MB-301 (Formula 4) through nitration, reduction, oxidative cyclization using potassium ferricyanide as an oxidant, and hydrolysis. In the reduction reaction, ammonia is used as a basic reagent and the reaction is carried out at 75°C. Under these conditions, ammonia is volatile, and the generated ammonia gas is harmful to the human body. Therefore, this reaction system poses a safety hazard. Another drawback of this synthetic route is that the yield of the oxidative cyclization reaction for preparing pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I') is only 21%, which severely limits the overall yield of the synthetic route. This results in low cost and is unsuitable for industrial production.

[0005] Synthesis Route 2

[0006]

[0007] Although the first report on the preparation method of MB-301 can be traced back to 1966 ( Dyes and Pigments (1999, 41, 183-191), however, after more than 50 years of development, serious problems such as low yield, poor safety and low cost-effectiveness are still not solved and it is not suitable for industrial production.

[0008] Therefore, there remains a need to develop improved methods for producing MB-301 and its synthetic intermediates (especially compounds of formula (I') or their salts) with high yields, high purity, high safety, and high cost-effectiveness, particularly methods suitable for industrial production. Improved preparation methods for synthetic intermediates (especially compounds of formula (I') or their salts) would translate into higher yields of MB-301, and consequently, higher yields of MB-102 and lower unit manufacturing costs. Invention Overview

[0010] In one aspect, this disclosure provides a method for preparing compounds of formula (I) or salts thereof (pteridine).

[0011]

[0012] Formula (I);

[0013] The method includes preparing an aqueous solution of a compound of formula (II) or a salt thereof.

[0014]

[0015] Equation (II),

[0016] Simultaneous contact in a container with an aqueous solution containing a metal oxidant and an aqueous solution containing a proton acceptor to form a compound of formula (I) or a salt thereof; and wherein X1 optionally present + and the optional existence of X2 + Independently selected from H + Li + Na + K + 、Rb + Cs + NH4 + Be 2+ Mg 2+ Ca 2+ 、Sr 2+ and Ba 2+ .

[0017] In one aspect, this disclosure provides a method for preparing a pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), said method comprising the steps of:

[0018]

[0019] (S2) 5-aminouracil of formula (II') in solution A is reacted with an oxidant in solution B in the presence of a base in a reactor to obtain pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), wherein solution A and solution B are added to the reactor simultaneously at constant flow rates and mixed, and wherein the constant flow rates of solution A and solution B may be the same or different.

[0020] The inventors discovered through research that by simultaneously adding the compound of formula (II') and the oxidant K3 [Fe(III)(CN)6] to the reactor at appropriate constant flow rates to mix them, the oxidative cyclization reaction from the compound of formula (II') to the compound of formula (I') in the above-mentioned synthetic route 2 can be carried out, which can greatly improve the yield of the compound of formula (I') and the overall yield of the entire synthetic route, and improve cost-effectiveness.

[0021] Furthermore, the inventors modified the alkali used in the reduction reaction of synthetic route 2 above, replacing ammonia water, thereby making the synthesis process safer and more environmentally friendly. Based on the above research and findings, the inventors completed this invention.

[0022] The above and other aspects of this disclosure are described in more detail below. Invention Details

[0024] In the first aspect, this paper provides a method for preparing pteridine (a key intermediate in the preparation of MB-301) in high yield and high purity. Advantageously, it has been found that the simultaneous addition of reactants increases the yield to approximately 90%, which is a significant improvement compared to prior art methods. The method disclosed herein includes other process improvements, such as the temperature at which the method is carried out, the optimal molar ratio of starting materials, the rate of addition of starting materials, the concentration of starting materials, and the rapid rate of reaction at common reaction temperatures.

[0025] I. Method for preparing compounds of formula (I)

[0026] This disclosure includes methods for preparing compounds of formula (I) or salts thereof.

[0027]

[0028] Formula (I);

[0029] The method includes preparing an aqueous solution of a compound of formula (II) or a salt thereof.

[0030]

[0031] Equation (II),

[0032] Simultaneous contact in a container with an aqueous solution containing a metal oxidant and an aqueous solution containing a proton acceptor to form a compound of formula (I) or a salt thereof; and wherein X1 optionally present + and the optional existence of X2 + Independently selected from H + Li + Na + K + 、Rb + Cs + NH4 + Be 2+ Mg 2+ Ca 2+ 、Sr 2+ and Ba 2+ Each of the starting materials is described in more detail below.

[0033] (a) An aqueous solution of the compound of formula (II)

[0034] The compounds of formula (II) have been described in detail above. In some embodiments, X1 + It can be hydrogen. In other embodiments, X1 + It can be selected from Li + Na + K + 、Rb + Cs + or NH4 + A monovalent cation. In other embodiments, X1 + It can be selected from Be 2+ Mg 2+ Ca 2+ 、Sr 2+ Or Ba 2+ A divalent cation. In a preferred embodiment, X1 + It is selected from Na + K + or NH4 + Monovalent cations.

[0035] The water used to prepare the aqueous solution of the compound of formula (II) can be deionized water, distilled water, distilled deionized water or drinking water (tap water).

[0036] An aqueous solution of the compound of formula (II) can be prepared using various methods. In one embodiment, X1 can be... + The compound of formula (II), which is a monovalent or divalent cation, is dissolved in water until homogeneity is achieved. In another embodiment, X1 can be... + For H +The compound of formula (II) can be suspended in water and an equimolar amount of proton acceptor can be added to form a salt of formula (II).

[0037] Generally, aqueous solutions of the compound of formula (II) can have a concentration of about 0.75 M to about 1.25 M. In various embodiments, aqueous solutions of the compound of formula (II) can have a concentration of about 0.75 M to about 1.25 M, about 0.8 M to about 1.0 M, or about 0.85 M to about 0.95 M. In a preferred embodiment, the concentration of the aqueous solution of the compound of formula (II) can be about 0.9 M.

[0038] (b) Aqueous solution of metal oxidizing agent

[0039] An aqueous solution of a metal oxidant is prepared by dissolving a suitable metal oxidant in water until a homogeneous solution is obtained.

[0040] Various metal oxidants can be used in the method. Typically, the metal oxidant contains Fe(III) or Mn(III). Non-limiting examples of useful metal oxidants containing Fe(III) or Mn(III) include potassium ferricyanide, lithium ferricyanide, sodium ferricyanide, ferric chloride, ferric bromide, manganese acetylacetonate(III), or manganese acetate(III). In a preferred embodiment, the metal oxidant may be potassium ferricyanide.

[0041] In some embodiments, the metal oxidant may also be sodium pentacyanocarbonylferric sulfate (Na2[Fe(CN)5(CO)]) or sodium pentacyanoammonium iron salt (Na3[Fe(CN)5NH3).

[0042] The water used to prepare the aqueous solution of the metal oxidant can be deionized water, distilled water, distilled deionized water, or drinking water (tap water).

[0043] Typically, aqueous solutions of metal oxidants containing Fe(III) or Mn(III) may have a concentration of about 0.75 M to about 1.25 M. In various embodiments, aqueous solutions of metal oxidants containing Fe(III) or Mn(III) may have a concentration of about 0.75 M to about 1.25 M, about 0.8 M to about 1.0 M, or about 0.85 M to about 0.95 M. In a preferred embodiment, the metal oxidant containing Fe(III) or Mn(III) may have a concentration of about 0.9 M.

[0044] Typically, the molar ratio of the metal oxidant to the compound of formula (II) can be from about 2.8:1.0 to about 3.5:1.0. In various embodiments, the molar ratio of the metal oxidant to the compound of formula (II) can be from about 2.8:1.0 to about 3.5:1.0, from about 2.9:1.0 to about 3.3:1.0, or from about 3.0:1.0 to about 3.2:1.0. In a preferred embodiment, the molar ratio of the metal oxidant to the compound of formula (II) can be from about 3.0:1.0 to about 3.2:1.0.

[0045] (c) Aqueous solution of proton acceptor

[0046] Aqueous solutions of proton acceptors can be prepared by dissolving an appropriate amount of proton acceptor in an appropriate amount of water until the desired concentration is achieved, or by adding an appropriate amount of water to a commercially available concentrated solution of proton acceptor.

[0047] A variety of proton acceptors can be used in this process. Non-limiting examples of suitable proton acceptors may be selected from Li₂CO₃, LiOH, Na₂CO₃, NaOH, K₂CO₃, KOH, Rb₂CO₃, RbOH, Cs₂CO₃, CsOH, NH₄OH, BeCO₃, Be(OH)₂, MgCO₃, Mg(OH)₂, CaCO₃, Ca(OH)₂, SrCO₃, Sr(OH)₂, BaCO₃, or Ba(OH)₂. In some embodiments, the proton acceptor may be Li₂CO₃, LiOH, Na₂CO₃, NaOH, K₂CO₃, KOH, Rb₂CO₃, RbOH, Cs₂CO₃, CsOH, or NH₄OH. In a preferred embodiment, the proton acceptor is Na₂CO₃, NaOH, K₂CO₃, KOH, NaHCO₃, (CH₃)₄NOH, CsOH, or NH₄OH.

[0048] The water used to prepare the aqueous solution of the proton acceptor can be deionized water, distilled water, distilled deionized water, or drinking water (tap water).

[0049] Typically, the aqueous solution of the proton acceptor can have a concentration of about 0.75 M to about 1.50 M. In various embodiments, the aqueous solution of the proton acceptor can have a concentration of about 0.75 M to about 1.50 M, about 0.8 M to about 1.4 M, or about 0.90 M to about 1.35 M. In a preferred embodiment, the concentration of the proton acceptor can be about 0.90 M to about 1.35 M.

[0050] Typically, the molar ratio of the proton acceptor to the compound of formula (II) can be from about 3.5:1.0 to about 6.0:1.0. In various embodiments, the molar ratio of the proton acceptor to the compound of formula (II) can be from about 3.5:1.0 to about 6.0:1.0, from about 3.8:1.0 to about 5.5:1.0, or from about 4.0:1.0 to about 4.2:1.0. In a preferred embodiment, the molar ratio of the proton acceptor to the compound of formula (II) can be from about 4.0:1.0 to about 4.2:1.0.

[0051] (d) Reaction conditions

[0052] The method involves simultaneously contacting an aqueous solution of the compound of formula (II), an aqueous solution of the metal oxidant, and an aqueous solution of the proton acceptor. For example, the aqueous solution of the compound of formula (II) and the aqueous solution of the metal oxidant can be simultaneously added (e.g., by injection) to a container containing an aqueous solution of the proton acceptor. Alternative addition strategies for simultaneous contact of the three solutions can be readily conceived by those skilled in the art.

[0053] An aqueous solution of the compound of formula (II) and an aqueous solution of the metal oxidant may be added to a container simultaneously at constant rates and mixed. The constant rates of the two aqueous solutions may be the same or different. In some embodiments, the ratio of the rate of the aqueous solution of the compound of formula (II) to the rate of the aqueous solution of the metal oxidant may be from about 1:10 to 1:1, including from about 1:8 to 1:1.5, about 1:6 to 1:2, or about 1:4 to 1:3. The two aqueous solutions may be added to the container simultaneously using a constant flow control device (e.g., a peristaltic pump or a syringe pump).

[0054] In some embodiments, the rate of the aqueous solution of the compound of formula (II) and the rate of the aqueous solution of the metal oxidant do not exceed about 1000 mL / min, for example, not more than about 900, about 800 mL / min, about 700 mL / min, about 600 mL / min, about 500 mL / min, about 400 mL / min, about 300 mL / min, about 200 mL / min or about 100 mL / min, or not more than about 90 mL / min, about 80 mL / min, about 60 mL / min, about 50 mL / min or about 30 mL / min, for example, not more than about 25 mL / min, not more than about 20 mL / min or not more than about 15 mL / min, for example, about 2 to 30 mL / min, about 4 to 25 mL / min, about 8 to 20 mL / min or about 10 to 15 mL / min.

[0055] In some embodiments, the proton acceptor and the compound of formula (II) may be contained together in the same aqueous solution.

[0056] In some embodiments, the container can be a microreactor, such as a microchannel reactor or a micromixer. In other embodiments, the container can be a conventional reactor, such as a tubular reactor or a batch reactor.

[0057] The methods described herein can be performed in batch mode, semi-continuous mode, or continuous mode.

[0058] Typically, the reaction is carried out at a temperature of about -6°C to about 25°C. In various embodiments, the reaction temperature can be about -6°C to about 25°C, about -6°C to about 10°C, or about -6°C to about 0°C. In one embodiment, the reaction can be carried out at a temperature of about 0°C. The reaction is typically carried out under ambient pressure. The reaction can also be carried out under an inert atmosphere, such as nitrogen, argon, or helium.

[0059] Typically, the reaction is considered to be completed within seconds after the simultaneous and complete addition of aqueous solutions of formula (II), the metal oxidant, and the proton acceptor. The completion time of this reaction indicates a rapid reaction rate.

[0060] In this context, "the reaction is considered complete" generally means that the reaction mixture contains a significantly reduced amount of the compound of formula (II). Typically, the amount of the compound of formula (II) remaining in the reaction mixture at the end of the reaction may be less than about 1.0%, less than about 0.5%, or less than about 0.1%.

[0061] For example, compounds of formula (I) can be separated by various methods known in the art, such as filtration or centrifugation. Compounds of formula (I) can be further washed with a minimal amount of water and dried using various methods known in the art.

[0062] The compound of formula (I) may have a yield of at least about 70%. In various embodiments, the compound of formula (I) may have a yield of at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 92.5%, or at least about 95%. In a particular embodiment, the yield may be at least about 90%.

[0063] Typically, the yield of compounds of formula (I) prepared by the methods disclosed herein is significantly higher than the yield of said compounds prepared by prior art methods.

[0064] The compound of formula (I) may have a purity greater than about 95%, as measured by high-performance liquid chromatography (HPLC) or other methods known in the art. In various embodiments, the compound of formula (I) may have a purity greater than about 95%, greater than about 97%, or greater than about 98%, as measured by HPLC. In a preferred embodiment, the compound of formula (I) has a purity greater than 98%, as measured by HPLC.

[0065] (e) Exemplary Implementation

[0066] In some embodiments, the proton acceptor is selected from Na₂CO₃, NaOH, K₂CO₃, KOH, NaHCO₃, (CH₃)₄NOH, or NH₄OH; the metal oxidant is selected from potassium ferricyanide, lithium ferricyanide, sodium ferricyanide, ferric chloride, ferric bromide, manganese acetylacetonate (III), or manganese acetate (III); the molar ratio of the proton acceptor to the compound of formula (II) is from about 3.5:1.0 to about 6.0:1.0; the molar ratio of the metal oxidant to the compound of formula (II) is from about 2.8:1.0 to about 3.5:1.0; and the method is carried out at a temperature from about -6°C to about 25°C. The compound of formula (I) is formed within seconds of simultaneous contact of an aqueous solution of the compound of formula (II), the proton acceptor, and the metal oxidant. The compound of formula (I) has a yield of at least 90% or at least 95% and a purity of at least 98%.

[0067] In another embodiment, the proton acceptor is selected from Na₂CO₃, NaOH, K₂CO₃, KOH, NaHCO₃, (CH₃)₄NOH, or NH₄OH; the metal oxidant is selected from potassium ferricyanide, lithium ferricyanide, sodium ferricyanide, ferric chloride, ferric bromide, manganese acetylacetone (III), or manganese acetate (III); the molar ratio of the proton acceptor to the compound of formula (II) is from about 4.0:1.0 to about 4.2:1.0; the molar ratio of the metal oxidant to the compound of formula (II) is from about 3.0:1.0 to about 3.2:1.0; and the method is carried out at a temperature of -6°C to about 0°C. The compound of formula (I) is formed within seconds of simultaneous contact of an aqueous solution of the compound of formula (II), the proton acceptor, and the metal oxidant. The compound of formula (I) has a yield of at least 90% or at least 95% and a purity of at least 98%.

[0068] In some embodiments, the proton acceptor is KOH; the metal oxidant is potassium ferricyanide; the molar ratio of KOH to the compound of formula (II) is from about 3.5:1.0 to about 6.0:1.0; the molar ratio of potassium ferricyanide to the compound of formula (II) is from about 2.8:1.0 to about 3.5:1.0; and the method is carried out at a temperature of about -6°C to about 25°C. The compound of formula (I) is formed within seconds of simultaneous contact of the compound of formula (II), the proton acceptor, and the aqueous solution of the metal oxidant. The compound of formula (I) has a yield of at least 90% or at least 95% and a purity of at least 98%.

[0069] In a particular embodiment, the proton acceptor is KOH; the metal oxidant is potassium ferricyanide; the molar ratio of KOH to the compound of formula (II) is about 4.0:1.0 to about 4.2:1.0; the molar ratio of potassium ferricyanide to the compound of formula (II) is about 3.0:1.0 to about 3.2:1.0; and the method is carried out at a temperature of -6°C to about 0°C. The compound of formula (I) is formed within seconds of simultaneous contact of the compound of formula (II), the proton acceptor, and the aqueous solution of the metal oxidant. The compound of formula (I) has a yield of at least 90% or at least 95% and a purity of at least 98%.

[0070] In a second aspect, this disclosure provides a method for preparing a pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), said method comprising the following steps:

[0071]

[0072] (S2) 5-aminouracil of formula (II') in solution A is reacted with an oxidant in solution B in the presence of a base in a reactor to obtain pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), wherein solution A and solution B are added to the reactor simultaneously at constant flow rates and mixed, and wherein the constant flow rates of solution A and solution B may be the same or different.

[0073] In some embodiments, the base may be added to the reactor as a separate solution. Alternatively, in other embodiments, the base is added to the reactor in only one of solutions A and B. In some embodiments, the base is contained in solution A together with the 5-aminouracil; in other embodiments, the base is contained in solution B together with the oxidant. This disclosure also covers embodiments in which a portion of the base is contained in solution A together with the 5-aminouracil, and another portion is contained in solution B together with the oxidant. In a preferred embodiment, the base is added to the reactor in solution A together with the 5-aminouracil.

[0074] In the reaction mixture obtained according to the oxidative cyclization step of synthetic route 2, the inventors detected the presence of urea, which is a byproduct of the oxidative cyclization reaction. Without wishing to be limited by any theory, the inventors hypothesize that the formation of a transient intermediate during this reaction, which undergoes severe degradation (generating urea), may be the main reason for the low yield of this reaction step; however, according to the method of this disclosure, by simultaneously adding the two solutions to the reactor at appropriate constant flow rates for mixing, for example by utilizing microfluidic technology (including, for example, precise control of the amount of reactants added and the degree of mixing), the degradation of the transient intermediate can be avoided or reduced, thereby greatly increasing the yield of the compound of formula (I'), up to 40% or higher, preferably 50% or higher, more preferably 60% or higher, and even more preferably 80% or higher (e.g., about 84%).

[0075] In some embodiments, solution A and solution B can be added to the reactor simultaneously via constant flow control devices, such as peristaltic pumps or syringe pumps.

[0076] In some embodiments, the flow rates of solution A and solution B do not exceed about 1000 mL / min, for example, not exceeding about 900, about 800, about 700, about 600, about 500, about 400, about 300, about 200, or about 100 mL / min, or not exceeding about 90, about 80, about 60, about 50, or about 30 mL / min, for example, not exceeding about 25 mL / min or not exceeding about 20 mL / min, for example, about 2 to 30 mL / min, about 4 to 25 mL / min, about 8 to 20 mL / min, or about 10 to 15 mL / min. Advantageously, the flow rates of solution A and solution B do not exceed about 15 mL / min. In some embodiments, the flow rate of solution A and the flow rate of solution B are each about 2 to 15 mL / min, for example, about 3 to 12 mL / min or about 6 to 10 mL / min. In some preferred embodiments, the flow rate of solution A is about 2 to 10 mL / min, for example, about 2, 3, 4, 5, 6, 7, 8, 9, or 10 mL / min. In some preferred embodiments, the flow rate of solution B is about 2 to 15 mL / min, for example, about 2, 3, 4, 6, 8, 10, 12, 14, or 15 mL / min.

[0077] The flow rates of solution A and solution B can be the same or different. Advantageously, the flow rate of solution A is less than or equal to the flow rate of solution B. In some embodiments, the ratio of the flow rate of solution A to the flow rate of solution B is about 1:10 to 1:1, including about 1:1, or about 1:10 to less than 1:1, for example about 1:8 to 1:1.5, about 1:6 to 1:2, or about 1:4 to 1:3; preferably about 1:3 to 1:1. In some preferred embodiments, the ratio of the flow rate of solution A to the flow rate of solution B is about 1:2 or about 1:3 (e.g., about 2 and 6 mL / min, respectively). Particularly advantageously, the inventors have found that adding both solutions simultaneously to the reactor at the same constant flow rate yields the compound of formula (I') in a higher yield. Therefore, in a particularly preferred embodiment, the ratio of the flow rate of solution A to the flow rate of solution B is about 1:1, for example, both are about 2, 3, 6 or 10 mL / min.

[0078] In some embodiments, the molar ratio of the base to the 5-aminouracil of formula (II') is from about 3.0:1.0 to about 6.0:1.0. In some preferred embodiments, the molar ratio of the base to the compound of formula (II') is from about 3.0:1.0 to about 5.5:1.0.

[0079] In some embodiments, the molar ratio of the oxidant to the 5-aminouracil of formula (II') is from about 3.0:1.0 to about 3.5:1.0. In some preferred embodiments, the molar ratio of the metal oxidant to the compound of formula (II) is from about 3.0:1.0 to about 3.4:1.0.

[0080] In some embodiments, the solvent in solution A and the solvent in solution B are each a polar solvent, preferably selected from one, two or more of water, methanol, ethanol, acetonitrile and tetrahydrofuran, more preferably water.

[0081] In some embodiments, solution A and solution B each have a temperature of about 0 to 8 °C, for example, about 0 to 4 °C or about 2 to 6 °C.

[0082] In some embodiments, the reaction described in step S2 is carried out at a temperature of about -20 to 20°C, preferably about -10 to 10°C, for example about -5 to 5°C, such as about -10, -5, 0 or 5°C.

[0083] In some embodiments, about 3 to 5 equivalents of the oxidant are used relative to the 5-aminouracil of formula (II').

[0084] In some embodiments, the oxidant is a reagent containing iron (III), preferably one or more selected from potassium ferricyanide (K3[Fe(III)(CN)6]), sodium pentacyanocarbonylferricate (Na2[Fe(CN)5(CO)]), and sodium pentacyanoammonium iron (Na3[Fe(CN)5NH3), with potassium ferricyanide being the most preferred. In some embodiments, the oxidant may also be one or more selected from lithium ferricyanide, sodium ferricyanide, ferric chloride, and ferric bromide. In other embodiments, the oxidant may also be a reagent containing Mn (III), such as manganese acetylacetonate (III) and manganese acetate (III).

[0085] In some embodiments, the alkali mentioned in step S2 is one or more selected from sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate, lithium hydroxide, and ammonia water, preferably potassium hydroxide. In some embodiments, the alkali may also be one or more selected from Li2CO3, Rb2CO3, RbOH, Cs2CO3, CsOH, BeCO3, Be(OH)2, MgCO3, Mg(OH)2, CaCO3, Ca(OH)2, SrCO3, Sr(OH)2, BaCO3, and Ba(OH)2.

[0086] There are no particular requirements for the amount of base used in step S2, as long as the reaction can proceed. In some embodiments, about 3 to 5 equivalents of the base are used relative to the 5-aminouracil of formula (II').

[0087] The reaction can proceed for any suitable time, such as from about 10 seconds to 10 minutes or longer, such as from about 20 seconds to 8 minutes, from about 30 seconds to 6 minutes, from about 40 seconds to 5 minutes, or from about 50 seconds to 4 minutes.

[0088] Examples of the reactors mentioned include, but are not limited to, microreactors and conventional reactors.

[0089] In some preferred embodiments, the reactor is a microreactor, such as a microchannel reactor or a micromixer. In a further preferred embodiment, the method of this disclosure for preparing pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I') comprises the following steps:

[0090] (S2) The 5-aminouracil of formula (II') and sodium hydroxide or potassium hydroxide, preferably potassium hydroxide in water at about 0 to 4 °C and an aqueous solution of potassium ferricyanide at about 0 to 4 °C, are simultaneously added to a microreactor at the same constant flow rate to mix and react at a temperature of about -5 to 5 °C to obtain the pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), wherein the constant flow rate is preferably about 3 to 10 mL / min.

[0091] In other preferred embodiments, the reactor is a conventional reactor, such as a tubular reactor or a batch reactor. Preferably, the reactor has been precooled to a temperature of about 0°C to -20°C, for example, about -5°C to -15°C or about -10°C to -15°C. Preferably, where stirring is permissible, the solutions A and B are mixed by stirring at a rate of, for example, about 100 to 1000 rpm (e.g., about 200 to 900 rpm, about 300 to 800 rpm, about 400 to 700 rpm, or about 500 to 600 rpm). According to such embodiments, the method of this disclosure for preparing pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I') comprises the following steps:

[0092] (S2) While stirring at a speed of about 200 to 600 rpm (e.g., about 300 to 500 rpm), 5-aminouracil of formula (II') and sodium hydroxide or potassium hydroxide, preferably potassium hydroxide in water at about 0 to 4 °C, and an aqueous solution of potassium ferricyanide at about 0 to 4 °C are simultaneously added at a constant flow rate to the reactor precooled to a temperature of about 0 °C to -20 °C, for example, about -10 °C, to obtain pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), wherein the flow rate ratio of the 5-aminouracil solution to the potassium ferricyanide solution is about 1:2.

[0093] In some embodiments, the method further includes the following post-processing operations: filtering the reaction mixture of step S2, washing (e.g., with water or 1N hydrochloric acid) the solid product obtained from the filtration, and drying the solid product.

[0094] In a third aspect, this disclosure provides a method for preparing 3,6-diaminopyrazine-2,5-dicarboxylic acid of formula 4, said method comprising the following steps:

[0095]

[0096] (S2') The preparation of a pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I') from a 5-aminouracil of formula (II') by the method described above according to the second aspect of this disclosure; and

[0097] (S3) Hydrolyze the pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I') in the presence of a base to give 3,6-diaminopyrazine-2,5-dicarboxylic acid of formula 4.

[0098] In some embodiments, the hydrolysis described in step S3 is carried out in a polar solvent. In some embodiments, the polar solvent is one or more selected from water, methanol, ethanol, acetonitrile, tetrahydrofuran, diethylene glycol dimethyl ether, and methyl isobutyl ketone, preferably water.

[0099] In some embodiments, the alkali mentioned in step S3 is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate, and lithium hydroxide, preferably sodium hydroxide.

[0100] In some embodiments, the hydrolysis described in step S3 is carried out at a temperature of about 150 to 200°C, preferably about 170 to 180°C.

[0101] The hydrolysis can be carried out for a suitable time, for example, about 4 to 8 hours.

[0102] In some embodiments, the method further includes the following post-processing operations: filtering the reaction mixture of step S3, washing (e.g., with water or 1N hydrochloric acid) the solid product obtained from the filtration, and drying the solid product.

[0103] In some implementations, the methods described above according to the second and third aspects of this disclosure may each further include the following steps:

[0104]

[0105] (S1) React 5-nitrouracil of formula (III) with a reducing agent in the presence of an inorganic base to obtain 5-aminouracil of formula (II'), wherein the inorganic base is not ammonia.

[0106] The reaction in step S1 can be carried out in a suitable solvent such as water. For example, the reaction can be carried out by adding the reducing agent in portions to an aqueous solution containing 5-nitrouracil of formula (III) and the inorganic base.

[0107] In some embodiments, in step S1, about 1 to 6 equivalents of the reducing agent are used relative to 5-nitrouracil of formula (III).

[0108] In some embodiments, in step S1, about 4 to 6 equivalents of the reducing agent are used relative to 5-nitrouracil of formula (III).

[0109] In some embodiments, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, preferably sodium bicarbonate.

[0110] There are no particular requirements for the amount of base used in step S1, as long as the reaction can proceed. In some embodiments, in step S1, about 2 to 9 equivalents of the inorganic base are used relative to the 5-nitrouracil of formula (III).

[0111] In some embodiments, the reducing agent is one or more selected from Na2S2O4, hydrogen, iron powder and zinc powder, preferably Na2S2O4.

[0112] In some embodiments, the reaction temperature in step S1 is about 60 to 90 °C, preferably about 70 to 85 °C, more preferably about 75 to 85 °C, for example about 75 to 80 °C or about 80 to 85 °C.

[0113] In some implementations, the reaction time in step S1 is about 1 to 10 hours, for example about 2 to 8 hours, preferably about 3 to 6 hours, for example about 3, 4, 5 or 6 hours.

[0114] In some embodiments, the method further includes the following post-processing operations: filtering the reaction mixture of step S1, washing (e.g., with water) the filtered solid product, and drying the solid product.

[0115] Surprisingly, by changing the inorganic base in step S1 to avoid the use of ammonia, in addition to improving the safety of the production process and reducing potential environmental pollution, the yield of the compound of formula (II') was significantly improved, for example, up to 92% (Example 11, compared with the 65% yield of synthetic route 2 (see Comparative Example 1)).

[0116] In a fourth aspect, this disclosure provides a method for preparing 5-aminouracil of formula (II'), the method comprising the following steps:

[0117]

[0118] (S1) React 5-nitrouracil of formula (III) with a reducing agent in the presence of an inorganic base to obtain 5-aminouracil of formula (II'), wherein the inorganic base is not ammonia.

[0119] Some implementation plans in this regard are described above.

[0120] definition

[0121] When describing the elements of the embodiments described herein, the articles “a,” “an,” “the,” and “the” are intended to indicate the presence of one or more elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that other elements may be present in addition to those listed.

[0122] The term “about”, especially when referring to a given quantity, means a deviation of ±10%, preferably ±5%, more preferably ±2%.

[0123] As used herein, the terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps, although such other unlisted elements or method steps may not necessarily exist (i.e., these terms also cover the terms “consistently made up of” and “comprises of”).

[0124] Since various changes can be made to the methods described above without departing from the scope of the invention, all content contained in the above description and the embodiments given below should be interpreted as illustrative rather than restrictive.

[0125] This disclosure covers the following embodiments and any two or more combinations thereof, unless such combinations are contradictory or impractical.

[0126] Implementation Scheme 1. A method for preparing a pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), wherein the method comprises the following steps:

[0127]

[0128] (S2) 5-aminouracil of formula (II') in solution A is reacted with an oxidant in solution B in the presence of a base in a reactor to obtain pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), wherein solution A and solution B are added to the reactor simultaneously at constant flow rates and mixed, and wherein the constant flow rates of solution A and solution B may be the same or different.

[0129] Implementation Scheme 2. The method of Implementation Scheme 1, wherein the alkali is added to the reactor in only one of the solutions A and B.

[0130] Implementation Scheme 3. The method of Implementation Scheme 1 or 2, wherein the base is contained in the solution A only together with the 5-aminouracil.

[0131] Implementation Scheme 4. The method of Implementation Scheme 1 or 2, wherein the base is contained in the solution B only together with the oxidizing agent.

[0132] Implementation Scheme 5. The method of Implementation Scheme 1 or 2, wherein a portion of the base is contained in solution A together with the 5-aminouracil, and another portion is contained in solution B together with the oxidant.

[0133] Implementation Scheme 6. The method of any one of Implementation Schemes 1 to 5, wherein the solution A and the solution B are simultaneously added to the reactor via a constant flow control device, such as a peristaltic pump or a syringe pump.

[0134] Implementation Scheme 7. The method of any one of Implementation Schemes 1 to 6, wherein the ratio of the flow rate of solution A to the flow rate of solution B is about 1:10 to 1:1, including about 1:1, or about 1:10 to less than 1:1, for example about 1:8 to 1:1.5, about 1:6 to 1:2 or about 1:4 to 1:3; preferably about 1:3 to 1:1.

[0135] Implementation Scheme 8. The method of Implementation Scheme 7, wherein the ratio of the flow rate of solution A to the flow rate of solution B is approximately 1:2 or 1:3.

[0136] Implementation scheme 9, the method of implementation scheme 7, wherein the ratio of the flow rate of solution A to the flow rate of solution B is approximately 1:1.

[0137] Implementation Scheme 10. The method of any one of Implementation Schemes 1 to 9, wherein the flow rate of the solution A and the flow rate of the solution B do not exceed about 1000 mL / min, for example, not exceeding about 900, about 800 mL / min, about 700 mL / min, about 600 mL / min, about 500 mL / min, about 400 mL / min, about 300 mL / min, about 200 mL / min or about 100 mL / min, or not exceeding about 90 mL / min, about 80 mL / min, about 60 mL / min, about 50 mL / min or about 30 mL / min, for example, not exceeding about 25 mL / min or not exceeding about 20 mL / min, for example, about 2 to 30 mL / min, about 4 to 25 mL / min, about 8 to 20 mL / min or about 10 to 15 mL / min.

[0138] Implementation Scheme 11. The method of any one of Implementation Schemes 1 to 10, wherein the flow rate of solution A and the flow rate of solution B do not exceed about 15 mL / min.

[0139] Implementation Scheme 12. The method of any one of Implementation Schemes 1 to 11, wherein the flow rate of solution A and the flow rate of solution B are each about 2 to 15 mL / min, for example about 3 to 12 mL / min or about 6 to 10 mL / min.

[0140] Implementation Scheme 13. The method of any one of Implementation Schemes 1 to 12, wherein the flow rate of the solution A is about 2 to 10 mL / min, for example about 2, 3, 4, 5, 6, 7, 8, 9 or 10 mL / min.

[0141] Implementation Scheme 14. The method of any one of Implementation Schemes 1 to 13, wherein the flow rate of the solution B is about 2 to 15 mL / min, for example about 2, 3, 4, 6, 8, 10, 12, 14 or 15 mL / min.

[0142] Implementation Scheme 14-A. The method of any one of Implementation Schemes 1 to 14, wherein the molar ratio of the base to the 5-aminouracil of Formula (II') is about 3.0:1.0 to about 6.0:1.0;

[0143] Preferably, the molar ratio of the base to the compound of formula (II') is about 3.0:1.0 to about 5.5:1.0.

[0144] Implementation Scheme 14-B. The method of any one of Implementation Schemes 1 to 14 and Implementation Scheme 14-A, wherein the molar ratio of the oxidant to the 5-aminouracil of Formula (II') is about 3.0:1.0 to about 3.5:1.0;

[0145] Preferably, the molar ratio of the metal oxidant to the compound of formula (II) is about 3.0:1.0 to about 3.4:1.0.

[0146] Implementation Scheme 15. The method of any one of Implementation Schemes 1 to 14 and Implementation Schemes 14-A and 14-B, wherein the solvent in solution A and the solvent in solution B are each a polar solvent.

[0147] Implementation Scheme 16. The method of Implementation Scheme 15, wherein the polar solvent is selected from one, two or more of water, methanol, ethanol, acetonitrile and tetrahydrofuran, preferably water.

[0148] Implementation Scheme 17. The method of any one of Implementation Schemes 1 to 16, wherein the solution A and the solution B each have a temperature of about 0 to 8 °C, for example about 0 to 4 °C or about 2 to 6 °C.

[0149] Implementation Scheme 18. The method of any one of Implementation Schemes 1 to 17, wherein the reaction described in step S2 is carried out at a temperature of about -20 to 20°C, preferably about -10 to 10°C, for example about -5 to 5°C, for example about -10, -5, 0 or 5°C.

[0150] Implementation Scheme 19. The method of any one of Implementation Schemes 1 to 18, wherein about 3 to 5 equivalents of the oxidant are used relative to the 5-aminouracil of Formula (II').

[0151] Implementation Scheme 20. The method of any one of Implementation Schemes 1 to 19, wherein the oxidant is a reagent containing iron(III) or Mn(III).

[0152] Implementation Scheme 21. The method of Implementation Scheme 20, wherein the oxidant is selected from one or more of potassium ferricyanide, sodium pentacyanocarbonylferricate (Na2[Fe(CN)5(CO)]), sodium pentacyanoammonium iron salt (Na3[Fe(CN)5NH3), lithium ferricyanide, sodium ferricyanide, ferric chloride, ferric bromide, manganese acetylacetone (III) and manganese acetate (III), preferably potassium ferricyanide.

[0153] Implementation Scheme 22. The method of any one of Implementation Schemes 1 to 21, wherein the alkali mentioned in step S2 is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate, lithium hydroxide, ammonia, Li2CO3, Rb2CO3, RbOH, Cs2CO3, CsOH, BeCO3, Be(OH)2, MgCO3, Mg(OH)2, CaCO3, Ca(OH)2, SrCO3, Sr(OH)2, BaCO3, and Ba(OH)2, preferably potassium hydroxide.

[0154] Implementation Scheme 23. The method of any one of Implementation Schemes 1 to 22, wherein about 3 to 5 equivalents of the base are used relative to the 5-aminouracil of Formula (II').

[0155] Implementation Scheme 24. The method of any one of Implementation Schemes 1 to 23, wherein the reaction described in step S2 is carried out for a period of about 10 seconds to 10 minutes or longer, such as about 20 seconds to 8 minutes, about 30 seconds to 6 minutes, about 40 seconds to 5 minutes, or about 50 seconds to 4 minutes.

[0156] Implementation Scheme 25. The method of any one of Implementation Schemes 1 to 24, wherein the reactor is a microreactor, such as a microchannel reactor or a micromixer.

[0157] Implementation Scheme 26. The method of any one of Implementation Schemes 1 to 25, wherein the method comprises the following steps:

[0158] (S2) The 5-aminouracil of formula (II') and sodium hydroxide or potassium hydroxide, preferably potassium hydroxide in water at about 0 to 4 °C and an aqueous solution of potassium ferricyanide at about 0 to 4 °C, are simultaneously added to a microreactor at the same constant flow rate to mix and react at a temperature of about -5 to 5 °C to obtain the pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), wherein the constant flow rate is preferably about 3 to 10 mL / min.

[0159] Implementation Scheme 27. The method of any one of Implementation Schemes 1 to 24, wherein the reactor is a conventional reactor, such as a tubular reactor or a batch reactor.

[0160] Implementation Scheme 28. The method of Implementation Scheme 27, wherein the reactor has been precooled to a temperature of about 0°C to -20°C, for example about -5°C to -15°C or about -10°C to -15°C.

[0161] Implementation Scheme 29. The method of Implementation Scheme 27 or 28, wherein the solution A and the solution B are mixed by stirring at a speed of about 100 to 1000 rpm (e.g., about 200 to 900 rpm, about 300 to 800 rpm, about 400 to 700 rpm, or about 500 to 600 rpm).

[0162] Implementation Scheme 30. The method of any one of Implementation Schemes 27 to 29, wherein the method comprises the following steps:

[0163] (S2) While stirring at a speed of about 200 to 600 rpm (e.g., about 300 to 500 rpm), 5-aminouracil of formula (II') and sodium hydroxide or potassium hydroxide, preferably potassium hydroxide in water at about 0 to 4 °C, and an aqueous solution of potassium ferricyanide at about 0 to 4 °C are simultaneously added at a constant flow rate to the reactor precooled to a temperature of about 0 °C to -20 °C, for example, about -10 °C, to obtain pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), wherein the flow rate ratio of the 5-aminouracil solution to the potassium ferricyanide solution is about 1:2.

[0164] Implementation Scheme 31. A method for preparing 3,6-diaminopyrazine-2,5-dicarboxylic acid of Formula 4, said method comprising the following steps:

[0165]

[0166] (S2') A pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I') is prepared from 5-aminouracil of formula (II') by the method described in any one of embodiments 1 to 30; and

[0167] (S3) Hydrolyze the pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I') in the presence of a base to give 3,6-diaminopyrazine-2,5-dicarboxylic acid of formula 4.

[0168] Implementation Scheme 32. The method of Implementation Scheme 31, wherein the hydrolysis described in step S3 is carried out in a polar solvent.

[0169] Implementation Scheme 33. The method of Implementation Scheme 32, wherein the polar solvent is one or more selected from water, methanol, ethanol, acetonitrile, tetrahydrofuran, diethylene glycol dimethyl ether and methyl isobutyl ketone, preferably water.

[0170] Implementation Scheme 34. The method of any one of Implementation Schemes 31 to 32, wherein the alkali mentioned in step S3 is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate and lithium hydroxide, preferably sodium hydroxide.

[0171] Implementation Scheme 35. The method of any one of Implementation Schemes 31 to 34, wherein the hydrolysis described in step S3 is carried out at a temperature of about 150 to 200°C, preferably about 170 to 180°C.

[0172] Implementation Scheme 36. The method of any one of Implementation Schemes 31 to 35, wherein the hydrolysis is carried out for about 4 to 8 hours.

[0173] Implementation Scheme 37. The method of any one of Implementation Schemes 1 to 36, wherein the method may further include the following steps:

[0174]

[0175] (S1) React 5-nitrouracil of formula (III) with a reducing agent in the presence of an inorganic base to obtain 5-aminouracil of formula (II'), wherein the inorganic base is not ammonia.

[0176] Implementation Scheme 38. A method for preparing 5-aminouracil of formula (II'), wherein the method comprises the following steps:

[0177]

[0178] (S1) React 5-nitrouracil of formula (III) with a reducing agent in the presence of an inorganic base to obtain 5-aminouracil of formula (II'), wherein the inorganic base is not ammonia.

[0179] Implementation Scheme 39. The method of Implementation Scheme 37 or 38, wherein in step S1, about 1 to 6 equivalents, preferably about 4 to 6 equivalents, of the reducing agent are used relative to the 5-nitrouracil of Formula (III).

[0180] Implementation Scheme 40. The method of any one of Implementation Schemes 37 to 39, wherein the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably sodium bicarbonate.

[0181] Implementation Scheme 41. The method of any one of Implementation Schemes 37 to 40, wherein in step S1, about 4 to 6 equivalents of the inorganic base are used relative to the 5-nitrouracil of Formula (III).

[0182] Implementation Scheme 42. The method of any one of Implementation Schemes 37 to 41, wherein the reducing agent is one or more selected from Na2S2O4, hydrogen, iron powder and zinc powder, preferably Na2S2O4.

[0183] Implementation Scheme 43. The method of any one of Implementation Schemes 37 to 42, wherein the reaction temperature in step S1 is about 60 to 90 °C, preferably about 70 to 85 °C, more preferably about 75 to 85 °C, for example about 75 to 80 °C or about 80 to 85 °C.

[0184] Implementation Scheme 44. The method of any one of Implementation Schemes 37 to 43, wherein the reaction time in step S1 is about 1 to 10 hours, for example about 2 to 8 hours, preferably about 3 to 6 hours, for example about 3, 4, 5 or 6 hours.

[0185] Beneficial effects

[0186] Regarding the methods according to the second, third, and fourth aspects of this disclosure, the present invention firstly makes the production process safer and more environmentally friendly by changing the inorganic base in step S1 to avoid the use of ammonia. It was also unexpectedly discovered that the yield of the improved step S1 is significantly increased, reaching up to 92%, compared to the reduction reaction of synthetic route 2 (DE10 2016 205 615 A1) (yield 65%, see Comparative Example 1) (see Example 11).

[0187] Furthermore, by improving step S2, by simultaneously adding the solution containing 5-aminouracil of formula (II') and the solution containing the oxidant to the reactor at appropriate constant flow rates for mixing, the reaction yield is significantly improved, for example, from 20% in synthetic route 2 (see Comparative Example 1) to 84% (see Example 11), thereby successfully eliminating the limitation on the overall yield in synthetic route 2. The total yield of steps S1, S2 (or S2') and S3 of this disclosure can reach 60% or higher (the total yield in Example 11 was about 62%), thereby greatly reducing production costs, improving production operability and economic efficiency, and making it more conducive to industrial production. In addition, through the improvement of step S2, the method of this disclosure also has the potential to reduce the emission of small molecules such as byproducts urea. Detailed Implementation

[0188] The present invention will be further described in detail below with reference to specific embodiments. These embodiments are only for understanding the method and core ideas of the present invention and are not intended to limit the scope of the invention. For those skilled in the art, any possible changes or substitutions made without departing from the concept of the present invention are within the protection scope of the present invention.

[0189] Experimental methods not specified in the examples are generally under conventional conditions or according to the conditions recommended by the raw material or product manufacturer; reagents not specified in the examples are generally commercially available conventional reagents or reagents that can be prepared by conventional methods from known reagents.

[0190] Example

[0191] Example 1: Preparation of pteridine from a single potassium salt of 5-aminouracil

[0192] An aqueous solution of K3Fe(III)(CN)6 was prepared by dissolving K3Fe(III)(CN)6 (1.797 g, 5.46 mmol, 3.00 equivalents) in water (6.0 mL, deionized water (DI)). An aqueous solution of the potassium salt of 5-aminouracil was prepared by transferring 5-aminouracil (0.232 g, 1.83 mmol, 1.00 equivalents) and water (1.0 mL, DI) into a centrifuge tube and slowly adding a solution of 1 equivalent of KOH (0.120 g, 1.82 mmol, 1.00 equivalents in 1.0 mL of DI water) under vigorous mixing. A second KOH solution was prepared in a similar manner to the above preparation; KOH (0.356 g, 5.39 mmol, 2.95 equivalents) was dissolved in water (2.0 mL, DI) in a reaction vessel. All solutions and the reaction vessel were cooled to 0 °C (NaCl / ice bath). All aqueous solutions were treated with nitrogen for several minutes. The potassium salt solution of 5-aminouracil and the K3Fe(III)(CN)6 solution were transferred to separate syringes. Both syringes were placed above the reaction vessel containing 4.0 mL of cold KOH solution maintained at 0°C (NaCl / ice bath). The aqueous solutions of the potassium salt of 5-aminouracil and K3Fe(III)(CN)6 were simultaneously and rapidly injected into the KOH solution maintained at 0°C (NaCl / ice bath) at a rate of 5–10 mL / min. A red precipitate formed immediately. The reaction mixture was rapidly stirred and allowed to stand at 0°C. After several minutes, the red solid was separated from the reaction mixture. The remaining red solid was air-dried and then dried over P2O5 and KOH. The dipotassium salt (pteridine) of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone was separated in 91% yield. All solids were then dissolved in water (10.0 mL, DI), diluted (100x), and quantified by rpHPLC (87%). According to rpHPLC (reversed-phase HPLC, C18) analysis, the product purity was approximately 98%.

[0193] Faster addition rates of the potassium salt of 5-aminouracil and aqueous solutions of K3Fe(III)(CN)6 are expected to work well. Slower addition rates are also effective.

[0194] Example 2: Preparation of pteridine from a single potassium salt of 5-aminouracil

[0195] A pre-prepared potassium salt of 5-aminouracil (5-AU) was prepared by adding 1 equivalent of potassium hydroxide solution to a mixture of 5-aminouracil (2.0 g) in water (250 mL, DI) to produce a light brown solution. The solution was frozen and lyophilized to produce a solid brown 5-AU potassium salt. This 5-AU potassium salt was used instead of the potassium salt formed in the two-step method of Example 1, while all other conditions remained the same. Quantitative analysis by HPLC showed that the reaction using the pre-prepared 5-AU potassium salt yielded 83% pteridine.

[0196] Example 3: Preparation of pteridine from a single potassium salt of 5-aminouracil

[0197] The conditions of Example 1 were used, except that KOH was replaced with K₂CO₃ (0.076 g, 0.55 mmol, 3.06 equivalents) dissolved in water (2.0 mL, DI). All other conditions were the same. The yield of pteridine was 88% by quantitative rpHPLC.

[0198] Example 4: Preparation of pteridine from a single potassium salt of 5-aminouracil

[0199] The conditions of Example 1 were used, except that KOH was replaced by an aqueous solution of NH4OH (22%, 0.086 mL, 0.54 mol, 3.00 equivalents), which was diluted with additional deionized water to a total volume of 2.0 mL (0.076 g, 0.55 mmol, 3.06 equivalents). All other conditions were the same. The yield of pteridine was 88% by quantitative rpHPLC.

[0200] Example 5: Preparation of pteridine from a single potassium salt of 5-aminouracil

[0201] The conditions of Example 1 were used, except that deionized water was replaced with drinking water (tap water). No difference in yield was found in the conversion from deionized water to drinking water.

[0202] Example 6: Preparation of Pteridine

[0203] An aqueous solution of K3Fe(III)(CN)6 was prepared by dissolving K3Fe(III)(CN)6 (0.907 g, 2.75 mmol, 3.02 equivalents) in water (6.0 mL, DI). An aqueous solution of a single potassium salt of 5-aminouracil was prepared by adding a solution of KOH (0.206 g, 3.67 mmol, 4.02 equivalents) in 2.0 mL of water (DI) dropwise to 5-aminouracil (0.116 g, 0.91 mmol, 1.00 equivalents) under vigorous mixing. The potassium / KOH solution of 5-aminouracil was transferred to a syringe, and the Fe(III) solution was transferred to a separate syringe. Both syringes were placed above an empty reaction flask, and both reagents were rapidly injected into the flask simultaneously. A red precipitate formed immediately. The reaction mixture was stirred rapidly and allowed to stand at room temperature. After a few minutes, the reaction tube was filtered. The remaining red solid was dissolved in water (10.0 mL, DI), diluted (100x), and quantified by rpHPLC (51%).

[0204] Example 7: Preparation of Pteridine

[0205] An aqueous solution of K3Fe(III)(CN)6 was prepared by dissolving K3Fe(III)(CN)6 (0.888 g, 2.70 mmol, 3.15 equivalents) in water (6.0 mL, DI). An aqueous solution of a single potassium salt of 5-aminouracil was prepared by adding a solution of KOH (0.201 g, 3.58 mmol, 4.18 equivalents) in 1.0 mL of water (DI) to a flask containing 5-aminouracil (0.1 g, 0.86 mmol, 1.00 equivalents) and water (1.0 mL, DI). All solutions in the reaction vessel were cooled to 0 °C in a NaCl / ice bath, and then all solutions were simultaneously treated with helium for several minutes. The 5-aminouracil potassium solution / KOH was transferred to a syringe, and the Fe(III) solution was transferred to a separate syringe. Both syringes were placed above an empty flask and the solution was added simultaneously. A red precipitate formed immediately. The reaction mixture was stirred rapidly and allowed to stand at 0 °C. After a few minutes, filter the reaction tube. Dissolve the remaining red solid in water (10.0 mL, DI), dilute (100x), and quantify by rpHPLC (54%).

[0206] Example 8: Large-scale preparation of pteridine

[0207] An aqueous solution of K3Fe(III)(CN)6 was prepared by dissolving K3Fe(III)(CN)6 (0.902 g, 2.74 mmol, 3.03 equivalents) in water (3.0 mL, DI). An aqueous solution of a single potassium salt of 5-aminouracil was prepared by dissolving 5-aminouracil (0.115 g, 0.90 mmol, 1.00 equivalents) in water (0.5 mL, DI) and slowly adding a solution of KOH (0.233 g, 3.53 mmol, 3.90 equivalents, in 0.5 mL of DI) under vigorous mixing. All aqueous solutions were cooled to 0 °C in a NaCl / ice bath and then simultaneously treated with helium for several minutes. The Fe(III) solution was transferred to a syringe and rapidly injected into the potassium / KOH solution of 5-aminouracil over approximately 15 seconds. After a few minutes, the reaction mixture was centrifuged and the supernatant was decanted. The remaining red solid was air-dried and then dried over P2O5 and KOH. The separation yield was 51%. All the separated red solids were then dissolved in water (10.0 mL, DI), diluted (100x), and quantified by rpHPLC (44%).

[0208] Example 9: Large-scale preparation of pteridine

[0209] An aqueous solution of K3Fe(III)(CN)6 was prepared by dissolving K3Fe(III)(CN)6 (3.25 g, 9.9 mmol, 3.2 equivalents) in water (10.0 mL, DI). An aqueous solution of a single potassium salt of 5-aminouracil was prepared by dissolving 5-aminouracil (0.394 g, 3.1 mmol, 1.0 equivalents) in water (5.0 mL, DI) and slowly adding a solution of KOH (0.200 g, 3.1 mmol, 1.0 equivalents) in water (5.0 mL, DI) under vigorous mixing. Another aqueous solution of KOH (0.614 g, 9.3 mmol, 3.0 equivalents) was prepared in water (13.5 mL, DI) and added to the bottom of a three-necked round-bottom flask. All solutions and reaction vessels were cooled to 0 °C in a NaCl / ice bath, and then all solutions were simultaneously treated with nitrogen for several minutes. The reaction was carried out under nitrogen at 0°C. A solution of potassium 5-aminouracil was transferred to a syringe, and a solution of Fe(III) was transferred to a separate syringe. Both syringes were used to puncture the diaphragm of the flask and injected simultaneously and rapidly into the flask containing KOH solution. A red precipitate formed immediately. The reaction mixture in the flask was stirred vigorously for several minutes and allowed to stand at 0°C. The contents of the reaction mixture were transferred to a centrifuge tube and washed with deionized water, centrifuged, and the supernatant was decanted. The supernatant was analyzed by HPLC and showed only a low concentration of the desired pteridine. The remaining red pteridine solid was air-dried and then dried over P₂O₅ and KOH for several days until a consistent weight was obtained. The reaction was repeated twice as described above, with an average isolated yield of 45.5% pteridine (47% in Experiment 1 and 44% in Experiment 2).

[0210] Example 10: Large-scale preparation of pteridine

[0211] An aqueous solution of K3Fe(III)(CN)6 was prepared by dissolving K3Fe(III)(CN)6 (3.25 g, 9.9 mmol, 3.2 equivalents) in water (10.0 mL, DI). An aqueous solution of a single potassium salt of 5-aminouracil was prepared by dissolving 5-aminouracil (0.394 g, 3.1 mmol, 1.0 equivalents) in water (5.0 mL, DI) and slowly adding an aqueous solution of KOH (0.200 g, 3.1 mmol, 1.0 equivalents) in water (5.0 mL, DI) under vigorous mixing. This potassium salt solution of 5-aminouracil was then added to the bottom of a three-necked round-bottom flask. All solutions and reaction vessels were cooled to 0 °C in a NaCl / ice bath, and all solutions were simultaneously treated with nitrogen for several minutes. The reaction was carried out under nitrogen at 0 °C. The Fe(III) solution was transferred to a syringe. The syringe was used to puncture the septum of the flask and rapidly inject into the flask containing a potassium salt solution of 5-aminouracil. A red precipitate (pteroidine) formed almost immediately. The reaction mixture in the flask was stirred for a few minutes and allowed to stand at 0°C. After a few minutes, the product from the flask was washed into a centrifuge tube with deionized water, centrifuged, and the supernatant was decanted. The remaining red solid was air-dried and then dried over P₂O₅ and KOH for several days. The yield of pteridine was 41%.

[0212] Example 11: Preparation of 3,6-diaminopyrazine-2,5-dicarboxylic acid

[0213] Step 1:

[0214] 50 g of Na₂S₂O₄ was added in batches to a saturated aqueous solution of 10 g of 5-nitrouracil and 20 g of sodium bicarbonate, and the mixture was stirred at 75 °C for 4 hours. The resulting white precipitate was filtered, washed with water, and dried to give 7.4 g of 5-aminouracil (yield: 92%).

[0215] MS [M+H] 128.11.

[0216] Step 2:

[0217] 70 g of 5-aminouracil and 93 g of potassium hydroxide were dissolved in 1.4 L of water to prepare a first solution, which was then cooled to 0 °C. 580 g of potassium ferricyanide was dissolved in 1.4 L of water to prepare a second solution, which was also cooled to 0 °C. The first and second solutions were simultaneously added to the mixing module of the microreactor at the same flow rate of 10 mL / min using a peristaltic pump and held in the mixing module for 20 seconds to react at -5 °C. The reaction mixture was then discharged into a collection tank, the resulting precipitate was filtered off and washed with 1 N hydrochloric acid, and then dried to give 57.3 g of solid pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone (purity: 99%, yield: 84%).

[0218] LC-MS [MH] 247.02.

[0219] 1 H NMR [500 MHz, DMSO-d6] 12.07 (br s, 2H), 11.79 (br s, 2H).

[0220] 13 C NMR [500 MHz, DMSO-d6] 160.5, 150.0, 145.7, 130.1.

[0221] Step 3:

[0222] 50 g of solid pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone was added to 400 mL of water, followed by 50 g of aqueous sodium hydroxide solution (500 mL). The resulting mixture was heated to 180 °C and reacted for 5 h, resulting in the precipitation of needle-like solids. The reaction mixture was cooled, filtered, and the precipitate was washed with 1 N hydrochloric acid and dried to give 31.9 g of solid 3,6-diaminopyrazine-2,5-dicarboxylic acid (purity: 99%, yield: 80%).

[0223] MS [MH] 197.02.

[0224] 13 C NMR [500 MHz, DMSO-d6] 167.8, 148.5, 126.0.

[0225] Example 12: Preparation of 3,6-diaminopyrazine-2,5-dicarboxylic acid

[0226] Step 1:

[0227] 50 g of Na₂S₂O₄ was added in batches to a saturated aqueous solution of 10 g of 5-nitrouracil and 10 g of sodium hydroxide, and the mixture was stirred at 85 °C for 3 hours. The resulting white precipitate was filtered and then dried to give 7.1 g of 5-aminouracil (yield: 88%). The characterization data of the obtained compound were the same as in step 1 of Example 11.

[0228] Step 2:

[0229] 30 g of 5-aminouracil and 50 g of sodium hydroxide were dissolved in 500 mL of water to prepare a first solution, which was then cooled to 5 °C. 230 g of potassium ferricyanide was dissolved in 1.4 L of water to prepare a second solution, which was then cooled to 2 °C. The first and second solutions were simultaneously added to the mixing module of the microreactor via peristaltic pumps at flow rates of 2 mL / min and 6 mL / min, respectively, and held in the mixing module for 30 seconds to react at 0 °C. The reaction mixture was then discharged into a collection tank, the resulting precipitate was filtered off and washed with 1N hydrochloric acid, and then dried to give 18.7 g of solid pyrimido[4,5-g]pteroidine-2,4,7,9(1H,3H,6H,8H)-tetraone (purity: 99%, yield: 64%). The characterization data of the obtained compound were the same as in step 2 of Example 11.

[0230] Step 3:

[0231] 50 g of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone was added to 600 mL of pure water, followed by 70 g of potassium hydroxide aqueous solution (500 mL). The resulting mixture was heated to 180 °C and reacted with stirring for 8 hours. The reaction solution was acidified with 1 N hydrochloric acid, filtered, and the resulting precipitate was slurried and dried to give 29.9 g of 3,6-diaminopyrazine-2,5-dicarboxylic acid (purity: 99%, yield: 75%). The characterization data of the obtained compound were the same as in step 3 of Example 11.

[0232] Example 13: Preparation of 3,6-diaminopyrazine-2,5-dicarboxylic acid

[0233] Step 1:

[0234] In a fractional manner, 50 g of Na₂S₂O₄ was added to a saturated aqueous solution of 10 g of 5-nitrouracil and 19 g of sodium carbonate, and the mixture was stirred at 60 °C for 6 hours. The resulting white precipitate was filtered and then dried to give 6.9 g of 5-aminouracil (yield: 85%). The characterization data of the obtained compound were the same as in step 1 of Example 11.

[0235] Step 2:

[0236] 70 g of 5-aminouracil and 93 g of potassium hydroxide were dissolved in 1.4 L of aqueous solution to prepare a first solution, which was then cooled to 0 °C. 600 g of potassium ferricyanide was dissolved in 1.4 L of water to prepare a second solution, which was also cooled to 0 °C. The first and second solutions were simultaneously added to the mixing module of the microreactor at the same flow rate of 3 mL / min using a peristaltic pump, and the mixture was held in the mixing module for 280 seconds to react at 5 °C. The reaction mixture was then discharged into a collection tank, the resulting precipitate was filtered off and washed with 1N hydrochloric acid, and then dried to give 54.5 g of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone in solid form (purity: 99%, yield: 79%). The characterization data of the obtained compound were the same as in step 2 of Example 11.

[0237] Step 3:

[0238] 50 g of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone was added to 400 mL of water, followed by 70 g of potassium hydroxide aqueous solution (600 mL). The resulting mixture was heated to 170 °C and reacted with stirring for 4 hours. The reaction solution was acidified with 1N hydrochloric acid, filtered, and the resulting precipitate was slurried and dried to give 31.1 g of 3,6-diaminopyrazine-2,5-dicarboxylic acid (purity: 99%, yield: 78%). The characterization data of the obtained compound were the same as in step 3 of Example 11.

[0239] Example 14: Preparation of 3,6-diaminopyrazine-2,5-dicarboxylic acid

[0240] 127 g of 5-aminouracil and 224 g of potassium hydroxide were dissolved in 1.4 L of water to prepare a first solution, which was then cooled to 4°C. 1060 g of potassium ferricyanide was dissolved in 2.8 L of water to prepare a second solution, which was also cooled to 4°C. The first and second solutions were simultaneously added to a reaction vessel pre-cooled to -10°C using a peristaltic pump at constant flow rates of 7 mL / min and 14 mL / min, respectively, while the mixture was stirred at 300 rpm. After mixing, the mixture was slowly brought back to room temperature. The reaction mixture was then filtered, and the resulting filter cake was acidified with 1N hydrochloric acid, filtered, washed, and dried to obtain 104 g of solid pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone (purity: 99%, yield: 84%). The characterization data of the obtained compound were the same as in step 2 of Example 11.

[0241] 80 g of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone was added to 1000 mL of water, followed by the addition of potassium hydroxide (105 g). The resulting mixture was heated to 180 °C and reacted with stirring for 6 hours. The reaction solution was acidified with 1N hydrochloric acid, then filtered. The resulting solid was pulped, filtered, and the filter cake was dried to obtain 48 g of 3,6-diaminopyrazine-2,5-dicarboxylic acid (purity: 99%, yield: 75%). The characterization data of the obtained compound were the same as in step 3 of Example 11.

[0242] Comparative Example 1: Preparation of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone and 3,6-diaminopyrazine-2,5-dicarboxylic acid

[0243] The compound of formula (I') was prepared according to the method of DE 10 2016 205 615 A1.

[0244] Step 1:

[0245] In a fractional batch, 50 g of Na₂S₂O₄ was added to 10 g of 5-nitrouracil and 35 mL of ammonia (25%) aqueous solution, and the mixture was stirred at 75°C for 4 hours. The resulting white precipitate was filtered and then dried to give 5.3 g of 5-aminouracil (yield: 65%). The characterization data of the obtained compound were the same as in step 1 of Example 11.

[0246] Step 2:

[0247] 70 g of 5-aminouracil and 93 g of potassium hydroxide were dissolved in 1.4 L of water. The resulting aqueous solution was cooled to 0°C, and a solution of potassium ferricyanide (600 g) in water (1.4 L) was slowly added dropwise over approximately 2 hours. The reaction mixture was then stirred for another hour, followed by filtration of the resulting precipitate, washing with 1N hydrochloric acid, and drying to give 13.7 g of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone in solid form (purity: 97%, yield: 20%). The yield of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone reported in DE 10 2016 205615A1 was 21% (see paragraph

[0095] ), which is similar to the yield described here. The characterization data of the obtained compound were the same as in step 2 of Example 11.

[0248] Step 3:

[0249] 50 g of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone was added to 800 mL of water, followed by 70 g of sodium hydroxide aqueous solution (500 mL). The resulting mixture was heated to 170 °C and reacted with stirring for 5 hours. The reaction solution was acidified with 1N hydrochloric acid, filtered, and the resulting precipitate was slurried and dried to give 29.9 g of 3,6-diaminopyrazine-2,5-dicarboxylic acid (purity: 98%, yield: 75%). The characterization data of the obtained compound were the same as in step 3 of Example 11.

[0250] Comparative Example 2: Preparation of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone and 3,6-diaminopyrazine-2,5-dicarboxylic acid

[0251] Except for adjusting only the order of drop addition in step 2, the compound of formula (I') was prepared according to the method of DE 10 2016 205 615 A1.

[0252] Step 1:

[0253] In a fractional batch, 50 g of Na₂S₂O₄ was added to 10 g of 5-nitrouracil and 35 mL of ammonia (25%) aqueous solution, and the mixture was stirred at 75°C for 4 hours. The resulting white precipitate was filtered and then dried to give 5.3 g of 5-aminouracil (yield: 65%). The characterization data of the obtained compound were the same as in step 1 of Example 11.

[0254] Step 2:

[0255] 70 g of 5-aminouracil and 93 g of potassium hydroxide were dissolved in 1.4 L of water. The resulting aqueous solution was cooled to 0°C and slowly added dropwise to a solution of potassium ferricyanide (600 g) in water (1.4 L) over approximately 2 hours. The reaction mixture was then stirred for 1 hour, followed by filtration of the resulting precipitate, washing with 1N hydrochloric acid, and drying to give 24 g of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone in solid form (purity: 97%, yield: 35%). The yield of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone reported in DE 10 2016205 615A1 was 21% (see paragraph

[0095] ). The characterization data of the obtained compound were the same as in step 2 of Example 11.

[0256] Step 3:

[0257] 50 g of pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone was added to 800 mL of water, followed by 70 g of sodium hydroxide aqueous solution (500 mL). The resulting mixture was heated to 170 °C and reacted with stirring for 5 hours. The reaction solution was acidified with 1N hydrochloric acid, filtered, and the resulting precipitate was slurried and dried to give 29.9 g of 3,6-diaminopyrazine-2,5-dicarboxylic acid (purity: 98%, yield: 75%). The characterization data of the obtained compound were the same as in step 3 of Example 11.

[0258] All references cited in this application (including all patents, patent applications, journal articles, books and any other publications) are incorporated herein by reference in their entirety.

Claims

1. A method for preparing a compound of formula (I) or a salt thereof, Formula (I); The method includes: An aqueous solution of a compound of formula (II) or a salt thereof and an aqueous solution of a metal oxidant are simultaneously added at constant rates to a container containing an aqueous solution of a proton acceptor and mixed, wherein the constant rates of the aqueous solution of the compound of formula (II) or a salt thereof and the constant rates of the aqueous solution of the metal oxidant are the same or different. or An aqueous solution of a compound of formula (II) containing a proton acceptor or a salt thereof, and an aqueous solution of a metal oxidant are added simultaneously to a container at constant rates and mixed, wherein the constant rates of the aqueous solution of the compound of formula (II) or its salt and the constant rates of the aqueous solution of the metal oxidant are the same or different. To make the compound of formula (II) or its salt Equation (II), Simultaneous contact with the metal oxidant and the proton acceptor in a container to form a compound of formula (I) or a salt thereof; wherein the compound of formula (I) is formed within seconds of simultaneous contact of the compound of formula (II) or salt thereof, a proton acceptor, and a metal oxidizing agent, and wherein X1 + and X2 + are independently selected from H + , Li + , Na + , K + , Rb + , Cs + , NH4 + , Be 2+ , Mg 2+ , Ca 2+ , Sr 2+ , and Ba 2+ .

2. The method of claim 1, wherein X1 + and X2 + are independently selected from Na + , K + , and NH4 + .

3. The method of claim 1, wherein the proton acceptor is selected from Li2CO3, LiOH, Na2CO3, NaOH, K2CO3, KOH, Rb2CO3, RbOH, Cs2CO3, CsOH, NH4OH, BeCO3, Be(OH)2, MgCO3, Mg(OH)2, CaCO3, Ca(OH)2, SrCO3, Sr(OH)2, BaCO3, and Ba(OH)2.

4. The method of claim 3, wherein the proton acceptor is selected from Na2CO3, NaOH, K2CO3, KOH and NH4OH.

5. The method of claim 3, wherein the proton acceptor is KOH.

6. The method of claim 1, wherein the molar ratio of the proton acceptor to the compound of formula (II) or a salt thereof is from 3.5:1.0 to 6.0:1.

0.

7. The method of claim 6, wherein the molar ratio of the proton acceptor to the compound of formula (II) or a salt thereof is from 4.0:1.0 to 4.2:1.

0.

8. The method of claim 1, wherein the metal oxidant comprises Fe(III) or Mn(III).

9. The method of claim 1, wherein the metal oxidant is selected from potassium ferricyanide, lithium ferricyanide, sodium ferricyanide, ferric chloride, ferric bromide, manganese acetylacetone (III), manganese acetate (III), sodium pentacyanocarbonylferricate (Na2[Fe(CN)5(CO)]) and sodium pentacyanoammonium iron (Na3[Fe(CN)5NH3]).

10. The method of claim 9, wherein the metal oxidant is potassium ferricyanide.

11. The method of claim 1, wherein the molar ratio of the metal oxidant to the compound of formula (II) or a salt thereof is 2.8:1.0 to 3.5:1.

0.

12. The method of claim 11, wherein the molar ratio of the metal oxidant to the compound of formula (II) or a salt thereof is 3.0:1.0 to 3.2:1.

0.

13. The method of claim 1, wherein the method is performed at a temperature of -6°C to 25°C.

14. The method of claim 13, wherein the method is performed at a temperature of -6°C to 0°C.

15. The method of claim 1, wherein the proton acceptor is selected from Li₂CO₃, LiOH, Na₂CO₃, NaOH, K₂CO₃, KOH, Rb₂CO₃, RbOH, Cs₂CO₃, CsOH, NH₄OH, BeCO₃, Be(OH)₂, MgCO₃, Mg(OH)₂, CaCO₃, Ca(OH)₂, SrCO₃, Sr(OH)₂, BaCO₃, and Ba(OH)₂; the metal oxidant comprises Fe(III) or Mn(III); the molar ratio of the proton acceptor to the compound of formula (II) or a salt thereof is from 3.5:1.0 to 6.0:1.0; the molar ratio of the metal oxidant to the compound of formula (II) or a salt thereof is from 2.8:1.0 to 3.5:1.0; and the method is carried out at a temperature from -6°C to 25°C.

16. The method of claim 15, wherein the molar ratio of the proton acceptor to the compound of formula (II) or a salt thereof is 4.0:1.0 to 4.2:1.0; the molar ratio of the metal oxidant to the compound of formula (II) or a salt thereof is 3.0:1.0 to 3.2:1.0; and the method is carried out at a temperature of -6°C to 0°C.

17. The method of claim 1, wherein the proton acceptor is selected from Na2CO3, NaOH, K2CO3, KOH and NH4OH; the metal oxidant is selected from potassium ferricyanide, lithium ferricyanide, sodium ferricyanide, ferric chloride, ferric bromide, manganese acetylacetone (III) or manganese acetate (III); the molar ratio of the proton acceptor to the compound of formula (II) or its salt is from 3.5:1.0 to 6.0:1.0; the molar ratio of the metal oxidant to the compound of formula (II) or its salt is from 2.8:1.0 to 3.5:1.0; and the method is carried out at a temperature from -6°C to 25°C.

18. The method of claim 17, wherein the molar ratio of the proton acceptor to the compound of formula (II) or a salt thereof is 4.0:1.0 to 4.2:1.0; the molar ratio of the metal oxidant to the compound of formula (II) or a salt thereof is 3.0:1.0 to 3.2:1.0; and the method is carried out at a temperature of -6°C to 0°C.

19. The method of claim 1, wherein the proton acceptor is KOH; the metal oxidant is potassium ferricyanide; the molar ratio of KOH to the compound of formula (II) or its salt is 3.5:1.0 to 6.0:1.0; the molar ratio of potassium ferricyanide to the compound of formula (II) or its salt is 2.8:1.0 to 3.5:1.0; and the method is carried out at a temperature of -6°C to 25°C.

20. The method of claim 19, wherein the molar ratio of KOH to the compound of formula (II) or a salt thereof is 4.0:1.0 to 4.2:1.0; the molar ratio of potassium ferricyanide to the compound of formula (II) or a salt thereof is 3.0:1.0 to 3.2:1.0; and the method is carried out at a temperature of -6°C to 0°C.

21. The method of claim 1, wherein the compound of formula (I) has a yield of at least 90%.

22. The method of claim 21, wherein the compound of formula (I) has a yield of at least 95%.

23. The method of claim 1, wherein the compound of formula (I) has a purity greater than 98%.

24. The method of any one of claims 1 to 23, wherein the aqueous solution of the compound of formula (II) or a salt thereof and the aqueous solution of the metal oxidant are added simultaneously at constant rates to the container containing the aqueous solution of the proton acceptor and mixed such that the aqueous solution of the compound of formula (II) or a salt thereof is simultaneously contacted with the aqueous solution of the metal oxidant and the aqueous solution of the proton acceptor in the container to form the compound of formula (I) or a salt thereof, and wherein the constant rate of the aqueous solution of the compound of formula (II) or a salt thereof and the constant rate of the aqueous solution of the metal oxidant are the same or different.

25. The method of any one of claims 1 to 23, wherein the ratio of the rate of the aqueous solution of the compound of formula (II) or its salt to the rate of the aqueous solution of the metal oxidant is 1:10 to 1:

1.

26. The method of claim 25, wherein the ratio of the rate of the aqueous solution of the compound of formula (II) or its salt to the rate of the aqueous solution of the metal oxidant is from 1:8 to 1:1.

5.

27. The method of claim 25, wherein the ratio of the rate of the aqueous solution of the compound of formula (II) or its salt to the rate of the aqueous solution of the metal oxidant is 1:6 to 1:

2.

28. The method of claim 25, wherein the ratio of the rate of the aqueous solution of the compound of formula (II) or its salt to the rate of the aqueous solution of the metal oxidant is 1:4 to 1:

3.

29. The method of any one of claims 1 to 23, wherein the aqueous solution of the compound of formula (II) or its salt and the aqueous solution of the metal oxidant are simultaneously added to the container via a constant flow control device.

30. The method of claim 29, wherein the constant flow control device is a peristaltic pump or a syringe pump.

31. The method of any one of claims 1 to 23, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 1000 mL / min.

32. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 900 mL / min.

33. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 800 mL / min.

34. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 700 mL / min.

35. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 600 mL / min.

36. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 500 mL / min.

37. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 400 mL / min.

38. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 300 mL / min.

39. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 200 mL / min.

40. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 100 mL / min.

41. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 90 mL / min.

42. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 80 mL / min.

43. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 60 mL / min.

44. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 50 mL / min.

45. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 30 mL / min.

46. ​​The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 25 mL / min.

47. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 20 mL / min.

48. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant do not exceed 15 mL / min.

49. The method of claim 31, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant are both 2 to 30 mL / min.

50. The method of claim 49, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant are both 4 to 25 mL / min.

51. The method of claim 49, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant are both 8 to 20 mL / min.

52. The method of claim 49, wherein the rate of the aqueous solution of the compound of formula (II) or its salt and the rate of the aqueous solution of the metal oxidant are both 10 to 15 mL / min.

53. The method of any one of claims 1 to 23, wherein an aqueous solution of the compound of formula (II) containing the proton acceptor or a salt thereof and an aqueous solution of the metal oxidant are simultaneously added to and mixed in a container at constant rates, such that the compound of formula (II) or a salt thereof is simultaneously contacted with the metal oxidant and the proton acceptor in the container to form the compound of formula (I) or a salt thereof, wherein the constant rate of the aqueous solution of the compound of formula (II) or a salt thereof and the constant rate of the aqueous solution of the metal oxidant are the same or different.

54. The method of any one of claims 1 to 23, wherein the container is a microreactor; or The container is a conventional reactor.

55. The method of claim 54, wherein the microreactor is a microchannel reactor or a micromixer.

56. The method of claim 54, wherein the conventional reactor is a tubular reactor or a batch reactor.

57. A method for preparing a pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), wherein the method comprises the following steps: (S2) 5-aminouracil of formula (II') in solution A is reacted with an oxidant in solution B in the presence of a base in a reactor to obtain pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), wherein solution A and solution B are added to the reactor simultaneously and mixed at constant flow rates, and wherein the constant flow rates of solution A and solution B are the same or different.

58. The method of claim 57, wherein the base and the 5-aminouracil are contained together in the solution A.

59. The method of claim 57, wherein solution A and solution B are simultaneously added to the reactor via a constant flow control device.

60. The method of claim 59, wherein the constant current control device is a peristaltic pump or a syringe pump.

61. The method of any one of claims 57 to 60, wherein the ratio of the flow rate of solution A to the flow rate of solution B is 1:10 to 1:

1.

62. The method of claim 61, wherein the ratio of the flow rate of solution A to the flow rate of solution B is 1:

1.

63. The method of claim 61, wherein the ratio of the flow rate of solution A to the flow rate of solution B is 1:10 to less than 1:

1.

64. The method of claim 61, wherein the ratio of the flow rate of solution A to the flow rate of solution B is from 1:8 to 1:1.

5.

65. The method of claim 61, wherein the ratio of the flow rate of solution A to the flow rate of solution B is 1:6 to 1:

2.

66. The method of claim 61, wherein the ratio of the flow rate of solution A to the flow rate of solution B is 1:4 to 1:

3.

67. The method of claim 61, wherein the ratio of the flow rate of solution A to the flow rate of solution B is 1:3 to 1:

1.

68. The method of claim 61, wherein the ratio of the flow rate of solution A to the flow rate of solution B is 1:2 or 1:

3.

69. The method of claim 61, wherein the flow rate of solution A is in the ratio of the flow rate of solution B to 1:

1.

70. The method of any one of claims 57 to 60, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 1000 mL / min.

71. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 900 mL / min.

72. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 800 mL / min.

73. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 700 mL / min.

74. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 600 mL / min.

75. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 500 mL / min.

76. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 400 mL / min.

77. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 300 mL / min.

78. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 200 mL / min.

79. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 100 mL / min.

80. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 90 mL / min.

81. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 80 mL / min.

82. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 60 mL / min.

83. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 50 mL / min.

84. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 30 mL / min.

85. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 25 mL / min.

86. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 20 mL / min.

87. The method of claim 70, wherein the flow rate of solution A and the flow rate of solution B are 2 to 30 mL / min, respectively.

88. The method of claim 87, wherein the flow rate of solution A and the flow rate of solution B are 4 to 25 mL / min, respectively.

89. The method of claim 87, wherein the flow rate of solution A and the flow rate of solution B are 8 to 20 mL / min, respectively.

90. The method of claim 87, wherein the flow rate of solution A and the flow rate of solution B are 10 to 15 mL / min, respectively.

91. The method of any one of claims 57 to 60, wherein the flow rate of solution A and the flow rate of solution B each do not exceed 15 mL / min.

92. The method of claim 91, wherein the flow rate of solution A and the flow rate of solution B are 2 to 15 mL / min, respectively.

93. The method of claim 91, wherein the flow rate of solution A and the flow rate of solution B are 3 to 12 mL / min, respectively.

94. The method of claim 91, wherein the flow rate of solution A and the flow rate of solution B are 6 to 10 mL / min, respectively.

95. The method of claim 91, wherein the flow rate of solution A is 2 to 10 mL / min; and the flow rate of solution B is 2 to 15 mL / min.

96. The method of claim 95, wherein the flow rate of solution A is 2, 3, 4, 5, 6, 7, 8, 9 or 10 mL / min; and the flow rate of solution B is 2, 3, 4, 6, 8, 10, 12, 14 or 15 mL / min.

97. The method of any one of claims 57 to 60, wherein the molar ratio of the base to the 5-aminouracil of formula (II') is from 3.0:1.0 to 6.0:1.

0.

98. The method of claim 97, wherein the molar ratio of the base to the compound of formula (II') is from 3.0:1.0 to 5.5:1.

0.

99. The method of any one of claims 57 to 60, wherein the molar ratio of the oxidant to the 5-aminouracil of formula (II') is 3.0:1.0 to 3.5:1.

0.

100. The method of claim 99, wherein the molar ratio of the oxidant to the compound of formula (II') is from 3.0:1.0 to 3.4:1.

0.

101. The method of any one of claims 57 to 60, wherein: The solvents in solution A and solution B are each polar solvents; and / or Solution A and solution B each have a temperature of 0 to 8 °C; and / or The reaction described in step S2 is carried out at a temperature of -20 to 20°C; and / or Use 3 to 5 equivalents of the oxidant relative to the 5-aminouracil of formula (II'); and / or The oxidant is a reagent containing iron(III) or Mn(III); and / or The alkali mentioned in step S2 is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate, lithium hydroxide, ammonia, Li2CO3, Rb2CO3, RbOH, Cs2CO3, CsOH, BeCO3, Be(OH)2, MgCO3, Mg(OH)2, CaCO3, Ca(OH)2, SrCO3, Sr(OH)2, BaCO3, and Ba(OH)2.

102. The method of claim 101, wherein: The solvent in solution A and the solvent in solution B are each selected from one, two or more of water, methanol, ethanol, acetonitrile, and tetrahydrofuran; and / or Solution A and solution B each have a temperature of 0 to 6°C; and / or The reaction described in step S2 is carried out at a temperature of -10 to 10°C; and / or The oxidant is selected from one or more of potassium ferricyanide, sodium pentacyanocarbonylferricate (Na2[Fe(CN)5(CO)]), sodium pentacyanoammonium ferric salt (Na3[Fe(CN)5NH3]), lithium ferricyanide, sodium ferricyanide, ferric chloride, ferric bromide, manganese acetylacetone (III), and manganese acetate (III); and / or The alkali mentioned in step S2 is potassium hydroxide.

103. The method of claim 101, wherein the solution A and the solution B each have a temperature of 0 to 4°C.

104. The method of claim 101, wherein the solution A and the solution B each have a temperature of 2 to 6°C.

105. The method of claim 101, wherein the reaction in step S2 is carried out at a temperature of -5 to 5°C.

106. The method of claim 102, wherein: The solvent in solution A and the solvent in solution B are each water; and / or The reaction described in step S2 is carried out at -10, -5, 0, or 5°C; and / or The oxidant is potassium ferricyanide.

107. The method of any one of claims 57 to 60, wherein the reactor is a microreactor.

108. The method of claim 107, wherein the reactor is a microchannel reactor or a micromixer.

109. The method of claim 107, wherein the method comprises the following steps: (S2) 5-aminouracil of formula (II') and a solution of sodium hydroxide or potassium hydroxide in water at 0 to 4 °C and an aqueous solution of potassium ferricyanide at 0 to 4 °C are simultaneously added to a microreactor at the same constant flow rate to mix and react at a temperature of -5 to 5 °C to obtain pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I').

110. The method of claim 109, wherein the method comprises the following steps: (S2) A solution of 5-aminouracil of formula (II') and potassium hydroxide in water at 0 to 4 °C and an aqueous solution of potassium ferricyanide at 0 to 4 °C are simultaneously added to a microreactor at the same constant flow rate to mix them and react at a temperature of -5 to 5 °C to obtain pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I').

111. The method of claim 109 or 110, wherein the constant flow rate is 3 to 10 mL / min.

112. The method of any one of claims 57 to 60, wherein the reactor is a conventional reactor.

113. The method of claim 112, wherein the reactor is a tubular reactor or a batch reactor.

114. The method of claim 112, wherein the reactor has been precooled to a temperature of 0°C to -20°C.

115. The method of claim 114, wherein the reactor has been precooled to a temperature of -5°C to -15°C.

116. The method of claim 114, wherein the reactor has been precooled to a temperature of -10°C to -15°C.

117. The method of claim 112, wherein the mixing is performed by stirring the solution A and the solution B at a speed of 100 to 1000 rpm.

118. The method of claim 117, wherein the speed is 200 to 900 revolutions per minute.

119. The method of claim 117, wherein the speed is 300 to 800 revolutions per minute.

120. The method of claim 117, wherein the speed is 400 to 700 revolutions per minute.

121. The method of claim 117, wherein the speed is 500 to 600 revolutions per minute.

122. The method of claim 112, wherein the method comprises the following steps: (S2) While stirring at a speed of 200 to 600 rpm, a solution of 5-aminouracil of formula (II') and sodium hydroxide or potassium hydroxide in water at 0 to 4 °C and an aqueous solution of potassium ferricyanide at 0 to 4 °C are simultaneously added at a constant flow rate to the reactor precooled to a temperature of 0 °C to -20 °C to mix, thereby obtaining pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), wherein the flow rate ratio of the 5-aminouracil solution to the potassium ferricyanide solution is 1:

2.

123. The method of claim 122, wherein the method comprises the following steps: (S2) While stirring at a speed of 200 to 600 rpm, a solution of 5-aminouracil of formula (II') and potassium hydroxide in water at 0 to 4 °C and an aqueous solution of potassium ferricyanide at 0 to 4 °C are simultaneously added at a constant flow rate to the reactor pre-cooled to a temperature of 0 °C to -20 °C to mix, thereby obtaining pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I'), wherein the flow rate ratio of the 5-aminouracil solution to the potassium ferricyanide solution is 1:

2.

124. The method of claim 122 or 123, wherein the stirring speed is 300 to 500 revolutions per minute.

125. The method of claim 122 or 123, wherein the reactor is precooled to -10°C.

126. A method for preparing 3,6-diaminopyrazine-2,5-dicarboxylic acid of formula 4, wherein the method comprises the following steps: (S2') Preparing a pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I') from a 5-aminouracil of formula (II') by the method of any one of claims 57 to 125; and (S3) Hydrolyze the pyrimido[4,5-g]pteridine-2,4,7,9(1H,3H,6H,8H)-tetraone of formula (I') in the presence of a base to give 3,6-diaminopyrazine-2,5-dicarboxylic acid of formula 4.

127. The method of claim 126, wherein: The hydrolysis described in step S3 is carried out in a polar solvent; and / or The alkali mentioned in step S3 is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate, and lithium hydroxide; and / or The hydrolysis described in step S3 is carried out at a temperature of 150 to 200°C; and / or The hydrolysis described in step S3 takes 4 to 8 hours.

128. The method of claim 127, wherein: The polar solvent mentioned in step S3 is one or more selected from water, methanol, ethanol, acetonitrile, tetrahydrofuran, diethylene glycol dimethyl ether, and methyl isobutyl ketone; and / or The alkali mentioned in step S3 is sodium hydroxide; and / or The hydrolysis described in step S3 is carried out at a temperature of 170 to 180°C.

129. The method of claim 128, wherein: The polar solvent mentioned in step S3 is water.

130. The method of any one of claims 57 to 60 and 126 to 128, wherein the method further comprises the step of: (S1) React 5-nitrouracil of formula (III) with a reducing agent in the presence of an inorganic base to obtain 5-aminouracil of formula (II'), wherein the inorganic base is not ammonia.

131. The method of claim 130, wherein: The inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; and / or In step S1, 1 to 6 equivalents of the reducing agent are used relative to 5-nitrouracil of formula (III); and / or The reducing agent is one or more selected from Na2S2O4, hydrogen, iron powder, and zinc powder; and / or The reaction temperature in step S1 is 60 to 90 °C; and / or The reaction time in step S1 is 1 to 10 hours.

132. The method of claim 130, wherein: The reaction temperature in step S1 is 70 to 85 °C; and / or The reaction time in step S1 is 2 to 8 hours.

133. The method of claim 130, wherein: The reaction temperature in step S1 is 75 to 85 °C; and / or The reaction time in step S1 is 3 to 6 hours.

134. The method of claim 130, wherein the reaction temperature in step S1 is 75 to 80 °C.

135. The method of claim 130, wherein the reaction temperature in step S1 is 80 to 85 °C.

136. The method of claim 131, wherein: The inorganic base is sodium bicarbonate; and / or In step S1, 4-6 equivalents of the reducing agent are used relative to 5-nitrouracil of formula (III); and / or The reducing agent is Na2S2O4; and / or The reaction time in step S1 is 3, 4, 5 or 6 hours.

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