Method for preparing 3,6-diaminopyrazine-2,5-dicarboxylic acid and synthetic intermediate thereof

1 . A method for preparing a compound of Formula (I) or a salt thereof, the method comprising:

simultaneously contacting an aqueous solution of a compound of Formula (II) or a salt thereof:

and an aqueous solution comprising a metal oxidant, each added at a constant flow rate through constant flow control equipment, into a vessel that contains an aqueous solution comprising a proton acceptor to form a reactant solution, and mixing the reactant solution to form the compound of Formula (I) or a salt thereof; or

simultaneously adding the aqueous solution of the compound of formula (II) or the salt thereof containing the proton acceptor and the aqueous solution of a metal oxidant at a constant rate respectively to the vessel to form the reactant solution, and mixing the reactant solution to form the compound of Formula (I) or a salt thereof;

wherein X 1 + and X 2 + are each independently selected from the group consisting of H + , Li + , Na + , K + , Rb + , Cs + , NH 4 + , Be 2+ , Mg 2+ , Ca 2+ , Sr 2+ , and Ba 2+ ;

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 may be same or different;

wherein the compound of Formula (I) or a salt thereof is formed within seconds of the simultaneous contacting of the aqueous solutions;

and wherein yield of the compound of Formula (I) or a salt thereof is at least 80%.

2 . The method of claim 1 , wherein X 1 + and X 2 + are independently selected from the group consisting of Na, K + , and NH 4 + .

3 . The method of claim 1 , wherein the proton acceptor is selected from the group consisting of Li 2 CO 3 , LiOH, Na 2 CO 3 , NaOH, K 2 CO 3 , KOH, Rb 2 CO 3 , RbOH, Cs 2 CO 3 , CsOH, NH 4 OH, BeCO 3 , Be(OH) 2 , MgCO 3 , Mg(OH) 2 , CaCO 3 , Ca(OH) 2 , SrCO 3 , Sr(OH) 2 , BaCO 3 and Ba(OH) 2 .

4 . The method of claim 1 , wherein a molar ratio of the proton acceptor to the compound of Formula (II) ranges from about 3.5:1.0 to about 6.0:1.0.

5 . The method of claim 1 , wherein the metal oxidant is selected from the group consisting of potassium ferricyanide, lithium ferricyanide, sodium ferricynide, ferric chloride, ferric bromide, manganese (III) acetylacetonate, manganese (III) acetate, sodium pentacyano-monocarbonylferroate (Na 2 [Fe(CN) 5 (CO)]) and sodium pentacyanoammineferroate (Na 3 [Fe(CN) 5 NH 3 ]).

6 . The method of claim 1 , wherein a molar ratio of the metal oxidant to the compound of Formula (II) ranges from about 2.8:1.0 to about 3.5:1.0.

7 . The method of claim 1 , wherein the method is conducted at a temperature ranging from about −6° C. to about 25° C.

8 . The method of claim 1 , wherein the proton acceptor is selected from the group consisting of Li 2 CO 3 , LiOH, Na 2 CO 3 , NaOH, K 2 CO 3 , KOH, Rb 2 CO 3 , RbOH, Cs 2 CO 3 , CsOH, NH 4 OH, BeCO 3 , Be(OH) 2 , MgCO 3 , Mg(OH) 2 , CaCO 3 , Ca(OH) 2 , SrCO 3 , Sr(OH) 2 , BaCO 3 and Ba(OH) 2 ; the metal oxidant comprises Fe(III) or Mn(III); a molar ratio of the proton acceptor to the compound of Formula (II) ranges 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) ranges from about 2.8:1.0 to about 3.5:1.0; and the method is conducted at a temperature ranging from about −6°° C. to about 25° C.

9 . The method of claim 1 , wherein the proton acceptor is selected from the group consisting of Na 2 CO 3 , NaOH, K 2 CO 3 , KOH, and NH 4 OH; the metal oxidant is selected from potassium ferricyanide, lithium ferricyanide, sodium ferricynide, ferric chloride, ferric bromide, manganese (III) acetylacetonate or manganese (III) acetate; a molar ratio of the proton acceptor to the compound of Formula (II) ranges 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) ranges from about 2.8:1.0 to about 3.5:1.0; and the method is conducted at a temperature ranging from about −6° C. to about 25° C.

10 . The method of claim 1 , wherein the proton acceptor is KOH; the metal oxidant is potassium ferricyanide; a molar ratio of KOH to the compound of Formula (II) ranges from about 3.5:1.0 to about 6.0:1.0; the molar ratio of potassium ferricyanide to the compound of Formula (II) ranges from about 2.8:1.0 to about 3.5:1.0; and the method is conducted at a temperature ranging from about −6°° C. to about 25° C.

11 . The method of claim 1 , wherein the compound of Formula (I) is formed within seconds of the simultaneous contacting of the aqueous solutions of the compound of Formula (II), the proton acceptor, and the metal oxidant.

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

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

14 . The method of claim 1 , wherein the aqueous solution of the compound of Formula (II) and the aqueous solution of the metal oxidant are simultaneously added to the vessel each at a constant rate, and mixed, and wherein the constant rate of the compound of Formula (II) and the constant rate of the metal oxidant may be the same or different.

15 . The method of claim 1 , wherein a 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 ranges from about 1:10 to 1:1.

16 . The method of claim 1 , wherein the constant flow control equipment comprises a peristaltic pump or a syringe pump.

17 . The method of claim 1 , wherein the rate of the aqueous solution of the compound of Formula (II) and the rate of the aqueous solution of the metal oxidant are each not more than about 1000 mL/min.

18 . The method of claim 1 , wherein the proton acceptor and the compound of Formula (II) are comprised together in an aqueous solution.

19 . The method of 1, wherein the vessel is a microreactor or an ordinary reactor.

20 . A method for preparing pyrimido [4,5-g]pteridine -2,4,7,9(1H,3H,6H,8H)-tetraone of Formula (I′), wherein the method comprises:

(S2) reacting 5-aminouracil of Formula (II′) in the form of a solution A with an oxidant in the form of a 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 the solution A and the solution B are simultaneously added each at a constant flow rate to the reactor, and mixed, and wherein the constant flow rate of the solution A and the constant flow rate of the solution B may be the same or different;

wherein reaction is complete within seconds of the addition; and

wherein yield of Formula (I′) is at least 80%.

21 . The method of claim 20 , wherein the base and the 5-aminouracil are comprised together in the solution A.

22 . The method of claim 20 , wherein the solution A and the solution B are simultaneously added, each through a constant flow control equipment to the reactor.

23 . The method of claim 20 , wherein a ratio of the flow rate of the solution A to the flow rate of the solution B ranges from about 1:10 to 1:1.

24 . The method of claim 20 , wherein the flow rate of the solution A and the flow rate of the solution B are each not more than about 1000 mL/min.

25 . The method of claim 20 , wherein the flow rate of the solution A and the flow rate of the solution B are each not more than about 15 mL/min.

26 . The method of claim 20 , wherein a molar ratio of the base to the 5-aminouracil of Formula (II′) ranges from about 3.0:1.0 to about 6.0:1.0.

27 . The method of claim 20 , wherein a molar ratio of the oxidant to the 5-aminouracil of Formula (II′) ranges from about 3.0:1.0 to about 3.5:1.0.

28 . The method of claim 20 , wherein:

the solvent in the solution A and the solvent in the solution B are each selected from the group consisting of water, methanol, ethanol, acetonitrile, tetrahydrofuran and any combination thereof; and/or

the solution A and the solution B each have a temperature ranging from about 0 to 8° C.; and/or

the reaction in step S2 is conducted at a temperature of from about −20 to 20° C.; and/or

the oxidant is used in 3 to 5 equivalents relative to the 5-aminouracil of Formula (II′); and/or

the oxidant is a reagent comprising iron(III) or Mn(III), preferably one or more selected from the group consisting of potassium ferricyanide, sodium pentacyano-monocarbonylferroate (Na 2 [Fe(CN) 5 (CO)]), sodium pentacyanoammineferroate (Na 3 [Fe(CN) 5 NH 3 ]), lithium ferricyanide, sodium ferricynide, ferric chloride, ferric bromide, manganese (III) acetylacetonate and manganese (III) acetate; and/or

the base in step S2 is one or more selected from the group consisting of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate, lithium hydroxide, aqueous ammonia, Li 2 CO 3 , Rb 2 CO 3 , RbOH, Cs 2 CO 3 , CsOH, BeCO 3 , Be(OH) 2 , MgCO 3 , Mg(OH) 2 , CaCO 3 , Ca(OH) 2 , SrCO 3 , Sr(OH) 2 , BaCO 3 and Ba(OH) 2 .

29 . The method of claim 20 , wherein the reactor is a microreactor.

30 . The method of claim 29 , wherein the method comprises the step of:

(S2) simultaneously adding a solution of 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. at the same constant flow rate to a microreactor for mixing, and reacting at a temperature ranging from about −5 to 5° C. to obtain pyrimido [4, 5-g] pteridine-2,4,7,9 (1H,3H,6H,8H)-tetraone of formula (I′).

31 . The method of claim 20 , wherein the reactor is an ordinary reactor.

32 . The method of claim 31 , wherein the reactor has been pre-cooled to a temperature ranging from about 0° C. to −20° C.

33 . The method of claim 31 , wherein the solution A and the solution B are mixed by stirring at a speed ranging from about 100 to 1000 rpm.

34 . The method of claim 31 , wherein the method comprises the step of:

(S2) under stirring at a speed ranging from about 200 to 600 rpm, simultaneously adding a solution of 5-aminouracil of Formula (II′) and sodium hydroxide or potassium hydroxide, in water at about 0 to 4° C. and an aqueous solution of potassium ferricyanide at about 0 to 4° C., each at a constant flow rate, to the reactor precooled to a temperature ranging from about 0° C. to about −20° C., for mixing, 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 solution of 5-aminouracil to the solution of potassium ferricyanide is about 1:2.

35 . A method for preparing 3,6-diaminopyrazine-2,5-dicarboxylic acid of Formula 4, wherein the method comprises the steps of:

(S2′) preparing pyrimido [4,5-g] pteridine-2,4,7,9 (1H,3H,6H,8H)-tetraone of Formula (I′) from 5-aminouracil of Formula (II′) by the method of any one of claims 20 to 34 ; and

(S3) hydrolyzing 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 obtain 3,6-diaminopyrazine-2,5-dicarboxylic acid of Formula 4.

36 . The method of claim 35 , wherein:

the hydrolysis in step S3 is conducted in a polar solvent, the polar solvent being one or more selected from the group consisting of water, methanol, ethanol, acetonitrile, tetrahydrofuran, diethylene glycol dimethyl ether, and methyl isobutyl ketone, and/or

the base in step S3 is one or more selected from the group consisting of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate and lithium hydroxide; and/or

the hydrolysis in step S3 is conducted at a temperature ranging from about 150 to 200°° C.; and/or

the hydrolysis in step S3 is conducted for about 4 to 8 hours.

37 . The method of claim 20 , wherein the method further comprises the step of:

(S1) reacting 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.

38 . The method of claim 37 , wherein:

the inorganic base is one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; and/or

in step S1, the reducing agent is used in about 1 to 6 equivalents, preferably about 4 to 6 equivalents, relative to 5-nitrouracil of Formula (III); and/or

the reducing agent is one or more selected from the group consisting of Na 2 S 2 O 4 , hydrogen, iron powder, and zinc powder; and/or

the reaction temperature in step S1 ranges from about 60 to 90° C.; and/or

the reaction time in step S1 is from about 1 to 10 hours.