Method for producing 4-amino-5-methyl-(1H)-pyridine-2-one and its derivatives

Abstract

To provide an alternative synthesis of 4-amino-5-methyl-(1H)-pyridine-2-one (formula IV) and its derivatives that is suitable for industrial production, avoids excessive use of solvents and reagents, especially ammonia, and can be carried out using standard equipment. [Solution] The present invention relates to an improved method for producing 4-amino-5-methyl-(1H)-pyridine-2-one and its derivatives, wherein by reacting 4-hydroxy-5-methyl-(1H)-pyridine-2-one with an ammonium salt under pressure without the addition of aqueous ammonia or the supply of gaseous ammonia, the target compound is obtained in high yield and with high purity.

Description

[Technical Field]

[0001] This application concerns 4-amino-5-methyl-(1H)-pyridine-2-one (formula IV) and its derivatives:

[0002] [ka]

[0003] Regarding improved manufacturing methods. [Background technology]

[0004] The compound of formula (IV) is an important intermediate for the synthesis of finerenone.

[0005] [ka]

[0006] Finerenone is effective as a nonsteroidal mineralocorticoid receptor antagonist (MRA). Finerenone is used as a pharmaceutical for the prevention and / or treatment of cardiovascular or renal diseases. The compound of formula (IV) is also an intermediate for the synthesis of omeprazole derivatives as disclosed in CN103193704 A.

[0007] The synthesis of compound (IV) in a single step, starting from a hydroxy-substituted isomer of compound (IV), is described in WO 2020 / 178177 A1 (Bayer AG). The publication discloses that the amino group can be introduced by reaction with ammonia while adding ammonium bromide salts in an autoclave (high-pressure reactor), thus yielding compound (IV) in a yield of over 90%. It is disclosed that 0.2 to 3 equivalents, preferably 1 equivalent, of ammonium bromides, such as ammonium bromide, trialkylammonium bromide, or tetraalkylammonium bromide, preferably ammonium bromide, react in the autoclave, to which ammonia is supplied by condensation to function as a reagent and solvent (having 40 to 100 equivalents, preferably 40 to 60 equivalents, for example, 50 equivalents of ammonia). WO 2020 / 178177 A1 discloses, for example, a reaction temperature of 150 to 200°C and an increase in autoclave pressure to 70 to 90 bar.

[0008] The method disclosed in WO 2020 / 178177 A1 has the disadvantage of requiring a large amount of ammonia as a solvent. Special equipment is required to carry out this reaction for the safe removal of ammonia after the reaction is complete, and for the recycling of ammonia. In addition, a dry powder is produced after the removal of ammonia, which is more difficult to handle and discharge from large reactors than the solution or slurry. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] CN103193704 A [Patent Document 2] WO 2020 / 178177 A1 [Non-patent literature]

[0010] [Non-Patent Document 1] Synthesis, 1984, volume 9, pages 765 - 766

Summary of the Invention

Problems to be Solved by the Invention

[0011] Therefore, there is a need to provide an alternative synthesis of 4 - amino - 5 - methyl - (1H) - pyridin - 2 - one (Formula IV) and derivatives, which is suitable for industrial production, avoids the excessive use of solvents and reagents, especially ammonia, and can be carried out with standard equipment.

Means for Solving the Problems

[0012] The present disclosure provides a method for producing 4 - amino - (1H) - pyridin - 2 - one of the following formula (II)

[0013]

Chemical Formula

[0014] characterized by reacting 4 - hydroxy - (1H) - pyridin - 2 - one of the following formula (I)

[0015]

Chemical Formula

[0016] with a salt containing an ammonium cation under pressure and in the absence of ammonia (NH3).

[0017] In particular, the present disclosure provides a method for producing 4 - amino - 5 - methyl - (1H) - pyridin - 2 - one of Formula (IV)

[0018]

Chemical Formula

[0019] characterized by the following formula (III)

[0020] [ka]

[0021] The present invention provides a method characterized by reacting 4-hydroxy-5-methyl-(1H)-pyridine-2-one with a salt containing an ammonium cation under pressure and in the absence of ammonia (NH3).

[0022] The method of this disclosure overcomes the aforementioned disadvantages of the prior art. The advantages of the method are that, since gaseous ammonia is not used as a reagent, the reaction mixture is not corrosive to the enamel coating on the surface of the reaction vessel, or is far less corrosive. Therefore, special, high-cost reactor coatings are not required. Glass lining can be used. Furthermore, special equipment for handling large amounts of gaseous ammonia, removing it after the reaction, and recycling it is not required. The reaction can be carried out with standard solvents such as water, which is environmentally friendly. The reaction can be carried out at much lower pressures (less than 10 bar) than in the prior art. Therefore, the reaction can be carried out with simpler and lower-cost reactors. Huge amounts of solvent are not required for the reaction or for the workup of the crude product. Workup of the reaction can be carried out more easily by draining the slurry from the reactor using standard equipment and then filtering the slurry. The method of this disclosure yields products in high to very high yields. [Modes for carrying out the invention]

[0023] Further aspects of the exemplary embodiments will become apparent from the following detailed description.

[0024] The patents, published applications, and scientific literature referenced herein establish the knowledge of those skilled in the art, and just as each is shown to be incorporated by reference specifically and individually, the whole is incorporated by reference.

[0025] As used herein, the terms “comprise(s)” and “comprising,” whether in a transitional clause or a claim body, shall be interpreted as having an open-ended meaning. That is, they shall be interpreted as synonymous with the phrases “having at least” or “including at least.” When used in the context of a method, the term “comprising” means that the method includes at least the listed steps, but may also include additional steps.

[0026] The terms "consists essentially of" or "consisting essentially of" are partially closed in meaning, meaning they do not permit the inclusion of steps, features, or components that substantially alter the essential characteristics of the method or composition, for example, steps, features, or components that significantly interfere with the desired properties of the compound or composition described herein. In other words, the method or composition is limited to those steps or substances that do not substantially affect the basic and novel characteristics of the method or composition. The terms "consists of" and "consists" are closed terms and only permit the inclusion of the listed steps, features, or components.

[0027] As used herein, the singular forms “a,” “an,” and “the” specifically include the plural forms of the terms they refer to, unless the context clearly indicates otherwise.

[0028] The term "about" is used herein to mean approximately, around, roughly, or roughly. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the upper and lower limits of the indicated number.

[0029] The terms “dissolved” or “substantially dissolved” are used herein to mean the solubilization of a solid in a solution. A solid may be considered “dissolved” or “substantially dissolved” in a solution if the resulting solution is clear or substantially clear.

[0030] When used herein, the enumeration of a numerical range for a variable is intended to convey that the variable can be equal to any value within that range. Thus, for a variable that is essentially distinct, the variable can be equal to any integer value in the numerical range, including the endpoint of the range. Similarly, for a variable that is essentially continuous, the variable can be equal to any real number in the numerical range, including the endpoint of the range. As an example, a variable described as having a value between 0 and 2 could be 0, 1, or 2 as an essentially distinct variable, and could be 0.0, 0.1, 0.01, 0.001, or any other real number as an essentially continuous variable.

[0031] In the specification and claims, unless the content clearly indicates otherwise, the singular form includes the plural referent.

[0032] Unless otherwise defined, the technical and scientific terms used herein have the meanings that are ordinarily understood by those skilled in the art to which this description belongs.

[0033] The method disclosed herein is given by the following formula (I)

[0034] [ka]

[0035] 4-hydroxy-(1H)-pyridine-2-one is reacted with a salt containing an ammonium cation under pressure and in the absence of ammonia (NH3) to obtain the following compound (II).

[0036] [ka]

[0037] The method is characterized by obtaining 4-amino-(1H)-pyridine-2-one.

[0038] In formulas (I) and (II), substituent R 1 and R 2 The substituent R can be independently selected from linear or branched alkyl groups, aryl groups, benzyl groups, or hydrogen groups. The alkyl group can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl groups. In formula (II), substituent R 3 This can be selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, aryl, or benzyl.

[0039] The starting material according to formula (I) can be a commercially available product or can be synthesized by a method known to those skilled in the art.

[0040] The method is preferably carried out at 120-220°C, 140-200°C, preferably 150-190°C, and more preferably 165-175°C. The method can be carried out with or without stirring, preferably with stirring.

[0041] The method is carried out under pressure. The method can be carried out in an autoclave under spontaneous pressure, i.e., the pressure inside the autoclave is generated by heating to achieve the above reaction temperature and is determined by the capacity of the autoclave. The pressure inside the autoclave may be 2 to 10 bar, preferably 2 to 7 bar, more preferably 3 to 6 bar, even more preferably 4 to 6 bar, or less than 4 to 6 bar. Alternatively, the method can be carried out in a pressure reactor by applying external pressure, for example, by exposing the reaction mixture to gas pressure. The pressure achieved in the pressure reactor may be as indicated above. Since the method is carried out at a much lower pressure (less than 10 bar) than the conventional method, a simpler and less expensive reactor can be used, especially when the reaction is carried out at less than 6 bar. Alternatively, the method can be carried out in a continuous manner using a tubular reactor, and the above pressure range can be applied to the solution by a pump effective in compressing the solution.

[0042] The aqueous ammonia solution is not mixed with the starting material or any other reagents (if present), nor is gaseous ammonia (NH3) supplied to the reaction solution. The substitution of the hydroxyl group with an amino group is achieved by adding a salt containing an ammonium cation or an alkyl-substituted ammonium cation. The salt can have a solubility of 0.5 mol / L to 25 mol / L, preferably at least 1 mol / L to 25 mol / L, and the solubility is measured at room temperature. The salt has a base equilibrium constant (pK) on a logarithmic scale. b The anion comprises a value of 20 or less, preferably 16 or less, more preferably 11 or less, and with a lower limit of 1 or more.

[0043] The salt is ammonium (NH4 + ) or monoalkyl-substituted ammonium (NR 3 H3 + ) may contain a cation selected from, where R 3 This is as defined above (excluding hydrogen).

[0044] The salt may contain anions selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, bisulfite, sulfite, tribasic phosphate, dibasic phosphate, monobasic phosphate, bicarbonate, acetate, propionate, butyrate, citrate, oxalate, formate, and other carboxylate salts, as well as mesylate, triflate, and tosylate.

[0045] The above salt can be added to formula (I) in an amount of 2 to 10, preferably 3 to 7, more preferably 4 to 6 molar equivalents, where the molar equivalent is calculated relative to the ammonium cation of the salt.

[0046] In certain embodiments of the method, the salt used in the method can be formed in insights by adding the corresponding base for the cation and the corresponding acid for the anion in the required molar ratios. The corresponding base and the corresponding acid can be added in molar equivalents to formula (I) as described in the paragraph above.

[0047] The method may be carried out by adding an acid until the pH of the reaction solution reaches 5-8, preferably 6-7. The acid may be a mineral acid, a carboxylic acid, or a sulfonic acid. The acid may be selected from the group consisting of hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid (H2SO4), sulfurous acid (H2SO3), nitric acid (HNO3), phosphoric acid (H3PO4), acetic acid, glacial acetic acid, citric acid, formic acid, lactic acid, oxalic acid, malic acid, tartaric acid, butyric acid, methanesulfonic acid, triflic acid, and toluenesulfonic acid. The preferred acid is acetic acid or glacial acetic acid. Adding an acid has the advantage of reducing the pressure rise in the reactor.

[0048] The method can be carried out by adding an inert salt to formula (I) at a concentration of 0.1 to 0.4, preferably 0.15 to 0.3 molar equivalents. The inert salt may be a salt containing an anion selected from the group consisting of alkali metal cations, alkaline earth metal cations, quaternary ammonium cations or transition metal cations, and fluorides, chlorides, bromides, iodides, sulfates, sulfites, tribasic phosphates, dibasic phosphates, monobasic phosphates, acetates, propionates, butyrates, citrates, formates, mesylates, triflates and tosylates, wherein the inert salt is water-soluble, meaning it can have a solubility of 0.5 mol / L to a maximum of 25 mol / L, preferably at least 1 mol / L to 25 mol / L, and the solubility is measured at room temperature. Preferred inert salts are sodium sulfate, potassium sulfate or sodium tosylate. As such inert salts, salts that do not exhibit any catalytic activity are used. The addition of an inert salt has the advantage of reducing the pressure rise in the reactor.

[0049] In particular, this disclosure relates to a method for producing 4-amino-5-methyl-(1H)-pyridine-2-one of formula (IV), and formula (III)

[0050] [ka]

[0051] 4-hydroxy-5-methyl-(1H)-pyridine-2-one is reacted with a salt containing an ammonium cation under pressure and in the absence of ammonia (NH3) to obtain formula (IV).

[0052] [ka]

[0053] The present invention provides a method for obtaining 4-amino-5-methyl-(1H)-pyridine-2-one.

[0054] The starting material, 4-hydroxy-5-methyl-(1H)-pyridin-2-one (Formula (III)), can be a commercially available product or can be synthesized according to the method described in the paper in Synthesis, 1984, volume 9, pages 765 - 766.

[0055] The method for producing 4-amino-5-methyl-(1H)-pyridin-2-one of Formula (IV) can be carried out under the above conditions and using the described reagents. The method can be carried out at the above temperature. The preferred range can be 150 - 190 °C, more preferably 165 - 175 °C. The method can be carried out within the above pressure range. The preferred pressure range can be 2 - 7 bar, more preferably 3 - 6 bar, even more preferably 4 - 6 bar, or less than 4 - 6 bar. These values respectively refer to the method carried out in an autoclave and the method of applying external pressure.

[0056] The production method of Formula (IV) is carried out while adding a salt containing an ammonium cation (NH4 + ). The salt may have the above solubility and may contain an anion whose pK b is as above. The anion can be selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, bisulfate, sulfite, tribasic phosphate, dibasic phosphate, monobasic phosphate, bicarbonate, acetate, propionate, butyrate, citrate, oxalate, formate and other carboxylates, mesylate, triflate and tosylate. Preferably, the salt can contain an anion selected from the group consisting of an ammonium cation and fluoride, sulfite, tribasic phosphate, dibasic phosphate, bicarbonate, acetate, citrate, oxalate, formate, mesylate. Even more preferably, the salt can be selected from the group consisting of ammonium acetate, ammonium tribasic phosphate and ammonium dibasic phosphate. The salt can be ammonium acetate. The above salt can be added in an amount of 2 - 10, preferably 3 - 7, more preferably 4 - 6 molar equivalents relative to Formula (III), and the molar equivalent is calculated based on the ammonium cation of the salt.

[0057] The method may also be carried out by adding acid until the reaction solution reaches a pH of 5-8, preferably 6-7. The acids that can be used are those listed above.

[0058] The method may also be carried out by adding an inert salt to formula (III) at a concentration of 0.1 to 0.4, preferably 0.15 to 0.3 molar equivalents. The salts that can be used are those listed above.

[0059] In another embodiment, the method as disclosed in the above paragraph is carried out by further adding a Lewis acid catalyst. Salts of metals such as magnesium, calcium, aluminum, boron, silicon, zinc, iron, copper, silver, titanium, and zirconium can be added to the reaction. The counterions of the salts may be inorganic anions such as halides, preferably fluorides, chlorides, bromides, and iodides, and sulfates, sulfites, phosphates, preferably tribasic phosphates, or organic anions such as carboxylates, e.g., acetates, formates, citrates, and sulfons, preferably mesylates, tosylates, and triflates. Zinc acetate, aluminum lactate, magnesium chloride, calcium chloride, or iron(III) chloride may be used as Lewis acid catalysts. The Lewis acid catalyst may be added in powder form. The proportion of the catalyst may be 5 to 20 mol%, or 5 to 15 mol%, or 7 to 13 mol%, or 8 to 12 mol%, relative to the starting material (1H)-pyridine-2-one. The proportion of the salt containing the ammonium cation may be as described above. In one example of the method, (1H)-pyridine-2-one reacts with ammonium acetate and a Lewis acid catalyst such as aluminum lactate, zinc acetate, magnesium chloride, calcium chloride, or iron(III) chloride. The applicable temperature in this embodiment may be as described above. However, the applicable temperature can be lower, such as 130-170°C, 140-160°C, or 145-155°C, preferably 150°C. The pressure of the method may be as described above. The advantage of adding a Lewis acid catalyst is that the reaction proceeds at lower temperatures and pressures, resulting in a higher yield.

[0060] Generally, the above method can be carried out using water as the sole solvent. This has the advantage of simple workup procedures. In one embodiment, the product crystallizes from the reaction solution with such purity that even recrystallization is unnecessary. Alternatively, solvents containing n-alkanols, branched alkanols, polyols, and polyethers can be added. The solvent can be added at 10-50% (v / v). For example, the solvent can be added as part of a solution containing the starting material (III) of (1H)-pyridine-2-one.

[0061] The above method can be carried out for 15 to 48 hours, preferably 20 to 30 hours. However, the method can be continued for up to two weeks without adversely affecting the yield.

[0062] After the reaction is complete, the crude reaction mixture can be subjected to standard post-treatment procedures. For example, the crude reaction mixture can be cooled to induce crystallization, and then the product can be isolated by filtration. In one embodiment, the final product crystallizes from the reaction solution with such high purity that even recrystallization is unnecessary. Further time-consuming and resource-intensive purification steps, such as chromatographic purification, are not required. The product is obtained with high purity (>99% by HPLC measurement). A yield of 50-80% is obtained.

[0063] The present invention will be better understood by referring to the following embodiments. These embodiments are intended to be representative specific embodiments of the present invention and are not intended to limit the scope of the invention. [Examples]

[0064] Materials and methods The starting material, 4-hydroxy-5-methyl-(1H)-pyridine-2-one (formula (I)), can be commercially available or synthesized according to the method described in Synthesis, 1984, volume 9, pp. 765-766. The remaining reagents can be commercially available. The autoclave used was a standard 100 ml capacity Buchi laboratory autoclave. HPLC analysis was performed using a Zorbax SB-Aq (Agilent) alkyl reversed-phase bonded phase as the stationary phase, maintained at 20 degrees Celsius. Ammonium acetate buffer at pH 5.7 was used as the mobile phase and injected at the first and last stages. 40-60 vol.% acetonitrile was intermittently added to the ammonium acetate buffer at pH 5.7. The yields in the following examples are those after workup and drying.

[0065] (Example 1) 12.5 g (0.1 mol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound III) was added to 39.9 g (0.5 mol) of ammonium acetate solution dissolved in 13 ml of water. Within 4 hours, the reaction mixture was heated to 170°C in a pressure reactor under spontaneous pressure (5.7 bar). After reaching 170°C, the mixture was held at that temperature for 48 hours, and then cooled to 60°C. The mixture was diluted with aqueous ammonia (25%) and cooled to 0°C. The precipitated crystalline solid was filtered, washed with ethanol, and dried under vacuum to obtain 8.9 g (70% yield) of 4-amino-5-methyl-2(1H)-pyridine-2-one (compound IV). Purity by HPLC: 99.8%, IR spectrum match.

[0066] When the salts shown in the table below were reacted under the same reaction conditions, the following results were obtained. (170°C, spontaneous pressure rising to approximately 5.7 bar, 1 equivalent of reagent)

[0067] [Table 1]

[0068] (Example 2) (Add acid to lower the pH) Glacial acetic acid was added to 39.9 g (0.5 mol) of ammonium acetate solution, dissolved in 13 ml of water, until the pH reached 7.0. 12.5 g (0.1 mol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound III) was added to the neutral ammonium acetate solution. Within 4 hours, the reaction mixture was heated to 170°C in a pressure reactor under spontaneous pressure (4.7 bar). After reaching 170°C, the mixture was held at that temperature for 48 hours, and then cooled to 60°C. The mixture was diluted with aqueous ammonia (25%) and cooled to 0°C. The precipitated crystalline solid was filtered, washed with ethanol, and dried under vacuum to obtain 8.6 g (yield 69%) of 4-amino-5-methyl-2(1H)-pyridine-2-one (compound IV). Purity by HPLC: 99.6%, IR spectrum match.

[0069] (Example 3) (Sodium sulfate is added as an inert salt.) 12.5 g (100 mmol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound III) and 2.0 g of sodium sulfate (14.1 mmol) were added to 39.9 g (0.5 mol) of ammonium acetate solution dissolved in 13 ml of water. Within 4 hours, the reaction mixture was heated to 170°C in a pressure reactor under spontaneous pressure (5.3 bar). After reaching 170°C, the mixture was held at that temperature for 48 hours, and then cooled to 60°C. The mixture was diluted with aqueous ammonia (25%) and cooled to 0°C. The precipitated crystalline solid was filtered, washed with ethanol, and dried under vacuum to obtain 9.2 g (yield 72%) of 4-amino-5-methyl-2(1H)-pyridine-2-one (compound IV). Purity by HPLC: 99.6%, IR spectrum match.

[0070] (Example 4) (Method using 190°C instead of 170°C) 7.0 g (0.06 mol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound III) was added to 27.9 g (0.36 mol) of ammonium acetate solution dissolved in 8.4 ml of water. Within 13 hours, the reaction mixture was heated to 190°C in a pressure reactor under spontaneous pressure (8 bar). After reaching 190°C, the mixture was held at that temperature for 48 hours, and then cooled to 20°C. The mixture was diluted with aqueous ammonia (25%) and cooled to 0°C. The precipitated crystalline solid was filtered, washed with ethanol, and dried under vacuum to obtain 5.5 g (yield 79%) of 4-amino-5-methyl-2(1H)-pyridine-2-one (compound IV). Purity by HPLC: 99.7%, IR spectrum match.

[0071] (Example 5) (Addition of Lewis acid) 0.33 g (2.65 mmol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound III) was added to 1.02 g (13.25 mmol) of ammonium acetate and 0.04 g (0.27 mmol) of iron(III) chloride in 0.38 g (21.2 mmol) of water. The reaction mixture was heated to 170°C in a pressure reactor under spontaneous pressure. After reaching 170°C, the mixture was held at that temperature for 72 hours and then cooled to 20°C. The conversion rate was monitored by HPLC and was 94%.

[0072] (Example 6) (Addition of Lewis acid double salt) 0.33 g (2.65 mmol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound III) was added to 3.51 g (13.25 mmol) of ammonium iron citrate in 0.38 g (21.2 mmol) of water. The reaction mixture was heated to 170°C in a pressure reactor under spontaneous pressure. After reaching 170°C, the mixture was held at that temperature for 72 hours and then cooled to 20°C. The conversion rate was monitored by HPLC and was 87%.

[0073] (Example 7) (Synthesis of 4-(N-methylamino)-5-methyl-1H-pyridine-2-one) 0.33 g (2.65 mmol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound III) was added to 1.21 g (13.25 mmol) of methylammonium acetate in 0.38 g (21.2 mmol) of water. The reaction mixture was heated to 170°C in a pressure reactor under spontaneous pressure. After reaching 170°C, the mixture was held at that temperature for 72 hours and then cooled to 20°C. The conversion rate was monitored by HPLC and was 87%. 1 H-NMR (DMSO-d6): δ 1.83 (3H, s), 2.65 (3H, s), 5.05 (1H, s), 6.84 (1H, s). This was confirmed by [method / method].

[0074] Embodiments section 1.Formula (II)

[0075] [ka]

[0076] A method for producing 4-amino-(1H)-pyridine-2-one of formula (I)

[0077] [ka]

[0078] The 4-hydroxy-(1H)-pyridine-2-one is reacted with a salt containing an ammonium cation under pressure and in the absence of ammonia. [In the formula, R 1 and R 2 This is independently selected from linear or branched alkyl groups, aryl groups, benzyl groups, or hydrogen groups. R 3 [Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, aryl or benzyl] A method characterized by the following features.

[0079] 2. The method according to Embodiment 1, characterized in that the reaction temperature is 120 to 220°C.

[0080] 3. The method according to Embodiment 1 or Embodiment 2, characterized in that the reaction temperature is 150 to 190°C.

[0081] 4. The method according to any one of Embodiments 1 to 3, characterized in that the reaction temperature is 165 to 175°C.

[0082] 5. The equilibrium constant (pK) of the base on a logarithmic scale for a salt. b The method according to any one of Embodiments 1 to 4, characterized in that it contains an anion whose value is 20 or less, preferably 16 or less, most preferably 11 or less, and has a lower limit of 1 or more.

[0083] 6. The method according to Embodiment 5, characterized in that the salt has a solubility of 0.5 mol / L to a maximum of 25 mol / L, preferably at least 1 mol / L to 25 mol / L, and the solubility is measured at room temperature.

[0084] 7. The salt is ammonium or (NH3R 3 ) + The method according to any one of Embodiments 1 to 6, characterized by comprising a cation containing, and an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, bisulfite, sulfite, tribasic phosphate, dibasic phosphate, monobasic phosphate, bicarbonate, acetate, citrate, propionate, butyrate, oxalate, formate, mesylate, triflate, and tosylate.

[0085] 8. The salt contains an ammonium cation or (NH3R 3 ) + The method according to Embodiment 7, characterized by comprising an anion selected from the group consisting of fluoride, sulfite, tribasic phosphate, dibasic phosphate, bicarbonate, acetate, citrate, oxalate, formate, and mesylate.

[0086] 9. The method according to Embodiment 8, characterized in that the salt comprises an ammonium cation or an N-methyl-ammonium cation or an N-ethyl-ammonium cation, and an anion selected from the group consisting of fluoride, tribasic phosphate, dibasic phosphate, bicarbonate, acetate, citrate, oxalate, and formate.

[0087] 10. The method according to any one of Embodiments 1 to 9, characterized in that the salt is selected from the group consisting of ammonium acetate, tribasic ammonium phosphate, and dibasic ammonium phosphate.

[0088] 11. The method according to any one of Embodiments 1 to 10, characterized in that the salt is ammonium acetate.

[0089] 12. The method according to any one of Embodiments 1 to 11, characterized in that the salt is added to formula (I) in an amount of 2 to 10, preferably 3 to 7, more preferably 4 to 6 molar equivalents, the molar equivalents being calculated relative to the ammonium cations of the salt.

[0090] 13.R 1 and R 2 The method according to any one of Embodiments 1 to 12, characterized in that the hydrogen is independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, benzyl, aryl, and hydrogen.

[0091] 14. The method according to any one of Embodiments 1 to 13, characterized in that the reactant is 4-hydroxy-5-methyl-(1H)-pyridine-2-one, and is reacted to obtain 4-amino-5-methyl-(1H)-pyridine-2-one.

[0092] 15. The method according to any one of Embodiments 1 to 14, characterized in that an acid is added so that the reaction solution reaches a pH of 5 to 8, preferably 6 to 7.

[0093] 16. The method according to Embodiment 15, characterized in that the acid is a mineral acid, a carboxylic acid, or a sulfonic acid.

[0094] 17. The method according to Embodiment 16, characterized in that the acid is selected from the group consisting of hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid (H2SO4), sulfurous acid (H2SO3), nitric acid (HNO3), phosphoric acid (H3PO4), acetic acid, glacial acetic acid, citric acid, formic acid, lactic acid, oxalic acid, malic acid, tartaric acid, butyric acid, methanesulfonic acid, triflic acid, and toluenesulfonic acid.

[0095] 18. The method according to any one of Embodiments 1 to 17, characterized in that an inert salt is added at a concentration of 0.1 to 0.4, preferably 0.15 to 0.3 molar equivalents, relative to formula (I).

[0096] 19. The method according to Embodiment 18, characterized in that the inert salt comprises a salt containing an alkali metal cation, alkaline earth metal cation, quaternary ammonium cation or transition metal cation, and an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, sulfite, tribasic phosphate, dibasic phosphate, monobasic phosphate, acetate, propionate, butyrate, citrate, formate, mesylate, triflate and tosylate, and the inert salt is water-soluble.

[0097] 20. The method according to any one of embodiments 1 to 19, characterized in that the pressure inside the autoclave increases.

[0098] 21. The method according to any one of Embodiments 1 to 19, characterized in that the reaction is carried out in a pressure reactor by applying an external pressure of 2 to 10 bar, preferably 2 to 7 bar, more preferably 3 to 6 bar, and even more preferably 4 to 6 bar.

[0099] 22. The method according to any one of Embodiments 1 to 21, characterized in that the reaction is carried out in the presence of a Lewis acid catalyst.

[0100] 23. The method according to any one of Embodiments 1 to 22, characterized in that the reaction is carried out in the presence of a Lewis acid catalyst in an amount of 5-20 mol%, 5-15 mol%, 7-13 mol%, or 8-12 mol% relative to formula (I).

[0101] 24. The method according to Embodiment 22 or 23, characterized in that the Lewis acid catalyst is selected from inorganic or organic salts of magnesium, calcium, aluminum, boron, silicon, zinc, iron, copper, silver, titanium, and zirconium.

[0102] 25. The method according to any one of Embodiments 22 to 24, characterized in that ammonium acetate reacts with aluminum lactate, zinc acetate, magnesium chloride, iron(III) chloride, or calcium chloride.

[0103] 26. The method according to any one of embodiments 22 to 25, characterized in that it is carried out at 130-170°C, 140-160°C, or 145-155°C, preferably 150°C.

[0104] 27. The method according to any one of Embodiments 1 to 26, characterized in that water is used as the sole solvent for the reaction.

[0105] 28. The method according to any one of Embodiments 1 to 27, characterized in that a solvent is added, selected from the group comprising n-alkanols, branched alkanols, polyols, and polyethers.

[0106] 29. The method according to any one of Embodiments 1 to 28, characterized in that the reaction is carried out for 15 to 48 hours, preferably 20 to 30 hours.

Claims

1. Formula (II) 【Chemistry 1】 A method for producing 4-amino-(1H)-pyridine-2-one of formula (I) 【Chemistry 2】 4-hydroxy-(1H)-pyridine-2-one is reacted with a salt containing an ammonium cation under pressure and in the absence of ammonia. [In the formula, R 1 and R 2 This is independently selected from linear or branched alkyl groups, aryl groups, benzyl groups, or hydrogen groups. R 3 [Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, aryl or benzyl] A method characterized by the following features.

2. The method according to claim 1, characterized in that the reaction temperature is 120 to 220°C.

3. The equilibrium constant (pK) of the base on a logarithmic scale for a salt. b The method according to claim 1 or 2, characterized in that it contains an anion whose ) is 20 or less, preferably 16 or less, most preferably 11 or less, and has a lower limit of 1 or more.

4. The method according to claim 3, characterized in that the salt has a solubility of 0.5 mol / L to a maximum of 25 mol / L, preferably at least 1 mol / L to 25 mol / L, and the solubility is measured at room temperature.

5. The salt is ammonium or (NH 3 R 3 ) + Cations containing The method according to any one of claims 1 to 4, characterized by comprising an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, bisulfite, sulfite, tribasic phosphate, dibasic phosphate, monobasic phosphate, bicarbonate, acetate, propionate, butyrate, citrate, oxalate, formate, mesylate, triflate, and tosylate.

6. The method according to any one of claims 1 to 5, characterized in that the salt is selected from the group consisting of ammonium acetate, tribasic ammonium phosphate, and dibasic ammonium phosphate.

7. The method according to any one of claims 1 to 6, characterized in that the salt is added to formula (I) in an amount of 2 to 10 molar equivalents, and the molar equivalents are calculated relative to the ammonium cations of the salt.

8. R 1 and R 2 where R and R are independently selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, aryl, benzyl and hydrogen, the method according to any one of claims 1 to 7.

9. The method according to any one of claims 1 to 8, characterized in that the reactant is 4-hydroxy-5-methyl-(1H)-pyridine-2-one, and is reacted to obtain 4-amino-5-methyl-(1H)-pyridine-2-one.

10. The method according to any one of claims 1 to 9, characterized in that an acid is added so that the reaction solution reaches a pH of 5 to 8, preferably 6 to 7.

11. The method according to claim 10, characterized in that the acid is a mineral acid, a carboxylic acid, or a sulfonic acid.

12. The method according to any one of claims 1 to 11, characterized in that an inert salt is added at a concentration of 0.1 to 0.4 molar equivalents relative to formula (I).

13. The method according to claim 12, wherein the inert salt comprises a salt containing an anion selected from the group consisting of alkali metal cations, alkaline earth metal cations, quaternary ammonium cations or transition metal cations, and tribasic phosphates, dibasic phosphates, monobasic phosphates, acetates, propionates, butyrates, citrates, formates, mesylates, triflates and tosylates, and the inert salt is water-soluble.

14. The method according to any one of claims 1 to 13, characterized in that the reaction is carried out in the presence of 5 to 20 mol% of a Lewis acid catalyst relative to formula (I).

15. The method according to claim 14, characterized in that it is carried out at 130 to 170°C.

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