Method for the production of 4-amino-5-methyl-(1H)-pyridine-2-one

Abstract

The present invention relates to an improved method for producing 4-amino-5-methyl-(1H)-pyridine-2-one (formula II), which provides the target compound in high yield and high purity by reacting 4-hydroxy-5-methyl-(1H)-pyridine-2-one (formula (I)) with aqueous ammonia and a salt or acid under pressure.

Description

Technical Field

[0001] This application relates to an improved method for the production of 4-amino-5-methyl-(1H)-pyridin-2-one (Formula II).

Chemical Formula

Background Art

[0002] The compound of Formula II is an important intermediate in the synthesis of finerenone

Chemical Formula

[0003] The compound of Formula II is also an intermediate in the synthesis of omeprazole derivatives, as disclosed in CN103193704 A.

[0004] The synthesis of 4-amino-5-methyl-(1H)-pyridin-2-one (Formula II) is described in the journal Synthesis, 1984, volume 9, pages 765 to 766 (see example 3c). In the first step, 4-hydroxy-5-methyl-(1H)-pyridin-2-one (Formula I) is reacted with benzylamine under reflux, thereby substituting the hydroxy group with a benzylamine group. In the second step, the benzylamine group is cleaved by catalytic hydrogenation over palladium on charcoal. The overall yield over both steps is 62.4%.

Chemical Formula

[0005] This synthesis is disadvantageous in that it requires a huge excess of benzylamine (approximately 9 times). Recycling the excess benzylamine is complex and expensive. The reaction requires a temperature of 185 degrees Celsius to achieve boiling and reflux temperatures and takes 36 hours. Such high temperatures cannot be achieved in a standard reflux reactor. Therefore, special equipment is required.

[0006] Furthermore, WO 2020 / 178177 A1 reports that, on a large scale, the following byproducts are formed at non-negligible concentrations in the first step of synthesis. [ka]

[0007] This compound is separated from the target compound using chlorinated solvents, but this is preferable to avoid. Hydrogenation requires large amounts of solvent and palladium charcoal. Testing the hydrogenation reaction requires a chromatographic step. Therefore, the synthesis is not economically feasible for large-scale production.

[0008] The reaction of phenol with ammonia is documented in the literature: EP 2543654 A1, 2013 (Sumitomo Rubber Industries, Ltd) discloses the reaction of phenol with ammonia at 450°C (yield 21.2%); IG Farbenind. Patent: DE570365, 1930; Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 18, p. 446; and Fischer; Bahr; Wiedeking Brennstoff-Chemie, 1934, vol. 15, pp. 101,103 describe a similar method under similarly harsh conditions. See also Chem. News J. Ind. Sci., 1867, vol. 16, p. 55; Helv. chim. Acta, 1924, vol. 7, p. 282; Gmelin Handbook: N: MVol.2, 5.2.2, pages 490 - 493.

[0009] Reactions related to naphthalene are described in WO2008 / 124812 A1, 2008 and Chemistry - An Asian Journal, 2010, vol. 5, # 9 p. 2053-2061 and US 2008 / 293766 A1, 2008 and EP 2075245 A2, 2009 and Synthetic Communications, 2001, vol. 31, # 14 p. 2143.

[0010] These are special variants of the so-called Bucherer reaction and cannot be applied to 4-amino-5-methyl-(1H)-pyridine-2-one (formula II).

[0011] According to WO 2020 / 178177 A1, conventional methods involve fairly harsh reaction conditions, such as temperatures exceeding 300°C, but achieve only very low yields. Methods involving the addition of sulfites and Bucherer-type reactions are not applicable to the conversion of compound (I) to compound (II). Furthermore, attempts at a direct conversion from compound (I) to compound (II) by exposing compound (I) to gaseous ammonia in an autoclave at temperatures up to 180°C yielded only very small amounts of the target compound (II).

[0012] A one-step conversion from compound (I) to compound (II) is described in WO 2020 / 178177 A1 (Bayer AG). The publication discloses that an amino group can be introduced to compound (I) by reacting compound (I) with ammonia under the addition of an ammonium bromide salt in an autoclave (high-pressure reactor), yielding compound (II) in a yield of over 90%. It is disclosed that 0.2 to 3 equivalents, preferably 1 equivalent, of ammonium bromide, for example, ammonium bromide or trialkylammonium bromide or tetraalkylammonium bromide, preferably ammonium bromide, react with compound (I) in an 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 a reaction temperature of 150 to 200°C, particularly preferably up to 170°C, and that, according to the examples, the pressure inside the autoclave rises to 70 to 90 bar.

[0013] The advantages of this method over prior art, particularly the method described in the paper published in the aforementioned journal Synthesis, 1984, volume 9, pages 765 to 766, are as follows: synthesis requires only one step, higher yields are achieved, catalysts such as palladium charcoal are not required, chromatographic purification of the raw product is unnecessary (the target compound (II) is obtained directly as a crystalline product in high purity), excessive use of organic solvents, especially chlorinated solvents, is unnecessary, and high reaction temperatures are not required.

[0014] However, the method disclosed in WO 2020 / 178177 A1 has the disadvantage of requiring a large amount of ammonia as a solvent. This necessitates special equipment for setting up the reaction for the safe removal of ammonia after the reaction is complete and for ammonia recycling. Furthermore, after the ammonia is removed, a dry powder is obtained, which is more difficult to handle and discharge from large reactors than a solution or slurry.

[0015] Therefore, there is a need to provide an alternative synthesis of 4-amino-5-methyl-(1H)-pyridine-2-one (formula II) that is suitable for industrial production, avoids the excessive use of solvents and reagents, especially ammonia, and can be carried out with standard equipment. [Overview of the Initiative]

[0016] This disclosure relates to the 4-hydroxy-5-methyl-(1H)-pyridine-2-one of formula (I). [ka] The 4-amino-5-methyl-(1H)-pyridine-2-one of formula (II) is characterized by reacting it with aqueous ammonia and a salt or acid under pressure. [ka] This provides a method for manufacturing.

[0017] The method of the present disclosure overcomes the above disadvantages. This method has the advantage that the reaction can be carried out with a standard solvent while ammonia as a solvent is eliminated and a significantly lower ammonia equivalent than WO 2020 / 178177 A1 is used. Therefore, no special equipment is required for handling large amounts of gaseous ammonia, removing ammonia after the reaction, and recycling ammonia. A very high reaction temperature is not required. A large amount of catalyst is not required either for the reaction or for the inspection of the crude product. The inspection of the reaction is carried out more easily by discharging the slurry from the reactor using standard equipment and then filtering the slurry. The method of the present disclosure results in compound (II) in a high to very high yield. Therefore, this method is suitable for industrial scale-up.

Embodiments for Carrying out the Invention

[0018] Further aspects, features, and advantages of the exemplary embodiments will become apparent from the following detailed description.

[0019] The patents, published applications, and scientific literature referred to herein are incorporated by reference in their entirety to establish the knowledge of those skilled in the art and to the same extent as if each were specifically and individually incorporated by reference.

[0020] As used herein, regardless of whether in a transitional phrase or within the body of a claim, the terms "comprise(s)" and "comprising" should be construed to have an open-ended meaning. That is, these terms should be construed synonymously with the phrase "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 recited steps, but may also include additional steps.

[0021] The terms "consists essentially of" or "consisting essentially of" have a partially closed meaning, i.e., they do not permit the inclusion of steps, features, or components that would substantially alter the essential characteristics of the method or composition; for example, they do not permit the inclusion of steps, features, or components that would significantly interfere with the desired properties of the compounds or compositions described herein. That is, the method or composition is limited to specific steps or materials and those 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 steps, features, or components described herein.

[0022] As used herein, the singular forms "a," "an," and "the" also include the plural forms of the terms they refer to, in particular, unless otherwise clearly indicated.

[0023] The term "about" is used herein to mean approximately, roughly, in the region of, roughly, or around. When the term "about" is used in combination with a numerical range, the range is modified by extending the upper and lower boundaries of the specified numerical range.

[0024] The terms “dissolved” or “substantially dissolved” are used herein to mean the solubilization of a solid in a solution. A solid can be considered “dissolved” or “substantially dissolved” in a solution if the resulting solution is clear or substantially clear.

[0025] Where used herein, the description of a numerical range for a variable is intended to convey that the variable can be equal to any value within that range. Therefore, if the variable is essentially discrete, it can be equal to any integer value within the numerical range, including the endpoints of the range. Similarly, if the variable is essentially continuous, it can be equal to any real value within the numerical range, including the endpoints of the range. For example, a variable described as having values ​​between 0 and 2 could be 0, 1, or 2 if it is essentially discrete, and could be 0.0, 0.1, 0.01, 0.001, or any other real number if it is essentially continuous.

[0026] In the specification and claims, the singular form includes multiple subjects unless the content clearly indicates otherwise.

[0027] The technical and scientific terms used herein have the meanings generally understood by those skilled in the art, unless otherwise defined.

[0028] The method disclosed herein relates to 4-hydroxy-5-methyl-(1H)-pyridine-2-one of formula (I). [ka] This is reacted under pressure with aqueous ammonia and a salt or acid to form 4-amino-5-methyl-(1H)-pyridine-2-one of formula (II). [ka] It is characterized by obtaining [something].

[0029] The starting material, 4-hydroxy-5-methyl-(1H)-pyridine-2-one (formula (I)), may be commercially available or synthesized according to the method described in the aforementioned journal, Synthesis, 1984, volume 9, pages 765 to 766.

[0030] The reaction is preferably carried out at 120 to 220°C, 140 to 200°C, preferably 150 to 190°C, and more preferably 165 to 175°C. The reaction may be carried out with or without stirring, preferably with stirring.

[0031] The reaction is carried out under pressure. The reaction may also be carried out in an autoclave under self-generated pressure, i.e., the pressure inside the autoclave is generated by heating to achieve the above reaction temperature and depends on the volume of the autoclave. The pressure inside the autoclave may be at least 5, 10, 20, 25, or 30 bar and up to 100, 110, 200, or even 340 bar. The pressure may preferably be 15 to 100 bar, more preferably 20 to 100 bar. The reaction may instead be carried out in a pressure reactor by applying external pressure, for example, by exposing the reaction mixture to gas pressure. The pressure in the pressure reactor may be at least 10, 20, 25, or 30 bar and up to 100, 110, 200, or even 340 bar. The pressure may preferably be 15 to 100 bar, more preferably 20 to 100 bar. The reaction may instead be carried out in continuous mode using a tubular reactor, and the aforementioned pressure range may be applied to the solution by a pump that causes compression of the solution.

[0032] This method requires the presence of aqueous ammonia. Ammonia may be present in the reaction solution in amounts of 10 to 20 molar equivalents, preferably 13 to 17 molar equivalents, and more preferably 14 to 16 molar equivalents, based on formula (I). In embodiments, a commercially available aqueous ammonia solution (25%) may be used. Alternatively, an aqueous ammonia solution having a concentration of 5 to 30% may be used. At concentrations below 5%, the reaction is unproductive. At concentrations much higher than 30%, the solution becomes unstable due to ammonia degassing at room temperature and atmospheric pressure. Using aqueous ammonia allows for the use of significantly less ammonia equivalents than in WO 2020 / 178177 A1. Handling of gaseous ammonia is no longer necessary. Special equipment for handling large amounts of gaseous ammonia before and after the reaction is no longer required.

[0033] This method is preferably carried out in the presence of a salt. The salt used in the method may be an inorganic salt or a salt containing an organic substituent. Suitable salts include salts based on cations selected from alkali metals or containing nitrogen-based cations. Suitable counterions may be selected from halides, preferably fluorides, chlorides, bromides, and iodides, as well as organic anions such as sulfates, sulfites, phosphates, preferably tribasic phosphates, and carboxylates, for example, acetates, formates, citrates, oxalates, tartrates, and sulfonates, preferably mesylates, tosylates, and triflates.

[0034] In one embodiment, the salt is [NR4] xThe formula M is given by R, where R is a C1 to C6 alkyl group or hydrogen, M is an inorganic or organic anion, and x corresponds to the charge number of the anion. In one embodiment, the salt comprises a nitrogen-based cation which may be selected from the group consisting of ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, tetraalkylammonium, pyridinium, and rutidinium, and an anion which may be selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, sulfite, triflate, tribasic phosphate, acetate, citrate, formate, oxalate, tallate, mesylate, triflate, and tosylate. Preferably, the nitrogen-based cation is selected from the group consisting of ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, and tetraalkylammonium, and the anion is selected from fluoride, chloride, bromide, iodide, sulfate, sulfite, tribasic phosphate, acetate, citrate, formate, oxalate, tartrate, mesylate, triflate, and tosylate. The salt may be added in amounts of 0.2 to 15 molar equivalents based on formula (I), where the molar equivalent is calculated relative to the ammonium cation of the salt. For example, monoammonium salts are added in amounts of 0.2 to 15 molar equivalents based on formula (I). Bisammonium salts are added in amounts of 0.1 to 7.5 molar equivalents based on formula (I). The alkyl group in the monoalkylammonium, dialkylammonium, trialkylammonium, and tetraalkylammonium cations may be a C1 to C6 alkyl group, preferably a methyl, ethyl, propyl, or butyl group.

[0035] The salt may be selected from the group consisting of ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium fluorides; ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium chlorides; ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium bromides; and ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium iodides; ammonium triflate, ammonium phosphate, ammonium acetate, ammonium citrate, ammonium oxalate, ammonium tartrate, ammonium mesylate, or ammonium tosylate, pyridinium bromide. The salt may preferably be an ammonium chloride. The particular salts described above may be added in amounts of 5 to 15 or 5 to 10 molar equivalents based on formula (I), preferably 6 to 8 molar equivalents based on formula (I), for example, about 7 molar equivalents, where the molar equivalents are calculated relative to the ammonium cation of the salt.

[0036] The salt may be selected from the group consisting of sulfates of ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium; and sulfites of ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium. The salt may be added in amounts of 0.1 to 6, 0.1 to 5, 0.2 to 4.0, 0.2 to 3.5, or 0.5 to 3.0 molar equivalents based on formula (I), where the molar equivalents are calculated relative to the ammonium cation of the salt.

[0037] The salts used in this method may be formed in situ by adding the corresponding base for the cation described in the above paragraph and the corresponding acid for the anion described in the above paragraph in the required molar ratios. As described in the three paragraphs above, the corresponding base and the corresponding acid may be added in molar equivalents based on formula (I).

[0038] In different embodiments, nitrogen-based cation-free salts, such as ammonium cations, may be added. Such salts may be selected from the group consisting of alkali metal halides and alkaline earth metal halides, particularly alkali metal fluorides, chlorides, bromides, iodides, tosylates, and triflates; and alkaline earth metal fluorides, chlorides, bromides, iodides, tosylates, triflates, or carbonates. The alkali metal may include lithium, sodium, or potassium. The alkaline earth metal may include magnesium, calcium, strontium, and barium. Sodium iodide and potassium iodide are preferred. These salts may be added in amounts of 0.25 to 9, 0.5 to 8, 0.75 to 7, or 1 to 6 molar equivalents based on formula (I).

[0039] In another embodiment, the reaction disclosed in the above paragraph is carried out by adding a Lewis acid catalyst. In some embodiments, the Lewis acid catalyst may be added instead of a nitrogen-based cation-free salt, such as an ammonium cation, as described in the preceding paragraph. Salts of metals such as magnesium, calcium, aluminum, boron, silicon, zinc, iron, copper, silver, titanium, and zirconium may be added to the reaction. The counterions of the salts may be inorganic anions, such as halides, preferably fluorides, chlorides, bromides, and iodides, as well as sulfates, sulfites, carbonates, phosphates, preferably tribasic phosphoric acids, and organic anions, such as carboxylates, such as acetates, formates, citrates, and sulfonates, preferably mesylates, tosylates, and triflates. Zinc acetate, aluminum lactate, magnesium chloride, iron acetate, copper sulfate, zinc chloride, or calcium chloride may be used as the Lewis acid catalyst. The Lewis acid catalyst may be added in powder form. The proportion of the catalyst may be 2 to 20 mol%, or 5 to 15 mol%, or 7 to 13 mol%, or 8 to 12 mol%, or 3 to 8 mol%, relative to formula (I).

[0040] The proportions of aqueous ammonia and ammonium salt may be as described above. In one example, aqueous ammonia, ammonium bromide, and aluminum lactate react. In another example, aqueous ammonia, ammonium bromide, and magnesium chloride react.

[0041] The temperatures applied to the reaction may be as described above. However, they can be lowered to 130 to 170°C, 140 to 160°C, or 145 to 155°C, preferably 150°C. The reaction pressure may be as described above. However, it can be lowered to 5 bar.

[0042] The advantages of adding a Lewis acid catalyst are that the reaction proceeds at a low temperature of 150°C and yields high yields. The reaction also proceeds at lower pressures.

[0043] In another embodiment, the reaction disclosed herein is carried out in the presence of an acid instead of the salt described above. The addition of the acid in the presence of ammonia allows for the in situ formation of the ammonium salt. The acid may be selected from organic or inorganic acids that exhibit at least moderate solubility in water. The acid may be added in an amount of 3 to 10, preferably 4 to 8 molar equivalents, based on formula (I). The organic acid may be a carboxylic acid or a sulfonic acid. The organic acid may be selected from citric acid, oxalic acid, tartaric acid, lactic acid, malonic acid, caproic acid, formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. The inorganic acid may be selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and sulfuric acid.

[0044] The proportion of ammonia, the temperature, and the pressure in this embodiment may be as described above.

[0045] The method disclosed herein may be carried out in which aqueous ammonia is used as the sole solvent in the reaction. Therefore, the reaction mixture does not contain any other solvents besides aqueous ammonia. This has the advantage of a simple inspection procedure. In embodiments, compound (II) is crystallized from the reaction solution to such a high degree of purity that even recrystallization is unnecessary.

[0046] The reaction may instead be carried out in the presence of a solvent containing n-alkanols, branched alkanols, polyols, and polyethers. The solvent may be added in an amount of 10 to 50% (v / v). For example, the solvent may be added as part of a solution containing compound (I).

[0047] The reaction may be carried out for 15 to 72 hours, 24 to 48 hours, preferably 20 to 30 hours. However, the reaction can be carried out for up to two weeks without adversely affecting the yield.

[0048] After the reaction is complete, the crude reaction mixture may be subjected to standard testing procedures. For example, the crude reaction mixture may be cooled to induce crystallization, and the product may then be isolated by filtration. In embodiments, compound (II) crystallizes from the reaction solution with such high purity that recrystallization is unnecessary. Further time-consuming and resource-intensive purification steps, such as chromatography, are not required. The product is obtained with high purity (based on HPLC measurements, >99%) and yields of 50 to 80%.

[0049] The present invention will be better understood by referring to the following embodiments and figures. These embodiments are intended to be representative of specific embodiments of the invention and are not intended to limit the scope of the invention. [Examples]

[0050] Materials and methods The starting material, 4-hydroxy-5-methyl-(1H)-pyridine-2-one (formula (I)), is commercially available or synthesized by the method described in Synthesis, 1984, volume 9, pages 765 to 766. The remaining drugs are commercially available.

[0051] The autoclaves used were either standard laboratory autoclaves with a volume of 1000 ml or autoclaves with a volume of 50 ml.

[0052] HPLC analysis was performed using a Zorbax SB-Aq (Agilent) type alkyl reversed-phase bonded phase as the stationary phase, maintained at 20°C. Ammonia acetate buffer at pH 5.7 was used as the mobile phase and injected during the initial and final stages. 40–60 vol.% acetonitrile was intermittently added to the ammonium acetate buffer at pH 5.7.

[0053] The yield was determined by 1H NMR using sodium tosylate, which is completely soluble in the solution, as an internal standard. For this purpose, 20 mol% of sodium tosylate (based on formula (I)) was added to the reaction solution. The reaction solution was then subjected to 1H NMR measurement, and the methyl groups of the tosyl residues in formula (I) were integrated. In some examples, the yield was determined by HPLC when the 1H NMR measurements were superimposed.

[0054] Example 1 25.0 g (0.2 mol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound I) was added to 74.9 g (1.4 mol) of ammonium chloride and 225 ml (3.0 mol) of 25% aqueous ammonia. Within 4 hours, the reaction mixture was heated to 170°C in a pressure reactor under self-forming pressure (maximum self-forming pressure 21.6 bar). After reaching 170°C, the mixture was held at that temperature for 24 hours and then cooled to 20°C. The mixture was diluted with 36 ml of water, cooled to 5°C, and held at that temperature for 1 hour. The precipitated crystalline solid was filtered, washed with 75 ml of water, and dried under vacuum at 50°C to obtain 19.7 g (yield 79%) of 4-amino-5-methyl-2(1H)-pyridine-2-one (compound II): purity by HPLC: 100%, IR spectrum corresponds to the reported IR spectrum.

[0055] In the reaction based on Example 1, compound I was reacted with 0.5 molar equivalents of ammonium chloride at 150°C to obtain a yield of 22% (the yield was determined by NMR using sodium tosylate as an internal standard).

[0056] In another reaction based on Example 1, compound I was reacted with 0.5 molar equivalents of ammonium chloride at 170°C, yielding a 50% yield (the yield was determined by NMR using sodium tosylate as an internal standard).

[0057] In the reaction based on Example 1, compound I was reacted with 2 molar equivalents of ammonium chloride at 150°C to obtain a yield of 34% (the yield was determined by NMR using sodium tosylate as an internal standard).

[0058] In another reaction based on Example 1, compound I was reacted with 2 molar equivalents of ammonium chloride at 170°C, yielding a 75% yield (yield was determined by NMR using sodium tosylate as an internal standard).

[0059] Example 2 125 mg (1.0 mmol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound I) was added to 225 mg (1.5 mmol) of sodium iodide and 1.12 ml (15.0 mol) of 25% aqueous ammonia. The reaction mixture was heated to 170°C in a pressure reactor under self-generating pressure. After reaching 170°C, the mixture was maintained at that temperature for 48 hours and then cooled to 20°C. The yield was determined by NMR (using sodium tosylate as an internal standard), yielding 54% of 4-amino-5-methyl-2(1H)-pyridine-2-one (compound II).

[0060] In the reaction based on Example 2, compound I was reacted with 0.5 molar equivalents of sodium iodide at 150°C to obtain a yield of 43% (the yield was determined by NMR using sodium tosylate as an internal standard).

[0061] In another reaction based on Example 2, compound I was reacted with 0.5 molar equivalents of sodium iodide at 160°C to obtain a 26% yield (the yield was determined by NMR using sodium tosylate as an internal standard).

[0062] In another reaction based on Example 2, compound I was reacted with 0.5 molar equivalents of sodium iodide at 170°C to obtain a 70% yield (the yield was determined by NMR using sodium tosylate as an internal standard).

[0063] In the reaction based on Example 2, compound I was reacted with 2 molar equivalents of sodium iodide at 150°C to obtain a yield of 31% (the yield was determined by NMR using sodium tosylate as an internal standard).

[0064] In another reaction based on Example 2, compound I was reacted with 2 molar equivalents of sodium iodide at 160°C to obtain a 30% yield (the yield was determined by NMR using sodium tosylate as an internal standard).

[0065] In another reaction based on Example 2, compound I was reacted with 2 molar equivalents of sodium iodide at 170°C (maximum self-regeneration pressure of 20 bar), yielding a 54% yield (yield was determined by NMR using sodium tosylate as an internal standard).

[0066] Example 3 330 mg (2.6 mmol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound I) was added to 1.29 g (13.2 mmol) of ammonium bromide, 33 mg (0.1 mmol) of aluminum lactate, and 3.0 ml (39.8 mmol) of 25% aqueous ammonia. The reaction mixture was heated to 150°C in a pressure reactor under self-generating pressure. After reaching 150°C, the mixture was maintained at that temperature for 72 hours and then cooled to 20°C. The yield was determined by HPLC, yielding 92% of 4-amino-5-methyl-2(1H)-pyridine-2-one (compound II).

[0067] Example 4 330 mg (2.6 mmol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound I) was added to 1.29 g (13.2 mmol) of ammonium bromide, 33 mg (0.1 mmol) of magnesium chloride, and 3.0 ml (39.8 mmol) of 25% aqueous ammonia. The reaction mixture was heated to 150°C in a pressure reactor under self-generating pressure. After reaching 150°C, the mixture was maintained at that temperature for 72 hours and then cooled to 20°C. The yield was determined by HPLC, yielding 91% of 4-amino-5-methyl-2(1H)-pyridine-2-one (compound II).

[0068] Example 5 25.0 g (0.2 mol) of 4-hydroxy-5-methyl-2(1H)-pyridinone (compound I) was added to 79.3 g (0.6 mol) of ammonium sulfate and 150 ml (2.0 mol) of 25% aqueous ammonia. Within 4 hours, the reaction mixture was heated to 170°C in a pressure reactor under self-forming pressure (24.0 bar). After reaching 170°C, the mixture was kept at that temperature for 24 hours and then cooled to 20°C. The mixture was diluted with 36 ml of water, cooled to 5°C, and kept at that temperature for 1 hour. The precipitated crystalline solid was filtered, washed with 72 ml of water, and dried under vacuum at 50°C to obtain 20.2 g (yield 81%) of 4-amino-5-methyl-2(1H)-pyridinone (compound II): purity by HPLC: 99.7%, according to IR spectrum.

[0069] Example 6 2.5 g (20 mmol) of 4-hydroxy-5-methyl-2(1H)-pyridinone (compound I) was added to 3.5 g (30 mmol) of ammonium sulfite ((NH4)2SO3) and 23 ml (300 mmol) of 25% aqueous ammonia. The reaction mixture was heated to 170°C in a pressure reactor under self-forming pressure (maximum pressure 20 bar). After reaching 170°C, the mixture was maintained at that temperature for 48 hours and then cooled to 20°C. The yield of 4-amino-5-methyl-2(1H)-pyridin-2-one (compound II) was determined by NMR (80%).

[0070] In the reaction based on Example 6, compound I was reacted with 0.2 molar equivalents of sulfite at 170°C, yielding a 45% yield detected by NMR.

[0071] In another reaction based on Example 6, compound I was reacted with 1 molar equivalent of sulfite at 170°C to obtain a 70% yield detected by NMR.

[0072] In another reaction based on Example 6, compound I was reacted with 2 molar equivalents of sulfite at 170°C to obtain an 85% yield detected by NMR.

[0073] In another reaction based on Example 6, compound I was reacted with 1 molar equivalent of sulfite at 150°C to obtain a 41% yield detected by NMR.

[0074] In another reaction based on Example 6, compound I was reacted with 2 molar equivalents of sulfite at 150°C to obtain a 70% yield detected by NMR.

[0075] Example 7 330 mg (2.6 mmol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound I) was added to 13.15 mmol (5 molar equivalents) of malonic acid and 3.0 ml (39.8 mmol, 15 equivalents) of 25% aqueous ammonia. The reaction mixture was heated to 170°C in a pressure reactor under self-generating pressure. After reaching 170°C, the mixture was maintained at that temperature and reacted for 48 hours, after which it was cooled to 20°C. The yield was determined by HPLC and yielded 87% of 4-amino-5-methyl-2(1H)-pyridine-2-one (compound II).

[0076] Example 8 330 mg (2.6 mmol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound I) was added to 13.15 mmol (5 molar equivalents) of caproic acid and 3.0 ml (39.8 mmol, 15 equivalents) of 25% aqueous ammonia. The reaction mixture was heated to 170°C in a pressure reactor under self-generating pressure. After reaching 170°C, the mixture was maintained at that temperature and reacted for 48 hours, after which it was cooled to 20°C. The yield was determined by HPLC and yielded 84% of 4-amino-5-methyl-2(1H)-pyridine-2-one (compound II).

[0077] Additional examples using the additives shown in the table below were carried out as follows: 330 mg (2.6 mmol) of 4-hydroxy-5-methyl-2(1H)-pyridine-2-one (compound I) was added to 13.15 mmol (5 equivalents) of the additives shown in the table and 3.0 ml (39.8 mmol, 15 equivalents) of 25% aqueous ammonia. The reaction mixture was heated to 170°C in a pressure reactor under self-generating pressure. After reaching 170°C, the mixture was maintained at that temperature and reacted for 48 hours, after which it was cooled to 20°C. The conversion from formula I to formula II was determined by HPLC. Furthermore, the selectivity of the reaction toward formula II was determined by HPLC. The results are also shown in the table below.

[0078] [Table 1]

[0079] Section of the embodiment:

[0080] Item 1. Formula (I) 4-hydroxy-5-methyl-(1H)-pyridine-2-one [ka] The 4-amino-5-methyl-(1H)-pyridine-2-one of formula (II) is characterized by reacting it with aqueous ammonia and a salt or acid under pressure. [ka] A method for manufacturing.

[0081] Item 2. The method according to Item 1, characterized in that the reaction temperature is between 120 and 220°C.

[0082] Item 3. The method according to item 1 or 2, characterized in that the reaction temperature is 150 to 190°C.

[0083] Item 4. The method according to any one of items 1 to 3, characterized in that the reaction temperature is 165 to 175°C.

[0084] Item 5. The method according to any one of items 1 to 4, characterized in that the salt comprises a cation selected from the group consisting of ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, tetraalkylammonium, pyridinium, and rutidinium, and an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, sulfite, tribasic phosphate, carboxylate, preferably acetate, citrate, tartrate, oxalate, formate, and sulfonate, preferably mesylate, triflate, and tosylate.

[0085] Item 6. The method according to Item 5, characterized in that the salt is added in an amount of 0.2 to 15 molar equivalents based on formula (I), the molar equivalents being calculated relative to the ammonium cations of the salt.

[0086] Item 7. The method according to any one of items 1 to 5, characterized in that the salt is selected from the group consisting of ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium fluorides; ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium chlorides; ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium bromides; and ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium iodides, ammonium triflate, ammonium phosphate, ammonium acetate, ammonium citrate, ammonium oxalate, ammonium tartrate, ammonium mesylate, or ammonium tosylate, or pyridinium bromide.

[0087] Item 8. The method according to any one of items 1 to 7, characterized in that the salt is ammonium chloride.

[0088] Item 9. The method according to item 7 or 8, characterized in that the salt is added in an amount of 5 to 10 molar equivalents based on formula (I), the molar equivalents being calculated relative to the ammonium cations of the salt.

[0089] Item 10. The method according to any one of items 7 to 9, characterized in that the salt is added in an amount of 6 to 8 molar equivalents based on formula (I), the molar equivalents being calculated relative to the ammonium cations of the salt.

[0090] Item 11. The method according to any one of items 1 to 5, characterized in that the salt is selected from the group consisting of ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium sulfates; and ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium sulfites.

[0091] Item 12. The method according to Item 11, characterized in that the salt is added in an amount of 0.1 to 6 molar equivalents based on formula (I), the molar equivalents being calculated relative to the ammonium cation of the salt.

[0092] Item 13. The method according to any one of items 1 to 12, characterized in that the salt is formed in situ by the addition of the corresponding base of the cation and the corresponding acid of the anion, and provides a molar equivalent.

[0093] Item 14. The method according to any one of items 1 to 4, characterized in that the salt is selected from the group consisting of alkali metal fluorides, chlorides, bromides, iodides, tosylates, or triflates; and alkaline earth metal fluorides, chlorides, bromides, iodides, tosylates, triflates, and carbonates.

[0094] Item 15. The method according to any one of items 1 to 4 and 14, characterized in that the salt is selected from sodium iodide or potassium iodide.

[0095] Item 16. The method according to item 14 or 15, characterized in that the salt is added in an amount of 0.5 to 8 molar equivalents based on formula (I).

[0096] Item 17. The method according to any one of items 1 to 16, characterized in that the reaction is carried out in the presence of a Lewis acid catalyst.

[0097] Item 18. The method according to any one of items 1 to 17, characterized in that the reaction is carried out in the presence of a Lewis acid catalyst in the presence of 2 to 20 mol%, or 5 to 15 mol%, or 7 to 13 mol%, or 8 to 12 mol%, relative to formula (I).

[0098] Item 19. The method according to Item 17 or 18, 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.

[0099] Item 20. The method according to any one of items 17 to 19, characterized in that ammonium bromide is reacted with aluminum lactate, zinc acetate, magnesium chloride, or calcium chloride.

[0100] The method according to any one of items 17 to 20, characterized in that it is carried out at 130 to 170°C, 140 to 160°C, or 145 to 155°C, preferably 150°C.

[0101] Item 22. The method according to any one of items 1 to 4, characterized in that the acid is an organic acid or an inorganic acid, and is added in an amount of 3 to 10, preferably 4 to 8 molar equivalents, based on formula (I).

[0102] Item 23. The method according to Item 22, characterized in that the organic acid is a carboxylic acid, preferably citric acid, oxalic acid, tartaric acid, lactic acid, malonic acid, caproic acid, formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, trifluoroacetic acid, or sulfonic acid, preferably methanesulfonic acid, p-toluenesulfonic acid, or trifluoromethanesulfonic acid, and the inorganic acid is preferably hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, or sulfuric acid.

[0103] Item 24. The method according to any one of items 1 to 23, characterized in that the aqueous ammonia contains 10 to 20 molar equivalents of ammonia based on formula (I).

[0104] Item 25. The method according to any one of items 1 to 24, characterized in that the aqueous ammonia contains 13 to 17 molar equivalents of ammonia based on formula (I).

[0105] Item 26. The method according to any one of items 1 to 25, characterized in that the aqueous ammonia contains 14 to 16 molar equivalents of ammonia based on formula (I).

[0106] Item 27. The method according to any one of items 1 to 26, characterized in that the pressure is increased in an autoclave.

[0107] Item 28. The method according to any one of items 1 to 26, characterized in that the reaction is carried out in a pressure reactor by applying an external pressure of 5 to 340 bar, preferably 15 to 100 bar.

[0108] Item 29. The method according to any one of items 1 to 28, characterized in that aqueous ammonia is used as the sole solvent in the reaction.

[0109] Item 30. The method according to any one of items 1 to 29, characterized in that a solvent is selected from the group comprising n-alkanols, branched alkanols, polyols, and polyethers and added.

[0110] Item 31. The method according to any one of items 1 to 30, characterized in that the reaction is carried out over a period of 15 to 72 hours, preferably 24 to 48 hours.

Claims

1. Formula (I) 4-hydroxy-5-methyl-(1H)-pyridine-2-one 【Chemistry 1】 The 4-amino-5-methyl-(1H)-pyridine-2-one of formula (II) is characterized by reacting it with aqueous ammonia and a salt or acid under pressure. 【Chemistry 2】 A method for manufacturing.

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

3. The method according to claim 1 or 2, characterized in that the salt comprises a cation selected from the group consisting of ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, tetraalkylammonium, pyridinium, and rutidinium, and an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, sulfite, tribasic phosphate, carboxylate, or sulfonate.

4. The method according to claim 3, characterized in that the salt is added in an amount of 0.2 to 15 molar equivalents based on formula (I), the molar equivalents being calculated relative to the ammonium cations of the salt.

5. The method according to any one of claims 1 to 4, characterized in that the salt is selected from the group consisting of ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium fluoride; ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium chloride; ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium bromide; and ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium iodide, ammonium triflate, ammonium phosphate, ammonium acetate, ammonium citrate, ammonium oxalate, ammonium tartrate, ammonium mesylate, ammonium tosylate, or pyridinium bromide.

6. The method according to any one of claims 1 to 5, characterized in that the salt is ammonium chloride.

7. The method according to claim 5 or 6, characterized in that the salt is added in an amount of 5 to 10 molar equivalents based on formula (I), the molar equivalents being calculated relative to the ammonium cations of the salt.

8. The method according to any one of claims 1 to 4, characterized in that the salt is selected from the group consisting of sulfates of ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium; and sulfites of ammonium, monoalkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium.

9. The method according to any one of claims 1 to 8, characterized in that the salt is formed in situ by the addition of a corresponding base for the cation and a corresponding acid for the anion, and provides a molar equivalent.

10. The method according to claim 1 or 2, characterized in that the salt is selected from the group consisting of alkali metal fluorides, chlorides, bromides, iodides, tosylates, or triflates; and alkaline earth metal fluorides, chlorides, bromides, iodides, tosylates, triflates, or carbonates.

11. The method according to any one of claims 1 to 10, characterized in that the reaction is carried out in the presence of a Lewis acid catalyst in an amount of 2 to 20 mol%, or 5 to 15 mol%, or 7 to 13 mol%, or 8 to 12 mol%, relative to formula (I).

12. The method according to any one of claims 1 to 4, characterized in that the acid is an organic acid or an inorganic acid, and is added in an amount of 3 to 10, preferably 4 to 8 molar equivalents, based on formula (I).

13. The method according to any one of claims 1 to 12, characterized in that the aqueous ammonia contains 10 to 20 molar equivalents of ammonia based on formula (I).

14. The method according to any one of claims 1 to 13, characterized in that the pressure is increased in an autoclave.

15. The method according to any one of claims 1 to 13, characterized in that the reaction is carried out in a pressure reactor by applying an external pressure of 5 to 340 bar, preferably 15 to 100 bar.

16. The method according to any one of claims 1 to 15, characterized in that aqueous ammonia is used as the sole solvent in the reaction.

17. The method according to any one of claims 1 to 16, characterized in that the reaction is carried out over a period of 15 to 72 hours, preferably 24 to 48 hours.

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