Synthesis of 4-AMINO-5-METHYL-1H-PYRIDIN-2(1H)-ONE (Intermediate in the Synthesis of the MR Antagonist Finerenone) from 2-Chloro-5-methyl-4-nitro-pyridine-1-oxide via the intermediate 2-Chloro-5-methyl-4-pyridinamine

Description

[0001] The present invention relates to a new and improved process for the preparation of 4-amino-5-methylpyridone of formula (I) 4-Amino-5-methylpyridone of formula (I) is prepared by reacting chloro-methyl-amino-pyridine (2) with KOH in methanol in an autoclave at elevated temperature.

[0002] The invention also relates to a process for the preparation of chloro-methyl-amino-pyridine (2)

[0003] Here, the nitro-N-oxide of formula (3) hydrogenated over a platinum catalyst to give chloro-methyl-amino-pyridine (2). The process according to the invention enables the preparation of nitro-N-oxide (3) via two chemical steps to produce the target compound (I) with an overall yield of 84% in a high purity (> 99%).

[0004] The compound of formula (I) is a key intermediate for the preparation of finerenone (II):

[0005] Finerenone (II) acts as a non-steroidal antagonist of the mineralocorticoid receptor and can be used as a means of preventing and / or treating cardiovascular and renal diseases such as heart failure and diabetic nephropathy.

[0006] CN 103 193 704 A discloses a process for preparing 4-amino-5-methyl-2(1H)-pyridinone by reacting 2-chloro-5-methyl-4-pyridinamine in ethylene glycol, and a process for preparing 2-chloro-5-methyl-4-pyridinamine by reducing 2-chloro-5-methyl-4-nitro-pyridine-1-oxide with iron powder in HCl. CN 1 311 185 A discloses a process for preparing 2-chloro-5-methyl-4-pyridinamine by reducing 2-chloro-5-methyl-4-nitro-pyridine-1-oxide by hydrogenation over a Raney nickel catalyst.

[0007] The compound of formula (II) and its preparation process are described in WO 2008 / 104306 and ChemMedChem 2012, 7, 1385, as well as in WO 2016 / 016287 A1 (Bayer Pharma AG), both of which contain a detailed discussion of the research synthesis. A disadvantage of the synthesis described therein is that it is not suitable for further large-scale production, as many steps are carried out at very high dilution, with very high reagent excesses, and thus with a relatively low overall yield.

[0008] There was therefore a need for an industrially viable synthesis that would reproducibly deliver the process intermediate of the compound of formula (I) in high overall yield, low cost and high purity, and meet all regulatory requirements to supply the clinical trials with active ingredient and be used for subsequent regulatory submission.

[0009] The preparation of compound (I) is described in Synthesis, p. 765 (1984) (Example 3c). Starting from malonic acid chloride and propionitrile, chloropyridine hydrochloride is obtained in 40% of theoretical yield, which is then directly hydrogenated with Pd / C: 86% of theoretical yield. The total yield over both steps is 34.4% of theoretical yield.

[0010] Starting from hydroxypridone (III), described in Example 1c of the Synthesis publication, benzylamine (IV) is converted into compound (V) in boiling benzylamine (IV). The benzyl group in compound (V) is then removed by catalytic hydrogenation over palladium / carbon. The total yield over both steps is 62.4% of theory:

[0011] The disadvantage of the process is the use of a very large excess of benzylamine. For 30 mmol of the compound of formula (III), 30 ml (275.2 mmol) are used, which is a 9.17-fold excess relative to compound (III). Recycling excess benzylamine is complex and associated with considerable costs. The reaction is carried out in boiling benzylamine (185°C), and the reaction time is 36 hours. Such high temperatures are not feasible in standard stirred reactors and require special technical equipment. When replicating the procedure, a byproduct (VI) was particularly noticeable, which is due to traces of palladium from the precursor to (III):

[0012] Under the drastic reaction conditions, dehydrogenation to benzlimine occurs, which then decomposes to benzaldehyde (water is formed during the reaction). The benzaldehyde condenses with a compound of formula (III) to form a compound of formula (VI). This byproduct is particularly formed during upscaling (up to > 10%) of the batches and persists until the compound of formula (I) is formed. For workup, after cooling the reaction solution to room temperature, the precipitated crystals are washed with methyl ethyl ketone and o-dichlorobenzene and then recrystallized from o-dichlorobenzene. Here, too, it would be advantageous to avoid chlorinated solvents and pursue more environmentally friendly alternatives.

[0013] The subsequent debenzylation takes place in glacial acetic acid, 10 mmol in 200 ml, which is 2.14 g of compound (V) in 200 ml. This corresponds to a 93.45-fold excess, meaning that 93.45 L of acetic acid would be required for 1 kg of (V). These are huge excesses that are unsuitable for an industrial process. Furthermore, 600 mg of Pd catalyst on carbon (10% and 30%) are used to convert 10 mmol. This means that 280 g of catalyst would be required to debenzylate 1 kg of compound (V). This also makes no sense from a technical or economic point of view. For workup, the catalyst is filtered off and the filtrate is evaporated to dryness. Any residual acetic acid is removed with toluene, and the residue is taken up in acetone or methyl ethyl ketone and filtered off. This process is technically impossible in upscaling, as the mixture cannot be evaporated to dryness in stirred reactors. Furthermore, three different solvents are required for isolation.The strongly colored reaction product is then purified by chromatography (dichloromethane / MeOH 1:1), which is also desirable for a large-scale process. The total yield over four chemical steps, starting from malonic acid dichloride, is 21.4% of theory.

[0014] The object of the present invention was to develop an alternative synthesis for the process intermediate 4-amino-5-methylpyridone as an intermediate for the preparation of compounds of formula (II), finerenone, in particular a process which can be carried out easily on an industrial scale, is cost-effective and avoids large solvent excesses and uses reagents which are more environmentally friendly.

[0015] With the present invention, a very efficient synthesis has been found that allows the aforementioned disadvantages to be avoided. Starting from the chloro-methyl-amino-pyridine (2) known from the literature, The target compound (I) is obtained by reacting compound (2) in an autoclave at elevated temperature under either acidic or basic conditions. A similar reaction with NaOH in methanol is described in Tetrahedron 55 (1999), p. 11985. Purification is carried out by chromatography. Unfortunately, the reaction of compound 2 under these conditions yielded a mixture of the target compound (I) and the 2-methyl ether (7):

[0016] This mixture could only be separated chromatographically.

[0017] Surprisingly, the reaction to the target compound proceeds very smoothly when potassium hydroxide (KOH) is used instead of sodium hydroxide. The reaction then also proceeds in methanol as the solvent, without the methyl ether (7) being obtained as a by-product. Pure methanol is preferably used as the solvent, but aqueous methanol can also be used. The reaction is carried out in an autoclave at temperatures of 160 to 200 °C, preferably at 180 °C. Reaction times are 15-48 hours, depending on the selected temperature; i.e., reaction times are shorter at higher temperatures. For workup, the mixture is neutralized with a mineral acid, for example, hydrochloric acid, sulfuric acid, or phosphoric acid, preferably hydrochloric acid (pH approx. 7), then largely concentrated, and water is removed azeotropically by adding it to ethanol. Finally, the mixture is redistilled into methanol, and the salts are filtered off.The mixture is concentrated by evaporation and distilled from water. For recrystallization, the mixture is concentrated to approximately three times the volume (relative to starting material 2). The mixture is cooled to 0°C and the product is isolated, for example, by chromatography.

[0018] Filtration, if necessary, washing with a little cold water and drying under vacuum at elevated temperature (30 - 70°C).

[0019] The present invention therefore relates to a process for the preparation of the process intermediate 4-amino-5-methylpyridone of the formula (I), which comprises reacting chloro-methyl-amino-pyridine (2) with KOH in methanol in an autoclave.

[0020] In a preferred embodiment, temperatures of 160°C to 200°C, in particular 180°C, are used.

[0021] Another object of the present invention relates to a process for the preparation of the process intermediate 4-amino-5-methylpyridone of the formula (I), characterized in that the intermediate nitro-N-oxide (3) is first hydrogenated over a platinum catalyst and then the resulting intermediate chloro-methyl-amino-pyridine (2) is reacted in an autoclave with potassium hydroxide (KOH) in methanol.

[0022] In one embodiment of the invention, chloro-methyl-amino-pyridine (2) is first prepared and can then be used in the process according to the invention:

[0023] In this reaction, the nitro group and the nitro-N-oxide are reduced simultaneously using a Pt catalyst. Such a catalytic hydrogenation reaction with such a substitution pattern on pyridine has not yet been described in the literature.

[0024] The preparation of compound 2 is known from the literature (WO 2005 / 100342 A1). The desmethyl compound of 2 is also known and is prepared using similar methods (Tetrahedron 55 (1999), p. 1195). However, the methods described therein are difficult to scale up on a larger industrial scale, as elemental zinc or iron are sometimes used under acidic conditions, preferably acetic acid. The use of Raney nickel as a hydrogenation catalyst is also possible, but upscaling is problematic because Raney nickel waste is extremely pyrophoric. Furthermore, the technical implementation is a safety challenge, as the reaction is difficult to control due to its strong exothermicity. Furthermore, the workup is very difficult and complex and, in addition, produces a large amount of metal-salt waste that must be disposed of, which is not insignificant when producing such products on a ton-scale.

[0025] A frequently occurring side reaction in the reduction of 2-chloro substituted pyridine derivatives is the simultaneous reduction of the chlorine atom to the hydrogen residue (compound 4).

[0026] This side reaction is not observed in this new inventive process, or only on a minor scale (<<1%), and was therefore surprising and unexpected for the skilled person. The reaction is preferably carried out in protic solvents, for example, alcohols such as ethanol, methanol, isopropanol, n-propanol, or n-butanol. However, solvents such as THF, dioxane, and 2-methyl-THF can be used. In some cases, the addition of water may be advantageous.

[0027] A platinum-containing catalyst is preferred. The following platinum catalysts can be used: 0.8% Pt + 0.6% Mo on Carbon powder 1% Pt + 2% V on Carbon powder 0.5% Pt + 0.3% Mo on Carbon powder

[0028] Particularly preferred is 0.8% Pt + 0.6% Mo on carbon powder (from BASF). The hydrogen pressure during hydrogenation should be between 2 and 7 bar, preferably 2 to 5, and particularly preferably 3 bar. The temperature should be between 20 and 50°C, but preferably between 25 and 30°C, particularly preferably 30°C. The reaction time is 10 to 30 hours, preferably 18 to 22 hours.

[0029] To isolate the product, the catalyst is filtered off, the solution is largely concentrated, and then distilled to obtain the solvent for the subsequent reaction, preferably methanol. The crude product is advantageously used directly in the subsequent step. The reaction proceeds quantitatively.

[0030] The preparation of nitro-N-oxide (3) is known from the literature, as described for example in Heterocycles, Vol. 78, No 11, 2009, p. 2811 or in WO 2005 / 100342 A1.

[0031] In Heterocycles, Vol. 78, No 11, 2009 the following yields for the preparation of compound 3 are described: Overall yield 64% of theory over 2 steps.

[0032] Another object of the present invention relates to a process for the preparation of the process intermediate 4-amino-5-methylpyridone of the formula (I), characterized in that the intermediate nitro-N-oxide (3) is first hydrogenated over a platinum catalyst and then the resulting intermediate chloro-methyl-amino-pyridine (2) is reacted in an autoclave with potassium hydroxide (KOH) in methanol.

[0033] One embodiment relates to a process for preparing the process intermediate chloro-methyl-amino-pyridine (2) by hydrogenating nitro-N-oxide (3) over a platinum catalyst.

[0034] In a preferred embodiment, 0.8% platinum (Pt) + 0.6% molybdenum (Mo) on carbon powder is used as catalyst.

[0035] In a further preferred embodiment, 1% platinum (Pt) + 2% vanadium (V) on carbon powder is used as catalyst.

[0036] In a further preferred embodiment, 0.5% platinum (Pt) + 0.3% molybdenum (Mo) on carbon powder is used as catalyst.

[0037] With the new inventive process, starting from the nitro-N-oxide (3) via two chemical steps to produce the target compound (I) in 84% overall yield with high purity (> 99%). A further advantage of the process is that compound (2) can be converted directly to compound (I) without further purification.

[0038] If the yields of the new process are combined with those known from the literature, starting from the inexpensive and commercially very cheap 2-chloromethylpyridine (5), a total yield of 54% of theory is achieved, which is an approximately 2.5-fold improvement in yield compared to the state-of-the-art process described in Synthesis.

[0039] Another object of the present invention relates to a process for the preparation of the process intermediate 4-amino-5-methylpyridone of the formula (I), characterized in that the intermediate nitro-N-oxide (3) is first hydrogenated over a platinum catalyst and then the resulting intermediate chloro-methyl-amino-pyridine (2) is reacted in an autoclave with potassium hydroxide (KOH) in methanol. Examples Example 1 Preparation of 2-chloro-5-methyl-pyridin-4-amine (compound 2)

[0040] 29 g (153.788 mmol) of 2-chloro-5-methyl-4-nitro-1-oxidopyridin-1-ium (compound 3, Heterocycles, Vol. 78, No. 11, 2009, p. 2811) were placed in a glass pressure reactor with a crossbar stirrer under argon, and 2.9 g of hydrogenation catalyst (0.8% Pt and 0.6% Mo on activated carbon (D505A-105 0.8% Pt + 0.6% Mo on Carbon powder BASF.) and 320 ml of ethanol were added. The reactor was sealed and inertized three times with 3 bar of argon overpressure each time. Subsequently, hydrogenation was carried out for 20 hours at 30°C under 3 bar of hydrogen overpressure (conversion > 98%). The reactor was inertized with argon, and the reaction solution was passed over 10 g of Diatomaceous earth was filtered. The filtrate was evaporated to dryness in vacuo. Yield: 23.0 g (quantitative, product still contained ethanol), purity: 97.5% (HPLC) MS (EIpos): m / z = 143 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ = 1.96 (s, 3H), 6.16 (br s, 2H), 6.50 (s, 1H), 7.68 (s, 1H)

[0041] Similarly, a conversion of approximately 98% was achieved using a catalyst consisting of 0.8% Pt and 0.3% Mo on activated carbon. Using 1% Pt + 2% V on activated carbon, a conversion of approximately 87% was achieved. Example 2 Preparation of 4-amino-5-methyl-1H-pyridin-2-one (I)

[0042] 4.0 g of the title compound from Example 1 (Compound 2) were placed in 40 ml of methanol in a pressure reactor, and 12.5 g of potassium hydroxide (KOH) were added. The mixture was then heated to 180°C for 16 hours (pressure buildup to 12.5 bar). The mixture was allowed to cool.

[0043] The reaction was carried out 5 times with 4.0 g of the title compound from Example 1 each time and the reaction solutions were combined after cooling.

[0044] Workup: The pH was adjusted to 7.0 with approximately 100 ml of 25% aqueous hydrochloric acid while cooling, then evaporated to dryness under vacuum, and the residue was azeotroped five times with 50 ml of ethanol each time (evaporated to dryness under vacuum to remove traces of water). 400 ml of methanol was added to the evaporation residue and stirred. The salt (KCl) was filtered off, and the salt was washed twice with 25 ml of methanol. The filtrate was evaporated to dryness under vacuum. The evaporation residue was recrystallized from 60 ml of water. The mixture was allowed to cool to 0°C, and the precipitated crystals were filtered off. The moist product was then dried under vacuum at 30°C. Yield: 13.5 g (77.53% of theory); Purity according to HPLC: 99.1%. A further 1.10 g (6.32% of theory) was isolated from the mother liquor, resulting in a total yield of approximately 84% of theory. MS (EIpos): m / z = 125 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ = 1.81 (s, 3H), 2.54 (s, 1H), 5.24 (s, 1H), 5.79 (s, 2H), 6.85 (s, 1H), 10.27 (br s, 1H)

[0045] From the above description it becomes clear that the disadvantage of the methods available so far is that (1) a multi-step synthesis is carried out, (2) the by-products of formula (VI) (up to > 10%), formula (4) and / or formula (7) are obtained, which occur as impurities in the preparation of the compound of formula (I) and have to be separated by complex chromatographic processes, (3) benzylamine is used in a very large excess, the recycling of which is complex and associated with considerable costs, (4) the reaction has to be carried out in boiling benzylamine at 185°C and with a reaction time of 36 hours because such high temperatures are not feasible in standard stirrers and require special technical equipment, (5) chlorinated solvents are used which are not environmentally friendly and (6) large amounts of Pd catalyst on carbon have to be used, the separation and work-up of which is not only complex but also hardly feasible in large-scale synthesis.

[0046] In contrast, these disadvantages are avoided by the method according to the invention and the following effects and advantages are achieved: (1) fewer process steps or synthesis stages are required to obtain the compound of formula (I) or the compound of formula (2), (2) the compound of formula (I) is obtained directly, without purification, in high purity, (3) the compounds of formulas (VI), (4) and / or (7) are not obtained as undesired by-products, (4) chromatographic purification, as described in the prior art, is not required and therefore makes this new inventive process very attractive with regard to up-scaling for large-scale production, (5) the multiple use of solvents, in particular chlorinated solvents, can be completely or partially dispensed with, so that the process according to the invention is significantly more environmentally friendly and (6) requires significantly shorter reaction times and / or reaction temperatures.

[0047] Overall, the process according to the invention represents a very efficient, shorter synthesis without the use of chromatography, which is also suitable for upscaling. Using the process according to the invention, starting from the nitro-N-oxide (3), the target compound (I) was prepared in two chemical steps with an overall yield of 84% and high purity (>99%).

Claims

1. Process for preparing the process intermediate 4-amino-5-methylpyridone of formula (I) wherein chloro-methyl-aminopyridine (2) is reacted with KOH in methanol in an autoclave.

2. Process according to Claim 1, wherein the reaction is carried out at a temperature in the range from 160°C to 200°C.

3. Process according to Claim 1 or 2, wherein the reaction is carried out at a temperature of 180°C.

4. Process for preparing the process intermediate 4-amino-5-methylpyridone of formula (I), wherein the process comprises the following steps a) and b): a) hydrogenation of the nitro-N-oxide of formula (3) on a platinum catalyst, with chloro-methyl-aminopyridine of formula (2) being obtained, and b) subsequent reaction of the obtained intermediate chloro-methyl-aminopyridine of formula (2) with KOH in methanol in an autoclave according to any of Claims 1 to 3.

5. Process according to Claim 4, wherein 0.8% platinum and 0.6% molybdenum on carbon powder is used as platinum catalyst in step a).

6. Process according to Claim 4, wherein 1% platinum and 2% vanadium on carbon powder is used as platinum catalyst in step a).

7. Process according to Claim 4, wherein 0.5% platinum and 0.3% molybdenum on carbon powder is used as platinum catalyst in step a).

8. Process according to any of Claims 4 to 7,\ wherein in step b) the reaction is carried out at a temperature in the range from 160°C to 200°C.

9. Process according to any of Claims 4 to 8, wherein in step b) the reaction is carried out at a temperature of 180°C.