Method for synthesizing 4-amino-5-methyl-1H-pyridin-2-one

Abstract

The present invention relates to a method for preparing 4-amino-5-methyl-2(1H)-pyridone of formula (I) by reacting 2-chloro-5-methyl-4-pyridinamine of formula 2 with KOH in methanol in a pressure reactor, and to a method for preparing 2-chloro-5-methyl-4-amino-pyridine-1-oxide of formula 3 by hydrogenating using a platinum catalyst. 4-amino-5-methyl-1H-pyridine-2(I)-one of formula (I) is an intermediate product for preparing phenelenone of formula (II), an MR antagonist.

Description

[0001] The present invention relates to a new and improved process for preparing 4-amino-5-methylpyridone of formula (I)

[0002]

[0003] 4-Amino-5-methylpyridone of formula (I) is prepared by reacting chloro-methyl-aminopyridine (2) with KOH in methanol in an autoclave at elevated temperature.

[0004]

[0005] The present invention also relates to a method for preparing chloro-methyl-aminopyridine (2)

[0006]

[0007] In the process, a nitro-N-oxide of formula (3) is hydrogenated over a platinum catalyst to give chloro-methyl-aminopyridine (2).

[0008]

[0009] By the process of the present invention, the target compound (I) can be prepared starting from the nitro-N-oxide (3) via two chemical steps with an overall yield of 84% and high purity (>99%).

[0010]

[0011] The compound of formula (I) is a key intermediate for the preparation of finerenone (II):

[0012]

[0013] Finerenone (II) acts as a nonsteroidal antagonist of mineralocorticoid receptors and is useful as an agent for preventing and / or treating cardiovascular and renal diseases such as heart failure and diabetic nephropathy.

[0014] Compounds of formula (II) and methods for their preparation are described in WO 2008 / 104306 and ChemMedChem 2012, 7, 1385 and WO 2016 / 016287 A1 (Bayer Pharma AG), which all disclose detailed discussions of the research synthesis. The disadvantage of the synthesis described therein is that it is not suitable for further industrial scale processes, because many steps are carried out at very high dilutions using very high excesses of reagents, resulting in relatively low overall yields.

[0015] Therefore, there is a need for a synthetic process which can be carried out on an industrial scale and which reproducibly provides process intermediates of formula (I) in high overall yield, at low production costs and in high purity and which meets all regulatory requirements in order to provide clinical trials with active substances and for subsequent regulatory submissions.

[0016] The preparation of compound (I) is described in Synthesis, p. 765 (1984) (Example 3c). Starting from malonyl chloride and propionitrile, chloropyridine hydrochloride is obtained in a yield of 40% of theory, which is then directly hydrogenated over Pd / C: 86% of theory. The total yield over two steps is 34.4% of theory.

[0017]

[0018] Starting from the hydroxypyridone (III) in Example 1c of the publication recorded in Synthesis, the compound (V) was reacted in boiling benzylamine (IV). The benzyl group in the compound (V) was then hydrolyzed and cleaved by catalytic hydrogenation over palladium / carbon. The total yield over two steps was 62.4% of the theoretical value.

[0019]

[0020] The disadvantage of the method is the use of a large excess of benzylamine: for 30mmol of the compound of formula (III), 30ml (275.2mmol) of benzylamine is used, which is 9.17 times in excess based on compound (III). The recycling of excess benzylamine is time-consuming and labor-intensive and is accompanied by high costs. The reaction is carried out in boiling benzylamine (185°C) for 36 hours. Such high temperatures are not feasible in standard stirring equipment, but require special technical equipment. When repeating this step, by-product (VI) is particularly observed, which is attributed to traces of palladium from the precursor of (III):

[0021]

[0022] Under severe reaction conditions, dehydrogenation to benzylimine and then decomposition to benzaldehyde (forming water in the reaction process) condenses with the compound of formula (III) to form the compound of formula (VI). This by-product is formed in particular during batch scale-up (up to >10%) and is carried over to the compound of formula (I). The reaction solution is worked up by cooling to room temperature, washing the precipitated crystals with methyl ethyl ketone and o-dichlorobenzene, and then recrystallizing from o-dichlorobenzene. In this context, it would also be advantageous to abandon chlorinated solvents and pursue more environmentally friendly variants.

[0023] The subsequent debenzylation reaction is carried out in glacial acetic acid, 10 mmol in 200 ml, i.e. 2.14 g of compound (V) in 200 ml. This is equivalent to an excess of 93.45 times. This means that for 1 kg (V), 93.45 L of acetic acid will be required. These are extremely large excesses that are impossible to occur in industrial processes. In addition, for the conversion of 10 mmol (V), 600 mg of carbon-supported Pd catalyst (10% and 30%) are used. This means that in order to debenzylate 1 kg of compound (V), 280 g of catalyst will be required. From an industrial and economic point of view, this is also impractical. For post-treatment, the catalyst is filtered out and the filtrate is evaporated to dryness, traces of acetic acid are removed by azeotropy with toluene, and the residue is dissolved in acetone or methyl ethyl ketone and filtered. Since the stirring equipment will not evaporate to dryness, this method is technically not feasible when upscaling. In addition, three different solvents are required for separation. The intensely colored reaction product was then further purified by chromatography (dichloromethane / MeOH 1:1), something else that might need to be avoided in an industrial scale process. The overall yield over 4 chemical steps was 21.4% of theory starting from malonyl chloride.

[0024] The problem addressed by the present invention is to develop an alternative synthesis process for 4-amino-5-methylpyridone, a process intermediate for the preparation of compounds of formula (II) (finerenone), in particular a process that is easy to implement on an industrial scale, is cost-effective and avoids large amounts of excess solvent and uses more environmentally friendly reagents.

[0025] The present invention has found a very effective synthesis method which avoids the above-mentioned disadvantages. Starting from chloro-methyl-aminopyridine (2) known in the literature,

[0026]

[0027] The target compound (I) is obtained by reacting compound (2) in an autoclave at high temperature under acidic or alkaline conditions. A similar reaction with NaOH in methanol is described in Tetrahedron 55 (1999), page 11985. The product is purified by chromatography. Unfortunately, the reaction of compound 2 under these conditions gives a mixture of the target compound (I) and 2-methyl ether (7):

[0028]

[0029] This mixture can only be separated by chromatography.

[0030] Surprisingly, when potassium hydroxide (KOH) is used instead of sodium hydroxide, the process of conversion into the target compound proceeds very smoothly. The reaction is then also carried out in methanol as a solvent, and methyl ether (7) is not obtained as a by-product. Preferably pure methanol is used as a solvent, but aqueous methanol can also be used. The reaction is carried out in an autoclave at a temperature of 160° C. to 200° C., preferably at 180° C. The reaction time is 15-48 hours, depending on the selected temperature, that is, especially the reaction time is often shorter at higher temperatures. For post-treatment, the reaction mixture is neutralized (to about pH 7) with an inorganic acid (such as hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid), then concentrated to a small volume and removed from water in an azeotropic manner by adding ethanol. Finally, it is redistilled in methanol and the salt is filtered out. It is concentrated to a small volume and redistilled in water. For recrystallization, it is concentrated to about three times the volume (based on the starting material 2). After cooling to 0° C., the product is isolated, for example by filtration, washed if necessary with a little cold water and dried at elevated temperature (30° C. to 70° C.) under reduced pressure.

[0031] The present invention therefore provides a process for preparing the process intermediate 4-amino-5-methylpyridone of formula (I), characterized in that chloro-methyl-aminopyridine (2) is reacted with KOH in methanol in an autoclave.

[0032] In a preferred embodiment, the process is carried out at a temperature of 160°C to 200°C, in particular at 180°C.

[0033] Another aspect of the present invention is a novel method for preparing chloro-methyl-aminopyridine (2):

[0034]

[0035] In this process, the nitro group and the nitro-N-oxide are reduced simultaneously using a Pd catalyst. Such catalytic hydrogenation reactions in pyridines with this type of substitution have not yet been described in the literature.

[0036] The preparation of compound 2 is known from the literature (WO 2005 / 100342 A1), and the demethylated compound of 2 is also known and prepared by a similar method (Tetrahedron 55 (1999), page 1195), but the industrial scale transfer (scale-up) difficulty of the method described therein is because they include using elemental zinc or iron to process under acidic conditions (preferably acetic acid). Raney nickel can be used as a hydrogenation catalyst equally, but scale-up is problematic because Raney nickel waste is very prone to spontaneous combustion. In addition, industrial implementation is also a safety challenge because strong heat release means that the reaction is difficult to control. In addition, aftertreatment becomes very difficult and time-consuming and labor-intensive, and the most important thing is that a large amount of metal salt waste that must be processed will be produced, which is not insignificant when preparing the product at a ton level.

[0037] A side reaction that often occurs in the reduction of 2-chloro-substituted pyridine derivatives is the simultaneous reduction of the chlorine atom to hydrogen (compound 4).

[0038]

[0039] This side reaction does not exist or is only observed to a very small extent (<<1%) in the novel method of the present invention, so this is unexpected and unexpected for those skilled in the art. The reaction is preferably carried out in a protic solvent, and the protic solvent is, for example, alcohols, such as ethanol, methanol, isopropanol, n-propyl alcohol and n-butyl alcohol. However, solvents such as THF, dioxane and 2-methyl-THF may also be used. In some cases, it may be advantageous to add water.

[0040] The catalyst used is preferably a platinum-containing catalyst. The following platinum catalysts can be used:

[0041] Carbon powder loaded with 0.8% Pt + 0.6% Mo Carbon powder loaded with 1% Pt + 2% V Carbon powder loaded with 0.5% Pt + 0.3% Mo

[0042] Particularly preferably, 0.8% Pt + 0.6% Mo on carbon powder (from BASF) is used. The hydrogen pressure during the hydrogenation should be 2 to 7 bar, preferably 2 to 5 bar, more preferably 3 bar. The temperature should be 20°C to 50°C, but preferably 25°C to 30°C, more preferably 30°C. The reaction time is 10 to 30 hours, preferably 18 to 22 hours.

[0043] For separation, the catalyst is filtered off and the solution is concentrated to a small volume and redistilled in a solvent (preferably methanol) for the subsequent reaction. It is advantageous when the crude product is used directly in the subsequent reaction. The reaction is carried out quantitatively.

[0044] The preparation of nitro-N-oxides (3) is known from the literature, as described, for example, in Heterocycles, Vol. 78, No. 11, 2009, p. 2811 or WO 2005 / 100342 A1.

[0045] Heterocycles, Vol. 78, No. 11, 2009, describes the following yield for preparing compound 3: the total yield over 2 steps was 64% of the theoretical value.

[0046]

[0047] The present invention also provides a method for preparing the process intermediate chloro-methyl-aminopyridine (2) by hydrogenating a nitro-N-oxide (3) over a platinum catalyst.

[0048] In a preferred embodiment, 0.8% platinum (Pt) + 0.6% molybdenum (Mo) supported on carbon powder is used as the catalyst.

[0049] In another preferred embodiment, 1% platinum (Pt) + 2% vanadium (V) supported on carbon powder is used as the catalyst.

[0050] In another preferred embodiment, 0.5% platinum (Pt) + 0.3% molybdenum (Mo) supported on carbon powder is used as the catalyst.

[0051] The novel method of the present invention can be started from nitro-N-oxide (3) and then reacted with nitro-N-oxide (3) via two chemical steps.

[0052]

[0053] The target compound (I) was prepared in high purity (>99%) with an overall yield of 84%. Another advantage of the method is that compound (2) can be directly converted to compound (I) without further purification.

[0054] If the yields of the new method are combined with those known from the literature, starting from the inexpensive and very commercially available 2-chloromethylpyridine (5), an overall yield of 54% of the theoretical value is achieved, which is about 2.5 times higher than the yield of the prior art method described in Synthesis.

[0055] The present invention also provides a method for preparing 4-amino-5-methylpyridone of the intermediate formula (I), characterized in that the intermediate nitro-N-oxide (3) is first hydrogenated over a platinum catalyst, and then the obtained intermediate chloro-methyl-aminopyridine (2) is reacted with potassium hydroxide (KOH) in methanol in an autoclave.

[0056] The following paragraphs relate to embodiments of the present invention:

[0057] 1. Preparation method of 4-amino-5-methylpyridone of intermediate formula (I)

[0058]

[0059] It is characterized in that chloro-methyl-aminopyridine (2) is reacted with KOH in methanol in an autoclave

[0060]

[0061] 2. The process according to paragraph 1, characterized in that the process is carried out at a temperature of 160°C to 200°C.

[0062] 3. A method for preparing the intermediate chloro-methyl-aminopyridine (2),

[0063]

[0064] The method is characterized in that the nitro-N-oxide (3) is hydrogenated over a platinum catalyst.

[0065]

[0066] 4. The method according to paragraph 3, characterized in that carbon powder supported with 0.8% platinum + 0.6% molybdenum is used as the catalyst.

[0067] 5. The method according to paragraph 3, characterized in that carbon powder supported 1% platinum + 2% vanadium is used as the catalyst.

[0068] 6. The method according to paragraph 3, characterized in that carbon powder supported with 0.5% platinum + 0.3% molybdenum is used as the catalyst.

[0069] 7. A method for preparing 4-amino-5-methylpyridone of intermediate formula (I), characterized in that the nitro-N-oxide (3) intermediate is first hydrogenated over a platinum catalyst and then the resulting chloro-methyl-aminopyridine (2) intermediate is reacted with KOH in methanol in an autoclave. Example

[0070] Example 1 Preparation of 2-chloro-5-methylpyridin-4-amine (Compound 2)

[0071] Under argon, a glass pressure reactor equipped with a cross-beam stirrer was charged with 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), and 2. 9 g of hydrogenation catalyst (0.8% Pt and 0.6% Mo on activated carbon (D505A-105 carbon powder with 0.8% Pt + 0.6% Mo, BASF) and 320 ml of ethanol. The reactor was closed and inerted 3 times, each time with 3 bar argon overpressure. The hydrogenation was then carried out at 3 bar hydrogen overpressure at 30° C. for 20 hours (conversion>98%). The reactor was inerted with argon and the reaction solution was filtered through 10 g of diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure.

[0072] Yield: 23.0 g (quantitative, the product still contains ethanol), purity: 97.5% (HPLC)

[0073] MS (EIpos): m / z = 143 [M + H] +

[0074] 1H-NMR (300MHz, DMSO-d6): δ=1.96(s,3H),6.16(br s,2H),6.50(s,1H),7.68(s,1H)

[0075] In a similar manner, about 98% conversion was achieved using a catalyst consisting of 0.8% Pt on activated carbon and 0.3% Mo. About 87% conversion was achieved using 1% Pt + 2% V on activated carbon.

[0076] Example 2 Preparation of 4-amino-5-methyl-1H-pyridin-2-one (I)

[0077] The pressure reactor was charged with 4.0 g of the title compound of Example 1 (Compound 2) in 40 ml of methanol and 12.5 g of potassium hydroxide (KOH) was added. It was then heated to 180° C. for 16 hours (pressure increased to 12.5 bar). It was allowed to cool.

[0078] The reaction was carried out 5 times, each time using 4.0 g of the title compound of Example 1, and the reaction solutions were combined after cooling.

[0079] Post-treatment: The pH of the mixture is adjusted to pH 7.0 with about 100 ml of 25% aqueous hydrochloric acid solution while cooling, then evaporated to dryness under reduced pressure, and the residue is azeotroped 5 times with ethanol (50 ml each time) (evaporated to dryness under reduced pressure to remove traces of water). 400 ml of methanol are added to the evaporation residue and the mixture is stirred. The salt (KCl) is filtered off and washed with two 25 ml portions of methanol. The filtrate is concentrated to dryness under reduced pressure. The evaporation residue is recrystallized from 60 ml of water. After cooling to 0° C., the precipitated crystals are filtered off. The wet product is then dried at 30° C. under reduced pressure.

[0080] Yield: 13.5 g (77.53% of theory); purity according to HPLC: 99.1%

[0081] A further 1.10 g (6.32% of theory) were isolated from the mother liquor, so that an overall yield of about 84% of theory was achieved.

[0082] MS (EIpos): m / z = 125 [M + H] +

[0083] 1H-NMR (300MHz, 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)

[0084] From what has been said above, it is apparent that the disadvantages of the methods available to date are:

[0085] (1) Perform multi-step synthesis,

[0086] (2) the formation of by-products of formula (VI) (up to >10%), by-products of formula (4) and / or by-products of formula (7), which occur as impurities in the preparation of compounds of formula (I) and need to be removed by time-consuming and laborious chromatography,

[0087] (3) benzylamine is used in large excess, and its recovery is time-consuming, labor-intensive and accompanied by high costs.

[0088] (4) The reaction needs to be carried out in boiling benzylamine at 185°C for 36 hours. Since such high temperatures are not feasible in standard stirring apparatus, special technical equipment is required.

[0089] (5) Use of chlorinated solvents is not environmentally friendly, and

[0090] (6) A large amount of carbon-supported Pd catalyst needs to be used, and its separation and handling are not only time-consuming and labor-intensive but also almost infeasible in industrial-scale synthesis.

[0091] In contrast, the method of the present invention avoids these disadvantages and achieves the following effects and advantages:

[0092] (1) the method / synthesis requires fewer steps to provide a compound of formula (I) or a compound of formula (2),

[0093] (2) The compound of formula (I) is obtained directly in high purity without purification,

[0094] (3) compounds of the formula (VI), (4) and / or (7) are not formed as undesirable by-products,

[0095] (4) No chromatographic separation as described in the prior art is required, making the novel process of the present invention very attractive for scale-up for large-scale production,

[0096] (5) The reuse of solvents, especially chlorinated solvents, can be partially or completely eliminated, thereby making the method of the present invention more environmentally friendly, and

[0097] (6) Shorter reaction times and / or lower reaction temperatures are required.

[0098] Overall, the method of the present invention represents a very efficient shorter synthesis method without the use of chromatography, which is also suitable for scale-up. By the method of the present invention, starting from nitro-N-oxide (3), the target compound (I) can be prepared in high purity (>99%) with an overall yield of 84% via two chemical steps.

Claims

1. A method for preparing the intermediate 4-amino-5-methylpyridone of formula (I) wherein chloro-methyl-aminopyridine (2) is reacted with KOH in methanol in an autoclave 2. The method according to claim 1, wherein the reaction is carried out at a temperature of 160°C to 200°C.

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

4. A method for preparing the intermediate chloro-methyl-aminopyridine (2), The hydrogenation of the nitro-N-oxide of formula (3) is carried out over a platinum catalyst The platinum catalyst is carbon powder loaded with 0.8% platinum and 0.6% molybdenum, carbon powder loaded with 1% platinum and 2% vanadium, or carbon powder loaded with 0.5% platinum and 0.3% molybdenum.

5. The method according to claim 4, wherein 0.8% platinum and 0.6% molybdenum supported on carbon powder is used as the platinum catalyst.

6. The method according to claim 4, wherein 1% platinum and 2% vanadium supported on carbon powder is used as the platinum catalyst.

7. The method according to claim 4, wherein 0.5% platinum and 0.3% molybdenum supported on carbon powder is used as the platinum catalyst.

8. A method for preparing the intermediate 4-amino-5-methylpyridone of formula (I), wherein the method comprises the following steps a) and b): a) treating a nitro-N-oxide of formula (3) Hydrogenation is carried out over a platinum catalyst according to any one of claims 4 to 7 to obtain chloro-methyl-aminopyridine of formula (2) b) According to any one of claims 1 to 3, the intermediate chloro-methyl-aminopyridine of formula (2) is subsequently reacted with KOH in methanol in an autoclave.

9. The method according to claim 8, wherein in step a) 0.8% platinum and 0.6% molybdenum supported on carbon powder is used as the platinum catalyst.

10. The method according to claim 8, wherein 1% platinum and 2% vanadium on carbon powder is used as the platinum catalyst in step a).

11. The method according to claim 8, wherein in step a) 0.5% platinum and 0.3% molybdenum supported on carbon powder are used as platinum catalyst.

12. The process according to any one of claims 8 to 11, wherein in step b), the reaction is carried out at a temperature of 160°C to 200°C.

13. The process according to any one of claims 8 to 12, wherein in step b), the reaction is carried out at a temperature of 180°C.

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