SYNTHESIS OF 4-AMINO-5-METHYL-1H-PYRIDIN-2(1H)-ON (INTERMEDIATE COMPOUND FOR THE SYNTHESIS OF THE MR ANTAGONIST FINERENONE) FROM 2-CHLORO-5-METHYL-4-NITRO-PYRIDINE-1-OXIDE USING THE INTERMEDIATE COMPOUND 2-CHLORO-5-METHYL-4-PYRIDINAMINE

Abstract

The present invention relates to a novel and improved method for preparing 4-amino-5-methylpyridone of the formula (I)

##STR00001##

which is an intermediate in the preparation of the MR antagonist finerenone.

Claims

1. Method A method for preparing the process intermediate 4-amino-5-methylpyridone of the formula (I) ##STR00021## comprising reacting chloro-methyl-aminopyridine (2) ##STR00022## with KOH in methanol in an autoclave.

2. The method according to claim 1, wherein the reaction is carried out at a temperature within a range from 160° C. to 200° C.

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

4. A method for preparing the process intermediate chloro-methyl-aminopyridine (2) ##STR00023## comprising hydrogenating a nitro-N-oxide of the formula (3) ##STR00024## on a platinum catalyst.

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

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

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

8. A method for preparing the process intermediate 4-amino-5-methylpyridone of the formula (I) ##STR00025## comprising the following steps a) and b): a) hydrogenating a nitro-N-oxide of the formula (3) ##STR00026##  on a platinum catalyst, affording chloro-methyl-aminopyridine of the formula (2) ##STR00027## and b) reacting the resulting intermediate chloro-methyl-aminopyridine of the formula (2) with KOH in methanol in an autoclave.

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

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 0.5% platinum and 0.3% molybdenum on carbon powder is used as the platinum catalyst in step a).

12. The method according to claim 8, wherein in step b) the reaction is carried out at a temperature within a range from 160° C. to 200° C.

13. The method according to claim 8, wherein in step b) the reaction is carried out at a temperature of 180° C.

Description

EXAMPLES

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

[0049] A glass pressure reactor with cross-beam stirrer was charged under argon 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 0.8% Pt+0.6% Mo on carbon powder, BASF) and 320 ml of ethanol were added. The reactor was closed and inertized three times, each time with 3 bar argon overpressure. Hydrogenation was then carried out for 20 hours at 30° C. under a 3 bar hydrogen overpressure (conversion >98%). The reactor was inertized with argon and the reaction solution filtered through 10 g of kieselguhr. The filtrate was concentrated to dryness under reduced pressure.

[0050] Yield: 23.0 g (quantitative, product still contained ethanol), purity: 97.5% (HPLC)

[0051] MS (EIpos): m/z=143 [M+H]+

[0052] 1H-NMR (300 MHz, DMSO-d6): δ=1.96 (s, 3H), 6.16 (br s, 2H), 6.50 (s, 1H), 7.68 (s, 1H)

[0053] In an analogous manner, a conversion of approx. 98% was achieved with a catalyst consisting of 0.8% Pt and 0.3% Mo on activated carbon. Use of 1% Pt+2% V on activated carbon achieved a conversion of approx. 87%.

Example 2 Preparation of 4-amino-5-methyl-1H-pyridin-2-One (I)

[0054] A pressure reactor was charged with 4.0 g of the title compound from Example 1 (compound 2) in 40 ml of methanol and 12.5 g of potassium hydroxide (KOH) was added. This was then heated to 180° C. for 16 hours (rise in pressure to 12.5 bar). It was allowed to cool.

[0055] The reaction was carried out 5 times with in each case 4.0 g of the title compound from Example 1 and the reaction solutions combined after cooling.

[0056] Workup: The mixture was adjusted to pH 7.0 with approx. 100 ml of aq. 25% hydrochloric acid while cooling, then evaporated to dryness under reduced pressure, and the residue azeotroped 5 times with ethanol, each time with 50 ml (evaporated to dryness under reduced pressure to remove traces of water). 400 ml of methanol was added to the evaporation residue and the mixture was stirred. The salt (KCl) was filtered off and washed with two 25 ml portions of methanol. The filtrate was concentrated to dryness under reduced pressure. The evaporation residue was recrystallized from 60 ml of water. After cooling to 0° C., the precipitated crystals were filtered off. The wet product was then dried under reduced pressure at 30° C.

[0057] Yield: 13.5 g (77.53% of theory); purity according to HPLC: 99.1%

[0058] A further 1.10 g (6.32% of theory) was isolated from the mother liquor, thereby achieving an overall yield of approx. 84% of theory.

[0059] MS (EIpos): m/z=125 [M+H]+

[0060] 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)

[0061] From what has been described above, it is clear that the methods available up to now have the disadvantages that [0062] (1) a multistep synthesis is carried out, [0063] (2) the by-products of the formula (VI) (up to >10%), of the formula (4) and/or of the formula (7) are formed, which occur as impurities in the preparation of the compound of the formula (I) and need to be removed by laborious chromatographic processes, [0064] (3) benzylamine is used in a very large excess, the recycling of which is laborious and associated with considerable costs, [0065] (4) the reaction needs to be carried out in boiling benzylamine at 185° C. and with a reaction time of 36 hours, since such high temperatures are not practicable in standard stirred apparatuses and require special technical equipment, [0066] (5) chlorinated solvents are used, which are not environmentally friendly, and [0067] (6) large amounts of Pd catalyst on carbon need to be used, the separation and processing of which is not only laborious, but also scarcely practicable in an industrial-scale synthesis.

[0068] By contrast, the method of the invention avoids these disadvantages and achieves the following effects and advantages: [0069] (1) the method/synthesis needs fewer steps in order to afford the compound of the formula (I) or the compound of the formula (2), [0070] (2) the compound of the formula (I) is obtained in high purity directly, without purification, [0071] (3) the compounds of the formulas (VI), (4) and/or (7) do not form as undesired by-products, [0072] (4) chromatographic separation, as is described in the prior art, is not required, thus making this novel inventive method very attractive as regards upscaling for production on a large scale, [0073] (5) the repeated use of solvents, in particular chlorinated solvents, can be eliminated in part or altogether, making the method of the invention much more environmentally friendly and [0074] (6) much lower reaction times and/or lower reaction temperatures are required.

[0075] Overall, the method of the invention represents a very efficient, shorter synthesis without the use of chromatography, that is also suitable for upscaling. With the method of the invention it was possible, starting from the nitro-N-oxide (3), to prepare via two chemical steps the target compound (I) in an overall yield of 84% in high purity (>99%).