Method for producing Arogabat

Abstract

The present invention relates to a novel method for producing 6-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazole-4-yl]methoxy]-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (1), or a pharmaceutically acceptable salt thereof. The method according to the present invention is particularly suitable for large-scale production of the compound of formula 1 under GMP conditions. TIFF2026512638000032.tif62169

Description

Technical Field

[0001] Field of the Invention The present invention relates to a novel method for producing 6-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methoxy]-N-tetrahydropyran-4-yl-pyridazine-3-carboxamide (1), or a pharmaceutically acceptable salt thereof.

Chemical Formula

[0002] The method according to the present invention is particularly suitable for the large-scale production of the compound of formula 1 under GMP conditions.

Background Art

[0003] Background of the Invention 6-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methoxy]-N-tetrahydropyran-4-yl-pyridazine-3-carboxamide (1) is a positive allosteric modulator (PAM) of the GABA , , ,

[0006] α5 receptor (International Publication No. WO 2018 / 104419), which is currently being investigated in clinical trials for the treatment of autism spectrum disorder (ASD).

[0004] Compound 1 is also known as the INN allogabut (WHO Drug Information, Vol. 35, No. 2, 2021, 366).

[0005] International Publication No. WO 2018 / 104419 discloses a laboratory-scale (6 mg) method for producing allogabut. This method is not suitable for the industrial-scale production of allogabut. That is, due to the use of toxic solvents such as DMF, the need for silica gel chromatography, the formation of by-products, and the low yield.

[0006] Therefore, there is a high unmet need for new methods of manufacturing allogabat in order to enable providing patients with this new treatment option for ASD. [Overview of the project]

[0007] Summary of the Invention The present invention provides an improved method for producing Arogabat (1) that overcomes the problems outlined above. [Modes for carrying out the invention]

[0008] Detailed description of the invention definition Features, integers, characteristics, compounds, chemical parts, or groups described in connection with a particular aspect, embodiment, or example of the present invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless they are incompatible. All features disclosed herein (including any appended claims and abstract) and / or all steps of any method or process disclosed herein may be combined in any combination, except for combinations in which at least a portion of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any of the embodiments described herein. The present invention extends to any novel or novel combination of features disclosed herein (including any appended claims and abstract) and any novel or novel combination of any steps of any method or process disclosed herein.

[0009] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base or free acid, and is not biologically or otherwise undesirable. Salts are formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and especially hydrochloric acid, as well as organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic base or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Examples of salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as salts of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyimine resins.

[0010] Manufacturing method Process A In a first aspect, the present invention relates to a method for producing allogabat (1) or a pharmaceutically acceptable salt thereof, [ka] [5-methyl-3-(6-methyl-3-pyridyl)isoxazole-4-yl]methanol (2), [ka] 6-Chloro-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (3), [ka] Provided is a method that includes reacting in the presence of a base to obtain the allogabat (1).

[0011] In one embodiment, the base used in the reaction of compound 2 and compound 3 is selected from Cs2CO3, NaO t Bu and sodium hydride.

[0012] In a preferred embodiment, the base is selected from NaO t Bu and sodium hydride.

[0013] In a particularly preferred embodiment, the base is sodium hydride.​​​​​​​​​​​​​​​​​​​​​​​Therefore, in one embodiment of the method according to the present invention, Arogabat (1) is purified by filtering the reaction mixture on activated carbon.

[0020] In one embodiment of the method according to the present invention, allogabat (1) is purified by crystallization.

[0021] In a preferred embodiment, the crystallization is from 1-propanol.

[0022] In one embodiment of the method according to the present invention, Arogabat (1) is purified by (i) filtering the reaction mixture through activated carbon, followed by (ii) crystallization.

[0023] In one embodiment of the method according to the present invention, the starting material 6-chloro-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (3) is 3,6-dichloropyridazine (4), [ka] Tetrahydro-2H-pyran-4-amine(5) [ka] It can also be obtained by reacting carbon monoxide with a base and a palladium catalyst.

[0024] In one embodiment, the palladium catalyst used in the reaction of compound 4 with compound 5 and carbon monoxide is selected from PdCl2(dppp), PdCl2(P(p-FC6H4)3)2, PdCl2(xanthophos), PdCl2(PPh3)2, PdCl2(dppf), and Pd(amphos)Cl2.

[0025] In a preferred embodiment, the palladium catalyst is PdCl2(dppp).

[0026] In one embodiment, the base used in the reaction of compound 4 with compound 5 and carbon monoxide is selected from triethylamine and N-ethyldiisopropylamine.

[0027] In a preferred embodiment, the base used in the reaction of compound 4 with compound 5 and carbon monoxide is N-ethyldiisopropylamine.

[0028] In one embodiment, the reaction of compound 4 with compound 5 and carbon monoxide is carried out in a solvent selected from THF, 2-propanol, ethyl acetate, toluene, and ethanol.

[0029] In preferred embodiments, the solvent is selected from THF and 2-propanol.

[0030] In a particularly preferred embodiment, the solvent is 2-propanol.

[0031] In one embodiment, the method according to the present invention is as shown in Scheme 1. [ka] Scheme 1

[0032] Process B 6-Chloro-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (3) is an important starting material in the manufacturing process of Arogabat (1) according to the present invention. Providing a method that enables the industrial-scale production of compound 3 is also an aspect of the present invention.

[0033] Therefore, in one embodiment, the present invention is a method for producing 6-chloro-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (3), [ka] 3,6-Dichloropyridazine (4) [ka] Tetrahydro-2H-pyran-4-amine(5) [ka] The present invention provides a method for obtaining the 6-chloro-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (3) by reacting it with carbon monoxide in the presence of a base and a palladium catalyst.

[0034] In one embodiment, the palladium catalyst used in the reaction of compound 4 with compound 5 and carbon monoxide is selected from PdCl2(dppp), PdCl2(P(p-FC6H4)3)2, PdCl2(xanthophos), PdCl2(PPh3)2, PdCl2(dppf), and Pd(amphos)Cl2.

[0035] In a preferred embodiment, the palladium catalyst used in the reaction of compound 4 with compound 5 and carbon monoxide is PdCl2(dppp).

[0036] In one embodiment, the base used in the reaction of compound 4 with compound 5 and carbon monoxide is selected from triethylamine and N-ethyldiisopropylamine.

[0037] In a preferred embodiment, the base used in the reaction of compound 4 with compound 5 and carbon monoxide is N-ethyldiisopropylamine.

[0038] In one embodiment, the reaction of compound 4 with compound 5 and carbon monoxide is carried out in a solvent selected from THF, 2-propanol, ethyl acetate, toluene, and ethanol.

[0039] In preferred embodiments, the solvent is selected from THF and 2-propanol.

[0040] In a particularly preferred embodiment, the solvent is 2-propanol.

[0041] In one embodiment, the present invention provides a method for producing compound 3 in the production of allogabat (1).

[0042] Process C In one embodiment, the present invention relates to a method for producing allogabat (1) or a pharmaceutically acceptable salt thereof, [ka] 4-[(6-chloropyridazine-3-yl)oxymethyl]-5-methyl-3-(6-methyl-3-pyridyl)isoxazole (6) [ka] Tetrahydropyran-4-amine(7) [ka] The present invention provides a method comprising reacting carbon monoxide with a base and a palladium catalyst to obtain the arogabat (1).

[0043] In one embodiment, the palladium catalyst used in the reaction of compound 6 with compound 7 and carbon monoxide is selected from PdCl2(dppp), PdCl2(P(p-FC6H4)3)2, PdCl2(xanthophos), PdCl2(PPh3)2, PdCl2(dppf), and Pd(amphos)Cl2.

[0044] In a preferred embodiment, the palladium catalyst used in the reaction of compound 6 with compound 7 and carbon monoxide is PdCl2(dppp).

[0045] In one embodiment, the base used in the reaction of compound 6 with compound 7 and carbon monoxide is selected from triethylamine and N-ethyldiisopropylamine.

[0046] In a preferred embodiment, the base used in the reaction of compound 6 with compound 7 and carbon monoxide is triethylamine.

[0047] In one embodiment, the reaction of compound 6 with compound 7 and carbon monoxide is carried out in a solvent selected from THF, 2-propanol, ethyl acetate, toluene, and ethanol.

[0048] In preferred embodiments, the solvent is selected from THF and 2-propanol.

[0049] In a particularly preferred embodiment, the solvent is THF.

[0050] In one embodiment, the method according to the present invention is as shown in Scheme 2. [ka] Scheme 2 [Examples]

[0051] The present invention will be better understood by referring to the following embodiments. However, the claims should not be construed as being limited to the scope of these embodiments.

[0052] The following abbreviations are used in this specification.

[0053] NaO t Bu = sodium tert-butoxide; PdCl2(dppp) = (1,3-bis(diphenylphosphin)propane)palladium(II) chloride (CAS 59831-02-6); DIPEA = N-ethyldiisopropylamine; THF = tetrahydrofuran; Ti = internal temperature.

[0054] Example 1 Preparation of 6-chloro-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (3) [ka] 3,6-Dichloropyridazine (4) (164.87 g, 1.11 mol) was dissolved in 2-propanol (442 ml) at Ti 40°C. N-ethyldiisopropylamine (150.18 g, 1.16 mol) was added to the yellow solution, followed by the addition of tetrahydro-2H-pyran-4-amine (5) (55.97 g, 0.553 ml) and PdCl2 (dppp) (1.08 g, 0.002 mol). The reaction mixture was stirred at 30°C for approximately 20 hours under CO pressure (10 bar). The resulting blue suspension was filtered and dried to obtain the labeled compound 3 as a white solid (124.3 g). This white solid was dissolved in a mixture of 2-propanol / water (95 / 5, 250 ml) at 80°C, then cooled to 15°C within 2 hours and stirred overnight. After filtration and drying, the labeled compound 3 was obtained as a white solid (96.6 g, yield 71%).

[0055] Example 2 6-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazole-4-yl]methoxy]-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (Arogabat, 1) [ka] [5-methyl-3-(6-methyl-3-pyridyl)isoxazole-4-yl]methanol 2 (20.0 g, 0.098 mol) was heated to 30°C in 250 ml of 2-methyl THF. To the orange suspension, a suspension of sodium hydride (3.92 g as 60% in oil) in 70 ml of 2-methyl THF was added. The mixture was stirred at 30°C for 1 hour. Then, 6-chloro-N-tetrahydropyran-4-ylpyridazine-3-carboxamide 3 (22.96 g, 0.095 mol) was added in five portions over 1 hour. The reaction mixture was stirred overnight and then quenched with water (200 ml). The resulting emulsion was heated to 50°C to separate the phases. The organic phase was washed with water (30 ml), then filtered through activated carbon and concentrated. After solvent exchange with 1-propanol, the resulting suspension was heated to 80°C to obtain a solution, which was then cooled to 64°C, seeded, and further cooled to 10°C within 10 hours. After filtration and drying, the labeled compound 1 was obtained as a white solid (32.0 g, yield 79.5%).

[0056] Example 3 6-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazole-4-yl]methoxy]-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (Arogabat, 1) [ka] 4-(((6-chloropyridazine-3-yl)oxy)methyl)-5-methyl-3-(6-methylpyridine-3-yl)isoxazole 6 (10 g, 31.1 mmol) was dissolved in THF (total solution 70.1 g). The solution was added to an autoclave and the flask was washed with 10 mL of THF. PdCl2 (dppp) (123.3 mg, 209.1 μmol) was added and washed with 2 mL of THF. Then, triethylamine (4.116 g, 40.47 mmol) and tetrahydro-2H-pyran-4-amine 7 (3.778 g, 37.36 mmol) were added. The resulting brown suspension was stirred at 80°C for about 23 hours under CO pressure (20 bar) and then cooled to room temperature. The three batches of the above reaction were combined and water (525 mL) was added. The solution was filtered through charcoal.

[0057] Ethyl acetate (880 mL) was added and the phases were separated. The organic layer was washed with 10% sodium chloride aqueous solution (440 mL), and then with water (440 mL). The aqueous layers were combined and extracted with ethyl acetate (880 mL). The organic layers were combined and concentrated. The solid was dissolved in dichloromethane (330 mL) containing 0.5% triethylamine. The solution was eluted on silica. The filtrate was evaporated to dryness. The obtained solid was dissolved in 2-propanol (385 mL) at 60°C, seeded, and then cooled to 25°C, followed by stirring for 60 hours. After filtration and drying, labeled compound 1 was obtained as a white solid (28.2 g, yield 72.2%).

Claims

1. A method for producing allogabat (1) or a pharmaceutically acceptable salt thereof, [Chemistry 18] [5-methyl-3-(6-methyl-3-pyridyl)isoxazole-4-yl]methanol (2), 【Chemistry 19】 6-Chloro-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (3), 【Chemistry 20】 A method comprising reacting in the presence of a base to obtain the allogabat (1).

2. The aforementioned base is Cs ２ CO ３ NaO ｔ The method according to claim 1, selected from Bu and sodium hydride.

3. The method according to claim 2, wherein the base is sodium hydride.

4. The method according to any one of claims 1 to 3, carried out in an aprotic organic solvent.

5. The method according to claim 4, wherein the aprotic organic solvent is selected from N,N-dimethylacetamide, THF, and 2-methyltetrahydrofuran.

6. The method according to claim 5, wherein the aprotic organic solvent is 2-methyltetrahydrofuran.

7. The method according to any one of claims 1 to 6, wherein the reaction mixture is filtered through activated carbon to purify Arogabat (1).

8. The method according to any one of claims 1 to 7, wherein allogabat (1) is purified by crystallization.

9. The method according to claim 8, wherein allogabat (1) is crystallized from 1-propanol.

10. The 6-chloro-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (3) contains 3,6-dichloropyridazine (4), 【Chemistry 21】 Tetrahydro-2H-pyran-4-amine(5) 【Chemistry 22】 The method according to any one of claims 1 to 9, obtained by reacting carbon monoxide with a base and a palladium catalyst.

11. The method according to any one of claims 1 to 10, which is as follows: 【Chemistry 23】

12. A method for producing 6-chloro-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (3), 【Chemistry 24】 3,6-dichloropyridazine (4) 【Chemistry 25】 Tetrahydro-2H-pyran-4-amine(5) 【Chemistry 26】 A method comprising reacting carbon monoxide with a base and a palladium catalyst to obtain the 6-chloro-N-tetrahydropyran-4-ylpyridazine-3-carboxamide (3).

13. Use of the method according to claim 12 in the manufacture of Arogabat (1).

14. A method for producing allogabat (1) or a pharmaceutically acceptable salt thereof, 【Chemistry 27】 4-[(6-chloropyridazine-3-yl)oxymethyl]-5-methyl-3-(6-methyl-3-pyridyl)isoxazole (6) 【Chemistry 28】 Tetrahydropyran-4-amine (7) 【Chemistry 29】 A method comprising reacting carbon monoxide with a base and a palladium catalyst to obtain the arogabat (1).

15. wherein the palladium catalyst is PdCl ２ (dppp), PdCl ２ (P(p-FC ６ H ４ )) ３ ), PdCl ２ (xantphos), PdCl ２ (PPh ２ )), PdCl ３ ), PdCl ２ (dppf), and Pd(amphos)Cl ２ (dppf), and Pd(amphos)Cl ２ selected from any one of claims 10, 12 and 14

16. The palladium catalyst is PdCl ２ The method according to claim 15, wherein (dppp).

17. The method according to any one of claims 10, 12, and 14-16, wherein the base is selected from triethylamine and N-ethyldiisopropylamine.

18. The method according to any one of claims 10, 12, and 14-17, carried out in a solvent selected from THF, 2-propanol, ethyl acetate, toluene, and ethanol.

19. The method according to any one of claims 10, 12, and 14-17, carried out in a solvent selected from THF and 2-propanol.

20. The method according to claim 14, which is as follows. 【Transformation 30】

21. The invention as described earlier in this specification.

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