Process for manufacture of ALOGABAT

Abstract

The present invention relates to a novel process for the manufacture of 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. The method according to the invention is particularly suitable for large-scale production of the compound of formula 1 under GMP conditions. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a new method for manufacturing 6-[[5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl]methoxy]-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (1) or a pharmaceutically acceptable salt thereof.

[0002]

[0003] The method according to the present invention is particularly suitable for large-scale manufacturing of the compound of formula 1 under GMP conditions. Background Art

[0004] 6-[[5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl]methoxy]-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (1) is a positive allosteric modulator (PAM) of the GABA A α5 receptor (WO2018104419), which is currently being investigated in clinical trials for the treatment of autism spectrum disorder (ASD).

[0005] Compound 1 is also known as the INN alogabat (WHO Drug Information, Volume 35, Issue 2, 2021, 366).

[0006] WO2018104419 discloses a laboratory-scale (6 mg) method for manufacturing alogabat. It has been found that this method is not suitable for industrial-scale manufacturing of alogabat because it uses toxic solvents (such as DMF), requires silica gel chromatography, forms by-products, and has a low yield.

[0007] Therefore, there is a high unmet need for a new method for manufacturing alogabat in order to be able to provide this new treatment option for ASD to patients. Summary of the Invention

[0008] The present invention provides an improved method for manufacturing alogabat (1) that overcomes the above problems. Detailed Description

[0009] Definition

[0010] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims and abstract) and / or all steps of any method or process disclosed thereby may be combined in any combination, except for at least some mutually exclusive combinations of such features and / or steps. The invention is not limited to the details of any foregoing embodiments. The invention extends to any new feature or any new combination of features disclosed in this specification (including any accompanying claims and abstract), or to any new step or any new combination of steps of any method or process disclosed thereby.

[0011] The term "pharmaceutical salt" refers to those salts that retain the biological effect and properties of free alkali or free acid, which are not undesirable in biology or other aspects. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. (particularly hydrochloric acid) and 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, methylsulfonic acid, ethylsulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. In addition, these salts can be prepared by adding inorganic bases or organic bases to free acids. Salts derived from inorganic bases include but are not limited to sodium, potassium, lithium, ammonium, calcium, magnesium salts, etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, and the like).

[0012] Manufacturing method

[0013] Method A

[0014] In a first aspect, the present invention provides a method for producing alogabat (1) or a pharmaceutically acceptable salt thereof.

[0015]

[0016] The method comprises making [5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methanol (2)

[0017]

[0018] With 6-chloro-N-tetrahydropyran-4-yl-pyridazine-3-carboxamide (3)

[0019]

[0020] The reaction is carried out in the presence of a base to obtain said alogabat (1).

[0021] In one embodiment, the base used in the reaction of compound 2 with compound 3 is selected from Cs 2 CO 3 、NaO t Bu and sodium hydride.

[0022] In a preferred embodiment, the base is selected from NaO t Bu and sodium hydride.

[0023] In a particularly preferred embodiment, the base is sodium hydride.

[0024] In one embodiment, the reaction of compound 2 with compound 3 is carried out in an aprotic organic solvent.

[0025] In one embodiment, the aprotic organic solvent is selected from N,N-dimethylacetamide, THF and 2-methyltetrahydrofuran.

[0026] In a preferred embodiment, the aprotic organic solvent is selected from THF and 2-methyltetrahydrofuran.

[0027] In a particularly preferred embodiment, the aprotic organic solvent is 2-methyltetrahydrofuran.

[0028] The method for manufacturing alogabat described in WO2018104419 requires purification of the final product by silica gel chromatography. However, silica gel chromatography is not suitable for the industrial-scale manufacture of pharmaceutical compounds. The alogabat obtained by the method of the present invention has an impurity profile that allows it to be purified to pharmaceutical-grade quality by filtration and crystallization under GMP conditions.

[0029] Thus, in one embodiment of the method according to the present invention, alogabat (1) is purified by filtering the reaction mixture through activated carbon.

[0030] In one embodiment of the method according to the present invention, alogabat (1) is purified by crystallization.

[0031] In a preferred embodiment, the crystallization is carried out from 1-propanol.

[0032] In one embodiment of the method according to the present invention, alogabat (1) is purified by (i) filtering the reaction mixture through activated carbon and then (ii) crystallization.

[0033] In one embodiment of the method according to the present invention, the starting material 6-chloro-N-tetrahydropyran-4-yl-pyridazine-3-carboxamide (3) is obtained by reacting 3,6-dichloropyridazine (4)

[0034]

[0035] with tetrahydro-2H-pyran-4-amine (5)

[0036]

[0037] and carbon monoxide in the presence of a base and a palladium catalyst.

[0038] In one embodiment, the palladium catalyst used in the reaction of compound 4 with compound 5 and carbon monoxide is selected from PdCl 2 (dppp), PdCl 2 (P(p-FC 6 H 4 ) 3 ) 2 、PdCl 2 (xantphos), PdCl 2 (PPh 3 ) 2 、PdCl 2 (dppf) and Pd(amphos)Cl 2 .

[0039] In a preferred embodiment, the palladium catalyst is PdCl 2 (dppp).

[0040] 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.

[0041] In a preferred embodiment, the base used in the reaction of compound 4 with compound 5 and carbon monoxide is N-ethyldiisopropylamine.

[0042] 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.

[0043] In a preferred embodiment, the solvent is selected from THF and 2-propanol.

[0044] In a particularly preferred embodiment, the solvent is 2-propanol.

[0045] In one embodiment, the method according to the present invention is as described in Scheme 1.

[0046]

[0047] Scheme 1

[0048] Method B

[0049] 6-Chloro-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide (3) is a crucial starting material in the process for the manufacture of alogabat (1) according to the present invention. Another aspect of the present invention is to provide a process allowing the manufacture of compound 3 on an industrial scale.

[0050] Thus, in one aspect, the present invention provides a process for the manufacture of 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide (3),

[0051]

[0052] which process comprises reacting 3,6-dichloropyridazine (4)

[0053]

[0054] with tetrahydro-2H-pyran-4-amine (5)

[0055]

[0056] and carbon monoxide in the presence of a base and a palladium catalyst to obtain the said 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide (3).

[0057] In one embodiment, the palladium catalyst used in the reaction of compound 4 with compound 5 and carbon monoxide is selected from PdCl 2 (dppp), PdCl 2 (P(p-FC 6 H 4 ) 3 ) 2 、PdCl 2 (xantphos), PdCl 2 (PPh 3 ) 2 、PdCl 2 (dppf) and Pd(amphos)Cl 2 .

[0058] In a preferred embodiment, the palladium catalyst used in the reaction of compound 4 with compound 5 and carbon monoxide is PdCl 2 (dppp).

[0059] 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.

[0060] In a preferred embodiment, the base used in the reaction of compound 4 with compound 5 and carbon monoxide is N-ethyldiisopropylamine.

[0061] 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.

[0062] In a preferred embodiment, the solvent is selected from THF and 2-propanol.

[0063] In a particularly preferred embodiment, the solvent is 2-propanol.

[0064] In one aspect, the present invention provides a method for manufacturing compound 3 for use in the manufacture of alogabat (1).

[0065] Method C

[0066] In one aspect, the present invention provides a method for manufacturing alogabat (1) or a pharmaceutically acceptable salt thereof,

[0067]

[0068] The method comprises reacting 4-[(6-chloropyridazin-3-yl)oxymethyl]-5-methyl-3-(6-methylpyridin-3-yl)isoxazole (6)

[0069]

[0070] with tetrahydropyran-4-amine (7)

[0071]

[0072] and carbon monoxide in the presence of a base and a palladium catalyst to obtain the alogabat (1).

[0073] In one embodiment, the palladium catalyst used in the reaction of compound 6 with compound 7 and carbon monoxide is selected from PdCl 2 (dppp), PdCl 2 (P(p-FC 6 H 4 ) 3 ) 2 、PdCl 2 (xantphos), PdCl 2 (PPh 3 )2 , PdCl 2 (dppf) and Pd(amphos)Cl 2 .

[0074] In a preferred embodiment, the palladium catalyst used in the reaction of compound 6 with compound 7 and carbon monoxide is PdCl 2 (dppp).

[0075] 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.

[0076] In a preferred embodiment, the base used in the reaction of compound 6 with compound 7 and carbon monoxide is triethylamine.

[0077] 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.

[0078] In a preferred embodiment, the solvent is selected from THF and 2-propanol.

[0079] In a particularly preferred embodiment, the solvent is THF.

[0080] In one embodiment, the method according to the invention is as described in Scheme 2.

[0081]

[0082] Scheme 2

[0083] Example

[0084] The present invention will be more fully understood by reference to the following examples. However, the claims should not be construed as limited to the scope of the examples.

[0085] The following abbreviations are used in this text:

[0086] NaO t Bu = sodium tert-butoxide; PdCl 2 (dppp) = dichlorobis(1,3-bis(diphenylphosphino)propane)palladium(II) (CAS 59831-02-6); DIPEA = N-ethyldiisopropylamine; THF = tetrahydrofuran; Ti = internal temperature.

[0087] Example 1

[0088] Preparation of 6-chloro-N-tetrahydropyran-4-yl-pyridazine-3-carboxamide (3)

[0089]

[0090] Dissolve 3,6-dichloropyridazine (4) (164.87 g, 1.11 mol) in 2-propanol (442 ml) at 40 °C. Add N-ethyldiisopropylamine (150.18 g, 1.16 mol) to the yellow solution, then add tetrahydro-2H-pyran-4-amine (5) (55.97 g, 0.553 ml) and PdCl 2 (dppp) (1.08 g, 0.002 mol). Stir the reaction mixture at 30 °C for about 20 h under a CO pressure (10 bar gauge). Filter and dry the resulting blue suspension to obtain the title compound 3 as a white solid (124.3 g). Dissolve this white solid in a mixture of 2-propanol / water (95 / 5, 250 ml) at 80 °C, then cool to 15 °C over 2 h and stir overnight. After filtration and drying, the title compound 3 is obtained as a white solid (96.6 g, 71% yield).

[0091] Example 2

[0092] Preparation of 6-[[5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl]methoxy]-N-tetrahydropyran-4-yl-pyridazine-3-carboxamide (alogabat, 1)

[0093]

[0094] Warm [5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl]methanol 2 (20.0 g, 0.098 mol) to 30 °C in 2-methyl-THF (250 ml). Add a suspension of sodium hydride (3.92 g, 60% in oil) in 2-methyl-THF (70 ml) to the orange suspension. Stir the mixture at 30 °C for 1 h. Then add 6-chloro-N-tetrahydropyran-4-yl-pyridazine-3-carboxamide 3 (22.96 g, 0.095 mol) in 5 portions over 1 h. Stir the reaction mixture overnight, then quench it with water (200 ml). Warm the resulting emulsion to 50 °C to allow phase separation. Wash the organic phase with water (30 ml), then filter through activated carbon and concentrate. After solvent exchange with 1-propanol, heat the resulting suspension to 80 °C to obtain a solution, cool this solution to 64 °C, seed and further cool to 10 °C over 10 h. After filtration and drying, the title compound 1 is obtained as a white solid (32.0 g, 79.5% yield).

[0095] Example 3

[0096] Preparation of 6-[[5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl]methoxy]-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (alogabat, 1)

[0097]

[0098] Dissolve 4-(((6-chloropyridazin-3-yl)oxy)methyl)-5-methyl-3-(6-methylpyridin-3-yl)isoxazole 6 (10 g, 31.1 mmol) in THF (total amount of solution 70.1 g). Add the solution to an autoclave and wash the flask with 10 mL of THF. Add PdCl 2 (dppp) (123.3 mg, 209.1 μmol) and wash it with 2 mL of THF. Then add triethylamine (4.116 g, 40.47 mmol) and tetrahydro-2H-pyran-4-amine 7 (3.778 g, 37.36 mmol). Under a CO pressure (20 bar relative pressure), stir the resulting brown suspension at 80 °C for about 23 h, then cool to room temperature. Combine the reactions of the above three batches and add water (525 mL). Filter the solution through charcoal.

[0099] Add ethyl acetate (880 mL) and separate the phases. Wash the organic layer with 10% aqueous sodium chloride solution (440 mL), then wash it with water (440 mL). Combine the aqueous layers and extract with ethyl acetate (880 mL). Combine the organic layers and concentrate. Dissolve the solid in dichloromethane (330 mL) containing 0.5% triethylamine. Elute the solution through silica. Evaporate the filtrate to dryness. Dissolve the resulting solid in 2-propanol (385 mL) at 60 °C, add seeds and further cool to 25 °C, then stir for 60 h. After filtration and drying, obtain the title compound 1 as a white solid (28.2 g, yield 72.2%).

Claims

1. A method for manufacturing alogabat (1) or a pharmaceutically acceptable salt thereof, The method comprising reacting [5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl]methanol (2) with 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide (3) in the presence of a base to obtain the alogabat (1).

2. The method according to claim 1, wherein the base is selected from Cs 2 CO 3 , NaO t 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, wherein the method is 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 alogabat (1) is purified by filtering the reaction mixture through activated carbon.

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

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

10. The method according to any one of claims 1 to 9, wherein the 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide (3) is obtained by reacting 3,6-dichloropyridazine (4) with tetrahydro-2H-pyran-4-amine (5) and carbon monoxide in the presence of a base and a palladium catalyst.

11. The method according to any one of claims 1 to 10, the method being 12. A method for manufacturing 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide (3), The method comprising reacting 3,6-dichloropyridazine (4) with tetrahydro-2H-pyran-4-amine (5) and carbon monoxide in the presence of a base and a palladium catalyst to obtain the 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide (3).

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

14. A method for manufacturing alogabat (1) or a pharmaceutically acceptable salt thereof, The method comprising reacting 4-[(6-chloropyridazin-3-yl)oxymethyl]-5-methyl-3-(6-methylpyridin-3-yl)isoxazole (6) with tetrahydro-2H-pyran-4-amine (7) and carbon monoxide in the presence of a base and a palladium catalyst to obtain the alogabat (1).

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

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

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

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

20. The method according to claim 14, wherein the method is 21. The present invention as described above.

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