Method for preparing risdiplum

Abstract

The present invention relates to a process for preparing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one derivatives which are useful as pharma- ceutically active compounds.

Description

Technical Field

[0001] The present invention relates to a method for preparing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, which is useful as a pharmaceutically active compound.

Mode for Carrying Out the Invention

[0002] In a first aspect, the present invention provides a hydrate, solvate or HCl salt of a compound of formula (I):

Chemical Formula

Chemical Formula

[0003] The method according to the first embodiment, in which anhydrous HCl is used. Similarly, HCl can be prepared in situ using an alcohol and acetyl chloride, particularly methanol, ethanol, n-propanol, isopropanol or n-butanol and acetyl chloride, particularly n-propanol and acetyl chloride.

[0004] In a particular embodiment, after adding and reacting a strong acid (for carrying out Boc deprotection and decarboxylation), the pH of the acidic solution of I obtained is adjusted by adding a base to isolate the free base. <00000�8> In particular, the preparation of the compound of formula (I) is carried out in the presence of an alcohol solvent such as methanol, ethanol, n-propanol, isopropanol, or n-butanol, especially n-propanol or isopropanol, and more particularly n-propanol.

[0006] In certain embodiments, the present invention provides a method according to which 5 to 20 equivalents, more particularly 7 to 10 equivalents, of HCl are used relative to the theoretical amount of the compound of formula (II).

[0007] In another embodiment, the present invention provides the above method for preparing the compound of formula (I), wherein the reaction is carried out at a temperature of 80°C to 120°C, particularly 85°C to 100°C, and more particularly 85°C to 95°C.

[0008] In another embodiment, the present invention provides a method herein in which HCl is prepared in situ using acetyl chloride in n-propanol at a temperature of 0 to 60°C, particularly 0 to 40°C, during the addition of acetyl chloride, and then heated to a maximum of 60°C, more particularly 10 to 20°C, during the addition of acetyl chloride, and then heated to a maximum of 60°C at atmospheric pressure.

[0009] In another embodiment, the present invention provides a method thereof that uses a pressurized reactor to reach a temperature higher than the boiling point of the solvent.

[0010] The compound of formula (I) is a valuable pharmaceutical compound, in particular 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidine-4-one, which is described in International Publication No. 2015173181.

[0011] Unless otherwise stated, the following terms used in this specification and in the claims have the meanings set forth below.

[0012] "(C1-C6) alkyl" refers to branched or linear hydrocarbon chains of 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl.

[0013] The term "(C3-C8) cycloalkyl" refers to a monovalent saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. Examples of monocyclic (C3-C8) cycloalkyl groups include cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0014] A “base” refers to a compound that, upon reaction with it, deprotonates another compound. Suitable bases for use in this disclosure include, but are not limited to, tertiary amines and basic alkali metal salts. In some embodiments, examples of tertiary amines include triethylamine, tributylamine, N-methylmorpholine, and diisopropylethylamine. In some embodiments, examples of basic alkali metal salts include lithium carbonate (Li2CO2). 3) Examples include sodium carbonate (Na2CO3), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), sodium bicarbonate (NaHCO3), lithium, cesium, sodium and potassium hydroxides, sodium and potassium t-butoxide, sodium and potassium n-propoxide, sodium and potassium i-propoxide, sodium and potassium ethoxide, sodium and potassium methoxide, sodium and potassium alkoxides, sodium amide (NaNH2), potassium amide (KNH2), and others.

[0015] "Crystallization" and "recrystallization" can be used interchangeably and refer to the process by which a compound dissolved or suspended in a solvent system yields a stable polymorph or crystalline form of a particular compound. For example, the crystallization process can be carried out by forming crystals using a solvent and a poor solvent.

[0016] "Strong acid" refers to an acid that completely dissociates in an aqueous solution with a pKa of less than -1.74. Examples of strong acids include sulfuric acid (H2SO4), hydrohalic acids (i.e., HX where X is I, Br, Cl, or F), methanesulfonic acid, trifluoromethanesulfonic acid, nitric acid (HNO3), phosphoric acid (H3PO4), and combinations thereof, but are not limited thereto. In particular, strong acids are hydrohalic acids where X is Br or Cl. Most particularly, strong acid is HCl.

[0017] "Tertiary amine" refers to an amine of the formula R a N(R b )R c (wherein R a , R b and R c are independently selected from (C1-C6)alkyl, (C3-C8)cycloalkyl or phenyl). Representative examples include, but are not limited to, triethylamine, tributylamine, diethyl-methylamine, dimethyl-ethylamine, N,N-dimethylaniline, N-methylmorpholine, and methylethylbutylamine. Preferably, the tertiary amine is selected from tributylamine, tripropylamine or triethylamine, more preferably selected from triethylamine or tributylamine. The most preferred tertiary amine is tributylamine.

[0018] "Ambient conditions" or "room temperature" refers to conditions experienced in a standard laboratory, such as ambient temperature of 18°C to 28°C under atmospheric pressure, Ar or N2.

[0019] In a specific embodiment of the first aspect, the present invention relates to a hydrate, solvate or HCl salt of a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

[0020] In another aspect (Aspect 1'), the present invention relates to a hydrate, solvate or HCl salt of a compound of formula (I):

Chemical formula

Chemical formula

[0021] In another aspect (Aspect 2), the present invention relates to a method for preparing a compound of formula (II):

Chemical formula

Chemical formula

[0022] In a specific embodiment 2, the present invention relates to formula (II): [ka] A method for preparing the compound The present invention provides a method comprising heating a mixture of compounds of formula (III) in n-propanol at 92°C ± 5°C. [ka]

[0023] In yet another embodiment (embodiment 3), the present invention relates to formula (III) [ka] A method for preparing the compound Formula (IV) [ka] The compound, Formula (IVa): [ka] This includes reacting with the compound, The present invention provides a method for reacting a tertiary amine, particularly in the presence of a tertiary amine, more particularly in the presence of a tertiary amine selected from triethylamine, tripropylamine, diisopropylethylamine, and tributylamine, most particularly in the presence of a tertiary amine that is tributylamine, particularly in the presence of a solvent, more particularly in the presence of a solvent selected from dichloromethane, MeTHF, and THF, most particularly in the presence of a solvent that is dichloromethane.

[0024] The amount of compound (IVa) is adjusted to ensure efficient conversion of compound (IV) to compound (III) while avoiding unnecessary excess.

[0025] In a particular embodiment of Embodiment 3, the present invention provides a method thereof in which 0.8 to 1.2 equivalents, more particularly 0.85 to 1 equivalent, and most particularly about 0.9 equivalents of the compound of formula (IVa) are used relative to the theoretical amount of the compound of formula (IV). It should be noted that using less than a stoichiometric amount, particularly 0.9 equivalents, of the compound of formula (Iva) relative to the theoretical amount of the compound of formula (IV) yields the best yield and lowest impurities.

[0026] In another embodiment of aspect 3, the present invention provides the above method for preparing the compound of formula (III), wherein the reaction is carried out at a temperature of 0°C to 40°C, particularly 20°C to 30°C, and more particularly about 25°C ± 5°C.

[0027] In yet another embodiment (embodiment 4), the present invention relates to formula (IV) [ka] A method for preparing the compound, Compounds of formula (V), or their respective tautomers [ka] The present invention provides a method comprising reacting with oxalyl chloride, particularly in the presence of a solvent, wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, and NMP, more particularly from 2-MeTHF, THF, and dichloromethane, and most particularly from dichloromethane.

[0028] In a particular embodiment of aspect 4, the present invention provides a method according to the foregoing, using 0.9 to 1.4 equivalents, particularly 0.9 to 1.3 equivalents, and more particularly 0.9 to 1.2 equivalents of oxalyl chloride relative to the theoretical amount of the compound of formula (V). In a more particular embodiment, oxalyl chloride is titrated from 0.9 equivalents to 1.2 to 1.3 equivalents relative to the theoretical amount of the compound of formula (V).

[0029] In a specific embodiment of Embodiment 4, the present invention provides a method thereof in which oxalyl chloride chlorodehydrates the compound of formula (V) after conversion by HPLC.

[0030] In another embodiment of aspect 4, the present invention provides the above method for preparing the compound of formula (IV), wherein the reaction is carried out at a temperature of 0°C to 40°C, particularly 15°C to 30°C, and more particularly 20°C ± 5°C.

[0031] In yet another embodiment (Embodiment 5), the present invention relates to formula (V) [ka] A method for preparing the compound, Equation (VI) [ka] The present invention provides a method comprising reacting a compound with 2,2-dimethyl-1,3-dioxane-4,6-dione, also known as meldrum acid, particularly in the presence of a solvent, more particularly the solvent being selected from dichloromethane, 2-MeTHF, THF, DMF, and NMP, more particularly selected from 2-MeTHF, THF, and dichloromethane, and most particularly the solvent being dichloromethane.

[0032] In a particular embodiment of Embodiment 5, the present invention provides a method thereof in which, more particularly, 2.5 to 5.0 equivalents, more particularly 3.0 to 4.0 equivalents, and most preferably about 3.2 equivalents, of DMAP relative to the theoretical amount of the compound of formula (VI). The defined amount of DMAP corresponds to the total amount present in the reaction, and when the method of Embodiment 5 is fitted into the method of Embodiment 6, it corresponds to the total amount used in the acid chloride formation and meldramic acid addition steps.

[0033] In a particular embodiment of Embodiment 5 in which the compound of formula VI is isolated, the present invention provides a method thereof in which 2 to 2.5 equivalents, more particularly 2.2 to 2.4 equivalents, most preferably about 2.3 equivalents of 2,2-dimethyl-1,3-dioxane-4,6-dione is used relative to the theoretical amount of the compound of formula (VI).

[0034] In another embodiment of aspect 5, the present invention provides the above method for preparing the compound of formula (V), wherein the reaction is carried out at a temperature of 0°C to 40°C, particularly 15°C to 30°C, and more particularly 20°C ± 5°C.

[0035] In another embodiment, the present invention provides a method for preparing the compound of formula (V) described above, into which embodiments 5 and 6 are fitted.

[0036] In yet another embodiment (embodiment 5'), the present invention relates to formula (V) [ka] A method for preparing the compound, Formula (VII) [ka] The present invention provides a method comprising reacting the compound with oxalyl chloride, particularly in the presence of a solvent (more particularly the solvent being selected from dichloromethane, 2-MeTHF, THF, DMF, and NMP, more particularly selected from 2-MeTHF, THF, and dichloromethane, and most particularly the solvent being dichloromethane), followed by the addition of 2,2-dimethyl-1,3-dioxane-4,6-dione, also known as meldrum acid, wherein, in the presence of DMAP, more particularly 2.5 to 5.0 equivalents, more particularly 3.0 to 4.0 equivalents, and most preferably about 3.2 equivalents of DMAP are present relative to the theoretical amount of the compound of formula (VII).

[0037] In another embodiment of aspect 5', the present invention provides the above method for preparing the compound of formula (V), wherein the reaction is carried out at a temperature of 0°C to 40°C, particularly 15°C to 30°C, and more specifically 20°C ± 5°C.

[0038] In yet another embodiment (embodiment 6), the present invention relates to formula (VI) [ka] A method for preparing the compound, Formula (VII) [ka] The present invention provides a method comprising reacting a compound with oxalyl chloride, particularly in the presence of a solvent, wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, and NMP, more particularly from 2-MeTHF, THF, and dichloromethane, and most particularly from dichloromethane.

[0039] In a particular embodiment of aspect 6, the present invention provides a method thereof in which, with respect to the theoretical amount of the compound of formula (VII), there is more particularly 1.5 to 4.0 equivalents, more particularly 2.0 to 3.0 equivalents, and most preferably about 2.0 equivalents of DMAP.

[0040] Surprisingly, the DMAP salt of the compound of formula (VII) was found to have increased solubility in dichloromethane compared to the compound of formula (VII), which is favorable in terms of mass transfer during the formation of the corresponding acid chloride.

[0041] In a particular embodiment of aspect 6, the present invention provides a method according to which 1 to 1.1 equivalents, most particularly 1 equivalent, of oxalyl chloride is used with respect to the compound of formula (VII).

[0042] In a particular embodiment of aspect 6, the present invention provides the method described herein, in which DMF is used in particular in an amount of 1.15 equivalents.

[0043] In another embodiment of aspect 6, the present invention provides the above method for preparing the compound of formula (VI), wherein the reaction is carried out at a temperature of 10°C±2°C to 40°C±2°C, particularly 25°C±2°C to 40°C±2°C, and more particularly 35°C±2°C to 40°C±2°C.

[0044] In yet another embodiment (embodiment 7), the present invention relates to formula (VII) [ka] A method for preparing the compound, Formula (VIII) [ka] The present invention provides a method further comprising reacting a compound with carbon monoxide in the presence of a catalyst (e.g., Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), especially PdCl2(dppf)), and a base, especially a tertiary amine, in the presence of acetonitrile, and in the presence of water and a solvent, wherein the solvent is particularly selected from MeOH, EtOH, iPrOH, AmOH, n-PrOH, DMF, DMA, toluene, THF, or 2-Me-THF, and most particularly the solvent is acetonitrile and water.

[0045] In a particular embodiment of Embodiment 7, the present invention provides a method thereof in which carbon monoxide at 1 to 150 bar, particularly 20 to 70 bar, and most particularly 50 to 70 bar, is used with respect to the compound of formula (VIII).

[0046] In a particular embodiment of Embodiment 7, the present invention provides a method thereof in which 0.01 mol% to 10 mol%, more particularly 0.1 mol% to 2 mol%, and most particularly 0.5 mol% to 1.5 mol% of the catalyst is used relative to the compound of formula (VIII).

[0047] In a particular embodiment of Embodiment 7, the present invention provides a method according to the Specified Method, in which 0.1 to 10 equivalents, more particularly 1.5 to 2.5 equivalents, of a tertiary amine are used relative to the compound of formula (VIII).

[0048] In another embodiment of aspect 7, the present invention provides the above method for preparing the compound of formula (VII), wherein the reaction is carried out at a temperature of 20°C±2°C to 150°C±2°C, particularly 60°C±2°C to 110°C±2°C, and more particularly 80°C±2°C to 100°C±2°C.

[0049] In yet another embodiment (embodiment 8), the present invention relates to formula (VIII) [ka] A method for preparing the compound, a) Formula (X) [ka] The compound is reacted with NH4OH to obtain compounds (IXa) and (IXb); b) Equations (IXa) and (IXb) [ka] The present invention provides a method for obtaining the compound of formula (VIII) by reacting the compound with 1-bromo-2,2-dimethoxypropane and pyridinium p-toluenesulfonate. Step b) is optionally followed by at least a purification step, in particular the purification step being reverse crystallization. Chromatographic purification may be performed after reverse crystallization.

[0050] In yet another embodiment (embodiment 8'), the present invention relates to formula (VIII) [ka] A method for preparing the compound, a) Formula (X) [ka] The compound is reacted with NH4OH to obtain the compound of formula (IXa). b) Formula (IXa) [ka] The present invention provides a method for obtaining the compound of formula (VIII) by reacting the compound with 1-bromo-2,2-dimethoxypropane and pyridinium p-toluenesulfonate. Step b) is optionally followed by at least a purification step, in particular the purification step being reverse crystallization. Chromatographic purification may be performed after reverse crystallization.

[0051] Alternatively, the compound of formula (VIII) may be prepared according to the methods described in International Publication No. 2015173181 and International Publication No. 2019057740.

[0052] Compared to the method described in International Publication No. 2015173181, the purity of the unpurified compound of formula (VIII) can be increased by reverse crystallization, and most of the undesirable positional isomers arising from the compound of formula (IXb) can be removed, facilitating final chromatographic purification.

[0053] In certain embodiments, the present invention provides the method described herein in accordance with embodiment 8, in which steps a) and b) are incorporated.

[0054] The compound of formula (IVa) can be prepared according to the following steps: [ka] Formula (IVb) [ka] The process involves reacting the compound with a heterogeneous transition metal hydrogenation catalyst, particularly if the heterogeneous transition metal hydrogenation catalyst is a Raney catalyst (e.g., Ra-Ni, Ra-Co, Pd / C, Pd(OH)2 / C, Pd / Al2O 3、 Au / TiO2, Rh / C, Ru / Al2O3, Ir / CaCO3, Pt-V / C, or Pt / C or combinations thereof, particularly Pt-V / C, more particularly 1% Pt and 2% V on activated carbon, can be prepared according to the method. In particular, for the preparation of the compound of formula (IVa), the reaction is carried out at a temperature of 0°C±2°C to 150°C±2°C, particularly 15°C±2°C to 70°C±2°C, and even more particularly 20°C±2°C to 35°C±2°C.

[0055] The compound of formula (IVb) can also be prepared according to scheme 1. Scheme 1: [ka]

[0056] The compounds of formulas (IVa and IVb) can be prepared by the method described in International Publication No. 2019057740.

[0057] In another embodiment (Aspect 9), the present invention relates to a compound of formula (I) or its HCl salt: [ka] A method for preparing a) Especially at temperatures above 70°C, especially between 80°C and 120°C, more especially between 90°C and 110°C, and most especially at 92°C ± 5°C, equation (III) [ka] A mixture of the compounds, particularly a solvent, more particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, or isopropanol, and especially the aforementioned n-propanol, is heated in the presence of the solvent to produce formula (II) [ka] To obtain the compound, b) A method is provided to obtain a compound of formula (I) by reacting a compound of formula (II) with a strong acid (for decarboxylation), particularly sulfuric acid, methanesulfonic acid, trifric acid, or hydrochloric acid, particularly methanesulfonic acid, trifric acid, and HCl, more particularly HCl, and most particularly preparing HCl in situ with alcohol and acetyl chloride as described above.

[0058] In another embodiment (Aspect 10), the present invention relates to a compound of formula (I) or its HCl salt: [ka] A method for preparing a) Equation (IV) [ka] The compound, Formula (IVa) [ka] The compound is reacted with a tertiary amine, particularly in the presence of a tertiary amine, more particularly in the presence of a tertiary amine selected from triethylamine, tripropylamine, diisopropylethylamine, and tributylamine, most particularly in the presence of a tertiary amine that is tributylamine, particularly in the presence of a solvent, more particularly in the presence of a solvent selected from dichloromethane, MeTHF, and THF, most particularly in the presence of the aforementioned dichloromethane, to obtain formula (III). [ka] To obtain the compound, b) Heating a mixture of the compounds of formula (III) in the presence of a solvent, particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, or isopropanol, and particularly the aforementioned n-propanol, at a temperature above 70°C, particularly 80°C to 120°C, more particularly 90°C to 110°C, most particularly 92°C ± 5°C, in the presence of a solvent, particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, or isopropanol, and particularly the aforementioned n-propanol, to obtain formula (II) [ka] To obtain the compound, c) A method is provided to obtain a compound of formula (I) by reacting a compound of formula (II) with a strong acid (for decarboxylation), particularly sulfuric acid, methanesulfonic acid, trifric acid, or hydrochloric acid, particularly methanesulfonic acid, trifric acid, and HCl, more particularly HCl, and most particularly preparing HCl in situ with alcohol and acetyl chloride as described above.

[0059] In another embodiment (Aspect 11), the present invention relates to a compound of formula (I) or its HCl salt: [ka] A method for preparing a) Compound of formula (V) or its tautomer [ka] This is reacted with oxalyl chloride, particularly in the presence of a solvent (more particularly, the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF, THF, and dichloromethane, and most particularly, the solvent is the aforementioned dichloromethane), to obtain formula (IV). [ka] To obtain the compound, b) The compound of formula (IV), formula (IVa): [ka] The compound is reacted with a tertiary amine, particularly in the presence of a tertiary amine, more particularly in the presence of a tertiary amine selected from triethylamine, tripropylamine, diisopropylethylamine, and tributylamine, most particularly in the presence of a tertiary amine that is tributylamine, particularly in the presence of a solvent, more particularly in the presence of a solvent selected from dichloromethane, MeTHF, and THF, most particularly in the presence of the aforementioned dichloromethane, to obtain formula (III). [ka] To obtain the compound, c) Heating a mixture of the compounds of formula (III) in a solvent, particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, isopropanol, n-propanol, n-butanol, or isopropanol, particularly the aforementioned n-propanol, at a temperature above 70°C, particularly 80°C to 120°C, more particularly 90°C to 110°C, most particularly 92°C ± 5°C, in the presence of a solvent, particularly a solvent, more particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, isopropanol, n-propanol, or isopropanol, and particularly the aforementioned n-propanol, to obtain formula (II) [ka] To obtain the compound, d) A method is provided to obtain a compound of formula (I) by reacting a compound of formula (II) with a strong acid (for decarboxylation), particularly sulfuric acid, methanesulfonic acid, trifric acid, or hydrochloric acid, particularly methanesulfonic acid, trifric acid, and HCl, more particularly HCl, and most particularly preparing HCl in situ with alcohol and acetyl chloride as described above.

[0060] In another embodiment (Aspect 12), the present invention relates to a compound of formula (I) or its HCl salt: [ka] A method for preparing a) Equation (VI) [ka] The compound is reacted with 2,2-dimethyl-1,3-dioxane-4,6-dione, also known as meldrum acid, in the presence of a solvent (more particularly, the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF, THF, and dichloromethane, and most particularly, the solvent is the aforementioned dichloromethane) to obtain the compound of formula (V) or its tautomers. [ka] To obtain b) Reacting the compound of formula (V) or its tautomer with oxalyl chloride in the presence of a solvent in particular (more particularly, the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly, from 2-MeTHF, THF, and dichloromethane, and most particularly, the solvent is the aforementioned dichloromethane) to obtain formula (IV) [ka] To obtain the compound, c) Compound of formula (IV), formula (IVa): [ka] The compound is reacted with a tertiary amine, particularly in the presence of a tertiary amine, more particularly in the presence of a tertiary amine selected from triethylamine, tripropylamine, diisopropylethylamine, and tributylamine, most particularly in the presence of a tertiary amine that is tributylamine, particularly in the presence of a solvent, more particularly in the presence of a solvent selected from dichloromethane, MeTHF, and THF, most particularly in the presence of the aforementioned dichloromethane, to obtain formula (III). [ka] To obtain the compound, d) Heating a mixture of the compounds of formula (III) in the presence of a solvent, particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, and isopropanol, and particularly the aforementioned n-propanol, at a temperature above 70°C, particularly 80°C to 120°C, more particularly 90°C to 110°C, and most particularly 92°C ± 5°C, in the presence of a solvent, particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, and isopropanol, and particularly the aforementioned n-propanol, to obtain formula (II) [ka] To obtain the compound, e) A method is provided to obtain a compound of formula (I) by reacting a compound of formula (II) with a strong acid (for decarboxylation), particularly sulfuric acid, methanesulfonic acid, trifric acid, or hydrochloric acid, particularly methanesulfonic acid, trifric acid, and HCl, more particularly HCl, and most particularly preparing HCl in situ using the aforementioned alcohol and acetyl chloride.

[0061] In another embodiment (Aspect 13), the present invention relates to a compound of formula (I) or its HCl salt: [ka] A method for preparing a) Equation (VII) [ka] The compound is reacted with oxalyl chloride, particularly in the presence of a solvent (more particularly, the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF, THF, and dichloromethane, and most particularly, the solvent is the aforementioned dichloromethane), to obtain formula (IV). [ka] To obtain the compound, b) Reacting the compound of formula (VI) with 2,2-dimethyl-1,3-dioxane-4,6-dione, also known as meldrum acid, in the presence of a solvent (more particularly, the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly, from 2-MeTHF, THF, and dichloromethane, and most particularly, the solvent is the aforementioned dichloromethane) to obtain the compound of formula (V) or its tautomers. [ka] To obtain c) Reacting the compound of formula (V) or its tautomer with oxalyl chloride, particularly in the presence of a solvent (more particularly, the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF, THF, and dichloromethane, and most particularly, the solvent is the aforementioned dichloromethane), to obtain formula (IV) [ka] To obtain the compound, d) Compound of formula (IV), formula (IVa): [ka] The compound is reacted with a tertiary amine, particularly in the presence of a tertiary amine, more particularly in the presence of a tertiary amine selected from triethylamine, tripropylamine, diisopropylethylamine, and tributylamine, most particularly in the presence of a tertiary amine that is tributylamine, particularly in the presence of a solvent, more particularly in the presence of a solvent selected from dichloromethane, MeTHF, and THF, most particularly in the presence of the aforementioned dichloromethane, to obtain formula (III). [ka] To obtain the compound, e) Heating a mixture of the compounds of formula (III) in the presence of a solvent, particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, isobutanol, n-propanol, n-butanol, or isopropanol, particularly the aforementioned n-propanol, at a temperature above 70°C, particularly 80°C to 120°C, more particularly 90°C to 110°C, most particularly 92°C ± 5°C, in the presence of a solvent, particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, or isopropanol, and particularly the aforementioned n-propanol, to obtain formula (II) [ka] To obtain the compound, f) A method is provided to obtain a compound of formula (I) by reacting a compound of formula (II) with a strong acid (for decarboxylation), particularly sulfuric acid, methanesulfonic acid, trifric acid, or hydrochloric acid, particularly methanesulfonic acid, trifric acid, and HCl, more particularly HCl, and most particularly preparing HCl in situ with alcohol and acetyl chloride as described above.

[0062] In another embodiment (Aspect 14), the present invention relates to a compound of formula (I) or its HCl salt: [ka] A method for preparing a) Equation (VIII) [ka] The compound is reacted with carbon monoxide in the presence of a catalyst (e.g., Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), especially PdCl2(dppf)), a base (especially a tertiary amine, acetonitrile), and water and a solvent (more particularly the solvent is selected from MeOH, EtOH, iPrOH, AmOH, n-PrOH, DMF, DMA, toluene, THF, or 2-Me-THF, and most particularly the solvent is the aforementioned acetonitrile and water) to produce formula (VII). [ka] To obtain the compound, b) The compound of formula (VII), Oxalyl chloride is reacted with a solvent in particular (more particularly, the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF, THF, and dichloromethane, and most particularly, the solvent is the aforementioned dichloromethane) to produce formula (VI). [ka] To obtain the compound, c) Reacting the compound of formula (VI) with 2,2-dimethyl-1,3-dioxane-4,6-dione, also known as meldrum acid, in the presence of a solvent (more particularly, the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly, from 2-MeTHF, THF, and dichloromethane, and most particularly, the solvent is the aforementioned dichloromethane) to obtain the compound of formula (V) or its tautomers. [ka] To obtain d) Reacting the compound of formula (V) or its tautomer with oxalyl chloride in the presence of a solvent (more particularly, the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF, THF, and dichloromethane, and most particularly, the solvent is the aforementioned dichloromethane) to obtain formula (IV) [ka] To obtain the compound, e) A compound of formula (IV), formula (IVa): [ka] The compound is reacted with a tertiary amine, particularly in the presence of a tertiary amine, more particularly in the presence of a tertiary amine selected from triethylamine, tripropylamine, diisopropylethylamine, and tributylamine, most particularly in the presence of a tertiary amine that is tributylamine, particularly in the presence of a solvent, more particularly in the presence of a solvent selected from dichloromethane, MeTHF, and THF, most particularly in the presence of the aforementioned dichloromethane, to obtain formula (III). [ka] To obtain the compound, f) Heating a mixture of the compounds of formula (III) in the presence of a solvent, particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, or isopropanol, and particularly the aforementioned n-propanol, at a temperature above 70°C, particularly 80°C to 120°C, more particularly 90°C to 110°C, most particularly 92°C ± 5°C, in the presence of a solvent, particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, or isopropanol, and particularly the aforementioned n-propanol, to obtain formula (II) [ka] To obtain the compound, g) A method is provided to obtain a compound of formula (I) by reacting a compound of formula (II) with a strong acid (for decarboxylation), particularly sulfuric acid, methanesulfonic acid, trifric acid, or hydrochloric acid, particularly methanesulfonic acid, trifric acid, and HCl, more particularly HCl, and most particularly preparing HCl in situ with alcohol and acetyl chloride as described above.

[0063] In another embodiment (Aspect 15), the present invention relates to a compound of formula (I) or its HCl salt: [ka] A method for preparing a) Formula (X) [ka] The compound is reacted with NH4OH to produce (IXa) and (IXb). [ka] To obtain the compound, b) Compounds of formulas (IXa) and (IXb) are reacted with 1-bromo-2,2-dimethoxypropane in the presence of pyridinium p-toluenesulfonate to obtain formula (VIII). [ka] To obtain the compound, c) The compound of formula (VIII) is reacted with carbon monoxide in the presence of a catalyst (e.g., Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), especially PdCl2(dppf)), a base, especially a tertiary amine, acetonitrile, water and a solvent (more particularly the solvent is selected from MeOH, EtOH, iPrOH, AmOH, n-PrOH, DMF, DMA, toluene, THF or 2-Me-THF, and most particularly the solvent is the aforementioned acetonitrile and water) to obtain formula (VII). [ka] To obtain the compound, d) The compound of formula (VII), Oxalyl chloride is reacted with a solvent in particular (more particularly, the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF, THF, and dichloromethane, and most particularly, the solvent is the aforementioned dichloromethane) to obtain formula (IV) [ka] To obtain the compound, e) Reacting the compound of formula (VI) with 2,2-dimethyl-1,3-dioxane-4,6-dione, also known as meldrum acid, in the presence of a solvent (more particularly, the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly, from 2-MeTHF, THF, and dichloromethane, and most particularly, the solvent is the aforementioned dichloromethane) to obtain the compound of formula (V) or its tautomers. [ka] To obtain f) Reacting the compound of formula (V) or its tautomer with oxalyl chloride, particularly in the presence of a solvent (more particularly, the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF, THF, and dichloromethane, and most particularly, the solvent is the aforementioned dichloromethane), to obtain formula (IV) [ka] To obtain the compound, g) A compound of formula (IV), formula (IVa): [ka] The compound is reacted with a tertiary amine, particularly in the presence of a tertiary amine, more particularly in the presence of a tertiary amine selected from triethylamine, tripropylamine, diisopropylethylamine, and tributylamine, most particularly in the presence of a tertiary amine that is tributylamine, particularly in the presence of a solvent, more particularly in the presence of a solvent selected from dichloromethane, MeTHF, and THF, most particularly in the presence of the aforementioned dichloromethane, to obtain formula (III). [ka] To obtain the compound, h) Heating a mixture of the compounds of formula (III) in the presence of a solvent, particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, or isopropanol, and particularly the aforementioned n-propanol, at a temperature above 70°C, particularly 80°C to 120°C, more particularly 90°C to 110°C, most particularly 92°C ± 5°C, in the presence of a solvent, particularly a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, or isopropanol, and particularly the aforementioned n-propanol, to obtain formula (II) [ka] To obtain the compound, I) A method is provided to obtain the compound of formula (I) by reacting the compound of formula (II) with a strong acid (for decarboxylation), particularly sulfuric acid, methanesulfonic acid, trifric acid, or hydrochloric acid, particularly methanesulfonic acid, trifric acid, and HCl, more particularly HCl, and most particularly preparing HCl in situ with alcohol and acetyl chloride as described above.

[0064] In another embodiment (Aspect 16), the present invention relates to formula (II) [ka] The compound is provided.

[0065] In another embodiment (Aspect 17), formula (III) [ka] The compound is provided.

[0066] In another embodiment (Aspect 18), the present invention relates to formula (IV) [ka] The compound is provided.

[0067] In another embodiment (Aspect 19), the present invention relates to a compound of formula (V) or a tautomer thereof. [ka] To provide.

[0068] In another embodiment (Aspect 20), the present invention relates to formula (VI) [ka] The compound is provided.

[0069] In another embodiment according to any of the embodiments of aspects 9 to 12, the process is fitted.

[0070] In any particular embodiment of the above embodiments of the present invention disclosed herein, at least a purification step may be carried out after step b), which yields compound formula (VIII), wherein the purification step is in particular reverse crystallization. Chromatographic purification may be performed after reverse crystallization.

[0071] Starting materials and reagents that do not have the synthetic routes expressly disclosed herein are generally available from commercial sources or can be readily prepared using methods well known to those skilled in the art.

[0072] In general, the nomenclature used in this application is based on AUTONOM® 2000, the Beilstein Institute's computerized system for generating IUPAC systematic nomenclature. The chemical structures shown herein were created using MDLISIS® version 2.5SP2. Any open valencies appearing on carbon, oxygen, or nitrogen atoms in the structures herein indicate the presence of hydrogen atoms.

[0073] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention. [Examples]

[0074] In this application, the following abbreviations and definitions are used: AmOH (Amzl alcohol); br (broad); BuLi (butyllithium); CDCl3 (deuterated chloroform); d (doublet); DCM (dichloromethane); DMA (dimethylacetamide); DMAP (4-dimethylaminopyridine); DMF (dimethylformamide); eq. (equivalent); EtOH (ethanol); g (gram); GC (gas chromatography); h (hour); HCl (hydrochloric acid); H2O (water); HPLC (high-performance liquid chromatography); iPrOH (isopropanol); ISP (isotopic spin allocation); KOH (potassium hydroxide); LDA (lithium diisopropylamide); LCMS (liquid chromatography) Raffy-Mass Spectrometry); M (moles); m (multiplet); MeOH (methanol); MS (mass spectrometry); mL (milliliters); NaOH (sodium hydroxide); NMP (N-methyl-2-pyrrolidone); NMR (nuclear magnetic resonance); Pd (xanthophos)Cl2 (dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene]palladium(II)); n-PrOH (n-propanol); s (singlet); sec (second); t (triplet); t-BuBrettPhos (2-(di-tert-butylphosphino)-2',4',6,-triisopropyl-3,6-dimethoxy-1,1'-biphenyl); THF (tetrahydrofuran); 2-Me-THF (2-methyltetrahydrofuran).

[0075] Example 1: [ka] 5-bromo-2-nitropyridine (800 g, 3.94 mol, equivalent: 1.00) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (944 g, 4.45 mol, equivalent: 1.13) were charged into the reactor, followed by acetonitrile (1.57 kg, 2 L, equivalent: -). A suspension of anhydrous potassium carbonate (1.5 kg, 10.9 mol, equivalent: 2.75) in acetonitrile (2.36 kg, 3 L, formula: -) was added. The suspension was stirred and heated at 80°C for 3 days.

[0076] The resulting orange suspension was cooled to 50°C and mixed with water (12 kg, 12 L, equivalent: -) for approximately 10 minutes (solution). A suspension was rapidly obtained and cooled to 20°C. After 1 hour at 20°C, the suspension was filtered. The filtered cake was sequentially washed with water (3 kg, 3 L, equivalent: -), ethanol (1.58 kg, 2 L, equivalent: -), and MTBE (740 g, 1 L, equivalent: -). The filtered cake was transferred to a reactor with ethanol (7.1 kg, 9 L, equivalent: -) and toluene (865 g, 1 L, equivalent: -). The suspension was heated to 60°C, stirred for 1 hour, and cooled to 20°C over 2 hours. The suspension was stirred overnight and filtered. The filtered cake was washed with ethanol (800 mL) and dried at less than 50°C / 10 mg / mcbar over the weekend to obtain 737 g of product (purity 99.5 a%) by HPLC. LCMS: 335.17 (M+1).

[0077] Example 2: tert-butyl 7-(6-aminopyridine-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate [ka] 230 g of tert-butyl 7-(6-nitropyridine-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (1 equivalent, 2.09 mol) was hydrogenated in AcOEt (7 L, 6.3 kg) under 1 bar of H2 at room temperature with moist 1% Pt / C + 2% vanadium (0.38% Pt, 0.065 mol%). After the reaction was complete, the reactor was evacuated and the reaction mixture was filtered. The reaction was repeated twice (totaling approximately 700 g of SM), and the combined product was concentrated to a volume of approximately 1 L. Heptane (3 L) was added, and the mixture was solvent-exchanged to heptane under constant volume. The resulting suspension was diluted with heptane (1 L) and filtered. The filtered cake was washed with heptane and dried at less than 50°C / 10 mmbar until constant weight was obtained, yielding 610 g of the labeled product (purity of over 99.5% by LC).

[0078] Example 3: 6-Chloro-2,8-dimethylimidazo[1,2-b]pyridazine [ka] 3,6-Dichloro-4-methylpyridazine (200 g, 1 equivalent, 1.23 mol) and a 25% NH4OH aqueous solution (1.8 kg, 2 L) were placed in an autoclave. The reaction mixture was heated at 100°C for 18 hours (at a pressure of approximately 7 bar) and then cooled to room temperature. The suspension was transferred to another reactor. The autoclave was washed with water (1 L). The combined suspension was stirred overnight at room temperature and then filtered. The filtered cake was washed with cold water (0-5°C) (1 L) and dried at less than 50°C / 10 millibars.

[0079] This reaction was repeated three times to obtain a total of approximately 334 g of aminochloropyridazine intermediate as a mixture of isomers.

[0080] The unpurified intermediate product (384 g) and pyridinium p-toluenesulfonate (43 g, 171 mmol, equivalent: 0.0736) were charged into the reactor, followed by the addition of 2-propanol (1.96 kg, 2.5 L, equivalent: -). The resulting suspension was heated to 80°C, and 1-bromo-2,2-dimethoxypropane (521 g, 385 mL, 2.79 mol, equivalent: 1.20) was added over 25 minutes. The reaction mixture was stirred overnight and cooled to room temperature. 1 M aqueous NaOH solution (3.78 kg, 2.8 L, 2.8 mol, equivalent: 1.2) was added over 30 minutes at room temperature. The suspension was partially concentrated under reduced pressure (distilled at approximately 3 L) at approximately 60°C, during which time a solution was obtained, followed by another suspension. The suspension was cooled to approximately 8°C (Tj 5°C) over 3 hours. After stirring overnight, water (3.00 kg, 3 L) was added. After stirring for 1 hour, the suspension was filtered. The filtered cake was washed with water (2.00 kg, 2 L) and dried under reduced pressure at 50°C to obtain 305 g of the product as a mixture of isomers. The unpurified product was digested in approximately 1.5 L of AcOEt. The suspension was filtered, and the filtered cake (containing mainly undesirable isomers) was discarded. The filtrate was concentrated and purified by chromatography (SiO2 / AcOEt) to obtain 128 g of the product (purity over 97% by LC, no undesirable isomers detected). LC-MS: 182(M+1).

[0081] Example 4: 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid [ka] 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine (400 g, 1 equivalent, 2.2 mol) was carbonylated at 90°C for 48 hours in a mixture of acetonitrile (3.2 L, 2.52 kg) and water (0.8 L, 0.8 kg) with PdCl2(dppp) (13 g, 0.01 equivalent), triethylamine (448 g, 617 ml, 2 equivalents), and CO (60 bar). After the reaction was complete, the reactor was cooled, evacuated, and the reaction mixture was filtered. The filtrate was concentrated to 2.4 L under reduced pressure at 60°C. The solution was azeotropically mixed at a constant volume. The resulting suspension was cooled to room temperature, dichloromethane (8 L) was added, followed by 5-6 N HCl (400 g, 440 mL, 1.1 equivalents) in iPrOH. The suspension was stirred for a further 1 hour and filtered. The filtered cake was washed with dichloromethane (5 L) and dried at 50°C / less than 10 mmbar until constant weight was obtained, yielding 397 g of the labeled product (99.8a% LC, 0.5% KFT). LCMS: 192.07 (M+1)

[0082] Example 5: 7-(4-(tert-butoxycarbonyl)-4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid [ka] 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid (300 g, 1.57 mol, equivalent: 1) and DMAP (422 g, 3.45 mol, equivalent: 2.2) were charged into the reactor, followed by DCM (7.92 kg, 6 L, equivalent: -) and DMF (132 g, 140 mL, 1.81 mol, equivalent: 1.15). The mixture was heated to 40°C, during which time a solution was obtained. A solution of oxalyl chloride (203 g, 138 mL, 1.57 mol, equivalent: 1) in DCM (792 g, 0.6 L, equivalent: -) was added dropwise over approximately 45 minutes. After the reaction was complete (less than 30 minutes, to obtain INT-1 by IPC by LC after derivatization), the resulting suspension was cooled to room temperature and added at room temperature to a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (meldrumic acid) (294 g, 2.04 mol, equivalent: 1.3) and DMAP (192 g, 1.57 mol, equivalent: 1) in DCM (5.28 kg, 4 L, equivalent: -). After 1 hour of reaction (IPC check to obtain INT-2), a solution of oxalyl chloride (184 g, 125 mL, 1.42 mol, equivalent: 0.905) in DCM (330 g, 250 ml, equivalent: -) was added over 30 minutes. Additional oxalyl chloride was added in fractions until the amount of intermediate INT-2 was less than 2a% (total oxalyl chloride: 68 g / 0.34 equivalents) ("titration"). After deoxychlorination was complete (to obtain INT-3), a solution of tert-butyl 7-(6-aminopyridine-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (430 g, 1.41 mol, equivalent: 0.9) and tributylamine (594 g, 764 ml, 3.14 mol, equivalent: 2) in DCM (1.58 kg, 1.2 L, equivalent: -) was added over 20 minutes. The reaction mixture was stirred overnight and concentrated (to obtain unpurified INT-4). Propanol (3 L) was added and the mixture was concentrated. The last two steps were repeated. Propanol (6 L) was added, and the reaction mixture was heated under reflux overnight to carry out cyclization, yielding an unpurified mixture containing INT-5.

[0083] In a separate reactor, acetyl chloride (829 g, 750 mL, 10.5 mol, equivalent: 7.16) was added to 1-propanol (2.56 kg, 3.2 L, equivalent: -) while maintaining the temperature at 10-20°C. After the reaction was complete, the HCl solution in the propanol was heated to 60°C, and the previously prepared unpurified INT-5 solution (heated to 90°C to obtain the solution, then cooled to 60°C) was added dropwise at 60°C for 25 minutes (this affects Boc deprotection and approximately 20% decarboxylation). The resulting reaction mixture was heated under reflux overnight (gradually decreasing from approximately 92°C to 89°C) to complete decarboxylation. The reaction mixture was cooled to room temperature and filtered. The filtered cake was washed with propanol. The filtered cake was dissolved in water (3 L) and ethanol (3 L) was added. A 32% NaOH aqueous solution (234 g, 173 mL, 1.87 mol, equivalent: 1.28) was added to adjust the pH to 13, during which time the product crystallized. The suspension was heated to approximately 50°C for 24 hours. The suspension was cooled to room temperature for 15 hours and filtered. The filtered cake was washed with a 1:2 ethanol / water mixture (2 L). The filtered cake was dried under reduced pressure at 50°C in a water-saturated atmosphere to obtain 384 g of the product as a trihydrate (LC, purity by water 98a%: 12.4% m / m).

Claims

1. Equation (I): 【Chemistry 1】 A method for preparing a compound or its HCl salt, Formula (II): 【Chemistry 2】 A method comprising reacting a compound with a strong acid.

2. The method according to claim 1, wherein the strong acid is HCl.

3. The method according to claim 2, wherein the HCl is prepared in situ using n-propanol and acetyl chloride.

4. Formula (II): 【Transformation 3】 A method for preparing the compound, Formula (III) 【Chemistry 4】 A method comprising heating a mixture of the compounds at a temperature above 70°C, at a temperature between 80°C and 120°C, at a temperature between 90°C and 110°C, or at 92°C ± 5°C.

5. Formula (III) 【Transformation 5】 A method for preparing the compound, Formula (IV) 【Transformation 6】 The compound, Formula (IVa): 【Transformation 7】 A method comprising reacting with a compound.

6. Formula (IV) 【Transformation 8】 A method for preparing the compound, Compound of formula (V), or its tautomer 【Chemistry 9】 A method comprising reacting with oxalyl chloride.

7. Formula (V) 【Chemistry 10】 A method for preparing the compound, Formula (VII) 【Chemistry 11】 A method comprising reacting a compound with oxalyl chloride, and then adding 2,2-dimethyl-1,3-dioxan-4,6-dione, also known as meldramic acid.

8. Formula (V) 【Chemistry 12】 A method for preparing the compound, Equation (VI) 【Chemistry 13】 A method comprising reacting the compound with 2,2-dimethyl-1,3-dioxan-4,6-dione, also known as meldrum acid.

9. Equation (VI) 【Chemistry 14】 A method for preparing the compound, Formula (VII) 【Chemistry 15】 A method comprising reacting a compound with oxalyl chloride.

10. Formula (III) 【Chemistry 21】 The compound of formula (II) is heated at a temperature above 70°C, at a temperature between 80°C and 120°C, at a temperature between 90°C and 110°C, or at 92°C ± 5°C. 【Chemistry 22】 The method according to any one of claims 1 to 3, further comprising the preparation of the compound.

11. Formula (IV) 【Chemistry 23】 The compound is given by formula (IVa) 【Chemistry 24】 This includes reacting with the compound, Formula (III) 【Chemistry 25】 The method according to claim 10, further comprising the preparation of the compound.

12. Compound of formula (V) or its tautomers 【Chemistry 26】 Formula (IV) involves reacting with oxalyl chloride. 【Chemistry 27】 The method according to claim 11, further comprising the preparation of the compound.

13. Equation (VI) 【Chemistry 28】 Formula (V) involves reacting the compound with 2,2-dimethyl-1,3-dioxan-4,6-dione, also known as meldramic acid. 【Chemistry 29】 The method according to claim 12, further comprising the preparation of the compound.

14. Formula (VII) 【Transformation 30】 The compound of formula (VI) is reacted with oxalyl chloride. 【Chemistry 31】 The method according to claim 13, further comprising the preparation of the compound.

15. Formula (VIII) 【Chemistry 32】 The compound is reacted with carbon monoxide in the presence of a catalyst selected from Pd(PPh ２ , ４ ), Pd(PPh ４ ), Pd(PPh ３ ), PdCl ２ Cl ２ , PdCl ２ (dppf), PdCl ２ (dppf)·CH<000000,Cl ２ , and PdCl ２ (dppp), which includes reacting with carbon monoxide, of formula (VII) 【Transformation 33】 The method according to claim 14, further comprising the preparation of the compound.

16. a) Formula (X) 【Transformation 34】 The compound, NH ４ To react with OH to obtain the compound of formula (IXa), b) Formula (IXa) 【Chemistry 35】 The compound is reacted with 1-bromo-2,2-dimethoxypropane in the presence of p-toluenesulfonate pyridinium to obtain the compound of formula (VIII). Formula (VIII) 【Transformation 36】 The method according to claim 15, further comprising the preparation of the compound.

17. Compounds of the following formula (II): 【Chemistry 37】 。

18. Compounds of the following formula (III): 【Transformation 38】 。

19. Compounds of the following formula (IV): 【Chemistry 39】 。

20. Compounds of the following formula (V): 【Chemistry 40】 。

21. Compounds of the following formula (V-tautomer): 【Chemistry 41】 。

22. Compounds of the following formula (VI): 【Chemistry 42】 。

23. The method according to claim 4, wherein the heating is carried out in the presence of a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, and isobutanol.

24. The method according to claim 5, wherein the reaction is carried out in the presence of a tertiary amine selected from triethylamine, tripropylamine, and diisopropylethylamine.

25. The method according to claim 5, wherein the reaction is carried out in the presence of tributylamine and a solvent selected from dichloromethane, MeTHF, and THF.

26. The method according to claim 6, wherein the reaction is carried out in the presence of a solvent selected from dichloromethane, 2-MeTHF, THF, DMF, and NMP.

27. The method according to claim 7, wherein the reaction is carried out in the presence of a solvent selected from dichloromethane, 2-MeTHF, THF, DMF, and NMP.

28. The method according to claim 7, wherein the reaction is carried out in the presence of dichloromethane and 2,2-dimethyl-1,3-dioxan-4,6-dione, also known as meldrumic acid.

29. The method according to claim 7, wherein the reaction is carried out in the presence of 2.5 to 5.0 equivalents, 3.0 to 4.0 equivalents, or 3.2 equivalents of DMAP relative to the theoretical amount of the compound of formula (VII).

30. The method according to claim 8, wherein the reaction is carried out in the presence of a solvent selected from dichloromethane, 2-MeTHF, THF, DMF, and NMP.

31. The method according to claim 8, wherein the reaction is carried out in the presence of 2.0 to 2.5 equivalents, 2.2 to 2.4 equivalents, or 2.3 equivalents of DMAP relative to the theoretical amount of the compound of formula (VI).

32. The method according to claim 9, wherein the reaction is carried out in the presence of a solvent selected from dichloromethane, 2-MeTHF, THF, DMF, and NMP.

33. The method according to claim 9, wherein the reaction is carried out in the presence of 1.5 to 4.0 equivalents, 2.0 to 3.0 equivalents, or 2.0 equivalents of DMAP relative to the theoretical amount of the compound of formula (VII).

34. The method according to claim 10, wherein the heating is carried out in the presence of a solvent selected from isopropanol, n-propanol, t-butanol, n-butanol, and isobutanol.

35. The method according to claim 11, wherein the reaction is carried out in the presence of a tertiary amine selected from triethylamine, tripropylamine, diisopropylethylamine, and tributylamine.

36. The method according to claim 11, wherein the reaction is carried out in the presence of a solvent selected from dichloromethane, MeTHF, and THF.

37. The method according to claim 12, wherein the reaction is carried out in the presence of a solvent selected from dichloromethane, 2-MeTHF, THF, DMF, and NMP.

38. The method according to claim 13, wherein the reaction is carried out in the presence of a solvent selected from dichloromethane, 2-MeTHF, THF, DMF, and NMP.

39. The method according to claim 13, wherein the reaction is carried out in the presence of 2.0 to 2.5 equivalents, 2.2 to 2.4 equivalents, or 2.3 equivalents of DMAP relative to the theoretical amount of the compound of formula (VI).

40. The method according to claim 14, wherein the reaction is carried out in the presence of a solvent selected from dichloromethane, 2-MeTHF, THF, DMF, and NMP.

41. The method according to claim 14, wherein the reaction is carried out in the presence of 1.5 to 4.0 equivalents, 2.0 to 3.0 equivalents, or 2.0 equivalents of DMAP relative to the theoretical amount of the compound of formula (VII).

42. The method according to claim 15, wherein the reaction is carried out in the presence of acetonitrile and water.

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