Process for preparation of lisethopram

Abstract

The present invention relates to a process for the preparation of lisethopram. Specifically, the present invention relates to a process for the preparation of 7-(4, 7-diazaspiro [2.5] octane-7-yl)-2-(2, 8-dimethylimidazo [1, 2-b] pyridazin-6-yl) pyrido [1, 2-a] pyrimidin-4-one derivatives, which can be used as pharmaceutically active compounds.

Description

[0001] This application is a divisional application of the PCT international application filed on March 16, 2022, with PCT international application number PCT / EP2022 / 056778, Chinese national application number 202280021947.3, and entitled "Method for preparing lisciphalan".

[0002] This invention relates to a method for preparing 7-(4,7-diazaspiro[2.5]octane-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, which can be used as a pharmaceutically active compound.

[0003] In a first aspect, the present invention provides a method for preparing a compound of formula (I), its hydrate, solvate or hydrochloride:

[0004]

[0005] It includes compounds of formula (II):

[0006]

[0007] It reacts with the following (to achieve decarboxylation and Boc-deprotection): strong acids, especially sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, particularly methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more particularly hydrochloric acid, especially where hydrochloric acid is prepared in situ with alcohol and acetyl chloride.

[0008] According to the method of the first embodiment, anhydrous hydrochloric acid is used. It can also be prepared in situ from alcohol and acetyl chloride (especially methanol, ethanol, n-propanol, isopropanol, or n-butanol and acetyl chloride, especially n-propanol and acetyl chloride).

[0009] In a particular embodiment, after the addition and reaction of a strong acid (to achieve Boc deprotection and decarboxylation), the pH of the resulting acidic solution of I is adjusted by adding a base to separate the free base.

[0010] 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.

[0011] In certain embodiments, the present invention provides a method as described herein, wherein 5 to 20 equivalents, more particularly 7 to 10 equivalents, of hydrochloric acid relative to the theoretical amount of the compound of formula (II) are used.

[0012] In another embodiment, the present invention provides a method for preparing compound of formula (I) as described above, wherein the reaction is carried out at a temperature between 80°C and 120°C, particularly between 85°C and 100°C, and more particularly between 85°C and 95°C.

[0013] In another embodiment, the present invention provides the method as described herein, wherein hydrochloric acid is prepared in situ from acetyl chloride in n-propanol at a temperature between 0-60°C, particularly between 0-40°C, during the addition of acetyl chloride followed by heating to up to 60°C, and more particularly at atmospheric pressure at a temperature between 10-20°C, during the addition of acetyl chloride followed by heating to up to 60°C.

[0014] In another embodiment, the present invention provides a method as described herein, wherein a pressurized reactor is required for the solvent to reach a temperature above the boiling point.

[0015] Compounds of formula (I) are valuable pharmaceutical compounds, particularly 7-(4,7-diazaspiro[2.5]octane-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as described in WO2015173181.

[0016] Unless otherwise stated, the following terms used in this specification and claims shall have the following meanings:

[0017] "(C1-C6)alkyl" refers to a branched or straight-chain hydrocarbon chain having one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0018] The term "(C3-C8)cycloalkyl" refers to a saturated monocyclic hydrocarbon group with 3 to 8 ring carbon atoms. Examples of monocyclic (C3-C8)cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0019] "Base" refers to a compound that deprotonates another compound when reacted with it. Suitable bases as used in this disclosure include, but are not limited to, tertiary amines and basic alkali metal salts. In some embodiments, tertiary amines include triethylamine, tributylamine, N-methylmorpholine, and diisopropylethylamine. In some embodiments, basic alkali metal salts include, for example, lithium carbonate (Li₂CO₃), sodium carbonate (Na₂CO₃), potassium carbonate (K₂CO₃), cesium carbonate (Cs₂CO₃), sodium bicarbonate (NaHCO₃), lithium, cesium, sodium and potassium hydroxides, sodium alkoxides and potassium alkoxides (including, but not limited to, tert-butoxides, n-propoxides, isopropoxides, ethanolates, methanolates, etc. of sodium and potassium), sodium amide (NaNH₂), potassium amide (KNH₂), etc.

[0020] "Crystallization" and "recrystallization" are used interchangeably; they refer to the process by which a compound dissolved or suspended in a solvent system produces a stable polymorph or crystalline form of that compound. For example, the crystallization step can be accomplished by forming crystals with a solvent and an antisolvent.

[0021] A "strong acid" is an acid that completely dissociates in aqueous solution and has a pKa < -1.74. Strong acids include, but are not limited to: 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. In particular, strong acids are hydrohalic acids, where X'' is Br or Cl. Most notably, strong acids are hydrochloric acid.

[0022] "Tertiary amine" refers to the formula R a N(R b )R c amines, of which R a R b and R c The amine is independently selected from (C1-C6) alkyl, (C3-C8) cycloalkyl, or phenyl groups. Representative examples include, but are not limited to, triethylamine, tributylamine, diethylmethylamine, dimethylethylamine, N,N-dimethylaniline, N-methylmorpholine, and methylethylbutylamine. Preferably, the tertiary amine is selected from tributylamine, tripropylamine, or triethylamine, more preferably triethylamine or tributylamine. The most preferred tertiary amine is tributylamine.

[0023] “Environmental conditions” or “room temperature” refers to the conditions experienced in a standard laboratory, such as atmospheric pressure, under Ar or N2, and ambient temperature between 18°C ​​and 28°C.

[0024] In a specific embodiment of the first aspect, the present invention provides a method for preparing a compound of formula (I), its hydrate, solvate, or hydrochloride thereof:

[0025]

[0026] It includes compounds of formula (II):

[0027]

[0028] The reaction with hydrochloric acid, most particularly, wherein the hydrochloric acid is prepared in situ from an alcohol and acetyl chloride, yields a compound of formula (IIa) or (IIb), which is then converted into a compound of formula (I).

[0029] .

[0030] In another aspect (aspect 1'), the present invention provides a method for preparing a compound of formula (I), its hydrate, solvate, or hydrochloride thereof:

[0031]

[0032] It includes compounds of formula (IIa):

[0033]

[0034] The reaction with hydrochloric acid, most particularly, wherein the hydrochloric acid is prepared in situ from an alcohol and acetyl chloride, yields the compound of formula (I). In more specific embodiments, the method may be heated.

[0035] In another aspect (aspect 2), the present invention provides a method for preparing compound of formula (II):

[0036]

[0037] It includes mixtures of heated (III) compounds, particularly above 70°C, particularly between 80°C and 120°C, more particularly between 90°C and 110°C, and most particularly at 92°C ± 5 Heating at a temperature of ℃

[0038]

[0039] The heating is carried out, particularly in the presence of a solvent, especially in the presence of isopropanol, n-propanol, tert-butanol, n-butanol, or isobutanol, wherein the solvent is n-propanol, n-butanol, or isopropanol, particularly n-propanol.

[0040] In a specific aspect 2, the present invention provides a method for preparing a compound of formula (II):

[0041]

[0042] It includes 92℃ ± 5 A mixture of compounds of formula (III) heated in n-propanol at ℃

[0043] 。

[0044] In another aspect (aspect 3), the present invention provides a method for preparing compounds of formula (III),

[0045]

[0046] It includes compounds of formula (IV).

[0047]

[0048] Reaction with compound of formula (IVa):

[0049]

[0050] The reaction is carried out, particularly in the presence of a tertiary amine, especially when the tertiary amine is selected from triethylamine, tripropylamine, diisopropylethylamine, tributylamine, and most particularly when the tertiary amine is tributylamine, particularly in the presence of a solvent, especially when the solvent is selected from dichloromethane, MeTHF, THF, and most particularly when the solvent is dichloromethane.

[0051] The amount of compound (IVa) is adjusted to ensure that compound (IV) is effectively converted into compound (III) while avoiding unnecessary excess.

[0052] In a specific embodiment of aspect 3, the invention provides the method as described herein, wherein 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 an amount lower than the stoichiometric amount relative to the theoretical amount of the compound of formula (IV), particularly 0.9 equivalents of the compound of formula (IVa), results in optimal yield and minimal impurities.

[0053] In another embodiment of aspect 3, the present invention provides a method for preparing a compound of formula (III) as described above, wherein the reaction is carried out at a temperature between 0°C and 40°C, particularly between 20°C and 30°C, and more particularly about 25°C ± 5°C.

[0054] In another aspect (aspect 4), the present invention provides a method for preparing a compound of formula (IV),

[0055]

[0056] It includes compounds of formula (V) or their corresponding tautomers.

[0057] ↔

[0058] The reaction with oxalyl chloride is particularly carried out in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF as well as dichloromethane, and most particularly wherein the solvent is dichloromethane.

[0059] In a specific embodiment of aspect 4, the invention provides the method as described herein, wherein 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 are used relative to the theoretical amount of the compound of formula (V). In a more specific embodiment, oxalyl chloride is titrated to 0.9 equivalents to a maximum of 1.2 to 1.3 equivalents relative to the theoretical amount of the compound of formula (V).

[0060] In a specific embodiment of aspect 4, the present invention provides the method as described herein, wherein oxalyl chloride causes the compound of formula (V) to undergo chlorination and dehydration by means of HPLC conversion.

[0061] In another embodiment of aspect 4, the present invention provides a method for preparing a compound of formula (IV) as described above, wherein the reaction is carried out at a temperature between 0°C and 40°C, particularly between 15°C and 30°C, and even more particularly at 20°C ± 5°C.

[0062] In another aspect (aspect 5), the present invention provides a method for preparing a compound of formula (V),

[0063]

[0064] It includes compounds of formula (VI).

[0065] ,

[0066] It reacts with 2,2-dimethyl-1,3-dioxane-4,6-dione (also known as Meldrum acid), the reaction being particularly carried out in the presence of a solvent, more particularly wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF and THF and dichloromethane, and most particularly wherein the solvent is dichloromethane.

[0067] In a specific embodiment of aspect 5, the invention provides a method as described above, wherein DMAP is present, more particularly wherein 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 (VI). The defined amount of DMAP corresponds to the total amount present during the reaction and corresponds to the sum of the amounts used during the acyl chloride formation and Meldrum acid addition steps when the method of aspect 5 overlaps with the method of aspect 6.

[0068] In a specific embodiment of aspect 5, wherein the isolated VI compound, the present invention provides as described herein, wherein 2 to 2.5 equivalents, more particularly 2.2 to 2.4 equivalents, and most preferably about 2.3 equivalents of 2,2-dimethyl-1,3-dioxane-4,6-dione are used relative to the theoretical amount of the compound of formula (VI).

[0069] In another embodiment of aspect 5, the present invention provides a method for preparing compound of formula (V) as described above, wherein the reaction is carried out at a temperature between 0°C and 40°C, particularly between 15°C and 30°C, and even more particularly at 20°C ± 5°C.

[0070] In another embodiment, the present invention provides a method for preparing compound of formula (V) as described above, wherein aspects 5 and 6 overlap.

[0071] In another aspect (aspect 5'), the present invention provides a method for preparing a compound of formula (V),

[0072]

[0073] It includes compounds of formula (VII).

[0074]

[0075] The reaction with oxalyl chloride, particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF as well as dichloromethane, most particularly wherein the solvent is dichloromethane, is followed by the addition of 2,2-dimethyl-1,3-dioxane-4,6-dione (also known as Meldrum acid), wherein DMAP is present, especially wherein 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).

[0076] In another embodiment of aspect 5', the present invention provides a method for preparing compound of formula (V) as described above, wherein the reaction is carried out at a temperature between 0°C and 40°C, particularly between 15°C and 30°C, and even more particularly at 20°C ± 5°C.

[0077] In another aspect (aspect 6), the present invention provides a method for preparing a compound of formula (VI),

[0078]

[0079] It includes compounds of formula (VII).

[0080]

[0081] The reaction with oxalyl chloride is particularly carried out in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF as well as dichloromethane, with dichloromethane being the most particularly preferred solvent.

[0082] In a specific embodiment of aspect 6, the present invention provides a method as described above, wherein DMAP is present, and more particularly wherein 1.5 to 4.0 equivalents, more particularly 2.0 to 3.0 equivalents, and most preferably about 2.0 equivalents of DMAP are present relative to the theoretical amount of the compound of formula (VII).

[0083] Surprisingly, it was found that the DMAP salt of compound (VII) had increased solubility in dichloromethane compared to compound (VII), which was advantageous for mass transfer during the formation of the corresponding acyl chloride.

[0084] In a specific embodiment of aspect 6, the present invention provides a method as described above, wherein 1 to 1.1 equivalents, most particularly 1 equivalent, of oxalyl chloride are used relative to the compound of formula (VII).

[0085] In a particular embodiment of aspect 6, the invention provides the method as described herein, wherein a particularly 1.15 equivalent of DMF is used.

[0086] In another embodiment of aspect 6, the present invention provides a method for preparing compound of formula (VI) as described above, wherein the reaction is carried out at a temperature between 10°C ± 2°C and 40°C ± 2°C, particularly between 25°C ± 2°C and 40°C ± 2°C, and more particularly between 35°C ± 2°C and 40°C ± 2°C.

[0087] In another aspect (aspect 7), the present invention provides a method for preparing compounds of formula (VII),

[0088]

[0089] It includes compounds of formula (VIII).

[0090]

[0091] The reaction with carbon monoxide is carried out in the presence of a catalyst (such as Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf), CH2Cl2, PdCl2(dppp), especially in the presence of PdCl2(dppf)), and in the presence of a base (especially a tertiary amine), acetonitrile, and water and a solvent, more particularly wherein the solvent is selected from MeOH, EtOH, iPrOH, AmOH, n-PrOH, DMF, DMA, toluene, THF or 2-Me-THF, and most particularly wherein the solvent is acetonitrile and water.

[0092] In a particular embodiment of aspect 7, the invention provides the method as described herein, wherein carbon monoxide is used at a concentration of 1 to 150 bar, particularly 20 to 70 bar, and most particularly 50 to 70 bar relative to the compound of formula (VIII).

[0093] In a specific embodiment of aspect 7, the present invention provides the method as described herein, wherein a catalyst is used at 0.01 mol% to 10 mol% relative to the compound of formula (VIII), more particularly 0.1 mol% to 2 mol%, and most particularly 0.5 mol% to 1.5 mol%.

[0094] In a particular embodiment of aspect 7, the invention provides the method as described herein, wherein a tertiary amine is used in an amount of 0.1 to 10 equivalents, more particularly 1.5 to 2.5 equivalents, relative to the compound of formula (VIII).

[0095] In another embodiment of aspect 7, the present invention provides a method for preparing compound of formula (VII) as described above, wherein the reaction is carried out at a temperature between 20°C ± 2°C and 150°C ± 2°C, particularly between 60°C ± 2°C and 110°C ± 2°C, and more particularly between 80°C ± 2°C and 100°C ± 2°C.

[0096] In another aspect (aspect 8), the present invention provides a method for preparing compounds of formula (VIII),

[0097]

[0098] It includes:

[0099] a) Make compound (X)

[0100] Reaction with NH4OH yields compounds of formulas (IXa) and (IXb);

[0101] b) Make compounds of formulas (IXa) and (IXb)

[0102]

[0103] In the presence of p-toluenesulfonic acid pyridinium salt, it is reacted with 1-bromo-2,2-dimethoxypropane to give compound (VIII). Step b) optionally follows at least one purification step, particularly wherein the purification step is reverse crystallization. Reverse crystallization is optionally followed by chromatographic purification.

[0104] In another aspect (aspect 8'), the present invention provides a method for preparing compounds of formula (VIII),

[0105]

[0106] It includes:

[0107] a) Make compound (X)

[0108] It reacts with NH4OH to give the compound of formula (IXa);

[0109] b) Make the compound of formula (IXa)

[0110]

[0111] In the presence of p-toluenesulfonic acid pyridinium salt, it is reacted with 1-bromo-2,2-dimethoxypropane to give compound (VIII). Step b) optionally follows at least one purification step, particularly wherein the purification step is reverse crystallization. Reverse crystallization is optionally followed by chromatographic purification.

[0112] Alternatively, the compound of formula (VIII) may be prepared according to the methods described in WO2015173181 and WO2019057740.

[0113] Compared with the method described in WO2015173181, the purity of the crude (VIII) compound can be improved by reverse crystallization, removing most of the unwanted positional isomers generated by the (IXb) compound, thereby facilitating final chromatographic purification.

[0114] In a particular embodiment, the present invention provides a method as described herein according to aspect 8, wherein steps a) and b) are overlapping.

[0115] Compounds of formula (IVa) can be prepared according to the following steps:

[0116]

[0117] It includes compounds of formula (IVb).

[0118]

[0119] The reaction is carried out with a heterogeneous transition metal hydrogenation catalyst, particularly a Raney catalyst (e.g., Ra-Ni, Ra-Co), Pd / C, Pd(OH)2 / C, Pd / Al2O3, Au / TiO2, Rh / C, Ru / Al2O3, Ir / CaCO3, Pt-V / C, or a combination thereof, especially Pt-V / C, and more particularly 1% Pt and 2% V on the activated carbon. Specifically, for the preparation of the (IVa) compound, the reaction is carried out at temperatures between 0 °C ± 2 °C and 150 °C ± 2 °C, particularly between 15 °C ± 2 °C and 70 °C ± 2 °C, and more particularly between 20 °C ± 2 °C and 35 °C ± 2 °C.

[0120] Compound of formula (IVb) can also be prepared according to scheme 1.

[0121] Option 1:

[0122]

[0123] Compounds of formulas (IVa and IVb) can also be prepared by the method described in WO2019057740.

[0124] In another embodiment (aspect 9), the present invention provides a method for preparing a compound of formula (I) or its hydrochloride salt:

[0125]

[0126] It includes

[0127] a) Heating of mixtures of compounds of type (III), particularly at temperatures above 70°C, particularly between 80°C and 120°C, more particularly between 90°C and 110°C, and most particularly at temperatures of 92°C ± 5°C.

[0128]

[0129] The heating is carried out, particularly in the presence of a solvent, and more particularly in the presence of isopropanol, n-propanol, tert-butanol, n-butanol, or isobutanol, wherein the solvent is n-propanol, n-butanol, or isopropanol, especially n-propanol, as previously described, to obtain the compound of formula (II).

[0130] ,

[0131] b) React the compound of formula (II) with a strong acid, particularly sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, especially methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more particularly hydrochloric acid, especially wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, as described above, to obtain the compound of formula (I).

[0132] In another embodiment (aspect 10), the present invention provides a method for preparing a compound of formula (I) or its hydrochloride salt:

[0133]

[0134] It includes

[0135] a) Make compound (IV)

[0136]

[0137] Reaction with compound of formula (IVa):

[0138]

[0139] The reaction is carried out, particularly in the presence of a tertiary amine, especially when the tertiary amine is selected from triethylamine, tripropylamine, diisopropylethylamine, or tributylamine, and most particularly when the tertiary amine is tributylamine, particularly in the presence of a solvent, especially when the solvent is selected from dichloromethane, MeTHF, or THF, and most particularly when the solvent is dichloromethane, as previously described, to obtain the compound of formula (III).

[0140] ,

[0141] b) Heating a mixture of compounds of formula (III), particularly at a temperature above 70°C, particularly between 80°C and 120°C, more particularly between 90°C and 110°C, and most particularly at 92°C ± 5°C, wherein the heating is particularly carried out in the presence of a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, tert-butanol, n-butanol, or isobutanol, wherein the solvent is n-propanol, n-butanol, or isopropanol, particularly n-propanol, as previously described, to obtain compounds of formula (II).

[0142] ,

[0143] c) React the compound of formula (II) with a strong acid, particularly sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, especially methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more particularly hydrochloric acid, especially wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, as described above, to obtain the compound of formula (I).

[0144] In another embodiment (aspect 11), the present invention provides a method for preparing a compound of formula (I) or its hydrochloride salt:

[0145]

[0146] It includes

[0147] a) Make a compound of formula (V) or its tautomers

[0148]

[0149] The reaction with oxalyl chloride, particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF, and dichloromethane, most particularly wherein the solvent is dichloromethane, as previously described, yields the compound of formula (IV).

[0150]

[0151] b) React compound (IV) with compound (IVa):

[0152]

[0153] The reaction is carried out, particularly in the presence of a tertiary amine, especially when the tertiary amine is selected from triethylamine, tripropylamine, diisopropylethylamine, or tributylamine, and most particularly when the tertiary amine is tributylamine, particularly in the presence of a solvent, especially when the solvent is selected from dichloromethane, MeTHF, or THF, and most particularly when the solvent is dichloromethane, as previously described, to obtain the compound of formula (III).

[0154] ,

[0155] c) Heating a mixture of compounds of formula (III) in a solvent, particularly at a temperature above 70°C, particularly between 80°C and 120°C, more particularly between 90°C and 110°C, and most particularly at 92°C ± 5°C, wherein the heating is particularly carried out in the presence of a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, tert-butanol, n-butanol, and isobutanol, wherein the solvent is n-propanol or n-butanol or isopropanol, particularly n-propanol, as previously described, to obtain compounds of formula (II).

[0156] ,

[0157] d) React the compound of formula (II) with a strong acid, particularly sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, especially methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more particularly hydrochloric acid, especially wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, as described above, to obtain the compound of formula (I).

[0158] In another embodiment (aspect 12), the present invention provides a method for preparing a compound of formula (I) or its hydrochloride salt:

[0159]

[0160] It includes

[0161] a) Make compound of formula (VI)

[0162]

[0163] The reaction with 2,2-dimethyl-1,3-dioxane-4,6-dione (also known as Meldrum acid), particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF as well as dichloromethane, most particularly wherein the solvent is dichloromethane, as previously described, yields a compound of formula (V) or its tautomer.

[0164] ;

[0165] b) Reacting a compound of formula (V) or its tautomer with oxalyl chloride, particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF, and dichloromethane, most particularly wherein the solvent is dichloromethane, as described above, to obtain a compound of formula (IV).

[0166]

[0167] c) Reacting compound (IV) with compound (IVa):

[0168]

[0169] The reaction is carried out, particularly in the presence of a tertiary amine, especially when the tertiary amine is selected from triethylamine, tripropylamine, diisopropylethylamine, or tributylamine, and most particularly when the tertiary amine is tributylamine, particularly in the presence of a solvent, especially when the solvent is selected from dichloromethane, MeTHF, or THF, and most particularly when the solvent is dichloromethane, as previously described, to obtain the compound of formula (III).

[0170] ,

[0171] d) Heating a mixture of compounds of formula (III), particularly at a temperature above 70°C, particularly between 80°C and 120°C, more particularly between 90°C and 110°C, and most particularly at 92°C ± 5°C, wherein the heating is particularly carried out in the presence of a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, tert-butanol, n-butanol, or isobutanol, wherein the solvent is n-propanol, n-butanol, or isopropanol, particularly n-propanol, as previously described, to obtain compounds of formula (II).

[0172] ,

[0173] e) React the compound of formula (II) with a strong acid, particularly sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, especially methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more particularly hydrochloric acid, especially wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, as described above, to obtain the compound of formula (I).

[0174] In another embodiment (aspect 13), the present invention provides a method for preparing a compound of formula (I) or its hydrochloride salt:

[0175]

[0176] It includes

[0177] a) Make the compound of formula (VII)

[0178]

[0179] The reaction with oxalyl chloride, particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF, and dichloromethane, most particularly wherein the solvent is dichloromethane, as previously described, yields the compound of formula (VI).

[0180] ,

[0181] b) Reacting the compound of formula (VI) with 2,2-dimethyl-1,3-dioxane-4,6-dione (also known as a Meldrum acid), particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF as well as dichloromethane, most particularly wherein the solvent is dichloromethane, as described above, to obtain the compound of formula (V) or its tautomer.

[0182] ;;

[0183] c) Reacting a compound of formula (V) or its tautomer with oxalyl chloride, particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF, and dichloromethane, most particularly wherein the solvent is dichloromethane, as described above, to obtain a compound of formula (IV).

[0184]

[0185] d) Reacting compound (IV) with compound (IVa):

[0186]

[0187] The reaction is carried out, particularly in the presence of a tertiary amine, especially when the tertiary amine is selected from triethylamine, tripropylamine, diisopropylethylamine, or tributylamine, and most particularly when the tertiary amine is tributylamine, especially in the presence of a solvent, especially when the solvent is selected from dichloromethane, MeTHF, or THF, and most particularly when the solvent is dichloromethane, as previously described, to obtain the compound of formula (III).

[0188] ,

[0189] e) Heating a mixture of compounds of formula (III), particularly at a temperature above 70°C, particularly between 80°C and 120°C, more particularly between 90°C and 110°C, and most particularly at 92°C ± 5°C, wherein the heating is particularly carried out in the presence of a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, tert-butanol, n-butanol, or isobutanol, wherein the solvent is n-propanol, n-butanol, or isopropanol, particularly n-propanol, as previously described, to obtain compounds of formula (II).

[0190] ,

[0191] f) React the compound of formula (II) with a strong acid, particularly sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, especially methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more particularly hydrochloric acid, especially wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, as described above, to obtain the compound of formula (I).

[0192] In another embodiment (aspect 14), the present invention provides a method for preparing a compound of formula (I) or its hydrochloride salt:

[0193]

[0194] It includes

[0195] a) Make compound of formula (VIII)

[0196]

[0197] The reaction with carbon monoxide, in the presence of a catalyst (such as Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf), CH2Cl2, PdCl2(dppp), especially in the presence of PdCl2(dppf),) and in the presence of a base (especially a tertiary amine), acetonitrile, and water and a solvent, more particularly wherein the solvent is selected from MeOH, EtOH, iPrOH, AmOH, n-PrOH, DMF, DMA, toluene, THF or 2-Me-THF, and most particularly wherein the solvent is acetonitrile and water, as previously described, yields the compound of formula (VII).

[0198]

[0199] b) Make the compound of formula (VII)

[0200] The reaction with oxalyl chloride, particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF, and dichloromethane, most particularly wherein the solvent is dichloromethane, as previously described, yields the compound of formula (VI).

[0201] ,

[0202] c) Reacting the compound of formula (VI) with 2,2-dimethyl-1,3-dioxane-4,6-dione (also known as a Meldrum acid), particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF as well as dichloromethane, most particularly wherein the solvent is dichloromethane, as described above, to obtain the compound of formula (V) or its tautomer.

[0203] ;

[0204] d) Reacting a compound of formula (V) or its tautomer with oxalyl chloride, particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF, and dichloromethane, most particularly wherein the solvent is dichloromethane, as described above, to obtain a compound of formula (IV).

[0205]

[0206] e) React compound (IV) with compound (IVa):

[0207]

[0208] The reaction is carried out, particularly in the presence of a tertiary amine, especially when the tertiary amine is selected from triethylamine, tripropylamine, diisopropylethylamine, or tributylamine, and most particularly when the tertiary amine is tributylamine, particularly in the presence of a solvent, especially when the solvent is selected from dichloromethane, MeTHF, or THF, and most particularly when the solvent is dichloromethane, as previously described, to obtain the compound of formula (III).

[0209] ,

[0210] f) Heating a mixture of compounds of formula (III), particularly at a temperature above 70°C, particularly between 80°C and 120°C, more particularly between 90°C and 110°C, and most particularly at 92°C ± 5°C, wherein the heating is particularly carried out in the presence of a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, tert-butanol, n-butanol, or isobutanol, wherein the solvent is n-propanol, n-butanol, or isopropanol, particularly n-propanol, as previously described, to obtain compounds of formula (II).

[0211] ,

[0212] g) React the compound of formula (II) with a strong acid, particularly sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, especially methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more particularly hydrochloric acid, especially wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, as described above, to obtain the compound of formula (I).

[0213] In another embodiment (aspect 15), the present invention provides a method for preparing a compound of formula (I) or its hydrochloride salt:

[0214]

[0215] It includes

[0216] a) Make compound (X)

[0217]

[0218] Reaction with NH4OH yields compounds of formulas (IXa) and (IXb). ;

[0219] b) React compounds of formula (IXa) and (IXb) with 1-bromo-2,2-dimethoxypropane in the presence of p-toluenesulfonic acid pyridinium salt to give compound (VIII).

[0220] ,

[0221] c) Reacting the compound of formula (VIII) with carbon monoxide in the presence of a catalyst (such as Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf), CH2Cl2, PdCl2(dppp), especially in the presence of PdCl2(dppf), and in the presence of a base (especially a tertiary amine), acetonitrile, and water and a solvent, more particularly wherein the solvent is selected from MeOH, EtOH, iPrOH, AmOH, n-PrOH, DMF, DMA, toluene, THF or 2-Me-THF, and most particularly wherein the solvent is acetonitrile and water, as described above, to obtain the compound of formula (VII).

[0222]

[0223] d) Make the compound of formula (VII)

[0224] The reaction with oxalyl chloride, particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF, and dichloromethane, most particularly wherein the solvent is dichloromethane, as previously described, yields the compound of formula (VI).

[0225] ,

[0226] e) Reacting the compound of formula (VI) with 2,2-dimethyl-1,3-dioxane-4,6-dione (also known as a Meldrum acid), particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF as well as dichloromethane, most particularly wherein the solvent is dichloromethane, as described above, to obtain the compound of formula (V) or its tautomer.

[0227] ;

[0228] f) Reacting a compound of formula (V) or its tautomer with oxalyl chloride, particularly in the presence of a solvent, especially wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, and more particularly from 2-MeTHF and THF, and dichloromethane, most particularly wherein the solvent is dichloromethane, particularly as described above, to obtain a compound of formula (IV).

[0229]

[0230] g) React compound (IV) with compound (IVa):

[0231]

[0232] The reaction is carried out, particularly in the presence of a tertiary amine, especially when the tertiary amine is selected from triethylamine, tripropylamine, diisopropylethylamine, or tributylamine, and most particularly when the tertiary amine is tributylamine, especially in the presence of a solvent, especially when the solvent is selected from dichloromethane, MeTHF, or THF, and most particularly when the solvent is dichloromethane, as previously described, to obtain the compound of formula (III).

[0233] ,

[0234] h) Heating a mixture of compounds of formula (III), particularly at a temperature above 70°C, particularly between 80°C and 120°C, more particularly between 90°C and 110°C, and most particularly at 92°C ± 5°C, particularly in the presence of a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, tert-butanol, n-butanol, or isobutanol, wherein the solvent is n-propanol, n-butanol, or isopropanol, particularly n-propanol, as previously described, to obtain compounds of formula (II).

[0235] ,

[0236] i) React the compound of formula (II) with a strong acid, particularly sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, especially methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more particularly hydrochloric acid, especially wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, as described above, to obtain the compound of formula (I).

[0237] In another embodiment (aspect 16), the present invention provides a compound of formula (II):

[0238] .

[0239] In another embodiment (aspect 17), the present invention provides a compound of formula (III):

[0240] .

[0241] In another embodiment (aspect 18), the present invention provides a compound of formula (IV):

[0242] .

[0243] In another embodiment (aspect 19), the present invention provides a compound of formula (V) or a tautomer thereof:

[0244] .

[0245] In another embodiment (aspect 20), the present invention provides a compound of formula (VI):

[0246] .

[0247] In another embodiment, according to any of the embodiments described in aspects 9 to 12, the steps are overlapping.

[0248] In any particular embodiment of any of the embodiments of the invention disclosed herein, step b) of obtaining the compound of formula (VIII) is optionally followed by at least one purification step, in particular, wherein the purification step is reverse crystallization. Reverse crystallization is optionally followed by chromatographic purification.

[0249] The starting materials and reagents for the synthetic routes not explicitly disclosed herein are generally available from commercial sources or can be readily prepared using methods well known to those skilled in the art.

[0250] Generally speaking, the nomenclature used in this case is based on AUTONOM. TM 2000, which is the Beilstein Institute computerized system used to generate the IUPAC system name. The chemical structures shown in this paper were prepared using MDL ISIS™ version 2.5SP2. Any open valence on the carbon, oxygen, or nitrogen atoms in the structures presented in this paper indicates the presence of a hydrogen atom.

[0251] The following embodiments are provided for illustrative purposes and are not intended to limit the scope of the claimed invention.

[0252] In this application, the following abbreviations and definitions are used: AmOH (Amzl alcohol); br (broad peak); BuLi (butyllithium); CDCl3 (deuterated chloroform); d (bimodal); 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 (isotope spin population); KOH (potassium hydroxide); LDA (lithium diisopropylamino); LCMS (liquid chromatography-mass spectrometry); M (molar); m (multiplex); MeOH (methanol); MS (mass spectrometry); mL (milliliter); NaOH (sodium hydroxide); NMP (N-methyl-2-pyrrolidone); NMR (nuclear magnetic resonance); Pd(Xantphos)Cl2 (dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)-[oxanthracene]]palladium(II)); n-PrOH (n-propanol); s (single); sec (second); t (triple); t-Bu Brett Phos (2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl); THF (tetrahydrofuran); 2-Me-THF (2-methyltetrahydrofuran).

[0253] Example 1: tert-butyl 7-(6-nitropyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0254]

[0255] 5-Bromo-2-nitropyridine (800 g, 3.94 mol, Eq: 1.00) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (944 g, 4.45 mol, Eq: 1.13) were added to the reactor, followed by acetonitrile (1.57 kg, 2 l, Eq: -). A suspension of anhydrous potassium carbonate (1.5 kg, 10.9 mol, Eq: 2.75) in acetonitrile (2.36 kg, 3 l, Eq: -) was added. The suspension was stirred and heated at 80 °C for 3 days.

[0256] The resulting orange suspension was cooled to 50°C, and water (12 kg, 12 L, Eq:-) (solution) was added over approximately 10 minutes. The suspension was rapidly obtained and cooled to 20°C. After maintaining this temperature at 20°C for 1 hour, the suspension was filtered. The filter cake was washed sequentially with water (3 kg, 3 L, Eq:-), ethanol (1.58 kg, 2 L, Eq:-), and MTBE (740 g, 1 L, Eq:-). The filter cake was transferred to a reactor along with ethanol (7.1 kg, 9 L, Eq:-) and toluene (865 g, 1 L, Eq:-). The suspension was heated to 60°C and stirred for 1 hour, then cooled to 20°C over 2 hours. The suspension was stirred overnight and filtered. The filter cake was washed with ethanol (800 mL) and dried at 50 °C / < 10 mbar for one weekend to give 737 g of product (purity 99.5% as determined by HPLC). LCMS: 335.17 (M+1).

[0257] Example 2: tert-butyl 7-(6-aminopyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0258]

[0259] 230 g of tert-butyl 7-(6-nitropyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (1 eq., 2.09 mol) was hydrogenated in an AcOEt (7 L, 6.3 kg) with wet 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 (total approximately 700 g SM) and the combined products were concentrated to a volume of approximately 1 L. Heptane (3 L) was added, and the mixture was solvent-exchanged for heptane at a constant volume. The resulting suspension was diluted with heptane (1 L) and filtered. The filter cake was washed with heptane and dried to constant weight at 50 °C / <10 mbar to give 610 g of the title product (purity >99.5 a% as determined by LC).

[0260] Example 3: 6-Chloro-2,8-dimethylimidazo[1,2-b]pyridazine

[0261]

[0262] 3,6-Dichloro-4-methylpyridazine (200 g, 1 eq., 1.23 mol) and 25% NH4OH aqueous solution (1.8 kg, 2 L) were added to an autoclave. The reaction mixture was heated at 100 °C for 18 hours (approximately 7 bar pressure), and then cooled to RT. The suspension was transferred to another reactor. The autoclave was washed with water (1 L). The combined suspensions were stirred overnight at RT and filtered. The filter cake was washed with cold (0–5 °C) water (1 L) and dried at 50 °C / < 10 mbar.

[0263] The reaction was repeated three times to obtain a total of approximately 334 g of aminochloropyridazine intermediates, which were a mixture of isomers.

[0264] The crude intermediate product (384 g) and pyridinium p-toluenesulfonate (43 g, 171 mmol, Eq: 0.0736) were added to a reactor, followed by the addition of 2-propanol (1.96 kg, 2.5 L, Eq: -). The resulting suspension was heated to 80 °C, and 1-bromo-2,2-dimethoxypropane (521 g, 385 ml, 2.79 mol, Eq: 1.20) was added over 25 minutes. The reaction mixture was stirred overnight and cooled to RT. At RT, a 1M aqueous solution of NaOH (3.78 kg, 2.8 L, 2.8 mol, Eq: 1.2) was added over 30 minutes. The suspension was partially concentrated under reduced pressure at approximately 60 °C (distillation of approximately 3 L), during which a solution was obtained, and then the suspension was obtained again. 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. The suspension was filtered after stirring for 1 hour. The filter cake was washed with water (2.00 kg, 2 L) and dried under reduced pressure at 50 °C to give 305 g of product, a mixture of isomers. The crude product was digested in approximately 1.5 L of AcOEt. The suspension was filtered, and the filter cake (containing mainly undesirable isomers) was discarded. The filtrate was concentrated and purified by chromatography (SiO2 / AcOEt) to give 128 g of product (purity > 97% by LC, no undesirable isomers detected) LC-MS: 182 (M+1).

[0265] Example 4: 2,8-Dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid

[0266]

[0267] 6-Chloro-2,8-dimethylimidazo[1,2-b]pyridazine (400 g, 1 eq., 2.2 mol) in a mixture of acetonitrile (3.2 L, 2.52 kg) and water (0.8 L, 0.8 kg) was carbonylated at 90 °C for 48 h with PdCl2(dppp) (13 g, 0.01 eq.), triethylamine (448 g, 617 mL, 2 eq.), 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 / 60 °C. The solution was azeotropically heated at a constant volume. The resulting suspension was cooled to RT, and dichloromethane (8 L) was added, followed by 5-6 N hydrochloric acid (400 g, 440 mL, 1.1 eq) in iPrOH. The suspension was further filtered for 1 hour and concentrated. The filter cake was washed with dichloromethane (5 L) and dried at 50 °C / < 10 mabr until constant weight was achieved to give 397 g of the title product (99.8 a% LC, 0.5% KFT). LCMS: 192.07 (M+1)

[0268] Example 5: 7-(4-(tert-butoxycarbonyl)-4,7-diazaspiro[2.5]octane-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid

[0269]

[0270] 2,8-Dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid (300 g, 1.57 mol, Eq: 1) and DMAP (422 g, 3.45 mol, Eq: 2.2) were added to the reactor, followed by DCM (7.92 kg, 6 l, Eq: -) and DMF (132 g, 140 ml, 1.81 mol, Eq: 1.15). The mixture was heated to 40 °C, during which time a solution was obtained. Oxaloyl chloride (203 g, 138 ml, 1.57 mol, Eq: 1) in a solution of DCM (792 g, 0.6 l, Eq: -) was added dropwise over approximately 45 minutes. After the reaction was complete (to obtain INT-1, < 30 min, IPC by LC after derivatization), the resulting suspension was cooled to RT and added at RT to a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum acid) (294 g, 2.04 mol, Eq: 1.3) and DMAP (192 g, 1.57 mol, Eq: 1) in DCM (5.28 kg, 4 l, Eq: -). After reacting for 1 hour (to obtain INT-2, IPC check), oxalyl chloride (184 g, 125 ml, 1.42 mol, Eq: 0.905) in DCM (330 g, 250 ml, Eq: -) was added over 30 min. Add an additional dose of oxalyl chloride (“titration”) until the amount of intermediate INT-2 is < 2a% (total oxalyl chloride: 68 g / 0.34 eq). After deoxychlorination (to obtain INT-3), add a solution of tert-butyl 7-(6-aminopyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (430 g, 1.41 mol, Eq: 0.9) and tributylamine (594 g, 764 ml, 3.14 mol, Eq: 2) in DCM (1.58 kg, 1.2 l, Eq: -). Stir the reaction mixture overnight and concentrate (to obtain crude INT-4). Add propanol (3 L) and concentrate the mixture. Repeat the last two steps. Propanol (6 L) was added, and the reaction mixture was heated under reflux overnight to induce cyclization, yielding a crude mixture containing INT-5.

[0271] In a separate reactor, acetyl chloride (829 g, 750 mL, 10.5 mol, Eq: 7.16) was added to 1-propanol (2.56 kg, 3.2 L, Eq: -) at a temperature maintained between 10 and 20 °C. After the reaction was complete, the hydrochloric acid solution in propanol was heated to 60 °C, and the previously prepared crude INT-5 solution (heated to 90 °C to obtain a solution, then cooled to 60 °C) was added dropwise over 25 minutes at 60 °C (thus achieving Boc deprotection and approximately 20% decarboxylation). The resulting reaction mixture was refluxed (decreasing from approximately 92 °C to 89 °C over time) overnight to complete decarboxylation. The reaction mixture was cooled to RT and filtered. The filter cake was washed with propanol. The filter 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, Eq: 1.28) was added to adjust the pH to 13, during which the product crystallized. The suspension was heated at approximately 50 °C for 24 hours. The suspension was cooled to RT over 15 hours and filtered. The filter cake was washed with a 1:2 ethanol / water mixture (2 L). The filter cake was dried at 50 °C under vacuum in a water-saturated atmosphere to give 384 g of the trihydrate product (purity determined by LC: 98% a%, water: 12.4% m / m).

Claims

1. A method for preparing formula (IV) compounds, It includes compounds of formula (V) or their tautomers. The reaction with oxalyl chloride is particularly carried out in the presence of a solvent, more particularly wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly 2-MeTHF and THF and dichloromethane, and most particularly wherein the solvent is dichloromethane.

2. A method for preparing compounds of formula (V), It includes compounds of formula (VII). The reaction with oxalyl chloride, the reaction being carried out particularly in the presence of a solvent, more particularly wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, followed by the addition of 2,2-dimethyl-1,3-dioxane-4,6-dione, also known as Meldrum acid, wherein DMAP is present, more particularly wherein 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).

3. A method for preparing a compound of formula (V), It includes compounds of formula (VI). ； The reaction is carried out with 2,2-dimethyl-1,3-dioxane-4,6-dione, also known as Meldrum acid, particularly in the presence of a solvent, more particularly wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, wherein DMAP is present, more particularly wherein 2.0 to 2.5 equivalents, more particularly 2.2 to 2.4 equivalents, and most preferably about 2.3 equivalents of DMAP are present relative to the theoretical amount of the compound of formula (VI).

4. A method for preparing compounds of formula (VI), It includes compounds of formula (VII). The reaction with oxalyl chloride, the reaction being carried out particularly in the presence of a solvent, more particularly wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, particularly wherein DMAP is present, more particularly wherein 1.5 to 4.0 equivalents, more particularly 2.0 to 3.0 equivalents, and most preferably about 2.0 equivalents of DMAP are present relative to the theoretical amount of the compound of formula (VII).

5. A compound of formula (IV), (V), or (V-tautomer): ， or .

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