Process for the preparation of riluzole

Abstract

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

Description

[0001] The present invention relates to a process for the preparation of 7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)pyrido[l,2-a]pyrimidin-4-one useful as a pharmaceutically active compound.

[0002] In a first aspect, the present invention provides a process for the preparation of a compound of formula (I):

[0003]

[0004] comprising reacting a compound of formula (II):

[0005]

[0006] with a strong acid, in particular sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, in particular methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more particularly hydrochloric acid, most particularly wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, to effect decarboxylation and Boc-deprotection.

[0007] According to a first embodiment, the process wherein anhydrous hydrochloric acid is used. It can also be prepared in situ with an alcohol and acetyl chloride, in particular methanol, ethanol, n-propanol, isopropanol or n-butanol and acetyl chloride, in particular n-propanol and acetyl chloride.

[0008] In a particular embodiment, after the addition of the strong acid and the reaction to effect Boc deprotection and decarboxylation, the pH of the resulting acid solution of I is adjusted via the addition of a base to isolate the free base.

[0009] In particular, the preparation of the compound of formula (I) is carried out in the presence of an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol or n-butanol, in particular n-propanol or isopropanol, more particularly n-propanol.

[0010] In a particular embodiment, the present invention provides a process 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.

[0011] In another embodiment, the present invention provides a process for the preparation of a compound of formula (I) as described above, wherein the reaction is carried out at a temperature between 80 °C and 120 °C, in particular between 85 °C and 100 °C, more particularly between 85 °C and 95 °C.

[0012] In another embodiment, the present application provides a process as described herein, wherein the hydrochloric acid is prepared in situ with acetyl chloride in n-propanol at between 0-60 °C, in particular between 0-40 °C during the addition of acetyl chloride followed by heating up to 60 °C, more in particular between 10-20 °C at atmospheric pressure during the addition of acetyl chloride followed by heating up to 60 °C.

[0013] In another embodiment, the present application provides a process as described herein, wherein to reach a temperature above the boiling point, the solvent requires a pressurized reactor.

[0014] 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[l,2-b]pyridazin-6-yl)pyrido[l,2- a]pyrimidin-4-one as described in WO2015173181.

[0015] The following terms as used in the present specification and claims have the following given meanings, unless stated otherwise:

[0016] “(C1-C6)alkyl” denotes a branched or straight hydrocarbon chain having from one to six carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl.

[0017] The term “(C3-C8)cycloalkyl” denotes a saturated monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Examples of monocyclic (C3-C8)cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0018] “Base” refers to a compound that, when reacted with another compound, deprotonates that other compound. Suitable bases as used in the present disclosure include, but are not limited to, for example, 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 and potassium alkoxides (including, but not limited to, sodium and potassium tert-butoxide, n-propoxide, isopropoxide, ethoxide, methoxide, and the like), sodium amide (NaNH2), potassium amide (KNH2), and the like.

[0019] “Crystallization” and “recrystallization” are used interchangeably; refer to the process of a compound dissolved or suspended in a solvent system to produce a stable polymorph or crystal form of the particular compound. For example, a crystallization step can be accomplished by forming crystals with a solvent and an antisolvent.

[0020] "Strong acid" refers to an acid that is completely dissociated in aqueous solution, having a pKa < -1.74. Strong acids include, but are not limited to, sulfuric acid (H2SO4), a hydrohalic acid (i.e., HX", where X" is I, Br, CI, or F), methanesulfonic acid, trifluoromethanesulfonic acid, nitric acid (HNO3), phosphoric acid (H3PO4), and combinations thereof. In particular, the strong acid is a hydrohalic acid, where X" is Br or CI. Most particularly, the strong acid is hydrochloric acid.

[0021] "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 (Ci-C6)alkyl, (C3-C8)cycloalkyl, or phenyl. 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. Most preferred tertiary amine is tributylamine.

[0022] "ambient conditions" or "room temperature" refers to conditions experienced in a standard laboratory, e.g., atmospheric pressure, under Ar or N2, ambient temperature between 18 °C and 28 °C.

[0023] In a particular embodiment of the first aspect, the present application provides a process for preparing a compound of formula (I), a hydrate, solvate thereof, or a hydrochloride salt thereof:

[0024]

[0025] comprising reacting a compound of formula (II):

[0026]

[0027] with hydrochloric acid, most particularly, wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, to give a compound of formula (IIa) or formula (IIb), which is then converted to a compound of formula (I)

[0028]

[0029] In another aspect (Aspect 1'), the present application provides a process for preparing a compound of formula (I), a hydrate, solvate thereof, or a hydrochloride salt thereof:

[0030]

[0031] comprising reacting a compound of formula (IIa):

[0032]

[0033] with hydrochloric acid, most particularly wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, to give a compound of formula (I). In a more particular embodiment, the present process can be heated.

[0034] In another aspect (aspect 2), the present application provides a process for preparing a compound of formula (II):

[0035]

[0036] which comprises heating a mixture of a compound of formula (III), particularly at a temperature above 70 °C, in particular between 80 °C and 120 °C, more particularly between 90 °C and 110 °C, most particularly at 92 °C ± 2 °C, 5 °C, in a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, tert-butanol, n-butanol, isobutanol, wherein the solvent is n-propanol or n-butanol or isopropanol, in particular n-propanol.

[0037]

[0038] The heating is particularly in the presence of a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, tert-butanol, n-butanol, isobutanol, wherein the solvent is n-propanol or n-butanol or isopropanol, in particular n-propanol.

[0039] In a particular aspect 2, the present application provides a process for preparing a compound of formula (II):

[0040]

[0041] which comprises heating a mixture of a compound of formula (III) in n-propanol at 92 °C ± 2 °C, 5 °C, in a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, tert-butanol, n-butanol, isobutanol, wherein the solvent is n-propanol or n-butanol or isopropanol, in particular n-propanol.

[0042]

[0043] In yet another aspect (aspect 3), the present application provides a process for preparing a compound of formula (III),

[0044]

[0045] which comprises reacting a compound of formula (IV)

[0046]

[0047] with a compound of formula (IVa):

[0048]

[0049] The reaction is in particular carried out in the presence of a tertiary amine, more in particular when the tertiary amine is selected from the group consisting of triethylamine, tripropylamine, diisopropylethylamine, tributylamine, most in particular when the tertiary amine is tributylamine, in particular in the presence of a solvent, more in particular wherein the solvent is selected from the group consisting of dichloromethane, MeTHF, THF, most in particular wherein the solvent is dichloromethane.

[0050] The amount of compound of formula (IVa) is adjusted so as to ensure an efficient conversion of the compound of formula (IV) into the compound of formula (III) while avoiding unnecessary excess.

[0051] In a particular embodiment of aspect 3, the present application provides a process as described herein, wherein 0.8 to 1.2 equivalents, more in particular 0.85 to 1 equivalent, most in particular about 0.9 equivalents of compound of formula (IVa) are used relative to the theoretical amount of compound of formula (IV). It is noted that using less than the stoichiometric amount, in particular 0.9 equivalents of compound of formula (IVa) relative to the theoretical amount of compound of formula (IV), results in the best yield and the least impurities.

[0052] In another embodiment of aspect 3, the present application provides a process 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, in particular between 20 °C and 30 °C, more in particular about 25 °C ± 5 °C.

[0053] In yet another aspect (aspect 4), the present application provides a process for preparing a compound of formula (IV),

[0054]

[0055] comprising reacting a compound of formula (V) or its corresponding tautomer

[0056]

[0057] with oxalyl chloride, the reaction being in particular carried out in the presence of a solvent, more in particular wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more in particular from 2-MeTHF and THF and dichloromethane, most in particular wherein the solvent is dichloromethane.

[0058] In a particular embodiment of aspect 4, the present application provides a process as described herein, wherein 0.9 to 1.4 equivalents, in particular 0.9 to 1.3 equivalents, more in particular 0.9 to 1.2 equivalents of oxalyl chloride are used relative to the theoretical amount of compound of formula (V). In a more particular embodiment, oxalyl chloride is titrated to 0.9 equivalents up to 1.2 to 1.3 equivalents relative to the theoretical amount of compound of formula (V).

[0059] In a particular embodiment of aspect 4, the present application provides a process as described herein, wherein the compound of formula (V) is chlorinated and dehydrated by oxalyl chloride by conversion in HPLC.

[0060] In another embodiment of aspect 4, the present application provides a process as described above for preparing a compound of formula (IV), wherein the reaction is carried out at a temperature between 0 °C and 40 °C, in particular between 15 °C and 30 °C, more particularly at 20 °C ± 5 °C.

[0061] In yet another aspect (aspect 5), the present application provides a process for preparing a compound of formula (V),

[0062]

[0063] comprising reacting a compound of formula (VI)

[0064]

[0065] with 2,2-dimethyl-1,3-dioxan-4,6-dione (also known as Meldrum’s acid), the reaction being carried out in particular in the presence of a solvent, more particularly wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly selected from 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane.

[0066] In a particular embodiment of aspect 5, the present application provides a process as described above, wherein DMAP is present, more particularly wherein 2.5 to 5.0 equivalents, more particularly 3.0 to 4.0 equivalents, most preferably about 3.2 equivalents of DMAP are present relative to the theoretical amount of 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’s acid addition steps when the process of aspect 5 overlaps with the process of aspect 6.

[0067] In a particular embodiment of aspect 5, wherein the compound of formula VI is isolated, the present application provides a process as described herein, wherein 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-dioxan-4,6-dione are used relative to the theoretical amount of compound of formula (VI).

[0068] In another embodiment of aspect 5, the present application provides a process as described above for preparing a compound of formula (V), wherein the reaction is carried out at a temperature between 0 °C and 40 °C, in particular between 15 °C and 30 °C, more particularly at 20 °C ± 5 °C.

[0069] In another embodiment, the present application provides a process for preparing a compound of formula (V) as described above, wherein aspects 5 and 6 overlap.

[0070] In yet another aspect (aspect 5'), the present application provides a process for preparing a compound of formula (V),

[0071]

[0072] comprising reacting a compound of formula (VII)

[0073]

[0074] with oxalyl chloride, which reaction is particularly carried out in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from the group consisting of 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's acid), wherein DMAP is present, more particularly wherein 2.5 to 5.0 equivalents, more particularly 3.0 to 4.0 equivalents, most preferably about 3.2 equivalents of DMAP are present relative to the theoretical amount of the compound of formula (VII).

[0075] In another embodiment of aspect 5', the present application provides a process for preparing a 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, more particularly at 20 °C ± 5 °C.

[0076] In yet another aspect (aspect 6), the present application provides a process for preparing a compound of formula (VI),

[0077]

[0078] comprising reacting a compound of formula (VII)

[0079]

[0080] with oxalyl chloride, which reaction is particularly carried out in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from the group consisting of 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane.

[0081] In a particular embodiment of aspect 6, the present application provides a process as described above, wherein DMAP is present, more particularly wherein 1.5 to 4.0 equivalents, more particularly 2.0 to 3.0 equivalents, most preferably about 2.0 equivalents of DMAP are present relative to the theoretical amount of the compound of formula (VII).

[0082] Surprisingly it was found that the solubility of the DMAP salt of the compound of formula (VII) in dichloromethane is increased compared to the compound of formula (VII) which is advantageous for mass transfer during the formation of the corresponding acyl chloride.

[0083] In a particular embodiment of aspect 6, the present application provides a process as described above, wherein 1 to 1.1 equivalents, most particularly 1 equivalent of oxalyl chloride relative to the compound of formula (VII) are used.

[0084] In a particular embodiment of aspect 6, the present application provides a process as described herein, wherein particularly 1.15 equivalents of DMF are used.

[0085] In another embodiment of aspect 6, the present application provides a process for preparing a compound of formula (VI) as described above, wherein the reaction is carried out at a temperature between 10°C ± 2°C to 40°C ± 2°C, particularly between 25°C ± 2°C to 40°C ± 2°C, more particularly between 35°C ± 2°C and 40°C ± 2°C.

[0086] In yet another aspect (aspect 7), the present application provides a process for preparing a compound of formula (VII),

[0087]

[0088] comprising reacting a compound of formula (VIII)

[0089]

[0090] with carbon monoxide, the reaction being carried out in the presence of a catalyst, such as Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), particularly in the presence of PdCl2(dppf), and in the presence of a base, particularly a tertiary amine, acetonitrile, and in the presence of 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, most particularly wherein the solvent is acetonitrile and water.

[0091] In a particular embodiment of aspect 7, the present application provides a process as described herein, wherein 1 to 150 bar, particularly 20 to 70 bar, most particularly 50 to 70 bar of carbon monoxide relative to the compound of formula (VIII) are used.

[0092] In a particular embodiment of aspect 7, the present application provides a process as described herein, wherein 0.01 to 10 mol%, more particularly 0.1 to 2 mol%, most particularly 0.5 to 1.5 mol% of catalyst relative to the compound of formula (VIII) is used.

[0093] In a particular embodiment of aspect 7, the present application provides a process as described herein, wherein 0.1 to 10 equivalents, more particularly 1.5 to 2.5 equivalents of tertiary amine relative to the compound of formula (VIII) is used.

[0094] In another embodiment of aspect 7, the present application provides a process for preparing a compound of formula (VII) as described above, wherein the reaction is carried out at a temperature comprised between 20°C ± 2°C to 150°C ± 2°C, in particular between 60°C ± 2°C to 110°C ± 2°C, more particularly between 80°C ± 2°C and 100°C ± 2°C.

[0095] In yet another aspect (aspect 8), the present application provides a process for preparing a compound of formula (VIII),

[0096]

[0097] comprising:

[0098] a) reacting a compound of formula (X)

[0099] with NH4OH to give a compound of formula (IXa) and (IXb);

[0100] b) reacting the compound of formula (IXa) and (IXb)

[0101]

[0102] with 1-bromo-2,2-dimethoxypropane in the presence of pyridinium p-toluenesulfonate to give a compound of formula (VIII). Step b) is optionally followed by at least one purification step, in particular wherein the purification step is recrystallization. The recrystallization is optionally followed by chromatographic purification.

[0103] In yet another aspect (aspect 8’), the present application provides a process for preparing a compound of formula (VIII),

[0104]

[0105] comprising:

[0106] a) reacting a compound of formula (X)

[0107] with NH4OH to give a compound of formula (IXa).

[0108] b) reacting the compound of formula (IXa)

[0109]

[0110] with 1-bromo-2,2-dimethoxypropane in the presence of pyridinium p-toluenesulfonate to obtain a compound of formula (VIII). Step b) is optionally followed by at least one purification step, in particular wherein the purification step is recrystallization. The recrystallization is optionally followed by chromatographic purification.

[0111] Alternatively, the compound of formula (VIII) can be prepared according to the method described in WO2015173181 and the method described in WO2019057740.

[0112] Compared to the method described in WO2015173181, the purity of the crude compound of formula (VIII) can be improved by recrystallization, removing most of the undesired regioisomer resulting from the compound of formula (IXb), to facilitate the final chromatographic purification.

[0113] In particular embodiments, the present application provides a method as described herein according to aspect 8, wherein steps a) and b) are overlapping.

[0114] The compound of formula (IVa) can be prepared according to the following steps:

[0115]

[0116] comprising reacting a compound of formula (IVb)

[0117]

[0118] with a heterogeneous transition metal hydrogenation catalyst, in particular wherein the heterogeneous transition metal hydrogenation catalyst is a Raney catalyst (e.g. Ra-Ni, Ra-Co), Pd / C, Pd(OH)2 / C, Pd / Al203, Au / Ti02, Rh / C, Ru / Al203, Ir / CaC03, Pt-V / C or Pt / C or a combination thereof, in particular Pt-V / C, more particularly Pt 1% and V 2% on activated carbon. In particular, to prepare the compound of formula (IVa), the reaction is carried out at a temperature comprised between 0°C ± 2°C and 150°C ± 2°C, in particular between 15°C ± 2°C and 70°C ± 2°C, more particularly between 20°C ± 2°C and 35°C ± 2°C.

[0119] The compound of formula (IVb) can also be prepared according to scheme 1.

[0120] Scheme 1:

[0121]

[0122] Compounds of formula (IVa and IVb) can also be prepared by the methods described in WO2019057740.

[0123] In another embodiment (aspect 9), the present application provides a process for preparing a compound of formula (I) or its hydrochloride salt:

[0124]

[0125] comprising

[0126] a) heating a mixture of compounds of formula (III), in particular at a temperature higher than 70 °C, in particular between 80 °C and 120 °C, more particularly between 90 °C and 110 °C, most particularly at 92 °C ± 5 °C,

[0127]

[0128] in particular in the presence of a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, tert-butanol, n-butanol, isobutanol, wherein the solvent is n-propanol or n-butanol or isopropanol, in particular n-propanol, as described before, to give a compound of formula

[0129] (II)

[0130]

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

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

[0133]

[0134] comprising

[0135] a) reacting a compound of formula (IV)

[0136]

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

[0138]

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

[0140]

[0141] b) heating the mixture of the compound of formula (III), particularly heating at a temperature higher than 70 °C, particularly between 80 °C and 120 °C, more particularly between 90 °C and 110 °C, most particularly at 92 °C ± 5 °C, the heating being particularly carried out in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of isopropanol, n-propanol, t-butanol, n-butanol, isobutanol, wherein the solvent is n-propanol or n-butanol or isopropanol, particularly n-propanol, as described previously, to yield a compound of formula (II)

[0142]

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

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

[0145]

[0146] which comprises

[0147] a) reacting a compound of formula (V) or its tautomer

[0148]

[0149] with oxalyl chloride, the reaction being particularly carried out in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, as described previously, to yield a compound of formula (IV)

[0150]

[0151] b) reacting the compound of formula (IV) with a compound of formula (IVa):

[0152]

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

[0154]

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

[0156]

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

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

[0159]

[0160] comprising

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

[0162]

[0163] with 2,2-dimethyl-1,3-dioxane-4,6-dione (also known as Meldrum’s 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 selected from 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, as described previously, to give a compound of formula (V) or its tautomer

[0164]

[0165] b) reacting the compound of formula (V) or a tautomer thereof with oxalyl chloride, particularly in the presence of a solvent, more particularly wherein the solvent is selected from dichloromethane, 2-

[0166] MeTHF, THF, DMF, NMP, more particularly selected from 2-MeTHF and THF

[0167] and dichloromethane, most particularly wherein the solvent is dichloromethane, as described previously, to give a compound of formula (IV)

[0168]

[0169] c) reacting the compound of formula (IV) with a compound of formula (IVa):

[0170]

[0171] the reaction particularly being carried out in the presence of a tertiary amine, more particularly when the tertiary amine is selected from triethylamine, tripropylamine, diisopropylethylamine, tributylamine, most particularly when the tertiary amine is tributylamine, particularly in the presence of a solvent, more particularly wherein the solvent is selected from dichloromethane, MeTHF or THF, most particularly wherein the solvent is dichloromethane, as described previously, to give a compound of formula (III)

[0172]

[0173] d) heating the mixture of the compound of formula (III), particularly at a temperature greater than 70 °C, particularly between 80 °C and 120 °C, more particularly between 90 °C and 110 °C, most particularly at 92 °C ± 5 °C, the heating particularly being carried out in the presence of a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, t-butanol, n-butanol, isobutanol, wherein the solvent is n-propanol or n-butanol or isopropanol, particularly n-propanol, as described previously, to give a compound of formula (II)

[0174]

[0175] e) reacting the compound of formula (II) with a strong acid, particularly sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, particularly methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more particularly hydrochloric acid, most particularly wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, as described previously, to give a compound of formula (I).

[0176] In another embodiment (aspect 13), the present application provides a process for preparing a compound of formula (I) or a hydrochloride salt thereof:

[0177]

[0178] comprising

[0179] a) reacting a compound of formula (VII)

[0180]

[0181] with oxalyl chloride, particularly in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly selected from the group consisting of 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, as described previously, to give a compound of formula (VI)

[0182]

[0183] b) reacting a compound of formula (VI) with 2,2-dimethyl-1,3-dioxane-4,6-dione (also known as Meldrum’s acid), particularly in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly selected from the group consisting of 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, as described previously, to give a compound of formula (V) or a tautomer thereof

[0184]

[0185] c) reacting a compound of formula (V) or a tautomer thereof with oxalyl chloride, particularly in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly selected from the group consisting of 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, as described previously, to give a compound of formula (IV)

[0186]

[0187] d) reacting a compound of formula (IV) with a compound of formula (IVa):

[0188]

[0189] particularly in the presence of a tertiary amine, more particularly when the tertiary amine is selected from the group consisting of triethylamine, tripropylamine, diisopropylethylamine, tributylamine, most particularly when the tertiary amine is tributylamine, particularly in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, MeTHF, THF, most particularly wherein the solvent is dichloromethane, as described previously, to give a compound of formula (III)

[0190]

[0191] e) heating the mixture of compounds of formula (III), in particular at a temperature higher than 70 °C, in particular between 80 °C and 120 °C, more particularly between 90 °C and 110 °C, most particularly at 92 °C ± 5 °C, the heating being in particular performed in the presence of a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, t-butanol, n-butanol, isobutanol, wherein the solvent is n-propanol or n-butanol or isopropanol, in particular n-propanol, as described previously, to give a compound of formula (II)

[0192]

[0193] f) reacting the compound of formula (II) with a strong acid, in particular sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, in particular methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more particularly hydrochloric acid, most particularly wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, as described previously, to give a compound of formula (I).

[0194] In another embodiment (aspect 14), the present application provides a process for preparing a compound of formula (I) or its hydrochloride salt:

[0195]

[0196] which comprises

[0197] a) reacting a compound of formula (VIII)

[0198]

[0199] with carbon monoxide, the reaction being performed in the presence of a catalyst, in particular Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2,

[0200] PdCl2(dppp), in particular in the presence of PdCl2(dppf), in the presence of a base, in particular a tertiary amine, acetonitrile, and in the presence of water and a solvent, more particularly wherein the solvent is selected from MeOH, EtOH, iPrOH, AmOH, n-PrOH,

[0201] DMF, DMA, toluene, THF or 2-Me-THF, most particularly wherein the solvent is acetonitrile and water, as described previously, to give a compound of formula (VII)

[0202]

[0203] b) reacting a compound of formula (VII)

[0204] with oxalyl chloride, in particular in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from the group consisting of 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, as described before, to give a compound of formula (VI)

[0205]

[0206] c) reacting a compound of formula (VI) with 2,2-dimethyl-1,3-dioxane-4,6-dione (also known as Meldrum’s acid), in particular in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from the group consisting of 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, as described before, to give a compound of formula (V) or

[0207] a tautomer thereof

[0208]

[0209] d) reacting a compound of formula (V) or a tautomer thereof with oxalyl chloride, in particular in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from the group consisting of 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, as described before, to give a compound of formula (IV)

[0210]

[0211] e) reacting a compound of formula (IV) with a compound of formula (IVa):

[0212]

[0213] in particular in the presence of a tertiary amine, more particularly when the tertiary amine is selected from the group consisting of triethylamine, tripropylamine, diisopropylethylamine, tributylamine, most particularly when the tertiary amine is tributylamine, in particular in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, MeTHF or THF, most particularly wherein the solvent is dichloromethane, as described before, to give a compound of formula (III)

[0214]

[0215] f) heating the mixture of compounds of formula (III), in particular at a temperature higher than 70 °C, in particular between 80 °C and 120 °C, more particularly between 90 °C and 110 °C, most particularly at 92 °C ± 5 °C, in particular under the presence of a solvent, more particularly wherein the solvent is selected from isopropanol, n-propanol, t-butanol, n-butanol, isobutanol, wherein the solvent is n-propanol or n-butanol or isopropanol, in particular n-propanol, as described previously, to yield a compound of formula (II)

[0216]

[0217] g) reacting the compound of formula (II) with a strong acid, in particular sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, in particular methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more particularly hydrochloric acid, most particularly wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, as described previously, to yield a compound of formula (I).

[0218] In another embodiment (aspect 15), the present application provides a process for preparing a compound of formula (I) or its hydrochloride salt:

[0219]

[0220] comprising

[0221] a) reacting a compound of formula (X)

[0222]

[0223] with NH4OH to yield compounds of formula (IXa) and (IXb)

[0224]

[0225] b) reacting the compounds of formula (IXa) and (IXb) with 1-bromo-2,2- dimethoxypropane in the presence of p-toluenesulfonic acid pyridinium salt to yield a compound of formula (VIII)

[0226]

[0227] c) reacting the compound of formula (VIII) with carbon monoxide, which reaction is carried out in the presence of a catalyst, such as Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), in particular in the presence of PdCl2(dppf), and in the presence of a base, in particular a tertiary amine, acetonitrile, and in the presence of 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, most particularly wherein the solvent is acetonitrile and water, as described before, to give a compound of formula (VII)

[0228] (VIII)

[0229]

[0230] d) reacting the compound of formula (VII)

[0231] (VII) with oxalyl chloride, which reaction is 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, most particularly wherein the solvent is dichloromethane, as described before, to give a compound of formula (VI)

[0232]

[0233] e) reacting the compound of formula (VI) with 2,2-dimethyl-1,3-dioxane-4,6-dione (also known as Meldrum's acid), which reaction is 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, most particularly wherein the solvent is dichloromethane, as described before, to give a compound of formula (V) or

[0234] a tautomer thereof

[0235]

[0236] f) reacting the compound of formula (V) or a tautomer thereof with oxalyl chloride, which reaction is carried out in the presence of a solvent, more particularly wherein the solvent is selected from dichloromethane, 2-

[0237] MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, in particular as described before, to give a compound of formula (IV)

[0238] (IV)

[0239]

[0240] g) reacting a compound of formula (IV) with a compound of formula (IVa):

[0241]

[0242] The reaction is in particular carried out in the presence of, in particular in the presence of a tertiary amine, more in particular when the tertiary amine is selected from the group consisting of triethylamine, tripropylamine, diisopropylethylamine, tributylamine, most in particular when the tertiary amine is tributylamine, in particular in the presence of a solvent, more in particular wherein the solvent is selected from the group consisting of dichloromethane, MeTHF, THF, most in particular wherein the solvent is dichloromethane, as described before, to yield a compound of formula (III)

[0243]

[0244] h) heating the mixture of a compound of formula (III), in particular at a temperature higher than 70 °C, in particular between 80 °C and 120 °C, more in particular between 90 °C and 110 °C, most in particular at 92 °C ± 5 °C, the heating being in particular carried out in the presence of a solvent, more in particular wherein the solvent is selected from the group consisting of isopropanol, n-propanol, t-butanol, n-butanol, isobutanol, wherein the solvent is n-propanol or n-butanol or isopropanol, in particular n-propanol, as described before, to yield a compound of formula (II)

[0245]

[0246] i) reacting a compound of formula (II) with a strong acid, in particular sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, in particular methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more in particular hydrochloric acid, most in particular wherein the hydrochloric acid is prepared in situ with an alcohol and acetyl chloride, as described before, to yield a compound of formula (I).

[0247] In another embodiment (aspect 16), the present application provides a compound of formula (II):

[0248]

[0249] In another embodiment (aspect 17), the present application provides a compound of formula (III):

[0250]

[0251] In another embodiment (aspect 18), the present application provides a compound of formula (IV):

[0252]

[0253] In another embodiment (aspect 19), the present application provides a compound of formula (V) or a tautomer thereof:

[0254]

[0255] In another embodiment (aspect 20), the present application provides a compound of formula (VI):

[0256]

[0257] In another embodiment, according to any one of the embodiments of aspects 9 to 12, wherein the steps are overlapping.

[0258] In a particular embodiment of any one of the mentioned embodiments of the application as disclosed herein, step b) to obtain a compound of formula (VIII) is optionally followed by at least one purification step, in particular wherein the purification step is recrystallization. The recrystallization is optionally followed by chromatographic purification.

[0259] Starting materials and reagents, the synthesis routes of which are not explicitly disclosed herein, are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art.

[0260] Generally, the nomenclature used in this application is based on AUTONOM TM 2000, a Beilstein Institute computerized system for generating IUPAC systematic nomenclature. The chemical structures shown herein use MDL ISIS Draw version 1.5. TM 2.5SP2 version. Any open valency appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.

[0261] The following examples are provided for further illustration purposes and are not intended to limit the scope of the claimed application.

[0262] In this application, the following abbreviations and definitions are used: AmOH (Amz1 alcohol); br (broad); BuLi (butyllithium); CDCl3 (deuterated chloroform); d (doublet); DCM (dichloromethane); DMA (dimethylacetamide); DMAP (4-dimethylaminopyridine); DMF (dimethylformamide); eq. (equivalents); EtOH (ethanol); g (grams); GC (gas chromatography); h (hours); HC1 (hydrochloric acid); H20 (water); HPLC (high performance liquid chromatography); iPrOH (isopropanol); ISP (isotope spin population); KOH (potassium hydroxide); LDA (lithium diisopropylamide); LCMS (liquid chromatography-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(Xantphos)Cl2 (dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)-[xanthene]]palladium(II)); n-PrOH (n-propanol); s (singlet); sec (seconds); t (triplet); 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).

[0263] Example 1: 7-(6-nitropyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester

[0264]

[0265] To a reactor was added 5-bromo-2-nitropyridine (800 g, 3.94 mol, Eq: 1.00) and 4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (944 g, 4.45 mol, Eq: 1.13), 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.

[0266] The resulting orange suspension was cooled to 50 °C and water (12 kg, 12 L, Eq: -) was added over ~10 min. A suspension was quickly obtained and it was cooled to 20 °C. After 1 h at 20 °C the suspension was filtered. The filter cake was washed with water (3 kg, 3 L, Eq: -), ethanol (1.58 kg, 2 l, Eq: -) and MTBE (740 g, 1 L, Eq: -) in sequence. The filter cake was transferred to a reactor 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 h before it was cooled to 20 °C over 2 h. The suspension was stirred overnight and filtered. The filter cake was washed with ethanol (800 mL) and dried at 50 °C / <10 mbar over the weekend to yield 737 g of product (purity 99.5a% by HPLC). LCMS: 335.17 (M+1).

[0267] Example 2: 7-(6-Aminopyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester

[0268]

[0269] Example 2: 7-(6-Aminopyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester

[0270] Example 3: 6-Chloro-2,8-dimethylimidazo[l,2-b]pyridazine

[0271]

[0272] A 3,6-dichloro-4-methylpyridazine (200 g, 1 eq., 1.23 mol) and 25% aqueous NH4OH (1.8 kg, 2 L) were added to an autoclave. The reaction mixture was heated at 100 °C for 18 h (pressure ca. 7 bar) and then cooled to RT. The suspension was transferred to another reactor. The autoclave was washed with water (1 L). The combined suspension was stirred at RT overnight and filtered. The filter cake was washed with cold (0-5 °C) water (1 L) and dried at 50 °C / <10 mbar.

[0273] This reaction was repeated 3 times to give a total of ca. 334 g of the amino chloropyridazine intermediate as a mixture of isomers.

[0274] The crude intermediate product (384 g) and p-toluenesulfonic acid pyridinium salt (43 g, 171 mmol, Eq: 0.0736) were added to a reactor followed by 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 within 25 min. The reaction mixture was stirred overnight and cooled to RT. At RT, 1 M aqueous NaOH (3.78 kg, 2.8 l, 2.8 mol, Eq: 1.2) was added within 30 min. The suspension was partially concentrated (distilled ca. 3 L) under reduced pressure at ca. 60 °C to give a solution and then again a suspension. This suspension was cooled to ca. 8 °C (Tj 5 °C) within 3 h. After stirring overnight, water (3.00 kg, 3 l) was added. After stirring for 1 h, the suspension was filtered. 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 as a mixture of isomers. The crude product was taken up in ca. 1.5 L AcOEt. The suspension was filtered and the filter cake was discarded (mainly comprising the undesired isomer). The filtrate was concentrated and purified by chromatography (SiO2 / AcOEt) to give 128 g of product (purity >97a% by LC, no undesired isomer detected) LC-MS: 182 (M+1).

[0275] Example 4: 2,8-dimethylimidazo[l,2-b]pyridazine-6-carboxylic acid

[0276]

[0277] A mixture of 6-chloro-2,8-dimethylimidazo[l,2-b]pyridazine (400 g, 1 eq., 2.2 mol) in acetonitrile (3.2 L, 2.52 kg) and water (0.8 L, 0.8 kg) was carbonylated with PdCl2(dppp) (13 g, 0.01 eq.), triethylamine (448 g, 617 ml, 2 eq.) and CO (60 bar) at 90 °C for 48 h. After completion of the reaction, the reactor was cooled, evacuated and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure / 60 °C to 2.4 L. The solution was azeotroped under constant volume. The resulting suspension was cooled to RT, to which dichloromethane (8 L) was added followed by 5-6 N hydrochloric acid in iPrOH (400 g, 440 mL, 1.1 eq). The suspension was further filtered for 1 h and concentrated. The filter cake was washed with dichloromethane (5 L) and dried at 50 °C / <10 mabr until constant weight was achieved to get 397 g of the title product (99.8a% LC, 0.5% KFT). LCMS: 192.07 (M+1)

[0278] Example 5: 7-(4-(tert-butoxycarbonyl)-4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8- dimethylimidazo[l,2-b]pyridazin-6-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-3-carboxylic acid

[0279]

[0280] Add 2,8-dimethylimidazo[l,2-b]pyridazine-6-carboxylic acid (300 g, 1.57 mol, Eq: 1) and DMAP (422 g, 3.45 mol, Eq: 2.2) to a reactor, followed by DCM (7.92 kg, 6 l, Eq: -) and DMF (132 g, 140 ml, 1.81 mol, Eq: 1.15). Heat the mixture to 40 °C, during which a solution is obtained. Add a solution of oxalyl chloride (203 g, 138 ml, 1.57 mol, Eq: 1) in DCM (792 g, 0.6 l, Eq: -) dropwise over approximately 45 minutes. After completion of the reaction (to give INT-1, < 30 min, IPC by LC after derivatization), cool the resulting suspension to RT and add to a solution of 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum’s 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: -) at RT. After 1 h of reaction (to give INT-2, IPC check), add a solution of oxalyl chloride (184 g, 125 ml, 1.42 mol, Eq: 0.905) in DCM (330 g, 250 ml, Eq: -) over 30 minutes. Add one more portion of oxalyl chloride (“titration”) until the amount of intermediate INT-2 is < 2a% (total amount of oxalyl chloride: 68 g / 0.34 eq). After completion of the deoxygenation (to give INT-3), add a solution of 7-(6-aminopyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (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: -) over 20 minutes. Stir the reaction mixture overnight and concentrate (to give crude INT-4). Add propanol (3 L) and concentrate the mixture. Repeat the last 2 operations. Add propanol (6 L) and heat the reaction mixture to reflux overnight to produce cyclization, resulting in a crude mixture comprising INT-5.

[0281] 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: -) which was kept at a temperature between 10-20 °C. Once the reaction was complete, the hydrochloric acid solution in propanol was heated to 60 °C and the previously prepared crude solution of INT-5 (heated to 90 °C to get a solution and then cooled to 60 °C) was added dropwise at 60 °C over 25 minutes (Boc deprotection and approximately 20% decarboxylation was achieved this way). The resulting reaction mixture was heated to reflux (decreased from about 92 °C to 89 °C over time) overnight to complete the 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% aqueous NaOH solution (234 g, 173 mL, 1.87 mol, Eq: 1.28) was added to adjust the pH to 13, in the process the product crystallized. The suspension was heated at about 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 under vacuum at 50 °C under water-saturated atmosphere to give 384 g of the product as a trihydrate (98a% purity by LC, water: 12.4% m / m).

Claims

1. A process for the preparation of a compound of formula (I): comprising reacting a compound of formula (II): ； with a strong acid.

2. The process according to claim 1, wherein the strong acid is hydrochloric acid.

3. The process according to claim 2, wherein the hydrochloric acid is prepared in situ with n-propanol and acetyl chloride.

4. A process for the preparation of a compound of formula (II): ； comprising heating a mixture of a compound of formula (III) at a temperature higher than 70°C, said heating being carried out in the presence of a solvent.

5. The process according to claim 4, wherein the solvent is selected from isopropyl alcohol, n-propanol, t-butyl alcohol, n-butyl alcohol, isobutyl alcohol.

6. A process for the preparation of a compound of formula (III), comprising reacting a compound of formula (IV) with a compound of formula (IVa): said reaction being carried out in the presence of a tertiary amine, in the presence of a solvent.

7. The process according to claim 6, wherein the tertiary amine is selected from triethylamine, tripropylamine, diisopropylethylamine, tributylamine. ； 8. The process according to any one of claims 1 to 2, further comprising preparing a compound of formula (II) ； said preparation of a compound of formula (II) comprising heating a compound of formula (III) at a temperature higher than 70°C, said heating being carried out in the presence of a solvent. ； 9. The process according to claim 8, wherein the solvent is selected from isopropyl alcohol, n-propanol, t-butyl alcohol, n-butyl alcohol, isobutyl alcohol.

10. The process according to claim 8, further comprising preparing a compound of formula (III) said preparation of a compound of formula (III) comprising reacting a compound of formula (IV) with a compound of formula (IVa): said reaction being carried out in the presence of a tertiary amine, in the presence of a solvent.

11. The process according to claim 10, further comprising preparing a compound of formula (IV), said preparation of a compound of formula (IV) comprising reacting a compound of formula (V) or a tautomer thereof with oxalyl chloride, said reaction being carried out in the presence of a solvent. ； 12. The process according to claim 11, further comprising preparing a compound of formula (V), said preparation of a compound of formula (V) comprising reacting a compound of formula (VI) with 2,2-dimethyl-1,3-dioxane-4,6-dione, also known as Meldrum’s acid, said reaction being carried out in the presence of a solvent, wherein DMAP is present.

13. The process according to claim 12, further comprising preparing a compound of formula (VI), said preparation of a compound of formula (VI) comprising reacting a compound of formula (VII) with oxalyl chloride, said reaction being carried out in the presence of a solvent.

14. The process according to claim 13, further comprising preparing a compound of formula (VII), said preparation of a compound of formula (VII) comprising reacting a compound of formula (VIII) with carbon monoxide, said reaction being carried out in the presence of a catalyst.

15. The process according to claim 14, wherein the catalyst is selected from Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp).

16. The process according to claim 15, further comprising preparing a compound of formula (VIII), said preparing a compound of formula (VIII) comprising: a) reacting a compound of formula (X) with NH4OH to give a compound of formula (IXa) b) reacting a compound of formula (IXa) in the presence of pyridinium p-toluenesulfonate with 1-bromo-2,2-dimethoxypropane to give a compound of formula (VIII).

17. A compound of formula (II): 。 18. A compound of formula (III): 。

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