A method for synthesis of harmine

Abstract

The invention relates to a method of synthesis of a compound of formula (I), harmine, according to the method comprising a step of transforming the compound of formula (II), into the compound of formula (I). The invention further relates to a compound of formula (II), which is an intermediate in synthesis of harmine according to the present invention.

Description

[0001] A method for synthesis of harmine

[0002] Field of the invention

[0003] The invention relates to a method of synthesis of a compound of formula (I), harmine. The invention further relates to a compound of formula (II), which is an intermediate in synthesis of harmine according to the present invention.

[0004] Background of the invention

[0005] Harmine (7-methoxy-1 -methyl-9H-pyrido[3, 4-b]-indole), i.e. the compound of formula (I): also known as banisterine or as telepathine, is an alkaloid that occurs in a number of different plants, including harmel (Peganum harmala) or Banisteriopsis caapi. It belongs to a group of beta-carbolines. Harmine reversibly inhibits monoamine oxidase A (MAO-A), but it does not inhibit the monoamine oxidase B (MAO-B). Several structural analogues of harmine include harmaline, tetrohydroharmine, harmol, harmalol, tetrahydroharmol, 2-methyl-1 ,2,3,4-tetra-hydro-0-carboline.

[0006] Harmine is known as a component of ayahuasca, and its synthetic analogue, pharmahuasca. Ayahuasca includes N, / V-dimethyltryptamine (DMT) and beta-carbolines (e.g. harmine, harmaline, tetrahydroharmine, among others), the presence of which is known to improve the bioavailability of DMT. It has been suggested that ayahuasca, as well as its synthetic analogue, pharmahuasca, can be potentially useful in treating a number of disorders, including depression and anxiety disorders. Potential side effects of harmine have also been investigated. It has been established that oral or intravenous harmine doses ranging from 30 to 300 mg may cause agitation, bradycardia or tachycardia, blurred vision, hypotension, paresthesias. The plasma elimination half-life of harmine is on the order of 1-3 hours.

[0007] Accordingly, in view of increasing interest in the medical application of harmine, access to its preparations that are suitable for medical applications, i.e. are of consistent, reproducible quality, give high yield, are scalable and suitable for the production according to the principles of the good manufacturing practice (GMP), needs to be provided. Historically, harmine has been obtained, in addition to the isolation from the natural sources, as described hereinabove, for example by dehydrogenation of harmaline.

[0008] Summary of the invention

[0009] It was thus an object of the present invention to provide an improved method for obtaining harmine. The present inventors have demonstrated that the transformation of the compound of formula (II) into the compound of formula (I) that is palladium catalyzed allows for clean and reproducible synthesis of the compound of formula (I) in high yield. Accordingly, the present inventors have made it possible to obtain harmine in high yield, high purity and in scalable manner according to the newly proposed synthesis route consisting of only two steps starting from commercially available materials.

[0010] The invention will be summarized in the following embodiments.

[0011] In a first embodiment, the present invention relates to a method for synthesis of the compound of formula the method comprising a step of transforming the compound of formula (II): into the compound of formula (I).

[0012] In a second embodiment, the present invention relates to a compound of formula (II): or its salt.

[0013] Brief description of figures

[0014] The invention will be illustrated in the following figures. These figures serve only illustrative purposes and are not to be considered limiting in any way.

[0015] Fig. 1 shows TLC analysis of the reaction mixture in the step of obtaining the compound of formula (II) from the compound of formula (Illa) and the compound of formula (lllb).

[0016] Fig. 2 shows1H NMR (400 MHz, DMSO-d6) spectrum of the compound of formula (II).

[0017] Fig. 3 shows TLC analysis of the reaction mixture in the step of obtaining the compound of formula (I) from the compound of formula (II).

[0018] Fig. 4 shows1H NMR (400 MHz, DMSO-d6) spectrum of the compound of formula (I).

[0019] Detailed description of the invention

[0020] As mentioned before, in one embodiment the present invention relates to a method for synthesis of the compound of formula (I): The compound of formula (I) is also known as harmine. The method comprises a step of transforming the compound of formula (II): into the compound of formula (I).

[0021] The step of transforming the compound of formula (II) into the compound of formula (I) involves a formal carbon-carbon bond formation with formal elimination of HCI. However, as it is apparent to the skilled person other electrophiles than -Cl are conceivable for the application in a transition-metal catalyzed cross-couplings, including bromide, iodide and triflate. Further suitable are mesylate, tosylate, fluorosulfonates, para-fluorobenzenesulfonates, and nonaflates.

[0022] Accordingly and preferably, encompassed in the present invention is an embodiments wherein in compound (II) -Cl is replaced with a leaving group LG, which is preferably selected from chloride, bromide, iodide, triflate, mesylate, tosylate, fluorosulfonate, para-fluorobenzenesulfonate, and nonaflate, preferably selected from chloride, bromide, and iodide, more preferably chloride.

[0023] It has been demonstrated by the present inventors that such a transformation is possible in the presence of palladium catalyst. In other words, the present invention is based, at least in part, on the discovery of the present inventors that the transformation of the compound of formula (I) into the compound of formula (II) can be performed by using palladium catalyst. Thus, preferably, the step of transforming the compound of formula (II) into the compound of formula (I) is palladium-catalyzed.

[0024] However, the present invention is not meant to be limited to palladium-catalyzed carbon-carbon bond formation. As it is apparent to the skilled person, a number of different ways of forming carbon-carbon bonds between two aryl moieties exist and could be applied herein, instead of said palladium-catalyzed reaction. Preferably, in the method of the present invention, the palladium-catalyzed reaction is understood to take place in the presence of a palladium compound and a tertiary phosphine. It is preferred that a base is further present.

[0025] The tertiary phosphine is defined as a compound of formula R1R2R3P, wherein each R1, R2, and R3, independently is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl, wherein said aryl and said heteroaryl can be optionally substituted by one or more groups selected from Hal, -CN, C1-6 alkyl, -0(Ci-6 alkyl), and -OH.

[0026] While the skilled person is in position to determine the tertriary phosphine compound suitable for a reaction as in the method of the present invention without undue burden, it is to be understood that particularly preferred are tertiary phosphines with steric hindrance, i.e. wherein each R1, R2, and R3, are not primary alkyl, alkenyl or alkynyl. Some suitable tertiary phosphines are tri-tertbutylphosphine, 2-(di- tertbutylphosphino)-1 ,1 '-biphenyl, 2-(di-tertbutylphosphino)-2'-methyl-1 ,1 '-biphenyl, 2-(di- tertbutylphosphino)-1 ,1 '-binaphthyl, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1 '-biphenyl, 2- dicyclohexylphosphino-2’,6’-di-iso-propoxy-1 ,1’-biphenyl, N-phenyl-2-(di-tert-butylphosphino)pyrrole, and 1-phenyl-2-(di- tert-butylphosphino) -1 H-indene. Accordingly, the reaction may be performed using a tertiary phosphine selected from tri-tertbutylphosphine, 2-(di-tertbutylphosphino)-1 ,1 '-biphenyl, 2-(di- tertbutylphosphino)-2'-methyl-1 ,1 '-biphenyl, 2-(di-tertbutylphosphino)-1 ,1 '-binaphthyl, 2- dicyclohexylphosphino-2',6'-dimethoxy-1,1 '-biphenyl, 2-dicyclohexylphosphino-2’,6’-di-iso-propoxy-1 ,1’- biphenyl, N-phenyl-2-(di-tert-butylphosphino)pyrrole, and 1-phenyl-2-(di- tert-butylphosphino) -1 H- indene. It is preferred that the tertiary phosphine is tri-tertbutylphosphine.

[0027] The definition of tertiary phosphine includes also a salt thereof, i.e., a salt comprising a phosphonium ion according to the formula R1R2R3PH+. Said phosphonium ion can also be referred to as tertiary phosphonium ion. It is to be understood that the salt of said tertiary phosphine can be transformed into the original tertiary phosphine in the presence of a suitable base. Thus, it is to be understood that performing reaction in the presence of a palladium compound and a tertiary phosphine (and a base, as required) also comprises, and specifically discloses, performing reaction in the presence of a palladium compound, a tertiary phosphonium salt and a base.

[0028] Accordingly, encompassed by the present invention is an embodiment wherein the tertiary phosphine is provided into the reaction mixture in a form of a salt, for example trialkylphosphonium salt. Particularly preferred trialkylphosphonium moieties include alkyl groups with high steric hindrance. In particular, it is preferred that said used alkyl groups are secondary or tertiary, more preferably tertiary, alkyl groups. In a particularly preferred embodiment, at least one alkyl group is tert-butyl, more preferably at least two alkyl groups are tert-butyl, even more preferably all three alkyl groups are tert-butyl groups. Thus, particularly preferred trialkylphosphonium salt is tri-terbutylphosphonium salt.

[0029] The counterion in the salt of tertiary phosphine, i.e. the counterion to the tertiary phosphonium ion, is not particularly limited and any suitable counterion can be used. Particularly preferred is tetrafluoroborate ion. Thus, particularly suitable tertriary phosphonium salt is trialkylphosphonium tetrafluoroborate, more preferably tri-terbutylphosphonium tetrafluoroborate.

[0030] The base is not particularly limited and any suitable base can be used in the method of the present invention. Suitable bases include K2CO3, Na2COs, CS2CO3, sodium or potassium alkoxide e.g. KO- tertbutyl (tBu) or NaOtBu, K3PO4, NasPCU, NaOH, KOH and tertiary amine, e.g. triethylamine. According to the present inventors, particularly suitable base is K2CO3.

[0031] Palladium compound is a compound that comprises palladium. Palladium can be present in the palladium compound in any oxidation state, however it is preferred that palladium (II) is present. Preferably, the palladium compound as defined herein refers to a salt and / or complex of palladium, preferably of palladium (II). Thus, palladium compound may be, for example, selected from sodium hexachloropalladate (IV) tetrahydrate, potassium hexachloropalladate (IV) , palladium (II) chloride, palladium (II) bromide, palladium (II) acetate, palladium (II) acetylacetonate, dichlorobis(benzonitrile)palladium (II), dichlorobis(acetonitrile)palladium(ll), dichlorobi(triphenylphosphine)palladium (II), dichlorotetraaminepalladium (II), dichloro(cycloocta-1 ,5- diene)palladium(ll), palladium(ll) trifluoroacetate, tris(dibenzylideneacetone)dipalladium (0), tris(dibenzylideneacetone)dipalladium (0) chloroform complex, and tetrakisf triphenylphosphine)palladium (0). Preferably, the palladium compound is selected from palladium (II) chloride, palladium (II) bromide, palladium (II) acetate, and palladium (II) acetylacetonate. According to the present inventors, particularly preferred palladium compound is palladium (II) acetate.

[0032] Palladium compound may also be an NHC-palladium complex. One exemplary palladium NHC complex suitable for the present reaction is the complex with 1 ,3-bis-(2,6-diisopropylphenyl)-imidazoliumchloride or with 1 ,3-dimesityl-1 H-imidazol-3-ium chloride. In the case when the reaction is performed in the presence of tertiary phosphine and palladium compound, or in the presence of tertiary phosphonium salt, a base and palladium compound, one can consider that the palladium catalyst is formed in situ, that is directly in the reaction mixture and is not purified before its use in the reaction.

[0033] In the method of the present invention, the tertiary phosphine or the tertiary phosphonium salt may be present at 5 to 15 mol% with respect to the compound of formula (II). Accordingly, the tertiary phosphine or the tertiary phosphonium salt may be present at 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15 mol% with respect to the compound of formula (II). Preferably, the tertiary phosphine or the tertiary phosphonium salt is present at between 8 and 12 mol% with respect to the compound of formula (II). More preferably, the tertiary phosphine or the tertiary phosphonium salt is present at between 9 and 11 mol% with respect to the compound of formula (II). Even more preferably, the tertiary phosphine or the tertiary phosphonium salt is present at about 10 mol% with respect to the compound of formula (II). Still more preferably, the tertiary phosphine or the tertiary phosphonium salt is present at 10 mol% with respect to the compound of formula (II). The tertiary phosphine or the tertiary phosphonium salt, as referred to herein, is preferably tertiary phosphonium salt, in particular tri-tertbutylphosphonium tetrafluoroborate.

[0034] In the method of the present invention the palladium compound may be present at between 3 and 7 mol% with respect to the compound of formula (II). Accordingly, the palladium compound may be present at 3, 4, 5, 6, and 7 mol% with respect to the compound of formula (II). Preferably, the palladium compound is present at between 4 and 6 mol% with respect to the compound of formula (II). More preferably, the palladium compound is present at about 5 mol% with respect to the compound of formula (II). Even more preferably, the palladium compound is present at 5 mol% with respect to the compound of formula (II). The palladium compound, as referred to herein, is preferably Pd(OAc)2.

[0035] It is to be understood that when tertiary phosphonium salt is used, a base must also be present. The base is to be used in excess with respect to the compound of formula (II). Accordingly, in an embodiment of the method of the present invention, wherein the tertiary phosphonium salt is used, the base may be present at 2.0 to 4.0 molar equivalents with respect to the compound of formula (II). Accordingly, the base may present at 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0 molar equivalents with respect to the compound of formula (II). Preferably, the base is present at between 2.5 and 3.5 molar equivalents with respect to the compound of formula (II). More preferably, the base is present at about 3.0 molar equivalents with respect to the compound of formula (II). Even more preferably, the base is present at 3.0 molar equivalents with respect to the compound of formula (II). The base, as referred to herein, is preferably K2CO3. However, it is to be understood that other bases can also be used, and the considerations of the molar ratio of the base and the compound of formula (II), as discussed hereinabove, regardless of with how many molar equivalents of e.g. HCI acid the base can react (for example, K2CO3 is capable of neutralizing two equivalent of HCI, but NaOH is capable of neutralizing only one molar equivalent of HCI).

[0036] The step of transforming the compound of formula (II) into the compound of formula (I), i.e. the corresponding chemical reaction, may be performed in a polar and aprotic solvent. A suitable polar and aprotic solvent is dimethylacetamide (DMA). Thus, preferably, the step of transforming the compound of formula (II) into the compound of formula (I), i.e. the corresponding chemical reaction, is performed in DMA. It is however conceivable to the skilled person that the reaction may also be performed in other dipolar aprotic solvents like NMP, DMSO, sulfolane, HMPA, acetonitrile, acetone, dioxane, dimethylpropyleneurea, or THF

[0037] The skilled person is capable of selecting a suitable concentration of the substrates, in particular of the compound of formula (II). The concentration of the compound of formula (II) may be between 0.3 M and 0.5 M. Accordingly, the reaction may be performed at a concentration of the compound of formula (II) of 0.30, 0.31 , 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41 , 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49 or 0.50 M. It is preferred that the concentration of the compound of formula (II) is between 0.35 and 0.45 M. More preferably, the concentration of the compound of formula (II) is about 0.4 M. Even more preferably, the concentration of the compound of formula (II) is 0.4 M.

[0038] The reaction in the step of transforming the compound of formula (II) into the compound of formula (I) may be performed in the presence of water in the reaction mixture. Accordingly, the water may be present in the reaction mixture at 0.1 to 0.3 molar equivalent with respect to the compound of formula (II). Thus, the water may be present in the reaction mixture at 0.10, 0.11 , 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21 , 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29 or 0.30 molar equivalent with respect to the compound of formula (II). Preferably, the water is present in the reaction mixture at between 0.15 and 0.25 molar equivalent with respect to the compound of formula (II). More preferably, the water is present in the reaction mixture at about 0.2 molar equivalent with respect to the compound of formula (II). Still more preferably, the water is present in the reaction mixture at 0.2 molar equivalent with respect to the compound of formula (II). The presence of water accelerates the reaction and thereby leads to a better conversion under the standard conditions. Without the addition of water, the reaction still takes place. However, as it is conceivable to the skilled person, under different reaction conditions, i.e., when using a different base, ligand, etc., the addition of water might not be necessary.

[0039] It is preferred that the reaction in the step of transforming the compound of formula (II) into the compound of formula (I) is performed at a at a temperature of between 120 and 140 °C. Accordingly, the reaction may be performed at 120, 121 , 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 137, 138, 139 or 140 °C. Preferably, the reaction is performed at a temperature of between 125 and 135 °C. More preferably, the reaction is performed at a temperature of 130 °C.

[0040] The progress of the reaction in the step of transforming the compound of formula (II) into the compound of formula (I) is monitored according to the consumption of the compound of formula (II), for example by using TLC chromatography or LC-MS or GC-based methods. It is preferred that the reaction is performed up to complete consumption of the compound of formula (II). In any case, it is further preferred that the reaction is performed for a time of at least 12 hours.

[0041] Once the progress of the reaction is sufficient (e.g. more than 90% of the compound of formula (II) have been consumed), the reaction can be worked up and the compound isolated and purified. The skilled person is capable of isolating the product of the reaction according to the standard techniques known in the art.

[0042] The compound of formula (I) obtainable according to the present invention from the compound of formula (II) can be, for example, purified as described in the following and as exemplified in the Examples section.

[0043] The compound of formula (I) may be precipitated from the reaction mixture upon addition of aqueous solution of N-acetylcysteine. The obtained suspension may be filtered, washed and dried according to the methods known to the skilled person. The obtained solid may then be subjected to acidic and basic workup upon its suspension in water (using e.g. glacial acetic acid, separating the filtrates from the solids, then treating the filtrate using e.g. 50% NaOH solution and separating obtained precipitate by filtration). The so obtained solid may be further purified by e.g. suspension in methanol, refluxing for e.g. 90 minutes, and precipitating the compound of formula (I) upon addition of MTBE and / or lowering the temperature (e.g. to 4 °C).

[0044] In a particularly preferred embodiment of the present invention, the step of transforming the compound of formula (II) into the compound of formula (I) is performed using of tri-tertbutylphosphonium tetrafluoroborate at between 9 and 11 mol% with respect to the compound of formula (II) (preferably at 10 mol% with respect to the compound of formula (II)), palladium (II) acetate at between 4 and 6 mol% with respect to the compound of formula (II) (preferably at about 5 mol% with respect to the compound of formula (II)), and fcCOsat between 2.5 and 3.5 molar equivalents with respect to the compound of formula (II) (preferably at 3.0 molar equivalents with respect to the compound of formula (II)), wherein the reaction is performed in DMA, preferably at a temperature of between 125 and 135 °C. It is further preferred that the water is present in the reaction mixture at 0.1 to 0.3 molar equivalent with respect to the compound of formula (II).

[0045] In the absence of any explicit indication to the contrary, it is to be understood that all the features of the step of transforming the compound of formula (II) into the compound of formula (I) can be combined with each other.

[0046] The method of the present invention may further comprise the step of preparing the compound of formula (II) according to Buchwald-Hartwig coupling starting from the compound of formula (Illa) and the compound of formula (lllb):

[0047] (Hla) (lllb)

[0048] Preferably, the step of preparing the compound of formula (II) is palladium catalyzed. Accordingly, the step of preparing the compound of formula (II) may be performed in the presence of: palladium compound, tertiary phosphonium salt / tertiary phosphine and a base.

[0049] The compound of the formula (Illa) and the compound of the formula (lllb) react with each other in 1 :1 stoichiometry. As recognizable to the skilled person, the reaction is nevertheless conducted in the presence of slight excess of one of the reagents. Accordingly, the compound of formula (Illa) may be present in the reaction mixture at 0.8 to 1.2 eq. with respect to the compound of formula (lllb). Thus, the compound of formula (Illa) may be present at 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, or 1.20 eq with respect to the compound of formula (lllb). The excess of the compound of formula (Illa) is preferred, and accordingly and preferably, the compound of formula (Illa) is present in the reaction mixture at between 1 .0 and 1 .2 eq with respect to the compound of formula (lllb). More preferably, the compound of formula (Illa) is present in the reaction mixture at about 1.1 eq with respect to the compound of formula (lllb). Even more preferably, the compound of formula (Illa) is present in the reaction mixture at 1.1 eq with respect to the compound of formula (lllb).

[0050] In the step of preparing the compound of formula (II) according to the present invention, the tertiary phosphonium salt preferably as described herein when discussing the step of transforming the compound of formula (II) to the compound of formula (I). Thus, it is particularly preferred that the tertiary phosphonium salt is tri-ferf-butylphosphonium tetrafluoroborate when discussing the step of transforming the compound of formula (II) to the compound of formula (I).

[0051] In the step of preparing the compound of formula (II) according to the present invention, the tertiary phosphonium salt (preferably tri-ferf-butylphosphonium tetrafluoro borate) may be present at between 1.0 and 2.0 mol% with respect to the compound of formula (lllb). Thus, the reaction may be performed with the tertiary phosphonium salt present at 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6., 1.7, 1.8, 1.9 or 2.0 mol% with respect to the compound of formula (lllb). Preferably, the tertiary phosphonium salt is present at between 1.2 and 1.6 mol% with respect to the compound of formula (lllb). More preferably, the tertiary phosphonium salt is present at between 1 .3 and 1 .5 mol% with respect to the compound of formula (lllb). Even more preferably the tertiary phosphonium salt is present at about 1.4mol% with respect to the compound of formula (lllb). Still more preferably, the tertiary phosphonium salt is present at 1.4% with respect to the compound of formula (lllb).

[0052] Within the scope of the present invention, tertiary phosphonium salt may also be replaced by a tertiary phosphine. Tertiary phosphine may be as described herein. One exemplary tertiary phosphine that has been found particularly suitable in the step of preparing the compound of formula (II) is di-(l-adamantyl)- n-butylphosphine. Said di-(1-adamantyl)-n-butylphosphine is commercially available as CataCXium A.

[0053] Thus, in the step of preparing the compound of formula (II) according to the present invention, wherein the tertiary phosphonium salt is replaced by the tertiary phosphine, the tertiary phosphine (preferably di- (l-adamantyl)-n-butylphosphine) may be present at between 1.7 and 2.7 mol% with respect to the compound of formula (lllb). Thus, the reaction may be performed with the tertiary phosphine present at 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, 2.3., 2.4, 2.5, 2.6 or 2.7 mol% with respect to the compound of formula (lllb). Preferably, the tertiary phosphine is present at between 2.0 and 2.4 mol% with respect to the compound of formula (lllb). More preferably, the tertiary phosphine is present at between 2.1 and 2.3 mol% with respect to the compound of formula (lllb). Even more preferably the tertiary phosphine salt is present at about 2.2mol% with respect to the compound of formula (lllb). Still more preferably, the tertiary phosphine is present at 1.4% with respect to the compound of formula (lllb).

[0054] In the step of preparing the compound of formula (II) according to the present invention, the palladium compound is as described herein, when discussing the step of transforming the compound of formula (II) to the compound of formula (I). Preferably, the palladium compound is Pd(0Ac)2.

[0055] In the step of preparing the compound of formula (II) according to the present invention, the palladium compound (preferably Pd(0Ac)2) may be present at between 0.5 and 1.5 mol% with respect to the compound of formula (lllb). Accordingly, said palladium compound may be present at 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, or 1.5 mol% with respect to the compound of formula (lllb). Preferably the palladium compound is present at between 0.8 and 1 .2 mol% with respect to the compound of formula (lllb). More preferably, the palladium compound is present about 1 .0 mol% with respect to the compound of formula (lllb). Even more preferably, the palladium compound is present at 1.0 mol% with respect to the compound of formula (lllb).

[0056] In the step of preparing the compound of formula (II) according to the present invention, the base is as discussed herein, when discussing the step of transforming the compound of formula (II) to the compound of formula (I). Preferably, the base is sodium alkoxide, preferably NaOtBu.

[0057] In the step of preparing the compound of formula (II) according to the present invention, the base (preferably sodium alkoxide, preferably NaOtBu), may be present at 1.5 to 2.5 eq. with respect to the compound of formula (lllb). Accordingly, the base may be present at 1.5, 1.6, 1.7, 1.8, 1.9. 2.0, 2.1 , 2.2, 2.3, 2.4 or 2.5 eq. with respect to the compound of formula (lllb). Preferably, the base is present at between 1.8 and 2.2 eq. with respect to the compound of formula (lllb). More preferably, the base is present at about 2.0 eq. with respect to the compound of formula (lllb). Even more preferably, the base is present at 2.0 eq. with respect to the compound of formula (lllb).

[0058] Preferred sodium alkoxide is NaOtBu, However, other suitable sodium alkoxides, for example sodium tertamyloxide (also referred to as sodium tert-pentoxide) may also be used.

[0059] The Buchwald-Hartwig coupling reaction in the step of preparing the compound of formula (II) according to the present invention is preferably performed in aromatic non-polar solvent, for example selected from benzene, toluene or xylene. Preferably, the reaction is performed in toluene. Furthermore, the reaction is preferably performed under reflux conditions. Thus, preferably, the reaction is performed in toluene under reflux.

[0060] According to the present inventors, the reaction is preferably performed until substantially all of the compound of formula (lllb) is consumed. Preferably, the reaction is carried out for preferably at least 8, at least 10, at least 12 or at least 15 hours. Particularly preferred is when the reaction is carried out for at least 15 hours.

[0061] However, the recited preferred reagents and reaction conditions are preferably not to be considered to be limiting, as the skilled person familiar with the Buchwald-Hartwig coupling reaction is capable of selecting reagents and conditions for the coupling between the compound of formula (Illa) and the compound of formula (lllb).

[0062] The work-up and purification of the product of the Buchwald-Hartwig coupling reaction in the step of preparing the compound of formula (II) according to the present invention is apparent to the skilled person. For example, in the first step, a filtration through a plug of silica gel in e.g. MTBE / IPA 10:1 v / v followed by removal of the solvent to yield the crude product can be performed.

[0063] The present inventors have proposed obtaining the final product through crystallization. For example, the crude product may be solubilized with isopropyl alcohol under heating, and water may be added to this composition, and the so obtained composition may be allowed to cool to the room temperature under constant stirring. The crystals of pure product may be obtained in these conditions, optionally in the presence of seed crystals and / or once the composition is placed at lower temperature, e.g. 4 °C. An exemplary purification is discussed in the Examples section.

[0064] Accordingly and preferably, the compound of formula (II) is crystalized from the mixture of isopropyl alcohol and water.

[0065] Alternatively, the product (II) may also be isolated as hydrochloride salt upon its crystallization from 4N HCI solution. It is conceivable to the skilled person that transforming such a salt to free base of the compound of formula (II), i.e., the freebasing process, performed by contacting the compound with a composition including basic aqueous layer (e.g. 30% w / w NaOH solution) with organic solvent, for example MeTHF, for an extended time, e.g. 2 h. The product is then isolated from the organic phase. It is further submitted that the compound of formula (II) may also be obtained in different routes than discussed herein. For example. The intermediate (II) can be prepared from 2-chloro-5-methoxy-aniline in combination with 3-bromo-2-methylpyridine.

[0066] The following definitions apply throughout the present description, unless so indicated to the contrary.

[0067] As used herein, the term “about” preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and in particular to the exact numerical value indicated. If the term “about” is used in connection with the endpoints of a range, it preferably refers to the range from the lower endpoint -10% of its indicated numerical value to the upper endpoint +10% of its indicated numerical value, more preferably to the range from of the lower endpoint -5% to the upper endpoint +5%, and even more preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint.

[0068] As used herein, the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia”, i.e., “containing, among further optional elements, ...”. In addition thereto, this term also includes the narrower meanings of “consisting essentially of’ and “consisting of’. For example, the term “A comprising B and C” has the meaning of “A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C” and the meaning of “A consisting of B and C” (i.e., no other components than B and C are comprised in A).

[0069] As used herein, the term “halogen” refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I).

[0070] The terms “bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.

[0071] As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to- carbon double bond or any carbon-to-carbon triple bond. A “C1-5 alkyl” denotes an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless defined otherwise, the term “alkyl” preferably refers to C1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl. As used herein, the term “alkenyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. The term “C2-5 alkenyl” denotes an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-

[0072] 1-en-1-yl, prop-1 -en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1-yl or buta-1 ,3-dien-

[0073] 2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term “alkenyl” preferably refers to C2-4 alkenyl.

[0074] As used herein, the term “alkynyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. The term “C2-5 alkynyl” denotes an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless defined otherwise, the term “alkynyl” preferably refers to C2- 4 alkynyl.

[0075] As used herein, the term “aryl” refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Aryl” may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1 ,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1 H-indenyl), anthracenyl, phenanthrenyl, 9H- fluorenyl, or azulenyl. Unless defined otherwise, an “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl. The term aryl may also refer to connected ring systems, wherein a monocyclic aromatic ring, a bridged ring and / or fused ring system containing at least one aromatic ring is connected by a carbon-carbon single bond to another a monocyclic aromatic ring, a bridged ring and / or fused ring system. An example of a connected ring system is biphenyl.

[0076] As used herein, the term “heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1- benzopyranyl or 4H-1 -benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3- pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, 0-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 , 10]phenanthrolinyl, [1 ,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl (i.e., furazanyl), or 1 ,3,4-oxadiazolyl), thiadiazolyl (e.g., 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, or 1 ,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1 ,5-a]pyrimidinyl (e.g., pyrazolo[1 ,5-a]pyrimidin-3-yl), 1 ,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1 H-1 ,2,3-triazolyl, 2H-1 ,2,3-triazolyl, 1 H-1 ,2,4-triazolyl, or 4H-1 ,2,4-triazolyl), benzotriazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1 ,2,4-triazinyl, or 1 ,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1 ,3-dihydrofuro[3,4- c]pyridinyl), imidazopyridinyl (e.g., imidazo[1 ,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1 ,3-benzodioxolyl, benzodioxanyl (e.g., 1 ,3-benzodioxanyl or 1 ,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term “heteroaryl” preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. The term heteroaryl may also refer to connected ring systems, wherein a monocyclic heteroaromatic ring, a bridged ring and / or fused ring system containing at least one heteroaromatic ring is connected by a carbon-carbon single bond to another a monocyclic aromatic or heteroaromatic ring, a bridged ring and / or fused ring system containing at least one aromatic or heteroaromatic ring.

[0077] As used herein, the term “cycloalkyl” refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkyl” may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless defined otherwise, “cycloalkyl” preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl. A particularly preferred “cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).

[0078] As used herein, the term “heterocycloalkyl” refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatomcontaining ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkyl” may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1 ,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholineyl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1 ,3-dioxolanyl, tetrahydropyranyl, 1 ,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1 ,3-dithiolanyl, thianyl, 1 ,1 -dioxothianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless defined otherwise, “heterocycloalkyl” preferably refers to a 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkyl” refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

[0079] As used herein, the term “cycloalkenyl” refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to- carbon double bonds and does not comprise any carbon-to-carbon triple bond. “Cycloalkenyl” may, e.g., refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless defined otherwise, “cycloalkenyl” preferably refers to a C3-11 cycloalkenyl, and more preferably refers to a C3-7 cycloalkenyl. A particularly preferred “cycloalkenyl” is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two; preferably one) carbon-to-carbon double bonds.

[0080] As used herein, the term “heterocycloalkenyl” refers to an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkenyl” may, e.g., refer to imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1 H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1 ,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1 ,2- dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1 ,2,3,4,4a,5,6,7-octahydroquinolinyl), or octahydroisoquinolinyl (e.g., 1 ,2,3,4,5,6,7,8-octahydroisoquinolinyl). Unless defined otherwise, “heterocycloalkenyl” preferably refers to a 3 to 11 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms; more preferably, “heterocycloalkenyl” refers to a 5 to 7 membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms.

[0081] As used herein, the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent. Whenever the term “optional”, “optionally” or “may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression “X is optionally substituted with Y” (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be “optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

[0082] Various groups are referred to as being “optionally substituted” in this specification. Generally, these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise, the “optionally substituted” groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted. The scope of the invention embraces all salt forms of the compound of formula (II) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N, N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p- toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Preferred salts of the compounds of formula (II), in particular pharmaceutically acceptable salts, include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. Accordingly, it is preferred that the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, or a phosphate salt, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt.

[0083] The present invention also specifically relates to the compound of formula (II) in non-salt form. Whenever a reference is made to a compound, preferably a compound or its salt, as defined hereinabove for the compound of formula (II), is meant.

[0084] The invention is summarized in the following examples. These are however not to be construed as limiting the scope of the invention, which is characterized in the appended claims.

[0085] Examples

[0086] Preparation of / V-(2-Chloro-5-methoxyphenyl)-2-methylpyridin-3-amine (3)

[0087] Pd(OAc)2(1 mol%) [tBu3P][HBF4] (1.4 mol%) .

[0088] Reaction conditions

[0089] • A two-neck flask was successively charged with 3-ami nopicoli ne (1 , 20.0 g, 185 mmol, 1 .0 eq.), 2-bromo- 1-chloro-4-methoxybenzene () (45.1 g, 203 mmol, 1.10 eq.), tri-ferf-butylphosphonium tetrafluoroborate (751 mg, 2.59 mmol, 1 .4mol%), Pd(OAc)2 (415 mg, 1 .85 mmol, 1 .0mol%), and NaOtBu (35.6 g, 370 mmol, 2.0 eq.) under air.

[0090] • A reflux condenser was attached, and the two exits were closed with septa.

[0091] • The air was exchanged for nitrogen by applying vacuum and refilling with a nitrogen-filled balloon (three times).

[0092] • Toluene (92.5 mL, 2 M) was added to give a suspension which was stirred using a magnetic stirring bar.

[0093] • The suspension was degassed by bubbling nitrogen through it for ten minutes using a nitrogen-filled balloon through the bottom septum and generating an exit at the top of the reflux condenser by installation of a syringe where occasionally vacuum was applied.

[0094] • The reaction mixture was heated to 130 °C (external oil bath temperature) and kept at this temperature for 20 hours.

[0095] • After 20 hours, the suspension was allowed to cool to room temperature.

[0096] • An aliquot was taken, and only traces of 3-aminopicoline (1) were observed via TLC (shown in Figure 3).

[0097] Work-up: • A glass frit (500 mL volume, porosity 4) was filled with silica (340 mL dry volume) and packed with MTBE / IPA 10 / 1 v / v.

[0098] • The reaction suspension was filtered through the thus prepared silica plug.

[0099] • The silica plug was washed with MTBE / IPA 10 / 1 v / v (1 .03 L)

[0100] • The solvent was removed under reduced pressure.

[0101] • The crude product was obtained as a brown solid (48.6 g).

[0102] Purification:

[0103] • IPA (200 mL) was added to the round-bottom flask containing the crude product.

[0104] • The mixture was heated to reflux with magnetic stirring (external temperature: 115 °C).

[0105] • Water (195 mL) was added slowly at this temperature.

[0106] • Heating was switched off, and the solution was allowed to cool to room temperature with magnetic stirring (100 rpm).

[0107] • After three days at room temperature, no crystals were observed. A spatula tip of seed crystals was added, and the flask was placed in a refrigerator (4 °C).

[0108] • After one night, crystallization was observed. The solvent was removed by filtration through a glass frit (por. 4), and the solids were washed with cold IPA / water (100 mL).

[0109] • The solids were dried in the frit under vacuum to yield the title compound as a pale yellow solid (33.0 g, 133 mmol, 71.7%).

[0110] 1 H NMR (400 MHz, DMSO-d6) 6 [ppm] = 8.18 (dd, J = 4.7, 1 .6 Hz, 1 H), 7.34 - 7.28 (m, 2H), 7.26 (s, 1 H), 7.18 (dd, J = 8.0, 4.6 Hz, 1 H), 6.48 (dd, J = 8.8, 2.9 Hz, 1 H), 6.17 (d, J = 2.9 Hz, 1 H), 3.64 (s, 3H), 2.37 (s, 3H).

[0111] The NMR spectrum is shown in Figure 2.

[0112] Preparation of harmine (4)

[0113] K2CO3(3 eq) Pd(OAc)2(5 mol%)

[0114] 3 4 Reaction conditions

[0115] • A sealable tube was successively charged with intermediate 3 (10.7 g, 185 mmol, 1.0 eq.), tri-ferf- butylphosphonium tetrafluoroborate (1.25 g, 4.30 mmol, 10mol%), Pd(OAc)2 (483 mg, 2.15 mmol, 5.0mol%), and K2CO3 (17.8 g, 129 mmol, 3.0 eq.) under air.

[0116] • The sealed tube was closed with a septum.

[0117] • The air was exchanged for nitrogen by applying vacuum and refilling with a nitrogen-filled balloon (three times).

[0118] • DMA (108 mL, 0.4 M) and water (155 pL, 155 mg, 8.60 mmol, 0.20 eq.) were added to give a suspension which was stirred using a magnetic stirring bar.

[0119] • The suspension was degassed by bubbling nitrogen through it for fifteen minutes using a nitrogen- filled balloon and a syringe as the exit with stirring.

[0120] • The septum was exchanged for an overpressure valve with integrated internal manometer under nitrogen.

[0121] • The sealed tube was heated to 130 °C (external oil bath temperature) and kept at this temperature for 16.5 hours.

[0122] • In the end of the reaction, the manometer did not reach the first calibration mark of 10 psi overpressure.

[0123] • After 16.5 hours, the suspension was allowed to cool to room temperature.

[0124] • An aliquot was taken, and full conversion of intermediate 3 was observed via TLC (shown in Figure 3).

[0125] Precipitation

[0126] • 5wt% aqueous / V-acetylcysteine solution (214 mL) was slowly added [foam-building], and the resulting suspension was stirred overnight.

[0127] • The suspension was filtered over a glass frit (por. 4), and the solids were washed with water (50 mL, then 25 mL, then 25 mL).

[0128] • The solids were dried in the glass frit by applying vacuum for ten minutes.

[0129] Acid / base filtration

[0130] • The solids were transferred into an Erlenmeyer flask and suspended in water (44 mL).

[0131] • Glacial acetic acid (24 mL) was added slowly so that the pH is 3-4 and the resulting suspension was stirred for 15 minutes.

[0132] • The suspension was filtered over a glass frit (por. 4), and the filter residue was washed with water / acetic acid 10 / 1 v / v (27.5 mL, then 11 mL). • To the combined filtrates 50wt% aqueous NaOH solution was added so that the pH is adjusted to 9-10 leading to precipitation of a yellow solid.

[0133] • The resulting suspension was stirred for 75 minutes.

[0134] • The solids were filtered off using a glass frit (por. 4), washed with water (53.5 mL), and dried in the glass frit by applying vacuum for 15 minutes to yield a yellow solid (7.29 g).

[0135] Purification

[0136] • To this solid, methanol (36.5 mL) was added.

[0137] • The resulting suspension was heated to reflux with magnetic stirring and kept at this temperature for 90 minutes.

[0138] • MTBE (50 mL) was added at elevated temperature (external oil bath temperature: 80 °C), and the resulting suspension is allowed to cool to room temperature.

[0139] • The round-bottom flask was sealed with a cap and placed in a fridge (4 °C) standing for one hour.

[0140] • The resulting solid were isolated via filtration through a glass frit, washed with MTBE (25 mL, then 25 mL) and dried in the glass frit by applying vacuum for 15 minutes to yield a yellow solid.

[0141] • The solids were dried in high vacuum to yield harmine (4, 6.21 g, 28.3 mmol, 96.8wt% purity (qNMR), 65.8%) as a pale-yellow solid.

[0142] 1 H NMR (400 MHz, DMSO-d6) 6 11.41 (s, 1 H), 8.15 (d, J= 5.3 Hz, 1 H), 8.04 (d, J= 8.7 Hz, 1 H), 7.79 (d, J = 5.3 Hz, 1 H), 7.02 (d, J = 2.2 Hz, 1 H), 6.84 (dd, J = 8.6, 2.3 Hz, 1 H), 3.87 (s, 3H), 2.73 (s, 3H).

[0143] The NMR spectrum is shown in Figure 4.

[0144] Scale-up of the preparation of harmine (50 q)

[0145] The experimental protocol and conditions for preparing harmine according to the present invention are scalable, and can be performed e.g. at gram scale (e.g. 50 g).

Claims

CLAIMS1 . A method for synthesis of the compound of formula (I):the method comprising a step of transforming the compound of formula (II):into the compound of formula (I).

2. The method of claim 1 , wherein the step of transforming the compound of formula (II) into the compound of formula (I) is performed in the presence of palladium compound and tertiary phosphine, or palladium compound, tertiary phosphonium salt and a base.

3. The method of claim 2, wherein the tertiary phosphonium salt is tri-tertbutylphosphonium tetrafluoroborate, the palladium compound is Pd(0Ac)2, and / or the base is K2CO3.

4. The method of claim 2 or 3, wherein the tertiary phosphonium salt (preferably tri- tertbutylphosphonium tetrafluoroborate) is present at 5 to 15 mol% with respect to the compoundof formula (II), preferably at about 10 mol% with respect to the compound of formula (II), more preferably at 10 mol% with respect to the compound of formula (II).

5. The method of any one of claims 2 to 4, wherein the palladium compound (preferably Pd(OAc)2) is present at 3 to 7 mol% with respect to the compound of formula (II), preferably at 5 mol% with respect to the compound of formula (II).

6. The method of any one of claims 2 to 5, wherein the base (preferably K2CO3) is present at 2.0 to 4.0 molar equivalents with respect to the compound of formula (II), preferably at about 3.0 molar equivalents with respect to the compound of formula (II), more preferably at 3.0 molar equivalents with respect to the compound of formula (II).

7. The method of any one of claims 1 to 6, wherein the step of transforming the compound of formula (II) into the compound of formula (I) is performed in DMA, preferably wherein the concentration of the compound of formula (II) is between 0.3 M and 0.5 M, preferably wherein the concentration of the compound of formula (II) is about 0.4 M, more preferably wherein the concentration of the compound of formula (II) is 0.4 M.

8. The method of any one of claims 1 to 7, wherein water is present in the reaction mixture, preferably at 0.1 to 0.3 molar equivalent with respect to the compound of formula (II), more preferably at about 0.2 molar equivalent with respect to the compound of formula (II), even more preferably at 0.2 molar equivalent with respect to the compound of formula (II).

9. The method of any one of claims 1 to 8, wherein the step of transforming the compound of formula (II) into the compound of formula (I) is performed at a temperature of between 120 and 140 °C, preferably 130 °C, and / or wherein the reaction is performed for a time of at least 12 hours.

10. The method of any one of claims 1 to 9, further comprising the step of preparing the compound of formula (II) according to Buchwald-Hartwig coupling starting from the compound of formula (Illa) and the compound of formula (lllb):11 . The method of claim 10, wherein the step of preparing the compound of formula (II) is performed in the presence of palladium compound, tertiary phosphonium salt or tertiary phosphine, and a base.

12. The method of claim 11 , wherein the tertiary phosphonium salt is tri-ferf-butylphosphonium tetrafluoroborate, the tertiary phosphine is di-(1 -adamantyl)-n-butylphosphine, the palladium compound is Pd(OAc)2, and / or the base is sodium alkoxide, preferably NaOtBu.

13. The method of claim 11 or 12, wherein the tertiary phosphonium salt (preferably tri-ferf- butylphosphonium tetrafluoroborate) is present at 1 .0 to 2.0 mol% with respect to the compound of formula (Illa), preferably at about 1.4mol% with respect to the compound of formula (Illa), more preferably at 1 .4% with respect to the compound of formula (Illa).

14. The method of any one of claims 11 to 13, wherein the palladium compound (preferably Pd(OAc)2) is present at 0.5 to 1 .5 mol% with respect to the compound of formula (Illa), preferably at about 1.0mol% with respect to the compound of formula (Illa), more preferably at 1.0mol% with respect to the compound of formula (Illa).

15. The method of any one of claims 11 to 14, wherein the base (preferably sodium alkoxide, preferably NaOtBu), is present at 1.5 to 2.5 eq. with respect to the compound of formula (Illa), preferably at about 2.0 eq. with respect to the compound of formula (Illa), more preferably at 2.0 eq. with respect to the compound of formula (Illa).

16. The method of any one of claims 11 to 15, wherein the step of preparing the compound of formula (II) is performed in toluene under reflux, preferably for at least 15 hours, and / or wherein the compound of formula (II) is crystalized from the mixture of isopropyl alcohol and water.

17. A compound of formula (II):or its salt.

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