DERIVATIVES THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of tryptamine and its substituted derivatives. This class of compounds is of particular interest as intermediates in the synthesis of more complex organic compounds. BACKGROUND OF THE INVENTION

Tryptamines and their derivatives are versatile synthetic intermediates well-known in the prior art.

A general approach towards the synthesis of this class of compounds is disclosed in WO2002078693, according to the below scheme. This synthetic approach employs the corresponding indole as a starting material; hence there is a certain degree of limitation related to those procedures, in respect of the availability of the starting material.

Patent application WO201 1076212A2 discloses a synthetic route oriented to 6- fluorotryptamine, a key fragment for the synthesis of Lu-AE-58054 (Idalopirdine, compound of formula 1 in said application), which is a potent and selective 5-HTe receptor antagonist. The overall synthetic scheme is shown below. A major drawback of this synthesis is obviously the use of cyanide salts for the formation of the intermediate cyanomethyl-6-fluoro-indole. Furthermore, this synthetic approach requires also the su ly of 6-fluoro-indole as a key starting material.

Consequently, there exists a need for an improved process for the preparation of tryptamine derivatives, starting from more simple and accessible materials and using safe chemical reagents.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a process for the preparation of compound of formula 1 or saits thereof, from compound of formula II.

It is a further object of the present invention to provide a process for the preparation of compound of formula I or salts thereof as described above, further comprising conversion of compound of formula III to compound of formula II.

It is another object of the present invention to provide a process for the preparation of compound of formula la from compound of formula Ha.

Yet another object of the present invention is the use of compounds of formula II for the preparation of organic compounds. DEFINITIONS

The term "alkyl" means a monovalent straight or branched chain group of the formula C _m H2m+i or a cyclic group of the formula C _m I¾m-i, with m being the number of carbon atoms. Preferable alkyl groups are Ci _-2 o alkyl groups, more preferably C MO alkyl groups, more preferably Ct_g alkyl groups. Particularly preferred alkyl groups include, for example, methyl, ethyl, n-propyl, wo-propyl, n-butyl, sec-butyl, /.vo-butyl, n- pentyl, w-hexyl, n-heptyl, w-octyi.

The term "haloalkyi" refers to alkyl groups substituted with one or more halogen atoms in one or more positions of the alkyl chain.

The term "alkenyl" means monovalent straight or branched chain moieties containing one or more carbon-carbon double bonds and at least 2 carbon atoms. These moieties conform to the formula C _m H(2 _m -i), with m being the number of carbon atoms present. Preferable alkenyl groups are C2-20 alkenyl groups, more preferably still a C2-10 alkenyl group, more preferably still a C _2- i ₀ , more preferably still a C?-8 alkenyl group.

The term "aikynyl" means monovalent straight or branched chain moieties containing one or more carbon-carbon triple bonds and at least 2 carbon atoms. These moieties conform to the formula C _M H ₍ 2tr,-3 with m being the number of carbon atoms present. Preferable aikynyl groups are C2-20 aikynyl groups, more preferably still a C2-10 aikynyl group, more preferably still a C _2- io aikynyl, more preferably still a C ₂ -s aikynyl group. The term "aryl" refers to a C6-18 cyclic aromatic group, formed by one or more rings, which may optionally be substituted with one or more substituents. Preferably, the aromatic ring is a C6-10 ring system. Typical examples include phenyl, naphthyl and anthracenyl.

The term "heteroaryl" refers to a cyclic aromatic group as defined above, wherein one or more of the carbon atoms have been replaced by one or more heteroatoms, selected from Nitrogen, Sulphur or Oxygen, which may optionally be substituted with one or more substituents. Preferably, the aromatic heterocycle is a pyrazole, pyrrole, imidazole, furane, thiophene, benzo[b]thiophene, pyrazine, pyridine, pyrimidine, pyridazine.

The term "substituent" refers to:

alkyl, optionally substituted with alkoxy or hydroxyl;

cycloalkyl;

aryl, optionally substituted with hydroxyl, alkyl, alkoxy, halogen, benzyloxy, carboxy, alkoxycarbonyl, amido, N-alkylamido, sulfonylamido, cyano, haloalkyl, haloalkoxy, nitro;

heteroaryl;

heterocyclyl;

alkeny ;

alkynyl;

halogen atoms;

hydroxyl groups;

alkoxy or aryloxy groups;

alkoxy or aryloxycarbonyl groups;

thiol group;

thioether group;

thioester group;

aldehyde group;

aryl or alkyl carbonyl group;

carboxyl groups;

carboxyl groups esterified with alkyl or aryl groups;

amide groups; amine groups;

nitrile group;

alkyl or arylsulfonyl;

amidosu!phonyl;

Preferred substituents are

alkyl, optionally substituted with alkoxy, hydroxyl;

cycloalkyl;

aryl;

heteroaryl;

alkylaryl or alkylheteroaryl;

halogen atoms;

hydroxyl groups;

alkoxy or aryloxy groups;

alkoxy or aryloxycarbonyl groups;

aryl or alkyl carbonyl group;

carboxyl groups;

carboxyl groups esterified with alkyl or aryl groups;

amide groups;

amine groups;

The term "reducing agent" means a reagent which is able to bring about a reduction in a chemical compound. A reduction, in the case of organic compounds, can be defined as a reaction wherein the oxidizing state of a carbon atom is reduced or, in other words, results in a net gain of electrons of a carbon atom. More than one carbon atoms or functional groups may be reduced in the course of a reduction reaction. More than one reducing agents may be used in one step.

Acceptable salts of the compounds prepared herein include suitable acid addition salts thereof. A review of suitable pharmaceutical salts may be found in Berge et al., J.

Pharm. ScL, 66, 1 , 19 (1 77). Salts are formed, for example, with strong acids such as mineral acids, e. g. sulphuric acid, phosphoric acid or hydrohalic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e. g., by halogen), such as acetic acid and trifiuoroacetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxy! ic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C l -4)-alkyl- or aryl-sulfonic acids which are substituted or unsubstituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. For example, the phrase "the compound" is to be understood as referring to various compounds of the invention or particular described aspect, unless otherwise indicated. Unless otherwise indicated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also provide a corresponding approximate measurement, modified by "about," where appropriate). The description herein of any aspect or aspect of the invention using terms such as "comprising", "having," "including," or "containing" with reference to an element or elements is intended to provide support for a similar aspect or aspect of the invention that "consists of, "consists essentially of, or "substantially comprises" that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of compounds of formula I or salts thereof. The process of the inventions offers the advantage of using more simple starting materials, that is to say substituted benzene derivatives. Compounds of formula I are accessible within four steps from the starting materials. The reactions employ simple and most importantly safe reagents, particularly avoiding the use of cyanide compounds with self-explanatory drawbacks. It is therefore an object of the present invention to provide a process for the preparation of compound of formula I or a salt thereof, wherein the benzene ring may be substituted by one or more substituents,

comprising conversion of compound of formula II, wherein the benzene ring may be substituted by one or more substituents

to compound of formula I or salt thereof, in the presence of a reducing agent.

The conversion of compound of formula II to compound of formula I encompasses the reduction of more than one functional groups. Carbon- 1 is reduced, by breaking a double bond with an oxygen atom and creating a double bond with another carbon atom. Carbon-2 is reduced by breaking a single bond with an oxygen atom and creating a double bond with another carbon atom. The nitrile group is reduced to the corresponding methylene amine group.

Due to the plurality of functional groups which need to be reduced to produce compound o formula I, a variety of reducing agents may be used. It may also be desirable to combine two or more reagents either to produce a reducing agent in situ, or to combine the properties of them. Additionally, a variety of reaction conditions, such as reaction time, solvent, temperature, equivalents, equipment, purity o starting and raw materials, as well as the presence or absence of air, may be chosen. All those factors, well-known to the skilled person, allow for control of the reduction, which can either result to the formation of intermediates of various oxidized states, as outlined above, or to the formation of compound of formula I. Those intermediates are encompassed by the process of the present invention and form part of its scope. The isolation of those intermediates is optional.

Compounds of formulae VI and VII are intermediates as those described above and will be discussed in further detail.

Reducing agents for several types of reduction reactions are disclosed in textbooks well-known in the art, such as March 's Advanced Organic Chemistry, M. B. Smith & J. March, John Wiley & Sons, ISBN 13:978-0-471 -72091-1. More recent discoveries in the field of reduction of chemical compounds involve the frustrated Lewis pair (FLP) reductions, described in the scientific literature. Representative examples are: a) Curr. Chem. 2013, 332, D. W. Stephan, G. Hrker; b) Org. Proc. Res, Dev. 2014, 18, 385, L. J. Hounjet, D. W. Stephan; c) J. Am. Chem. Soc. 2015, 137, 10018, D. W. Stephan and references cited therein. Representative FLP reagents are p- (Mes ₂ P)C ₆ F ₄ [B(C _fi F ₅ ) ₂ ], B(C ₆ F ₅ ) ₃ , C _i0 H ₆ (PPh ₂ ) ₂ / B(C ₆ F _S ) _3.

Preferable reducing agents are boranes, mixtures of borohydrides and boran halides, borohydrides, metal hydrides, metal catalysts, metal cations, metal amalgams, hydrazines, silanes, siloxanes. hydrosulfite, dithionite, sulfonate, phosphines, phosphites, hypophosphites, phosphorous acid, carbon, carbon monoxide, oxalic acid, formic acid, ascorbic acid, FLP reagents, hydrogen and mixtures thereof.

More preferable reducing agents are boranes, mixtures of borohydrides and boron halides, borohydrides, metal hydrides, metal catalysts, FLP reagents, hydrogen and mixtures thereof.

The conversion of compound of formula II to compound of formula I may be performed in an organic solvent or mixtures thereof. Preferable organic solvents are aprotic polar organic solvents.

The temperature of the reaction may be from 0 °C to the boiling point of the solvent. Preferable temperatures are from 0 °C to 160 °C. It is a further object of the present invention to provide intermediate compounds of the above process.

It is a further object of the present invention to provide a process for the preparation of compound of formula VI, comprising conversion of compound of formula II to compound of formula VI in the presence of a reducing agent. Said reducing agent should be capable of partially reducing compound of formula II, with respect to the three functional groups described above. Accordingly, the nitrile carbon is reduced to the respective amine, carbon-2 is reduced by eliminating the hydroxyl group and carbon- 1 is p

As already disclosed above, more than one reducing agents may be used to bring about this conversion. Additionally, the role of reaction conditions, as disclosed above, controls this reduction in the same way.

Preferable reducing agents are boranes, borohydrides, metal hydrides and mixtures thereof. It is another object of the present invention to provide a process for the preparation of compound of formula VII, comprising conversion of compound of formula II to compound of formula VII in the presence of a reducing agent. Said reducing agent should be capable of reducing only two of the three functional groups of compound of formula II as described above. Accordingly, carbon- 1 is reduced, by breaking the double bond with the oxygen atom and creating a double bond with carbon-2 which is also reduced by eliminating the hydroxyl group. The nitrile moiety remains intact.

As already disclosed above, more than one reducing agents may be used to bring about this conversion. Additionally, the role of reaction conditions, disclosed above, controls this reduction in the same way. Preferable reducing agents are boranes, mixtures of borohydrides and boran halides, borohydrides, metal hydrides, metal catalysts, metal cations, metal amalgams, hydrazines, silanes, siloxanes, hydrosulfite, dithionite, sulfonate, phosphines, phosphites, hypophosphites, phosphorous acid, carbon, carbon monoxide, oxalic acid, formic acid, ascorbic acid, FLP reagents, hydrogen and mixtures thereof.

More preferable reducing agents are boranes, mixtures of borohydrides and boron halides, borohydrides, metal hydrides, metal catalysts, FLP reagents, hydrogen and mixtures thereof. Another object of the present invention is use of compound of formula II for the preparation of compounds I, VI and VIL In a preferred embodiment, substituent A is a fluoro-atom at position 6 of the bicyclic core and compounds of formulae I, VI andVIl are compounds of formulae la, Via andVIIa respectively. In a preferred embodiment of the present invention, there is provided a process for the preparation of compound of formula la or a salt thereof, comprising conversion of compound of formula Ila, to compound of formula la in the presence of a reducing agent. The reducing agent used in this conversion should be capable of reducing all functional groups, as set forth above, i.e. carbon- 1 , carbon-2 and the nitrile group. This may require more than one reducing agents and a variety of conditions as discussed above.

Preferable reducing agents are boranes, mixtures of borohydrides and boran halides, borohydrides, metal hydrides, metal catalysts, metal cations, metal amalgams, hydrazines, silanes, siloxanes, hydrosulfite, dithionite, sulfonate, phosphines, phosphites, hypophosphites, phosphorous acid, carbon, carbon monoxide, oxalic acid, formic acid, ascorbic acid, FLP reagents, hydrogen and mixtures thereof.

More preferable reducing agents are boranes, mixtures of borohydrides and boron halides, borohydrides, metal hydrides, metal catalysts, FLP reagents,hydrogen and mixtures thereof.

The conversion of compound of formula Ila to compound of formula la may be performed in an organic solvent or mixtures thereof. Preferable organic solvents are aprotic polar organic solvents.

The temperature of the reaction may be from 0 °C to the boiling point of the solvent. Preferable temperatures are from 0 °C to 160 °C.

The conversion of compound of formula Ila to compound of formula la may involve a plurality of intermediates, as described above.

It is a further object of the present invention to provide said intermediate compounds and processes for their preparation.

It is a further object of the present invention to provide a process for the preparation of compound of formula Via, comprising conversion of compound of formula Ila to compound of formula Via in the presence of a reducing agent, as described above.

Preferable reducing agents are boranes, borohydrides, metal hydrides and mixtures thereof. More preferable reducing agents are metal hydrides. Even more preferable reducing agent is sodium bis(2-methoxyethoxy)aluminumhydride.

It is another object of the present invention to provide a process for the preparation of compound of formula Vila, comprising conversion of compound of formula Ila to compound of formula Vila in the presence of a reducing agent, as described above.

Preferable reducing agents are boranes. mixtures of borohydrides and boran halides, borohydrides, metal hydrides, metal catalysts, metal cations, metal amalgams, hydrazines, si lanes, siloxancs, hydrosulfite, dithionite, sulfonate, phosphines, phosphites, hypophosphites, phosphorous acid, carbon, carbon monoxide, oxalic acid, formic acid, ascorbic acid, FLP reagents, =hydrogen and mixtures thereof.

More preferable reducing agents are boranes, mixtures of borohydrides and boron halides, borohydrides, metal hydrides, metal catalysts, FLP reagents, hydrogen and mixtures thereof.

In a preferred embodiment o the present invention there is provided a process for the preparation of compound of formula la or a salt thereof, comprising conversion of compound of formula Ila, to compound of formula la in the presence of a reducing agent, characterized in that compound of formula Ila is first convened to compound of formula Vila and then compound of formula Vila is converted to compound of formula la. Intermediate compound of formula Vila may optionally be isolated.

In a preferred embodiment of the present invention the above mentioned process is performed without isolation of compound of formula Vila.

It is a further object of the present invention to provide a process for the preparation of compound of formula I or salt thereof as defined above, further comprising the reaction f compound of formula III, wherein the benzene ring may be substituted by one or more substituents, with cyanoacetic acid (VIII), to provide compound of formula II, as defined above.

The reaction of compound of formula III with cyanoacetic acid may be performed in an organic solvent or mixtures thereof. Preferable organic solvents are polar organic solvents. More preferable organic solvents are aprotic polar organic solvents.

The temperature of the reaction may be from 20 °C to the boiling point of the solvent. Preferable temperatures are from 20 °C to 160 °C.

In a preferred embodiment of the invention, compound of formula I is compound of formula la, compound of formula II is compound of formula Ila and compound of formula III is compound of formula Ilia.

It is a further object of the present invention to provide a process for the preparation of compound of formula VI from compound of formula II, as described above, further comprising the reaction of compound of formula III, as defined above, with a cyanoacetic acid (VIII), to provide compound of formula II, as described above.

In a preferred embodiment of the invention, compound of formula III is compound of formula Ilia, compound of formula II is compound of formula Ila and compound of formula VI is compound of formula Via. It is a further object of the present invention to provide a process for the preparation of compound of formula VII from compound of formula II, as described above, further comprising the reaction of compound of formula III, as defined above, with a cyanoacetic acid ( VIII), to provide compound of formula II, as described above. In a preferred embodiment of the invention, compound of formula III is compound of formula Ilia, compound of formula II is compound of formula lla and compound of formula VII is compound of formula Vila.

It is another object of the present invention to provide a process for the preparation of compound of formula la or salt thereof as defined above, further comprising the conversion of compound o formula IVa to compound of formula Va by reaction with chloral hydrate and hydroxylamine and conversion of formula Va to compound of formula Ilia, by cyclization of compound of formula Va in the presence of an acid.

Conversion of compound of formula IVa to compound of formula Va may be performed in a polar solvent or water.

Conversion of compound of formula Va to compound of formula Ilia may be performed under acidic conditions involving Brawnsted-Lowry acids. Non limiting examples are hydrohalic acids, sulfuric acid, acetic acid or similar. The step may also be performed with Lewis acids. Preferable are Brawnsted-Lowry acids.

It is yet another object of the present invention to provide compounds of formula II.

In a preferred embodiment of the invention, compound of formula II is compound of formula I la.

Compounds of formula I (tryptamines) and salts thereof, as defined above, may be used in the preparation of organic compounds, according to prior art. Preferred organic compounds are pharmaceutical organic compounds. More preferred organic compounds are indole-containing compounds. Indolc-containing compounds and their properties are discussed in the review "Biomedical importance of indoles", Molecules, 2013, 18, 6620 by N. K. Kaushik, N, Kaushik, P. Attri, N, Kumar, C. H. Kim, A. K. Verma and E, H. Choi.

Use of compounds of formula I (tryptamines) in the preparation of indole-containing compounds include the preparation of polycyclic compounds, containing the bicyclic core of the indole fused with another ring, which may be mono- or polycyclic. Examples from the art can be found in the following:

"Synthesis of naked amino-pyrroloindoline via direct aminocyclization of tryptamine", Org. Biom. Chem. 2015, 13, 5381, Z. Shen, Z. Xia, H, Zhao, J. Hu, X. Wan, Y. Lai, C, Zhu, W, Xie ;

"Synthesis of pyrroloindolines and furoindolines via cascade dearomatization of indole derivatives with carbenium ion", Chem. Comm. 2015, 51, 5971, C, Liu, Q. Yin, L.-X. Dai, S.-L. You;

- "Asymmetric Dearomatization of Indoles through a Michael/Friedcl - -Crafts- Type Cascade To Construct Polycyclic Spiroindolines" Angew. Chem. Int. Ed. 2015, 54, 4032, X. Zhao, X. Liu, H. Mei, J. Guo, L. Lin, X. Feng;

"Expedient Preparation of Nazlinine and a Small Library of Indole Alkaloids Using Flow Electrochemistry as an Enabling Technology", Organic Letters 2014, 16(17), 4618, M. A. Kabeshov, B. Musio, P. R. D. Murray, D. L. Browne, S. V. Ley;

- "Rhodium(I)-Catalyzed Cycloisomcrization of Nitrogen-Tethered Indoles and Alky lidenecyclopro panes: Convenient Access to Polycyclic Indole

Derivatives" Chem. Eur. 1 2013, 19, 13668, D.-H. Zhang, X.-Y. Tang, Y, Wei, M. Shi;

- "Gold(I)-Catalyzed Cascade Approach for the Synthesis of Tryptamine-Based

Polycyclic Privileged Scaffolds as a 1 -Adrenergic Receptor Antagonists", Journal of Organic Chemistry, 2013, 78, 10802, Z. Li, J. Li, N. Yang, Y. Chen, Y, Zhou, X. Ji, L. Zhang, J. Wang, X. Xie, H. Liu;

- "Gold and BINOL-Phosphoric Acid Catalyzed Enantioselective Hydroamination/ -Sulfonyliminium Cyclization Cascade" Organic Letters, 2013, 15, 4330, A. W. Gregory, P. Jakubec, P. Turner, D. J. Dixon; - "Enantioselective Michael Additioe/Iminium Ion Cyclization Cascades of Tryptam inc-Deri ved Ureas" Organic Letters, 2013, 15, 2946, I. Aillaud, D. M.

Barber, A. L. Thompson, D. J. Dixon;

"Access to Electron-Rich Arene-Fused Hexahydroquinolizinones through a Gold-Catalysis-Initiated Cascade Process" Angewandte Chemie International Edition 2012, 51 (29), 7301, L. Liu, L. Zhang;

"Racemic and diastereoselective construction of indole alkaloids under solvent- and catalyst-free microwave-assisted Pictet Spengler condensation"

Green Chemistry 2012, 14, 909, M. Jida, O.-M. Soueidan, B. Deprez, G. Laconde, R. Deprez-Poulain;

- "Enantioselective Bransted Acid-Catalyzed N-Acyliminium Cyclization Cascades" J. Am. Chem, Soc. 2009, 131, 10796, M. E. Muratore, C. A. Hollo way, A, W. Pilling, R. I. Storer, G, Trevitt, D, J. Dixon;

- "Enantioselective Pictet Spengler-Type Cyclizations of Hydroxy-lactams: H-

Bond Donor Catalysis by Anion Binding" J. Am. Chem. Soc. 2007, 129, 13404, I. T. Raheem, P. S. Thiara, E. A. Peterson, E. N. Jacobsen;

- "Spirocyclic cyclohexane derivatives", WO2004043967;

'Azepinoindole derivatives as pharmaceutical agents", WO2005056554;

- "Phenethyl amide derivatives and their heterocyclic analogues", WO2010044054;

- "Antitumoral analogs", WO2003014127;

- "Substituted beta-carbolines with ikb-kinase inhibiting activity", WO2001068648;

- "Beta-carbolines useful for treating inflammatory disease", WO2004092167, WO20051 1 1037,

Further use of compounds of formula I (tryptamines) in the preparation of indole- containing compounds include the use of tryptamines as building blocks as such or with small modifications on their core.

For instance, compound of formula la is used, according to WO2002078693, for the synthesis of Lu-AE-58054, which is a potent and selective 5-HTV, receptor antagonist. Further examples from the art are: "Design, Synthesis, and Structure-Activity Relationship of a Novel Series of GluN2C-Selective Potentiators", J. Med. Chem. 2014, 57, 2334, S. S. Zimmerman, A. hatri, E. C. Gamier-Amblard, P. Mullasseril, N, L, Kurtkaya, S. Gyoneva, K. B. Hansen, S. F. Traynelis, D. C. Liotta;

- "New Melatonin-N,N-Dibenzyl(N-methyl)amine Hybrids: Potent Neurogenic

Agents with Antioxidant, Cholinergic, and Neuroprotective Properties as Innovative Drags for Alzheimer's Disease" J. Med. Chem. 2014, 57, 3773, B. Lopez-Iglesias, C. Perez, J. A. Morales-Garcia, S. Alonso-Gil, A. Perez- Castillo, A. Romero, M. G. Lopez, M, Villarroya, S. Conde, M, I. Rodriguez- Franco;

"Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases", WO201 0142081 ;

- ' ryptamine sulfonamides as 5-HT ₆ antagonists", WO20090731 18;

- "Pyrimidine derivatives as AL -5 inhibitors", WO2008006583 ;

- "Piperidine-containing compounds and use thereof, W02Q 10080864;

- "Pyrazinone thrombin inhibitors", WO9740024;

"Novel substituted tryptamines, phenalkylamines and related compounds", W09526723. Another object of the present invention is, therefore, the use of compounds of Formula I and Formula II, as defined above, prepared according to the present invention, for the preparation of organic compound.

Yet another object of the present invention is the use of compound of formula II, as defined above, as an intermediate in the synthesis of an organic compound. Its usefulness derives from the property of providing access to compound of formula I or salt thereof. Compound of formula II preferably is compound of formula Ila. Organic compound may preferably be pharmaceutical organic compound. Even more preferably, organic compound may be indole-eontaining compound. Still more preferably, indole-eontaining compound is Idalopirdine.

A further object of the present invention is a process for the preparation of an organic compound, comprising the step of conversion of compound of formula II to compound of formula I in the presence of a reducing agent and further conversion of compound of formula I to an organic compound. Compound of formula II is preferably compound of formula I la. Organic compound may preferably be pharmaceutical organic compound. Even more preferably, organic compound may be indole-contairiing compound. Still more preferably, indole-containing compound is Idalopirdine.

EXAMPLESUriless otherwise noted, the materials used in the examples are obtained from readily available commercial sources or synthesized by standard methods well known to the person skilled in the art.

Example 1 : Preparation of compound of formula Va

Va

In a RB flask charge 6.0 gr of 3-fluoroaniline (IVa) (0.054 mole) in 375 ml D.M. water at 25-30 °C. To the above solution add 10.74 gr chloral hydrate (0.065 mole), 13.68 gr hydroxylamine hydrochloride (0.197 mole) and 61.38 gr sodium sulfate (0.432 mole). Warm up reaction mass to 50 °C and stir about 5 hours. Allow reaction mass to slowly cool down (25-30 °C). Continue stirring overnight at ambient temperature. To reaction mixture add, 18.6 ml hydrogen chloride 2N, under stirring, at 25-30 °C and stir about 30 minutes. Filter off precipitated solid through Buchner funnel and spray wash filter cake with 24 ml chilled D.M. water. Unload wet cake and dry in rotary under vacuum at 38-40 °C for 60 min, to provide 8.628 gr of crude compound of formula Va.

Ή NMR (300 MHz, DMSO-d6) 12.2 (s, 1H), 10.4 (s, 1H), 7.7 (m, 1H), 7.6 (s, 1H), 7.5 (m, 1 H), 7.4 (dd, J, = 15.1 Hz, J ₂ = 8.1 Hz, 1 H), 6.9 (td, J) = 8.4 Hz, J ₂ = 2.4 Hz, H I). °C NMR (75 MHz, DiMSO-d6) 162.0, 160.6, 143.9, 140.2, 130.4, 1 15.6, 1 10.3, 106.6. Example 2: Preparation of compound of formula Ilia

llla

In a RB flask charge under stirring 30 ml sulfuric acid and warm to 70 °C. Add in portions the crude wet cake (8,628 gr) of compound of formula Va and continue stirring at 80-90 °C. When reaction is completed, allow reaction mass to cool down to

25-30 °C. In a RB flask charge 282 ml D.M. water and ice and 180 ml ethyl acetate and stir vigorously. Add reaction mixture into the RB. Allow reaction mixture to warm up to 25-30 °C and further stir for about 10 minutes. Collect organic layer. Extract aqueous layer twice with 180 ml ethyl acetate (each time). Combine organic layers, dry over sodium sulfate, filter off and evaporate solvent till total dryness, to provide 6.914 gr of crude compound of formula Ilia.

Ή NMR (300 MHz, DMSO-d6) 1 1.2 (br, 1H) 7.6 (dd, J _/ = 8.3 Hz, J ₂ = 5.8 Hz, 1H), 6.9 (ddd, J _/ = 10.4 Hz, J ₂ = 8.5 Hz, J ₃ = 2.2 Hz, 1H), 6.7 (dd, J, = 9,2 Hz, J-> = 2.2 Hz, 1H). ^{i 3} C NMR (75 MHz, DMSO-d6) 182.3, 168.0, 159.7, 153.3, 127.8, 1 14.7, 109.6,

100.2.

Example 3: Preparation of compound of formula Ila

In a RB flask charge under stirring at 25-30 °C, 3.36 gr of crude compound of formula Ilia (0.0203 mole) and dissolve in 33.6 mL tetrahydrofuran. To the clear solution add 1.902 gr cyanoacetic acid (0.0224 mole) and 2.7 mL triethylamine (0.0194 mo!e). Warm up reaction mass to reflux and continue stirring overnight. When reaction is completed, allow reaction mass to cool down (25-30 °C). Concentrate solvent till total dryness. To the oily residue add 168 mL D.M. water and extract three times with 336 mL ethyl acetate (each time). Combine organic layers, dry over sodium sulfate, filter and evaporate solvent till total dryness, to provide 4.1 16 gr of crude compound of formula Ila.

1 H NMR (300 MHz, DMSO-d6) 7.47 (dd, Jl = 8.2 Hz, J2 = 5.6 Hz, IH), 6.89 - 6.82 (m, I H), 6.7 (dd, Jl = 9.2 Hz, J2 - 2.4 Hz, I H), 6.64 (s, 111), 3.36 (s, IH), 3.09- 2.94 (m, 2H). 13C NMR (75 MHz, DMSO-d6) 177.4, 163.6, 143.9, 143.8, 126.2, 1 17.4, 108.5, 98.7, 72.0, 26.4.

Example 4: Preparation of compound of formula la as the hydrochloride salt

ia

In a RB flask, charge 0.2 gr of compound of formula Ila (0.00097 mole) under argon atmosphere and dilute with 5 ml dry tetrahydrofuran at 25-30 °C. Add to the clear solution 1.2 ml borane dimethyl sulfide (2M in THF) (0.0024 mole) and continue stirring at ambient temperature (25-30 °C). When the starting material is consumed add to the reaction mass 0.085 gr of sodium borohydride (0.0023 mole) at 25-30 °C. When the intermediate compound is consumed, add to reaction mass 10 mi sodium hydroxide 10% and stir vigorously. Collect organic layer and concentrate to dryness. Dilute with 5 ml dichloromethane and add 5 ml hydrogen chloride 6N. Extract and collect aqueous layer. Distill off solvent till total dryness under reduced pressure, to provide 0.067 gr light yellow solid of compound of Formula la as the hydrochloride salt.

Ή NMR (300 MHz, CD ₃ OD) 7.56 (dd, J, = 8.6 Hz, J ₂ = 5.2 Hz, 1H), 7.21 (s, 1H),

7.10 (dd, Ji = 10.0 Hz, J ₂ = 2.1 Hz, 1 H), 6.85 (td, J _/ = 9.7 Hz, J ₂ = 2.3 Hz, IH), 3.3 (s, 2H), 3.25 (tr, J = 7.2 Hz, 2H), 3.15 (tr, J = 7.3 Hz, 2H). ⁱ³ C NMR (75 MHz, CD ₃ OD) 159.0, 136.9, 123.5, 123.4, 1 18.5, 109.2, 107.1, 97.0, 39.9, 23.0. Example 5: Preparation of compound of formula la as the hydrochloride salt

In a RB flask, charge 0.5 gr of compound of formula Ila (0.00243 mole) under argon atmosphere and dilute with 15 ml dry Tetrahydrofuran at 25-30 °C. Add to the clear solution 4.2 ml borane dimethyl sulfide (2M in 1 ^' HF) (0.0084 mole) and continue stirring at ambient temperature (25-30 °C). When the starting material is consumed add to the reaction mass 0.23 gr of sodium borohydride (0.0061 mole) at 25-30 °C. When the intermediate compound is consumed, cool down reaction mass (0-5 °C) and add 42 ml sodium hydroxide 10% and stir vigorously. Collect organic layer and acidify using 1.2 ml hydrogen chloride 2M in diethyl ether (0.0243 mole). Distill off solvent till total dryness under reduced pressure. To the residue add 20 ml dichloromethane. Filter through Buchner funnel. 0.5 gr of off-yellow solid of compound of formula la as the hydrochloride salt isolated. Example 6: Preparation of compound of formula la

la

In a RB flask, charge 20 ml 1 ,2-dimethoxyethane and then add 0.64 gr sodium borohydride (0.0169 mole). Cool suspension mass to (0-5 °C) and add 1.0 gr of compound of formula Ila and 4.4 ml boron tri fluoride etherate (0.0347 mole). Let reaction mass to warm to room temperature and continue stirring till reaction completion. Cool down reaction mixture (0-5 °C) and quench with 50 ml Methanol. Let to warm and concentrate solvent till total dryness. Add to suspension mass 50 ml ethyl acetate and 25 mi sat. sodium hydrogen carbonate. Extract one more time the aqueous layer with 50 ml ethyl acetate. Combine organic layers, dry over sodium sulfate and concentrate till dryness to afford 1.3 gr of crude compound of Formula la as free base.

In a RB flask, charge 0.1 gr of compound Ila (0.485 mmole) and dilute with 2 ml tetrahydrofuran (25-30 °C). To the clear solution add 0.42 ml sodium bis(2- methoxyethoxy)aluminumhydride (Red-Al) (0.00145 mole). When reaction is completed, add to reaction mixture 5 ml D.M. water and 10 ml ethyl acetate. Collect organic layer. Extract the aqueous layer with 10 ml ethyl acetate. Combine organic layers and extract with 5 ml D. M. water. Collect organic layer, dry over sodium sulfate, filter and concentrate till dryness to afford 0.124 gr of crude red oil. Purify the above oil using column chromatography to isolate 0.054 gr of light yellow oil (compound of formula Via).

Ή NMR (300 MHz, DMSO-d6) 7.03 (dd, J _/ = 7.9 Hz, J ₂ = 6.2 Hz, 1H), 6.24 (m, 1H), 6.13 (m, 1 H), 4.7 (s, 1H), 2.88 (m, 1H), 2.52 (m, 1H), 1.94 (m, 3H).

Example S: Preparation of compound of formula Vila

Vila

In a RB flask charge under stirring at 25-30 "C, 0.1 gr of crude compound of formula Ila (0.485 mmole) and dissolve in 2 ml tetrahydrofuran. To the clear solution add 0.55 ml borane dimethyl sulfide (2M in THF) (0.0023 mole). When reaction is completed, add 5 ml ethyl acetate and 5 ml hydrogen chloride IN and stir. Collect organic layer, dry over sodium sulfate, filter and evaporate solvent till total dryness, to provide 0.1 gr of crude compound of formula Vila. Purification with column chromatography provided 0.74 g of said compound.

Ή NMR (300 MHz, CDC13) 8.17 (br, 1H), 7.50 (dd, J _/ = 8.6 Hz, J ₂ = 5.2 Hz, 7.21 (s, H I), 7.08 (d, J= 9.5 Hz, 1H), 6.96 (tr, J= 9.2 Hz, 1H), 3.82 (s, 2H). Example 9: Preparation of compound of formula Vila

In a RJB flask charge under Argon atmosphere, at 25-30 °C, 0.1 gr of compound of formula Ila (0.485 mmoles) and dissolve in 2 ml dry tetrahydrofuran. To the clear solution add 0.055 gr sodium borohydride (1.455 mmoles) and continue stirring. Add dropwise, to reaction mass 0.3 ml boron tri fluoride etherate (1.3 1 mmoles) and continue stirring at ambient temperature. Thin layer chromatography analysis shows the consumption of the starting material and the formation of compound of formula Vila.

Example 10: Preparation of compound of formula Vila

In a RB flask charge under Argon atmosphere at 25-30 °C, 1.4 gr of crude compound of formula Ila and dissolve in 20 ml dry tetrahydrofuran. To the clear solution add dropwise 6.1 ml borane dimethyl sulfide (2M in THF) (12.12 mmoles) and continue stirring at ambient temperature. Add to reaction mass 0.46 gr of sodium borohydride (12.12 mmoles) and continue stirring. Thin layer chromatography analysis shows the consumption of the starting material and the formation of compound of formula Vila.