RU2772513C2 - Methods for producing indolinobenzodiazepine derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to methods for producing indolinobenzodiazepine monomer precursors, namely to a method for producing a compound of the formula (I) or its salt, including bringing into interaction a compound of the formula (II) or its salt with Fe in the presence of NH₄Cl, where R₁, R₂, R₃ and R₄, each independently, is -H; R₅ is OR, where R is selected from (C₁-C₃)alkyl. The invention also relates to a method for producing a compound of the formula (III) or its salt, including bringing into interaction the compound of the formula (I) or its salt with a hydrogenating agent in the presence of a palladium catalyst, where the hydrogenating agent is 1,4-cyclohexadiene; the palladium catalyst is Pd/Alox catalyst; R₁, R₂, R₃ and R₄, each independently, is -H; R₅ is -OR, where R is selected from (C₁-C₃)alkyl.

EFFECT: methods for producing indolinobenzodiazepine monomer precursors are developed that are more effective and suitable for large-scale process of production of cytotoxic indolinobenzodiazeoine dimeric compounds.

85 cl, 3 ex

Description

RELATED APPLICATION

This application, pursuant to USC 35 §119(e), claims priority over the filing date of U.S. Provisional Application No. 62/487,695, filed April 20, 2017, the entire contents of which are incorporated herein by reference.

FIELD OF TECHNOLOGY

This invention relates to new processes for the preparation of indolinobenzodiazepine derivatives.

BACKGROUND OF THE INVENTION

Benzodiazepine derivatives are useful in the treatment of various disorders and include drugs such as antiepileptics (imidazo[2,1-b][1,3,5]benzothiadiazepines, US Pat. No. 4,444,688; US Pat. No. 4,062,852, antibacterial agents (pyrimido[1 ,2-c][1,3,5]benzothiadiazepines, GB 1476684), diuretics and antihypertensives (pyrrolo(1,2-b)[1,2,5]benzothiadiazepine 5.5 dioxide, US patent No. 3506646), lipid-lowering agents (WO 03091232), antidepressants (US patent No. 3453266), osteoporosis treatment agents (JP 2138272).

It has recently been shown that cell-binding agent conjugates of indolinobenzodiazepine dimers can inhibit tumor growth in vitro and in vivo in animal models. See, for example, WO 2010/091150, WO 2016/036801, WO 2016/036804. In addition, indolinobenzodiazepine dimer cell-binding agent conjugates that contain one imine functional group and one amine functional group have been shown to exhibit a much higher therapeutic index (the ratio of the maximum tolerated dose to the minimum effective dose) in vivo compared to those described. formerly benzodiazepine derivatives containing two imine functional groups. See, for example, WO 2012/128868.

Thus, there is a need for improved methods for the preparation of precursors of indolinobenzodiazepine monomers that are more efficient and applicable to large scale manufacturing processes for the production of cytotoxic indolinobenzodiazepine dimer compounds.

SUMMARY OF THE INVENTION

The present invention provides improved synthetic methods for the preparation of indolinobenzodiazepine monomeric compounds and their synthetic precursors. Compared to the previously described methods, the methods of the present invention are more suitable for a large scale manufacturing process.

In one embodiment, this invention provides a process for preparing a compound of formula (I):

(I),

(I)

or a salt thereof, comprising bringing into interaction a compound of formula (II):

(II)

(II)

or its salt with Fe in the presence of NH ₄ Cl, where:

R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from -H, optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl containing from 1 to 10 carbon atoms, -(CH ₂ CH ₂ X) _n -R ^c , halogen, -NH(C=NH)NH ₂ , -OR, -NR'R'', -NCO, -NR'COR'', -SR, -SOR', -SO ₂ R', - SO ₃ H, -OSO ₃ H, -SO ₂ NR'R'', cyano, azido, -COR', -OCOR' and -OCONR'R'';

X is O, NH or S;

R ₅ is -H, -R, -OR, -SR, -NR'R'' or halo;

R for each occurrence is independently selected from -H, optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl containing from 1 to 10 carbon atoms, polyethylene glycol unit -(CH ₂ CH ₂ X) _n -R ^c , optionally substituted aryl, containing from 6 to 18 carbon atoms, an optionally substituted 5-18-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 3-18-membered heterocyclic ring containing from 1 to 6 heteroatoms , independently selected from O, S, N and P;

R' and R'' are each independently selected from -H, -OH, -OR, -NHR, -NR ₂ , -COR, optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl containing from 1 to 10 atoms carbon, polyethylene glycol link -(CH ₂ CH ₂ X) _n -R ^c and optionally substituted 3-18-membered heterocyclic ring containing from 1 to 6 heteroatoms independently selected from O, S, N and P;

R ^c represents -H or substituted or unsubstituted linear or branched alkyl containing from 1 to 4 carbon atoms; and

n is an integer from 1 to 24.

In another embodiment, this invention provides a process for preparing a compound of formula (III):

(III),

(III)

or a salt thereof, comprising bringing into interaction a compound of formula (I):

(I),

(I)

or a salt thereof with a hydrogenating agent in the presence of a palladium catalyst, the variables being as defined above.

In another embodiment, this invention provides a process for preparing a compound of formula (III):

(III),

(III)

or a salt thereof, comprising the steps of:

a) bringing into interaction the compounds of formula (II):

(II)

(II)

with Fe in the presence of NH ₄ Cl to give a compound of formula (I):

(I); и

(I); and

b) reacting a compound of formula (I) with a hydrogenating agent in the presence of a palladium catalyst to give a compound of formula (III), the variables being as defined above.

This invention also provides the compounds described herein, such as compounds of formula (IV), (V), (IVA), (VA) or salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The following is a detailed description of some embodiments of the present invention, examples of which are illustrated by the accompanying structures and formulas. Although the present invention will be described in accordance with the numbered embodiments, it should be understood that they are not intended to limit the present invention to the indicated embodiments. On the contrary, this invention attempts to cover all alternatives, modifications and equivalents that may be included within the scope of this invention as defined by the claims. Those skilled in the art will recognize numerous methods and materials similar or equivalent to those described herein that may be used in the practice of the present invention.

It should be understood that any of the embodiments described herein may be combined with one or more other embodiments of the present invention, unless expressly disproved or not possible. The combination of implementation options is not limited to those specific combinations that are claimed in numerous dependent claims.

DEFINITIONS

" Alkyl " in this context refers to a saturated linear or branched monovalent hydrocarbon radical. In preferred embodiments, straight or branched alkyl contains thirty or fewer carbon atoms (eg, C ₁ -C ₃₀ for a straight chain alkyl group and C ₃ -C ₃₀ for a branched alkyl group), and more preferably twenty or fewer carbon atoms. Even more preferably, straight or branched alkyl contains ten or fewer carbon atoms (ie, C ₁ -C ₁₀ for straight alkyl and C ₃ -C ₁₀ for branched alkyl). In other embodiments, straight or branched alkyl contains six or fewer carbon atoms (ie, C ₁ -C ₆ for straight alkyl or C ₃ -C ₆ for branched alkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, -CH ₂ CH(CH ₃ ) ₂ , 2-butyl, 2-methyl -2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1 -hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl , 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, and the like. In addition, the term "alkyl" in the context of this description, examples and claims includes both "unsubstituted alkyls" and "substituted alkyls", and the latter refers to alkyl fragments having substituents replacing hydrogen on one or more carbon atoms in a hydrocarbon skeleton. In this context, (C _x -C _xx )alkyl or C _x-xx alkyl means linear or branched alkyl containing x-xx carbon atoms.

" Alkenyl " in this context refers to a linear or branched monovalent hydrocarbon radical containing from two to twenty carbon atoms and at least one center of unsaturation, i.e. a carbon-carbon double bond, wherein alkenyl radicals include radicals having "cis" and "trans" orientations, or alternatively "E" and "Z" orientations. Examples include, but are not limited to, ethyleneyl or vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), and the like. Preferably, alkenyl contains from two to ten carbon atoms. More preferably, alkyl contains two to four carbon atoms.

" Alkynyl " in this context refers to a linear or branched monovalent hydrocarbon radical containing from two to twenty carbon atoms and at least one center of unsaturation, i.e. triple carbon-carbon bond. Examples include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, hexynyl, and the like. Preferably, the alkynyl contains two to ten carbon atoms. More preferably, alkynyl contains two to four carbon atoms.

The terms " cyclic alkyl " and " cycloalkyl " may be used interchangeably. As used herein, these terms refer to a saturated ring radical. In preferred embodiments, cycloalkyls contain 3-10 carbon atoms in their ring structure, and more preferably 5-7 carbon atoms in their ring structure. In some embodiments, two cyclic rings may share two or more atoms, for example, such rings are "fused rings". Useful cycloalkyls include cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl. In some embodiments, cycloalkyl is a monocyclic group. In some embodiments, cycloalkyl is a bicyclic group. In some embodiments, the cycloalkyl is a tricyclic group.

The term " cyclic alkenyl " refers to a carbocyclic ring radical containing at least one double bond in the ring structure.

The term " cyclic alkynyl " refers to a carbocyclic ring radical containing at least one triple bond in the ring structure.

The term " aryl " as used herein includes substituted or unsubstituted single ring aromatic groups in which each ring atom is a carbon. Preferably, the ring is a 5-7 membered ring, more preferably a 6 membered ring. Aryl groups include phenyl, phenol, aniline, and the like. The term "aryl" also includes "polycyclyl", "polycycle" and "polycyclic" ring systems containing two or more rings, in which two or more atoms are shared by two adjacent rings, for example, the rings are "fused" rings, and at least one of the rings is aromatic, for example other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls. In some preferred embodiments, the polycycles contain 2-3 rings. In some preferred embodiments, polycyclic ring systems contain two cyclic rings, both rings being aromatic. Each of the polycycle rings may be substituted or unsubstituted. In some embodiments, each polycycle ring contains 3 to 10 ring atoms, preferably 5 to 7. For example, aryl groups include, but are not limited to, phenyl (benzene), tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl, and the like.

In some embodiments, the aryl is a single ring aromatic group. In some embodiments, the aryl is a two ring aromatic group. In some embodiments, the aryl is a three ring aromatic group.

The terms " heterocycle ", " heterocyclyl " and " heterocyclic ring " in this context refer to substituted or unsubstituted non-aromatic ring structures of 3-18 membered rings, preferably 3-10-membered rings, more preferably 3-7-membered rings, ring whose structures contain at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. In some embodiments, the ring structure may contain two cyclic rings. In some embodiments, two cyclic rings may share two or more atoms, for example, such rings are "fused rings". Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968), in particular chapters 1, 3, 4, 6, 7 and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 b.c.), in particular vols. 13, 14, 16, 19 and 28; and J. Am. Chem. soc. (1960) 82:5566. Examples of heterocyclic rings include, but are not limited to, tetrahydrofuran, dihydrofuran, tetrahydrothien, tetrahydropyran, dihydropyran, tetrahydrothiopyranyl,

thiomorpholine, thioxazine, homopiperazine, azetidine, oxetane, thietane, homopiperidine, oxepan, thiepane, oxazepine, diazepine, thiazepine, 2-pyrroline, 3-pyrroline, indoline, 2H-pyran, 4H-pyran, dioxanil, 1,3-dioxolane, pyrazoline, dithian, dithiolane, dihydropyran, dihydrothien, dihydrofuran, pyrazolidinylimidazoline, imidazolidine, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptane, and azabicyclo[2.2.2]hexane. This definition also includes spiro moieties. Examples of a heterocyclic group in which ring atoms are substituted with oxo (=O) moieties are pyrimidinone and 1,1-dioxo-thiomorpholine.

The term " heteroaryl " as used herein refers to substituted or unsubstituted aromatic single ring structures, preferably 5-7 membered rings, more preferably 5-6 membered rings, whose ring structures contain at least one heteroatom (e.g. 0, N or S ), preferably one to four or one to 3 heteroatoms, more preferably one or two heteroatoms. When there are two or more heteroatoms in the heteroaryl ring, they may be the same or different. The term "heteroaryl" also includes "polycyclyl", "polycycle" and "polycyclic" ring systems containing two or more rings, in which two or more atoms are shared by two adjacent rings, for example, the rings are "fused" rings, and at at least one of the rings is heteroaromatic, eg other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. In some preferred embodiments, preferred polycycles contain 2-3 rings. In some embodiments, preferred polycyclic ring systems contain two cyclic rings, both rings being aromatic. In some embodiments, each polycycle ring has 3 to 10 ring atoms, preferably 5 to 7. For example, heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine , pyridazine, quinoline, pyrimidine, indolizine, indole, indazole, benzimidazole, benzothiazol, benzofuran, benzothiophene, cinnoline, phthalazine, quinazoline, carbazole, phenoxazine, quinoline, purine, etc.

In some embodiments, heteroaryl is a single ring aromatic group. In some embodiments, heteroaryl is a two ring aromatic group. In some embodiments, heteroaryl is a three ring aromatic group.

Heterocyclic or heteroaryl groups may be attached via a carbon atom (carbon-linked) or via a nitrogen atom (nitrogen-linked), if possible. By way of example, and not limitation, carbon-linked heterocycles or heteroaryls are bonded at the 2, 3, 4, 5, or 6 position of pyridine, at the 3, 4, 5, or 6 position of pyridazine, at the 2, 4, 5, or 6 position of pyrimidine, at position 2, 3, 5 or 6 of pyrazine, position 2, 3, 4 or 5 of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4 or 5 of oxazole, imidazole or thiazole, position 3, 4 or 5 isoxazole, pyrazole or isothiazole, in position 2 or 3 of aziridine, in position 2, 3 or 4 of azetidine, in position 2, 3, 4, 5, 6, 7 or 8 of quinoline or in position 1, 3, 4, 5, 6, 7 or 8 isoquinoline.

By way of example, and not limitation, nitrogen-linked heterocycles or heteroaryls are linked at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, at position 2 of isoindole or isoindoline, at position 4 of morpholine, and at position 9 of carbazole or O-carboline.

Heteratoms present in heteroaryl or heterocyclyl include oxidized forms such as NO, SO and SO ₂ .

The term " halide " or " halogen " refers to F, Cl, Br, or I. In one embodiment, the halide is Cl.

The term " compound " includes compounds or any derivatives thereof, the structure or formula of which is described in this invention, or compounds or any derivatives thereof, the structure or formula of which is incorporated by reference. The term also includes stereoisomers, geometric isomers or tautomers. The specific reference to "stereoisomers", "geometric isomers", "tautomers", "salts" in certain aspects of the present invention described in this application should not be construed as an intentional omission of these forms in other aspects of the present invention, where the term "compound" is used without indications of such other forms.

The term " predecessor " of a given group refers to any group that can lead to the preparation of this group by any deprotection, chemical modification, or coupling reaction.

The term " chiral " refers to molecules that have the mirror-image misalignment property, while the term "achiral" refers to molecules that, when superimposed, match their mirror image.

The term " stereoisomer " refers to compounds that have the same chemical nature and bond sequence, but a different orientation of atoms in space, which cannot be converted into each other by rotation around single bonds.

" Diastereomer " refers to a stereoisomer with two or more centers of chirality whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high resolution analytical techniques such as crystallization, electrophoresis and chromatography.

" Enantiomers " refers to two stereoisomers of a compound that are mismatched mirror images of each other when superimposed.

Stereochemical definitions and conventions used in this context are generally those of S. P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and therefore may exist in various stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of this invention, including but not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, form part of this invention. Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane polarized light. When describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule with respect to its chiral center(s). The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane polarized light by the compound, where (-) or 1 indicates that the compound is left-handed. Connection with a prefix (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. An individual stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may be the case if the chemical reaction or method is not stereoselective or stereospecific. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species devoid of optical activity.

The term " tautomer " or " tautomeric form " refers to structural isomers of different energies that cannot be converted into each other across a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include proton migration interconversions, such as keto-enol and imine-enamine isomerization. Valence tautomers involve interconversions by rearranging some of the bonding electrons.

The expression " salt " in this context refers to organic or inorganic salts of the compounds according to this invention. Illustrative salts include, but are not limited to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, hydrophosphate, isonicotinate, lactate, salicylate, hydrocitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate , succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e. 1,1'-methylene-bis-( 2-hydroxy-3-naphthoate)) salts, alkali metal salts (eg sodium and potassium), alkaline earth metal salts (eg magnesium) and ammonium salts. The salt may include another molecule such as an acetate ion, a succinate ion, or another counterion. The counterion can be any organic or inorganic fragment that stabilizes the charge of the parent compound. Also, a salt can have more than one charged atom in its structure. In those cases in which multiply charged atoms are part of the salt, there may be several counterions. Therefore, the salt may contain one or more charged atoms and/or one or more counterions.

If the compound of this invention is a base, then the desired salt can be obtained by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidilic acid such as glucuronic acid or galacturonic acid, an alpha hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid, etc.

If the compound of this invention is an acid, then the desired salt may be obtained by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, or the like. P. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

In some embodiments, the salt is a pharmaceutically acceptable salt. The phrase " pharmaceutically acceptable " means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients in the composition and/or with the body of the mammal being treated.

METHODS OF THE INVENTION

In the first embodiment of the present invention, a method for preparing a compound of formula (I) is provided:

(I),

(I)

or a salt thereof, comprising bringing into interaction a compound of formula (II):

(II)

(II)

or its salt with Fe in the presence of NH ₄ Cl, where:

R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from -H, optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl containing from 1 to 10 carbon atoms, -(CH ₂ CH ₂ X) _n -R ^c , halogen, -NH(C=NH)NH ₂ , -OR, -NR'R'', -NCO, -NR'COR'', -SR, -SOR', -SO ₂ R', - SO ₃ H, -OSO ₃ H, -SO ₂ NR'R'', cyano, azido, -COR', -OCOR' and -OCONR'R'';

X is O, NH or S;

R ₅ is -H, -R, -OR, -SR, -NR'R'' or halo;

R for each occurrence is independently selected from -H, optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl containing from 1 to 10 carbon atoms, polyethylene glycol unit -(CH ₂ CH ₂ X) _n -R ^c , optionally substituted aryl, containing from 6 to 18 carbon atoms, an optionally substituted 5-18-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 3-18-membered heterocyclic ring containing from 1 to 6 heteroatoms , independently selected from O, S, N and P;

R' and R'' are each independently selected from -H, -OH, -OR, -NHR, -NR ₂ , -COR, optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl containing from 1 to 10 atoms carbon, polyethylene glycol link -(CH ₂ CH ₂ X) _n -R ^c and optionally substituted 3-18-membered heterocyclic ring containing from 1 to 6 heteroatoms independently selected from O, S, N and P;

R ^c represents -H or substituted or unsubstituted linear or branched alkyl containing from 1 to 4 carbon atoms; and

n is an integer from 1 to 24.

In a second embodiment of the present invention, a process for preparing a compound of formula (IA) is provided:

(IA),

(IA)

or a salt thereof, comprising reacting a compound of formula (IIA):

(IIA)

(IIA)

or its salt with Fe in the presence of NH ₄ Cl.

In the third embodiment of the present invention, a method for preparing a compound of formula (III) is provided:

(III),

(III)

or a salt thereof, comprising bringing into interaction a compound of formula (I):

(I),

(I)

or a salt thereof with a hydrogenating agent in the presence of a palladium catalyst, the variables being as defined above in the first embodiment. Reaction of a compound of formula (I) with a hydrogenating agent and a palladium catalyst results in debenzylation of the benzyl group to form a compound of formula (III).

In a fourth embodiment of the present invention, a process for preparing a compound of formula (IIIA) is provided:

(IIIA),

(IIIA),

or a salt thereof, comprising reacting a compound of formula (IA):

(IA),

(IA)

or a salt thereof with a hydrogenating agent in the presence of a palladium catalyst.

In a fifth embodiment of the present invention, a process for preparing a compound of formula (III) is provided:

(III),

(III)

or a salt thereof, comprising the steps of:

a) bringing into interaction the compounds of formula (II):

(II)

(II)

with Fe in the presence of NH ₄ Cl to give a compound of formula (I):

(I); и

(I); and

b) reacting a compound of formula (I) with a hydrogenating agent in the presence of a palladium catalyst to give a compound of formula (III), the variables being as defined above in the first embodiment.

In a sixth embodiment of the present invention, a process for preparing a compound of formula (IIIA) is provided:

(IIIA),

(IIIA),

or a salt thereof, comprising the steps of:

a) bringing into interaction the compounds of formula (IIA):

(IIA)

(IIA)

with Fe in the presence of NH ₄ Cl to give a compound of formula (IA):

(IA); и

(IA); and

b) reacting a compound of formula (IA) with a hydrogenating agent in the presence of a palladium catalyst to give a compound of formula (IIIA).

In ^{the 1st} specific embodiment, for the method of the first, second, fifth or sixth embodiment, the reaction of a compound of formula (II) or (IIA) and Fe/NH ₄ Cl is carried out in a solvent or mixture of solvents. Any suitable solvent or mixtures of solvents may be used. Illustrative solvents include, but are not limited to, tetrahydrofuran (THF), 2-methyltetrahydrofuran (Me-THF), N-methyl-2-pyrrolidone (NMP), methanol, ethanol, isopropanol, dichloromethane, dichloroethane, acetonitrile, dimethylformamide (DMF) , dimethylacetamide, cyclopentyl methyl ether (CPME), ethyl acetate, water, and combinations thereof. In some embodiments, the reaction is carried out in a mixture of water and one or more organic solvents. Any suitable organic solvents described above can be used. In a more specific embodiment, the reaction is carried out in a mixture of THF, methanol and water.

In ^{the 2nd} embodiment, for the method of the 1st, 2nd, 5th or 6th embodiment or the 1st ^embodiment , the reaction between a compound of formula (II) or (IIA) and Fe/NH ₄ Cl is carried out at a temperature of 0° C to 100 °C, 20 °C to 100 °C, 40 °C to 90 °C, 50 °C to 80 °C or 60 °C to 70 °C. In a more specific embodiment, the reaction is carried out at 65°C.

In this context, the term value1 to value2 means a value that is greater than or equal to value1 and less than or equal to value2.

In this context, the term "value1 - value2" means a value that is greater than or equal to value1 and less than or equal to value2.

In some embodiments, for the method of the first, second, fifth, or sixth embodiment, or the ^1st or 2nd ^specific embodiment, the reaction between a compound of formula (II) or (IIA) and Fe/NH ₄ Cl may be carried out for a suitable a time interval such as 1 hour to 1 week, 4 hours to 72 hours, 10 hours to 72 hours, 24 hours to 72 hours, 4 hours to 10 hours, or 10 hours to 24 hours. In a particular embodiment, the reaction is carried out for 48 hours.

In some embodiments, for the method of the first, second, fifth, or sixth embodiment, or the ^1st or 2nd ^specific embodiment, the reaction between a compound of formula (II) or (IIA) and Fe/NH ₄ Cl is carried out under an inert atmosphere, for example, in an atmosphere of N ₂ , Ar, etc. In a particular embodiment, the reaction is carried out under N ₂ atmosphere.

In some embodiments, for the method of the first, second, fifth, or sixth embodiment, or of the ^1st or 2nd ^specific embodiment, a compound of formula (I) or (IA) obtained by reaction between a compound of formula (II) or (IIA ) and Fe/NH ₄ Cl, purified. Any suitable purification methods may be used, such as precipitation, recrystallization, column chromatography, or combinations thereof. In some embodiments, precipitation, recrystallization, or a combination of both can be used to purify a compound of formula (I) or (IA). Thus, multiple (eg, two, three, four, etc.) precipitations or recrystallizations, or combinations thereof, may be used to purify a compound of formula (I) or (IA).

As used herein, " recrystallization " refers to a process for purifying a solid by which the atoms, molecules or ions of the resulting purified solid are arranged in a highly organized structure(s) known as crystalline form(s). Recrystallization can be carried out in various ways such as cooling, evaporation, addition of a second solvent (i.e., anti-solvent), etc.

In this context, " precipitation " refers to a purification process by which a solid is formed from a solution containing a solid dissolved in it. Precipitation can often be accomplished by lowering the temperature of the solution, or by adding a second solvent (ie, anti-solvent) that substantially reduces the solubility of the desired solid in solution. The solid produced by the precipitation process may be in one or more amorphous forms, one or more crystalline forms, or combinations thereof.

In the ^3rd specific embodiment, for the method of the first, second, fifth or sixth embodiment or the ^1st or 2nd ^specific embodiment, a compound of formula (I) or (IA) obtained by reaction between a compound of formula (II) or (IIA) and Fe/NH ₄ Cl, purified by recrystallization or precipitation in a mixture of dichloromethane and ethanol. In a more specific embodiment, the volume ratio of dichloromethane to ethanol is 5:1 to 1:2, 4:1 to 1:1.5, 3:1 to 1:1.5, or 2:1 to 1:1 ,2. In a particular embodiment, the volume ratio of dichloromethane to ethanol is 1:1. In some embodiments, the recrystallization is carried out overnight.

Alternatively, the compound of formula (I) or (IA) is purified by recrystallization or precipitation in a mixture of toluene and acetonitrile. In one embodiment, the compound of formula (I) or (IA) is dissolved in toluene at an elevated temperature, for example at 40°C to 90°C, 50°C to 90°C, 60°C to 90°C , from 70 °С to 90 °С or from 75 °С to 85 °С. In another, even more specific embodiment, the compound of formula (I) or (IA) is dissolved in toluene at 80°C followed by the addition of acetonitrile to recrystallize or precipitate the compound of formula (I) or (IA). Optionally, the compound of formula (I) or (IA) is filtered after being dissolved in toluene before adding acetonitrile. In one embodiment, the volume ratio of toluene to acetonitrile is 1:10 to 2:1, 1:5 to 1:1, 1:3 to 1:1, or 1:2 to 1:1. In a particular embodiment, the volume ratio of toluene to acetonitrile is 1:1.5.

In ^{the 4th} embodiment, for the methods of ^the 3rd embodiment described above, the compound of formula (I) or (IA) is further purified by recrystallization or precipitation. In a more specific embodiment, the compound of formula (I) or (IA) is further purified by recrystallization or precipitation in a mixture of toluene and acetonitrile. In an even more specific embodiment, a compound of formula (I) or (IA) is dissolved in toluene at an elevated temperature, for example at 40°C to 90°C, 50°C to 90°C, 60°C to 90°C. °C, 70 °C to 90 °C or 75 °C to 85 °C. In another, even more specific embodiment, the compound of formula (I) or (IA) is dissolved in toluene at 80°C followed by the addition of acetonitrile to recrystallize or precipitate the compound of formula (I) or (IA). Optionally, the compound of formula (I) or (IA) is filtered after being dissolved in toluene before adding acetonitrile. In one embodiment, the volume ratio of toluene to acetonitrile is 1:10 to 2:1, 1:5 to 1:1, 1:3 to 1:1, or 1:2 to 1:1. In a particular embodiment, the volume ratio of toluene to acetonitrile is 1:1.5.

In ^{the 5th} embodiment, for the method of the third, fourth, fifth, or sixth embodiment, or the ^1st , 2nd, 3rd ^, or 4th ^embodiment , the ^{debenzylation} reaction of a compound of formula (I) or (IA) is carried out in the presence of a Pd/Alox catalyst (also known as palladium on alumina (i.e. on alumina)). Any suitable Pd/Alox catalysts can be used. Exemplary palladium/Alox catalysts include, but are not limited to, palladium on alumina with 10% Pd (i.e., 10% by weight Pd/Alox) such as Sigma- ^Aldrich® No. 76000, palladium on alumina with 5% Pd (i.e. 5 wt % Pd/Alox) such as Johnson Matthey 5R325 in powder form, Johnson Matthey A302099-5, Noblyst® ^P1159 , STREM 46-1960, 46-1951, palladium on alumina with 0, 5% Pd (i.e. 0.5 wt. % Pd/Alox) such as STREM 46-1920, Alfa Aesar #41383, #38786, #89114, #38289. In a more specific embodiment, the implementation of the palladium catalyst is 5% wt. Pd/Alox (i.e. palladium on alumina with 5% Pd).

In ^{the 6th} embodiment, for the method of the third, fourth, fifth, or sixth embodiment, or the ^1st , 2nd, 3rd ^, or 4th ^embodiment , the ^{debenzylation} reaction of a compound of formula (I) or (IA) is carried out in the presence of Pd/C catalyst (also known as palladium on carbon). Any suitable Pd/C catalysts can be used. Exemplary Pd/C catalysts include, but are not limited to, palladium on activated carbon with 20% Pd (i.e. 20 wt% Pd/C) such as STREM 46-1707, palladium on activated carbon with 10% Pd ( i.e. 10 wt % Pd/C) such as Sigma-Aldrich® # ⁷⁵⁹⁹⁰ , #75993, Johnson Matthey 10R39, 10R394, 10R487 in powder form, 10R87L in powder form, 10T755, Evonik Noblyst® ^P1070 , STREM 46 -1900, palladium on activated carbon with 5% Pd (i.e. 5 wt % Pd/C) such as Sigma-Aldrich® # ⁷⁵⁹⁹² , #75991, Johnson Matthey 5R338M, 5R369, 5R374, 5R39, 5R395, 5R424 , 5R434, 5R437, 5R440, 5R452, 5R487, 5R487 powder, 5R58, 5R87L, 5T761, A102023-5, A103023-5, A105023-5, A302002-5, A302023-10, A302023-2 A405028-5 A405032-5 A405129-5 A501023-10 A503002-5 A503023-5 A503032-5 A702023-10 Noblyst® ^P1086 , P1090, P1092, P1109, palladium on activated carbon with 3% Pd (i.e. 3% wt Pd/C) such as STREM 46-1907, palladium on active carbon modified carbon with 0.5% Pd (i.e. 0.5% wt. Pd/CAlox), such as Alfa Aesar #38289.

In ^{the 7th} embodiment, for the method of the ^5th or 6th embodiment, the ^{debenzylation} reaction of a compound of formula (I) or (IA) is carried out in the presence of 0.05 to 0.5 equivalents of Pd for every 1 equivalent of a compound of formula (I). ) or (IA). In one embodiment, 0.05 to 0.4, 0.05 to 0.35, 0.05 to 0.3, 0.05 to 0.25, 0.05 to 0.2, 0.05 to 0.15, 0.075 to 0.15, 0.075 to 0.1, or 0.08 to 0.1 equivalents of Pd catalyst for each 1 equivalent of compound of formula (I). In a more specific embodiment, 0.09 or 0.1 equivalents of Pd catalyst is used for every 1 equivalent of a compound of formula (I). In another embodiment, the amount of palladium catalyst used depends on the type and manufacturer of the palladium catalyst used, and a suitable amount of palladium catalyst can be determined experimentally.

In ^{the 8th} embodiment, for the method of the third, fourth, fifth, or sixth embodiment, or of the ^1st , ^2nd , 3rd ^{, 4th} , ^5th , 6th, or 7th ^embodiments , a ^{debenzylation} reaction of a compound of formula ( I) or (IA) is carried out in the presence of 1,4-cyclohexadiene and a palladium catalyst (eg as described in the ^5th or ^6th embodiment). In one embodiment, 1.0 to 5.0 equivalents of 1,4-cyclohexadiene are used for every 1 equivalent of a compound of formula (I) or (IA). In another embodiment, 1.0 to 4.5, 1.0 to 4.0, 1.0 to 3.5, 1.0 to 3.0, 1.0 to 2.5, 1.1 to 2.0, 1.3 to 1.8 or 1.5 to 1.7 equivalents of 1,4-cyclohexadiene for each 1 equivalent of a compound of formula (I) or (IA). In another embodiment, 1,4-cyclohexadiene is added in portions. In another embodiment, 1,4-cyclohexadiene is added in portions: 2 parts, 3 parts, 4 parts, or 5 parts. In another embodiment, 1,4-cyclohexadiene is added in parts: 2 parts, 3 parts, 4 parts. In another embodiment, 1,4-cyclohexadiene is added in portions, in 2 portions of 1.0-4.5, 1.0-4.0, 1.0-3.5, 1.0-3.0, 1, 0-2.5, 1.1-2.0, 1.3-1.8, or 1.5-1.7 equivalents. In another embodiment, 1,4-cyclohexadiene is added in portions, in 2 portions of 1.0-2.0 equivalents. In another embodiment, 1,4-cyclohexadiene is added in portions, in 2 portions of 1.5 equivalents. In another embodiment, 1,4-cyclohexadiene is added in portions, in 3 portions of 1.0-4.5, 1.0-4.0, 1.0-3.5, 1.0-3.0, 1, 0-2.5, 1.1-2.0, 1.3-1.8, or 1.5-1.7 equivalents. In another embodiment, 1,4-cyclohexadiene is added in portions, in 3 portions of 1.0-2.0 equivalents. In another embodiment, 1,4-cyclohexadiene is added in portions, in 3 portions of 1.5 equivalents.

In the 9th embodiment, for the method of the third, fourth, fifth, or sixth embodiment, or the ^1st , ^2nd , 3rd ^{, 4th} , ^5th , or 6th embodiment, the ^{debenzylation} reaction comprises ^reacting a compound of formula (I) or (IA) with 1,4-cyclohexadiene in the presence of a Pd/Alox catalyst (e.g., 5% Pd/Alox) using 1.1 to 2.0 equivalents of 1,4-dicyclohexadiene and 0 .05 to 0.25 equivalents of Pd for each 1 equivalent of a compound of formula (I) or (IA). In a more specific embodiment, 1.3 to 1.8 equivalents of 1,4-cyclohexadiene and 0.05 to 0.2 equivalents of a Pd/Alox catalyst (e.g., 5% Pd/Alox) are used for every 1 equivalent of a compound of formula ( I) or (IA). In another particular embodiment, 1.5 to 1.7 equivalents of 1,4-cyclohexadiene and 0.075 to 0.15 equivalents of a Pd/Alox catalyst (e.g., 5% Pd/Alox) are used for every 1 equivalent of a compound of formula (I) or (IA).

In ^{the 10th} embodiment, for the method of the third, fourth, fifth, or sixth embodiment, or of the ^1st , ^2nd , 3rd ^{, 4th} , ^5th , ^6th , 7th, ^8th , or ^{9th embodiments} , the debenzylation reaction is carried out in a solvent or in a mixture of solvents. You can use any suitable solvents described in this document. Illustrative solvents include, but are not limited to, tetrahydrofuran (THF), 2-methyltetrahydrofuran (Me-THF), N-methyl-2-pyrrolidone (NMP), methanol, ethanol, isopropanol, dichloromethane, dichloroethane, acetonitrile, dimethylformamide (DMF) , dimethylacetamide, cyclopentyl methyl ether (CPME), ethyl acetate, water, and combinations thereof. In a more specific embodiment, the debenzylation reaction is carried out in a solvent mixture containing a Pd catalyst poison such as lead, copper, sulfur, sulfur-containing compounds, nitrogen-containing heterocycles, or amines. In some embodiments, the Pd catalyst poison is a thiol, thiophene, pyridine, quinoline, 3,6-dithia-1,8-octanediol, or DMSO. In an even more specific embodiment, the debenzylation reaction is carried out in a mixture of DMSO and ethanol. DMSO may be present in very small amounts. For example, a mixture of solvents (for example, DMSO and ethanol) may contain 0.01-1%, 0.05-0.75%, 0.1-0.5%, 0.1-0.3%, or 0.1 -0.2% by volume DMSO.

In ^{the 11th} specific embodiment, for the method of the third, fourth, fifth, or sixth embodiment, or of the ^1st , ^2nd , 3rd ^{, 4th} , ^5th , ^6th , ^7th , ^8th , ^9th , or ^10th In a particular embodiment, the debenzylation reaction is carried out at 30°C to 90°C, 40°C to 70°C, 40°C to 60°C, or 45°C to 55°C. In a more specific embodiment, the reaction is carried out at 50°C.

In ^{the 12th} embodiment, for the method of the third, fourth, fifth, or sixth embodiment, or of the ^1st , ^2nd , 3rd ^{, 4th} , ^5th , 6th, or 7th ^embodiments , a ^{debenzylation} reaction of a compound of formula ( I) or (IA) is carried out in the presence of 1,4-cyclohexadiene and a palladium catalyst (for example, such as described in the ^5th or 6th embodiment, such as a Pd/ ^Alox catalyst (for example, 5% Pd/Alox )) , and 1,4-cyclohexadiene are added in portions. In a more specific embodiment, 1.1 to 2.0 equivalents (e.g., 1.4 to 1.6 equivalents or 1.1, 1.2, 1.3 , 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 equivalents) of 1,4-cyclohexadiene in the presence of a palladium catalyst (e.g. 5% Pd/Alox) and heated reaction mixture to an elevated temperature (for example, from 40 to 60 °C) for 1 hour to 24 hours (for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 15 hours, 20 hours or 24 hours). Then, after cooling (for example, to room temperature), another 1.1 to 2.0 equivalents are added (for example, from 1.4 to 1.6 equivalents or 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 equivalents) of 1,4-dicyclohexadiene and heat the reaction mixture to an elevated temperature (e.g., 40 to 60°C) for 1 hour to 24 hours (for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 15 hours, 20 hours, or 24 hours). Optionally, 1.1 to 2.0 more equivalents may be added (e.g., 1.4 to 1.6 equivalents or 1.1, 1.2, 1.3, 1.4, 1.5, 1.6 , 1.7, 1.8, 1.9, or 2.0 equivalents) of 1,4-dicyclohexadiene and heat the reaction mixture to an elevated temperature (e.g., 40 to 60°C) for 1 hour to 24 hours (e.g. , 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 15 hours, 20 hours or 24 hours). In an even more specific embodiment, the debenzylation reaction is carried out in a mixture of DMSO and ethanol. DMSO may be present in very small amounts. For example, a mixture of solvents (for example, DMSO and ethanol) may contain 0.01-1%, 0.05-0.75%, 0.1-0.5%, 0.1-0.3%, or 0.1 -0.2% by volume DMSO.

In ^{the 13th} specific embodiment, for the method according to the third, fourth, fifth or sixth embodiment or according to the ^1st , ^2nd , 3rd ^{, 4th} , ^5th , ^6th , ^7th , ^8th , ^9th , ^10th , ^11th or ^12th specific embodiment, the compound of formula (III) or (IIIA) can be purified by precipitation. In a more specific embodiment, the compound is purified by precipitating the compound from an ethyl acetate (EtOAc) solution containing the compound using water. In an even more specific embodiment, the volume of water used for precipitation is 1-10% (1-5%, 2-5%, 1%, 2%, 3%, or 4%) by volume of EtOAc.

In ^{the 14th} specific embodiment, for the method according to the third, fourth, fifth or sixth embodiment or according to the ^1st , ^2nd , 3rd ^{, 4th} , ^5th , ^6th , ^7th , ^8th , ^9th , ^10th , ^11th , ^12th , or ^13th specific embodiment, the proposed method further comprises reducing a compound of formula (III) to obtain a compound of formula (VI):

(VI),

(VI)

or its salt. In some embodiments, the compound of formula (III) is reduced with a suitable reducing agent. Illustrative reducing agents include, but are not limited to, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride (LiAlH ₄ ), hydrogen gas, ammonium formate, borane (BH ₃ ), diborane (B ₂ H ₆ ), borane-dimethyl sulfide complex (DMS), borane-amine complexes (e.g., ammonia borane (or borazan), borane-trimethylamine complex, borane- N,N -diisopropylethylamine complex, or borane-tert-butylamine complex), 9-borabicyclo[3.3.1]nonane ( 9-BBN), diisobutylaluminum hydride (DIBAL), lithium borohydride (LiBH ₄ ), potassium borohydride (KBH ₄ ), sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), silicon-based reducing agent (e.g. PhSiH ₃ , Ph ₂ SiH ₂ or Et ₃ SiH). In some embodiments, the reduction is carried out in the presence of a catalyst, such as a ruthenium catalyst, a rhodium catalyst, or an iridium catalyst. In a more specific embodiment, a compound of formula (III) is reacted with BH ₃ (eg, a solution of BH ₃ ⋅THF) to give a compound of formula (VI) or a salt thereof. In an even more specific embodiment, an excess of BH ₃ is used relative to the compound of formula (III). For example, 1.0 to 2.0 equivalents, 1.0 to 1.5 equivalents, or 1.1 to 1.3 equivalents of BH ₃ can be used. In one embodiment, 1.2 equivalents of BH ₃ are used. The reduction reaction can be carried out in any suitable organic solvent. In one embodiment, the reduction reaction is carried out in THF. The reaction can be carried out at a suitable temperature, for example 10°C to 30°C or 15°C to 25°C. In one embodiment, the reaction is carried out at 20°C. The reduction reaction can be carried out for 10 minutes to 10 hours, such as 30 minutes to 5 hours, 30 minutes to 3 hours, or 30 minutes to 2 hours. In another embodiment, the reaction is carried out for 1 hour or 2 hours. In another embodiment, upon completion of the reaction, the mixture is quenched with a saturated solution of NH ₄ Cl. In another embodiment, a compound of formula (VI) or a salt thereof can be purified by precipitating the compound from a 2-methyltetrahydrofuran (Me-THF) solution containing said compound using heptane. In some embodiments, the compound of formula (VI) can be purified by azeotropic distillation with Me-THF to remove water.

In one embodiment, for the method described in the 14th ^embodiment above, the compound of formula (III) is represented by formula (IIIA):

and the proposed method includes reducing the compound of formula (IIIA) to obtain the compound of formula (VIA):

(VIA),

(VIA)

or its salt.

In ^{the 15th} specific embodiment, for the method according to the first or fifth embodiment or according to ^1st , ^2nd , 3rd ^{, 4th} , ^5th , ^6th , ^7th , ^8th , ^9th , ^10th , ^11th , In the ^12th , ^13th or ^14th specific embodiment, the compound of formula (II) is prepared by a process comprising the following steps:

a) reducing the compound of formula (IV):

(IV)

(iv)

reducing agent to obtain a compound of formula (V):

(V); и

(V); and

b) oxidizing a compound of formula (V) with an oxidizing agent to give a compound of formula (II).

In addition, in the ^15th embodiment, for the method of the second or sixth embodiment, or of ^1st , ^2nd , 3rd ^{, 4th} , ^5th , ^6th , ^7th , ^8th , ^9th , ^10th , In the ^11th , 12th, ^13th , or ^{14th specific} embodiment, a compound of formula (IIA) is prepared by a process comprising the following steps:

a) reducing the compound of formula (IVA):

(IVA)

(IVA)

reducing agent to obtain a compound of formula (VA):

(VA); и

(VA); and

b) oxidizing a compound of formula (VA) with an oxidizing agent to give a compound of formula (IIA).

In ^{the 16th} embodiment, for the method described in the ^15th embodiment, the reducing agent for the reaction in step a) is a hydride reducing agent. In another embodiment, the reducing agent is sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogen gas, ammonium formate, borane, 9-borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminum hydride (DIBAL), borohydride lithium (LiBH ₄ ), potassium borohydride (KBH ₄ ), or sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al). In a more specific embodiment, the reducing agent is sodium borohydride.

In one embodiment, an excess amount of reducing agent may be used relative to the compound of formula (IV) or (IVA). For example, 1.1 to 10 equivalents, 1.5 to 5 equivalents, 2.0 to 4.0 equivalents, or 2.5 to 3.5 equivalents of reducing agent can be used for every 1 equivalent of the compound of formula (IV) or (IVA).

The reduction reaction in step a) can be carried out in a suitable solvent or solvent mixtures as described herein. In one embodiment, the reaction is carried out in a mixture of THF and ethanol.

The reduction reaction can be carried out at a suitable temperature, for example at 0°C to 50°C, 0°C to 30°C or 10°C to 25°C. In one embodiment, the reduction reaction is carried out at room temperature or at 20°C.

At 14^ohm specific implementation, for the method described in 12^ohm or 13^ohm in a particular embodiment, the oxidizing agent for the reaction in step b) is Dess-Martin periodinane (DMP), 2-iodoxybenzoic acid, Collins reagent (CrO₃⋅Py₂), pyridinium dichromate (PDC), pyridinium chlorochromate (PCC), tetrapropylammonium perruthenate (TPAP)/ N-methylmorpholine-N-oxide (NMO), (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO)/NaClO, DMSO/oxalyl chloride, DMSO/carbodiimide or DMSO/SO₃Py. In a more specific embodiment, the oxidizing agent is a DMP.

In one implementation, you can use an excess amount of oxidizing agent relative to the compounds of formula (V). For example, 1.01 to 10 equivalents, 1.01 to 5 equivalents, 1.05 to 2.0 equivalents, or 1.1 to 1.5 equivalents of an oxidizing agent can be used for every 1 equivalent of the compound of formula (V) .

The oxidation reaction in step b) can be carried out in a suitable solvent or solvent mixtures as described herein. In one embodiment, said reaction is carried out in dichloromethane.

The oxidation reaction can be carried out at a suitable temperature, for example at 0°C to 50°C, 0°C to 30°C or 10°C to 25°C. In one embodiment, the oxidation reaction is carried out at room temperature or at 20°C.

COMPOUNDS OF THE INVENTION

This invention also provides the compounds described herein. In one embodiment, this invention relates to compounds of formula (IV), (IVA), (V) or (VA), or their salts.

All references in this document and in the following examples are expressly incorporated herein by reference in their entirety.

EXAMPLES

Hereinafter, the present invention will be illustrated with reference to non-limiting examples. Unless otherwise stated, all percentages, ratios, fractions, etc. expressed by weight.

The following solvents, reagents, protecting groups, moieties, and other designations may be referred to using the abbreviations given in parentheses:

aq = water

Bn = benzyl

BnBr = benzyl bromide

CH ₃ CN = acetonitrile

DCM or CH ₂ Cl ₂ = dichloromethane

DMF = dimethylformamide

DMP = Dess-Martin Periodinan

EtOAc = ethyl acetate

Et ₃ N = triethylamine

g = grams

h = hour

HPLC = high performance liquid chromatography

LC = liquid chromatography

LCMS = Liquid Chromatomass Spectroscopy

min. = minutes

mg = milligrams

ml = milliliters

mmol = millimoles

mole = moth

Me = methyl

MeOH = methanol

MS = mass spectrometry

NMR = nuclear magnetic resonance spectroscopy

Room t-ra or room. t. = room temperature (ambient temperature, approx. 25 °C)

us. or sat. = saturated

SLC = supercritical liquid chromatography

THF = tetrahydrofuran

TLC = thin layer chromatography

Example 1 Synthesis of Compound IIIA

Stage 1:

To a solution of compound 1 (500 g, 2.74 mol) in DMF (2.50 L) was added K ₂ CO ₃ (757.39 g, 5.48 mol) in one portion, then BnBr (702, 93 g, 4.11 mol, 488.15 ml), the mixture was stirred at 20°C for 72 hours. TLC (petroleum ether: ethyl acetate = 5:1) showed that the reaction was complete. The mixture was quenched by pouring it into ice water (3 L) and the precipitated solid was collected by filtration, the filter cake was triturated with petroleum ether (500 ml x 2). Filter and dry under vacuum to give compound 2 (1.00 kg, crude) as a white solid which was used in the next step without any further purification.

^one H NMR: (CDCl₃ 400 MHz): δ 7.62-7.59 (dd,J _one = 2.0 Hz,J ₂ = 8.4 Hz, 1H), 7.57-7.56 (d,J = 2.0 Hz, 1H), 7.44-7.26 (m,5H), 6.91-6.89 (d,J = 8.4 Hz, 1H), 5.21 (s, 2H), 3.94 (s, 3H), 3.88 (s, 3H).

Stage 2:

To a solution of compound 2 (200 g, 734.48 mmol) in CH ₃ COOH (1.0 L) was slowly added HNO ₃ (92.56 g, 1.47 mol, 66.11 ml) while cooling to 0-10 ° C in an ice bath. After adding to the mixture, concentrated H ₂ SO ₄ (108.06 g, 1.10 mol, 58.73 ml) was added dropwise at 0-10 °C until a yellow precipitate formed. The mixture was then allowed to warm to 20°C and stirred for 3 hours. TLC (petroleum ether: ethyl acetate = 5:1) showed that the reaction was complete. The mixture was slowly poured into stirred ice water (3 L) to form a slurry. The solid was collected by filtration. Dry under vacuum to give compound 3 (250 g, crude) as a yellow solid.

Stage 3:

To a solution of compound 3 (2.50 kg, 7.93 mol) in THF (20 L) and H ₂ O (20 L) was added LiOH in one portion ^. H ₂ O (332.68 g, 7.93 mol) at 20°C to obtain a suspension, the reaction mixture was stirred at the same temperature for 16 hours. TLC (petroleum ether: ethyl acetate = 2:1) showed that the reaction was complete. The solvent was evaporated under vacuum to remove THF. The residue was acidified with 2N. HCl to pH=2 to give a yellow precipitate. The solid was collected by filtration, washed with H ₂ O (10 L), the filter cake was dissolved in CH ₂ Cl ₂ (15 L) and THF (3 L), separated to remove H ₂ O, dried over Na ₂ SO ₄ , concentrated under high vacuum to give compound 4 (1.5 kg, 62.39% yield) as a yellow solid. ¹ H NMR: (DMSO-d ₆₄₀₀ MHz): δ 7.69 (s, 1H), 7.47-7.36 (m, 5H), 7.30 (s, 1H), 5.23 (s , 2H), 3.91 (s, 3H).

Stage 4:

DMF (6.03 g, 82.50 mmol) was added to a solution of compound 4 (500 g, 1.65 mol) in CH ₂ Cl ₂ (2.0 L) and THF (500 ml), cooled in an ice bath to 0 -10°C. (COCl) ₂ (418.54 g, 3.30 mol, 288.65 ml) was added dropwise to the mixture while maintaining the temperature in the range of 0-10°C. The mixture was then heated to 20°C and stirred at the same temperature for 16 hours. TLC (petroleum ether: ethyl acetate = 2:1) showed that the reaction was complete. The solvent was removed in vacuo to give compound 5 (550 g, crude) as a yellow solid.

Stage 5:

To a mixture of compound 6 (1.00 kg, 6.13 mol) in MeOH (10 L) SOCl ₂ (1.46 kg, 12.26 mol, 889.37 ml) was added dropwise at 0 °C. After the addition, the resulting mixture was stirred at 25°C for 16 hours. TLC (petroleum ether: ethyl acetate = 1:1, Rf = 0.47) indicated that the reaction was complete. 5 batches of this reaction mixture were pooled and concentrated under reduced pressure to dryness. Compound 6a (5.21 kg, 89.50% yield, HCl) was obtained as a gray solid.

Stage 6:

A solution of compound 6a (2.71 kg, 12.68 mol) in THF (8.0 L) was cooled to 0-10 °C, Et ₃ N (4.01 kg, 39.63 mol, 5.49 l), keeping the temperature below 10 °C. The mixture was stirred at the same temperature for 30 minutes, a solution of compound 5 (4.40 kg, 13.21 mol) in THF (16.0 L) was added dropwise at 0-10°C. After the addition, the resulting reaction mixture was allowed to warm to 20°C and stirred for 16 hours. TLC (petroleum ether: ethyl acetate = 2:1) showed that the reaction was complete. The mixture was quenched with H ₂ O (10 L), THF was removed under vacuum, the aqueous layer was extracted with EtOAc (10 L x 3), the organic layers were combined and washed with brine (10 L), dried over Na ₂ SO ₄ , concentrated to give black -brown oily substance. The oil was recrystallized with MeOH (15 L), filtered and dried under vacuum to give compound 7 (3.38 kg, 55.34% yield) as a yellow solid.

^one H NMR: (DMSO-d _{6 ,}400 MHz):δ 8.12-7.91 (m, 1H), 7.52-6.89 (m, 8H), 5.33-5.29 (m, 2H), 5.1-4.7 (m, 1H ), 3.94-3.91 (m, 2H), 3.76-3.64 (m, 2H), 3.61 (s, 3H), 3.19-3.13 (m, 1H).HPLC:99.16%.LC-MS: MS (ESI, m/z): 485.1 (M + 23)⁺.SLC:e.i. 100%

Stage 7:

Compound 7 (1.69 kg, 3.65 mol) was added to a mixture of THF (17 L) and EtOH (17 L), cooled to 0–10°C. LiCl (309.45 g, 7.30 mol) was added to the mixture in one portion. NaBH ₄ (345.20 g, 9.13 mol) was added to the mixture in portions while maintaining the temperature at 0-10°C. After the addition, the mixture was heated to 20°C and stirred for 16 hours. TLC (petroleum ether: ethyl acetate = 1:1) indicated that the reaction was complete. The mixture was poured into H ₂ O (10 L), the solvent was evaporated under vacuum to remove most of the THF and EtOH. The residue was extracted with CH ₂ Cl ₂ (10 L x 3), the organic layers were combined and dried over Na ₂ SO ₄ , concentrated to give a yellow solid. The crude product was purified by silica gel column chromatography (eluted from petroleum ether/ethyl acetate/dichloromethane = 50/12/1 to dichloromethane/methanol = 10/1) to give a yellow solid. The solid was triturated with EtOAc (5 L) for 16 hours. Filter and dry under vacuum to give compound 8 (2.11 kg, 66.21% yield) as a yellow solid. ¹ H NMR: (DMSO- d _{6 ,} 400 MHz): δ 8.04-7.85 (m, 2H), 7.51-7.36 (m, 7H), 7.32-7.22 (m , 2H), 7.12-7.09 (m, 1H), 6.96-6.80 (m, 1H), 5.31-5.25 (m, 2H), 5.03-4.79 (m, 2H), 3.98-3.95 (m, 3H), 3.32-2.95 (m, 4H). HPLC: 98.51%. LCMS: (ESI, m/z): 457 (M + H) ⁺ . SLC: e.i. 100%.

Stage 8:

To a compound solutioneight (4.30 kg, 9.90 mol) in DCM (25 L) NaHCO was added in one portion₃ (557.11 g, 6.63 mol). DMP (5.04 kg, 11.88 mol) was added in portions and the resulting mixture was stirred at 20°C for 16 hours. TLC (petroleum ether: ethyl acetate = 1:1) showed that the reaction was complete. The mixture was poured into a saturated solution of Na₂S₂O₃ (7.5 kg in 25 L) to bind excess DMP. The solvent was separated and the aqueous layer was extracted with DCM (5 L x 3), the combined organic layers were washed with brine (10 L x 3), separated and dried over Na₂SO_four, was concentrated to give a black-brown oil. The crude oily substance was triturated with EtOAc (5 L). Filtered and dried under vacuum to give the compoundIIA (3.50 kg, 81.76% yield) as a yellow solid. ^one H NMR: (CDCl_3,400 MHz): δ 10.00-9.44 (m, 1H), 7.92-7.77 (m, 2H), 7.49-6.82 (m, 9H), 5.77-5, 22 (m, 3H), 4.12-3.93 (m, 3H), 3.50-3.25 (m, 2H).HPLC: 92.15%.SLC:e.i. 100%.

Stage 9:

To a solution of compound IIA (1.10 kg, 2.54 mol) in THF (3.30 L), MeOH (16.50 L) and H ₂ O (3.30 L) was added NH ₄ Cl (1, 36 kg, 25.40 mol) at 20°C. Fe (425.58 g, 7.62 mol) was added to the mixture in one portion at 20°C. After the addition, the mixture was heated to 65°C and stirred under N ₂ for 48 hours. HPLC indicated that the reaction was complete. The mixture was cooled to 20°C and poured into DCM (10 L) to give a black suspension, filtered over celite; the filtrate was evaporated under high vacuum to remove THF and MeOH. The filter cake was dispersed in DCM (15 L x 2) and stirred at 45°C for 1 hour. Filter and combine the filtrate with the aqueous layer. The combined layers were washed with H ₂ O (10 L), brine (10 L), separated and dried over Na ₂ SO ₄ , concentrated to give a brown solid. The solid was recrystallized in DCM/EtOH (1/1.5 L) overnight, filtered and dried under vacuum to give compound IA (720 g, 71.63% yield, 97.15% purity) as a brown solid . The crude material was subjected to recrystallization in the following way. 300 g of the crude material was dissolved in toluene (1.20 L) and quickly heated to 80 °C, the mixture was stirred at 80 °C for 10 minutes and filtered while hot, CH ₃ CN (1.80 L) was slowly added to the mixture after 10 minutes, and a large amount of solid precipitated, after the addition the temperature was lowered to 60 °C. The mixture was cooled to 20°C, stirred at the same temperature for 16 hours. Two batches of this solid were filtered and washed with CH ₃ CN (200 mL x 3), dried under high vacuum to give compound IA (465.85 g, 1.21 mol, 77.64% yield) as an off-white solid .

^one H NMR: (CDCl₃, 400 MHz) :δ 8.28-8.26 (d,J = 8.0 Hz, 1H), 7.86-7.85 (d,J = 4.0 Hz, 1H), 7.58 (s, 1H), 7.47-7.25 (m, 7H), 7.13-7.09 (m, 1H), 6.87 (s, 1H), 5.27-5.19 (m, 2H), 4.49-4.44 (m, 1H), 3.98 (s, 3H), 3.74-3.67 (m, 1H) , 3.51-3.46 (m, 1H).HPLC purity: 96.38%.

Stage 10:

To a 100 ml round bottom flask containing methanesulfonic acid (67.50 g, 702.32 mmol, 50.0 ml) was added compound IA (5.0 g, 13.01 mmol, 18 batches) in one portion, the mixture was stirred at 20 °C for 1 hour. TLC (petroleum ether: ethyl acetate = 1:1) indicated that the reaction was complete. The mixture was poured into a saturated solution of CH ₃ COONa (8 kg in 40 L of water) to adjust the pH to 6-7, resulting in the precipitation of a yellow solid. The solid was collected by filtration to give compound IIIA (60.00 g, crude) as a yellow solid. The crude material was subjected to recrystallization in the following way. (55 g, 374.76 mmol, 2 lots) was dissolved in 5 L of DCE (warmed to 100°C), filtered while hot, the filtrate was concentrated in vacuo to give a yellow solid. The solid was redissolved in DCM (500 ml), H ₂ O (500 ml) was added to the solution, and a large amount of a yellow solid precipitated, which was filtered and the precipitate was triturated on the filter with CH ₃ CN (500 ml) for 1 hours. Filter and dry under high vacuum to give compound IIIA (90.0 g, 81.82% yield) as an off-white solid. ¹ H NMR: (CDCl3, 400 MHz): δ 8.30-8.28 (d, J = 8.0 Hz, 1H), 7.91-7.90 (d, J = 4.0 Hz, 1H ), 7.58 (s, 1H), 7.32-7.28 (m, 2H), 7.15-7.11 (m, 1H), 6.94 (s, 1H), 6.16 ( s, 1H), 4.52-4.47 (m, 1H), 4.00 (s, 3H), 3.76-3.69 (m, 1H), 3.55-3.50 (m, 1H). HPLC: 96.79%. SLC: e.i. 100%.

Example 2 Debenzylation of Compound IA

To a suspension of (12aS)-9-benzyloxy-8-methoxy-12a,13-dihydroindolo[2,1-c][1,4]benzodiazepin-6-one (compound IA, 80 g, 188.02 mmol) and DMSO (1.32 g, 16.92 mmol, 1.32 ml, 0.09 eq.) in EtOH (200 ml) was added Pd/Alox (40.02 g, 18.80 mmol, 5% purity, 0.10 equiv.) and cyclohexa-1,4-diene (25 g, 312.12 mmol, 29.42 ml, 1.66 equiv.) at 25 °C under N ₂ atmosphere. After the addition, the reaction mixture was heated to 50°C and stirred at 50°C for 2 hours under N ₂ atmosphere. HPLC analysis showed that the starting material was completely consumed.

After cooling, the reaction mixture was filtered and the filter cake was washed with EtOH (100 ml x 4). The combined 2 batches of filtrate were concentrated under reduced pressure to give a residue.

The residue was dissolved in EtOAc (160 ml) and stirred at 25°C for 15 minutes. H ₂ O (5 ml) was then slowly added to the mixture over 5 minutes and a large amount of solid precipitated. After the addition, the reaction mixture was stirred at 25°C for 120 hours. The solid was filtered off and washed with EtOAc (50 mL x 2), dried under high vacuum to give compound IIIA as a white solid (105 g, 337.87 mmol, 89.85% yield, 94.7% purity).

A suspension of compound IIIA (5.0 g, 17.0 mmol, 1.0 equiv.) in dichloroethane (75 ml) was heated to 100°C and stirred at 100°C for 1 hour under N ₂ atmosphere. After cooling to 25°C, the suspension was filtered and washed with dichloroethane (20 ml x 2), dried under high vacuum to give compound IIIA (3.5 g, 75.0% yield) as a white solid.

In another experiment, compound IA (5.09 g, 1.0 eq.) was suspended in EtOH (50.9 ml, 10 vol.) and DMSO (87 μl, 0.017 vol.) was added. 5% Pd/Alox was charged, then cyclohexa-1,4-diene (1.7 ml, 1.5 eq.) was added dropwise at room temperature. The reaction mixture was heated at 50°C for 1 hour. After cooling the reaction mixture, another portion of cyclohexa-1,4-diene (1.7 ml, 1.5 equiv.) was added and the mixture was left to warm to 50°C for 1 hour. After cooling the reaction mixture, another portion of cyclohexa-1,4-diene (1.7 ml, 1.5 equiv.) was added and the mixture was left to warm to 50°C for 1 hour. The reaction mixture was cooled to room temperature and filtered through a filter cartridge with a pore size of 0.45 μm, and washed with EtOH (3 x 10 vol.). The organic solution was concentrated to dryness to give a yellow foam. The foam was dissolved in EtOAc (10 vol) and stored below -15°C. To a solution of the crude compound IIIA (4.04 g) in EtOAc was added water (0.3 vol.) and the resulting mixture was stirred at 20°C. The product quickly precipitated out of solution and the resulting thin yellow suspension was stirred. Filter, wash with EtOAc (2 vols) and dry under vacuum at 30°C to give the final product (2.7 g, 97% purity).

Example 3 Recovery of Compound IIIA

Compound IIIA (23.25 g, 1 eq.) was suspended in THF (233 ml, 10 vol.). BH ₃ ⋅THF (1.05 M, 90.3 ml, 1.2 equiv.) was added slowly at ~21°C. The reaction mixture was stirred at 20°C±5°C for 1 hour. The reaction mixture was quenched by adding a saturated solution of NH ₄ Cl (5 vol.), then water (5 vol.). The organic phases were washed with 15% NaCl solution (2 x 5 vol.). Then the organic layer was diluted with Me-THF (40 vol.) and washed with water (5 vol.). The organic layer was separated and concentrated under vacuum to 10 vol. Co-evaporation was carried out with Me-THF to remove water (3 x 10 vol.). The resulting suspension was concentrated to 5 vol., then added heptane (40 vol.). The resulting suspension was stirred at 20°C, then filtered, washed with heptane and dried under vacuum at 30°C to give a pale yellow solid (19.5 g, 99.14% purity).

Claims (112)

1. Process for the preparation of a compound of formula (I)

or a salt thereof, comprising bringing into interaction a compound of formula (II)

or its salt with Fe in the presence of NH ₄ Cl, where R ₁ , R ₂ , R ₃ and R ₄ each independently represents -H; R ₅ represents -OR, where R is selected from (C ₁ -C ₃ )alkyl. 2. The method according to claim 1, characterized in that the reaction is carried out in a solvent selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran (Me-THF), N-methyl-2-pyrrolidone (NMP), methanol, ethanol, isopropanol, dichloromethane, dichloroethane, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), cyclopentyl methyl ether (CPME), ethyl acetate, water, and combinations thereof. 3. The method according to p. 2, characterized in that the reaction is carried out in a mixture of water and one or more organic solvents. 4. The method according to any one of paragraphs. 1-3, characterized in that the reaction is carried out in a mixture of THF, methanol and water. 5. The method according to any one of paragraphs. 1-4, characterized in that the reaction is carried out at a temperature of from 40 to 90°C. 6. The method according to p. 5, characterized in that the reaction is carried out at a temperature of from 50 to 80°C. 7. The method according to p. 6, characterized in that the reaction is carried out at a temperature of from 60 to 70°C. 8. The method according to p. 7, characterized in that the reaction is carried out at 65°C. 9. The method according to any one of paragraphs. 1-8, characterized in that the reaction is carried out for 1 hour to 1 week. 10. The method according to p. 9, characterized in that the reaction is carried out for 24 to 72 hours. 11. The method according to p. 9, characterized in that the reaction is carried out within 48 hours. 12. The method according to any one of paragraphs. 1-11, characterized in that the reaction is carried out in an inert atmosphere. 13. The method according to p. 12, characterized in that the reaction is carried out in an atmosphere of N ₂ . 14. The method according to any one of paragraphs. 1-13, characterized in that the compound of formula (I) is purified by one or more precipitations, recrystallizations, or a combination thereof. 15. Process according to claim 14, characterized in that the compound of formula (I) is subjected to recrystallization or precipitation in a mixture of dichloromethane and ethanol. 16. The method according to p. 15, characterized in that the volume ratio of dichloromethane and ethanol is 1:1. 17. The method according to any one of paragraphs. 14-16, characterized in that the compound of formula (I) is further purified by recrystallization or precipitation. 18. The method according to claim 17, characterized in that the compound of formula (I) is subjected to recrystallization or precipitation in a mixture of toluene and acetonitrile. 19. The method according to claim 18, characterized in that the compound of formula (I) is subjected to recrystallization by dissolving the compound in toluene at an elevated temperature and adding acetonitrile. 20. The method according to claim 19, characterized in that the compound of formula (I) is subjected to recrystallization by dissolving the compound in toluene at 80°C, followed by filtration and addition of acetonitrile. 21. Process for the preparation of a compound of formula (III)

or a salt thereof, comprising bringing into interaction a compound of formula (I)

or a salt thereof with a hydrogenating agent in the presence of a palladium catalyst, wherein the hydrogenating agent is 1,4-cyclohexadiene; the palladium catalyst is a Pd/Alox catalyst; R ₁ , R ₂ , R ₃ and R ₄ each independently represents -H; R ₅ represents -OR, where R is selected from (C ₁ -C ₃ )alkyl. 22. The method according to p. 21, characterized in that the palladium catalyst is 5 wt.% Pd/Alox. 23. The method according to p. 21 or 22, characterized in that from 0.05 to 0.5 equivalents of Pd are used for each 1 equivalent of the compound of formula (I). 24. The method according to p. 23, characterized in that from 0.075 to 0.15 equivalents of Pd are used for every 1 equivalent of the compound of formula (I). 25. The method according to p. 23, characterized in that from 0.09 to 0.1 equivalents of Pd are used for every 1 equivalent of the compound of formula (I). 26. The method according to any one of paragraphs. 21-25, characterized in that from 1.0 to 5.0 equivalents of 1,4-cyclohexadiene are used for each 1 equivalent of the compound of formula (I). 27. The method according to any one of paragraphs. 21-25, characterized in that 1.1 to 2.0 equivalents of 1,4-cyclohexadiene are used for each 1 equivalent of the compound of formula (I). 28. The method according to any one of paragraphs. 21-25, characterized in that 1.3 to 1.8 equivalents of 1,4-cyclohexadiene are used for each 1 equivalent of the compound of formula (I). 29. The method according to any one of paragraphs. 21-25, characterized in that from 1.5 to 1.7 equivalents of 1,4-cyclohexadiene are used for each 1 equivalent of the compound of formula (I). 30. The method according to p. 21, characterized in that this method includes bringing the compound of formula (1) into interaction with 1,4-cyclohexadiene in the presence of 5 wt.% Pd / Alox, and using from 1.5 to 1, 7 equivalents of 1,4-cyclohexadiene; and 0.075 to 0.15 equivalents of Pd for each 1 equivalent of the compound of formula (I). 31. The method according to any one of paragraphs. 21-30, characterized in that the reaction is carried out in a solvent or in a mixture of solvents. 32. The method according to p. 31, characterized in that the solvent is selected from dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 2-methyltetrahydrofuran (Me-THF), N-methyl-2-pyrrolidone (NMP), methanol, ethanol, isopropanol , dichloromethane, dichloroethane, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), cyclopentyl methyl ether (CPME), ethyl acetate, water, and combinations thereof. 33. The method according to p. 32, characterized in that the reaction is carried out in a mixture of DMSO and ethanol. 34. The method according to any one of paragraphs. 21-33, characterized in that the reaction is carried out at a temperature of from 30 to 90°C. 35. The method according to p. 34, characterized in that the reaction is carried out at a temperature of from 40 to 70°C. 36. The method according to p. 34, characterized in that the reaction is carried out at a temperature of from 40 to 60°C. 37. The method according to p. 34, characterized in that the reaction is carried out at a temperature of from 45 to 55°C. 38. The method according to p. 34, characterized in that the reaction is carried out at 50°C. 39. Process for the preparation of a compound of formula (III)

or a salt thereof, comprising the steps of: a) bringing into interaction the compounds of formula (II)

with Fe in the presence of NH ₄ CI to give a compound of formula (I)

b) reacting a compound of formula (I) with a hydrogenating agent in the presence of a palladium catalyst to obtain a compound of formula (III), where R ₁ , R ₂ , R ₃ and R ₄ each independently represents -H; R ₅ represents -OR, where R is selected from (C ₁ -C ₃ )alkyl. 40. The method according to p. 39, characterized in that the solvent is selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran (Me-THF), N-methyl-2-pyrrolidone (NMP), methanol, ethanol, isopropanol, dichloromethane, dichloroethane, acetonitrile, dimethylformamide (DMF), dimethylacetamide, cyclopentyl methyl ether (CPME), ethyl acetate, water, and combinations thereof. 41. The method according to p. 40, characterized in that the reaction in stage (a) is carried out in a mixture of water and one or more organic solvents. 42. The method according to any one of paragraphs. 39-41, characterized in that the reaction in step (a) is carried out in a mixture of THF, methanol and water. 43. The method according to any one of paragraphs. 39-42, characterized in that the reaction in stage (a) is carried out at a temperature of from 40 to 90°C. 44. The method according to p. 43, characterized in that the reaction in stage (a) is carried out at a temperature of from 50 to 80°C. 45. The method according to p. 44, characterized in that the reaction in stage (a) is carried out at a temperature of from 60 to 70°C. 46. The method according to p. 45, characterized in that the reaction in stage (a) is carried out at 65°C. 47. The method according to any one of paragraphs. 39-46, characterized in that the reaction in step (a) is carried out for 1 hour to 1 week. 48. The method according to p. 47, characterized in that the reaction in stage (a) is carried out for 24 to 72 hours. 49. The method according to p. 48, characterized in that the reaction in stage (a) is carried out for 48 hours. 50. The method according to any one of paragraphs. 39-49, characterized in that the reaction in step (a) is carried out in an inert atmosphere. 51. The method according to p. 50, characterized in that the reaction in stage (a) is carried out in an atmosphere of N ₂ . 52. The method according to any one of paragraphs. 39-51, characterized in that the compound of formula (I) is purified by one or more precipitations, recrystallizations, or a combination thereof prior to carrying out the reaction in step (b). 53. The method according to p. 52, characterized in that the compound of formula (I) is subjected to recrystallization or precipitation in a mixture of dichloromethane and ethanol. 54. The method according to p. 53, characterized in that the volume ratio of dichloromethane and ethanol is 1:1. 55. The method according to any one of paragraphs. 52-54, characterized in that the compound of formula (I) is further purified by recrystallization or precipitation. 56. The method according to p. 55, characterized in that the compound of formula (I) is subjected to recrystallization or precipitation in a mixture of toluene and acetonitrile. 57. The method according to p. 56, characterized in that the compound of formula (I) is subjected to recrystallization by dissolving the compound in toluene at an elevated temperature and adding acetonitrile. 58. The method according to p. 56, characterized in that the compound of formula (I) is subjected to recrystallization by dissolving the compound in toluene at 80°C, followed by filtration and addition of acetonitrile. 59. The method according to any one of paragraphs. 39-58, characterized in that the palladium catalyst in step (b) is a Pd/Alox catalyst. 60. The method according to p. 59, characterized in that the palladium catalyst in step (b) is 5 wt.% Pd/Alox. 61. The method according to any one of paragraphs. 39-58, characterized in that the palladium catalyst is a Pd/C catalyst. 62. The method according to any one of paragraphs. 59-61, characterized in that from 0.05 to 0.2 equivalents of Pd are used for each 1 equivalent of the compound of formula (I). 63. The method according to p. 62, characterized in that from 0.075 to 0.15 equivalents of Pd are used per 1 equivalent of the compound of formula (I). 64. The method according to p. 62, characterized in that from 0.09 to 0.1 equivalents of Pd are used per 1 equivalent of the compound of formula (I). 65. The method according to any one of paragraphs. 39-64, characterized in that the hydrogenating agent in step (b) is 1,4-cyclohexadiene. 66. The method according to p. 65, characterized in that from 1.0 to 5.0 equivalents of 1,4-cyclohexadiene are used for each 1 equivalent of the compound of formula (I). 67. The method according to p. 66, characterized in that from 1.1 to 2.0 equivalents of 1,4-cyclohexadiene are used for each 1 equivalent of the compound of formula (I). 68. The method according to p. 66, characterized in that from 1.3 to 1.8 equivalents of 1,4-cyclohexadiene are used for each 1 equivalent of the compound of formula (I). 69. The method according to p. 66, characterized in that from 1.5 to 1.7 equivalents of 1,4-cyclohexadiene are used for every 1 equivalent of the compound of formula (I). 70. The method according to any one of paragraphs. 39-58, characterized in that the reaction in stage (b) includes bringing into the interaction of the compound of formula (I) with 1,4-cyclohexadiene in the presence of 5 wt.% Pd/Alox, and at the same time from 1.5 to 1, 7 equivalents of 1,4-cyclohexadiene; and 0.075 to 0.15 equivalents of Pd for each 1 equivalent of the compound of formula (I). 71. The method according to any one of paragraphs. 39-70, characterized in that the reaction in step (b) is carried out in a solvent or in a mixture of solvents. 72. The method according to p. 71, characterized in that the solvent is selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran (Me-THF), N-methyl-2-pyrrolidone (NMP), methanol, ethanol, isopropanol, dichloromethane, dichloroethane, acetonitrile, dimethylformamide (DMF), dimethylacetamide, cyclopentyl methyl ether (CPME), ethyl acetate, water, and combinations thereof. 73. The method according to p. 71, characterized in that the reaction is carried out in a mixture of DMSO and ethanol. 74. The method according to any one of paragraphs. 39-73, characterized in that the reaction in stage (b) is carried out at a temperature of from 30 to 90°C. 75. The method according to p. 74, characterized in that the reaction is carried out at a temperature of from 40 to 70°C. 76. The method according to p. 74, characterized in that the reaction is carried out at a temperature of from 40 to 60°C. 77. The method according to p. 74, characterized in that the reaction is carried out at a temperature of from 45 to 55°C. 78. The method according to p. 74, characterized in that the reaction is carried out at 50°C. 79. The method according to any one of paragraphs. 1-20 and 39-78, characterized in that the compound of formula (II) is obtained by a method comprising the following steps: a) reduction of the compound of formula (IV)

reducing agent to obtain a compound of formula (V)

b) oxidizing a compound of formula (V) with an oxidizing agent to give a compound of formula (II). 80. The method of claim 79, wherein the reducing agent is a hydride reducing agent. 81. The method according to p. 79, characterized in that the reducing agent is sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogen gas, ammonium formate, borane, 9-borabicyclo[3.3.1]nonane (9-BBN) , diisobutylaluminum hydride (DIBAL), lithium borohydride (LiBH ₄ ), potassium borohydride (KBH ₄ ), or sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al). 82. The method according to p. 79, characterized in that the reducing agent is sodium borohydride. 83. The method according to any one of paragraphs. 79-82, characterized in that the oxidizing agent is Dess-Martin periodinane (DMP), 2-iodoxybenzoic acid, Collins reagent (CrO ₃ ⋅Py ₂ ), pyridinium dichromate (PDC), pyridinium chlorochromate (PCC), tetrapropylammonium perruthenate ( TPAP)/N-methylmorpholine-N-oxide (NMO), (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO)/NaClO, DMSO/oxalyl chloride, DMSO/carbodiimide or DMSO/SO ₃ ⋅Py . 84. The method according to p. 83, characterized in that the oxidizing agent is DMP. 85. The method according to any one of paragraphs. 1-84, characterized in that R ₅ is OMe.