EA046399B1 - IMPROVED SYNTHETIC METHODS FOR PRODUCING (2H-1,2,3-TRIAZOL-2-YL)PHENYL COMPOUNDS AS OREXIN RECEPTOR MODULATORS - Google Patents

Description

Scope of the invention

The present invention relates to synthetic methods for preparing the compound (((3aR,6aS)-5-(4,6dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4ω]pyrrol-2(1H)-yl)(2-Fluoro-6 -(2H-1,2,3-triazol-2-yl)phenyl)methanone (Seltorexant), used to modulate orexin receptors and for the treatment of pathological conditions, disorders and diseases that are mediated by orexin receptor activity.

Prerequisites for creating the invention

Orexin (or hypocretin) signaling is mediated by two receptors and two peptide agonists. Two orexin peptides (orexin A and orexin B), hereinafter referred to as orexins, bind to two high-affinity receptors called orexin-1 and orexin-2 receptors. The orexin-1 receptor is selective for orexin A, and the orexin-2 receptor binds both orexins with similar affinities. Orexins are cleavage products of the same preproorexin gene. Central nervous system neurons expressing the preproorexin precursor from which orexin is formed are found in the perifornical nucleus, dorsal hypothalamus, and lateral hypothalamus (C. Peyron et al., J. Neurosci., 1998, 18(23), 9996-10015 ). Orexinergic cells in these nuclei project to many areas of the brain and extend rostrally to the olfactory bulbs and caudally to the spinal cord (van den Pol A.N. et al., J. Neuroscience., 1999, 19(8), 3171-3182).

The citation of a reference herein should not be construed as an admission that such reference indicates prior art of the present invention. All publications referenced herein are incorporated herein by reference in their entirety.

Substituted diazabicyclic compounds are described as active agents of the central nervous system (international publication No. WO 2001081347, November 1, 2001; US 2002/0019388, February 14, 2002), α-modulators of 7 acetylcholine receptors (US 2005/101602, May 12 2005; US 2005/0065178, March 24, 2005, and Frost et al, Journal of Medicinal Chemistry, 2006, 49(26), 78437853), proline transporter inhibitors for the treatment of cognitive impairment (WO 2008067121, June 5, 2008 and for improving cognitive function (WO 2006 124897, November 23, 2006, and US 20060258672, November 16, 2006), as androgen receptor ligands for the treatment of androgen receptor-associated conditions, including cancer (WO 2009081197, 2 July 2009), and as histone deacetylase inhibitors for the treatment of cancer, neurodegenerative and autoimmune diseases (WO 20060123121, November 23, 2006).

It was found that among the developed compounds (((3aR,6aS)-5-(4,6-dimethylnirimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6- (2H-1,2,3-triazol-2-yl)phenyl)methanone acts as an inhibitor of the orexin-2 receptor and is used to treat sleep disorders and major depressive illness (US 8653263 B2). The compound was created from two key compounds. components, as shown below in Diagram 1:

Scheme 1

SOCIj

The original synthesis used direct coupling of phenyl to a triazole. The mixture of products was formed as a result of non-selective binding to different nitrogen atoms contained in the triazole, as shown in Scheme 2 below.

Scheme 2

desired unwanted

K _2- aryltriazole N,-aryltriazole

Exclusive synthesis of 2-aryltriazoles can be achieved by Cu(II)-mediated bishydrazone cyclization as shown in Scheme 3. However, this approach has the disadvantage of low atomic efficiency since the bis-addition of phenylhydrazine to glyoxal results in 50% aryl groups are spent to produce the by-product aniline (see, for example, J. Org. Chem. 1948, 13, 815; for information on current optimizations of the dihydrazone approach, see Russian Journal of Organic Chemistry 2009, 45, 1683; and Chemistry of Heterocyclic Compounds

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2010, 46, 79).

Scheme 3

Cu(ll)

desired product

leaving group, waste

Other attempts to obtain 2-substituted triazoles have been reported (Tome, A.C. Science of Synthesis 2004, Section 13.13.2, pp 528-540; Topics Heterocycl. Chem. 2015, 40, 51; Org. Let. 2009, 11, 5026; OPRD 2019, 23, 234; Angew. Chem. Ed. 2011, 50, 8944; and Heterocycles 1980, 14, 1279), but in all cases approaches involving cyclization of 2-aryltriazole derivatives were low-yielding. when positions 4 and 5 of the triazole ring are unsubstituted.

The purpose of the invention is to provide a process for the production of (((3aR,6aS)-5-(4,6dimethylpyrimidin-2-yl)hexαhydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6- (2H-1,2,3-triαzol-2-yl)phenyl)methanone using exclusive production of N-2-aryltriazole to reduce waste, eliminate the need to separate unwanted binding products and reduce production costs.

Summary of the invention

The invention includes a process for producing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2ul)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H- 1,2,3-triazol-2-yl)phenyl)methanone

wherein said process comprises the step described below:

cyclization of a hydrazone of formula I to give 2-phenyl-2H-1,2,3-triazole of formula II in one step

Where

R ¹ is -H, -CO2H or -C.O2C | _-4 ,alkyl;

X represents -OH, -OC( _1-4 ^km, -OCH2Ph, -OPh, -OC(O)CH ₃ , -OSO ₂ CH ₃ , -N(CH ₃ ) ₂ , piperidin-1-yl, - NHC(O)CH ₃ , -NHSO ₂ PhCH ₃ or -N(CH ₃ ) ₃ I.

Detailed Description of the Invention

The invention includes a process for producing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexa hydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6- (2H-1,2,3-triazol-2-yl)phenyl)methanone

wherein said process comprises the step described below:

cyclization of hydrazine of formula I to give 2-phenyl-2H-1,2,3-triazole of formula II in one step

Where

R ¹ represents -H, -CO2H or -C.O2C _1-4 , alkyl;

X represents -OH, -OC( _1-4 ^ku^ -OCH ₂ Ph, -OPh, -OC(O)CH ₃ , -OSO2CH3, -N(CH ₃ ) ₂ , piperidin-1-yl, -NHC (O)CH ₃ , -NHSO ₂ PhCH ₃ or -N(CH ₃ ) ₃ I.

In another embodiment, the invention includes a process for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2- fluorine-6-(2H- 2 046399

1,2,3-triazol-2-yl)phenyl)methanone

wherein said process comprises the step described below:

cyclization of hydrazine of formula I to give 2-phenyl-2H-1,2,3-triazole of formula II in one step

Where

R ¹ represents -H or -CO ₂ CH ₃ ;

X is -OC( _1-2 )alkyl, -OC( _CH3 ) ₃ , _-OCH2Ph , -N( _CH3 ) ₂ or -N( _CH3 ) _3I .

In another embodiment, the invention includes a process for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2- fluoro-6-(2H1,2,3-triazol-2-yl)phenyl)methanone

wherein said process includes the steps described below:

a) cyclization of hydrazine of formula I to obtain 2-phenyl-2H-1,2,3-triazole of formula II in one step

Where

R ¹ represents -H;

X is -OC( _1-2 )alkyl, -OC( _CH3 ) ₃ , _-OCH2Ph , -N( _CH3 ) ₂ or -N( _CH3 ) _3I .

b) carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to produce 2-fluoro-6-(2H-1.2.3-triazol2-yl)benzoic acid,

wherein said carboxylation differs in that isopropyl-MgCl and CO2 are used.

In another embodiment, the invention includes a process for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2- fluoro-6-(2H1,2,3-triazol-2-yl)phenyl)methanone

wherein said process includes the steps described below:

a) cyclization of hydrazine of formula I to obtain 2-phenyl-2H-1,2,3-triazole of formula II in one step

Where

R ¹ represents -H;

X is -OC( _1-2 )alkyl, -OC(CH ₃ ) ₃ , -OCH ₂ Ph, -N(CH ₃ ) ₂ or -N(CH ₃ ) ₃ I;

b) carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to give 2-fluoro-6-(2H-1,2,3-triazol2-yl)benzoic acid

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wherein said carboxylation is characterized in that isopropyl-MgCl and CO2 are used;

c) reaction of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid with (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3, 4-c]pyrrole to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

wherein said reaction differs in that SOCl ₂ is used.

In another embodiment, the invention includes a process for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2- fluoro-6-(2H1,2,3-triazol-2-yl)phenyl)methanone

wherein said process includes the steps described below:

a) cyclization of hydrazine of formula I to obtain 2-phenyl-2H-1,2,3-triazole of formula II in one step

Where

R ¹ represents -H;

X represents -O^-^alkyl, -OC(CH ₃ ) ₃ , -OCH ₂ Ph, -N(CH ₃ )2 or -N(CH ₃ ) ₃ I;

b) carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to give 2-fluoro-6-(2H-1,2,3-triazol2-yl)benzoic acid

wherein said carboxylation is characterized in that it uses LiCl, isopropyl-MgCl and

CO2;

c) reaction of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid with (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3, 4-c]pyrrole to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

wherein said reaction differs in that SOCl ₂ is used.

The invention also includes a method for preparing a compound of formula I comprising

- 4 046399 reaction of (3-fluorophenyl)hydrazine hydrochloride with glyoxal in the presence of water and/or methanol to form (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde with a yield of more than 90%;

Where

R1 represents H, CO ₂ H or -C.O2C _|-4 ,alkyl and

X is -OH, -OC( _1-4 )alkyl, -OCH ₂ Ph, -OPh, -OAc, -N(CH ₃ ) ₂ , piperidinyl, -NHC(O)CH ₃ , -NHSO ₂ PhCH ₃ or -N(CH ₃ ) ₃ I.

Another embodiment of the invention is a compound of formula I

Where

R ¹ represents H, CO2H or -CO ₂ C( _1-4 )alkyl.

Another embodiment of the invention is a compound selected from the group consisting of

Another embodiment of the invention is a compound selected from the group consisting of

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Another embodiment of the invention is a compound selected from the group consisting of

And

The invention may be more fully appreciated by reference to the following description, which includes the following definitions of terms and concluding examples. For brevity, the descriptions of all publications cited herein, including patents, are incorporated herein by reference.

As used herein, the terms including, containing, and consisting of are used in their open, non-limiting meaning.

Definitions

The term (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2Fluoro-6-(2H- 1,2 ,3-triazol-2-yl)phenyl)methanone means

The products of the chemical reactions described herein can be directly reacted with additional reagents or separated before subsequent reaction. The term separated means partial or complete separation of the reaction product from other materials in the reaction vessel. These other materials include, but are not limited to, solvents, unreacted starting material, reactants used in the reaction, by-products, impurities and products of reactants used in the reaction.

The term preparation means synthesis by chemical processes.

In addition, any formula provided herein also includes hydrates, solvates and polymorphs of such compounds, as well as mixtures thereof, even if such forms are not expressly indicated.

Any formula given herein also represents both unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures shown by the formulas presented herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be present in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H, ³ H, C. ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O , ¹⁷ O respectively. Such

- 6 046399 isotopically labeled compounds are used in studies of metabolism (preferably using ¹⁴ C), reaction kinetics (for example using ² H or ³ H), detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)), including analysis of the distribution of a drug or substrate in tissues, or during radiotherapy of patients. Substitution with heavier isotopes such as deuterium (ie, ² H) may further provide certain therapeutic benefits due to greater metabolic stability of the compounds, such as greater in vivo half-life or reduced dosage requirements. The isotopically labeled compounds of the invention and their prodrugs can be prepared substantially by following the procedures described below in the Schemes or in the Examples and Preparation Methods described below by replacing a readily available reagent containing no isotope-labeled atoms with a reagent containing isotope-labeled atoms.

Those skilled in the art will appreciate that compounds of the invention in which at least one double bond is present may exist as stereoisomers. The invention relates to both stereoisomers (E) and (Z) and to all mixtures thereof.

Those skilled in the art will appreciate that the compounds and reagents used in the reactions of the invention may exist in the form of salts. The present invention contemplates the use of all salts of any compound used in the reaction exemplified herein.

Examples of salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates , propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butine-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulfonates , phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates.

If the compound or reagent used in the reaction of the invention contains a basic nitrogen atom, the salt can be prepared 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, sulfamic acid, nitric acid , boric acid, phosphoric acid, etc., or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid , fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidylic acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as mandelic acid, citric acid or tartaric acid, an amino acid such as aspartic acid, glutaric acid or glutamic acid, an aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, a sulfonic acid such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid acid, ethanesulfonic acid, any compatible mixture of acids, such as those set forth in the examples herein, and any other acid or mixture of acids that are considered to be equivalent or acceptable substitutes in light of the usual state of knowledge in the art.

Those skilled in the art will understand that for saponification of an ester, impurities of o. .. ._____ . . _____ ______..... ... ....

There are many reagents available, ^and these reagents are varied and known to one skilled in the art. The invention contemplates the use of all common means of converting an ester into a carboxylic acid, including those described in Protective Groups in Organic Synthesis by TW Green, and PGM Wuts, Wiley-Interscience, New York, 1999, 579-580, 744-747.

Examples of reactions used in the methods of the invention are described below by reference to the following illustrative synthesis schemes for their general preparation and the following specific examples. Those skilled in the art will appreciate that the reactions can be performed in any suitable solvent. Those skilled in the art will also appreciate that, subject to specific limitations, reactions can be performed over a wide range of temperatures. The reactions can be carried out in the range between the melting point and the reflux temperature of the solvent, and preferably between 0°C and the reflux temperature of the solvent. Reaction mixtures can be heated traditionally or in a microwave oven. Reactions can also be carried out in sealed pressure vessels at temperatures above the normal reflux temperature of the solvent.

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Abbreviations

The following abbreviations may be used here and in the description text.

Reduction Term Ac acetyl ACN acetonitrile Bn benzyl DXM dichloromethane DMSO dimethyl sulfoxide EG ethylene glycol EtOAc or EA ethyl acetate Et ethyl HPLC high performance liquid chromatography iPr or iPr isopropyl LC liquid chromatography Me methyl nBu or ^nBu n-butyl OAc acetate OTf triflate (= trifluoromethanesulfonyl) Ph phenyl tBu or tBu tert-butyl THF tetrahydrofuran Ts tosyl (= p-toluenesulfonyl)

Examples

Unless otherwise noted, the following experimental and analytical protocols were used to obtain the compounds described in the examples below and the corresponding analytical data.

Unless otherwise stated, reaction mixtures were stirred at room temperature (rt) under a nitrogen atmosphere. If mixtures, solutions and extracts were concentrated, they were usually concentrated under reduced pressure. Microwave reactions were performed in a Biotage initiator or a CEM Discover instrument.

Normal phase flash column chromatography (FCC) was performed on silica gel (SiO ₂ ) using prefilled cartridges, eluting with the indicated solvents.

Unless otherwise stated, mass spectra (MS) were acquired on either a Bruker QTOF, Waters QTOF Ultima using electrospray ionization (ESI) in positive mode, or a Waters GC-TOF using electron impact (EI). The calculated (calculated) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker spectrometers. The following is the format for representing 1H NMR data: chemical shift in ppm downfield from the signal used as a tetramethylsilane standard (multiplicity, spin-spin coupling constant J in Hz, integral).

Chemical names were generated using ChemDraw Ultra 6.0.2 (CambridgeSoft Corp., Cambridge, Massachusetts, USA) or ACD/Name version 9 (Advanced Chemistry Development, Toronto, Ontario, Canada).

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General scheme

where R ¹ = COiCi^.alkyl;

CH ₃ OH/H ₂ O/LiOH

Phenylhydrazines III or the corresponding salts in the presence of sodium acetate can be reacted with glyoxal and water or a water-methanol mixture to form acetaldehyde hydrazone IV. The present invention uses a water-glyoxal mixture, in which phenylhydrazine is poorly soluble, to achieve the desired monocondensation with a relatively small excess of glyoxal. The desired monocondensate can be produced in high yield by using an appropriate solvent such as water, or a mixture of methanol and water, which minimizes the concentration of the hydrazine starting material in solution and also allows the monocondensate to precipitate out of solution as it forms.

Condensation with H2N-X allows one to obtain hydrazone I. The product is formed as a mixture of E/Z stereoisomers, which undergo mutual transformation when heated; there is no need to separate stereoisomers from each other. Cyclization of the hydrazone mixture provides the production of 2-phenyl-2H-1,2,3triazole II of formula I in one step.

Conversion of 2-phenyl-2H-1,2,3-triazole II is achieved by saponification when R ¹ is -CO^Q.^OKnn, or by carboxylation when R ¹ is H, to produce 2-fluoro- 6-(2H-1,2,3-triazol-2-yl)benzoic acid. The addition of LiCl to the reaction mixture reduced unwanted bis-addition-CO ₂ .

The resulting 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid is activated using thionyl chloride or any suitable activating agent and reacted with (3aR,6aS)-2-(4,6dimethylpyrimidine ^-yl^ctahydropyrrolo^^-^pyrrole to form ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)( 2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

Example 1. Synthesis of acetaldehyde hydrazones of formula IV

Example 1a. Synthesis of (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde.

A solution of glyoxal in water (40 w/w%; 613 g, 4.22 mol) was added to a suspension of 177 g (1.06 mol) (3-fluorophenyl)hydrazine (HCl salt) in 1.24 L water, followed by by adding a solution of 129.9 g (1.58 mol) of sodium acetate in 708 ml of water over 2 hours. After stirring for several hours at room temperature, the suspension was filtered and the precipitate was washed with 0.89 L of water and dried under vacuum to obtain 172.8 g (95% yield) of the title compound as a yellow solid.

Melting point (mp) 118-119°C.

¹ H NMR (DMSO-de) δ: 11.80 (br.s, 1H), 9.49 (d, J=7.7 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.32-7.39 (m, 1H), 6.96-7.03 (m, 2H), 6.75-6.83 (m, 1H). ¹³ C NMR (DMSO^6) δ: 190.4, 163.0 (br. d, J=242.7 Hz), 144.7 (b. s, J=10.8 Hz), 136.3, 131.2 (d, J=10.0 Hz), 110.0 (d, J=2.3 Hz), 108.5 (d, J=21.6 Hz), 100.6 (d, J= 27.0 Hz). ^19F NMR (DMSO^ ₆ ) δ: -111.72.

High resolution mass spectrometry (HRMS) (ionization time-of-flight mass spectrometry)

- 9 046399 electrospray (ESI-TOF)) m/z: [M+H]+, calculated for C ₈ H ₈ FN2O: 167.0621; the resulting value is 167.0611.

Example 1b. Synthesis of methyl (E)-2-fluoro-6-(2-(2-oxoethylidene)hydrαzinyl)benzoate

A solution of methyl 2-fluoro-6-hydrazinyl benzoate (17.65 g, 0.08 mol) in a solution of methanol in water (90 ml + 180 ml) was added at 10°C to a mixture of 40 wt.% solution of glyoxal in water (58, 04 g, 0.8 mol), water (100 ml) and sodium acetate (9.85 g, 0.12 mol) for 10 minutes. The mixture was then stirred for approximately 1.5 hours before filtering. The filter cake was washed in water (2*50 ml) and dried under vacuum conditions. The dried solid (16.12 g) was redissolved at 50°C in ethyl acetate (50 ml) before crystallization, which was achieved by slowly adding heptane (200 ml) and cooling to 5°C. The resulting solid was filtered, washed in heptane (2*15 ml) and dried under vacuum. The desired product (13.33 g, 74% yield) was obtained as a yellow solid. mp 110.8°C.

1H NMR (DMSO-d;) δ: 11.74 (s, 1H), 9.41 (d, 1H), 7.49 (m, 2H), 7.19 (d, 1H), 6.92 ( m, 1H), 3.84 (s, 3H).

MS (ESI-TOF) m/z: 225.1 ([M+H]+).

Example 1c. Synthesis of (E)-2-fluoro-6-(2-(2-oxoethylidene)hydrazinyl)benzoic acid

2-Fluoro-6-hydrazinylbenzoic acid was reacted with excess glyoxal in water to give 64% yield of the desired compound 2-fluoro-6-(2-(2-oxoethylidene)hydrazinyl)benzoic acid as a yellow solid. The compound was used without further purification in the next step.

Example 2. Synthesis of hydrazones of formula I

Example 2a. Synthesis of (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime

A solution of 59.7 g (715 mmol) methoxylamine hydrochloride and 58.6 g (715 mmol) sodium acetate in 210 ml water was added to a solution of 70 g (408 mmol) (E)-2-(2-(3-fluorophenyl)hydrazono )acetaldehyde in 350 ml of methanol for 1.5 hours, followed by the addition of 210 ml of water. After 2 hours of stirring at room temperature, the suspension was cooled to 0°C and stirred overnight at this temperature before filtration. The filter cake was washed with 70 mL of water and dried under vacuum to obtain 77.4 g (92% yield) of the title compound as a yellow solid. NMR analysis revealed the presence of 2 isomers (ratio ~ 1 : 1).

Separation of isomers

isomer 1 isomer 2

Isomers of 10 g of the reaction product from Example 2a were separated using supercritical fluid chromatography (SFC; eluent: isocratic 7% acetonitrile in supercritical CO2) to give 6 g (63% yield) of isomer 1 (E, E) and 2.7 g (yield 28%) isomer 2 (E, Z).

Isomer 1 (E, E):

mp: 90°C.

1H NMR (DMSO-d;) δ: 10.89 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.54 (dd, J=8.8, 0.7 Hz, 1H), 7.20-7.28 (m, 1H), 6.74-6.83 (m, 2H), 6.54-6.62 (m, 1H), 3.84 (s, 3H). ¹³ C NMR (DMSO-Y6) δ: 163.2 (br.d, J=241.2 Hz), 148.3, 146.1 (br.d, J=10.8 Hz), 132.8, 130.8 (d, J=10.0 Hz), 108.4 (d, J=2.3 Hz), 105.9 (d, J=21.6 Hz), 98.9 (d, J= 27.0 Hz), 61.7. ¹⁹ F NMR (DMSO^) δ: -112.30.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₉ HnFN ₃ O: 196.0881; the resulting value is 196.0876.

Isomer 2 (E, Z):

mp 114°C.

1H NMR (DMSOL) δ: 11.04 (s, 1H), 7.96 (dd, J=8.6, 0.9 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H ), 7.21-7.29 (m, 1H), 6.78-6.86 (m, 2H), 6.59-6.66 (m, 1H), 3.85 (s, 3H). ¹³ C NMR (DMSO^) δ=163.2 (br.d, J=242.0 Hz), 145.8 (br.d, J=10.8 Hz), 145.4, 130.8 (d , J=10.0 Hz), 127.9, 108.8 (d, J=2.3 Hz), 106.6 (d, J=21.6 Hz), 99.3 (d, J=26 .2 Hz), 61.7. ¹⁹ F NMR (DMSO δ: -112.18.

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High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C9H11FN3O: 196.0881; the resulting value is 196.0876.

Example 2b. Alternative synthesis of (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde Omethyloxime from the compound (3-fluorophenyl)hydrazine (HCl salt), glyoxal and methoxylamine HCl without drying (E)-2-(2- (3-fluorophenyl)hydrazono)acetaldehyde.

The first reactor was loaded with 4.5 kg of (3-fluorophenyl)hydrazine (HCl salt) and 36 liters of water. The suspension was stirred at 65°C for one hour. The second reactor was loaded with 6.15 kg of glyoxal and 4.6 l of water and cooled to 10°C. An aqueous solution of (3-fluorophenyl)hydrazine (HCl salt) was transferred from the first reactor to the second reactor over 2 hours. The reaction mixture was stirred for an additional 3 hours before filtering and washing the solid (E)-2-(2-(3-fluorophenyl )hydrazono)acetaldehyde with water. The wet sludge was loaded into the reactor along with 18 kg of methanol. 3.77 kg of hydroxylamine HCl, 3.7 kg of sodium acetate and 9 kg of water were then added with efficient stirring. The suspension was stirred for 3060 minutes, 18 kg of water was added, and the resulting mixture was cooled to 5°C and stirred for 1-2 hours. Product mixture (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime and (1E,2Z)-2-(2-(3fluorophenyl)hydrazono)acetaldehyde O-methyloxime were filtered, washed with water and dried under vacuum to obtain 5.01 kg of yellow solid (yield: 93%) with purity >99%.

Example 2c. Synthesis of compounds of formula I from (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde and XNH2.

Unless otherwise stated, compounds of formula I wherein R1 is H were prepared from (E)-2-(2-(3fluorophenyl)hydrazono)acetaldehyde and X-NH2 following the procedure of Example 2a or a very similar procedure and used either crude or purified by crystallization or chromatography. The results are presented in table. 1.

Table 1

X-NH2 H % yield isomer ratio (2 to 4 isomers observed) HO-NH2HCl ZI z z Q I 71 85:15 EtO-NH2^HC’l Ш p z \\ \\ z 0 91 76:24 ^tBuO -NH2-HCl ZI z z about CT 80 74:18:10:4 BnO-NH2^HC’l H 79 95:5 PhO-NH^HCl 99 67:33 HO-NH^HCl then Ac ₂ O H ^F T5 ^N ' ^N ^ ^N ' ^0AC 65 86:10:4 Me ₂ N-NH ₂ ^Ρ -0- ^Κ Ν^ ^Ν Ν _Μβ2 89 Single isomer l ,NH ₃ < N ² p z z IZ p 90 Single isomer AcNH-NH2 ABOUT T z z ? z IZ 53 <95 : >5 (the main isomer shows rotamerization) TsNH-NH2 uo Z Z 85 Single isomer

- 11 046399

Me ₂ N-NH ₂ Then MeI Η K λ, ,Ν. _t ^N N Μθ3 Г 90 Single isomer

(1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde oxime

Yellow solid. mp 135°C.

Isomer 1 (main): 1H NMR (400 MHz, DMSO-de) δ=11.33 (s, 1H), 10.70 (s, 1H), 7.77 (d, J=8.6 Hz, 1H ), 7.59 (dd, J=0.4, 8.8 Hz, 1H), 7.27-7.17 (m, 1H), 6.80-6.76 (m, 1H), 6, 75 (d, J=1.5 Hz, 1H), 6.59-6.51 (m, 1H). ¹³ C NMR (101 MHz, DMSOO δ=163.24 (br. d, J=241.2 Hz), 147.88, 146.46 (br. d, J=10.8 Hz), 134.44, 130.74 (d, J=10.0 Hz), 108.29 (d, J=2.3 Hz), 105.56 (d, J=21.6 Hz), 98.71 (d, J= 26.2 Hz) ¹⁹ F NMR (377 MHz, DMSOHO δ=-112.36.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C8H9FN3O: 182.0730; the resulting value is 182.0726.

Isomer 2 (minor): 1H NMR (400 MHz, DMSO-^) δ=11.28 (s, 1H), 10.90 (s, 1H), 8.06 (dd, J=0.7, 8, 4 Hz, 1H), 7.27-7.17 (m, 2H), 6.83-6.80 (m, 1H), 6.80-6.76 (m, 1H), 6.63-6 .59 (m, 1H). ¹³ C NMR (101 MHz, DMSO^) δ=163.21 (br.d, J=241.2 Hz), 146.16 (br.d, J=10.8 Hz), 144.96, 130, 82 (d, J=10.0 Hz), 128.71, 108.65 (d, J=2.3 Hz), 106.14 (d, J=21.6 Hz), 99.09 (d, J=26.2 Hz). 19F NMR (377 MHz, DMSO^) δ=112.26.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C8H9FN3O: 182.0730; the resulting value is 182.0727.

(1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)acetaldehyde O-ethyloxime

Yellow solid. mp: 82.7 and 101.7°C (mixture of isomers).

Isomer 1 (main): 1H NMR (400 MHz, DMSO^ ₆ ) δ=10.88 (s, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.56 (d, J =8.8 Hz, 1H), 7.29-7.18 (m, 1H), 6.85-6.73 (m, 2H), 6.61-6.52 (m, 1H), 4, 10 (sq., J=7.0 Hz, 2H), 1.22 (t, J=7.0 Hz, 3H). ¹³ C NMR (101 MHz, DMSO-de) δ=163.21 (br.d, J=241.2 Hz), 148.02, 146.20 (br.d, J=10.8 Hz), 133 .08, 130.73 (d, J=10.0 Hz), 108.40 (d, J=2.3 Hz), 105.84 (d, J=20.8 Hz), 98.86 (d , J=26.2 Hz), 69.24, 14.31. ¹⁹ F NMR (377 MHz, DMSO^6) δ=-112.34.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₀ H ₁₃ FN ₃ O: 210.1043; the resulting value is 210.1035.

Isomer 2 (minor): 1H NMR (400 MHz, DMSOL) δ=11.05 (s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.29-7.18 (m , 2H), 6.85-6.73 (m, 2H), 6.66-6.58 (m, 1H), 4.11 (q.v., J=7.0 Hz, 2H), 1.22 (b. t, J=7.0 Hz, 3H). ¹³ C NMR (101 MHz, DMSO<) δ=163.16 (br. d, J=241.2 Hz), 145.86 (br. d, J=11.6 Hz), 145.17, 130, 80 (br.d, J=10.0 Hz), 128.15, 108.78 (d, J=2.3 Hz), 106.46 (d, J=21.6 Hz), 99.25 ( d, J=27.0 Hz), 69.20, 14.38. ¹⁹ F NMR (377 MHz, DMSO-b ₆ ) δ=-112.22.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₀ H ₁₃ FN ₃ O: 210.1043; the resulting value is 210.1035.

(1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)acetaldehyde O-(tert-butyl)oxime

Yellow solid. mp: 93.8°C (mixture of isomers).

Isomer 1: 1H NMR (400 MHz, DMSO^) δ=10.80 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.29-7.18 (m, 1H), 6.84-6.75 (m, 2H), 6.60-6.53 (m, 1H), 1.28 (s, 9H). ¹³ C NMR (101 MHz, DMSOO δ=163.23 (br. d, J=241.2 Hz), 147.19, 146.33 (br. d, J=10.8 Hz), 133.76, 130.63 (d, J=10.0 Hz), 108.35 (d, J=2.3 Hz), 105.66 (d, J=21.6 Hz), 98.84 (d, J= 26.2 Hz), 78.78, 27.18. ¹⁹ F NMR (377 MHz, DMSOO δ=-112.36.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₂ H ₁₇ FN ₃ O: 238.1356; the resulting value is 238.1351.

Isomer 2: 1H NMR (400 MHz, DMSO-b ₆ ) δ=11.02 (s, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.29-7.18 (m , 2H), 6.84-6.75 (m, 2H), 6.60-6.53 (m, 1H), 1.29 (s, 9H). ¹³ C NMR (101 MHz, DMSO-b ₆ ) δ=163.18 (br.d, J=242.0 Hz), 146.01 (br.d, J=10.8 Hz), 144.37, 130.69 (br. d, J=10.0 Hz), 128.56, 108.70 (d, J=2.3 Hz), 99.17 (d, J=26.2 Hz), 78, 40, 27,18. ¹⁹ F NMR (377 MHz, DMSO<) δ=-112.29.

- 12 046399

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C12H17FN3O: 238.1356; the resulting value is 238.1351.

Isomer 3: 1H NMR (400 MHz, DMSO-de) δ=10.93 (s, 1H) 7.80 (m, 1H), 6.89 (m, 1H), 7.29-7.18 (m , 1H), 6.84-6.75 (m, 2H), 6.60-6.53 (m, 1H), 1.34 (s, 9H). ¹³ C NMR (101 MHz, DMSO-de) δ=163.30 (br. d, J=241.2 Hz), 146.66 (d, J=11.6 Hz), 141.90, 137.58 , 130.69 (br. d, J=10.0 Hz, 1C), 130.63 (d, J=10.0 Hz, 1C), 130.56 (d, J=10.0 Hz, 1C) , 128.56, 127.44, 108.13 (d, J=2.3 Hz), 105.04 (d, J=21.6 Hz), 98.49 (d, J=26.2 Hz) , 79.63, 27.11. ¹⁹ F NMR (377 MHz, DMSOO δ=-112.16.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₂ H ₁₇ FN ₃ O: 238.1356; the resulting value is 238.1351.

Isomer 4: 1H NMR (400 MHz, DMSO^) δ=11.35 (s, 1H), 8.28 (d, J=6.8 Hz, 1H), 7.29-7.18 (m, 1H ), 6.84-6.75 (m, 3H), 6.60-6.53 (m, 1H), 1.27 (s, 9H). ¹³ C NMR (101 MHz, DMSO^ ₆ - detected signals) δ=163.30 (br.d, J=241.2 Hz, 1C), 163.23 (br.d, J=241.2 Hz, 1C ), 163.18 (br.d, J=242.0 Hz, 1C), 144.28, 127.44, 108.86 (d, J=2.3 Hz), 106.56 (d, J= 21.6 Hz), 99.38 (br.d, J=26.2 Hz), 27.06. ¹⁹ F NMR (377 MHz, DMSOHO δ=-112.22.

(1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)acetaldehyde O-benzyloxime

Yellow solid. mp: 105.6°C (mixture of isomers).

Isomer 1 (main): 1H NMR (400 MHz, DMSO^) δ=10.91 (s, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.56 (d, J= 9.0 Hz, 1H), 7.42-7.27 (m, 5H), 7.27-7.19 (m, 1H), 6.87-6.76 (m, 2H), 6.62 -6.54 (m, 1H), 5.13 (s, 1H). ¹³ C NMR (101 MHz, DMSO-de) δ=163.20 (d, J=241.2 Hz), 148.86, 146.13 (br.d, J=10.8 Hz, 1C), 137 .43, 132.71, 130.74 (d, J=9.2 Hz), 128.25, 128.00, 127.74, 108.46 (d, J=2.3 Hz), 105.96 (d, J=21.6 Hz), 98.95 (d, J=26.2 Hz), 75.51. ¹⁹ F NMR (377 MHz, DMSOO δ=-112.23.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₅ H ₁₅ FN ₃ O: 272.1199; the resulting value is 272.1198.

Isomer 2 (minor): 1H NMR (400 MHz, DMSO-de) δ=11.08 (s, 1H), 8.06 (d, J=9.0 Hz, 1H), 7.56 (d, J =9.0 Hz, 1H), 7.42-7.27 (m, 5H), 7.27-7.19 (m, 1H), 6.87-6.76 (m, 2H), 6, 66-6.62 (m, 1H), 5.14 (br.s, 1H). ¹³ C NMR (101 MHz, DMSOO δ=163.16 (br. d, J=241.2 Hz), 145.94, 137.50, 108.83 (d, J=2.3 Hz), 106, 58 (d, J=21.6 Hz), 99.31 (d, J=26.2 Hz) 75.56. ¹⁹ F NMR (377 MHz, DMSOO δ=-112.12.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₅ H ₁₅ FN ₃ O: 272.1199; the resulting value is 272.1199.

Isomer 3: High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₅ H ₁₅ FN ₃ O: 272.1199; the resulting value is 272.1200.

(III^^-^-p-FluorophenylHydrazono^ethaldehyde O-phenyloxime

Yellow solid. mp: 93.4°C (mixture of isomers).

Isomer 1 (main): 1H NMR (400 MHz, DMSO^) δ=11.17 (s, 1H), 8.28 (d, J=8.6 Hz, 1H), 7.70 (d, J= 8.8 Hz, 1H), 7.45-7.32 (m, 2H), 7.32-7.23 (m, 1H), 7.18 (d, J=7.9 Hz, 2H), 7.09-7.01 (m, 1H), 6.93-6.81 (m, 2H), 6.64 (dt, J=2.2, 8.6 Hz, 1H). ¹³ C NMR (101 MHz, DMSO-de) δ=163.17 (br.d, J=241.2 Hz), 158.61, 151.99, 145.82 (b.d, J=11.6 Hz), 131.57, 130.87 (d, J=9.2 Hz), 129.44, 122.43, 114.18, 108.72 (d, J=2.3 Hz), 106.48 (d, J=21.6 Hz), 99.62 (d, J=26.2 Hz). ¹⁹ F NMR (377 MHz, DMSO^) δ=-112.13.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₄ H ₁₃ FN ₃ O: 258.1043; the resulting value is 258.1038.

Isomer 2 (minor): 1H NMR (400 MHz, DMSO-de) δ=11.38 (s, 1H), 8.19 (d, J=8.6 Hz, 1H), 7.69 (br. d , J=8.4 Hz, 1H), 7.45-7.32 (m, 2H), 7.32-7.23 (m, 1H), 7.18 (d, J=7.9 Hz, 2H), 7.09-7.01 (m, 1H), 6.93-6.81 (m, 2H), 6.69 (dt, J=2.2, 8.6 Hz, 1H). ¹³ C NMR (101 MHz, DMSO-de) δ=163.13 (br.d, J=242.0 Hz), 158.66, 148.82, 145.47 (b.d, J=10.8 Hz), 130.95 (d, J=10.0 Hz), 129.44, 127.23, 122.33, 114.21, 109.14 (d, J=2.3 Hz), 107.14 (d, J=21.6 Hz), 99.62 (d, J=26.2 Hz). ¹⁹ F NMR (377 MHz, DMSOO δ=-112.02.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₄ H ₁₃ FN ₃ O: 258.1043; the resulting value is 258.1038.

- 13 046399 (1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)acetaldehyde O-acetyloxime

1.16 ml of an aqueous solution (50 wt.%) of hydroxylamine (19 mmol) was added to a solution of 3 g (18 mmol) of compound (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde in 15 ml of methanol. After stirring overnight at room temperature, 3.6 ml (19 mmol) of acetic anhydride was added in two portions. After stirring overnight at room temperature, 15 ml of water was added to complete the precipitation. The desired compound was filtered, washed with a few ml of water and dried under vacuum to give 2.6 g (65% yield) of a yellow solid.

Yellow solid. mp: 100.8°C (mixture of isomers).

Isomer 1:

1H NMR (400 MHz, DMSO-b6) δ=11.31 (br.s, 1H), 8.20 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.367.22 (m, 1H), 6.93-6.79 (m, 2H), 6.78-6.60 (m, 1H), 2.15 (s, 3H). ¹³ C NMR (101 MHz, DMSO-de) δ=167.88, 163.15 (br.d, J=242.0 Hz), 155.53, 145.54 (b.d, J=10.8 Hz), 131.12 (d, J=10.0 Hz), 130.58, 108.93 (d, J=2.3 Hz), 106.94 (d, J=21.6 Hz), 99 .44 (d, J=26.2 Hz), 19.25. ¹⁹ F NMR (377 MHz, DMSO<) δ=-112.07.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₀ H _n FN ₃ O ₂ : 224.0835; the resulting value is 224.0835.

Isomer 2:

1H NMR (400 MHz, DMSO-dfe visible signals) δ=11.46 (br. s, 1H), 7.36-7.22 (m, 1H), 6.99 (s, 1H), 6.93 -6.79 (m, 2H), 6.78-6.60 (m, 1H), 1.91 (s, 3H). ¹³ C NMR (101 MHz, DMSO<) δ=171.93, 163.02 (br.d, J=242.7 Hz), 151.84, 144.63 (b.d, J=10.8 Hz ), 130.95 (d, J=10.0 Hz), 130.97, 109.45 (d, J=2.3 Hz), 108.23 (d, J=21.6 Hz), 100, 16 (d, J=26.2 Hz), 21.00. ¹⁹ F NMR (377 MHz, DMSO<) δ=-111.71.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₀ H _n FN ₃ O ₂ : 224.0835; the resulting value is 224.0836.

Isomer 3:

1H NMR (400 MHz, DMSO-b6) δ=11.85 (br.s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.367.22 (m, 1H), 6.93-6.79 (m, 2H), 6.78-6.60 (m, 1H), 2.17 (s, 3H). ¹³ C NMR (101 MHz, DMSO^) δ=167.91, 163.11 (br.d, J=242.0 Hz), 155.53, 145.20 (b.d, J=10.0 Hz ), 131.66 (d, J=9.3 Hz), 126.80, 109.35 (d, J=2.3 Hz), 107.57 (d, J=21.6 Hz), 99, 85 (d, J=27.0 Hz), 19.37. ¹⁹ F NMR (377 MHz, DMSO<) δ=-111.95.

(E)-2-((E)-2-(2-(3-Fluorophenyl)hydrazono)ethylidene)-1,1-dimethylhydrazine

Yellow solid. mp: 134.4°C (single isomer).

1H NMR (400 MHz, DMSOL) δ=10.27 (s, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.23-7.13 (m, 1H), 7. 02 (d, J=8.1 Hz, 1H), 6.77-6.67 (m, 2H), 6.52-6.42 (m, 1H), 2.89 (s, 6H). ¹³ C NMR (101 MHz, DMSO<) δ=163.33 (br. d, J=240.4 Hz), 147.21 (d, J=10.8 Hz), 139.63, 130.69, 130.55 (d, J=10.0 Hz), 107.80 (d, J=1.5 Hz), 104.33 (d, J=21.6 Hz), 98.06 (d, J= 26.2 Hz), 42.24. 19F NMR (377 MHz, DMSO-de) δ=-112.61.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₀ H ₁₄ FN ₄ : 209.1202; the resulting value is 209.1200.

(1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)-N-(piperidin-1-yl)ethan-1-imine

Yellow solid. mp: 155.4°C (single isomer).

1H NMR (400 MHz, DMSOO δ=10.36 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.25-7.08 (m, 1H), 6.83-6.62 (m, 2H), 6.48 (dt, J=2.3, 8.5 Hz, 1H), 3.06 ( br. t, J=5.4 Hz, 4H), 1.81-1.52 (m, 4H), 1.521.23 (m, 2H). ¹³ C NMR (101 MHz, DMSO<) δ=163, 31 (d, J=240.4 Hz, 1C), 147.05 (d, J=10.8 Hz, 1C), 139.45, 132.82, 130.55 (br. d, J=10, 0 Hz, 1C), 107.88 (br.d, J=2.3 Hz, 1C), 104.54 (d, J=21.6 Hz, 1C), 98.17 (br.d, J= 26.2 Hz, 1C), 51.14, 24.43, 23.48. ¹⁹ F NMR (377 MHz, DMSO<) δ=-112.59.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C ₁₃ H ₁₈ FN ₄ : 249.1515; the resulting value is 249.1518.

N'-((1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)ethylidene)acetohydrazide

Yellow solid. mp: 265.1°C (mixture of isomers).

- 14 046399

Isomer 1 (rotamer 1, main):

1H NMR (400 MHz, DMSO-d6) δ=11.22 (s, 1H), 10.85 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.57 ( d, J=8.6 Hz, 1H), 7.25 (sq., J=7.8 Hz, 1H), 6.93-6.73 (m, 2H), 6.59 (br. t, J=7.8 Hz, 1H), 2.13 (s, 3H). ¹³ C NMR (101 MHz, DMSOHO δ=190.43, 171.62, 163.26 (d, J=241.2 Hz, 1C), 146.20 (br.d, J=10.8 Hz, 1C ), 142.49, 136.15, 130.79 (d, J=10.0 Hz, 1C), 108.44 (d, J=2.3 Hz, 1C), 105.84 (br. d, J=21.6 Hz, 1C), 98.86 (br. d, J=26.2 Hz, 1C), 20.07. ¹⁹ F NMR (377 MHz, DMSO-de) δ=-112.21.

Isomer 1 (rotamer 2, minor):

1H NMR (400 MHz, DMSO-f) δ=11.37 (s, 1H), 10.92 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.62 ( d, J=8.4 Hz, 1H), 7.25 (sq., J=7.8 Hz, 1H), 6.93-6.73 (m, 2H), 6.59 (br. t, J=7.8 Hz, 1H), 1.96 (s, 3H). ¹³ C NMR (101 MHz, DMSO<) δ=190.43, 165.52, 163.26 (d, J=241.2 Hz, 1C), 146.17 (br.d, J=10.8 Hz , 1C), 145.05, 136.32, 130.79 (d, J=10.0 Hz, 1C), 108.48 (br. d, J=2.3 Hz, 1C), 105.91 ( br.d, J=21.6 Hz, 1C), 98.89 (br.d, J=26.2 Hz, 1C), 21.56. ¹⁹ F NMR (377 MHz, DMSO^) δ=-112.21.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for Ci ₀ Hi ₂ FN ₄ O: 223.0995; the resulting value is 223.0994.

N-((1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)ethylidene)-4-methylbenzenesulfonohydrazide

Yellow solid. mp: 146.7°C (single isomer).

1H NMR (400 MHz, D MSO-f) δ=11.48 (s, 1H), 10.84 (s, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.42 (br. d, J=8.6 Hz, 1H), 7.41 (br. d, J=8.1 Hz, 2H), 7 .27-7.17 (m, 1H), 6.79-6.70 (m, 2H), 6.63-6.52 (m, 1H), 2.37 (s, 3H). ¹³ C NMR (101 MHz, DMSOO δ=163.18 (br.d, J=241.2 Hz), 146.37, 145.99 (br.d, J=10.8 Hz), 143.46, 136.07, 135.31, 130.83 (d, J=10.0 Hz), 129.68, 127.05, 108.52 (d, J=2.3 Hz), 106.07 (d, J=21.6 Hz), 98.92 (d, J=26.2 Hz), 20.96. ¹⁹ F NMR (377 MHz, DMSO-de) δ=-112.20.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for Ci ₅ Hi ₆ FN ₄ O ₂ S: 335.0978; the resulting value is 335.0982.

(E)-2-((E)-2-(2-(3-Fluorophenyl)hydrazono)ethylidene)-1,1,1-trimethylhydrazin-1-ium iodide n

Ν Ν Me ₃ 1'

To a solution of (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde (1 mmol, 1.0 eq.) and NaOAc (1.5 mmol, 1.5 eq.) in MeOH (3 ml) was added 1,1-dimethylhydrazine hydrochloride salt (1.2 mmol, 1.2 eq.) in one portion at 25°C. After consumption of the starting material (within approximately 30 min), water (3 ml) was added to the reaction mixture. The suspension was then filtered and the precipitate was washed with water. The intermediate dihydrazone (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1-dimethylhydrazine was dried under vacuum at 50°C for 3 hours. as (E)-2-((E)-2-(2-(3fluorophenyl)hydrazono)ethylidene)-1,1-dimethylhydrazine (1.0 mmol, 1.0 eq.) (isolated or unisolated intermediate) in ACN (2 ml) was added with MeI (5.0 mmol, 5.0 eq.) in one portion at 25°C. After stirring overnight or until the starting material was consumed, EtOAc (3 ml) was added to the suspension. The suspension was filtered and the precipitate was washed with EtOAc. The hydrazonium salt of (E)2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1,1-trimethylhydrazin-1-ium iodide was dried under vacuum at 30°C to give 315 mg yellow solid (yield: 90%).

mp: 166.8°C.

1H NMR (400 MHz, DMSO-de): δ 11.82 (s, 1H), 8.73 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.35 (dd, J=15.1, 8.2 Hz, 1H), 6.99-6.90 (m, 2H), 6.82-6.71 (m, 1H), 3 .47 (s, 9H). ¹³ C NMR (101 MHz, DMSO-46): δ 164.73, 163.18, 162.32, 145.32, 145.22, 131.81, 131.72, 131.12, 110.01, 108 .77, 108.56, 100.55, 100.29, 55.52, 55.46.

MSHR (ESI), calculated for CnH ₁₆ FN ₄ ⁺ [M + ]: 223.1359, determined: 223.1348. Melting Point (MP): 166.8°C.

Example 2d. Synthesis of methyl 2-fluoro-6-(2-(2-(methoxyimino)ethylidene)hydrazinyl)benzoate

A solution of methoxylamine hydrochloride (3.61 g, 43.2 mmol) and sodium acetate (3.55 g, 43.2 mmol) in water (80 ml) was added to a solution of methyl (E)-2-fluoro-6-(2 -(2-oxoethylidene)hydrazinyl)benzoate (8.07 g, 36.0 mmol) in methanol (40 ml). After stirring overnight at room temperature, the title compound was filtered, washed with water (2^15 ml) and dried under vacuum. The desired product (7.85 g, 79% yield) was obtained as a yellow solid. NMR shows the presence of several isomers. mp 90.0°C.

- 15 046399 ¹ H NMR (DMSO-de - main isomer) δ: 10.87 (s, 1H), 7.76 (m, 2H), 7.40 (m, 1H), 7.11 (m, 1H ), 6.72 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H).

MS (ESI-TOF) m/z: 254.2 ([M+H]+).

Example 2e. Synthesis of (E)-2-((E)-2-(2-(3-fluoro-2-(methoxycarbonyl)phenyl)hydrazinylidene)ethylidene)1,1,1-trimethylhydrazin-1-ium iodide

A suspension of 1,1-dimethylhydrazine hydrochloride (0.76 g, 7.9 mmol) and sodium acetate (0.74 g, 9.0 mmol) in methanol (10 ml) was slowly added to a solution of methyl (E)-2-fluoro -6-(2-(2oxoethylidene)hydrazinyl)benzoate (1.68 g, 7.5 mmol) in a mixture of toluene and methanol (25 ml + 6 ml). After 1 hour of stirring at room temperature, the mixture was concentrated in vacuo and the residue was partitioned between water and ethyl acetate (10 ml+20 ml). After phase separation, the aqueous layer was extracted with ethyl acetate (20 ml) and the combined organic layers were concentrated in vacuo. The resulting oil was purified by chromatography (silica gel, eluent: ethyl acetate: heptane, 1:8) to obtain the dihydrazone intermediate (1.8 g) as a yellow solid. The intermediate (1.6 g) was then redissolved in acetonitrile (12 ml), iodomethane (5.11 g, 36.0 mmol) was added and the reaction mixture was stirred at 36°C for 8 hours. After cooling to room temperature the solid was filtered, washed with acetonitrile (2*20 ml) and dried under vacuum to give the desired compound (2.0 g, 65% overall yield) as a yellow solid. mp: 177.5°C.

1H NMR (DMSO^ ₆ ) δ: 11.51 (s, 1H), 8.57 (d, 1H), 7.84 (m, 2H), 7.50 (m, 1H), 7.25 (m , 1H), 6.88 (m, 1H), 3.86 (s, 3H), 3.45 (s, 9H). ¹⁹ F NMR (DMSO^) δ: -111.49.

MS (ESI-TOF) m/z: 281.1 ([hydrazonium ion] ⁺ ).

Example 2f. Synthesis of 2-fluoro-6-(2-((1E,2E)-2-(methoxyimino)ethylidene)hydrazinyl)benzoic acid

2-fluoro-6-(2-(2-oxoethylidene)hydrazinyl)benzoic acid was reacted with methoxylamine hydrochloride and sodium acetate in a mixture of water - methanol to obtain 2-fluoro-6-(2-((1E,2E)-2 (methoxyimino)ethylidene)hydrazinyl)benzoic acid in 52% yield as a yellow solid. The desired compound was used without further purification in the next step.

Example 3. Synthesis of 2-phenyl-2H-1,2,3-triazoles of formula II

Example 3a. Synthesis of 2-(3-fluorophenyl)-2H-1,2,3-triazole, X is -N+Me ₃ I ^- .

To a solution of hydrazonium salt (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1,1trimethylhydrazin-1-ium iodide (X=-N+Me ₃ I ^- - 1.0 mmol, 1.0 eq.) in dimethylformamide (DMF) (3 ml) was added K ₂ CO ₃ or KHCO3 (2.0 mmol, 2.0 eq.) in one portion at 25°C. The suspension was heated to 50°C. After stirring for 2 hours or until the starting material reacted, the reaction mixture was cooled to 25°C and treated with H2O and EtOAc. The organic layer was separated and extracted twice with EtOA. The combined organic matter was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography using heptane/ethyl acetate as eluent afforded 2-(3-fluorophenyl)-2H-1,2,3-triazole in 87% yield.

The yield increased to 96% when replacing K ₂ CO ₃ with KHCO3.

Example 3b. Synthesis of 2-(3-fluorophenyl)-2H-1,2,3-triazole using other -X groups.

The synthesis of 2-(3-fluorophenyl)-2H-1,2,3-triazole from compounds of formula I where R ¹ is H can be carried out with various -X leaving groups according to the procedure below:

mmol of a solution/suspension of a compound of formula I, where R ¹ is H, and 0.25 mmol of copper sulfate pentahydrate or copper mesylate hydrate in 5-7 ml of n-butanol or ethylene glycol (EG) was stirred for several hours at 110°C before cooled to room temperature, washed with 7.5 ml of aqueous 1 M HCl and analyzed by LC for 2-(3-fluorophenyl)-2H-1,2,3-triazole.

In the table below. Figure 2 shows the yield values for each leaving group -X under the specified conditions. The reaction conditions are not optimized, and the invention assumes reaction conditions for each -X group, as well as obvious variations thereof. An example of various screening conditions that can be used to optimize the reaction for any leaving group -X is shown in Example 3c, where -X is -OCH3.

- 16 046399

table 2

Outgoing group -X Conditions (copper salt, solvent) % yield in situ N^\ -OMe C'uSO.r5H ₂ O, n-butanol 70 -OH CuSO<5H ₂ O, ethylene glycol 28 -OEt CuSO.r5H ₂ O. n-butanol 70 -OtBu CuSO<5H ₂ O, ethylene glycol 41 -OtBu copper mesylate, n-butanol 54 -OBn CuSO<5H ₂ O, n-butanol 54 -OPh CuSO<5H ₂ O, n-butanol 18 -OAc CuSO<5H ₂ O, n-butanol 20 -OMs CuSO<5H ₂ O, ethylene glycol 0 -NMe2 CuSO<5H ₂ O, ethylene glycol 50 ->3 CuSO ₄ ^5H ₂ O, ethylene glycol 32 -NHAc CuSO<5H ₂ O, ethylene glycol 25 -NHTs CuSO<5H ₂ O, ethylene glycol 4

Example 3c. Synthesis of 2-(3-fluorophenyl)-2H-1,2,3-triazole from (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime (screening conditions).

A solution of (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime (1 eq.) and the catalyst in the solvent were heated to 110°C-120°C for a period of 20 minutes to overnight before cooling to room temperature and LC analysis for 2-(3-fluorophenyl)-2H-1,2,3-triazole. The reaction conditions and yields are given in table. 3.

Table 3

Conditions Total reaction time Dedicated output CuSO4 (5 mol%), EG (5 l/kg), 120°C 40 min 60% CuSO ₄ (5 mol%), EG (3 l/kg), 120°C 40 min 64% CuSO ₄ (5 mol%), EG (10 l/kg), 120°C 65 min 68% CuSO ₄ (5 mol%), MeOH (5 l/kg), 66°C (ref. cold) 13 days - CuSO4 (5 mol%), MeOH (5 l/kg), 120°C (MW, gauge pressure) 50 h 80% CuSO ₄ (5 mol%), n-BuOH (5 l/kg), 110°C 2 hours 82% Cu(OTf) ₂ (5 mol%), EG (5 l/kg), 120°C 1 hour 20 minutes 40% Cu(OTf) ₂ (5 mol%), toluene (5 l/kg), 100°C 160 h 71% Cu(OTf)2 (5 mol%), DMF (5 l/kg), 120°C 160 h 53% Cu(OMs) ₂ (5 mol%), n-BuOH (5 l/kg), 110°C 1 hour 30 minutes 86% CuOTf (5 mol%), n-BuOH (5 l/kg), 110°C 2 hours 30 minutes 73% Cu(OTf)2 (5 mol%), n-BuOH (5 l/kg), 110°C 3 hours 30 minutes 55% CuOAc (5 mol%), n-BuOH (5 l/kg), 110°C 20 minutes 66% Cu(OAc) ₂ (5 mol%), n-BuOH (5 l/kg), 110°C 20 minutes 72% Ni(OAc) ₂ (5 mol%), n-BuOH (5 l/kg), 110°C 24 hours - Zn(OAc) ₂ (5 mol%), n-BuOH (5 l/kg), 110°C 24 hours - Au(I) complex (5 mol%), n-BuOH (5 l/kg), 110°C 24 hours - EG (5 l/kg), CH ₃ SO ₃ H (1 eq.), 120°C 24 hours decomposition

- 17 046399

EG (5 l/kg), K ₂ CO ₃ (1 eq.), 120°C 24 hours decomposition EG (5 l/kg), MeONa (1 eq.), 120°C 24 hours decomposition DMF (5 l/kg), K2CO ₃ (1 eq.), 120°C 24 hours < 5% of product

3d example. Formation and isolation of 2-(3-fluorophenyl)-2H-1,2,3-triazole from (1E,2E)-2-(2-(3fluorophenyl)hydrazono)acetaldehyde O-methyloxime.

0.31 kg of copper sulfate pentahydrate and 26.8 kg of EG were loaded into the reactor, inerted and heated to 120-130°C with stirring. 4.8 kg (III^^-^-p-fluorophenyl-Hydrazono-ethaldehyde Omethyloxime was added in 5 portions. After 1 hour of stirring at 120-130°C, part of the reaction mixture was distilled under vacuum conditions. Distillate (13 l, 2-(3-fluorophenyl )-2H-1,2,3-triazole+EG) were distributed between 3.3 kg of heptane and 4.8 kg of 2 w/w aqueous HCl. The two layers were separated and the polar layer was extracted with 3.3 kg of heptane. The heptane layers were combined, washed with 4.8 kg of water and concentrated in vacuo to give 3.09 kg of 2-(3-fluorophenyl)-2H-1,2,3-triazole as a colorless to slightly yellow oil (yield: 77%).

1H NMR (400 MHz, DMSO^) δ=8.14 (s, 2H), 7.87 (dd, J=1.3, 8.1 Hz, 1H), 7.79 (td, J=2, 2, 10.1 Hz, 1H), 7.60 (dt, J=6.4, 8.3 Hz, 1H), 7.26 (ddt, J=0.9, 2.5, 8.5 Hz , 1H). ¹³ C NMR (101 MHz, DMSO<) δ=162.38 (br. d, J=244.3 Hz), 140.32 (d, J=1.5 Hz), 136.88, 131.63 ( d, J=9.2 Hz), 114.34 (d, J=3.1 Hz), 114.37 (d, J=20.8 Hz), 105.79 (d, J=27.7 Hz ). 19F NMR (377 MHz, DMSOL) δ=-110.88.

HRMS (VP-ESI) m/z: [M] ⁺ calculated for C ₈ H ₆ FN ₃ : 163.0546; the resulting value is 163.0521.

Example 3e, part 1. Synthesis of methyl 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoate from methyl 2-fluoro-6-(2(2-(methoxyimino)ethylidene)hydrazinyl) benzoate

Methyl 2-fluoro-6-(2-(2-(methoxyimino)ethylidene)hydrazinyl)benzoate (4.05 g, 16 mmol) was added in four portions to a solution of copper sulfate pentahydrate (250 mg, 1.0 mmol) in ethylene glycol ( 25 ml) stored at 125°C. The resulting mixture was stirred at 125°C for an additional 3 hours before cooling to 60°C. Water (60 ml), heptane (30 ml) and ethyl acetate (20 ml) were added and the layers were separated. Concentration of the organic layer and purification of the residue by column chromatography (silica gel, heptane-ethyl acetate 8:1) gave 1.3 g (yield 37%) of the desired product. mp 56.9°C.

The yield of methyl 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoate increased to 54% when methyl 2-fluoro6-(2-(2-(methoxyimino)ethylidene)hydrazinyl)benzoate ( 633 mg, 2.50 mmol) and copper sulfate pentahydrate (31 mg, 0.125 mmol) were first mixed at room temperature in ethylene glycol (5 ml) and then heated to 120°C (complete dissolution of the chemicals was achieved by heating) for about 4 hours before cooling to room temperature, dissolving in water, extracting with isopropyl acetate and purifying by column chromatography. A yield of 57% was achieved by repeating the above procedure with 1.00 mmol of starting material, 0.05 mmol of copper sulfate pentahydrate in 10 ml of ethylene glycol and heating for about 8 hours.

1H NMR (DMSO δ: 8.18 (s, 2H), 7.87 (d, 1H), 7.75 (m, 1H), 7.48 (t, 1H), 3.78 (s, 3H) ^.13C NMR (DMSO δ: 163.68, 159.40(d), 137.63, 137.6(d), 133.27(d), 118.00(d), 115.86(d) , 115.8(d), 53.28. 19F NMR (DMSOL) δ: -114.28.

Example 3e, part 2. Synthesis of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid from methyl 2-fluoro-6(2H-1,2,3-triazol-2 - yl)benzoate

A solution of methyl 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoate (360 mg) and lithium hydroxide hydrate (66 mg, 10.2 mmol) in THF-water (2 ml each ) stirred until complete conversion. After neutralization and isolation, the desired product was obtained in 86% yield.

Example 3f. Synthesis of methyl 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoate from (E)-2-((E)-2-(2-(3fluorophenyl)hydrazono)ethylidene)-1 ,1,1-trimethylhydrazin-1-ium iodide

Solution of methyl 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoate from (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene) -1,1,1-trimethylhydrazin-1-ium iodide (0.61 g, 1.5 mmol) and potassium bicarbonate (0.75 g, 7.5 mmol) in DMF (10 ml) were stirred at 56°C in for 1 hour before concentration under vacuum. The residue was partitioned between heptane and water (15 ml+6 ml). After phase separation, the aqueous layer was extracted with heptane (15 ml), and the combined organic layers were concentrated under conditions

- 18 046399 vacuum to obtain the desired product (0.27 g, 81% yield) in the form of a yellow powder.

Example 3g. Synthesis of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid from 2-fluoro-6-(2-((1E,2E)-2(methoxyimino)ethylidene)hydrazinyl)benzoic acid acids

2-Fluoro-6-(2-((1E,2E)-2-(methoxyimino)ethylidene)hydrazinyl)benzoic acid was reacted in the presence of copper sulfate pentahydrate in warm ethylene glycol to obtain 2-Fluoro-6-(2H-1, 2,3triazol-2-yl)benzoic acid with a yield of about 25%.

Example 4. Synthesis of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid from 2-(3-fluorophenyl)-2H-1,2,3triazole

Example 4a: Screening of Bases and Additives

A base was added to a solution of the compound 2-(3-fluorophenyl)-2H-1,2,3-triazole and the mixture was stirred before bubbling CO2 gas until the anionic and acidic treatment of the reaction mixture had completely ceased. The resulting mixture was analyzed by LC, and 2-fluoro-6-(2H-1,2,3-triazol2-yl)benzoic acid was isolated after treatment was stopped. The results are presented in table. 4 below.

Table 4

Conditions Mixture after reaction cessation, LC (area %) % yield iC,N N-N - 1 N^ BUT, WITH N'N NO ₂ WITH Ν.Λ) NO ₂ WITH Ν-Ν iPrMgCl (1.2 eq), THF, 35-40°C, then CO2 (1.3 eq), -5°C. Treatment: toluene - aqueous HCl. Separation: change of solvent ^ mixture of toluene - water, reflux to maintain 25°C 1.5 95.3 1.4 78 iPrMgCl (1.2 eq), LiCl (0.5 eq), THF, 3540°C, then CO2 (1.3 eq), 5°C. Treatment: aqueous toluene HCl. Separation: change of solvent ^ mixture of toluene - water, reflux to maintain 25°C 5.7 93.1 0.3 87 iPrMgCl (1.2 eq), LiCl (1 eq), THF, 35-40°C, then CO2 (1.3 eq), -5°C. Treatment: toluene - aqueous HCl. Separation: change solvent ^ mixture toluene water, reflux to maintain 25°C 14.8 84.4 0.2 78

Example 4b. Synthesis and isolation of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

A solution of 2 M isopropylmagnesium chloride in THF (735 ml, 1.47 mol) was added to a heated (35-40°C) solution of 200 g (1.23 mol) 2-(3-fluorophenyl)-2H-1,2,3- triazole and 25.98 g (0.61 mol) lithium chloride in one liter of THF. The resulting mixture was stirred for 6 hours at 35-40°C before cooling to -5°C. The mixture was bubbled with CO2 gas (67.44 g, 1.53 mol) at a rate that did not allow

- 19 046399 reaction rate exceed 10°C. The reaction mixture was quenched by adding 800 ml of toluene, 800 ml of water and 144 ml of concentrated HCl solution. After dissolving the insoluble particles, the two layers were separated and the aqueous layer was discarded. The organic layer was filtered through charcoal and concentrated under vacuum before redissolving the residue in 1.80 L of toluene and 800 ml of water; the two-phase mixture was heated to boiling in a reflux condenser for several minutes, cooled to 7580°C, seeded and further cooled to 10°C. After crystallization, the product was isolated by filtration, washed with a few ml of water and toluene and dried under vacuum to give 2fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (212-217 g, yield 83-85 %) white to light yellow solid.

Melting point (mp) 153-155°C.

¹ H NMR (400 MHz, DMSO-dg) δ=13.70 (br.s, 1H), 8.14 (s, 2H), 7.79 (d, J=8.1 Hz, 1H), 7 .66 (dt, J=6.1, 8.3 Hz, 1H), 7.42 (ddd, J=1.0, 8.4, 9.3 Hz, 1H). ¹³ C NMR (101 MHz, DMSO-dg) δ=164.09, 158.90 (br.d, J=247.4 Hz), 136.97, 136.77 (b.d, J=6.2 Hz), 131.82 (d, J=9.2 Hz), 118.03 (d, J=3.1 Hz), 117.25 (br. d, J=23.1 Hz), 115.48 (d, J=22.3 Hz). 19F NMR (377 MHz, DMSO-dg) δ=-114.93.

High resolution mass spectrometry (HRMS) (electrospray ionization time-of-flight mass spectrometry (ESI-TOF)) m/z: [M+H]+ calculated for C9H7FN3O2: 208.0517; the resulting value is 208.0517.

Example 5. Synthesis of (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol2(1H)-yl)(2-fluoro-6-(2H- 1,2,3-triazol-2-yl)phenyl)methanone

Thionyl chloride (60 mmol, 4.3 ml) was added to a suspension of 2-fluoro-6-(2I-1,2,3-triazol-2yl)benzoic acid (9.5 g, 46 mmol) in toluene (110 ml) and heated to 55°C for 2.5 hours. The reaction mixture was concentrated under vacuum until a residual volume of about 100 ml (about 20 ml of distilled solvent) was achieved and added to the well-mixed two-phase mixture of (3aR,6aS)-2-(4, 6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (10.2 g, 45.7 mmol) in toluene (44 ml) and aqueous sodium carbonate (44 ml, 68.5 mmol). The resulting two-phase mixture was heated at 30°C for 3.5 hours and then heated to 70°C. The organic layer was washed twice with 57 ml of water and concentrated in vacuo to a residual volume of about 64 ml. The concentrated mixture was heated to 90°C to obtain a solution, after which it was cooled to room temperature and cyclohexane (64 ml) was added. The resulting suspension was stirred overnight, filtered, washed with cyclohexane (12 ml), washed with water (11 ml) and dried under vacuum to give (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl) hexahydropyrrolo[3,4-c]pyrrol-2(1I)-yl)(2-fluoro6-(2I-1,2,3-triazol-2-yl)phenyl)methanone (18.1 g, 97% yield) as a solid. 1I NMR (400 MHz, pyridine^) δ ppm 2.33 (s, 12I), 2.81-2.97 (m, 4I), 3.27 (dd, J=10, 6, 5.0 Hz, 1 I) 3.33 (dd, J=10.5, 4.7 Hz, 1 I) 3.57 (br. t, J=7.1 Hz, 1 I) 3, 59 (us.t, J=7.0 Hz, 1 I) 3.67 (dd, J=11.7, 4.5 Hz, 1 I) 3.70-3.75 (m, 1 I) 3 .75-3.82 (m, 2 I) 3.82-3.98 (m, 7 I) 4.11 (dd, J=12.4, 7.6 Hz, 1 I) 6.29 (s , 1 I) 6.29 (s, 1 I) 7.19 (td, J=8.7, 1.0 Hz, 1 I) 7.26 (td, J=8.6, 0.9 Hz, 1 I) 7.46 (td, J=8.3, 6.2 Hz, 1 I) 7.46 (td, J=8.3, 6.0 Hz, 1 I) 7.90 (dt, J =8.2, 0.8 Hz, 1 I) 7.90 (s, 2 I) 7.98 (dt, J=8.2, 0.8 Hz, 1 I) 8.04 (s, 2 I ). ¹³ C NMR (101 MHz, pyridind ₅ ) δ ppm 24.47, 24.48, 41.74, 41.82, 42.71, 42.93, 50.76, 50.82, 50, 90, 51.03, 51.43, 51.62, 51.87, 52.06, 109.27, 109.44, 115.88 (br. d, J=22.4 Hz), 115.89 (br.d, J=22.4 Hz), 118.82 (br.d, J=3.3 Hz), 118.97 (br.d, J=3.3 Hz), 120.48 (d, J=24.9 Hz), 120.55 (d, J=24.6 Hz), 131.53 (br. d, J=9.2 Hz ), 131.54 (d, J=9.2 Hz), 137.33, 137.47, 138.04 (d, J=7.0 Hz), 138.07 (br. d, J=7, 0 Hz), 159.71 (d, J=245.8 Hz), 159.81 (d, J=245.4 Hz), 161.53, 161.61, 162.99 (d, J=7, 3 Hz), 162.99 (d, J=7.3 Hz), 167.61, 167.63. High resolution MS (ER, m/z): calculated for ^I^^O (M+I)+: 408.1943; defined: 408.1946.

While the foregoing description sets forth the principles of the present invention with examples given for illustration, it is to be understood that the practice of the invention is intended to embrace all normal variations, adaptations and/or modifications included within the scope of the following claims and their equivalents.

All documents cited herein are incorporated by reference.

Claims (13)

1. Method for preparing the intermediate 2-phenyl-2H-1,2,3-triazole of formula II, intended for the preparation of (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3, 4c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone wherein said method comprises the step described below: cyclization of hydrazine of formula I to give 2-phenyl-2H-1,2,3-triazole of formula II in a single step using a metal salt and a solvent Where R ¹ represents -H, -CO2H or _{-CO 2} C( _1.4 )alkyl; X represents -OC^alkyl, -OC(CH ₃ ) ₃ , -OCH ₂ Ph, -N(CH ₃ )2 or -N(CH ₃ ) ₃ I. 2. The method according to claim 1, in which R ¹ represents -H or -CO2CH3. 3. The method according to claim 2, wherein said method includes the steps described below: a) cyclization of hydrazine of formula I to obtain 2-phenyl-2H-1,2,3-triazole of formula II in one step Where R ¹ represents -H; X represents -OS( _1-2 )alkyl, -OS( _CH3 ) ₃ , -OCH2Ph, -N( _CH3 )2 or -N( _CH3 ) _3I , b) carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to give 2-fluoro-6-(2H-1,2,3-triazol2-yl)benzoic acid wherein said carboxylation differs in that isopropyl-MgCl and CO2 are used. 4. Method of obtaining (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol- 2( 1 H)-yl)(2-Fluoro-6-(2H- 1,2,3-triazol-2-yl)phenyl)methanone wherein said method includes the steps described below: a) cyclization of hydrazine of formula I to obtain 2-phenyl-2H-1,2,3-triazole of formula II in a single step using a metal salt and a solvent Where R ¹ represents -H, -CO2H or -CO ₂ C( _1-4 )alkyl; X represents -OC( _1-2 )alkyl, -OC( _CH3 ) ₃ , _-OCH2Ph , -N( _CH3 )2 or -N( _CH3 ) _3I ; b) carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to give 2-fluoro-6-(2H-1,2,3-triazol2-yl)benzoic acid - 21 046399, wherein said carboxylation differs in that isopropyl-MgCl and CO2 are used; c) reaction of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid with (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3, 4-c]pyrrole to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triαzol-2-yl)phenyl)methanone wherein said reaction differs in that SOCl ₂ is used. 5. The method according to claim 4, in which R ¹ represents -H or -CO ₂ CH ₃ . 6. The method according to claim 5, wherein said method includes the steps described below: a) cyclization of hydrazine of formula I to obtain 2-phenyl-2H-1,2,3-triazole of formula II in a single step using a metal salt and a solvent Where R ¹ represents -H; X represents -OC( _1-2 )alkyl, -OC( _CH3 ) ₃ , _-OCH2Ph , -N( _CH3 )2 or -N( _CH3 ) _3I ; b) carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to give 2-fluoro-6-(2H-1,2,3-triazol2-yl)benzoic acid wherein said carboxylation differs in that isopropyl-MgCl and CO2 are used; c) reaction of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid with (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3, 4-c]pyrrole to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triαzol-2-yl)phenyl)methanone wherein said reaction differs in that SOCl ₂ is used. 7. The method according to claim 6, wherein said method includes the steps described below: a) cyclization of hydrazine of formula I to obtain 2-phenyl-2H-1,2,3-triazole of formula II in one step Where R ¹ represents -H; X represents -OC( _1-2 )alkyl, -OC( _CH3 ) ₃ , _-OCH2Ph , -N( _CH3 )2 or -N( _CH3 ) _3I ; b) carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to give 2-fluoro-6-(2H-1,2,3-triazol2-yl)benzoic acid wherein said carboxylation differs in that LiCl, isopropyl-MgCl and CO2 are used; c) reaction of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid with (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3, 4-c]pyrrole to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2-yl)phenyl)methanone - 22 046399 Moreover, this reaction differs in that SOCl2 is used. 8. Method for preparing the compound of formula I wherein said method involves the reaction of (3-fluorophenyl)hydrazine hydrochloride with glyoxal in the presence of water and/or methanol to form (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde with a yield of more than 90%; where R ¹ represents H, CO2H or -CO ₂ C( _1-4 )alkyl and X is -OH, -OC( _1-4 )alkyl, -OCH ₂ Ph, -OPh, -OAc, -N(CH ₃ )2, piperidinyl, -NHC(O)CH ₃ , -NHSO ₂ PhCH ₃ or -N(CH ₃ ) ₃ I. 9. Compound of formula I where R ¹ represents H, CO2H or -CO ₂ C( _1-4 )alkyl. 10. A compound according to claim 9, selected from the group consisting of 11. A connection selected from the group consisting of - 23 046399 12. A connection that represents 13. A connection that represents