Improved method for the synthesis of (2H-1,2,3-triazol-2-yl)phenyl compounds as orexin receptor modulators

Abstract

(((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: [Formula 1] A process for preparing JPEG2022543286000082.jpg23128 is described, which is useful for commercial manufacture. The compound is an orexin receptor modulator and may be useful in pharmaceutical compositions and methods for treating disease states, disorders, and health conditions mediated by orexin activity, such as insomnia and depression.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 883,857, filed August 7, 2019, and U.S. Provisional Patent Application No. 62 / 971,265, filed February 7, 2020, the disclosures of which are incorporated by reference in their entireties herein.

[0002] FIELD OF THEINVENTION The present invention relates to a synthetic method for making (((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 (also known as sertrexant), a compound useful in modulating orexin receptors and treating disease states, disorders, and health conditions mediated by orexin receptor activity. [Background technology]

[0003] Orexin (or hypocretin) signaling is mediated by two receptors and two peptide agonists. The two orexin peptides (orexin A and orexin B), hereafter referred to as orexins, bind to two high affinity receptors, named orexin-1 and orexin-2 receptors. The orexin-1 receptor is selective in favor of orexin A, while the orexin-2 receptor binds both orexins with similar affinity. These orexins are cleavage products of the same gene, prepro-orexin. In the central nervous system, neurons expressing prepro-orexin, the precursor from which orexins are made, are found in the perifornical nucleus, dorsal hypothalamus and lateral hypothalamus (C. Peyron et al., J. Neurosci., 1998, 18(23), 9996-10015). Orexinergic cells within these nuclei project to many areas of the brain, extending rostrally to the olfactory bulb and caudally to the spinal cord (van den Pol, ANet al., J. Neuroscience., 1999, 19(8), 3171-3182).

[0004] The citation of a reference herein should not be construed as an admission that such reference is prior art to the present invention. All publications mentioned herein are incorporated by reference in their entirety.

[0005] Active central nervous system agents (WO 2001081347 (November 1, 2001); U.S. Patent Application Publication No. 2002 / 0019388 (February 14, 2002)) include α7 acetylcholine receptor modulators (U.S. Patent Application Publication Nos. 2005 / 101602 (May 12, 2005), 2005 / 0065178 (March 24, 2005), and Frost et al., Journal of Medicinal Chemistry, 2006, 49(26), 7843-7853), as proline transporter inhibitors for the treatment of cognitive disorders (WO 2008067121 (June 5, 2008)), as proline transporter inhibitors for cognitive improvement (WO 2006124897 (November 23, 2006) and U.S. Patent Application Publication No. 20060258672 (November 16, 2006)), as androgen receptor ligands for the treatment of androgen receptor-associated conditions such as cancer (WO 2009081197 (July 2, 2009)), and as histone deacetylase inhibitors for the treatment of cancer, neurodegenerative diseases and autoimmune diseases (WO 20060123121 (November 23, 2006)).

[0006] Among the compounds developed, (((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 acts as an inhibitor of the orexin-2 receptor and has been found to be useful in the treatment of sleep disorders and major depressive disorders (U.S. Pat. No. 8,653,263(B2)). The compound was assembled from two main building blocks as shown in Scheme 1 below:

[0007] [ka]

[0008] The original synthesis employed direct coupling of phenyl with triazole, as shown in Scheme 2 below, where non-selective coupling to different nitrogen atoms on the triazole gave a mixture of products.

[0009] [ka]

[0010] The exclusive synthesis of 2-aryltriazoles can be achieved by Cu(II)-mediated bis-hydrazone cyclization reaction, as shown in Scheme 3. However, this approach results in poor atom economy, since 50% of the aryl building blocks are converted to aniline by-products as a result of the bis-addition of phenylhydrazine to glyoxal (see, e.g., J. Org. Chem., 1948, 13, 815; see also Russian Journal of Organic Chemistry, 2009, 45, 1683, and Chemistry of Heterocyclic Compounds, 2010, 46, 79, for recent improvements in the dihydrazone approach).

[0011] [ka]

[0012] Other attempts to make 2-substituted triazoles have been reported (Tome, AC, Science of Synthesis, 2004, Section 13.13.2, pp528-540; Topics Heterocycl. Chem., 2015, 40, 51; Org. Let., 2009, 11, 5026; OPRD, 2019, 23, 234; Angew. Chem. Int. Ed., 2011, 50, 8944; and Heterocycles, 1980, 14, 1279). However, in all cases, when the 4- and 5-positions of the triazole ring are unsubstituted, the approach via cyclization to intermediate 2-aryltriazole derivatives results in low yields. Summary of the Invention [Problem to be solved by the invention]

[0013] It is an object of the present invention to provide a process for preparing (((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 that uses an exclusive N2-aryltriazole product to reduce waste, eliminate the need to separate undesired coupling products, and reduce manufacturing costs. [Means for solving the problem]

[0014] The present invention relates to (((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:

[0015] [ka] The process includes the step of preparing Cyclization of the hydrazone of formula I to give the 2-phenyl-2H-1,2,3-triazole of formula II in a single step:

[0016] [ka] (In the formula, R 1 is -H, -CO2H, or -CO2C (1~4) is alkyl, X is -OH, -OC (1~4) alkyl, -OCH2Ph, -OPh, -OC(O)CH3, -OSO2CH3, -N(CH3)2, piperidin-1-yl, -NHC(O)CH3, -NHSO2PhCH3, or -N(CH3)3I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The present invention relates to (((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:

[0018] [ka] The process includes the step of preparing Cyclization of hydrazines of formula I to give 2-phenyl-2H-1,2,3-triazoles of formula II in a single step:

[0019] [ka] (In the formula, R 1 is -H, -CO2H, or -CO2C (1~4) is alkyl, X is -OH, -OC (1~4)alkyl, -OCH2Ph, -OPh, -OC(O)CH3, -OSO2CH3, -N(CH3)2, piperidin-1-yl, -NHC(O)CH3, -NHSO2PhCH3, or -N(CH3)3I.

[0020] In another embodiment of the present invention, The present invention relates to (((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:

[0021] [ka] The process includes the step of preparing Cyclization of hydrazines of formula I to give 2-phenyl-2H-1,2,3-triazoles of formula II in a single step:

[0022] [ka] (In the formula, R 1 is H or -CO2CH3, X is -OC (1~2) alkyl, -OC(CH3)3, -OCH2Ph, -N(CH3)2, or -N(CH3)3I.

[0023] In another embodiment of the present invention, The present invention relates to (((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:

[0024] [ka] The process includes the step of preparing a) cyclization of hydrazines of formula I to give 2-phenyl-2H-1,2,3-triazoles of formula II in a single step:

[0025] [ka] (In the formula, R 1 is -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 give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid:

[0026] [ka] wherein the carboxylation comprises the steps characterized by the use of isopropyl-MgCl and CO2.

[0027] In another embodiment of the present invention, The present invention relates to (((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:

[0028] [ka] The process includes the step of preparing a) cyclization of hydrazines of formula I to give 2-phenyl-2H-1,2,3-triazoles of formula II in a single step:

[0029] [ka] (In the formula, R1 is -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 give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid:

[0030] [ka] wherein the carboxylation is characterized by the use of 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:

[0031] [ka] wherein the reaction comprises a step characterized by the use of SOCl2.

[0032] In another embodiment of the present invention, The present invention relates to (((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:

[0033] [ka] The process includes the step of preparing a) cyclization of hydrazines of formula I to give 2-phenyl-2H-1,2,3-triazoles of formula II in a single step:

[0034] [ka] (In the formula, R 1 is -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 give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid:

[0035] [ka] wherein the carboxylation is characterized by the use of 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:

[0036] [ka] wherein the reaction is characterized by the use of SOCl2.

[0037] The present invention also relates to a compound of formula I:

[0038] [ka] The method includes a method for producing a compound of the formula: Reacting (3-fluorophenyl)hydrazine hydrochloride with glyoxal in the presence of water and / or methanol to form (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde in greater than 90% yield:

[0039] [ka] (In the formula, R 1 is H, CO2H, or -CO2C (1~4) is alkyl, and, X is -OH, -OC (1~4) alkyl, -OCH2Ph, -OPh, -OAc, -N(CH3)2, piperidinyl, -NHC(O)CH3, -NHSO2PhCH3, or -N(CH3)3I.

[0040] Another embodiment of the present invention is a compound of formula I:

[0041] [ka] (In the formula, R 1 is H, CO2H, or -CO2C (1~4) (alkyl).

[0042] Another embodiment of the present invention comprises:

[0043] [ka] The compound is selected from the group consisting of:

[0044] Another embodiment of the present invention comprises:

[0045] [ka]

[0046] [ka] The compound is selected from the group consisting of:

[0047] Another embodiment of the present invention comprises:

[0048] [ka] The compound is selected from the group consisting of:

[0049] The present invention may be more fully understood by reference to the following description, including the following glossary and concluding examples. For purposes of brevity, the disclosures of the publications, including patents, cited in this specification are hereby incorporated by reference.

[0050] As used herein, the terms "including," "containing," and "comprising" are used herein in their open, non-limiting sense.

[0051] definition "(((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" is

[0052] [ka] means.

[0053] The products of the chemical reactions described herein can be reacted directly with additional reagents or can be separated prior to subsequent reactions. The term "isolated" means that the reaction products are partially or completely separated from other materials in the reaction vessel. These other materials include, but are not limited to, solvents, unreacted starting materials, reagents used in the reaction, by-products, impurities, and products of the reagents used in the reaction.

[0054] The term "preparing" refers to synthesis by a chemical process.

[0055] Additionally, any formula given herein is intended to refer to hydrates, solvates, and polymorphs of such compounds, and mixtures thereof, even if these forms are not explicitly stated.

[0056] Any formula given herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. Isotopically labeled compounds have the structure depicted in the formula given herein except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 Such isotope-labeled compounds are useful in metabolic studies (preferably 14 C), reaction kinetic studies (e.g., 2 H or 3H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)), including drug or substrate tissue distribution assays, or in radiotherapy of patients. Additionally, heavier isotopes, such as deuterium (i.e., 2 H), may result in greater metabolic stability and may result in certain therapeutic advantages, such as longer in vivo half-lives or reduced dosage requirements. The isotopically labeled compounds of the present invention and prodrugs thereof may generally be prepared by following the procedures disclosed in the schemes or examples and preparations set forth below, by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0057] Those skilled in the art will recognize that compounds of the present invention in which at least one double bond is present may exist as stereoisomers. The present invention contemplates the (E) and (Z) stereoisomers and all mixtures thereof.

[0058] Those of skill in the art will recognize that the compounds and reagents used in the reactions of the present invention may exist as salts, and the present invention contemplates the use of all salts of any of the compounds used in the reactions exemplified herein.

[0059] Examples of salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, These include, but are not limited to, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methane-sulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate salts.

[0060] When a compound or reagent used in a reaction of the invention contains a basic nitrogen, a salt can be prepared by any suitable method available in the art, for example, from an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc.), or from an organic acid (e.g., 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, pyranosidyl acids (e.g., glucuronic acid or galacturonic acid), α-hydroxybutyric acid, ... The free bases can be prepared by treating them with any compatible mixture of acids such as hydroxy acids (e.g., mandelic acid, citric acid, or tartaric acid), amino acids (e.g., aspartic acid, glutaric acid, or glutamic acid), aromatic acids (e.g., benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid), sulfonic acids (e.g., laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid), as well as any other acids and mixtures thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary skill in the art.

[0061] Those skilled in the art will recognize that esters

[0062] [ka] It will be appreciated that many reagents may be used for the saponification of , and these are varied and known to those of skill in the art. The present invention contemplates the use of all conventional means for converting esters to carboxylic acids, including those described in Protective Groups in Organic Synthesis by TW Green and PG Mughuts (Wiley-Interscience, New York, 1999), pages 579-580 and 744-747.

[0063] Exemplary reactions useful in the methods of the present invention will now be described by reference to the following exemplary synthetic schemes for their general preparation followed by specific examples. Those skilled in the art will recognize that the reactions can be carried out in any suitable solvent. Those skilled in the art will also recognize that the reactions can be carried out at a wide range of temperatures, unless specifically limited. Unless otherwise stated, the reactions can be carried out between the melting point and the reflux temperature of the solvent, preferably between 0° C. and the reflux temperature of the solvent. The reactions can be carried out under heating using conventional or microwave heating. The reactions can also be carried out in a closed pressure vessel at a temperature higher than the normal reflux temperature of the solvent.

[0064] Abbreviation: The following abbreviations may be used herein and throughout this application:

[0065] [Table A] EXAMPLES

[0066] In obtaining the compounds described in the Examples below and the corresponding analytical data, the following experimental and analytical protocols were followed, unless otherwise indicated.

[0067] Unless otherwise noted, reaction mixtures were stirred under nitrogen at room temperature (rt). When mixtures, solutions, and extracts were "concentrated", they were typically concentrated under reduced pressure. Reactions under microwave irradiation conditions were carried out on a Biotage Initiator or CEM Discover instrument.

[0068] Normal phase flash column chromatography (FCC) was performed on silica gel (SiO2) using prepackaged cartridges and eluting with the indicated solvents.

[0069] Mass spectra (MS) were obtained either on a Bruker QTOF, a Waters QTOF Ultima instrument using electrospray ionization (ESI) in positive mode unless otherwise indicated, or on a Waters GC-TOF using electronic impact (EI). Calculated masses correspond to exact masses.

[0070] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker spectrometer. 1 The format of the H NMR data is chemical shift (ppm) downfield relative to tetramethylsilane (multiplicity, coupling constant J (Hz), integral).

[0071] Chemical names were generated using ChemDraw Ultra 6.0.2 (CambridgeSoft Corp., Cambridge, MA) or ACD / Name Version 9 (Advanced Chemistry Development, Toronto, Ontario, Canada).

[0072] General Scheme

[0073] [ka]

[0074] Phenylhydrazine III or the corresponding salt can be reacted with glyoxal and water or water-methanol in the presence of sodium acetate to form hydrazonoacetaldehyde IV. The present invention uses a water-glyoxal mixture in which phenylhydrazine is sparingly soluble to achieve the desired monocondensation with a relatively small amount of excess glyoxal. The desired monocondensation product can be obtained in high yields with a suitable solvent such as water, or a mixture of methanol and water, minimizing the concentration of the hydrazine starting material in the solution and also allowing the monocondensation product to precipitate out of solution as it is formed.

[0075] Condensation with H2N-X affords hydrazone I. This product is formed as a mixture of E / Z stereoisomers that interconvert upon heating, making it unnecessary to separate the stereoisomers from one another. Cyclization of the hydrazone mixture affords 2-phenyl-2H-1,2,3-triazole II from I in a single step.

[0076] The formation of 2-phenyl-2H-1,2,3-triazole II is 1 Ga-CO2C (1~4) In the case of alkyl, by saponification or by R 1 When is H, this is accomplished by carboxylation to give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid. Addition of LiCl to the reaction mixture reduced the undesired bis-addition of -CO2.

[0077] The product, 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-(4,6-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.

[0078] Example 1: Synthesis of hydrazonoacetaldehyde of formula IV Example 1a: Synthesis of (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde.

[0079] [ka] A 40 wt% aqueous solution of glyoxal (613 g, 4.22 mol) was added to a suspension of 177 g (1.06 mol) of (3-fluorophenyl)hydrazine (HCl salt) in 1.24 L of water. A solution of 129.9 g (1.58 mol) of sodium acetate in 708 mL of water was then added over 2 h. After stirring at room temperature for several hours, the suspension was filtered and the cake was washed with 0.89 L of water and dried under vacuum to give 172.8 g (95% yield) of the title compound as a yellow solid.

[0080] Melting point (mp): 118~119℃.

[0081] 1 H NMR (DMSO-d6)δ: 11.80 (br s, 1H), 9.49 (d, J=7.7Hz, 1H), 7.36 (d, J=7.9Hz, 1H), 7.32~7.39 (m, 1H), 6.96~7.03 (m, 2H), 6.75~6.83 (m, 1H). 13 C NMR(DMSO-d6)δ:190.4, 163.0(br d, J=242.7Hz), 144.7(br d, J=10.8Hz), 136.3, 131.2(d, J=10.0Hz), 110.0(d, J=2.3Hz), 108.5(d, J=21.6Hz), 100.6(d, J=27.0Hz). 19 F NMR(DMSO-d6) δ: -111.72.

[0082] HRMS(ESI-TOF)m / z:[M+H] + Calculated value for C8H8FN2O: 167.0621, found value: 167.0611.

[0083] Example 1b: Synthesis of methyl (E)-2-fluoro-6-(2-(2-oxoethylidene)hydrazinyl)benzoate

[0084] [ka] A solution of methyl 2-fluoro-6-hydrazinylbenzoate (17.65 g, 0.08 mol) in methanol-water (90 mL, 180 mL, respectively) was added to a mixture of 40 wt% aqueous solution of glyoxal (58.04 g, 0.8 mol), water (100 mL), and sodium acetate (9.85 g, 0.12 mol) over 10 min at 10° C. The mixture was stirred for about 1.5 h and then filtered. The filter cake was rinsed with water (50 mL×2) and dried under vacuum. The dried solid (16.12 g) was redissolved in ethyl acetate (50 mL) at 50° C., then heptane (200 mL) was added slowly and cooled to 5° C. to crystallize. The resulting solid was filtered, rinsed with heptane (15 mL×2), and dried under vacuum. The desired product was obtained as a yellow solid (13.33 g, 74% yield) having a melting point of 110.8° C.

[0085] 1 H NMR (DMSO-d6) 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).

[0086] MS(ESI-TOF)m / z:225.1([M+H] + ).

[0087] Example 1c: Synthesis of (E)-2-fluoro-6-(2-(2-oxoethylidene)hydrazinyl)benzoic acid

[0088] [ka] 2-Fluoro-6-hydrazinylbenzoic acid was reacted with excess glyoxal in water to give the desired compound, 2-fluoro-6-(2-(2-oxoethylidene)hydrazinyl)benzoic acid, in 64% yield as a yellow solid, which was used directly in the next step.

[0089] Example 2: Synthesis of hydrazones of formula I Example 2a: Synthesis of (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime.

[0090] [ka] A solution of 59.7 g (715 mmol) of methoxylamine hydrochloride and 58.6 g (715 mmol) of sodium acetate in 210 mL of water was added to a solution of 70 g (408 mmol) of (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde in 350 mL of methanol over 1.5 hours, followed by the addition of 210 mL of water. After stirring at room temperature for 2 hours, the suspension was cooled to 0° C. and stirred at this temperature overnight before filtering. The filter cake was washed with 70 mL of water and dried under vacuum to give 77.4 g (92% yield) of the title compound as a yellow solid. NMR analysis revealed the presence of two isomers (approximately 1 / 1 ratio).

[0091] Separation of isomers.

[0092] [ka] The isomers of 10 g of the reaction product of Example 2a were separated by 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 (28% yield) of isomer 2 (E,Z).

[0093] Isomer 1 (E,E): Melting point: 90℃.

[0094] 1 H NMR (DMSO-d6) δ: 10.89 (s, 1H), 7.83 (d, J=8.8Hz, 1H), 7.54 (dd, J=8.8, 0.7Hz , 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-d6)δ:163.2(br d, J=241.2Hz), 148.3, 146.1((br d, J=10.8Hz), 132.8, 130.8 (d, J=10.0Hz), 108.4 (d, J=2.3Hz), 105.9 (d, J=21.6Hz), 98.9 (d, J=27.0Hz), 61.7. 19 F NMR (DMSO-d6) δ: -112.30.

[0095] HRMS (ESI-TOF) m / z: [M+H] + C9H 11 FN3O's calculated value: 196.0881, measured value: 196.0876.

[0096] Heteromorph 2 (E, Z): Melting point: 114℃.

[0097] 1 H NMR (DMSO-d6) δ: 11.04 (s, 1H), 7.96 (dd, J=8.6, 0.9Hz, 1H), 7.25 (d, J=8.4Hz , 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-d6)δ=163.2(br d, J=242.0Hz), 145.8(br d, J=10.8Hz), 145.4, 130.8 (d, J=10.0Hz), 127.9, 108.8 (d, J=2.3Hz), 106.6 (d, J=21.6Hz), 99.3 (d, J26.2Hz), 61.7. 19 F NMR (DMSO-d6) δ: -112.18.

[0098] HRMS(ESI-TOF)m / z:[M+H] + C9H 11 Calculated value of FN3O: 196.0881, measured value: 196.0876.

[0099] Example 2b: Alternative synthesis of (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime from the compound (3-fluorophenyl)hydrazine (HCl salt), glyoxal, and methoxylamine HCl without drying (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde.

[0100] The first reactor was charged with 4.5 kg of (3-fluorophenyl)hydrazine (HCl salt) and 36 L of water. The suspension was stirred at 65° C. for 1 hour. The second reactor was charged with 6.15 kg of glyoxal and 4.6 L of water and cooled to 10° C. The 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 another 3 hours, then filtered and the solid of (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde was washed with water. The wet cake was charged again into the reactor with 18 kg of methanol. Then 3.77 kg of hydroxylamine HCl, 3.7 kg of sodium acetate and 9 kg of water were added with efficient stirring. The suspension was stirred for 30-60 min, 18 kg of water was added, and the final mixture was cooled to 5° C. and stirred for 1-2 h. The product mixture of (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime and (1E,2Z)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime was filtered, washed with water, and dried under vacuum to give 5.01 kg of a yellow solid (yield: 93%) with a purity of >99%.

[0101] Example 2c: Synthesis of compound of formula I from (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde and X-NH2.

[0102] [ka] Unless otherwise stated, the compound of formula I, 1 is H. Compounds of formula (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde and X-NH2 were prepared according to the procedure of Example 2a or a very similar procedure and used crude or purified by crystallization or chromatography. The results are reported in Table 1.

[0103] [Table 1]

[0104] (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde oxime

[0105] [ka] Yellow solid. Melting point: 135°C.

[0106] Isomer 1 (major): 1 H NMR (400MHz, DMSO-d6) δ=11.33(s, 1H), 10.70(s, 1H), 7.77(d, J=8.6Hz, 1H), 7.59(dd, J=0.4 , 8.8Hz, 1H), 7.27~7.17(m, 1H), 6.80~6.76(m, 1H), 6.75(d, J=1.5Hz, 1H), 6.59~6.51(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ=163.24(br d, J=241.2Hz), 147.88, 146.46(br d, J=10.8Hz), 134.44, 130.74(d, J=10.0Hz), 108.29(d, J=2.3Hz), 105.56(d, J=21.6Hz), 98.71(d, J=26.2Hz). 19 F NMR (377MHz, DMSO-d6) δ=-112.36.

[0107] HRMS(ESI-TOF)m / z:[M+H] + Calculated value for C8H9FN3O: 182.0730, found value: 182.0726.

[0108] Isomer 2 (minority): 1 H NMR (400MHz, DMSO-d6) δ=11.28(s, 1H), 10.90(s, 1H), 8.06(dd, J=0.7, 8.4Hz, 1 H), 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 (101MHz, DMSO-d6) δ=163.21(br d, J=241.2Hz), 146.16(br d, J=10.8Hz), 144.96, 130.82(d, J=10.0Hz), 128.71, 108.65(d, J=2.3Hz), 106.14(d, J=21.6Hz), 99.09(d, J=26.2Hz). 19 F NMR (377MHz, DMSO-d6) δ=-112.26.

[0109] HRMS(ESI-TOF)m / z:[M+H] + Calculated for C8H9FN3O: 182.0730, found: 182.0727.

[0110] (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-ethyl oxime

[0111] [ka] Yellow solid. Melting points: 82.7° C. and 101.7° C. (mixture of isomers).

[0112] Isomer 1 (major): 1H NMR (400MHz, DMSO-d6) δ = 10.88 (s, 1H), 7.82 (d, J = 8.6Hz, 1H), 7.56 (d, J = 8.8Hz, 1H), 7.29~7. 18(m, 1H), 6.85~6.73(m, 2H), 6.61~6.52(m, 1H), 4.10(q, J=7.0Hz, 2H), 1.22(t, J=7.0Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ=163.21(br d, J=241.2Hz), 148.02, 146.20(br d, J=10.8Hz), 133.08, 130.73 (d, J=10.0Hz), 108.40 (d, J=2.3Hz), 105.84 (d, J=20.8Hz), 98.86 (d, J=26.2Hz), 69.24, 14.31. 19 F NMR (377MHz, DMSO-d6) δ=-112.34.

[0113] HRMS (ESI-TOF) m / z: [M+H] + C 10 H 13 FN3O's calculated value: 210.1043, measured value: 210.1035.

[0114] Heterosexual 2 (minority): 1 H NMR (400MHz, DMSO-d6) δ=11.05(s, 1H), 8.00(d, J=8.6Hz, 1H), 7.29~7.18(m, 2H), 6.85~6.73(m, 2H), 6.66~6.58(m, 1H), 4.11(q, J=7.0Hz, 2H), 1.22(br t, J=7.0Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ=163.16 (br d, J=241.2Hz), 145.86 (br d, J=11.6Hz), 145.17, 130.80 (br d, J=10.0Hz), 128.15, 108.78 (d, J=2.3Hz), 106.46 (d, J=21.6Hz), 99.25 (d, J=27.0Hz), 69.20, 14.38. 19 F NMR(377MHz, DMSO-d6)δ=-112.22.

[0115] HRMS(ESI-TOF)m / z:[M+H] + C 10 H 13 Calculated value of FN3O: 210.1043, measured value: 210.1035.

[0116] (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-(tert-butyl)oxime

[0117] [ka] Yellow solid. Melting point: 93.8°C (mixture of isomers).

[0118] Isomer 1: 1 H NMR (400MHz, DMSO-d6) δ=10.80(s, 1H), 7.80(d, J=8.6Hz, 1H), 7.60(d, J=9.0H z, 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 (101MHz, DMSO-d6) δ=163.23(br d, J=241.2Hz), 147.19, 146.33(br d, J=10.8Hz), 133.76, 130.63(d, J=10.0Hz), 108.35(d, J=2.3Hz), 105.66(d, J=21.6Hz), 98.84(d, J=26.2Hz), 78.78, 27.18. 19 F NMR (377MHz, DMSO-d6) δ=-112.36.

[0119] HRMS(ESI-TOF)m / z:[M+H] + C 12 H 17 Calculated value of FN3O: 238.1356, measured value: 238.1351.

[0120] Isomer 2: 11H NMR (400 MHz, DMSO-d6) 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 13C NMR (101 MHz, DMSO-d6) 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 19F NMR (377 MHz, DMSO-d6) δ = -112.29.

[0121] HRMS (ESI-TOF) m / z: [M+H] + C 12 H 17 Calculated value for C

[0122] Isomer 3: 1 1H NMR (400 MHz, DMSO-d6) 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 13C NMR (101 MHz, DMSO-d6) 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 19F NMR (377 MHz, DMSO-d6) δ = -112.16.

[0123] HRMS (ESI-TOF) m / z: [M+H] + C 12H 17 FN3O's calculated value: 238.1356, measured value: 238.1351.

[0124] Heterosexual 4: 1 H NMR (400MHz, DMSO-d6) δ=11.35(s, 1H), 8.28(d, J=6.8Hz, 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-d6-detected signal) 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(377MHz, DMSO-d6)δ=-112.22.

[0125] (1E,2E)-2-(2-(3-フルオロフェニル)ヒドラゾノ)アセトアルデヒドO-ベンジルオキシム

[0126]

change

[0127] Heterosexual 1(Main): 1 H NMR (400MHz, DMSO-d6) δ = 10.91 (s, 1H), 7.94 (d, J = 8.8Hz, 1H), 7.56 (d, J = 9.0Hz, 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). 13C NMR(101MHz, DMSO-d6)δ=163.20(d, J=241.2Hz), 148.86, 146.13(br d, J=10.8Hz, 1C), 137.43, 132.71, 130.74 (d, J=9.2Hz), 128.25, 128.00, 127 .74, 108.46 (d, J=2.3Hz), 105.96 (d, J=21.6Hz), 98.95 (d, J=26.2Hz), 75.51. 19 F NMR (377MHz, DMSO-d6) δ=-112.23.

[0128] HRMS (ESI-TOF) m / z: [M+H] + C 15 H 15 FN3O's calculated value: 272.1199, measured value: 272.1198.

[0129] Heterosexual 2 (minority): 1 H NMR (400MHz, DMSO-d6) δ=11.08 (s, 1H), 8.06 (d, J=9.0Hz, 1H), 7.56 (d, J=9.0Hz, 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 (101MHz, DMSO-d6) δ = 163.16 (br d, J = 241.2Hz), 145.94, 137.50, 108.83 (d, J = 2.3Hz), 106.58 (d, J = 21.6Hz), 99.31 (d, J = 26.2Hz) 75.56. 19 F NMR (377MHz, DMSO-d6) δ=-112.12.

[0130] HRMS (ESI-TOF) m / z: [M+H] + C 15 H 15 FN3O's calculated value: 272.1199, measured value: 272.1199.

[0131] Isoform 3: HRMS (ESI-TOF) m / z: [M+H] + C 15 H 15Calculated value of FN3O: 272.1199, measured value: 272.1200.

[0132] (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-phenyloxime

[0133] [ka] Yellow solid. Melting point: 93.4°C (mixture of isomers).

[0134] Isomer 1 (major): 1 H NMR (400MHz, DMSO-d6)δ=11.17(s, 1H), 8.28(d, J=8.6Hz, 1H), 7.70(d, J=8.8Hz, 1H), 7.45~7.32(m, 2H), 7. 32~7.23(m, 1H), 7.18(d, J=7.9Hz, 2H), 7.09~7.01(m, 1H), 6.93~6.81(m, 2H), 6.64(dt, J=2.2, 8.6Hz, 1H). 13 C NMR (101MHz, DMSO-d6) δ=163.17(br d, J=241.2Hz), 158.61, 151.99, 145.82(br d, J=11.6Hz), 131.57, 130.87(d, J=9.2Hz), 129.44, 122.43, 114.18, 108.72(d, J=2.3Hz), 106.48(d, J=21.6Hz), 99.62(d, J=26.2Hz). 19 F NMR (377MHz, DMSO-d6) δ=-112.13.

[0135] HRMS(ESI-TOF)m / z:[M+H] + C 14 H 13 Calculated value of FN3O: 258.1043, measured value: 258.1038.

[0136] Isomer 2 (minority): 1H NMR (400MHz, DMSO-d6) δ=11.38(s, 1H), 8.19(d, J=8.6Hz, 1H), 7.69(br d, J=8.4Hz, 1H), 7.45~7.32(m, 2H), 7.32~7.23(m, 1H), 7.18(d, J=7.9Hz , 2H), 7.09~7.01(m, 1H), 6.93~6.81(m, 2H), 6.69(dt, J=2.2, 8.6Hz, 1H). 13 C NMR (101MHz, DMSO-d6) δ=163.13(br d, J=242.0Hz), 158.66, 148.82, 145.47(br d, J=10.8Hz), 130.95(d, J=10.0Hz), 129.44, 127.23, 122.33, 114.21, 109.14(d, J=2.3Hz), 107.14(d, J=21.6Hz), 99.62(d, J=26.2Hz). 19 F NMR (377MHz, DMSO-d6) δ=-112.02.

[0137] HRMS(ESI-TOF)m / z:[M+H] + C 14 H 13 Calculated value of FN3O: 258.1043, measured value: 258.1038.

[0138] (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-acetyloxime

[0139] [ka] 1.16 mL of 50 wt% aqueous hydroxylamine solution (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, 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.

[0140] Yellow solid. Melting point: 100.8℃ (mixture of heterosexual bodies).

[0141] Opposite sex body 1: 1 H NMR(400MHz, DMSO-d6)δ=11.31(br s, 1H), 8.20 (d, J=8.8Hz, 1H), 7.63 (d, J=8.8Hz, 1H), 7.36~7.22 (m, 1H), 6.93~6.79 (m, 2H), 6.78~6.60 (m, 1H), 2.15 (s, 3H). 13 C NMR (101MHz, DMSO-d6) δ=167.88, 163.15(br d, J=242.0Hz), 155.53, 145.54(br d, J=10.8Hz), 131.12 (d, J=10.0Hz), 130.58, 108.93 (d, J=2.3Hz), 106.94 (d, J=21.6Hz), 99.44 (d, J=26.2Hz), 19.25. 19 F NMR (377MHz, DMSO-d6) δ=-112.07.

[0142] HRMS (ESI-TOF) m / z: [M+H] + C 10 H 11 FN3O2's calculated value: 224.0835, measured value: 224.0835.

[0143] Opposite sex body 2: 1 H NMR (400 MHz, DMSO-d6, visible signal) 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 (101MHz, DMSO-d6) δ = 171.93, 163.02 (br d, J = 242.7Hz), 151.84, 144.63 (br d, J=10.8Hz), 130.95 (d, J=10.0Hz), 130.97, 109.45 (d, J=2.3Hz), 108.23 (d, J=21.6Hz), 100.16 (d, J=26.2Hz), 21.00. 19F NMR (377MHz, DMSO-d6) δ=-111.71.

[0144] HRMS(ESI-TOF)m / z:[M+H] + C 10 H 11 Calculated value of FN3O2: 224.0835, measured value: 224.0836.

[0145] Isomer 3: 1 H NMR (400MHz, DMSO-d6)δ=11.85(br s, 1H), 7.97(d, J=8.4Hz, 1H), 7.74(d, J=8.4Hz, 1H), 7.36~7.22(m, 1H), 6.93~6.79(m, 2H), 6.78~6.60(m, 1H), 2.17(s, 3H). 13 C NMR (101MHz, DMSO-d6) δ=167.91, 163.11(br d, J=242.0Hz), 155.53, 145.20(br d, J=10.0Hz), 131.66(d, J=9.3Hz), 126.80, 109.35(d, J=2.3Hz), 107.57(d, J=21.6Hz), 99.85(d, J=27.0Hz), 19.37. 19 F NMR (377MHz, DMSO-d6) δ=-111.95.

[0146] (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1-dimethylhydrazine

[0147] [ka] Yellow solid. Melting point: 134.4 °C (only one isomer).

[0148] 1 H NMR (400MHz, DMSO-d6) δ=10.27(s, 1H), 7.58(d, J=7.9Hz, 1H), 7.23~7.13(m, 1 H), 7.02(d, J=8.1Hz, 1H), 6.77~6.67(m, 2H), 6.52~6.42(m, 1H), 2.89(s, 6H).13 C NMR (101MHz, DMSO-d6)δ=163.33(br d, J=240.4Hz), 147.21(d, J=10.8Hz), 139.63, 130.69, 130.55(d, J=10.0Hz ), 107.80(d, J=1.5Hz), 104.33(d, J=21.6Hz), 98.06(d, J=26.2Hz), 42.24. 19 F NMR (377MHz, DMSO-d6) δ=-112.61.

[0149] HRMS(ESI-TOF)m / z:[M+H] + C 10 H 14 Calculated value of FN4: 209.1202, measured value: 209.1200.

[0150] (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)-N-(piperidin-1-yl)ethan-1-imine

[0151] [ka] Yellow solid. Melting point: 155.4 °C (only one isomer).

[0152] 1 H NMR (400MHz, DMSO-d6) δ=10.36(s, 1H), 7.58(d, J=8.1Hz, 1H), 7.31(d, J=7.9Hz, 1H), 7.25~7.08(m, 1H), 6.83~6.62(m, 2H), 6.48(dt, J=2.3, 8.5Hz, 1H), 3.06(br t, J=5.4Hz, 4H), 1.81~1.52(m, 4H), 1.52~1.23(m, 2H). 13C NMR (101MHz, DMSO-d6) δ = 163.31 (d, J = 240.4Hz, 1C), 147.05 (d, J = 10.8Hz, 1C), 139.45, 132.82, 130.55 (br d, J = 10.0Hz, 1C), 107.88 (br d, J=2.3Hz, 1C), 104.54 (d, J=21.6Hz, 1C), 98.17 (br d, J=26.2Hz, 1C), 51.14, 24.43, 23.48. 19 F NMR (377MHz, DMSO-d6) δ=-112.59.

[0153] HRMS (ESI-TOF) m / z: [M+H] + C 13 H 18 FN4's calculated value: 249.1515, measured value: 249.1518.

[0154] N'-((1E,2E)-2-(2-(3-フルオロフェニル)ヒドラゾノ)エチリデン)アセトヒドラジド

[0155]

change

[0156] Heteromorph 1 (reverse heteromorph 1, main): 1 H NMR (400MHz, DMSO-d6) δ=11.22(s, 1H), 10.85(s, 1H), 7.75(d, J=8.4Hz, 1H), 7.57(d, J=8.6Hz, 1H), 7.25(q, J=7.8Hz, 1H), 6.93~6.73(m, 2H), 6.59(br t, J=7.8Hz, 1H), 2.13 (s, 3H). 13C NMR (101MHz, DMSO-d6) δ = 190.43, 171.62, 163.26 (d, J = 241.2Hz, 1C), 146.20 (br d, J=10.8Hz, 1C), 142.49, 136.15, 130.79 (d, J=10.0Hz, 1C), 108.44 (d, J=2.3Hz, 1C), 105.84 (br d, J=21.6Hz, 1C), 98.86 (br d, J=26.2Hz, 1C), 20.07. 19 F NMR(377MHz, DMSO-d6)δ=-112.21.

[0157] Opposite-sex body 1 (return to opposite-sex body 2, minority): 1 H NMR (400MHz, DMSO-d6) δ=11.37(s, 1H), 10.92(s, 1H), 7.87(d, J=8.4Hz, 1H), 7.62(d, J=8.4Hz, 1H), 7.25(q, J=7.8Hz, 1H), 6.93~6.73(m, 2H), 6.59(br t, J=7.8Hz, 1H), 1.96 (s, 3H). 13 C NMR (101MHz, DMSO-d6) δ = 190.43, 165.52, 163.26 (d, J = 241.2Hz, 1C), 146.17 (br d, J=10.8Hz, 1C), 145.05, 136.32, 130.79 (d, J=10.0Hz, 1C), 108.48 (br d, J=2.3Hz, 1C), 105.91 (br d, J=21.6Hz, 1C), 98.89 (br d, J=26.2Hz, 1C), 21.56. 19 F NMR(377MHz, DMSO-d6)δ=-112.21.

[0158] HRMS (ESI-TOF) m / z: [M+H] + C 10 H 12 FN4O's calculated value: 223.0995, measured value: 223.0994.

[0159] N'-((1E,2E)-2-(2-(3-フルオロフェニル)ヒドラゾノ)エチリデン)-4-メチルベンゼンスルホノヒドラジド

[0160] [ka] Yellow solid. Melting point: 146.7 °C (only one isomer).

[0161] 1 H NMR (400MHz, DMSO-d6) δ=11.48(s, 1H), 10.84(s, 1H), 7.71(d, J=8.4Hz, 2H), 7.61(d, J=8.4Hz, 1H), 7.42(br d, J=8.6Hz, 1H), 7.41(br d, J=8.1Hz, 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 (101MHz, DMSO-d6) δ=163.18(br d, J=241.2Hz), 146.37, 145.99(br d, J=10.8Hz), 143.46, 136.07, 135.31, 130.83(d, J=10.0Hz), 129.68, 127. 05, 108.52(d, J=2.3Hz), 106.07(d, J=21.6Hz), 98.92(d, J=26.2Hz), 20.96. 19 F NMR (377MHz, DMSO-d6) δ=-112.20.

[0162] HRMS(ESI-TOF)m / z:[M+H] + C 15 H 16 Calculated value of FN4O2S: 335.0978, measured value: 335.0982.

[0163] (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1,1-trimethylhydrazin-1-ium iodide

[0164] [ka] To a solution of (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde (1 mmol, 1.0 equiv.) and NaOAc (1.5 mmol, 1.5 equiv.) in MeOH (3 mL) was added 1,1-dimethylhydrazine hydrochloride (1.2 mmol, 1.2 equiv.) in one portion at 25° C. After consumption of the starting material (after about 30 min), water (3 mL) was added to the reaction mixture. The suspension was then filtered and the cake 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 h. To a solution of the so obtained (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1-dimethylhydrazine (1.0 mmol, 1.0 equiv.) (either isolated or not isolated intermediate) in ACN (2 mL) was added MeI (5.0 mmol, 5.0 equiv.) 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 cake was washed with EtOAc. The hydrazinium salt (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 of a yellow solid (yield: 90%).

[0165] Melting point: 166.8°C. 1 H NMR (400MHz, DMSO-d6):δ 11.82(s, 1H), 8.73(d, J=8.0Hz, 1H), 7.63(d, J=8.1Hz, 1H), 7.35(dd, J=15.1, 8.2Hz, 1H), 6.99~6.90(m, 2H), 6.82~6.71(m, 1H), 3.47(s, 9H). 13 C NMR (101MHz, DMSO-d6):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.

[0166] C11 H 16 FN4 + [M + HRMS(ESI) calculated for 223.1359, found: 223.1348. Melting point: 166.8°C.

[0167] Example 2d: Synthesis of methyl 2-fluoro-6-(2-(2-(methoxyimino)ethylidene)hydrazinyl)benzoate

[0168] [ka] 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 (E)-2-fluoro-6-(2-(2-oxoethylidene)hydrazinyl)methyl benzoate (8.07 g, 36.0 mmol) in methanol (40 mL). After stirring at room temperature overnight, the title compound was filtered, rinsed with water (2 x 15 mL) and dried under vacuum. The desired compound (7.85 g, 79% yield) was obtained as a yellow solid. NMR indicates the presence of several isomers. Melting point 90.0 °C.

[0169] 1 H NMR (DMSO-d6, major 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).

[0170] MS(ESI-TOF)m / z:254.2([M+H] + ).

[0171] Example 2e: Synthesis of (E)-2-((E)-2-(2-(3-fluoro-2-(methoxycarbonyl)phenyl)hydrazinylidene)ethylidene)-1,1,1-trimethylhydrazin-1-ium iodide

[0172] [ka] 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-(2-oxoethylidene)hydrazinyl)benzoate (1.68 g, 7.5 mmol) in toluene-methanol (25 mL, 6 mL, respectively). After stirring for 1 h, the mixture was concentrated in vacuo and the residue was partitioned between water and ethyl acetate (10 mL, 20 mL, respectively). 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 give the intermediate dihydrazone (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 h. After cooling to room temperature, the solid was filtered, rinsed with acetonitrile (2×20 mL), and dried under vacuum to give the desired compound (2.0 g, 65% overall yield) as a yellow solid. Melting point: 177.5° C.

[0173] 1 H NMR(DMSO-d6)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-d6) δ: -111.49.

[0174] MS(ESI-TOF) m / z: 281.1 ([hydrazonium ion] + ).

[0175] Example 2f: Synthesis of 2-fluoro-6-(2-((1E,2E)-2-(methoxyimino)ethylidene)hydrazinyl)benzoic acid

[0176] [ka] 2-Fluoro-6-(2-(2-oxoethylidene)hydrazinyl)benzoic acid was reacted with methoxylamine hydrochloride and sodium acetate in water-methanol to give 2-fluoro-6-(2-((1-(E,2E)-2-(methoxyimino)ethylidene)hydrazinyl)benzoic acid as a yellow solid in 52% yield. The desired compound was used directly in the next step.

[0177] Example 3: Synthesis of 2-phenyl-2H-1,2,3-triazoles of formula II

[0178] [ka] Example 3a: X is -N + Me3I - Synthesis of 2-(3-fluorophenyl)-2H-1,2,3-triazole when

[0179] (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1,1-trimethylhydrazin-1-ium iodide hydrazinium salt (X=-N + Me3I - To a solution of 3-(2,4-dichlorophenyl)-2H-1,2,3-triazole (-1.0 mmol, 1.0 equiv.) was added K2CO3 or KHCO3 (2.0 mmol, 2.0 equiv.) in one portion at 25° C. The suspension was heated to 50° C. After stirring for 2 h or until the starting material was consumed, the reaction was cooled to 25° C. and treated with H2O and EtOAc. The organic layer was partitioned and extracted twice with EtOAc. The combined organics were washed with brine, dried over Na2SO4, 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.

[0180] Substituting KHCO3 for K2CO3 improved the yield to 96%.

[0181] Example 3b: Synthesis of 2-(3-fluorophenyl)-2H-1,2,3-triazole using other -X groups.

[0182] R 1 The synthesis of 2-(3-fluorophenyl)-2H-1,2,3-triazoles from compounds of formula I where is H can be achieved for a variety of -X leaving groups according to the following procedures.

[0183] 5mmol R 1 A solution / suspension of the compound of formula I, where 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 at 110° C. for several hours, then cooled to room temperature, washed with 7.5 mL of 1 M aqueous HCl, and assayed by LC for 2-(3-fluorophenyl)-2H-1,2,3-triazole.

[0184] Table 2 below shows the yields obtained for each -X leaving group under the conditions listed. The reaction conditions are not optimized, and the present invention contemplates the reaction conditions for each -X group and obvious variations thereof. An example of various screening conditions that can be used for reaction optimization of any -X leaving group is shown for example, Example 3c, where -X is -OCH3.

[0185] [Table 2]

[0186] Example 3c: Synthesis of 2-(3-fluorophenyl)-2H-1,2,3-triazole from (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime (screening of conditions).

[0187] [ka]

[0188] A solution of (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime (1 equivalent) and catalyst in solvent was heated at 110-120°C for 20 minutes to overnight, then cooled to room temperature and assayed by LC for 2-(3-fluorophenyl)-2H-1,2,3-triazole. The reaction conditions and yields are summarized in Table 3.

[0189] [Table 3]

[0190] Example 3d: Formation and isolation of 2-(3-fluorophenyl)-2H-1,2,3-triazole from (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime.

[0191] The reactor was inerted with 0.31 kg copper sulfate pentahydrate and 26.8 kg EG and heated to 120-130°C with stirring. 4.8 kg (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime was added in 5 portions. After stirring at 120-130°C for 1 hour, a portion of the reaction mixture was distilled under vacuum. The distillate (13 L of 2-(3-fluorophenyl)-2H-1,2,3-triazole + EG) was partitioned between 3.3 kg heptane and 4.8 kg of 2 wt% aqueous HCl. The two layers were separated and the polar 1 side was extracted with 3.3 kg heptane. The two heptane layers were combined, washed with 4.8 kg of water and concentrated under vacuum to give 3.09 kg of 2-(3-fluorophenyl)-2H-1,2,3-triazole as a colorless to slightly yellow oil (yield: 77%).

[0192] 1 H NMR (400MHz, DMSO-d6) δ=8.14(s, 2H), 7.87(dd, J=1.3, 8.1Hz, 1H), 7.79(td, J=2 .2, 10.1Hz, 1H), 7.60 (dt, J=6.4, 8.3Hz, 1H), 7.26 (ddt, J=0.9, 2.5, 8.5Hz, 1H). 13C NMR (101MHz, DMSO-d6)δ=162.38(br d, J=244.3Hz), 140.32(d, J=1.5Hz), 136.88, 131.63(d, J=9.2Hz), 114.34(d, J=3.1Hz), 114.37(d, J=20.8Hz), 105.79(d, J=27.7Hz). 19 F NMR (377MHz, DMSO-d6) δ=-110.88.

[0193] HRMS(EI-TOF)m / z:[M] + Calculated value for C8H6FN3: 163.0546, measured value: 163.0521.

[0194] 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)hydrazineyl)benzoate

[0195] [ka] 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) maintained at 125° C. The resulting mixture was stirred at 125° C. for 3 hours or more and then cooled to 60° C. Water (60 mL), heptane (30 mL), and ethyl acetate (20 mL) were added and the layers were separated. The organic layer was concentrated and the residue was purified by column chromatography (silica gel, heptane-ethyl acetate: 8 / 1) to give 1.3 g (37% yield) of the desired product. Melting point: 56.9° C.

[0196] Methyl 2-fluoro-6-(2-(2-(methoxyimino)ethylidene)hydrazinyl)benzoate (633 mg, 2.50 mmol) and copper sulfate pentahydrate (31 mg, 0.125 mmol) were first mixed in ethylene glycol (5 mL) at room temperature, then heated to 120° C. for about 4 hours (heating to completely dissolve the chemicals) and cooled to room temperature. Dilution with water, extraction with isopropyl acetate, and purification by column chromatography improved the yield of methyl 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoate to 54%. The above procedure was repeated with 1.00 mmol of starting material, 0.05 mmol of copper sulfate pentahydrate in 10 mL of ethylene glycol, and a heating time of about 8 hours, giving a yield of 57%.

[0197] 1 H NMR (DMSO-d6) δ: 8.18 (s, 2H), 7.87 (d, 1H), 7.75 (m, 1H), 7.48 (t, 1H), 3.78 (s, 3H). 13 C NMR(DMSO-d6)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. 19 F NMR(DMSO-d6) δ: -114.28.

[0198] 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

[0199] [ka] A stirred 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) gave complete conversion, neutralization and isolation to give the desired product in 86% yield.

[0200] Example 3f: Synthesis 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

[0201] [ka] A 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) was stirred at 56° C. for 1 h and then concentrated under vacuum. The residue was partitioned between heptane and water (15 mL and 6 mL, respectively). After phase separation, the aqueous layer was extracted with heptane (15 mL) and the combined organic layers were concentrated under vacuum to give the desired product (0.27 g, 81% yield) as a yellow powder.

[0202] 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

[0203] [ka] 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 give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid in approximately 25% yield.

[0204] Example 4: Synthesis of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid from 2-(3-fluorophenyl)-2H-1,2,3-triazole

[0205] [ka] Example 4a: Screening of bases and additives Base was added to the solution of compound 2-(3-fluorophenyl)-2H-1,2,3-triazole, and the mixture was stirred until the anion was completely quenched and the acid was worked up before CO2 gas was bubbled in. The resulting mixture was analyzed by LC, and 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid was isolated after the work-up was completed. The results are reported in Table 4 below.

[0206] [Table 4]

[0207] Example 4b: Synthesis and isolation of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid A solution of 2M isopropylmagnesium chloride in THF (735 mL, 1.47 mol) was added to a heated (35-40°C) solution of 200 g (1.23 mol) of 2-(3-fluorophenyl)-2H-1,2,3-triazole and 25.98 g (0.61 mol) of lithium chloride in 1 L of THF. The reaction mixture was stirred at 35-40°C for 6 hours and then cooled to -5°C. CO2 gas (67.44 g, 1.53 mol) was bubbled through the mixture at such a rate that the temperature of the reaction did not exceed 10°C. The reaction mixture was quenched by the addition of 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, after which the residue was redissolved in 1.80 L of toluene and 800 mL of water. The biphasic mixture was heated to reflux for several minutes, cooled to 75-80° C., seeded with crystal seeds, and further cooled to 10° C. After crystallization, the product was isolated by filtration, washed with several mL of water and toluene, and dried under vacuum to give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (212-217 g, 83-85% yield) as a white to pale yellow solid.

[0208] Melting point: 153~155℃.

[0209] 1 H NMR (400MHz, DMSO-d6) δ = 13.70 (br s, 1H), 8.14 (s, 2H), 7.79 (d, J = 8.1Hz, 1H), 7.66 (dt, J = 6.1, 8.3Hz, 1H), 7.42 (ddd, J = 1.0, 8.4, 9.3Hz, 1H). 13 C NMR (101MHz, DMSO-d6) δ=164.09, 158.90(br d, J=247.4Hz), 136.97, 136.77(br d, J=6.2Hz), 131.82(d, J=9.2Hz), 118.03(d, J=3.1Hz), 117.25(br d, J=23.1Hz), 115.48(d, J=22.3Hz). 19 F NMR (377MHz, DMSO-d6) δ=-114.93.

[0210] HRMS(ESI-TOF)m / z:[M+H] + Calculated value for C9H7FN3O2: 208.0517, found value: 208.0517.

[0211] Example 5: Synthesis of (((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

[0212] [ka] Thionyl chloride (60 mmol, 4.3 mL) was added to a suspension of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (9.5 g, 46 mmol) in toluene (110 mL) and heated to 55° C. for 2.5 h. The reaction was concentrated under vacuum to a residual volume of about 100 mL (solvent distillation volume was about 20 mL) and added to a well-stirred biphasic 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 biphasic mixture was stirred at 30° C. for 3.5 h and then heated to 70° C. The organic layer was washed twice with 57 mL of water and concentrated under vacuum to a residual volume of approximately 64 mL. The concentrated mixture was heated to 90° C. to give a solution, then 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(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (18.1 g, 97% yield) as a solid. 11H NMR (400 MHz, pyridine-d5) δ ppm 2.33 (s, 12H) 2.81 - 2.97 (m, 4H) 3.27 (dd, J = 10.6, 5.0 Hz, 1H) 3.33 (dd, J = 10.5, 4.7 Hz, 1H) 3.57 (br t, J = 7.1 Hz, 1H) 3.59 (br t, J = 7.0 Hz, 1H) 3.67 (dd, J = 11.7, 4.5 Hz, 1H) 3.70 - 3.75 (m, 1H) 3.75 - 3.82 (m, 2H) 3.82 - 3.98 (m, 7H) 4.11 (dd, J = 12.4, 7.6 Hz, 1H) 6.29 (s, 1H) 6.29 (s, 1H) 7.19 (td, J = 8.7, 1.0 Hz, 1H) 7.26 (td, J = 8.6, 0.9 Hz, 1H) 7.46 (td, J = 8.3, 6.2 Hz, 1H) 7.46 (td, J = 8.3, 6.0 Hz, 1H) 7.90 (dt, J = 8.2, 0.8 Hz, 1H) 7.90 (s, 2H) 7.98 (dt, J = 8.2, 0.8 Hz, 1H) 8.04 (s, 2H). 13 13C NMR (101 MHz, pyridine-d5) 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 (ES, m / z): C 21 H 23 FN7O (M + H) + Calculated value for: 408.1943, Measured value: 408.1946.

[0213] While the foregoing specification, together with examples given for purposes of illustration, teaches the principles of the invention, it will be understood that the practice of the invention encompasses all ordinary modifications, adaptations and / or alterations that come within the scope of the following claims and equivalents thereto.

[0214] All documents cited are incorporated herein by reference. The present invention may include the following aspects. [1] (((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: [ka] A process for preparing Cyclization of hydrazines of formula I to give 2-phenyl-2H-1,2,3-triazoles of formula II in a single step: [ka] (In the formula, R 1 -H, -CO 2 H or -CO 2 C (1~4) is alkyl, X is -OH, -OC (1~4) Alkyl, -OCH 2 Ph, -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 It is I.) The process comprising: [2]R 1 is -H or -CO 2 CH 3 and X is -OC (1~2) Alkyl, -OC(CH 3 ) 3 , -OCH 2 Ph, -N(CH 3 ) 2 , or -N(CH 3 ) 3 I am, The process described in [1] above. [3] The process comprises: a) obtaining in a single step said 2-phenyl-2H-1,2,3-triazole of formula II by cyclization of said hydrazine of formula I:

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[10]

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Claims

1. (((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: 【Chemistry 1】 A process for preparing Cyclization of hydrazines of formula I to give 2-phenyl-2H-1,2,3-triazoles of formula II in a single step: 【Chemistry 2】 (In the formula, R １ is -H, -CO ２ H, or -CO ２ C （１～４） is alkyl, X is -OC(1-2)alkyl, -OC(CH3)3, -OCH2Ph, -N(CH3)2, or -N(CH3)3I. The process comprising:

2. R １ is -H or -CO ２ CH ３ That is, 2. The process of claim 1.

3. The process comprises: a) obtaining in a single step said 2-phenyl-2H-1,2,3-triazole of formula II by cyclization of said hydrazine of formula I: 【Chemistry 3】 (In the formula, R １ is -H, X is -OC （１～２） Alkyl, -OC(CH ３ ) ３ , -OCH ２ Ph, -N(CH ３ ) ２ , or -N(CH ３ ) ３ It is I.) and, b) Carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid: 【Chemistry 4】 wherein the carboxylation is carried out using isopropyl-MgCl and CO ２ and The process of claim 2, comprising:

4. a) obtaining in a single step said 2-phenyl-2H-1,2,3-triazole of formula II by cyclization of said hydrazine of formula I: 【Chemistry 5】 (In the formula, R １ is -H, X is -OC （１～２） Alkyl, -OC(CH ３ ) ３ , -OCH ２ Ph, -N(CH ３ ) ２ , or -N(CH ３ ) ３ It is I.) and, b) Carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid: 【Chemistry 6】 wherein the carboxylation is carried out using isopropyl-MgCl and CO ２ and 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: 【Chemistry 7】 The reaction is carried out by reacting SOCl ２ and The process of claim 3, comprising:

5. a) obtaining in a single step said 2-phenyl-2H-1,2,3-triazole of formula II by cyclization of said hydrazine of formula I: 【Chemistry 8】 (In the formula, R １ is -H, X is -OC （１～２） Alkyl, -OC(CH ３ ) ３ , -OCH ２ Ph, -N(CH ３ ) ２ , or -N(CH ３ ) ３ It is I.) and, b) Carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid: 【Chemistry 9】 wherein the carboxylation is carried out using LiCl, isopropyl-MgCl, and CO ２ and 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: 【Chemistry 10】 The reaction is carried out by reacting SOCl ２ and a step characterized by the use of: Claim 6: Formula I: 【Chemistry 11】 The method further comprises the step of producing a compound of The step of preparing the compound of formula I comprises reacting (3-fluorophenyl)hydrazine hydrochloride with glyoxal in the presence of water and / or methanol to form (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde in greater than 90% yield: 【Chemistry 12】 Including, In formula I, R １ H, CO ２ H, or -CO ２ C （１～４） is alkyl, and, The process of any one of claims 1 to 5, wherein X is -OC(1-2)alkyl, -OC(CH3)3, -OCH2Ph, -N(CH3)2, or -N(CH3)3I.

7. The method of claim 1, further comprising the step of preparing a compound of formula I comprising the steps of: 【Chemistry 13】 (In the formula, R １ H, CO ２ H, or -CO ２ C （１～４） It is an alkyl group.

7. The process of claim 6, comprising forming a compound of formula:

8. The method of claim 1, further comprising the step of preparing a compound of formula I comprising the steps of: 【Chemistry 14】 8. The process of claim 7, comprising forming a compound selected from the group consisting of:

9. The compound of formula I, 【Chemistry 15】 【Chemistry 16】 2. The process of claim 1, wherein the compound is selected from the group consisting of:

10. The compound of formula II, 【Chemistry 17】 2. The process of claim 1, wherein the compound is selected from the group consisting of:

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