Process for producing 5-bromo-3,4-dimethylpyridin-2-amine and 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

Abstract

5-Bromo-3,4-dimethylpyridin-2-amine and 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine: A method for producing TIFF2025524632000048.tif23150 is disclosed.

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Application No. 63 / 388,860, filed Jul. 13, 2022, which is hereby incorporated by reference in its entirety.

[0002] Technical field The present invention generally relates to methods for producing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine and 5-bromo-3,4-dimethylpyridin-2-amine.

Background Art

[0003] WO2018 / 005586 discloses compounds useful for the treatment of inflammatory and autoimmune diseases such as lupus, rheumatoid arthritis, multiple sclerosis, and Sjögren's syndrome, as well as methods for producing such compounds and synthetic intermediates. WO2018 / 005586 discloses two methods for producing intermediates using the intermediates 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (intermediate F-4) and 5-bromo-3,4-dimethylpyridin-2-amine as starting materials.

Summary of the Invention

Problems to be Solved by the Invention

[0004] In the art, there is a need for an improved method for producing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine. In the art, there is a need for a method for producing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine in high yield. In the art, there is a need for a method for producing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine in high yield and adaptable to large-scale production.

[0005] In addition, in the art, an improved method for producing 5-bromo-3,4-dimethylpyridin-2-amine is required. In the art, a method for producing 5-bromo-3,4-dimethylpyridin-2-amine in a high yield is required. In the art, a method for producing 5-bromo-3,4-dimethylpyridin-2-amine in a high yield and minimizing the formation of by-products is required. In the art, a method for producing 5-bromo-3,4-dimethylpyridin-2-amine in a high yield and adaptable to large-scale production is required. In the art, a method for producing 5-bromo-3,4-dimethylpyridin-2-amine in a high yield, minimizing the generation of by-products, and adaptable to large-scale production is required.

[0006] In the art, a method for producing 5-bromo-3,4-dimethylpyridin-2-amine that is adaptable to large-scale production and does not require the use of a palladium catalyst is required. In the art, a method for producing 5-bromo-3,4-dimethylpyridin-2-amine that does not require the use of a palladium catalyst is required. In the art, a method for producing 5-bromo-3,4-dimethylpyridin-2-amine in a high yield, minimizing the formation of by-products, adaptable to large-scale production, and not requiring the use of a palladium catalyst is required.

Means for Solving the Problem

[0007] The applicant has discovered a new synthetic method for producing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine. This method provides 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine in a high yield and is adaptable to large-scale production.

[0008] The applicant has discovered a new synthetic method for manufacturing 5-bromo-3,4-dimethylpyridin-2-amine. This method provides 5-bromo-3,4-dimethylpyridin-2-amine in high yield, minimizes the generation of by-products, is adaptable to large-scale manufacturing, and / or does not use a palladium catalyst.

[0009] The present invention provides a synthetic method for manufacturing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine. The present invention provides an intermediate for manufacturing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine and a method for manufacturing the intermediate. Furthermore, the present invention also provides a synthetic method for manufacturing 5-bromo-3,4-dimethylpyridin-2-amine. Furthermore, the present invention provides a synthetic method for manufacturing (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformimidamide.

[0010] Furthermore, the present invention provides a synthetic method for manufacturing (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformimidamide. These features and other features of the present invention will be described in an expanded form as the disclosure continues.

Brief Description of the Drawings

[0011]

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0012] Detailed description Figure 2 shows the synthesis of 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine from 5-bromo-3,4-dimethylpyridin-2-amine as disclosed in WO2018 / 005586.

[0013] The first aspect of the present invention is a method for producing a compound represented by formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0014] The second aspect of the present invention is a compound represented by formula (I):

Chemical formula

[0015] A third aspect of the present invention is a method for producing a compound represented by formula (IV), comprising reacting a compound represented by formula (II) with a compound represented by formula (III): [ka] to react with a compound of formula (IV): [ka] (IV) and obtaining a compound represented by the formula:

[0016] A fourth aspect of the present invention is a compound of formula (IV): [ka] (IV) The present invention provides a method for producing a compound having the structure:

[0017] A fifth aspect of the present invention is a compound of formula (VI): [ka] (VI) A method for preparing a compound represented by the following steps: (i) Formula (IV):

Chem.

Chem.

[0018] The sixth aspect of the present invention is a method for producing a compound represented by the formula (VI):

Chem.

Chem.

[0019] The seventh aspect of the present invention is a method for producing a compound represented by the formula (V):

Chem.

Chem.

[0020] Method for producing 5-bromo-3,4-dimethylpyridin-2-amine The method for producing the compound represented by formula (I) includes forming a carbon-carbon bond by substituting the 3-bromo substituent on the pyridine ring of 2-amino-3,5-dibromo-4-methylpyridine, which is the starting material, with a methyl group.

Chemical formula

Chemical formula

[0021] In the second step (step (b)) of this method, the compound represented by formula (IV) is reacted with a methylzinc compound or a methylzinc salt in the presence of a nickel catalyst to substitute the 3-bromo substituent with a methyl group to obtain the compound represented by formula (I).

Chemical formula

[0022] After replacing the 3-bromo substituent with a methyl group, hydrolysis can be carried out in the presence of an acid to remove the orienting group and regenerate the amine group in the compound represented by formula (I). The compound represented by formula (V) can also be hydrolyzed without isolation to obtain the compound represented by formula (I), or it can be isolated, redissolved, and then hydrolyzed to obtain the compound represented by formula (I).

[0023] In the second step of this method, a Negishi coupling reaction is used to replace the 3-bromo group of (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamide with a methyl group. The Negishi coupling reaction is discussed in Haas et al., ACS Catalysis 2016, 6, 1540-1553; Phapale et al., Chemical Society Reviews 2009, 38, 1598-1607; Jana et al., Chemical Reviews 2011, 111, 1417-1492; Eckert et al., Angew. Chem. Int. Ed. 2021, 60, 12224-12241; Nielson et al., Journal of the American Chemical Society, 2013. 135, 13605-13609; and Tollefson et al., Accounts of Chemical Research 2015, 48, 2344-2353.

[0024] Step (a): Various synthetic conditions can be employed to react the compound represented by formula (II) with the compound represented by formula (III) to produce the compound represented by formula (IV).

[0025] This reaction is sensitive to oxygen. Before the start of the reaction, the reagents and / or the reaction mixture can be sparged with an inert gas such as nitrogen or argon to displace the dissolved oxygen.

[0026] Since the compound represented by formula (III) is decomposed by water, the reaction is sensitive to water. The water content of the reagents and the reaction mixture needs to be minimized to an appropriate water level, such as less than 0.2 wt%, less than 0.15 wt%, less than 0.1 wt%, and less than 0.05 wt%.

[0027] The reaction of a compound of formula (II) with a compound of formula (III) to give a compound of formula (IV) can be carried out in a variety of solvents or mixtures thereof. Examples of suitable solvents include polar aprotic solvents such as dimethylformamide and N-methyl-2-pyrrolidone; ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, and 1,2-dimethoxyethane; alcohol solvents such as 2-propanol; and other solvents such as toluene.

[0028] In one embodiment, the process of step (a) is carried out in a solvent selected from 2-propanol and 2-methyltetrahydrofuran. In one embodiment, the process of step (a) is carried out in a solvent selected from 2-propanol. In one embodiment, the process of step (a) is carried out in a solvent selected from 2-methyltetrahydrofuran.

[0029] Suitable reaction temperatures for the reaction of the compound represented by formula (II) with the compound represented by formula (III) include temperatures in the range of about 70°C to about 80°C, temperatures in the range of about 75°C to about 80°C, and temperatures in the range of about 78°C to about 80°C.

[0030] The compound of formula (IV) can be isolated and / or purified by various methods known in the art, suitable methods include chromatography, crystallization from 2-propanol at about 0° C., and collection of the solid by filtration (purity >98%).

[0031] Step (b): A variety of synthetic conditions can be employed in step (b) to prepare compounds of formula (V). Examples of suitable nickel catalysts include nickel chloride (NiCl2) having ligands such as 1,1-bis(diphenylphosphino)methane (dppm), (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (binap), 1,3-bis(dicyclohexylphosphino)propane (dcpp), 1,2-bis(diphenylphosphino)benzene (dppbz), 1,2-bis(dicyclohexylphosphino)ethane (dcpe), 1,1'-bis(diisopropylphosphino)ferrocene (dippf), and triphenylphosphine (PPh3).

[0032] In one embodiment, the method of step (b) is carried out in the presence of a catalyst selected from (bis(diphenylphosphino)propane) nickel chloride.

[0033] Examples of suitable methylzinc compounds and methylzinc salts include dimethylzinc, combinations of anhydrous zinc bromide and Grignard reagents, etc. Examples of suitable Grignard reagents include methylmagnesium chloride, methylmagnesium bromide, and methylmagnesium iodide, etc.

[0034] The reaction to obtain the compound represented by formula (V) from the compound represented by formula (IV) in step (b) can be carried out in the presence of various optional synthetic aids including alkali metal halides and carboxylates such as LiCl, LiBr, NaBr, lithium acetate, lithium pivalate; alkaline earth metal halides and carboxylates such as MgCl2, MgBr2, magnesium pivalate.

[0035] The reaction of step (b) is sensitive to oxygen, and it is necessary to remove dissolved oxygen by sparging the reagents and / or the reaction mixture with an inert gas such as nitrogen or argon before adding the methylzinc compound or methylzinc salt to the reaction mixture.

[0036] The reaction in step (b) can be carried out in the presence of a low level of moisture of 0.4% by weight or less. The moisture content of the reagents and the reaction mixture needs to be minimized to an appropriate moisture level, such as less than 0.3% by weight, less than 0.2% by weight, less than 0.1% by weight, less than 0.05% by weight, etc.

[0037] The reaction to obtain the compound represented by formula (V) from the compound represented by formula (IV) in step (b) can be carried out in various solvents or mixtures thereof. Examples of suitable solvents include, but are not limited to, ether solvents such as tetrahydrofuran or 2 - methyltetrahydrofuran.

[0038] Suitable reaction temperatures for reacting the compound represented by formula (IV) in step (b) to obtain the compound represented by formula (V) include temperatures in the range of about - 20°C to about 25°C, temperatures in the range of about - 10°C to about 5°C, and temperatures in the range of about 0°C to about 5°C.

[0039] The compound represented by formula (V) can be isolated and / or purified by various methods known in the art. Suitable methods include chromatography and crystallization from acetonitrile, acetone, or tetrahydrofuran using water as an anti - solvent at about 0°C, followed by collecting the solid by filtration. Alternatively, the compound represented by formula (V) can be hydrolyzed in step (c) without being isolated from the solution.

[0040] Step (c): To produce the compound of formula (I), various synthetic conditions can be employed in step (c). After the methylation reaction is completed, the amidine - orienting group can be removed under acidic aqueous conditions to obtain the compound represented by formula (I). Suitable acids include aqueous acids such as HCl, HBr, HI, and H2SO4.

[0041] The compound of formula (I) can be isolated and / or purified by various methods known in the art. Suitable methods include chromatography and crystallization from acetonitrile at about 0° C. using water as an antisolvent, followed by collection of the solid by filtration.

[0042] The compound of formula (I), 5-bromo-3,4-dimethylpyridin-2-amine, is useful as a starting material in the synthesis of 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine, as shown in FIG. 2 and disclosed in WO 2018 / 005586.

[0043] 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine A process for preparing a compound of formula (VI) from the starting material (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformimidamide is shown in Figure 3. The first step of this process, step (i), involves replacing the 3-bromo substituent on the pyridine ring of the compound of formula (IV), (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformimidamide, with a methyl group to form a carbon-carbon bond; [ka] The method includes obtaining a compound of formula (V), (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformimidamide. In the second step (step (ii)) of the method, the compound of formula (V) is reacted to form a triazole ring to obtain a compound of formula (VI), 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine. [ka]

[0044] Step (i): In step (i), various synthetic conditions can be adopted in the reaction of substituting the 3-bromo substituent of the compound represented by formula (IV) with a methyl group to obtain the compound represented by formula (V).

[0045] Examples of suitable nickel catalysts include nickel chloride (NiCl2) having ligands such as 1,1-bis(diphenylphosphino)methane (dppm), (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (binap), 1,3-bis(dicyclohexylphosphino)propane (dcpp), 1,2-bis(diphenylphosphino)benzene (dppbz), 1,2-bis(dicyclohexylphosphino)ethane (dcpe), 1,1'-bis(diisopropylphosphino)ferrocene (dippf), and triphenylphosphine (PPh3).

[0046] In one embodiment, the method of step (i) is carried out in the presence of a catalyst selected from (bis(diphenylphosphino)propane) nickel chloride.

[0047] Examples of suitable methylzinc compounds and methylzinc salts include dimethylzinc, a combination of anhydrous zinc bromide and a Grignard reagent, etc. Examples of suitable Grignard reagents include methylmagnesium chloride, methylmagnesium bromide, and methylmagnesium iodide, etc.

[0048] The reaction of obtaining the compound represented by formula (V) from the compound represented by formula (IV) in step (i) can be carried out, for example, in the presence of various optional synthetic aids including alkali metal halides and carboxylates such as LiCl, LiBr, NaBr, lithium acetate, lithium pivalate; alkaline earth metal halides and carboxylates such as MgCl2, MgBr2, magnesium pivalate.

[0049] The reaction in step (i) is sensitive to oxygen, and it is necessary to purge the reagents and / or the reaction mixture with an inert gas such as nitrogen or argon to remove dissolved oxygen before adding dimethylzinc to the reaction mixture.

[0050] The reaction in step (i) can be carried out in the presence of a low level of moisture of 0.4 wt% or less. The moisture content of the reagents and the reaction mixture needs to be minimized to an appropriate moisture level, such as less than 0.3 wt%, less than 0.2 wt%, less than 0.1 wt%, less than 0.05 wt%, etc.

[0051] The reaction to obtain the compound represented by formula (V) from the compound represented by formula (IV) in step (i) can be carried out in various solvents or mixtures thereof. Examples of suitable solvents include, but are not limited to, ether solvents such as tetrahydrofuran or 2-methyltetrahydrofuran.

[0052] Suitable reaction temperatures for reacting the compound represented by formula (IV) in step (i) to obtain the compound represented by formula (V) include temperatures in the range of about -20°C to about 25°C, in the range of about -15°C to about 10°C, in the range of about -15°C to about 5°C, and in the range of about -5°C to about 5°C.

[0053] The compound represented by formula (V) can be isolated and / or purified by various methods. Suitable methods include chromatography and crystallization from acetonitrile, acetone, or tetrahydrofuran using water as an anti-solvent at about 0°C, followed by collecting the solid by filtration.

[0054] Step (ii): In step (ii), the compound represented by formula (V) is reacted to form a triazole ring to obtain the compound represented by formula (VI), and various synthetic conditions can be employed in this reaction.

[0055] This reaction can be carried out in the presence of dimethylformamide-dimethylacetal (DMF-DMA) and a suitable acid such as hydroxylamine-O-sulfonic acid. Suitable levels of DMF-DMA include amounts in the range of 0.5 to 1.3 equivalents, 0.7 to 1.2 equivalents, and 0.8 to 1.1 equivalents. Suitable levels of hydroxylamine-O-sulfonic acid include amounts in the range of 1.0 to 2.0 equivalents, 1.1 to 1.7 equivalents, and 1.4 to 1.6 equivalents.

[0056] The reaction for obtaining the compound represented by formula (VI) from the compound represented by formula (V) can be carried out in various solvents or mixtures thereof. Examples of suitable solvents include, for example, polar aprotic solvents such as dimethylformamide and N-methyl-2-pyrrolidone; ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, and 1,2-dimethoxyethane; alcohol solvents such as 2-propanol; and other solvents such as toluene.

[0057] In one embodiment, the method of step (ii) is carried out in a solvent selected from 2-propanol and 2-methyltetrahydrofuran. In one embodiment, the method of step (ii) is carried out in a solvent selected from 2-propanol. In one embodiment, the method of step (ii) is carried out in a solvent selected from 2-methyltetrahydrofuran.

[0058] Suitable reaction temperatures for the reaction to form the compound represented by formula (VI) from the compound represented by formula (V) include temperatures in the range of about 40 degrees to about 70 °C, temperatures in the range of about 40 °C to about 60 °C, and temperatures in the range of about 45 °C to about 55 °C.

[0059] The compound represented by formula (VI) can be isolated and / or purified by various methods known in the art. Suitable methods include chromatography, crystallization from 2-propanol at about 0 °C, and collection by filtration.

[0060] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention encompasses any combination of aspects and / or embodiments of the invention described herein. It is understood that any and all embodiments of the present invention can be combined with any other embodiment to form additional embodiments, and that individual elements of the embodiments can be combined with any and all other elements of any other embodiment for purposes of describing additional embodiments.

[0061] Definition The features and advantages of the present invention will be more readily understood by those skilled in the art upon reading the following detailed description. For the sake of clarity, it should be understood that the specific features of the present invention described above and below in the context of separate embodiments can also be combined to form a single embodiment. Conversely, for the sake of brevity, the various features of the present invention described in the context of a single embodiment can also be combined to form sub-combinations thereof. The embodiments specifically identified herein as exemplary or preferred are intended to be illustrative and not limiting.

[0062] Unless otherwise specifically stated herein, references to the singular may include the plural, e.g., "a" and "an" may indicate one or more than one.

[0063] Unless otherwise indicated, an atom having an unsatisfied valence is considered to have sufficient hydrogen atoms to satisfy that valence.

[0064] The definitions in this specification shall prevail over any definitions described in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0065] The following are definitions of various terms used to describe the present invention. These definitions apply to the terms used throughout the specification, either individually or as part of a larger group (unless otherwise specifically limited in a particular instance).

[0066] The compounds represented by formulas (I), (II), (III), (IV), (V), and (VI) can be obtained as amorphous solids or crystalline solids. Lyophilization can be used to obtain the compounds as solids.

[0067] Furthermore, after preparing the compounds represented by formulas (I), (II), (III), (IV), (V), and (VI), they can be isolated and purified to obtain a composition containing at least 93% by weight of the compounds represented by formulas (I), (II), (III), (IV), (V), and (VI) (substantially pure), and then used as described herein. Such "substantially pure" compounds represented by formulas (I), (II), (III), (IV), (V), and (VI) are also contemplated herein as part of the present invention.

[0068] "Stable compound" and "stable structure" mean compounds that are sufficiently robust to withstand isolation from a reaction mixture to useful purity.

[0069] The compounds of the present invention are intended to include all isotopes of the atoms present in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. Common examples include, but are not limited to, deuterium (D) and tritium (T) as isotopes of hydrogen. Isotopes of carbon include , 13 , , 14 , ,

[0069] ,

[0068] , C and 14It contains C. The isotope-labeled compounds of the present invention can usually be prepared by using appropriate isotope-labeled reagents in place of unlabeled reagents by conventional techniques known to those skilled in the art or by methods similar to those described herein. For example, methyl (-CH3) also includes deuterated methyl groups such as -CD3.

Examples

[0070] The present invention is further defined in the following examples. It should be understood that the examples are for illustrative purposes only. From the above description and examples, those skilled in the art can grasp the essential features of the present invention and make various changes and modifications to adapt the present invention to various applications and conditions without departing from the spirit and scope of the present invention. As a result, the present invention is not limited to the exemplary examples shown below in this specification, but is defined by the scope of the claims attached hereto.

[0071] Abbreviation anhyd. Anhydrous aq. Aqueous DMF Dimethylformamide dmf·dma N,N-Dimethylformamide-dimethylacetal dppp 1,3-Bis(diphenylphosphino)propane (dppp)NiCl2 [1,3-Bis(diphenylphosphino)propane]dichloronickel(II) h, hr or hrs Hour IPA Isopropyl alcohol HPLC High-performance liquid chromatography HOSA Hydroxylamine-O-sulfonic acid iPrOH Isopropanol LC Liquid chromatography LCMS Liquid chromatography-mass spectrometry M Mole mM Millimole Me Methyl MeCN Acetonitrile MeMgCl Methylmagnesium chloride 2-MeTHF 2-Methyltetrahydrofuran MHz Megahertz min. Minute mins Minutes MS Mass spectrometry NH2OSO3H Hydroxylamine-O-sulfonic acid nM Nanomole Ret Time or Rt Retention time sat. Saturated SFC Supercritical fluid chromatography THF Tetrahydrofuran wt% Weight % ZnMe2 Dimethylzinc

[0072] Synthesis of 5-bromo-3,4-dimethylpyridin-2-amine using a nickel catalyst Step (a): (E)-N'-(3,5-Dibromo-4-methylpyridin-2-yl)-N,N-dimethylformimidamide preparation

Chem.

[0073] Steps (b) and (c): Preparation of 5-bromo-3,4-dimethylpyridin-2-amine

Chemical formula

[0074] Comparison of Ni and Pd in the preparation of (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformimidamide

Chemical formula

[0075] Table 1: Comparison of the synthesis of catalyst (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformimidamide using Ni or Pd

Table 1

[0076] According to the comparison of the synthesis of (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformimidamide using the above Ni or Pd catalyst, the results in Table 1 show that in the method using the Ni catalyst, (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformimidamide was produced in a higher yield than the method using the Pd catalyst (compound shown in formula (V): 91.7 AP vs. 28.2 AP respectively), and that the starting materials were completely consumed (compound shown in formula (IV): <0.05 AP vs. 52.5 AP respectively). Furthermore, in this experiment, it can be seen from the results in Table 1 that the use of the Ni catalyst reduces the amount of by-products generated compared to the method using the Pd catalyst (compounds B - E: <8.5 AP vs. approximately 19.3 AP respectively).

[0077] The applicant has discovered a new synthetic method for producing 5-bromo-3,4-dimethylpyridin-2-amine. The new synthetic method minimizes the generation of by-products. The new synthetic method is applicable to large-scale production.

[0078] (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformimidamide synthesis

Chemical formula

[0079] Synthesis of 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-A]pyridine [Chemical Structure] Into a 40 mL scintillation vial, (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformimidamide (2.87 g, 11.2 mmol, crude product from the reaction), hydroxylamine-O-sulfonic acid (2.00 g, 16.8 mmol), and a magnetic stirrer were added. After purging the vial with N2 for 10 minutes, 2-propanol (25.8 mL) and dimethylformamide dimethylacetal (2.04 mL, 14.6 mmol) were added. The vial was sealed and heated to 60 °C and stirred for 18 hours. Initially, a thick slurry formed and became an almost homogeneous solution at 60 °C. IPC confirmed the consumption of the starting material (in-process yield: 81%). The reaction mixture was transferred to a 250 mL flask, and then water (37 mL, 13 L / kg) was poured in over ~2 hours, and then cooled to 30 °C over 2 hours. Next, a 2.26 M aqueous solution of Na2CO3 was added to the flask to adjust the pH to 4 - 5. Then, the flask was cooled to 0 - 5 °C over ~2 hours, the batch was aged for 2 - 3 hours, and then filtered. The slurry was filtered, and the wet cake was washed with 2-propanol (about 1 mL) and water (about 5 mL). Then, the solid was dried in vacuo at 50 °C for 24 hours. 1 1H NMR (CDCl3, 300 MHz, 23 °C): δ 8.66 (s, 1H), 8.24 (s, 1H), 2.65 (s, 6H), 2.47 (s, 6H).

[0080] (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformimidamide synthesis [Chemical formula] (E)-N'-(3,5-Dibromo-4-methylpyridin-2-yl)-N,N-dimethylformimidamide (30.0 g, 93.5 mmol, limiting reagent) and (dppp)NiCl2 (2.47 g, 4.68 mmol) were charged into a 1 L reactor under a N2 stream. Next, anhydrous 2-methyltetrahydrofuran (450 mL, 15 L / kg, 0.21 M) was introduced into the reactor with a syringe under a N2 stream. After cooling the reaction mixture to 0 °C (internal temperature), a 1.0 M ZnMe2 heptane solution (103.0 mL, titrated before use) was added to the reactor with a syringe over 15 minutes while maintaining the internal temperature of the reaction mixture below 5 °C. During the addition process, the reaction color changed from light orange to bright yellow and then to dark red. The reaction mixture was aged at 0 °C for 6 hours. By IPC, it was confirmed that the starting material was completely consumed. 0.5 M aqueous K2CO3 solution (300 mL, 1.5 equivalents) was charged into the reactor, and the mixture was stirred for 15 hours. After separating the layers, the aqueous layer was discarded, the organic layer was washed with water (300 mL), and filtered through a polish filter (Whatman). The batch was solvent-exchanged into acetone by quantitative distillation of 70 mL using 448 mL of acetone at 300 mbar. At the end of the distillation, the stream was a uniform orange color. For crystallization, 84 mL of water was added over 3 hours, followed by 196 mL of water added over 2 hours. Spontaneous nucleation was observed at 36.4 mL during the first water addition. The crystallization slurry was aged overnight. The batch was filtered and washed once with 56 mL of water and 14 mL of acetone. The yield loss of the mother liquor was 5% and the yield loss of the cake wash was 0.3%. The batch was dried in a vacuum oven at 45 °C under a nitrogen bleed at 23 mm Hg for 12 hours. The IPC at the end of drying was <1.0 wt%. The isolated yield was 87.6%. 1 1H NMR (CDCl3, 500 MHz, 23 °C): δ 8.28 (s, 1H), 8.14 (s, 1H), 3.08 (br s, 6H), 2.36 (s, 3H), 2.34 (s, 3H).

[0081] (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformimidamide synthesis In this procedure, ZnBr2 and MeMgCl were used for the in situ generation of ZnMe2. Into a 250 mL reactor, (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformimidamide (5.0 g, 15.6 mmol, limiting reagent), (dppp)NiCl2 (411 mg, 0.778 mmol), and ZnBr2 (3.51 g, 15.6 mmol) were charged under a N2 stream. Next, anhydrous 2-methyltetrahydrofuran (75 mL, 15 L / kg, 0.21 M) was syringe-charged under N2. The reaction mixture was cooled to 0 °C (internal temperature), and then a 3.8 M MeMgCl solution in THF (8.2 mL, titrated before use) was added to the reactor via syringe over 15 minutes while maintaining the internal temperature of the reaction mixture below 5 °C. During the addition, the reaction color changed from a light orange to a bright yellow and then to a dark red. The reaction mixture was aged at 0 °C for 3 hours. By IPC, it was confirmed that the starting materials were completely consumed. 0.5 M aqueous K2CO3 solution (100 mL, 3.5 equivalents) was charged into the reactor, warmed to 25 °C, and the mixture was stirred for 1 hour. The biphasic mixture was filtered (Whatman) and washed twice with 10 mL of THF. After separating the layers, the aqueous layer was discarded, and the organic layer was washed with water (110 mL). Mass of the final organic layer: (93.3 g, in-process yield: 92.0%).

[0082] (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformimidamide synthesis

Chemical formula

[0083] Synthesis of 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-A]pyridine [Chem.] 2-Propanol (15 L / kg) was added to reactor 1 and the temperature was adjusted to 22 °C. Next, 1.0 equivalent of (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformimidamide (129.2 kg, limiting reagent) and 0.5 equivalent of DMF-DMA were sequentially charged. The temperature was raised to 50 °C and HOSA was added in 6 portions. The mixture was aged for 19.5 hours. After completion of the reaction (IPC), the mixture was distilled under vacuum at 45 °C to 3 vol and the temperature was adjusted to 20 °C. DCM (5 vol) and water (8 vol) were charged, and an Na2CO3 solution (12 wt%) was charged to adjust the pH to 6 at 20 °C. The layers were separated and the bottom organic layer was collected. The upper aqueous layer was discarded. An aqueous HCl solution (0.5 M, 2 L / kg) was prepared and the organic mixture was washed twice with 0.5 M HCl (2 L / kg) and subsequently with water (4 L / kg). The separated organic mixture was filtered through a polish filter, concentrated under vacuum at 16 °C to 2 L / kg, and 2-propanol (2 L / kg) was charged to concentrate to 2 vol. The residual DCM level in the mixture was ≦1 wt%. The temperature was adjusted to 23 °C and water (8 L / kg) was charged. The batch was cooled to 0 °C and aged for 8 hours. The slurry was filtered and the wet cake was washed with 3:1 water:2-propanol (total 1 L / kg). The batch was dried under vacuum at 63 °C for 32 hours (KF NMT 0.5 wt%, IPC residue NMT 0.5 wt%). 6-Bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine was isolated in 73% yield (99.3% LCAP, 99.8 wt%).

Claims

1. A process for preparing a compound represented by formula (I): 【Chemical 1】 (I) comprising the following steps: (a) reacting a compound represented by formula (II) with a compound represented by formula (III): 【Chemical Formula 2】 to provide a compound represented by formula (IV): [Chemical 3] (IV) and (b) reacting the compound represented by formula (IV) with a methylzinc compound or a methylzinc salt in the presence of a nickel catalyst to provide a compound represented by formula (V): 【Chemical Formula 4】 (V) and (c) hydrolyzing the compound represented by formula (V) to obtain the compound represented by formula (I).

2. The nickel catalyst has a ligand selected from 1,1-bis(diphenylphosphino)methane, (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), 1,3-bis(dicyclohexylphosphino)propane, triphenylphosphine, 1,2-bis(diphenylphosphino)benzene, 1,2-bis(dicyclohexylphosphino)ethane, and 1,1'-bis(diisopropylphosphino)ferrocene, and NiCl 2 The method according to claim 1, wherein the method is as described above.

3. The process according to claim 1, wherein the nickel catalyst is (bis(diphenylphosphino)propane)nickel chloride.

4. The process according to claim 1, wherein the methylzinc compound or the methylzinc salt is a combination of dimethylzinc or zinc bromide anhydrous and a Grignard reagent.

5. A process for preparing a compound represented by formula (I): 【Chemical Formula 5】 (I) comprising reacting a compound represented by formula (IV): 【Chemical Formula 6】 (IV) with a methylzinc compound or a methylzinc salt in the presence of a nickel catalyst to obtain a compound represented by formula (I).

6. The nickel catalyst has a ligand selected from 1,1-bis(diphenylphosphino)methane, (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), 1,3-bis(dicyclohexylphosphino)propane, triphenylphosphine, 1,2-bis(diphenylphosphino)benzene, 1,2-bis(dicyclohexylphosphino)ethane, and 1,1'-bis(diisopropylphosphino)ferrocene, and NiCl 2 The method according to claim 5, wherein the method is as described above.

7. The process according to claim 5, wherein the nickel catalyst is (bis(diphenylphosphino)propane)nickel chloride.

8. The process according to claim 5, wherein the methylzinc compound or the methylzinc salt is a combination of dimethylzinc or zinc bromide anhydrous and a Grignard reagent.

9. A process for preparing a compound represented by formula (IV), comprising reacting a compound represented by formula (II) with a compound represented by formula (III): 【Chemical Formula 7】 to obtain a compound represented by formula (IV).

10. A compound having the structure represented by formula (IV): 【Chemical 8】

11. A process for preparing a compound represented by formula (VI): (VI) 【Chemical Formula 9】 comprising the following steps: (i) reacting a compound represented by formula (IV): (IV) 【Chemical 10】 with a methylzinc compound or a methylzinc salt in the presence of a nickel catalyst to provide a compound represented by formula (V): and 【Chemical 11】 (V) (ii) reacting the compound represented by formula (V) with hydroxylamine-O-sulfonic acid and 0.5 to 1.3 equivalents of dimethylformamide-dimethylacetal to obtain a compound represented by formula (VI).

12. A process for preparing a compound represented by formula (VI): (VI) 【Chemical 12】 comprising reacting a compound represented by formula (V): ​ 【Chemical 13】 (V) A method comprising the step of reacting the compound represented by with hydroxylamine-O-sulfonic acid and 0.5 to 1.3 equivalents of dimethylformamide-dimethylacetal to obtain the compound represented by formula (VI). **Claim 13** Formula (V): 【Chemical Formula 14】 (V) A method for producing a compound represented by formula (V), comprising the step of reacting a compound represented by formula (IV): 【Chemical Formula 15】 (IV) with a methylzinc compound or a methylzinc salt in the presence of a nickel catalyst to obtain the compound represented by formula (V).

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