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

Abstract

Disclosed is a process for the preparation of 5-bromo-3, 4-dimethylpyridin-2-amine and 6-bromo-7, 8-dimethyl-[1, 2, 4] triazolo [1, 5-a] pyridines: (I), (VI). # imgabs0 #

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 388,860, filed on July 13, 2022, which is incorporated herein in its entirety. Technical Field

[0003] The present invention generally relates to methods for preparing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine and 5-bromo-3,4-dimethylpyridin-2-amine. Background Art

[0004] WO 2018 / 005586 discloses a method for treating inflammatory and autoimmune diseases such as lupus, rheumatoid arthritis, multiple sclerosis and Sjögren's syndrome ( syndrome), and methods for preparing the compounds and synthetic intermediates. WO 2018 / 005586 discloses an intermediate 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (intermediate F-4) and two methods for preparing the intermediate using 5-bromo-3,4-dimethylpyridine-2-amine as a starting material.

[0005] There is a need in the art for improved processes for preparing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine.

[0006] There is a need in the art for methods for preparing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine with high yields.

[0007] There is a need in the art for a process for preparing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine with high yield and suitable for large-scale production.

[0008] There is also a need in the art for improved processes for preparing 5-bromo-3,4-dimethylpyridin-2-amine.

[0009] There is a need in the art for methods for preparing 5-bromo-3,4-dimethylpyridin-2-amine with high yields.

[0010] There is a need in the art for a process for preparing 5-bromo-3,4-dimethylpyridin-2-amine with high yield and which minimizes the formation of by-products.

[0011] There is a need in the art for a process for preparing 5-bromo-3,4-dimethylpyridin-2-amine with high yield and which is suitable for large-scale production.

[0012] There is a need in the art for a process for preparing 5-bromo-3,4-dimethylpyridin-2-amine with high yield, which minimizes the formation of by-products and is suitable for large-scale production.

[0013] There is a need in the art for a process for preparing 5-bromo-3,4-dimethylpyridin-2-amine that is suitable for large-scale production and does not require the use of a palladium catalyst.

[0014] There is a need in the art for a process for preparing 5-bromo-3,4-dimethylpyridin-2-amine that does not require the use of a palladium catalyst.

[0015] There is a need in the art for a process for preparing 5-bromo-3,4-dimethylpyridin-2-amine with high yield, which minimizes the formation of by-products, is suitable for large-scale production, and does not require the use of a palladium catalyst.

[0016] The applicant has discovered a new synthetic method for preparing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine. The method provides 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine in high yield and is suitable for large-scale production.

[0017] Applicants have discovered a novel synthetic method for preparing 5-bromo-3,4-dimethylpyridin-2-amine. The method provides 5-bromo-3,4-dimethylpyridin-2-amine in high yield, minimizes the formation of by-products, is suitable for large-scale production, and / or does not use a palladium catalyst. Summary of the invention

[0018] The invention provides a synthetic method for preparing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine.

[0019] The present invention provides intermediates and methods for preparing intermediates used in methods for preparing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine.

[0020] In addition, the present invention also provides a synthetic method for preparing 5-bromo-3,4-dimethylpyridin-2-amine.

[0021] Furthermore, the present invention provides a synthetic method for preparing (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine.

[0022] Furthermore, the present invention provides a synthetic method for preparing (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformamidine.

[0023] These and other features of the present invention will be set forth in expanded form as the disclosure proceeds. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Shown is a general reaction scheme for the synthesis of 5-bromo-3,4-dimethylpyridin-2-amine from 2-amino-3,5-dibromo-4-methylpyridine, where dmf·dma is N,N-dimethylformamide dimethyl acetal.

[0025] Figure 2 A general reaction scheme for the synthesis of 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine as disclosed in WO 2018 / 005586 is shown.

[0026] Figure 3 Shown is a general reaction scheme for the synthesis of 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine. DETAILED DESCRIPTION

[0027] Figure 2 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 WO 2018 / 005586 is shown.

[0028] A first aspect of the present invention provides a method for preparing a compound of formula (I):

[0029]

[0030] It includes the following steps:

[0031] (a) reacting a compound of formula (II) with a compound of formula (III):

[0032]

[0033] To provide a compound of formula (IV):

[0034]

[0035] (b) reacting the compound of formula (IV) with a methyl zinc compound or a methyl zinc salt in the presence of a nickel catalyst to provide the compound of formula (V):

[0036]

[0037] as well as

[0038] (c) hydrolyzing the compound of formula (V) to provide the compound of formula (I).

[0039] A second aspect of the present invention provides a method for preparing a compound of formula (I):

[0040]

[0041] It comprises reacting a compound of formula (IV):

[0042]

[0043] The step of reacting with a methyl zinc compound or a methyl zinc salt to provide the compound of formula (V):

[0044]

[0045] and hydrolyzing the compound of formula (V) to provide the compound of formula (I).

[0046] A third aspect of the present invention provides a method for preparing a compound of formula (IV), comprising the step of reacting a compound of formula (II) with a compound of formula (III):

[0047]

[0048] To provide the compound of formula (IV):

[0049]

[0050] A fourth aspect of the present invention provides a compound having a structure of formula (IV):

[0051]

[0052] A fifth aspect of the present invention provides a method for preparing a compound of formula (VI):

[0053]

[0054] It includes the following steps:

[0055] (i) in the presence of a nickel catalyst, reacting a compound of formula (IV):

[0056]

[0057] Reaction with a methyl zinc compound or a methyl zinc salt to provide the compound of formula (V):

[0058]

[0059] as well as

[0060] (ii) reacting the compound of formula (V) with hydroxylamine-O-sulfonic acid and dimethylformamide-dimethylacetal to provide the compound of formula (VI).

[0061] A sixth aspect of the present invention provides a method for preparing a compound of formula (VI):

[0062]

[0063] It comprises making a compound of formula (V):

[0064]

[0065] A step of reacting with hydroxylamine-O-sulfonic acid and dimethylformamide-dimethylacetal to provide the compound of formula (VI).

[0066] A seventh aspect of the present invention provides a method for preparing a compound of formula (V):

[0067]

[0068] It comprises reacting a compound of formula (IV):

[0069]

[0070] A step of reacting with a methyl zinc compound or a methyl zinc salt to provide a compound of formula (V).

[0071] Method for preparing 5-bromo-3,4-dimethylpyridin-2-amine

[0072] The process for preparing the compound of formula (I) involves forming a carbon-carbon bond by replacing the 3-bromo substituent on the pyridine ring of the starting material 2-amino-3,5-dibromo-4-methylpyridine with a methyl group.

[0073]

[0074] The first step (step (a)) of the process is to place a directing group on the amino group by reacting 2-amino-3,5-dibromo-4-methylpyridine, a compound of formula (II), with a suitable directing group such as 1,1-dimethoxy-N,N-dimethylmethanamine to provide (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine, a compound of formula (IV):

[0075]

[0076] In the second step (step (b)) of the process, the 3-bromo substituent is replaced with a methyl group by reacting the compound of formula (IV) with a methyl zinc compound or methyl zinc salt in the presence of a nickel catalyst to provide a compound of formula (V):

[0077]

[0078] After the 3-bromo substituent is replaced with a methyl group, the directing group can be removed by hydrolysis in the presence of an acid to regenerate the amino group in the compound of formula (I). The compound of formula (V) can be hydrolyzed to provide the compound of formula (I) without isolation; or alternatively, isolated, redissolved, and then hydrolyzed to provide the compound of formula (I).

[0079] The second step of the method uses a Negishi coupling reaction to replace the 3-bromo group of (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine with a methyl group. The Negishi coupling reaction is discussed in Haas et al., ACSCatalysis 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.

[0080] Step (a):

[0081] By reacting a compound of formula (II) with a compound of formula (III), a variety of synthetic conditions can be used to prepare a compound of formula (IV).

[0082] The reaction is sensitive to oxygen. Before the reaction begins, the reagents and / or reaction mixture may be sparged with an inert gas such as nitrogen or argon to displace any dissolved oxygen.

[0083] Since the compound of formula (III) is degraded by water, the reaction is sensitive to water. The water content of the reagents and reaction mixture should be minimized to a suitable level, such as less than 0.2 wt%, less than 0.15 wt%, less than 0.1 wt% and less than 0.05 wt%.

[0084] The reaction between the compound of formula (II) and the compound of formula (III) to provide the compound of formula (IV) can be carried out in various solvents or mixtures thereof. 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.

[0085] In one embodiment, the process of step (a) is carried out in a solvent selected from 2-propanol and 2-methyltetrahydrofuran.

[0086] In one embodiment, the process of step (a) is carried out in a solvent selected from 2-propanol.

[0087] In one embodiment, the process of step (a) is carried out in a solvent selected from 2-methyltetrahydrofuran.

[0088] Suitable reaction temperatures for the reaction between the compound of formula (II) and the compound of formula (III) include temperatures ranging from about 70°C to about 80°C, temperatures ranging from about 75°C to about 80°C, and temperatures ranging from about 78°C to about 80°C.

[0089] The compound of formula (IV) can be isolated and / or purified by various methods known in the art. Suitable methods include chromatography and crystallization from 2-propanol at about 0°C and collecting the solid by filtration (purity >98%).

[0090] Step (b):

[0091] Various synthetic conditions may be used in step (b) to prepare the compound of formula (V).

[0092] Suitable nickel catalysts include nickel chloride (NiCl2) with 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).

[0093] In one embodiment, the process of step (b) is carried out in the presence of a catalyst selected from (bis(diphenylphosphino)propane)nickel chloride.

[0094] Examples of suitable methyl zinc compounds and methyl zinc salts include dimethyl zinc and a combination of anhydrous zinc bromide and a Grignard reagent. Suitable Grignard reagents include methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide.

[0095] The reaction of the compound of formula (IV) in step (b) to provide the compound of formula (V) can be carried out in the presence of various optional synthesis auxiliary agents, including, for example, alkali metal halides and carboxylates such as LiCl, LiBr, NaBr, lithium acetate and trimethyllithium acetate; and alkaline earth metal halides and carboxylates such as MgCl2, MgBr2 and trimethylmagnesium acetate.

[0096] The step (b) reaction is sensitive to oxygen and requires bubbling the reagents and / or the reaction mixture with an inert gas such as nitrogen or argon to remove dissolved oxygen before adding the methylzinc compound or methylzinc salt to the reaction mixture.

[0097] Step (b) reaction can be carried out in the presence of low content (such as 0.4wt% or less) of water. The water content of reagents and reaction mixtures should be minimized to a suitable level, such as, less than 0.3wt%, less than 0.2wt%, less than 0.1wt% and less than 0.05wt%.

[0098] The reaction of the compound of formula (IV) to provide the compound of formula (V) 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.

[0099] Suitable reaction temperatures for the reaction of the compound of formula (IV) to provide the compound of formula (V) in step (b) include temperatures ranging from about -20°C to about 25°C, temperatures ranging from about -10°C to about 5°C, and temperatures ranging from about 0°C to about 5°C.

[0100] The compound of 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 at about 0°C using water as an antisolvent, followed by collection of the solid by filtration. Alternatively, the compound of formula (V) can be hydrolyzed in step (c) without isolation from solution.

[0101] Step (c):

[0102] In step (c) a variety of synthetic conditions may be used to prepare the compound of formula (I).

[0103] After the methylation reaction is complete, the amidine directing group can be removed under acidic aqueous conditions to provide a compound of formula (I). Suitable acids include aqueous solutions of acids such as HCl, HBr, HI and H2SO4.

[0104] The compounds of formula (I) may be isolated and / or purified by a variety of 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.

[0105] like Figure 2 As shown and disclosed in WO 2018 / 005586, the compound of formula (I), 5-bromo-3,4-dimethylpyridin-2-amine, can be used as a starting material in the synthesis of 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine.

[0106] Method for preparing 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

[0107] A method for preparing a compound of formula (VI) from the starting material (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine is as follows Figure 3 The first step of the method, i.e., step (i), comprises forming a carbon-carbon bond by replacing the 3-bromo substituent on the pyridine ring of (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine, i.e., a compound of formula (IV), with a methyl group:

[0108]

[0109] To provide (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformamidine, i.e., a compound of formula (V). In the second step (step (ii)) of the method, the compound of formula (V) is reacted to form a triazole ring:

[0110]

[0111] To provide 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine, that is, a compound of formula (VI).

[0112] Step (i):

[0113] A variety of synthetic conditions may be employed in step (i), the reaction of replacing the 3-bromo substituent of the compound of formula (IV) with a methyl group to provide the compound of formula (V).

[0114] Suitable nickel catalysts include nickel chloride (NiCl2) with 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).

[0115] In one embodiment, the process of step (i) is carried out in the presence of a catalyst selected from (bis(diphenylphosphino)propane)nickel chloride.

[0116] Examples of suitable methyl zinc compounds and methyl zinc salts include dimethyl zinc and a combination of anhydrous zinc bromide and a Grignard reagent. Suitable Grignard reagents include methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide.

[0117] The reaction of the compound of formula (IV) in step (i) to provide the compound of formula (V) can be carried out in the presence of various optional synthesis auxiliary agents, including, for example, alkali metal halides and carboxylates such as LiCl, LiBr, NaBr, lithium acetate and trimethyllithium acetate; and alkaline earth metal halides and carboxylates such as MgCl2, MgBr2 and trimethylmagnesium acetate.

[0118] The step (i) reaction is oxygen sensitive and requires bubbling the reagents and / or the reaction mixture with an inert gas such as nitrogen or argon to remove dissolved oxygen prior to adding dimethylzinc to the reaction mixture.

[0119] Step (i) reaction can be carried out in the presence of low content (such as 0.4wt% or less) of water. The water content of reagents and reaction mixtures should be minimized to a suitable level, for example, less than 0.3wt%, less than 0.2wt%, less than 0.1wt% and less than 0.05wt%.

[0120] The reaction of the compound of formula (IV) to provide the compound of formula (V) 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.

[0121] Suitable reaction temperatures for the reaction in step (i) of providing a compound of formula (V) with a compound of formula (IV) include temperatures in the range of about -20°C to about 25°C, temperatures in the range of about -15°C to about 10°C, temperatures in the range of about -15°C to about 5°C, and temperatures in the range of about -5°C to about 5°C.

[0122] The compound of formula (V) may be isolated and / or purified by a variety of methods. Suitable methods include chromatography and crystallization from acetonitrile, acetone or tetrahydrofuran at about 0°C using water as an antisolvent, followed by collection of the solid by filtration.

[0123] Step (ii):

[0124] In step (ii), i.e. the reaction of the compound of formula (V) to form a triazole ring to provide the compound of formula (VI), various synthetic conditions may be used.

[0125] The reaction can be carried out in the presence of dimethylformamide-dimethyl acetal (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.

[0126] The reaction of the compound of formula (V) to provide the compound of formula (VI) 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.

[0127] In one embodiment, the process of step (ii) is carried out in a solvent selected from 2-propanol and 2-methyltetrahydrofuran.

[0128] In one embodiment, the process of step (ii) is carried out in a solvent selected from 2-propanol.

[0129] In one embodiment, the process of step (ii) is carried out in a solvent selected from 2-methyltetrahydrofuran.

[0130] Suitable reaction temperatures for the reaction of the compound of formula (V) to form the compound of formula (VI) include temperatures ranging from about 40°C to about 70°C, temperatures ranging from about 40°C to about 60°C, and temperatures ranging from about 45°C to about 55°C.

[0131] The compound of formula (VI) can be isolated and / or purified by various methods known in the art. Suitable methods include chromatography and crystallization from 2-propanol at about 0°C and collection by filtration.

[0132] The present invention can be implemented in other specific forms without departing from its purport or essential attributes. The present invention encompasses all combinations of aspects of the present invention and / or embodiments described herein. It should be understood that any and all embodiments of the present invention can be combined with any other embodiment or embodiments to describe other embodiments. It should also be understood that each individual element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe other embodiments.

[0133] definition

[0134] Those of ordinary skill in the art can more easily understand the features and advantages of the present invention after reading the following specific embodiments. It should be understood that certain features of the present invention described above and below with respect to separate embodiments for clear reasons may also be combined to form an embodiment. On the contrary, various features of the present invention described with respect to an embodiment for the sake of brevity may also be combined to form its sub-combination. It is intended that the embodiments identified herein as exemplary or preferred are illustrative and not restrictive.

[0135] Unless otherwise clearly stated herein, references expressed in the singular may also include the plural. For example, "a" and "an" may refer to one or more.

[0136] Unless otherwise indicated, any atom with unsatisfied valences is presumed to have hydrogen atoms sufficient to satisfy the valences.

[0137] Definitions as set forth herein take precedence over definitions as set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0138] Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms when they are used throughout the specification, either individually or as part of a larger group (unless they are otherwise limited in specific instances).

[0139] The compounds of formula (I), (II), (III), (IV), (V) and (VI) may be provided as an amorphous solid or a crystalline solid. Lyophilization may be used to provide the compound as a solid.

[0140] In addition, the compounds of formula (I), (II), (III), (IV), (V) and (VI) can be isolated and purified after preparation to obtain a composition containing equal to or greater than 93% by weight of the compound of formula (I), (II), (III), (IV), (V) and (VI) ("substantially pure"), which is then used as described herein. Such "substantially pure" compounds of formula (I), (II), (III), (IV), (V) and (VI) are also encompassed herein as part of the present invention.

[0141] "Stable compound" and "stable structure" are meant to refer to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.

[0142] The compounds of the present invention are intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and not limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14C. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using an appropriate isotopically labeled reagent to replace the otherwise used non-labeled reagent. For example, methyl (-CH3) also includes deuterated methyl groups such as -CD3.

[0143] Example

[0144] The present invention is further defined in the following examples. It should be understood that the examples are provided by way of illustration only. From the above discussion and examples, those skilled in the art can determine the essential characteristics of the present invention, and various changes and modifications can be made to adapt the present invention to various uses and conditions without departing from the spirit and scope thereof. Therefore, the present invention is not limited by the illustrative embodiments as listed below herein, but is defined by the appended claims.

[0145] abbreviation

[0146] anhyd. anhyd

[0147] aq. containing water DMF Dimethylformamide

[0148] dmf·dma N,N-dimethylformamide dimethyl acetal

[0149] dppp 1,3-bis(diphenylphosphino)propane

[0150] (dppp)NiCl2 [1,3-bis(diphenylphosphino)propane] nickel(II) chloride

[0151] h,hr or hrs hours

[0152] IPA Isopropyl Alcohol

[0153] HPLC High Performance Liquid Chromatography

[0154] HOSA Hydroxylamine-O-sulfonic acid

[0155] iPrOH Isopropyl alcohol

[0156] LC Liquid Chromatography

[0157] LCMS liquid chromatography mass spectrometry

[0158] M molar concentration

[0159] mM millimolar concentration

[0160] Me Methyl

[0161] MeCN Acetonitrile

[0162] MeMgCl Methyl magnesium chloride

[0163] 2-MeTHF 2-Methyltetrahydrofuran

[0164] MHz Megahertz

[0165] min.

[0166] mins minutes

[0167] MS

[0168] NH2OSO3H Hydroxylamine-O-sulfonic acid

[0169] nM nanomolar concentration

[0170] Ret Time or Rt retention time

[0171] sat. saturated SFC Supercritical Fluid Chromatography

[0172] THF Tetrahydrofuran

[0173] wt% mass%

[0174] ZnMe2 Dimethylzinc

[0175] Synthesis of 5-bromo-3,4-dimethylpyridin-2-amine using Ni catalyst

[0176] Step (a): Preparation of (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine

[0177]

[0178] 2-Propanol (150mL, 0.500M, 7.50L / kg) and 2-amino-3,5-dibromo-4-methylpyridine (20.0g, 75.2mmol) were charged into a 250mL reactor. The reaction mixture was bubbled with N2 under agitation for 15 minutes at ambient temperature. N,N-dimethylformamide-dimethyl acetal (13.0mL, 97.8mmol, 1.3 equivalents) was added to the reaction mixture via a syringe under N2. The reactor jacket was heated to 80°C and the reaction mixture was aged for 6 hours. The reaction mixture was sampled at 80°C under nitrogen gas flow pressure and analyzed via UHPLC-MS (ultra-high performance liquid chromatography-mass spectrometry), where it was observed that all starting materials were consumed. The sample aliquot was taken out from the reaction mixture at 80°C under nitrogen gas flow and diluted in MeCN. After the reaction was completed, the contents in the reactor were cooled to 0°C over 2 hours and the resulting slurry was filtered. The solid was collected, transferred to a bottle and dried in a vacuum oven at 50 °C for 24 hours to afford (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine as a solid in >98% yield (24.0 g). 1 H NMR (CDCl3, 500 MHz, 23°C): δ8.34 (s, 1H), 8.16 (s, 1H), 3.15 (s, 3H), 3.10 (s, 3H), 2.56 (s, 3H). Trace amounts of water and isopropanol were detected in the product.

[0179] Steps (b) and (c): Preparation of 5-bromo-3,4-dimethylpyridin-2-amine

[0180]

[0181] (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine (125 g, 389.4 mmol), (dppp)NiCl2 (10.5 g, 19.47 mmol) and ZnBr2 (87.7 g, 389.4 mmol) were charged into a 5 L reactor under a stream of N2. 2-MeTHF (2.5 L, 20 L / kg) was added to the reactor. As the contents of the reactor cooled to 0-1°C (internal temperature), the entire solution was bubbled with N2 for 30 minutes under the surface. 2.8M MeMgCl solution (278 mL, titrated with sec-butanol with 1,10-phenanthroline as an indicator before use) was added to the reactor via a syringe over 30 minutes while keeping the internal temperature of the reaction mixture below 4°C. The reaction mixture was aged at 0-1°C for 6 hours. The reaction mixture was sampled under nitrogen flow pressure and analyzed by UHPLC-MS, and the reaction was confirmed to be complete with no starting material present (98AP product, 2AP bis-methylated; AP = area percentage). The reactor was then charged with 3M HCl (10.0 eq, 1.3 L) over 30 minutes. The batch was heated to 65°C with agitation for 18 hours. The batch was then cooled to 20°C and sampled under nitrogen flow pressure and analyzed by UHPLC-MS to give 5-bromo-3,4-dimethylpyridin-2-amine of 95AP. Next, 25% NH4OH aqueous solution (~10.0 eq) was charged to the reactor with agitation until the pH was adjusted to 5.0-5.5. Agitation was stopped and the layers were allowed to separate for 15 minutes. The bottom aqueous layer was drained from the reactor and discarded as waste. Next, 25% NH4OH aqueous solution (5.0 equivalents, 145mL) was added to the reactor, and the batch was heated to 50°C under agitation and kept for 18 hours. The batch was then cooled to 20°C and agitation was stopped. Each layer was allowed to settle for 15 minutes and the bottom water layer was discharged from the reactor and discarded as waste. The batch was distilled to 10L / kg at 60°C jacket temperature and ~100mbar. Acetonitrile (10L / kg, 1.25L) was charged into the reactor and the batch was distilled to 4L / kg. Water (10L / kg, 1.25L) was added to the reactor at ~50°C internal temperature over 15 minutes. The batch was cooled to 10°C over 2 hours to obtain a slurry, which was aged for 12 hours. The solid was collected on a polypropylene filter funnel with a 40-micron polyethylene sintered disk. The reactor was rinsed with 1:2MeCH:water (total 2L / kg, 250mL), and the eluent was passed through the filter cake. The solid was then dried in vacuo at 50-55 °C to give 5-bromo-3,4-dimethylpyridin-2-amine in 83% yield (64.9 g, 95% purity). 1H NMR (CDCl3, 500MHz, 23℃): δ8.02(s,1H), 4.34(br s,2H), 2.34(s,3H), 2.11(s,3H).

[0182] Comparison of Ni and Pd Catalysts in the Preparation of (E)-N'-(5-Bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformamidine

[0183]

[0184] A 40 mL scintillation vial was charged with (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine (250 mg, 0.779 mmol) and (i) (dppp) NiCl2 (21.1 mg, 0.0390 mmol) or (ii) PdCl2 (7.0 mg, 0.0390 mmol) and dppp (16.1 mg, 0.0390 mmol). A magnetic stirrer was added to the bottle. Tetrahydrofuran (6.0 mL, 24 L / kg) was added to the bottle via a syringe. The solution was bubbled with N2 for 15 minutes under rapid stirring. The reaction mixture was cooled to 0-1 ° C (the aluminum reaction block was immersed in ice) and ZnMe2 (0.83 mL, 0.545 mmol) was added to the reaction mixture as a 0.66 M solution in hexane via a syringe under N2. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. An aliquot was taken from the reaction mixture and analyzed via UPLC-MS. AP = integrated area percentage of the chromatographic peak.

[0185] Table 1: Comparison of the synthesis of (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformamidine using Ni or Pd catalysts

[0186]

[0187]

[0188] According to the above comparison of the synthesis of (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformamidine using Ni or Pd catalysts, the results in Table 1 show that the method using the Ni catalyst produces (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformamidine in higher yields (compound of formula (V): 91.7AP vs. 28.2AP, respectively) with complete consumption of the starting material (compound of formula (IV): <0.05AP vs. 52.5AP, respectively) compared to the method using the Pd catalyst. Additionally, in this experiment, the results in Table 1 show that the use of the Ni catalyst results in less and smaller amounts of by-product formation compared to the method using the Pd catalyst (compounds B to E: <8.5AP vs. about 19.3AP, respectively).

[0189] The applicant has discovered a new synthetic method for preparing 5-bromo-3,4-dimethylpyridin-2-amine. The new synthetic method minimizes the formation of by-products. The new synthetic method is suitable for large-scale production.

[0190] Synthesis of (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformamidine

[0191]

[0192] (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine (3.00 g, 9.35 mmol, limiting reagent) and (dppp)NiCl2 (261 mg, 0.467 mmol) were charged in a 250 mL reactor under N2 flow. Then, anhydrous THF (72 mL, 0.13 M) was charged via a syringe under N2, followed by bubbling zinc (2-ethylhexanoate) (2.97 mL, 9.35 mmol). The reaction mixture was cooled to 0-1°C (internal temperature), and then a 4.1 M solution of MeMgCl (4.6 mL, titrated before use) was added to the reactor via a syringe over 15 minutes, while keeping the internal temperature of the reaction mixture below 4°C. During the addition, the color of the reaction mixture changed from light orange to bright yellow and then to dark red. The reaction mixture was aged between 0-1°C for 6 hours. IPC confirmed complete consumption of starting material (95AP product, 5AP bis-methylated). The reactor was charged with saturated aqueous NH4Cl solution (~100 mL) and the mixture was agitated for 1 minute. After allowing the layers to separate, the aqueous layer was discarded and the organic layer was washed twice with brine. Final organic layer mass: 62.3 g, process yield: 92.1%. The organic layer was concentrated in vacuo to give the product as a yellow solid. 1H NMR (CDCl3, 500MHz, 23℃): δ8.28(s,1H), 8.14(s,1H), 3.08(br s,6H), 2.36(s,3H), 2.34(s,3H).

[0193] Synthesis of 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

[0194]

[0195] A 40 mL scintillation vial was charged with (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformamidine (2.87 g, 11.2 mmol, crude from the reaction), hydroxylamine-O-sulfonic acid (2.00 g, 16.8 mmol) and a magnetic stirrer. The vial was purged with N2 for 10 minutes and then charged with 2-propanol (25.8 mL) and dimethylformamide-dimethylacetal (2.04 mL, 14.6 mmol). The vial was sealed and then heated to 60°C and stirred for 18 hours. A thick slurry was initially formed, which formed a nearly homogeneous solution at 60°C. IPC confirmed complete consumption of the starting material (process yield: 81%). The reaction mixture was transferred to a 250 mL flask and then charged with water (37 mL, 13 L / kg) over ~2 hours and then cooled to 30°C over 2 hours. The flask was then charged with a solution of 2.26 M NaCO in water and the pH was adjusted to 4-5. The flask was then cooled to 0-5°C over ~2 hours and the batch aged for 2-3 hours before filtering. The slurry was filtered and the wet cake was washed with 2-propanol (~1 mL) and water (~5 mL). The solid was then dried at 50°C in vacuum for 24 hours. 1 H NMR (CDCl3, 300MHz, 23℃): δ8.66(s,1H), 8.24(s,1H), 2.65(s,6H), 2.47(s,6H).

[0196] Synthesis of (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformamidine

[0197]

[0198] (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine (30.0 g, 93.5 mmol, limiting reagent) and (dppp)NiCl2 (2.47 g, 4.68 mmol) were charged in a 1L reactor under N2 gas flow. Anhydrous 2-methyltetrahydrofuran (450 mL, 15 L / kg, 0.21 M) was then charged via a syringe under N2. The reaction mixture was cooled to 0°C (internal temperature) and then a 1.0 M solution of ZnMe2 in heptane (103.0 mL, titrated before use) was added to the reactor via a syringe over 15 minutes while keeping the internal temperature of the reaction mixture below 5°C. During the addition, 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. IPC confirmed that the starting material was completely consumed. The reactor was charged with 0.5M aqueous K2CO3 solution (300 mL, 1.5 equiv.) and the mixture was agitated for 15 hours. After allowing the layers to separate, the aqueous layer was discarded and the organic layer was washed with water (300 mL) and finely filtered (Whatman). The batch was solvent exchanged to acetone by 70 mL constant volume distillation at 300 mbar with 448 mL acetone. At the end of the distillation, the fraction was uniformly orange. For crystallization, 84 mL of water was charged over 3 hours, followed by 196 mL of water over 2 hours. Spontaneous nucleation was observed at the first addition of 36.4 mL of water. The crystal slurry was aged overnight. The batch was filtered and rinsed with a single wash of 56 mL of water and 14 mL of acetone. The mother liquor yield loss was 5% and the filter cake wash yield loss was 0.3%. The batch was dried in a vacuum oven at 45°C and 23 mm Hg under nitrogen bleed for 12 hours. IPC at the end of drying was <1.0 wt%. The isolated yield was 87.6%. 1 HNMR (CDCl3, 500MHz, 23℃): δ8.28(s,1H), 8.14(s,1H), 3.08(br s,6H), 2.36(s,3H), 2.34(s,3H).

[0199] Synthesis of (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformamidine

[0200] This method uses ZnBr2 and MeMgCl for the in situ generation of ZnMe2.

[0201] (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine (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 into a 250 mL reactor under a stream of N2. Anhydrous 2-methyltetrahydrofuran (75 mL, 15 L / kg, 0.21 M) was then charged via a syringe under N2. The reaction mixture was cooled to 0°C (internal temperature) and then a 3.8 M solution of MeMgCl in THF (8.2 mL, titrated before use) was added to the reactor via a syringe over 15 minutes while keeping the internal temperature of the reaction mixture below 5°C. During the addition, the reaction color changed from light orange to bright yellow and then to dark red. The reaction mixture was aged at 0°C for 3 hours. IPC confirmed that the starting material was completely consumed. The reactor was charged with 0.5 M aqueous K2CO3 solution (100 mL, 3.5 equiv.), the temperature was raised to 25°C and the mixture was stirred for 1 hour. The biphasic mixture was filtered (Whatman) and washed twice with 10 ml THF. After allowing the layers to separate, the aqueous layer was discarded and the organic layer was washed with water (110 mL). Final organic layer mass: 93.3 g, process yield: 92.0%.

[0202] Synthesis of (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformamidine

[0203]

[0204] Reactor 1 was charged with 2-methyltetrahydrofuran (15 L / kg) at 20°C, followed by ZnBr2 (10.6 kg, 1.0 equiv). The reaction mixture was stirred until the ZnBr2 was completely dissolved. (E)-N'-(3,5-dibromo-4-methylpyridin-2-yl)-N,N-dimethylformamidine (15.2 kg, limiting reagent) was charged. The reaction mixture was cooled to -13°C. The reaction mixture was bubbled with N2 under the surface for 30 minutes. Next, (dppp)NiCl2 (1.26 kg, 0.05 equiv) was charged, and the resulting orange-red slurry was bubbled with N2 under the surface for 30 minutes. A solution of MeMgCl in THF (26.0 kg, 3.0 M, titrated before use) was added to the reactor over 3 hours, while the internal temperature was maintained in the range of -5 to -15°C. During the addition, the reaction color changed from light orange to bright yellow to dark red. The reaction mixture was aged at -5 to -15 ° C for 14 hours. IPC confirmed that the starting material was completely consumed. Then, a 1.0M K2CO3 solution (3.0 equivalents) was prepared in reactor 2 at 5 ° C and mixed with diatomaceous earth (15 kg). The mixture in reactor 1 was transferred to reactor 2 while maintaining the transfer temperature at -5 to -15 ° C. After the transfer, the temperature was raised to 16 ° C. The biphasic mixture was centrifuged and transferred to reactor 1. Stirring was stopped and the layers were allowed to separate for 30 minutes. The bottom aqueous layer was discarded and the organic layer was washed with 5% NaCl solution (10 vol). The aqueous layer was discarded and the organic layer was concentrated to 2-3 vol (T≤45 ° C, P≤-0.06 MPa). Then 6 vol acetone was charged and the mixture was concentrated to 3 vol. At 20 ° C, antisolvent water was added over 3 hours to obtain a slurry, which was aged for 2 hours. The solid was collected by filtration and the reactor was rinsed with a solution of 1.34 vol water and 0.66 vol acetone. The rinse was passed through the filter cake. The wet cake was deliquified and the batch was transferred to a suction filter and dried at 36°C under nitrogen for 15 hours. The batch was then sampled for KF (KF NMT 0.5 wt%), acetone remained (NMT 0.5 wt%). The product was isolated with a yield of 81% (97.4% LCAP, 97.7 wt%).

[0205] Synthesis of 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

[0206]

[0207] 2-Propanol (15L / kg) was added to the reactor 1, and the temperature was adjusted to 22°C. Next, 1.0eq (E)-N'-(5-bromo-3,4-dimethylpyridin-2-yl)-N,N-dimethylformamidine (129.2kg, limiting reagent) and 0.5eq. DMF-DMA were charged in sequence. The temperature was raised to 50°C and HOSA was added in 6 batches. The mixture was aged for 19.5h. After the reaction was completed (IPC), the mixture was distilled to 3vol at 45°C under vacuum and the temperature was adjusted to 20°C. DCM (5vol) and water (8vol) were charged at 20°C, and Na2CO3 solution (12wt%) was charged to adjust the pH to 6. The layers were separated and the bottom organic layer was collected. The upper aqueous layer was discarded. Prepare HCl aqueous solution (0.5M, 2L / kg), and wash the organic mixture with 0.5M HCl (2L / kg) twice, then wash with water (4L / kg). The separated organic mixture is finely filtered and concentrated to 2L / kg at 16°C under vacuum, charged with 2-propanol (2L / kg) and concentrated to 2vol. The DCM residual level in the mixture is ≤1wt%. The temperature is adjusted to 23°C and charged with water (8L / kg). The batch is cooled to 0°C and aged for 8 hours. The slurry is filtered, and the wet cake is washed with 3:1 water:2-propanol (total 1L / kg). The batch is dried at 63°C for 32 hours under vacuum (KF NMT 0.5wt%, IPC residual NMT 0.5wt%). 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 method for preparing a compound of formula (I): It includes the following steps: (a) reacting a compound of formula (II) with a compound of formula (II): To provide a compound of formula (IV): (b) reacting the compound of formula (IV) with a methyl zinc compound or a methyl zinc salt in the presence of a nickel catalyst to provide the compound of formula (V): as well as (c) hydrolyzing the compound of formula (V) to provide the compound of formula (I).

2. The method according to claim 1, wherein the nickel catalyst is NiCl2 having 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.

3. The method of claim 1, wherein the nickel catalyst is bis(diphenylphosphino)propane)nickel chloride.

4. The method according to claim 1, wherein the methyl zinc compound or methyl zinc salt is a combination of dimethyl zinc or anhydrous zinc bromide and a Grignard reagent.

5. A method for preparing a compound of formula (I): It comprises reacting a compound of formula (IV): A step of reacting with a methyl zinc compound or a methyl zinc salt to provide the compound of formula (I).

6. The method of claim 5, wherein the nickel catalyst is NiCl2 having 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.

7. The method of claim 5, wherein the nickel catalyst is bis(diphenylphosphino)propane)nickel chloride.

8. The method according to claim 5, wherein the methyl zinc compound or methyl zinc salt is a combination of dimethyl zinc or anhydrous zinc bromide and a Grignard reagent.

9. A method for preparing a compound of formula (IV): It comprises reacting a compound of formula (II) with a compound of formula (III): to provide the compound of formula (IV).

10. A compound having a structure of formula (IV):

11. A method for preparing a compound of formula (VI): It includes the following steps: (i) in the presence of a nickel catalyst, reacting a compound of formula (IV): Reaction with a methyl zinc compound or a methyl zinc salt to provide the compound of formula (V): as well as (ii) reacting the compound of formula (V) with hydroxylamine-O-sulfonic acid and 0.5 to 1.3 equivalents of dimethylformamide-dimethylacetal to provide the compound of formula (VI).

12. A method for preparing a compound of formula (VI): It comprises making a compound of formula (V): A step of reacting with hydroxylamine-O-sulfonic acid and 0.5 to 1.3 equivalents of dimethylformamide-dimethyl acetal to provide the compound of formula (VI).

13. A method for preparing a compound of formula (V): It comprises reacting a compound of formula (IV): A step of reacting with a methyl zinc compound or a methyl zinc salt to provide the compound of formula (V).

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