Intermediates for synthesis of tgf-beta inhibitors and methods of making tgf-beta inhibitors using the intermediates

Abstract

This invention provides an intermediate for synthesizing a TGF-β inhibitor represented by Formula 1, and an improved method for preparing the TGF-β inhibitor represented by Formula 1 using the intermediate. The preparation method according to the invention not only allows the use of inexpensive and safe reagents, but also simplifies the synthetic steps and purification methods to improve reaction yield, thereby maximizing the production efficiency of the TGF-β inhibitor represented by Formula 1 for large-scale production.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to Korean Patent Application No. 2022-0037241, filed on March 25, 2022, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This invention relates to intermediates for the synthesis of TGF-β inhibitors and methods for preparing TGF-β inhibitors. Background Technology

[0004] Transforming growth factor (TGF)-β is a cytokine that regulates cell proliferation and differentiation, wound healing, and extracellular matrix production. The TGF-β family belongs to the TGF-β superfamily, which includes activin, inhibin, bone morphogenetic protein, and an anti-Müllerian hormone. Tumor cells and stromal cells in advanced cancers typically overexpress TGF-β. TGF-β can induce angiogenesis, stimulate cell migration, suppress the immune system, and increase the interaction between tumor cells and the extracellular matrix. TGF-β receptors are serine / threonine kinase receptors, classified into TGF-β receptor 1, TGF-β receptor 2, and TGF-β receptor 3. TGF-β receptor 1 is also known as activin A receptor type II-like kinase (ALK5).

[0005] Regarding TGF-β inhibitors, Korean Patent No. 10-1500665 (Patent Document 1) provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof and a method for preparing the same, which exhibits excellent TGF-β signaling pathway inhibitory activity through a 2-pyridyl-substituted imidazole disclosed as a therapeutic ALK5 and / or ALK4 inhibitor.

[0006] [Chemical Formula 1]

[0007]

[0008] Korean Patent No. 10-1500665 discloses a method for preparing a 2-pyridyl-substituted imidazole (I) represented by the above chemical formula 1. The method includes: preparing an N,P-acetal compound (III) by reacting a pyridine-2-carboxaldehyde compound (II) with aniline and diphenyl phosphite, as shown in reaction scheme A below; combining the N,P-acetal compound (III) with [1,2,4]triazolo[1,5-a]pyridine-6-carboxaldehyde, and then preparing a monoketide under acidic conditions. Compound (IV); preparation of diketone compound (V) by oxidation of monoketone compound (IV); preparation of acetal-protected imidazole compound (VI) by condensation of diketone compound (V) with 2,2-glyoxal dimethyl acetal; preparation of imidazole-2-carboxaldehyde compound (VII) by hydrolysis of acetal-protected imidazole compound (VI) under acidic conditions; and combination of imidazole-2-carboxaldehyde compound (VII) with aniline compound (VIII) under acidic conditions to generate an imine compound and reduction of the imine compound.

[0009] [Reaction Scheme A]

[0010]

[0011] However, because this method involves a long process to prepare the compound, the reaction yield is low, the reaction takes a long time, and expensive reagents and complex purification processes are required, making this method unsuitable for large-scale commercial production.

[0012] Therefore, the inventors have determined a preparation method suitable for large-scale production, which is not only economically feasible using inexpensive, low-toxicity, and low-hazard reagents, but also allows for the preparation of the final compound in increased yield by reducing reaction steps, thus completing the present invention.

[0013] [Related Technical Documents]

[0014] [Patent Documents]

[0015] (Patent 0001) Korean Patent No. 10-1500665 Summary of the Invention

[0016] The present invention aims to provide a novel method for preparing compounds of formula 2, formula 4 and formula 5, which are intermediates for the synthesis of TGF-β inhibitors.

[0017] The inventors have developed a synthetic method with short reaction steps and high overall yield, which achieves this invention by using more commercially available starting materials in the synthesis of compounds of the following chemical formula 1.

[0018] The following are compounds of chemical formula I that serve as the final target compound and the active ingredient used as a TGF-β inhibitor.

[0019] [Chemical Formula 1]

[0020]

[0021] In the formula,

[0022] X is a halogen (e.g., F, Cl, Br, or I);

[0023] R a Independently, it is hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, hydroxyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -O-C3-6 cycloalkyl, amino, -NH-C1-6 alkyl, -NH-C1-6 haloalkyl, -NH-C3-6 cycloalkyl, -S-C1-6 alkyl, -S-C1-6 haloalkyl, -S-C3-6 cycloalkyl, cyano, or nitro; and

[0024] m can be 0, 1, 2, 3, or 4.

[0025] For example, a compound of chemical formula 1 can be a compound of chemical formula 1a.

[0026] [Chemical Formula 1a]

[0027]

[0028] The present invention provides a method for preparing a compound of chemical formula 1, the method comprising the following steps.

[0029] Compound of formula 4 is obtained by reacting a compound of formula 2 with a compound of formula 3.

[0030] Compounds of formula 1 are obtained by removing the protection from compounds of formula 4.

[0031] [Chemical Formula 2]

[0032]

[0033] [Chemical Formula 3]

[0034]

[0035] [Chemical Formula 4]

[0036]

[0037] In the formula,

[0038] X and Y are each independently a halogen (e.g., F, Cl, Br, or I);

[0039] PG is a protecting group selected from the group consisting of butyryloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzoyl and toluenesulfonyl;

[0040] In this case, R a Independently, it is hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, hydroxyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -O-C3-6 cycloalkyl, amino, -NH-C1-6 alkyl, -NH-C1-6 haloalkyl, -NH-C3-6 cycloalkyl, -S-C1-6 alkyl, -S-C1-6 haloalkyl, -S-C3-6 cycloalkyl, cyano, or nitro; and

[0041] m can be 0, 1, 2, 3, or 4.

[0042] For example, a compound of chemical formula 2 can be a compound of chemical formula 2a.

[0043] [Chemical Formula 2a]

[0044]

[0045] For example, a compound of chemical formula 3 can be a compound of chemical formula 3a.

[0046] [Chemical Formula 3a]

[0047]

[0048] For example, a compound of chemical formula 4 can be a compound of chemical formula 4a.

[0049] [Chemical Formula 4a]

[0050]

[0051] In Korean Patent No. 10-1500665 (Patent Document 1), the method for preparing the compound of Formula 1 consists of a total of 6 steps (Reaction Scheme A). Furthermore, when using II as the starting material, dibenzyl phosphate and [1,2,4]triazolo[1,5-a]pyridine-6-carboxaldehyde can be used for the reaction. However, in this case, not only is the cost of purchasing reagents high, but 3 of the 6 steps require purification using column chromatography, making this method difficult to apply to large-scale production.

[0052] To address these problems in the related art, in an exemplary embodiment of the present invention, commercially available 2-fluoroaniline (hereinafter, compounds of Formula 8), 2-(2-fluorophenylamino)acetonitrile (hereinafter, compounds of Formula 7), cyanomethyl (2-fluorophenyl)carbamate tert-butyl ester (hereinafter, compounds of Formula 6), or 2-amino-2-iminoethyl (2-fluorophenyl)carbamate tert-butyl ester (hereinafter, compounds of Formula 3) (including salt forms) can be used as starting materials to obtain compounds of Formula 1.

[0053] Compared to the existing method according to Korean Patent No. 10-1500665 (Patent Document 1), which involves a three-step column chromatography purification process with a total of five steps, the exemplary embodiment of the present invention, using 2-fluoroaniline (hereinafter, a compound of Formula 8) as a starting material and forming an imidazole by introducing a Boc protecting group, allows the compound of Formula 1 to be purified by a simple washing method, except for a single column chromatography step. Furthermore, production efficiency can be maximized by reducing the number of synthesis steps to a total of five. Moreover, the compound can be produced even in large-scale production, and its economic feasibility is greatly improved due to the ability to produce it in high yields.

[0054] In an exemplary embodiment, since the method for preparing a compound of formula 1 according to the present invention can prepare a compound of formula 1 by including steps 1 to 5, and a compound of formula 8, a compound of formula 7, a compound of formula 6 or a compound of formula 3 can be selected as the starting material, one or more of steps 1 to 3 may be omitted if necessary.

[0055] Obtaining compounds of formula 7 from compounds of formula 8 (step 1),

[0056] Obtaining a compound of formula 6 from a compound of formula 7 (step 2),

[0057] Obtaining a compound of formula 3 from a compound of formula 6 (step 3),

[0058] The compound of formula 3 is reacted with the compound of formula 2 to obtain the compound of formula 4 (step 4), and

[0059] Obtain the compound of formula 1 from the compound of formula 4 (step 5).

[0060] [Chemical Formula 8]

[0061]

[0062] [Chemical Formula 7]

[0063]

[0064] [Chemical Formula 6]

[0065]

[0066] In the formula, Y is a halogen; and

[0067] PG is a protecting group selected from the group consisting of butyryloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzoyl and toluenesulfonyl.

[0068] Obtaining a compound of formula 7 from a compound of formula 8 (step 1) may include obtaining a compound of formula 3 by introducing acetonitrile into an amine of the compound of formula 8 in the presence of a base.

[0069] The base can be selected from the group consisting of sodium bicarbonate, sodium carbonate, and potassium carbonate.

[0070] Step 1 can be performed at 70°C to 90°C to maximize yield.

[0071] Obtaining a compound of formula 6 from a compound of formula 7 (step 2) may include obtaining a compound of formula 6 by introducing an amine protecting group into a compound of formula 7.

[0072] The amino protecting group can be selected from the group consisting of butyryloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzoyl and toluenesulfonyl.

[0073] Obtaining a compound of formula 3 from a compound of formula 6 (step 3) may include obtaining a compound of formula 6' by converting the nitrile of the compound of formula 6 into an acetylinic acid ester, and obtaining a compound of formula 3 converted into amidine by reacting the compound of formula 6' with ammonia.

[0074] [Chemical Formula 6']

[0075]

[0076] In the formula, Y is a halogen; and

[0077] PG is a protecting group selected from the group consisting of butyryloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzoyl and toluenesulfonyl.

[0078] Step 3 may include step 3-1, which obtains the compound of formula 6' by converting the nitrile of the compound of formula 6 into an acetylinic acid ester, and step 3-2, which obtains the compound of formula 3 converted into amidine by reacting the compound of formula 6' with ammonia.

[0079] Considering the reaction temperature and the ease of subsequent concentration and solvent removal, it may be advantageous to use methanol as the solvent for obtaining compound of formula 6' from compound of formula 6 (step 3-1) and obtaining compound of formula 3 from compound of formula 6' (step 3-2).

[0080] The preparation of compounds of formula 6' from compounds of formula 6 and compounds of formula 3 from compounds of formula 6' can be carried out at temperatures ranging from 20°C to 50°C, but this temperature is not limited to these temperatures. Depending on the choice of solvent, the preferred reaction temperature can be set to a temperature at which the solvent can be refluxed.

[0081] The preferred reaction time for step 3-1 is 36 to 60 hours, for example, 36 to 48 hours. When the reaction time exceeds the above range, there may be problems such as insufficient reaction or additional reaction, resulting in a decrease in yield.

[0082] The preferred reaction time for step 3-2 is 2 to 96 hours. When the reaction time exceeds the above range, there is a problem that the reaction cannot proceed fully or additional reactions may occur, resulting in a decrease in yield.

[0083] Ammonia can be selected from the group consisting of methanol ammonia solution, ammonium chloride, and ammonium bicarbonate.

[0084] When using a methanol-ammonia solution, a metal salt can be further included as a catalyst to shorten the reaction time.

[0085] In step 3, after step 3-1 is completed, step 3-2 can be performed without a separate post-processing or purification process.

[0086] In an exemplary embodiment of the present invention, obtaining a compound of formula 6' from a compound of formula 6 and obtaining a compound of formula 3 from a compound of formula 6' can be carried out in methanol and at a reaction temperature of 1°C to 35°C.

[0087] The process of synthesizing a compound of formula 6' from a compound of formula 6 using methanol, and then synthesizing the hydrochloride salt of a compound of formula 3 from a compound of formula 6' again using ammonium chloride, is exemplarily represented by the following reaction scheme.

[0088]

[0089] NaOMe: Sodium methoxide

[0090] MeOH: Methanol

[0091] NH4Cl: Ammonium chloride

[0092] In step 3-2, which yields a compound of formula 3 from a compound of formula 6', the compound of formula 3 is obtained by reacting the compound of formula 6' with ammonium chloride. In this case, a high-purity compound of formula 3 can be obtained by forming a hydrochloride salt.

[0093] Obtaining a compound of formula 4 by reacting a compound of formula 3 with a compound of formula 2 (step 4) may include obtaining a compound of formula 2' by substituting the halogen of the compound of formula 3 with an amine of the compound of formula 2 in the presence of a base, and

[0094] The compound of formula 4 is obtained by forming an imidazole through a dehydration reaction between an amine and the carbonyl group of a compound of formula 2'.

[0095] [Chemical Formula 2']

[0096]

[0097] Y is a halogen;

[0098] PG is a protecting group selected from the group consisting of butyryloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzoyl and toluenesulfonyl;

[0099] R a Independently, it is hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, hydroxyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -O-C3-6 cycloalkyl, amino, -NH-C1-6 alkyl, -NH-C1-6 haloalkyl, -NH-C3-6 cycloalkyl, -S-C1-6 alkyl, -S-C1-6 haloalkyl, -S-C3-6 cycloalkyl, cyano, or nitro; and

[0100] m can be 0, 1, 2, 3, or 4.

[0101] Step 4 may include step 4-1, which obtains the following compound of formula 2' by substituting the halogen of the compound of formula 3 with the amine of the compound of formula 2, and step 4-2, which obtains the compound of formula 4 by forming an imidazole through a dehydration reaction between the carbonyl group of the compound of formula 2' and the amine.

[0102] In step 4, dimethylformamide (N,N-dimethylformamide, DMF), acetonitrile, tetrahydrofuran (THF), toluene, or mixtures thereof can be used as reaction solvents.

[0103] The reaction in step 4 can be carried out at 20°C-95°C, for example, 30°C-80°C, 30°C-70°C, and 40°C-60°C. To minimize the formation of related substances and reaction intermediates, the reaction can preferably be carried out at 30°C-60°C.

[0104] The base can be selected from the group consisting of potassium bicarbonate, potassium carbonate, potassium phosphate, sodium acetate, 1,4-diazabicyclo[2.2.2]octane (DABCO) and triethylamine.

[0105] A base may be used in amounts of 3 to 5 equivalents, preferably 3 to 4 equivalents, relative to 1 equivalent of a compound of formula 3, but this amount is not limited thereto.

[0106] The reaction further includes a desiccant to prevent side reactions. As a desiccant, those selected from molecular sieves, sodium sulfate, and magnesium sulfate can be used.

[0107] Step 4 can be carried out for a reaction time of 3 to 36 hours, preferably 24 to 36 hours, to minimize the generation of relevant raw materials and reaction intermediates.

[0108] In an exemplary embodiment of the present invention, the preparation of compound 2' from compound 3 and compound 4 from compound 2' can be carried out at temperatures ranging from 20°C to 95°C, but this temperature is not limited thereto. Depending on the choice of solvent, a preferred reaction temperature can be set to a temperature at which the solvent can be refluxed. In an exemplary embodiment of the present invention, the preparation of compound 2' from compound 3 and compound 4 from compound 2' can be carried out in acetonitrile, and can be carried out at temperatures ranging from 30°C to 60°C.

[0109] The process of synthesizing a compound of formula 2' using acetonitrile and then resynthesizing a compound of formula 4 from the compound of formula 2' is exemplarily represented by the following reaction scheme.

[0110]

[0111] K2CO3: Potassium carbonate

[0112] MeCN: Acetonitrile

[0113] Using acetonitrile as a reaction solvent increases the solubility of the reactants, facilitating large-scale production. Furthermore, using molecular sieves as a drying agent can improve reaction efficiency.

[0114] Obtaining a compound of formula 1 from a compound of formula 4 (step 5) may include obtaining a compound of formula 1 by deprotecting a compound of formula 4.

[0115] The amine protecting group can be removed by reacting the compound of formula 4 under acidic conditions. In order to remove the protecting group, when the amine protecting group is butoxycarbonyl (Boc), the protecting group can be removed by reaction under acidic conditions, such as trifluoroacetic acid / dichloromethane, ethyl acetate / hydrogen chloride, diethyl acetate / hydrogen chloride, hydrogen chloride / dichloromethane, or methanol / hydrogen chloride. When the amine protecting group is benzyloxycarbonyl (Cbz), the protecting group can be removed by hydrogenation in the presence of palladium / carbon.

[0116] In step 5, dichloromethane, ethyl acetate, methanol, or a mixture thereof can be used as the reaction solvent.

[0117] The acid can be used in amounts of 8 to 12 equivalents, preferably 9 to 11 equivalents, relative to 1 equivalent of a compound of formula 4, but is not limited thereto.

[0118] In another exemplary embodiment of the invention, the compound of formula 2 can be prepared by a method comprising obtaining the compound of formula 2 from the compound of formula 5, and the method may include obtaining the compound of formula 2 from the compound of formula 5 (step A).

[0119] [Chemical Formula 5]

[0120]

[0121] In the formula,

[0122] R a Independently, it is hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, hydroxyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -O-C3-6 cycloalkyl, amino, -NH-C1-6 alkyl, -NH-C1-6 haloalkyl, -NH-C3-6 cycloalkyl, -S-C1-6 alkyl, -S-C1-6 haloalkyl, -S-C3-6 cycloalkyl, cyano, or nitro; and

[0123] m is 0, 1, 2, 3 or 4;

[0124] R b It is hydrogen, hydroxyl, cyano, nitro or amino.

[0125] Obtaining a compound of formula 2 from a compound of formula 5 (step A) may include using a halogenating agent to oxidize the compound of formula 5. b The substituents are converted into halogens to obtain compounds of formula 2.

[0126] In step A, acetic acid, dioxane, or a mixture thereof may be used as the reaction solvent.

[0127] When R bWhen the hydrogen is present, acetic acid is preferably used to form a salt, thereby effectively removing impurities generated during the reaction and obtaining a compound of high purity of formula 2.

[0128] In step A, the reactants can be washed with a solvent to remove impurities, and preferably, a washing process with MTBE can be additionally included.

[0129] The present invention also provides a compound of formula 2 or a salt thereof, which is a useful intermediate for the synthesis of a compound of formula 1.

[0130] [Chemical Formula 2]

[0131]

[0132] In the formula,

[0133] X is a halogen;

[0134] R a Independently, it is hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, hydroxyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -O-C3-6 cycloalkyl, amino, -NH-C1-6 alkyl, -NH-C1-6 haloalkyl, -NH-C3-6 cycloalkyl, -S-C1-6 alkyl, -S-C1-6 haloalkyl, -S-C3-6 cycloalkyl, cyano, or nitro; and

[0135] m can be 0, 1, 2, 3, or 4.

[0136] In an exemplary embodiment of the present invention, the compound of chemical formula 2 may be a compound of chemical formula 2a.

[0137] [Chemical Formula 2a]

[0138]

[0139] Although not limited thereto, salts of compounds of formula 2 may be hydrofluoric acid (HF), hydrobromic acid (HBr), hydrochloric acid (HCl), or hydroiodic acid (HI). The present invention also provides compounds of formula 4 or salts thereof, which are useful intermediates for the synthesis of compounds of formula 1.

[0140] [Chemical Formula 4]

[0141]

[0142] In the formula,

[0143] PG is a protecting group selected from the group consisting of butyryloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzoyl and toluenesulfonyl;

[0144] Y is a halogen;

[0145] R a Independently, it is hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, hydroxyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -O-C3-6 cycloalkyl, amino, -NH-C1-6 alkyl, -NH-C1-6 haloalkyl, -NH-C3-6 cycloalkyl, -S-C1-6 alkyl, -S-C1-6 haloalkyl, -S-C3-6 cycloalkyl, cyano, or nitro; and

[0146] m can be 0, 1, 2, 3, or 4.

[0147] In an exemplary embodiment of the present invention, the compound of chemical formula 4 may be a compound of chemical formula 4a.

[0148] [Chemical Formula 4a]

[0149]

[0150] Although not limited to this, the salts of compounds of formula 4 can be hydrofluoric acid (HF), hydrobromic acid (HBr), hydrochloric acid (HCl) or hydroiodic acid (HI). Detailed Implementation

[0151] The present invention will be described in more detail below through embodiments. However, the following embodiments are merely illustrative and the scope of the invention is not limited to these embodiments.

[0152] [Abbreviations]

[0153] The abbreviations described in the following examples have the following meanings.

[0154] -AcOH: Acetic acid

[0155] -Boc2O: Ditert-butyl dicarbonate

[0156] -Br2: Bromine

[0157] -2-butanone: 2-Butanone

[0158] -chloroacetonitrile: chloroacetonitrile

[0159] -CH2Cl2: Dichloromethane

[0160] -DABCO: 1,4-diazabicyclo[2.2.2]octane

[0161] -DMAP: 4-Dimethylaminopyridine

[0162] -DMF: N,N-dimethylformamide

[0163] -Et3N: Triethylamine

[0164] -EtOH: Ethanol

[0165] -EtOAc: Ethyl acetate

[0166] -HBr: hydrobromic acid

[0167] -HCl: hydrochloric acid

[0168] -K₂CO₃: Potassium carbonate

[0169] -KHCO3: Potassium bicarbonate

[0170] -K3PO4: Potassium phosphate

[0171] -MeOH: Methanol

[0172] -MeCN: Acetonitrile

[0173] -MgSO4: Magnesium sulfate

[0174] -MS: Molecular sieve

[0175] -MTBE: Methyl tert-butyl ether

[0176] -NaHCO3: Sodium bicarbonate

[0177] -NaI: Sodium iodide

[0178] -NaOAc: Sodium acetate

[0179] -NaOMe: Sodium methoxide

[0180] -NH4Cl: Ammonium chloride

[0181] -NH4HCO3: Ammonium bicarbonate

[0182] -THF: Tetrahydrofuran

[0183] -toluene: toluene

[0184] -Zn(OTf)2: Zinc trifluoromethanesulfonate

[0185] In the following examples, Example 1 illustrates the process of synthesizing a compound of chemical formula 1a, which is a preferred example of a compound of chemical formula 1, and Example 2 illustrates the process of synthesizing a compound of chemical formula 2a, which is a preferred example of a compound of chemical formula 2.

[0186] The following reaction scheme 1 schematically illustrates the process for synthesizing the compound of chemical formula 1a.

[0187] [Reaction Scheme 1]

[0188]

[0189] [Example]

[0190] Example 1: N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazolium

[0191] Preparation of 2-yl)methyl)-2-fluoroaniline (compound 1a)

[0192] Step 1: Preparation of 2-(2-fluorophenylamino)acetonitrile (compound 7a)

[0193]

[0194] 2-Fluoroaniline (1 equivalent) and chloroacetonitrile (1 equivalent) were added to 2-butanone and stirred to obtain a mixture. Sodium bicarbonate (1.5 equivalent) and sodium iodide (0.5 equivalent) were then added, and the mixture was refluxed. After the reaction was complete, the product was cooled to room temperature, and the solvent was removed under reduced pressure. The solvent-free mixture was washed with methyl butyl ether and dried to give 50 g of the target compound 2-(2-fluorophenylamino)acetonitrile in 95% yield.

[0195] Step 2: Preparation of tert-butyl cyanomethyl (2-fluorophenyl)carbamate (compound 6a)

[0196]

[0197] 2-(2-fluorophenylamino)acetonitrile was added to dichloromethane and stirred to obtain a mixture. Triethylamine, di-tert-butyl dicarbonate, and 4-dimethylaminopyridine were then added, and the mixture was refluxed. After the reaction was complete, the product was cooled to room temperature, and the solvent was removed under reduced pressure. The solvent-free mixture was subjected to column chromatography (silica, ethyl acetate / heptane) to remove residual 4-dimethylaminopyridine, yielding 5 g of the target product, tert-butyl cyanomethyl(2-fluorophenyl)carbamate, in a 76% yield.

[0198] Step 3: Preparation of tert-butyl 2-amino-2-iminoethyl (2-fluorophenyl)carbamate hydrochloride (compound 3a) Preparation

[0199]

[0200] The NH3+ catalyst Zn(OTf)2 / NH4Cl / NH4HCO3 in MeOH(7N) can be used as an ammonia reagent in the synthesis of compound 3a.

[0201] [Table 1]

[0202]

[0203] Considering the reaction time and ease of subsequent purification, NH4Cl (ammonium chloride) was chosen.

[0204] Based on the above results, the preferred synthesis embodiments are as follows.

[0205] 3.25 g (13.0 mmol) of cyanomethyl (2-fluorophenyl)carbamate tert-butyl ester was dissolved in anhydrous methanol, and sodium methoxide solution (5.4 M, 0.24 mL, 1.30 mmol in methanol) was added. The mixture was allowed to react for 44 hours. When the reaction was complete, ammonium chloride (0.695 g, 12.99 mmol) was added, and the mixture was allowed to react for 2 hours at room temperature. After the reaction was complete, the solvent was removed under reduced pressure. The solvent-free mixture was washed with methyl butyl ether and dried to give 3.3 g of the target compound, 2-amino-2-iminoethyl (2-fluorophenyl)carbamate tert-butyl ester hydrochloride, in 92% yield.

[0206] Step 4: Preparation of (5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)-1H- Imidazol-2-yl)methyl(2-fluorophenyl)carbamate tert-butyl ester (compound 4a)

[0207]

[0208] K2CO3 / KHCO3 / K3PO4 / NaOAc / DABCO / Et3N can be used as a base in the synthesis of compound 4a.

[0209] [Table 2]

[0210]

[0211]

[0212] Considering the yield, solvent optimization experiments were conducted after selecting K2CO3 (potassium carbonate). The reaction solvent was selected from those that could dissolve compound 3a well and allow the reaction to proceed in a homogeneous state, and DMF / THF / MeCN / toluene could be used as the solvent.

[0213] By confirming that water molecules generated during the reaction participate in the reaction to produce impurities, the yield was further improved by adding a desiccant, and molecular sieves were used. MgSO4 can be used as a desiccant.

[0214] [Table 3]

[0215]

[0216]

[0217] MS Molecular sieve

[0218] Based on the above results, the preferred synthesis embodiments are as follows.

[0219] The tert-butyl 2-amino-2-iminoethyl (2-fluorophenyl)carbamate hydrochloride (81 mg, 0.267 mmol), potassium carbonate (0.134 g, 0.971 mmol), and MS were used in the treatment. After adding 200 mg of the product to acetonitrile and stirring the resulting mixture, 100 mg (0.243 mmol) of 2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-bromo-1-(6-methylpyridin-2-yl)acetone bromate was added at room temperature. The reactants were heated from room temperature to 50 °C and reacted for 30 hours. After the reaction was complete, the solvent was removed from the filtrate obtained by filtration under reduced pressure. The solvent-free mixture was extracted with saturated ammonium chloride aqueous solution and ethyl acetate. After washing the organic solvent layer with brine and sodium sulfate, the solvent in the extract was removed under reduced pressure to give 98 mg of the target product (5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl(2-fluorophenyl)carbamate tert-butyl ester) in 81% yield.

[0220] 1 H NMR(CDCl3,400MHz)δ10.94(br s,1H),8.93(br s,1H),8.35(s,1H),7.77(m,2H),7.47(t,1H),7.23(m,3H),7.17(m,3H),4.86(s,2H),2.58(s,3H),1.45(br s,9H)

[0221] C 27 H 26 FN7O2 (M+H) + Calculated value: 499.2; Measured value: 500.2

[0222] Step 5: N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazolium Preparation of (2-(2-yl)methyl)-2-fluoroaniline (compound 1a)

[0223]

[0224] CH2Cl2 / EtOAc / MeOH can be used as a reaction solvent in the synthesis of compound 1a.

[0225] [Table 4]

[0226] Solvent type Acid type reaction time Compound 4a Compound 1a <![CDATA[CH2Cl2]]> HCl 1h 1.1％ 98.4％ EtOAc HCl 1h 37.8％ 62.2％ MeOH HCl 1h 92.8％ 6.8％ <![CDATA[CH2Cl2]]> HCl 3h 0.0％ 98.6％ EtOAc HCl 3h 7.2％ 92.2％ MeOH HCl 3h 64.0％ 35.7％

[0227] Considering the yield and the ease of subsequent concentration and solvent removal, CH2Cl2 (dichloromethane) was chosen as the solvent.

[0228] Based on the above results, the preferred synthesis embodiments are as follows.

[0229] After adding (98 mg, 0.196 mmol) of (5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl(2-fluorophenyl)carbamate tert-butyl ester (2-fluorophenyl) to dichloromethane and stirring the resulting mixture, hydrochloric acid (4 M, 0.49 mL, 1.96 mmol in dioxane) was slowly added to the mixture, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the product was washed with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The solvent in the extract was removed under reduced pressure, and 71 mg of the target product N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline was obtained in 91% yield.

[0230] 1 H NMR(CDCl3,400MHz)δ8.96(br s,1H),8.38(s,1H),7.76-7.83(m,2H),7.45(t,1H),7.22(d,1H),6.97-7.00(m,3H),6.75(m,2H),4.58(m,1H),4.54(s,2H),2.42(s,3H)

[0231] C 22 H 18 FN7's (M+H) + Calculated value: 399.2; Actual measurement: 400.3

[0232] Example 2: 2-([1,2,4]triazolo[1,5-A]pyridin-6-yl)-2-bromo-1-(6-methylpyridin-2-yl)ethyl Preparation of ketobromate (compound 2a) (Step A)

[0233]

[0234] After adding 2.47 g (9.79 mmol) of 2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(6-methylpyridin-2-yl) ethyl ketone to acetic acid and stirring the resulting mixture, a bromine solution (1.57 g, 9.79 mmol, in acetic acid) was added to the mixture, and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, the solvent was removed under reduced pressure. The solvent-free mixture was washed with methyl butyl ether and dried to give 2.66 g of the target compound 2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-bromo-1-(6-methylpyridin-2-yl) ethyl ketone bromate in 66% yield.

[0235] 1H NMR(DMSO,400MHz)δ8.66(d,2H),7.90(m,2H),7.60(m,2H),7.37(s,1H),6.69(s,1H),2.61(d,3H)

[0236] The preparation method according to the present invention not only allows the use of inexpensive and safe reagents, but also simplifies the synthesis steps and purification methods to improve the reaction yield, thereby maximizing the production efficiency of the TGF-β inhibitor represented by Formula 1 for large-scale production.

Claims

1. A method for preparing a compound of chemical formula 1, the method comprising: Compound of formula 4 is obtained by reacting a compound of formula 2 with a compound of formula 3. Compounds of formula 1 are obtained by deprotecting compounds of formula 4: [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 1] In the formula, X and Y are each halogens independently; PG is a protecting group selected from the group consisting of butyryloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzoyl and toluenesulfonyl; R a independently hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, hydroxyl, -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, -O-C3-6 cycloalkyl, amino, -NH-Ci-6 alkyl, -NH-Ci-6 haloalkyl, -NH-C3-6 cycloalkyl, -S-Ci-6 alkyl, -S-Ci-6 haloalkyl, -S-C3-6 cycloalkyl, cyano, or nitro; and m is 0, 1, 2, 3, or 4; and The method of obtaining a compound of formula 4 by reacting a compound of formula 2 with a compound of formula 3 includes coupling an amine of the compound of formula 3 to the position of the X substituent of the compound of formula 2 in the presence of a base, and then forming an imidazole by a dehydration reaction, wherein the base is selected from the group consisting of potassium bicarbonate, potassium carbonate and potassium phosphate. In the reaction between the compound of chemical formula 2 and the compound of chemical formula 3, dimethylformamide, acetonitrile, tetrahydrofuran, toluene or a mixture thereof are used as reaction solvents; The reaction between the compound of chemical formula 2 and the compound of chemical formula 3 takes place for 3 to 36 hours; and The reaction between the compound of chemical formula 2 and the compound of chemical formula 3 is carried out at temperatures ranging from 20°C to 95°C.

2. The method according to claim 1, wherein the compound of formula 1 is a compound of formula 1a. [Chemical Formula 1a] 。 3. The method according to claim 1, wherein the compound of chemical formula 2 is a compound of chemical formula 2a. [Chemical Formula 2a] 。 4. The method according to claim 1, wherein the compound of formula 3 is a compound of formula 3a. [Chemical Formula 3a] 。 5. The method according to claim 1, wherein the compound of formula 4 is a compound of formula 4a. [Chemical Formula 4a] 。 6. The method according to claim 1, wherein the reaction between the compound of formula 2 and the compound of formula 3 further comprises a desiccant to prevent side reactions, and said desiccant is selected from molecular sieves, sodium sulfate and magnesium sulfate.

7. The method according to claim 1, wherein dichloromethane, ethyl acetate, methanol, or a mixture thereof are used as reaction solvents in the process of obtaining the compound of formula 1 by deprotecting the compound of formula 4.

8. The method according to claim 1, wherein the compound of formula 2 is obtained by passing the R of the compound of formula 5. b It is obtained by converting the substituents into halogens. [Chemical Formula 5] In the formula, R a Independently, it is hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, hydroxyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -O-C3-6 cycloalkyl, amino, -NH-C1-6 alkyl, -NH-C1-6 haloalkyl, -NH-C3-6 cycloalkyl, -S-C1-6 alkyl, -S-C1-6 haloalkyl, -S-C3-6 cycloalkyl, cyano, or nitro; m is 0, 1, 2, 3, or 4; and R b It is hydrogen, hydroxyl, cyano, nitro or amino.

9. The method according to claim 8, wherein the compound of formula 5 is a compound of formula 5a. [Chemical Formula 5a] 。 10. The method according to claim 1, wherein the compound of formula 3 is obtained by the Pinner reaction of the nitrile of formula 6 to form amidine. [Chemical Formula 6] In the formula, Y is a halogen; and PG is a protecting group selected from the group consisting of butyryloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenyloxycarbonyl (Fmoc), acetyl, benzoyl and toluenesulfonyl.

11. The method of claim 10, wherein obtaining the compound of formula 3 comprises obtaining the compound of formula 6' by converting the nitrile of the compound of formula 6 to an acetylinic acid ester, and then obtaining the compound of formula 3 converted to amidine by reacting the compound of formula 6' with ammonia. [Chemical Formula 6'] ， in, In the formula, Y is a halogen; and PG is a protecting group selected from the group consisting of butyryloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzoyl and toluenesulfonyl.

12. The method of claim 10, wherein the compound of formula 6 is obtained by introducing a protecting group into the amine of the compound of formula 7. [Chemical Formula 7] In the formula, Y is a halogen.

13. The method according to claim 12, wherein the compound of formula 7 is obtained by introducing acetonitrile into the amine of the compound of formula 8 in the presence of a base. [Chemical Formula 8] In the formula, Y is a halogen.

14. Compounds represented by chemical formula 4: [Chemical Formula 4] In the formula, Y is a halogen; PG is a protecting group selected from the group consisting of butyryloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzoyl and toluenesulfonyl; R a Independently, it is hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, hydroxyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -O-C3-6 cycloalkyl, amino, -NH-C1-6 alkyl, -NH-C1-6 haloalkyl, -NH-C3-6 cycloalkyl, -S-C1-6 alkyl, -S-C1-6 haloalkyl, -S-C3-6 cycloalkyl, cyano, or nitro; and m can be 0, 1, 2, 3, or 4.

15. The compound according to claim 14, wherein the compound is represented by chemical formula 4a: [Chemical Formula 4a] 。

Images