KR20230072438A - Preparation method of isoxazole derivatives and intermediates thereof - Google Patents

Abstract

The present invention relates to a novel method for manufacturing isoxazole derivatives useful as agonists for farnesoid X receptors (FXR, NR1H4), a novel derivative used in the manufacturing method, and a method for manufacturing the intermediates. The present invention is superior in that it makes it easier to remove the organic solvent remaining in a final material and enables large-scale production more simply and efficiently than the prior art.

Description

Preparation method of isoxazole derivatives and intermediates thereof {Preparation method of isoxazole derivatives and intermediates thereof}

The present invention relates to a novel process for preparing an isoxazole derivative useful as an agonist for farnesoid X receptor (FXR, NR1H4), a novel intermediate used in the process, and a process for preparing the intermediate. .

Isoxazole derivative compounds that act as agonists for farnesoid X receptors (FXR, NR1H4) and can be usefully used in the manufacture of pharmaceuticals for treating metabolic diseases, cholestatic liver diseases or organ fibrosis diseases are known ( International Publication WO 2018/190643, Patent Document 1).

For use as a medicine, it is necessary to develop a simple and productive manufacturing method capable of preparing a compound of an isoxazole derivative in high yield and high purity, and furthermore, enabling commercial supply of medicines on a large scale.

International Publication WO 2018/190643

One aspect is to provide a method for preparing an isoxazole derivative.

Another aspect is to provide a novel intermediate that can be used in the above production method.

Another aspect is to provide a method for preparing a novel intermediate that can be used in the above method.

Other objects and advantages of this application will become more apparent from the following detailed description taken in conjunction with the appended claims. Contents not described in this specification can be fully recognized and inferred by those skilled in the art of the present application or similar technical fields, so the description thereof will be omitted.

One aspect provides a method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an isoxazole derivative.

Another aspect provides a compound of Formula 2 or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the preparation method.

Another aspect provides a method for preparing the compound of Formula 2 or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the above preparation method.

The manufacturing method according to the present invention can produce isoxazole derivative compounds in high yield and high purity, minimizes the production of by-products during the manufacturing process, and is more suitable for manufacturing pharmaceuticals by using commercially available and safe reagents. . In addition, it is easier to remove the organic solvent remaining in the final material, and it is superior in that large-scale production is possible more conveniently and efficiently than the prior art.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention, unless defined otherwise, are used with the same meaning as commonly understood by one of ordinary skill in the art related to the present invention. In addition, although preferred methods or samples are described in this specification, those similar or equivalent thereto are also included in the scope of the present invention.

One aspect provides a method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an isoxazole derivative.

In one embodiment, the method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof,

A step of preparing a compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof may be included.

[Formula 1]

[Formula 2]

[Formula 3]

In Formula 1, Formula 2, or Formula 3,

each R ¹ is independently hydrogen, halogen, or trifluoromethyl;

each R ² is independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy;

R ³ is -CO ₂ -C _1-3 alkyl;

R ⁴ is a carboxyl group;

X ₁ is halogen;

p is an integer from 0 to 4;

q is an integer from 0 to 4;

In one embodiment, the step of preparing the compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof, while the water (H ₂ O) molecule leaves the ring condensation reactions that form

In one embodiment, the step of preparing a compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof,

An azodicarboxylate compound, triphenylphosphine (PPh ₃ ), or a combination thereof may be added.

In one embodiment, a catalyst may be used in the step of preparing the compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof.

In one embodiment, the step of preparing the compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof may use an azodicarboxylate compound as a catalyst. there is.

In one embodiment, the azodicarboxylate compound is diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD), di-tert-butyl azodicarb It may be selected from di-tert-butyl azodicarboxylate (DBAD), dibenzyl azodicarboxylate, diphenyl azodicarboxylate, and combinations thereof. In one embodiment, the azodicarboxylate compound may be diisopropyl azodicarboxylate (DIAD).

Since the azodicarboxylate compound has an electron-deficient N=N double bond, a condensation reaction between a carbonyl group and an alcohol may occur in the compound of Formula 2.

In one embodiment, in the step of preparing the compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof, triphenylphosphine (PPh ₃ ) may be added. there is.

In one embodiment, the preparation step may proceed through a Mitsunobu reaction using an azodicarboxylate compound and triphenylphosphine (PPh ₃ ).

In one embodiment, the azodicarboxylate compound and triphenylphosphine (PPh ₃ ) may be added in combination in a molar ratio of 1:0.5 to 1:2.5, for example, about 1:1 to 1:2.

In one embodiment, the azodicarboxylate compound and triphenylphosphine (PPh ₃ ) may be added in an amount of 0.5 to 2.5 moles, respectively, based on 1 mole of the compound of Formula 2 or a pharmaceutically acceptable salt thereof. .

In one embodiment, the step may be performed in an organic solvent, preferably the organic solvent may be tetrahydrofuran (THF).

Accordingly, the step of preparing the compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof may be carried out under mild reaction conditions, for example, at a low temperature and a relatively short reaction time. In addition, reaction by-products such as triphenylphosphine oxide and DIAD residues can be removed through a simple process, and the target compound can be prepared in high yield of about 90% and high purity of about 90%.

In one embodiment, the preparation method comprises the compound of Formula 5 or a pharmaceutically acceptable salt thereof by reacting the compound of Formula 3 or a pharmaceutically acceptable salt thereof with the compound of Formula 4 or a pharmaceutically acceptable salt thereof. It may further include the step of preparing.

[Formula 4]

[Formula 5]

In Formula 4 or Formula 5,

each R ¹ is independently hydrogen, halogen, or trifluoromethyl;

each R ² is independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy;

R ³ is -CO ₂ -C _1-3 alkyl;

p is an integer from 0 to 4;

q is an integer from 0 to 4;

In one embodiment, preparing the compound of Formula 5 or a pharmaceutically acceptable salt thereof by reacting the compound of Formula 3 or a pharmaceutically acceptable salt thereof with the compound of Formula 4 or a pharmaceutically acceptable salt thereof. may be due to the Sonogashira reaction.

In one embodiment, the reaction may use a palladium catalyst under base conditions. The palladium catalyst is bis(tri-tert-butylphosphine)palladium(0)(Pd[P( t -Bu) ₃ ]); bis(allyl)dichloropalladium (Pd(allyl)Cl] ₂ ) and tri-tert-butylphosphonium tetrafluoroborate ([HP( t- Bu) ₃ ]BF ₄ ); bis(tri-tert-butylphosphine)palladium(0) (Pd( t -Bu ₃ P) ₂ ); or bis(allyl)dichloropalladium ([Pd(allyl)Cl] ₂ ), but is not limited thereto.

The base may be 1,4-diazabicyclo[2.2.2] octane (DABCO) or 4-dimethylaminopyridine (MDAP), but is not limited thereto.

In one embodiment, based on 1 mole of the compound of Formula 3 or a pharmaceutically acceptable salt thereof, the base may be added in an amount of 0.5 to 4 moles, and the palladium catalyst may be added in an amount of 0.005 to 0.02 moles. can

In one embodiment, the reaction may be conducted in an organic solvent. Examples of organic solvents that can be used include nitriles such as acetonitrile; alcohols such as ethanol and isopropanol; ethers such as tetrahydrofuran, diisopropyl ether, dioxane, and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene and toluene; Amides such as dimethylacetamide and dimethylformamide may be exemplified, but are not limited thereto.

In one embodiment, preparing the compound of Formula 5 or a pharmaceutically acceptable salt thereof by reacting the compound of Formula 3 or a pharmaceutically acceptable salt thereof with the compound of Formula 4 or a pharmaceutically acceptable salt thereof. added 1,4-diazabicyclo[2.2.2]octane (DABCO) and bis(tri-tert-butylphosphine)palladium(0)(Pd[P(t-Bu) ₃ ]) in an organic solvent. can proceed.

Preferably, the organic solvent may be acetonitrile (MeCM).

In one embodiment, the compound of Formula 3 or a pharmaceutically acceptable salt thereof and the compound of Formula 4 or a pharmaceutically acceptable salt thereof may be added in a molar ratio of 1:0.5 to 1:2, for example about 1:1. there is.

In one embodiment, 1,4-diazabicyclo[2.2.2]octane may be added in an amount of 0.5 to 4 moles based on 1 mole of the compound of Formula 3 or a pharmaceutically acceptable salt thereof, and bis( Tri-tert-butylphosphine)palladium(0) may be added in an amount of 0.005 to 0.01 mol.

Accordingly, in the step, the generation of by-products other than the compound of Formula 5, such as homocoupled by-products that may be produced by combining the compounds of Formula 4 with each other, is minimized, and the yield is about 80% and about 99%. The target compound can be prepared with a high purity of % or more.

In addition, since all reagents used in the above step are commercially available and safe, they are more suitable for manufacturing pharmaceuticals.

In one embodiment, the preparation method may further include reducing the compound of Formula 5 or a pharmaceutically acceptable salt thereof. The reduction step may be performed by adding a reducing agent such as lithium hydroxide in an organic solvent such as tetrahydrofuran (THF).

Accordingly, Formula 1 or a pharmaceutically acceptable salt thereof may be prepared from the compound of Formula 5 or a pharmaceutically acceptable salt thereof.

In one embodiment, the manufacturing method

To prepare a compound of Formula 2 or a pharmaceutically acceptable salt thereof by reacting a compound of Formula 2-1 or a pharmaceutically acceptable salt thereof with a compound of Formula 2-2 or a pharmaceutically acceptable salt thereof Further steps may be included.

[Formula 2-1]

[Formula 2-2]

In Formula 2-1 or Formula 2-2,

R ³ is -CO ₂ -C _1-3 alkyl;

X ₁ and X ₂ are each a halogen independently selected from chlorine, bromine, and iodine.

In one embodiment, the substituent of X ₂ is removed by a substitution reaction between the compound of Formula 2-1 or a pharmaceutically acceptable salt thereof and the compound of Formula 2-2 or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof.

The present inventors have conducted synthesis experiments under various conditions to find reaction conditions that can minimize the production of byproducts in the substitution reaction, and as a result, when the substitution reaction is performed under THF solvent and free base conditions, other It is possible to minimize the formation of unnecessary by-products other than the target compound of Formula 2 compared to the treatment with an organic solvent such as DIPEA, TEA, pyridine, or another kind of inorganic base such as KHCO ₃ , K ₂ CO ₃ , NaHCO ₃ , and NaOH. I found something that could be done.

Accordingly, in one embodiment, the step of preparing the compound of Formula 2 or a pharmaceutically acceptable salt thereof may be performed in an organic solvent, and preferably, the organic solvent may be tetrahydrofuran (THF).

Also, in one embodiment, the above step may be performed under conditions in which no base is added (free base).

Accordingly, there is an advantage in that the target compound can be prepared with a high yield of about 97% and a high purity of about 99%.

In one embodiment, the step of preparing the compound of Formula 2 or a pharmaceutically acceptable salt thereof may be performed at 10 to 40°C, for example, 15 to 30°C.

In the above step according to one embodiment, the compound of Formula 2-1 or a pharmaceutically acceptable salt thereof and the compound of Formula 2-2 or a pharmaceutically acceptable salt thereof are mixed in a relative molar ratio of 1:0.5 to 1:2. may be added.

The pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt of the compound of the present invention, which can be prepared by any suitable method useful to those skilled in the art.

Another aspect provides a compound of Formula 2 or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the above preparation method.

[Formula 2]

In Formula 2,

R ³ is -CO ₂ -C _1-3 alkyl;

X ₁ is halogen.

Another aspect provides a method for preparing the compound of Formula 2 or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the above preparation method.

In one embodiment, the manufacturing method

A step of reacting a compound of Formula 2-1 or a pharmaceutically acceptable salt thereof with a compound of Formula 2-2 or a pharmaceutically acceptable salt thereof may be included.

[Formula 2-1]

[Formula 2-2]

[Formula 2]

In Formula 2-1, Formula 2-2, or Formula 2-3,

R ³ is -CO ₂ -C _1-3 alkyl;

X ₁ and X ₂ are each a halogen independently selected from chlorine, bromine, and iodine.

In one embodiment, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be Formula 1a below or a pharmaceutically acceptable salt thereof.

[Formula 1a]

.

.

Hereinafter, a method for preparing Formula 1a or a pharmaceutically acceptable salt thereof, a novel intermediate used in the production method, and a method for preparing the intermediate are described. Alternatively, the description in the manufacturing method of the intermediate can be equally applied.

In one embodiment, the method for preparing the compound of Formula 1a or a pharmaceutically acceptable salt thereof,

A step of preparing a compound of Formula 3a or a pharmaceutically acceptable salt thereof from a compound of Formula 2a below or a pharmaceutically acceptable salt thereof may be included.

[Formula 2a]

[Formula 3a]

In one embodiment, the step of preparing a compound of Formula 3a or a pharmaceutically acceptable salt thereof from the compound of Formula 2a or a pharmaceutically acceptable salt thereof,

An azodicarboxylate compound, triphenylphosphine (PPh ₃ ), or a combination thereof may be added.

In one embodiment, a catalyst may be used in the step of preparing the compound of Formula 3a or a pharmaceutically acceptable salt thereof from the compound of Formula 2a or a pharmaceutically acceptable salt thereof.

In one embodiment, the step of preparing the compound of Formula 3a or a pharmaceutically acceptable salt thereof from the compound of Formula 2a or a pharmaceutically acceptable salt thereof may use an azodicarboxylate compound as a catalyst. there is.

In one embodiment, the azodicarboxylate compound is diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD), di-tert-butyl azodicarboxylate (DBAD), dibenzyl azodicarboxylate, diphenyl azodicarboxylate, and combinations thereof.

In one embodiment, in the step of preparing the compound of Formula 3a or a pharmaceutically acceptable salt thereof from the compound of Formula 2a or a pharmaceutically acceptable salt thereof, triphenylphosphine (PPh ₃ ) may be added. there is.

In one embodiment, the step may be performed in an organic solvent, preferably the organic solvent may be tetrahydrofuran (THF).

In one embodiment, the preparation method includes the compound of Formula 5a or a pharmaceutically acceptable salt thereof by reacting the compound of Formula 3a or a pharmaceutically acceptable salt thereof with a compound of Formula 4a or a pharmaceutically acceptable salt thereof. It may further include the step of preparing.

[Formula 4a]

[Formula 5a]

In one embodiment, the preparation method may further include reducing the compound of Formula 5a or a pharmaceutically acceptable salt thereof. Accordingly, Formula 1a or a pharmaceutically acceptable salt thereof may be prepared from the compound of Formula 5a or a pharmaceutically acceptable salt thereof.

In one embodiment, the manufacturing method

To prepare a compound of Formula 2a or a pharmaceutically acceptable salt thereof by reacting a compound of Formula 2-1a or a pharmaceutically acceptable salt thereof with a compound of Formula 2-2a or a pharmaceutically acceptable salt thereof Further steps may be included.

[Formula 2-1a]

[Formula 2-2a]

In one embodiment, the step of preparing the compound of Formula 2 or a pharmaceutically acceptable salt thereof may be performed in an organic solvent, and preferably, the organic solvent may be tetrahydrofuran (THF).

In one embodiment, the step may be performed under conditions in which no base is added (free base).

As the compound of Formula 2 or a pharmaceutically acceptable salt thereof is prepared in the THF solvent and free base conditions, the production of unnecessary by-products in addition to the target compound can be minimized.

Another embodiment provides a compound of Formula 2a or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the above preparation method.

[Formula 2a]

In another embodiment, the method for preparing the compound of Formula 2a or a pharmaceutically acceptable salt thereof,

A step of reacting a compound of Formula 2-1a or a pharmaceutically acceptable salt thereof with a compound of Formula 2-2a or a pharmaceutically acceptable salt thereof may be included.

[Formula 2-1a]

[Formula 2-2a]

[Formula 2a]

In one embodiment, a method for preparing the compound of Formula 1a or a pharmaceutically acceptable salt thereof is shown in Formula 1 below together with the yield and purity of the compound obtained in each step.

[Equation 1]

The meaning of the abbreviation used in the above formula is as follows.

THF: tetrahydrofuran

DIAD: diisopropyl azodicarboxylate

PPh ₃ : triphenylphosphine

Pd[P( t -Bu) ₃ ]: Bis(tri-tert-butylphosphine)palladium(0) (bis(tri-tert-butylphosphine)palladium(0))

DABCO: 1,4-diazabicyclo[2.2.2]octane

MeCM: acetonitrile

Compounds not shown in the above formulas may be prepared by modification according to any method known in the art, for example, according to the method described in WO 2018/190643.

In one embodiment, a compound of Formula 1 or a pharmaceutically acceptable salt thereof, for example, an isoxazole derivative represented by a compound of Formula 1a or a pharmaceutically acceptable salt thereof, is an FXR agonist or a pharmaceutical containing the same. can be used in manufacturing.

In one embodiment, the compound or a pharmaceutically acceptable salt thereof is an agonist of the farnesoid X receptor (FXR, NR1H4), which can be used for various physiological processes such as bile acid (BA) regulation, lipid/sugar metabolism, inflammation and fibrosis. It can be used in the manufacture of pharmaceuticals to control

For example, the compound or a pharmaceutically acceptable salt thereof is a drug for treating metabolic disease, cholestatic liver disease or organ fibrosis disease, such as high cholesterol, cycloproteinemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, It can be used for the manufacture of medicines for the treatment of cholestasis/fibrosis, cholesterol gallstone disease, hyperglycemia, diabetes, insulin resistance, metabolic rigidity, nephropathy, liver disease, atherosclerosis, cancer, inflammatory disorders, osteoporosis, or skin aging.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

As used herein, expressions such as "has", "can have", "includes", or "may include" indicate the existence of a corresponding feature (eg, a numerical value or a component such as a component). indicated, and does not preclude the presence of additional features.

Numerical values described herein are considered to include the meaning of "about" even if not explicitly stated. As used herein, the term “about” means within 5% of a given value or range, preferably within 1% to 2%. For example, "about 10%" means between 9.5% and 10.5%, preferably between 9.8% and 10.2%. For another example, "about 100°C" means from 95°C to 105°C, preferably from 98°C to 102°C.

The contents of all publications incorporated by reference herein are incorporated herein by reference in their entirety.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are intended to illustrate the present invention by way of example, and the scope of the present invention is not limited to these examples.

Example 1: 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2 -Cyclopropylbenzo[ d Preparation of ]oxazole-7-carboxylic acid

Step 1: Preparation of methyl 5-bromo-3-(cyclopropanecarboxamido)-2-hydroxybenzoate

To a vessel, methyl 3-amino-5-bromo-2-hydroxybenzoate (compound of Formula 2-1a) (800 g, 3.25 mol, 1 wt, 1.0 eq.) and tetrahydrofuran (THF) (8000 mL, 10 vol, 8.9 wt) and stirred under nitrogen conditions at 15 degrees to 25 degrees, and then cyclopropanecarbonyl chloride (Formula 2-2a compound) (344mL, 3.74mol, 0.43vol, 0.49wt, 1.15eq.) and tetra A mixture of hydrofuran (THF) (2400 mL, 3 vol, 2.7 wt) was added slowly. The reaction mixture was heated to 45 degrees to 50 degrees and stirred for 1 hour to 3 hours. After confirming the completion of the reaction, the reaction mixture was cooled to 15 degrees to 25 degrees. To the reaction mixture, 7.5% w/w aqueous sodium chloride solution (3200 mL) and 18% w/w aqueous potassium bicarbonate solution (3200 mL) were slowly added in that order and stirred for 15 minutes. The separated organic layer was extracted, washed with 7.5% w/w aqueous sodium chloride solution, and then concentrated at 40 degrees or less. Then, n-heptane was slowly added to the fluid slurry, cooled to 15 to 25 degrees, and the resulting solid was filtered, washed with n-heptane, and dried to obtain the title compound (compound of Formula 2a) (987 g, yield 97% yield, purity 99.74). %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.28 (s, 1H), 8.78-8.77 (d, 1H), 8.03 (br, 1H), 7.66 (d, 1H), 3.99 (s, 3H), 1.63- 1.60 (m, 1H), 1.13-1.10 (m, 2H), 0.94-0.90 (m, 2H); MS: m/z = 314 [M+H] ⁺ , 316 [M+2+H] ⁺ .

Step 2: Methyl 5-bromo-2-cyclopropylbenzo[ d Preparation of ]oxazole-7-carboxylate

Methyl 5-bromo-3-(cyclopropanecarboxamido)-2-hydroxybenzoate (compound of formula 2a) prepared in step 1 (950 g, 3.02 mol, 1.0 wt, 1.0 eq.), triphenyl Phosphine (PPh ₃ ) (1,235g, 4.83mol, 1.3wt, 1.6eq.) and tetrahydrofuran (THF) (9,500mL, 10.0vol., 8.9wt.) were charged into a reaction vessel and separated after stirring under nitrogen conditions. A mixture of tetrahydrofuran (THF) (3,800mL, 3.6wt) and azodicarboxylate (DIAD) (1,045mL, 3.32mol, 1.1vol, 1.1wt, 1.7eq.) It was added slowly within The reaction mixture was stirred at 30 to 35 degrees for 8 to 10 hours, and after checking the completion of the reaction, the reaction mixture was cooled to 15 to 20 degrees and magnesium chloride (475g, 0.5wt., 1.6eq) was added. The resulting pale brown slurry was stirred for 1 hour to 2 hours, concentrated by filtration, and methanol was slowly added to the fluid slurry, followed by stirring for 1 hour. The slurry was filtered, washed with methanol and dried to obtain the title compound (compound of Formula 3a) (782g, yield 87%, purity 99.20%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, 1H), 7.89-7.88 (d, 1H), 4.00 (s, 3H), 2.29-2.45 (m, 1H), 1.36-1.32 (m, 2H) ), 1.27-1.22 (m,2H).

Step 3: Methyl 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2- Cyclopropylbenzo[ d Preparation of ]oxazole-7-carboxylate

Into a reaction vessel, the compound of Formula 3a obtained in step 2 (900 g, 1 wt, 1.0 eq.), 4-((3-chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2, 6-dichlorophenyl) isoxazole (compound of Formula 4a) (1,179 g, 1.3 wt, 0.92 eq.), 1,4-diazabicyclo [2.2.2] octane (DABCO) (684 g, 0.76 wt, 2.0 eq . ) _, and acetonitrile (MeCM) (9,000 mL, 10 vol) was filled and stirred for 16 to 24 hours under nitrogen conditions at 15 to 25 degrees. After confirming the completion of the reaction mixture, water (5,400 mL, 6 vol) was slowly added, followed by stirring for 30 to 90 minutes. Then, the flowable slurry was filtered, washed with a mixture of acetonitrile and water, and residual metal was removed with a metal remover and activated carbon. The filtrate was concentrated, stirred after addition of tert-butyl methyl ester (MTBE), and the slurry was filtered and washed with tert-butyl methyl ester (MTBE). The solid was dried to obtain the title compound (compound of Formula 5a) (1,296 g, yield 68.6%, purity 99.76%) from the reaction mixture.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (d, 1 H), 7.91 (d, 1 H), 7.45-7.38 (m, 3 H), 7.36-7.30 (m, 1 H), 6.88 (d , 1 H), 6.69 (dd, 1 H), 4.83 (s, 2 H), 4.01 (s, 3 H), 2.32-2.23 (m, 1 H), 2.20-2.11 (m, 1 H), 1.37 -1.31 (m, 2 H), 1.31-1.27 (m, 2 H), 1.27-1.20 (m, 2 H), 1.20-1.13 (m, 2 H)

Step 4: 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2-cyclo propyl benzo[ d Preparation of ]oxazole-7-carboxylic acid

To the reaction vessel was added methyl 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2- Cyclopropylbenzo[ d ]oxazole-7-carboxylate (Formula 5a compound) (1,280g, 1wt, 1.0eq.) and tetrahydrofuran (THF) (8,960mL, 7vol, 6.2wt) were filled and heated to 20 degrees The mixture was warmed to 30 degrees to dissolve completely under nitrogen conditions and the reaction mixture was cooled to 10 to 15 degrees. After sufficiently dissolving lithium hydroxide (422.4g, 0.33wt, 2.3eq.) and purified water (3,840mL, 3vol, 3wt) in a separate suitable container, the reaction mixture was slowly added while maintaining 10 to 15 degrees, and then 5 time to 7 hours. After confirming the completion of the reaction mixture, pH was adjusted by adding a mixture of 1N aqueous hydrochloric acid and 18% w/w aqueous sodium chloride solution, and then the organic layer was extracted and washed with 18% w/w aqueous sodium chloride solution. A solid, tetrahydrofuran (THF), and isopropanol (iPrOH) are filled in a reaction vessel, heated to 70 to 80 degrees, completely dissolved, and slowly cooled to 0 to 5 degrees to crystallize. The resulting solid was filtered, washed with cold isopropanol (iPrOH), and dried to obtain the title compound (compound of Formula 1a) (951 g, yield 75.7%, purity 99.49%).

¹ H NMR (400 MHz, DMSO-d6) δ 13.66 (br., 1 H), 7.98 (d, 1 H), 7.90 (d, 1 H), 7.68-7.60 (m, 2 H), 7.60-7.51 (m, 2 H), 7.11 (d, 1 H), 6.85 (dd, 1 H), 5.01 (s, 2 H), 2.55-2.48 (m, 1 H), 2.40-2.30 (m, 1 H), 1.30-1.11 (m, 8H)

Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a limiting point of view. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the equivalent scope will be construed as being included in the present invention.

Claims (16)

A method for producing a compound of Formula 1 or a pharmaceutically acceptable salt thereof,
A preparation method comprising the step of preparing a compound of Formula 3 or a pharmaceutically acceptable salt thereof from a compound of Formula 2 or a pharmaceutically acceptable salt thereof:
[Formula 1]

[Formula 2]

[Formula 3]

In Formula 1, Formula 2, or Formula 3,
each R ¹ is independently hydrogen, halogen, or trifluoromethyl;
each R ² is independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy;
R ³ is -CO ₂ -C _1-3 alkyl;
R ⁴ is a carboxyl group;
X ₁ is halogen;
p is an integer from 0 to 4;
q is an integer from 0 to 4;
The method according to claim 1, wherein the step of preparing a compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof,
A manufacturing method comprising the addition of an azodicarboxylate compound, triphenylphosphine (PPh ₃ ), or a combination thereof.
The method according to claim 2, wherein the azodicarboxylate compound is diisopropyl azodicarboxylate (diisopropyl azodicarboxylate, DIAD), diethyl azodicarboxylate (diethyl azodicarboxylate, DEAD), di-tert-butyl azodicar characterized in that it is selected from di-tert-butyl azodicarboxylate (DBAD), dibenzyl azodicarboxylate, diphenyl azodicarboxylate, and combinations thereof. method.
The method according to claim 1, wherein the step of preparing a compound of Formula 5 or a pharmaceutically acceptable salt thereof by reacting a compound of Formula 3 or a pharmaceutically acceptable salt thereof with a compound of Formula 4 or a pharmaceutically acceptable salt thereof. A manufacturing method characterized in that it further comprises:
[Formula 4]

[Formula 5]

In Formula 4 or Formula 5,
each R ¹ is independently hydrogen, halogen, or trifluoromethyl;
each R ² is independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy;
R ³ is -CO ₂ -C _1-3 alkyl;
p is an integer from 0 to 4;
q is an integer from 0 to 4;
The method according to claim 4, further comprising reducing the compound of Formula 5 or a pharmaceutically acceptable salt thereof.
The method according to claim 1, wherein the compound of Formula 2 or a pharmaceutically acceptable salt thereof is reacted with the compound of Formula 2-1 or a pharmaceutically acceptable salt thereof, and the compound of Formula 2 or a pharmaceutically acceptable salt thereof is reacted. Process characterized by further comprising the step of preparing a possible salt:
[Formula 2-1]

[Formula 2-2]

In Formula 2-1 or Formula 2-2,
R ³ is -CO ₂ -C _1-3 alkyl;
X ₁ and X ₂ are each a halogen independently selected from chlorine, bromine, and iodine.
A compound of Formula 2 or a pharmaceutically acceptable salt thereof:
[Formula 2]

In Formula 2,
R ³ is -CO ₂ -C _1-3 alkyl;
X ₁ is halogen.
Characterized in that it comprises the step of reacting a compound of Formula 2-1 or a pharmaceutically acceptable salt thereof with a compound of Formula 2-2 or a pharmaceutically acceptable salt thereof,
A method for preparing a compound of Formula 2 or a pharmaceutically acceptable salt thereof:
[Formula 2-1]

[Formula 2-2]

[Formula 2]

In Formula 2-1, Formula 2-2, or Formula 2,
R ³ is -CO ₂ -C _1-3 alkyl;
X ₁ and X ₂ are each a halogen independently selected from chlorine, bromine, and iodine.
A method for preparing a compound of Formula 1a or a pharmaceutically acceptable salt thereof,
A preparation method comprising the step of preparing a compound of Formula 3a or a pharmaceutically acceptable salt thereof from a compound of Formula 2a or a pharmaceutically acceptable salt thereof:
[Formula 1a]

[Formula 2a]

[Formula 3a]

.
The method according to claim 9, wherein the step of preparing the compound of Formula 3a or a pharmaceutically acceptable salt thereof from the compound of Formula 2a or a pharmaceutically acceptable salt thereof,
A manufacturing method comprising the addition of an azodicarboxylate compound, triphenylphosphine (PPh ₃ ), or a combination thereof.
The method according to claim 10, wherein the azodicarboxylate compound is diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD), di-tert-butyl azodicarboxylate (DBAD), characterized in that selected from dibenzyl azodicarboxylate, diphenyl azodicarboxylate, and combinations thereof.
The method according to claim 9, wherein the compound of Formula 5a or a pharmaceutically acceptable salt thereof is prepared by reacting the compound of Formula 4a or a pharmaceutically acceptable salt thereof with the compound of Formula 3a or a pharmaceutically acceptable salt thereof. A manufacturing method characterized in that it further comprises:
[Formula 4a]

[Formula 5a]

.
The method according to claim 12, further comprising reducing the compound of Formula 5a or a pharmaceutically acceptable salt thereof.
The method according to claim 9, wherein the compound of Formula 2-1a or a pharmaceutically acceptable salt thereof is reacted with the compound of Formula 2-2a or a pharmaceutically acceptable salt thereof to react the compound of Formula 2a or a pharmaceutically acceptable salt thereof. Process characterized by further comprising the step of preparing a possible salt:
[Formula 2-1a]

[Formula 2-2a]

.
A compound of Formula 2a or a pharmaceutically acceptable salt thereof:
[Formula 2a]

.
Characterized in that it comprises the step of reacting a compound of Formula 2-1a or a pharmaceutically acceptable salt thereof with a compound of Formula 2-2a or a pharmaceutically acceptable salt thereof,
Method for preparing a compound of Formula 2a or a pharmaceutically acceptable salt thereof:
[Formula 2-1a]

[Formula 2-2a]

[Formula 2a]

.