TWI833451B - Preparation method of isoxazole derivatives and intermediates thereof - Google Patents

Abstract

Disclosed are a novel preparation method of isoxazole derivatives which are useful as agonists for a farnesoid X receptor (FXR, NR1H4) and intermediates for preparing the agonists, and a method of preparing the preparation intermediates of the same.

Description

Preparation method of isoxazole derivatives and intermediates thereof

The present disclosure relates to preparation methods and intermediates of isoxazole derivatives that can be used to prepare agonists of farnesoid X receptors (FXR, NR1H4). More specifically, the present disclosure relates to the preparation of isoxazole derivatives. Novel methods, novel intermediates used therein and methods for preparing the intermediates.

Isoxazole derivative compounds that are agonists of farnesoid X receptors (FXR, NR1H4) are known (International Publication WO 2018/190643, Patent Document 1) and are useful in the treatment of metabolic diseases and cholestasis. Pharmaceutical products for stagnant liver diseases or organ fibrotic diseases, or used in the preparation of such pharmaceutical products.

The method for producing an isoxazole derivative compound used as an FXR agonist shown in Patent Document 1 can be expressed as the following Scheme 1: Scheme 1

The method is as follows: reacting 3-chloro-4-iodophenol (formula a) with tert-butyldimethylsilyl chloride and purifying it by silica gel chromatography The reaction product is to obtain tert-butyl(3-chloro-4-iodophenoxy)dimethylsilane (formula b); by using a palladium catalyst (PdCl ₂ (PPh ₃ ) ₂ ) React formula b with trimethylsilylacetylene and purify the reaction product by silica gel chromatography to obtain tert-butyl (3-chloro-4-((trimethylsilyl) )ethynyl)phenoxy)dimethylsilane (tert-butyl(3-chloro-4-((trimethylsilyl)ethynyl)phenoxy)dimethylsilane, formula c); and formula c is then reacted with potassium fluoride to obtain 3 -Chloro-4-((trimethylsilyl)ethynyl)phenol (3-chloro-4-((trimethylsilyl)ethynyl)phenol, formula d); Subsequently, formula d is combined with 4-(bromomethyl) -5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole, formula e) reacts and borrows The reaction product is purified by silica gel chromatography to prepare the isoxazole derivative compound of formula f. However, this method is not only time-consuming and costly in the art due to the need for a four-step synthesis process, but is also unsuitable for industrial manufacturing, difficult to operate and, most importantly, limited in the final material obtainable from the starting materials. The total yield (yield) is only 46%, which is uneconomical from an industrial point of view. In addition, each of the compounds of formula b, formula c and formula f obtained in steps 1, 2 and 4 is purified by column chromatography, and is difficult to manufacture on an industrial scale. In addition, since the compounds of formula b and formula d (which are the intermediate compounds prepared and obtained in steps 1 and 3 respectively) are viscous oils, they are not easy to operate and are difficult to manufacture industrially.

Furthermore, because step 2 of the method uses an expensive palladium (Pd) catalyst under high temperature conditions, this step is not suitable as a method for industrial mass production, and in particular, according to the International Consortium on Medical Regulations (ICH) guidelines (Q3D metal impurities) , because palladium (Pd) is a toxic substance to humans, its permissible daily exposure (PDE) must be managed to 100 (μg/day) when administered orally. In order to provide the final compound as a drug, it is necessary to implement There is the inconvenience of additional processing to remove the palladium present from the final compound, and there is also the difficulty of removing the heavy metal palladium used in the final synthesis step.

What's more, in step c of the above method, the selectivity for the deprotection of the TBS protective group of the compound of formula c is low, and the compound of formula d' in which both the TBS protective group and the TMS protective group are deprotected is used as a compound in addition to Scheme 1 By-products other than compound d are produced. Therefore, the compound of formula d' produced as a by-product also randomly participates in the reaction, and it is difficult to maintain the reproducibility of the synthesis process and to quantitatively calculate the reactants and products.

Therefore, the present inventors have completed the present disclosure by devising a new manufacturing method that can more efficiently prepare isoxazole derivative compounds.

Prior technical literature [Patent Document]

Patent Document 1 International Publication WO 2018/190643

One aspect provides a method for preparing an isoxazole derivative.

Another aspect provides intermediates useful in the preparation method.

Yet another aspect provides methods for preparing intermediates that can be used in the above methods.

Other objects and advantages of the present application will become more apparent from the following detailed description in conjunction with the accompanying patent claims. Contents not described in this specification will be omitted because those with ordinary knowledge in the technical field of the present application or similar technical fields can fully identify and deduce the contents.

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

Another aspect provides a compound of formula 4 or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the preparation method.

Yet another aspect provides a method for preparing a compound of Formula 4 or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the preparation method.

Yet another aspect provides a method for preparing a compound of Formula 5 as an isoxazole derivative or a pharmaceutically acceptable salt thereof.

The present disclosure can solve the problems in the technical field, such as the obtained intermediate material is in the form of a viscous oil and is difficult to operate, low yield, complicated manufacturing steps and toxicity from the use of palladium catalysts, time and cost issues, and side effects generated during the process. Product reproducibility and productivity (productivity) is reduced, and in terms of time and cost, novel preparation methods for preparing isoxazole derivatives, intermediates used therein and preparation methods of intermediates can be provided in a more effective and convenient manner.

Therefore, the present disclosure provides a method in which intermediates can be obtained in solid phase during the manufacturing process, making the operation easier and eliminating the need for isolation and purification of compounds by using column chromatography as is the case in the art. It is more suitable for large-scale synthesis, and the manufacturing productivity of the final material from the starting material can be high. In addition, since no catalyst such as palladium is used, no additional steps for removing metal impurities harmful to humans are required, and fewer manufacturing steps are required, allowing the target compound to be synthesized more economically. In addition, the reproducibility of the manufacturing process can be increased by reducing the generation of unnecessary by-products, and the manufacturing productivity can be improved by reducing the time and cost required for the manufacturing process. Therefore, the isoxazole derivative compound of Formula 1 can be prepared on a scale that can commercially prepare pharmaceutical products.

This disclosure will be explained in more detail below.

All terms used herein, unless otherwise specified, have the same meanings as commonly understood by one of ordinary skill in the art. Furthermore, although this article describes better methods or samples, those that are similar or equivalent are also included in the scope of this disclosure.

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

其中，式1或式4中，R¹各自獨立地為氫、鹵素或三氟甲基，R²各自獨立地為氫、鹵素、三氟甲基或三氟甲氧基，0p為0至4之整數，以及q為0至4之整數。 In a specific example, the method may include preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof from a compound of Formula 4 or a pharmaceutically acceptable salt thereof: Formula 1

Wherein, in Formula 1 or Formula 4, R ¹ is each independently hydrogen, halogen or trifluoromethyl, R ² is each independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy, and 0p is 0 to 4 is an integer, and q is an integer from 0 to 4.

The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

In specific examples, the compound of Formula 1 or a pharmaceutically acceptable salt thereof can be prepared by using α-diazophosphonate (α-diazophosphonate, also known as α-diazo-β-carbonylphosphonate (α-diazo- The reaction of β-carbonyl phosphonates)) reagent is prepared from the compound of formula 4 or its pharmaceutically acceptable salt.

In specific examples, the reaction may be Seyferth-Gilbert homologation reaction, Bestmann-Ohira reaction, etc., but is not limited to them.

For the reaction, Seifert-Gilbert homologation reaction reagents or Bestmann-Ohira reaction reagents can be used, which are known to those skilled in the art.

The reaction can be a reaction commonly known in the art by acetylenizing the aldehyde or ketone to add an extra carbon unit to the starting material, and the reaction can be transformed into one that can add carbon units. Other reactions.

In a specific example, the preparation method includes the step of preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof from the compound of Formula 4 or a pharmaceutically acceptable salt thereof through a Seifert-Gilbert homology reaction or a Bestmann-Dahira reaction.

In a specific example, the Bestmann-Ohira reaction can be achieved by adding COCH ₃ C(N ₂ )P(O)(OCH ₃ ) ₂ , COCH ₃ C(N ₂ )P(O)(OCH ₂ CH ₃ ) ₂ or a combination thereof, and a base selected from K ₂ CO ₃ , Na ₂ CO ₃ or a combination thereof.

In a specific example, the compound of Formula 1 or its pharmaceutically acceptable salt can be prepared by adding COCH ₃ C(N ₂ )P(O)(OCH ₃ ) ₂ and K ₂ CO ₃ to the compound of Formula 4 or its pharmaceutically acceptable salt. be implemented.

In specific examples, based on the compound of Formula 4 or its pharmaceutically acceptable salt, Bestmann-Dahira reagent can be added at a relative molar ratio of 1:0.5 to 1:5. For example, the molar ratio of the compound of Formula 4 or its pharmaceutically acceptable salt to Bestmann-Dahira reagent can be 1:0.5, 1:0.8, 1:1, 1:1.5, 1:1.8, 1:2, 1: 3. 1:4, 1:5 or a range with the upper or lower limit of the above values.

In specific examples, based on the compound of Formula 4 or its pharmaceutically acceptable salt, the base can be added at a relative molar ratio of 1:1 to 1:5. For example, the molar ratio of the compound of Formula 4 or its pharmaceutically acceptable salt to the base can be 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 4:1, 5:1 or have the above values. The upper or lower limit of the range.

In specific examples, the compound of formula 4 or its pharmaceutically acceptable salt: Bestmann-Dahira reagent: base can be added in a relative molar ratio of 1:1:1 to 1:1:3. For example, the compound of formula 4 or its pharmaceutically acceptable salt: Bestmann-Dahira reagent: base can be added in a relative molar ratio of 1:1:2.

In specific examples, the preparation can be carried out in water, organic solvents or mixtures thereof. The organic solvent may be an alcohol having 1 to 3 carbon atoms, such as methanol, ethanol or propanol.

The organic solvent used in this regard may be 1 mL to 50 mL, for example, 5 mL to 15 mL, for example, 10 mL, relative to 1 g of the compound of Formula 4 or a pharmaceutically acceptable salt thereof.

In specific examples, the preparation can be carried out at a temperature of 5°C to 50°C, for example, 10°C to 30°C or 10°C to 20°C.

In specific examples, the preparation can be carried out for 1 hour to 10 hours, 3 hours to 8 hours, or 4 hours to 7 hours.

其中，式1、式4或式9中，R¹各自獨立地為氫、鹵素或三氟甲基，R²各自獨立地為氫、鹵素、三氟甲基或三氟甲氧基，p為0至4之整數，以及q為0至4之整數。 In another specific example, the preparation method may include: preparing a compound of Formula 9 or a pharmaceutically acceptable salt thereof from a compound of Formula 4 or a pharmaceutically acceptable salt thereof; and preparing a compound of Formula 1 or a pharmaceutical thereof from the compound of Formula 9 or a pharmaceutically acceptable salt thereof. Acceptable salt:

Wherein, in Formula 1, Formula 4 or Formula 9, R ¹ is each independently hydrogen, halogen or trifluoromethyl, R ² is each independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy, and p is an integer from 0 to 4, and q is an integer from 0 to 4.

The preparation method may include: (i) adding tetrabromomethane (CBr ₄ ) and triphenylphosphine (PPh ₃ ) to the compound of formula 4 or its pharmaceutically acceptable salt in a DCM solvent at -5°C to 5°C, and reacting ; and (ii) adding isopropylmagnesium chloride (i-PrMgCl) in toluene solvent at -5°C to 5°C, and reacting.

The reaction can be described as follows to prepare an intermediate compound of Formula 9 from a compound of Formula 4, and to prepare a compound of Formula 1 from an intermediate compound of Formula 9:

其中，式2、式3或式4中，R¹各自獨立地為氫、鹵素或三氟甲基，R²各自獨立地為氫、鹵素、三氟甲基或三氟甲氧基，X為鹵素，p為0至4之整數，以及q為0至4之整數。 In specific examples, in Formula 1, Formula 4 or Formula 9, R ¹ and R ² can each be independently a halogen selected from chlorine, bromine and iodine, and p and q can each be 1 or 2. In specific examples, the The method may further include preparing a compound of Formula 4 or a pharmaceutically acceptable salt thereof by reacting a compound of Formula 2 or a pharmaceutically acceptable salt thereof with a compound of Formula 3 or a pharmaceutically acceptable salt thereof:

Wherein, in Formula 2, Formula 3 or Formula 4, R ¹ is each independently hydrogen, halogen or trifluoromethyl, R ² is each independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy, and X is For halogen, p is an integer from 0 to 4, and q is an integer from 0 to 4.

In specific examples, in Formula 2, Formula 3 or Formula 4, R ¹ , R ² and X may each be independently a halogen selected from chlorine, bromine and iodine, and p and q may each be 1 or 2.

In specific examples, the compound of Formula 2 or a pharmaceutically acceptable salt thereof and the compound of Formula 3 or a pharmaceutically acceptable salt thereof may be added at a relative molar ratio of 1:0.5 to 1:1.5, and for example, the molar ratio may be 1: 1.

In specific examples, a base selected from K ₂ CO ₃ , Na ₂ CO ₃ , NaOH or KOH may be added during preparation.

In specific examples, the base may be added at a relative molar ratio of 1:1 to 1:5 relative to the compound of Formula 2 or its pharmaceutically acceptable salt. For example, the molar ratio of the compound of formula 4 or its pharmaceutically acceptable salt to the base can be 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 4:1, 5:1 or have the above values. The upper or lower limit of the range.

In a specific example, a dechlorination activator selected from KI or NaI can be added during preparation.

In specific examples, the dechlorination activator can be added at a relative molar ratio of 1:0.01 to 1:0.8 relative to the compound of Formula 3 or its pharmaceutically acceptable salt. For example, a compound of formula 3 or a pharmaceutically acceptable compound thereof The salt and KI can be added in a relative molar ratio of the compound of formula 3 or its pharmaceutically acceptable salt to KI of 1:0.05 to 1:0.5.

In specific examples, the preparation can be carried out in water, organic solvents or mixtures thereof. The organic solvent can be dimethylformamide (DMF), tetrahydrofuran (THF), acetone, ethyl acetate, chloroform or toluene

In specific examples, the preparation can be carried out at a temperature of 5°C to 70°C, for example, 10°C to 60°C or 20°C to 50°C.

In specific examples, the preparation can be carried out for 1 hour to 30 hours, 3 hours to 20 hours, or 5 hours to 10 hours.

In a specific example, the preparation of the compound of Formula 4 or its pharmaceutically acceptable salt can be carried out by adding K ₂ CO ₃ and KI to the compound of Formula 2 or its pharmaceutically acceptable salt and the compound of Formula 3 or its pharmaceutically acceptable salt. For example, the compound of formula 2 or its pharmaceutically acceptable salt: the compound of formula 3 or its pharmaceutically acceptable salt: K ₂ CO ₃ : KI can be added in a molar ratio of 1:0.95:2:0.1.

In a specific example, the compound of formula 1 with a total yield of about 76.4% can be prepared in two steps.

In specific examples, the compound of formula 1 or its pharmaceutically acceptable salt can be the compound of formula 5 or its pharmaceutically acceptable salt:

其中，式11中，R¹各自獨立地為氫、鹵素或三氟甲基，R²各自獨立地為氫、鹵素、三氟甲基或三氟甲氧基，R⁴為羧基，p為0至4之整數，q為0至4之整數，以及r為0至3之整數。 In specific examples, the compound of formula 1 or a pharmaceutically acceptable salt thereof can be used as an intermediate for preparing the compound of formula 11 or a pharmaceutically acceptable salt thereof:

Wherein, in formula 11, R ¹ is each independently hydrogen, halogen or trifluoromethyl, R ² is each independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy, R ⁴ is carboxyl, and p is 0 to 4, q is an integer from 0 to 4, and r is an integer from 0 to 3.

In specific examples, the compound of Formula 11 or a pharmaceutically acceptable salt thereof can be prepared by using the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an intermediate compound.

In specific examples, the method for preparing the compound of Formula 11 or a pharmaceutically acceptable salt thereof from the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be a method described in International Publication WO 2018/190643.

其中，式4中，R¹各自獨立地為氫、鹵素或三氟甲基，R²各自獨立地為氫、鹵素、三氟甲基或三氟甲氧基，X為鹵素，p為0至4之整數，以及q為0至4之整數。 Another aspect provides intermediates useful in the preparation method. In specific examples, the intermediate can be a compound of the following formula 4 or a pharmaceutically acceptable salt thereof: formula 4

Wherein, in Formula 4, R ¹ is each independently hydrogen, halogen or trifluoromethyl, R ² is each independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy, X is halogen, and p is 0 to 4, and q is an integer from 0 to 4.

Yet another aspect provides a method for preparing a compound of formula 4 or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the preparation method.

其中，式2、式3或式4中，R¹為氫、鹵素或三氟甲基，R²各自獨立地為氫、鹵素、三氟甲基或三氟甲氧基，X為鹵素，p為0至4之整數，以及q為0至4之整數。 In a specific example, the method includes preparing a compound of Formula 4 or a pharmaceutically acceptable salt thereof by reacting a compound of Formula 2 or a pharmaceutically acceptable salt thereof with a compound of Formula 3 or a pharmaceutically acceptable salt thereof.

Wherein, in Formula 2, Formula 3 or Formula 4, R ¹ is hydrogen, halogen or trifluoromethyl, R ² is each independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy, X is halogen, p is an integer from 0 to 4, and q is an integer from 0 to 4.

In specific examples, the compound of formula 1 or a pharmaceutically acceptable salt thereof can be prepared by a method including the following steps: preparing a compound of formula 2 or a pharmaceutically acceptable salt thereof and a compound of formula 3 or a pharmaceutically acceptable salt thereof. a compound of Formula 4 or a pharmaceutically acceptable salt thereof (step 1); and preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof (step 2) from the compound of Formula 4 or a pharmaceutically acceptable salt thereof.

The preparation method can be expressed as the following Scheme 2: Scheme 2

In specific examples, the isoxazole derivative can be the following compound of formula 5 or a pharmaceutically acceptable salt thereof:

In specific examples, the compound of Formula 5 or a pharmaceutically acceptable salt thereof can be prepared by a method including the following steps: preparing a compound of Formula 6 or a pharmaceutically acceptable salt thereof and a compound of Formula 7 or a pharmaceutically acceptable salt thereof. A compound of formula 8 or a pharmaceutically acceptable salt thereof (step 1); and Prepare a compound of formula 5 or a pharmaceutically acceptable salt thereof from a compound of formula 8 or a pharmaceutically acceptable salt thereof (step 2).

In a specific example, the method for preparing an isoxazole derivative includes a total of 2 steps, including step 1 in which the phenolic compound is alkylated, and step 2 in which the aldehyde compound thus produced is converted into an alkyne.

The preparation method according to the specific example can be expressed as the following scheme 3:

Step 1 can be implemented on a kilogram scale.

Additional steps may be further included to obtain a good quality product in step 1. For example, a reslurry step may be further included. For example, the repulping step can be performed by adding ethyl acetate (EA) and heptane to the reactants.

Step 2 can also be implemented on a kilogram scale.

Additional steps may further be included to increase the purity of the product obtained in step 2. For example, a recrystallization step may be further included.

The preparation method according to specific examples may further include stirring, heating, cleaning, drying or concentrating steps if necessary.

Compounds not represented in Scheme 2 or Scheme 3 can be prepared by modification according to any method commonly known in the art, for example, according to the method described in WO 2018/190643.

Alternatively, in another specific example, the compound of Formula 5 or a pharmaceutically acceptable salt thereof may be prepared as follows: the intermediate compound of Formula 10 is prepared from the compound of Formula 8, and the compound of Formula 5 is prepared from the intermediate compound of Formula 10:

In specific examples, the compound of formula 5 or its pharmaceutically acceptable salt can be an intermediate for preparing the compound of formula 12 or its pharmaceutically acceptable salt::

In specific examples, the method for preparing the compound of Formula 12 or its pharmaceutically acceptable salt from the compound of Formula 5 or its pharmaceutically acceptable salt can be based on the method described in International Publication WO 2018/190643. For example, the compound of formula 12 or a pharmaceutically acceptable salt thereof can be prepared in the following manner.

(i) 4-((3-chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (4-((3 -chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole), compound of formula 5, dissolved in solvent, 5-bromo-2-cyclopropylbenzo[ d ]oxazole -7-carboxylic acid methyl ester (methyl 5-bromo-2-cyclopropylbenzo[ d ]oxazole-7-carboxylate), then add bis(triphenylphosphine)palladium(II) dichloride (PdCl ₂ (PPh ₃ ) ₂ ), copper (I) iodide and triethylamine, then the reaction mixture was stirred at 80°C, diluted with ethyl acetate, and then washed with distilled water. Subsequently, the reaction mixture was dried over magnesium sulfate, filtered and concentrated, and purified by silica gel chromatography to obtain 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorobenzene) methyl)isoxazole)-4-yl)methoxy)phenyl)ethynyl)-2-cyclopropylbenzo[ d ]oxazole-7-carboxylate (methyl 5-((2-chloro -4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole)-4-yl)methoxy)phenyl)ethynyl)-2-cyclopropylbenzo[ d ]oxazole-7-carboxylate) (step 1).

(ii) The compound prepared in step 1 is dissolved in the solvent, lithium hydroxide is added, the mixture is stirred at room temperature, adjusted to pH 2 to pH 3, diluted with ethyl acetate, and then washed with distilled water. Subsequently, the sample was dried over magnesium sulfate, filtered and concentrated to obtain the target compound 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazole-4 -yl)methoxy)phenyl)ethynyl)-2-cyclopropylbenzo[ d ]oxazole-7-carboxylic acid (5-((2-chloro-4-((5-cyclopropyl-3- (2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2-cyclopropylbenzo[ d ]oxazole-7-carboxylic acid) (compound of formula 12) (step 2).

Another aspect provides intermediates useful in preparation methods. In specific examples, the intermediate is a compound of formula 8 or a pharmaceutically acceptable salt thereof:

In specific examples, the isoxazole derivative represented by the compound of Formula 1 or a pharmaceutically acceptable salt thereof, or the compound of Formula 5 or a pharmaceutically acceptable salt thereof, can be used as an FXR agonist or in pharmaceutical products containing the same.

In specific examples, the compound or its pharmaceutically acceptable salt can be used as an agonist of panasoid , inflammation and fibrosis pharmaceutical products.

For example, the compound or its pharmaceutically acceptable salt can be used to manufacture pharmaceutical products for the treatment of metabolic diseases, cholestatic liver diseases or organ fibrotic diseases, such as hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia Glyceridemia, dyslipidemia, lipodystrophy, cholestasis/fibrosis, cholesterol gallstone disease, hyperglycemia, diabetes, insulin resistance, metabolic inflexibility, renal disease, liver disease, arteriosclerosis, cancer, inflammatory disorders , osteoporosis or skin aging.

Pharmaceutically acceptable salts refer to pharmaceutically acceptable organic or inorganic salts of the compounds of the present disclosure, and can be prepared by any suitable method available to those of ordinary skill in the art.

As used herein, the terms "have," "may have," "includes," or "may include" indicate the presence of corresponding characteristics (for example, values or components, such as ingredients), and do not exclude the presence of additional characteristics.

In addition, the numerical values stated herein are considered to include the meaning of "about", but are not specified. The term "about" used herein means within 5% of a specified value or range, preferably within 1% to 2%. For example, "about 10%" means 9.5% to 10.5%, preferably 9.8% to 10.2%. For another example, "about 100°C" means between 95°C and 105°C, preferably between 98°C and 102°C.

The contents of all publications referenced herein are incorporated into this disclosure in their entirety.

Hereinafter, the present disclosure is described in more detail through embodiments. However, these examples are intended to illustrate the present disclosure, and the scope of the present disclosure is not limited to these examples.

Example 1: Preparation of 4-((3-chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (4-((3-chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole)

Step 1: Preparation of 2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)benzaldehyde (2-chloro-4 -((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)benzaldehyde)

The reaction vessel was fed with the compound of formula 6 (1933g, 1.0eq, 12.34mol), the compound of formula 7 (3548g, 0.95eq, 11.73mol) and dimethylformamide (DMF) (19L), and then added potassium carbonate (K ₂ CO ₃ ) (3395g, 2.0eq, 24.68mol) and potassium iodide (KI, 204g, 0.1eq, 1.234mol), the mixture was heated to 35°C to 40°C and stirred for 16 hours. After confirming that the reaction of the reaction mixture was completed, water (35L) and ethyl acetate (EA) (18L) were slowly added, and the organic layer was extracted. The organic layer was washed with 50% sodium chloride aqueous solution, dried over sodium sulfate (Na ₂ SO ₄ ) and concentrated. After adding n-heptane to the obtained slurry, the slurry was cooled to 10°C to 15°C and stirred for 1 hour. The solid was filtered and washed with n-heptane. The solid was dried to obtain the title compound (compound of formula 8) (8500 g, yield 91%, purity 98.4%).

¹ H NMR (400MHz, CDCl ₃ )δ 10.32(s,1H),7.85-7.83(d,1H),7.44-7.41(m,2H),7.37-7.28(m,1H),6.85(d,1H) ,6.81-6.78(m,1H),4.90(s,2H),2.20-2.15(m,1H),1.34-1.26(m,2H),1.23-1.18(m,2H); MS: m/z= 422.0[M+H] ⁺ ,424.0[M+2+H] ⁺ .

Step 2: Preparation of 4-((3-chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (4-(( 3-chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole)

The reaction vessel was fed with the compound of formula 8 (3500g, 1.0eq, 8.28mol) and methanol (35L), and potassium carbonate (K ₂ CO ₃ ) (2288g, 2.0eq, 16.56mol) and (1-diazo-2- were slowly added Dimethyl(1-diazo-2-oxopropyl)phosphonate (Bestmann-Dahira reagent) (1748g, 1.1eq, 9.11mol) and stirred for 16 hours.

After confirming that the reaction of the reaction mixture was completed, water (71L) and tertiary butyl methyl ester (MTBE) (36L) were slowly added, and the organic layer was extracted. The organic layer was washed with 50% sodium chloride aqueous solution, dried with sodium sulfate (Na ₂ SO ₄ ), and mixed with other reaction batches (3500g and 1500g scale) of similar in-process control (IPC). Concentrate. Isopropyl alcohol (iPrOH) was added to the concentrated yellow oil, the sample was slowly heated to 60°C to 65°C to completely dissolve the isopropyl alcohol, and then the sample was slowly cooled to 15°C to 20°C, followed by stirring for 16 hours. n-heptane was added to the obtained yellow solid and stirred at 15°C to 20°C for 1 to 3 hours. The solid was filtered and washed with n-heptane. The solid was dried to obtain the title compound (compound of formula 5) (7150 g, yield 84% and purity 98.91%).

¹ H NMR (400MHz, CDCl ₃ ) δ 7.42-7.28 (m, 4 H), 6.83 (d, 1 H), 6.65 (dd, 1 H), 4.80 (s, 2 H), 3.26 (s, 1 H) ),2.14(tt,1 H),1.32-1.24(m,2 H),1.19-1.09(m,2 H); MS: m/z=418.1[M+H] ⁺ ,420.1[M+2H] ⁺ .

Example 2: Preparation of 4-((3-chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (4-( (3-chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole)

Step 1: Preparation of 4-((3-chloro-4-(2,2-dibromovinyl)phenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl) Isoxazole (4-((3-chloro-4-(2,2-dibromovinyl)phenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole)

The reaction vessel was fed triphenylphosphine (PPh ₃ ) (6230g, 3.1eq, 23.78mol) and dichloromethane (50L, 15v/w). The mixture was stirred under nitrogen conditions, cooled to -5°C to 5°C and placed at - Slowly add a mixture of tetrabromomethane (CBr ₄ ) (3940g, 1.55eq, 11.89mol) and dichloromethane (10.0L, 3v/w), and triethylamine (2770g, 3.56eq, 27.34mol) at 5°C to 5°C. ) to separate appropriate vessels. Then, slowly add the compound of formula 8 (3240g, 1.0eq, 7.67mol) and dichloromethane (6.5L, 2v/ w) mixture and stir for 1 hour to 2 hours. After confirming that the reaction of the reaction mixture is complete, water (32.4L, 10v/w) is slowly added at 10°C or lower, and the organic layer is extracted. Isopropyl alcohol (iPrOH) and water are added to the slurry resulting from the concentrated organic layer, and the sample is cooled to 10°C to 15°C and stirred for 2 to 4 hours. The solid was filtered and washed with a mixture of isopropyl alcohol (iPrOH) and water. The solid was dried to obtain the title compound (compound of formula 10) (3900 g, yield 90%, purity 99.5%).

¹ H NMR (400MHz, CDCl ₃ )δ 7.54(d,1H),7.47(s,1H),7.42-7.28(m,3H),6.83(d,1H),6.71(dd,1H),4.80(s ,2H),2.20-2.06(m,1H),1.34-1.22(m,2H),1.20-1.07(m,2H).

Step 2: Preparation of 4-((3-chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (4-(( 3-chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole)

The reaction vessel is fed with the compound of formula 10 (3800g, 1.0eq, 6.67mol) and toluene (32,900g, 10v/w). After stirring, cool to -5°C to 5°C, and slowly add 2N isopropylmagnesium chloride (i-PrMgCl). (9600g, 3.0eq) solution and stirred for 30 to 60 minutes. After confirming that the reaction of the reaction mixture is completed, an aqueous ammonium chloride solution is slowly added at 10° C. or lower, and the organic layer is extracted. The organic layer was washed with water and saturated sodium chloride aqueous solution, mixed with another reaction batch (3800g scale) of a similar in-process control (IPC), and concentrated to obtain the title compound (compound of formula 5) (6,000g, crude product Rate>100%, purity 98.0%).

¹ H NMR (400MHz, CDCl ₃ ) δ 7.42-7.28 (m, 4 H), 6.83 (d, 1 H), 6.65 (dd, 1 H), 4.80 (s, 2 H), 3.26 (s, 1 H) ),2.14(tt,1 H),1.32-1.24(m,2 H),1.19-1.09(m,2 H); MS: m/z=418.1[M+H] ⁺ ,420.1[M+2H] ⁺ .

The above description of the present disclosure is for illustrative purposes, and those with ordinary skill in the art will be able to understand that the examples and specific examples can be easily modified without changing the technical concepts or essential features of the present disclosure. Accordingly, the examples described herein are in all respects illustrative and not restrictive, and all numbers expressing amounts of ingredients, properties such as molecular weights, reaction conditions, etc. used herein are to be understood in all cases to be defined by the term "about ” modification unless otherwise specified. Accordingly, the numbers specified herein are approximations and may vary depending on the desired properties obtained by the present disclosure.

It will be understood by those of ordinary skill in the art that the present disclosure may be implemented in modified forms without departing from the essential characteristics of the present disclosure. Accordingly, the disclosed examples should be considered illustrative rather than restrictive. The scope of the present disclosure is defined by the claimed scope rather than the above description, and all differences within the scope of equivalence thereto shall be construed as being included in the present disclosure.

Claims (12)

A method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof, the method comprising preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof from a compound of Formula 4 or a pharmaceutically acceptable salt thereof,

Wherein, in Formula 1 or Formula 4, R ¹ is each independently hydrogen, halogen or trifluoromethyl, R ² is each independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy, and p is 0 to 4 is an integer, and q is an integer from 0 to 4. The preparation method as described in claim 1, including through Seyferth-Gilbert homologation reaction or Bestmann-Dahira reaction (Bestmann-Ohira reaction), prepare the compound of formula 1 or its pharmaceutically acceptable salt from the compound of formula 4 or its pharmaceutically acceptable salt. The preparation method as described in claim 2, wherein the Bestmann-Dahira reaction is carried out by adding COCH ₃ C(N ₂ )P(O)(OCH ₃ ) ₂ and COCH ₃ C(N ₂ )P (O) Bestmann-Dahira reagent of (OCH ₂ CH ₃ ) ₂ or combinations thereof, and a base selected from K ₂ CO ₃ , Na ₂ CO ₃ or combinations thereof are implemented. The preparation method as described in claim 3, wherein the Bestmann-Dahira reagent is added at a relative molar ratio of 1:0.5 to 1:5 relative to the compound of Formula 4 or its pharmaceutically acceptable salt. The preparation method as described in claim 1, comprising preparing a compound of Formula 9 or a pharmaceutically acceptable salt thereof from a compound of Formula 4 or a pharmaceutically acceptable salt thereof; and preparing a compound of Formula 1 or a pharmaceutical thereof from a compound of Formula 9 or a pharmaceutically acceptable salt thereof. Salt is acceptable,

Formula 9

Wherein, in Formula 1, Formula 4 or Formula 9, R ¹ is each independently hydrogen, halogen or trifluoromethyl, R ² is each independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy, and p is an integer from 0 to 4, and q is an integer from 0 to 4. The preparation method as claimed in claim 1 or claim 5, wherein R ¹ and R ² are each independently a halogen selected from chlorine, bromine and iodine, and p and q are each 1 or 2. The preparation method as described in claim 1, further comprising preparing the compound of Formula 4 or a pharmaceutically acceptable salt thereof by reacting the compound of Formula 2 or a pharmaceutically acceptable salt thereof with a compound of Formula 3 or a pharmaceutically acceptable salt thereof.

Wherein, in Formula 2, Formula 3 or Formula 4, R ¹ is each independently hydrogen, halogen or trifluoromethyl, R ² is each independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy, and X is For halogen, p is an integer from 0 to 4, and q is an integer from 0 to 4. The preparation method as claimed in claim 7, wherein R ¹ , R ² and X are each independently a halogen selected from chlorine, bromine and iodine, and p and q are each 1 or 2. The preparation method as claimed in claim 1, wherein the compound of formula 1 or a pharmaceutically acceptable salt thereof is a compound of formula 5 or a pharmaceutically acceptable salt thereof:

The preparation method as claimed in claim 1, wherein the compound of formula 1 or its pharmaceutically acceptable salt is used as an intermediate for preparing the compound of formula 11 or its pharmaceutically acceptable salt:

Wherein, in formula 11, R ¹ is each independently hydrogen, halogen or trifluoromethyl, R ² is each independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy, R ⁴ is carboxyl, and p is 0 to 4, q is an integer from 0 to 4, and r is an integer from 0 to 3. A method for preparing formula 5 or a pharmaceutically acceptable salt thereof, comprising: preparing a compound of formula 8 or a pharmaceutically acceptable salt thereof by reacting a compound of formula 6 or a pharmaceutically acceptable salt thereof with a compound of formula 7 or a pharmaceutically acceptable salt thereof; and preparing a compound of Formula 5 or a pharmaceutically acceptable salt thereof from a compound of Formula 8 or a pharmaceutically acceptable salt thereof: Formula 5

The preparation method as claimed in claim 11, wherein the compound of formula 5 or its pharmaceutically acceptable salt is used as an intermediate for preparing the compound of formula 12 or its pharmaceutically acceptable salt: