WO2025127790A1 - Method for preparing relugolix - Google Patents

Abstract

The present invention provides a method for economically preparing high-purity relugolix at high yield.

Description

Method of manufacturing relugolix

The present invention relates to a method for producing relugolix, and more specifically, to a method for economically producing high-purity relugolix with a high yield.

Relugolix (1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea), of the following chemical formula 1, is the active pharmaceutical ingredient (API) of Orgovyx ^® , a drug for the treatment of prostate cancer.

[Chemical Formula 1]

U.S. Patent No. 10,150,778 discloses a method for producing relugolix by a total of 7 steps using ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate as a starting material, as shown in the following reaction scheme 1.

[Reaction Formula 1]

One object of the present invention is to provide a method for economically producing high-purity relugolix in high yield.

One embodiment of the present invention relates to a method for producing relugolix of the following chemical formula 1, wherein the method of the present invention comprises:

(i) a step of obtaining a compound of the following chemical formula 4 by subjecting a compound of the following chemical formula 2 to an amide bond reaction with a compound of the following chemical formula 3;

(ii) a step of subjecting a compound of chemical formula 4 below to an alkylation reaction with a compound of chemical formula 5 below to obtain a compound of chemical formula 6 below;

(iii) a step of obtaining a compound of chemical formula 7 by subjecting a compound of chemical formula 6 to a bromide reaction;

(iv) a step of obtaining a compound of chemical formula 8 by subjecting the bromide of the compound of chemical formula 7 below to a substitution reaction with a dimethylamine salt;

(v) a step of reducing the nitro group of the compound of the following chemical formula 8 and reacting it with HBr to obtain an HBr salt of the compound of the following chemical formula 9;

(vi) a step of reacting the HBr salt of the compound of the following chemical formula 9 in the presence of a carbonylating agent and methoxy ammonium chloride and a base to obtain a compound of the following chemical formula 10;

(vii) a step of subjecting a compound of chemical formula 10 below to an ester hydrolysis reaction to obtain a compound of chemical formula 11 below;

(viii) a step of subjecting a compound of the following chemical formula 11 to a dehydration condensation reaction with a compound of the following chemical formula 12 in the presence of a coupling agent and a base to obtain a compound of the following chemical formula 13; and

(ix) A step of subjecting a compound of the following chemical formula 13 to an ester hydrolysis reaction in the presence of a base, followed by a cyclization reaction is included.

[Chemical Formula 1]

[Chemical formula 2]

[Chemical Formula 3]

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical formula 6]

[Chemical formula 7]

[Chemical formula 8]

[Chemical formula 9]

[Chemical Formula 10]

[Chemical Formula 11]

[Chemical Formula 12]

[Chemical Formula 13]

In the above formula,

R ¹ is a halogen atom or a hydrogen atom,

R ² is a halogen atom, a tosylate group, a mesylate group, or a nitrobenzenesulfonate group.

Hereinafter, the manufacturing method of the present invention will be described in more detail with reference to the following reaction scheme 2. The method described in the following reaction scheme 2 is merely an example of a representatively used method, and the reaction reagents, reaction conditions, etc. may be changed at any time depending on the case.

[Reaction Formula 2]

Step 1: Preparation of compound of chemical formula 4

The compound of chemical formula 4 can be prepared by an amide bond reaction of the compound of chemical formula 2 with the compound of chemical formula 3.

Examples of the compound of the above chemical formula 3 include methyl haloformate or methyl hydrogen carbonate.

As the above methyl haloformate, methyl chloroformate, methyl bromoformate, methyl iodoformate, methyl fluoroformate, etc. can be used, and methyl chloroformate is particularly preferred.

The compound of the above chemical formula 3 can be used in an amount of 1 to 4 moles, preferably 2 to 3 moles, per 1 mole of the compound of the above chemical formula 2.

The above amide bond reaction can be performed with or without a base.

The above base is not particularly limited, and any known base can be used.

The above amide coupling reaction can be performed in the presence or absence of a coupling reagent.

Toluene, hexane, heptane, pentane, benzene, cyclohexane, diethyl ether, etc. can be used as the reaction solvent, and toluene is particularly preferred.

The reaction temperature can be about 0 to 200°C, preferably 90 to 110°C.

The reaction time can be from 1 to 24 hours, preferably from 1 to 4 hours.

Step 2: Preparation of compound of chemical formula 6

The compound of chemical formula 6 can be prepared by alkylating the compound of chemical formula 4 with the compound of chemical formula 5.

Examples of compounds of the above chemical formula 5 that can be used include 2-(chloromethyl)-1,3-difluorobenzene, 2-(bromomethyl)-1,3-difluorobenzene, 2-(iodomethyl)-1,3-difluorobenzene, 2,6-difluorobenzyl 4-methylbenzenesulfonic acid, 2,6-difluorobenzyl methanesulfonic acid, and 2,6-difluorobenzyl 4-nitrobenzenesulfonic acid.

The above alkylation reaction can be carried out in the presence or absence of a base.

The above base is not particularly limited, and any known base can be used.

For example, the base may include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, etc., and these may be used alone or in combination of two or more. In particular, the base may be potassium carbonate.

The above alkylation reaction can be carried out with or without a catalyst.

Examples of the catalyst that can be used include potassium iodide, sodium iodide, cesium iodide, etc., and these can be used alone or in combination of two or more. In particular, the catalyst can be potassium iodide.

The reaction is carried out in the presence of a solvent. There is no particular limitation on the type of reaction solvent as long as the reaction proceeds.

For example, DMF, DMC, NMP, DMSO, THF, etc. can be used as the reaction solvent, and DMF can be preferably used.

The reaction temperature may be 0 to 100°C, preferably 20 to 30°C.

The reaction time is generally 1 to 48 hours, preferably 18 to 24 hours.

Step 3: Preparation of compound of chemical formula 7

The compound of chemical formula 7 can be prepared by bromiding the compound of chemical formula 6.

The above bromide reaction can be performed using a bromide reagent.

As the above bromide reagent, for example, N-bromosuccinimide (NBS) can be used.

The above bromide reagent can be used in an amount of 1 to 5 moles per 1 mole of the compound of chemical formula 6.

Preferably, the bromide reaction can be performed in the presence of a catalytic amount of a radical generating reagent.

As the radical generating reagent, for example, azobisisobutyronitrile (AIBN) can be used.

The above radical generating reagent can be used in an amount of 0.1 to 0.3 mol per 1 mol of the compound of chemical formula 6.

As the above reaction solvent, ethyl acetate, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, a mixed solvent of ethyl acetate and acetonitrile, etc. can be used. At this time, ethyl acetate (EA): acetonitrile (ACN) can be 8:1 by volume.

The reaction temperature may be from 0°C to reflux temperature, and preferably from 70 to 80°C.

Response times can range from 3 to 48 hours.

Step 4: Preparation of compound of chemical formula 8

The compound of chemical formula 8 can be prepared by a substitution reaction of the bromide of the compound of chemical formula 7 with a dimethylamine salt.

The above substitution reaction may be an SN2 substitution reaction.

The above dimethylamine salt may be at least one of dimethylamine hydrogen chloride, dimethylamine hydrogen bromide and dimethylamine hydrogen iodide, and preferably dimethylamine hydrogen chloride.

The above dimethylamine salt can be used in an amount of 2 to 8 moles per 1 mole of the compound of chemical formula 7.

The above substitution reaction can be carried out in the presence or absence of a base.

The above base may be an organic base or an inorganic base.

Examples of the organic bases include triethylamine, tributylamine, diisopropylethylamine, pyridine, etc., and these may be used alone or in combination of two or more.

Examples of the above inorganic base include alkali metal carbonates such as cesium carbonate, potassium carbonate, and sodium carbonate; or alkali metal hydrides such as sodium hydride and potassium hydride. These may be used alone or in combination of two or more.

In particular, it is preferable to use triethylamine as the base.

The above base can be used in an amount of 4 to 10 moles per 1 mole of the compound of chemical formula 7.

Dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, chloroform, etc. can be used as reaction solvents.

The reaction temperature may be -10°C to reflux temperature, and preferably 0 to room temperature.

Reaction times can range from 10 minutes to 30 hours.

Step 5: Preparation of the compound of chemical formula 9 and its HBr salt

The compound of chemical formula 9 can be prepared by reducing the nitro group of the compound of chemical formula 8.

The above reduction reaction can be performed using a metal as a reducing agent in the presence of an acid.

The metal used may be iron (Fe), tin (Sn), zinc (Zn), copper (Cu), or nickel (Ni), and iron (Fe) is preferred.

The above metal can be used in an amount of 1 to 5 moles, preferably 2 to 3 moles, per 1 mole of the compound of chemical formula 8.

The above acid can be hydrochloric acid, sulfuric acid, acetic acid, formic acid, phosphoric acid, nitric acid, etc., and hydrochloric acid is preferably used.

Water, methanol, ethanol, acetic acid, dioxane, toluene, hydrochloric acid, etc. can be used as a reaction solvent, and water is preferred.

The reaction temperature may be 0°C to reflux temperature, and preferably room temperature.

The reaction time can generally be from 1 to 120 hours, preferably from 6 to 14 hours.

The HBr salt of the compound of formula 9 can be prepared by reacting the compound of formula 9 with HBr.

The HBr salt of the compound of the above chemical formula 9 may be a 2HBr salt of the compound of the above chemical formula 9.

The 2HBr salt of the compound of the above chemical formula 9 may be in a crystal form.

Although the compound of chemical formula 9 has a sticky characteristic, the 2HBr salt of the compound of chemical formula 9 is in a crystalline form, so it has excellent handleability during the process and its purity is also high, which is also advantageous in terms of the purity and yield of relugolix manufactured using it.

Step 6: Preparation of compound of chemical formula 10

The compound of formula 10 can be prepared by reacting the compound of formula 9 or its HBr salt in the presence of a carbonylating agent and methoxy ammonium chloride and a base.

The above carbonylating agent may be carbonyldiimidazole (CDI).

The above carbonylating agent can be used in an amount of 1 to 2 moles per mole of the compound of chemical formula 9 or its HBr salt.

The above methoxy ammonium chloride can be used in an amount of 1 to 2 moles per mole of the compound of chemical formula 9 or its HBr salt.

As the above base, triethylamine, diisopropylethylamine, tributylamine, pyridine, etc. can be used, and these can be used alone or in combination of two or more. In particular, the base can be triethylamine.

The above base can be used in an amount of 1 to 5 moles, preferably 1 to 2 moles, per 1 mole of the compound of chemical formula 9 or its HBr salt.

Dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, etc. can be used as reaction solvents.

The reaction temperature may be 0°C to reflux temperature, and preferably room temperature.

The reaction time can be from 10 minutes to 24 hours, preferably from 10 to 16 hours.

Step 7: Preparation of compound of chemical formula 11

The compound of chemical formula 11 can be prepared by ester hydrolysis reaction of the compound of chemical formula 10.

The above ester hydrolysis reaction can be performed in the presence of a base.

As the above base, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. can be used, and these can be used alone or in combination of two or more. In particular, the base can be potassium hydroxide.

The above base can be used in an amount of 2 to 10 moles, preferably 5 to 6 moles, per 1 mole of the compound of chemical formula 10.

As the reaction solvent, methanol, ethanol, isopropanol, acetonitrile, N,N-dimethylformamide, water, a mixed solvent of methanol and water, or a mixed solvent of ethanol and water can be used, and preferably, a mixed solvent of ethanol and water can be used.

The reaction temperature may be 0°C to reflux temperature, and preferably room temperature.

The reaction time can be from 30 minutes to 36 hours, preferably from 12 to 24 hours.

Step 8: Preparation of compound of chemical formula 13

The compound of chemical formula 13 can be prepared by a dehydration condensation reaction of the compound of chemical formula 11 with the compound of chemical formula 12 in the presence of a coupling agent and a base.

The coupling agent includes propanephosphonic acid anhydride (T3P), 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxide (T4P), hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. At least one selected from the group consisting of hydrochloride (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, EDC·HCl) can be used, and preferably T4P can be used.

The above base is not particularly limited, and any known base can be used.

For example, the base may be pyridine, lutidine, triethylamine, N,N-diisopropylethylamine (DIPEA), t-butylamine, etc. These may be used alone or in combination of two or more. In particular, the base may be N,N-diisopropylethylamine (DIPEA).

The compound of the above chemical formula 12 can be used in an amount of 1 to 2 moles per 1 mole of the compound of the above chemical formula 11.

The above coupling agent and base can be used in amounts of 1 to 3 mol and 1 to 5 mol, respectively, per 1 mol of the compound of chemical formula 11.

The type of reaction solvent is not particularly limited as long as the reaction proceeds.

For example, the reaction solvents include dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, and the like.

The reaction temperature may be from 0°C to reflux temperature, and preferably from 0°C to room temperature.

Reaction times can range from 10 minutes to 36 hours.

Step 9: Preparation of relugolix of chemical formula 1

The compound of chemical formula 1 can be prepared by subjecting the compound of chemical formula 13 to an ester hydrolysis reaction in the presence of a base, followed by a cyclization reaction.

The above base may be an organic base or an inorganic base.

Examples of the organic bases include sodium methoxide, sodium ethoxide, potassium t-butoxide, etc. These may be used alone or in combination of two or more.

Examples of the above inorganic base include alkali metal carbonates such as cesium carbonate, potassium carbonate, and sodium carbonate; or alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide. These may be used alone or in combination of two or more.

In particular, it is preferable to use sodium methoxide as the base.

Methanol, ethanol, acetonitrile, tetrahydrofuran, water, etc. can be used as reaction solvents.

The reaction temperature may be from 0°C to reflux temperature, and preferably from 20°C to 30°C.

Response times can range from 30 minutes to 24 hours.

The compound of the above chemical formula 1 may be in crystalline form.

One embodiment of the present invention relates to a method for producing an HBr salt of the compound of the above chemical formula 9, and the production method according to one embodiment of the present invention is

(i) a step of obtaining a compound of the following chemical formula 4 by subjecting a compound of the following chemical formula 2 to an amide bond reaction with a compound of the following chemical formula 3;

(ii) a step of subjecting a compound of chemical formula 4 below to an alkylation reaction with a compound of chemical formula 5 below to obtain a compound of chemical formula 6 below;

(iii) a step of obtaining a compound of chemical formula 7 by subjecting a compound of chemical formula 6 to a bromide reaction;

(iv) a step of obtaining a compound of the following chemical formula 8 by substitution reaction of the bromide of the compound of the following chemical formula 7 with a dimethylamine salt; and

(v) a step of reducing the nitro group of the compound of the following chemical formula 8 and reacting it with HBr.

[Chemical formula 2]

[Chemical Formula 3]

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical formula 6]

[Chemical formula 7]

[Chemical formula 8]

[Chemical formula 9]

The above steps (i) to (v) are the same as steps (i) to (v) described in the method for manufacturing relugolix of the above chemical formula 1, and thus a detailed description is omitted.

One embodiment of the present invention relates to an HBr salt of a compound of the following chemical formula 9, which is an intermediate for producing relugolix.

[Chemical formula 9]

The HBr salt of the compound of the above chemical formula 9 is the same as that described in the method for preparing relugolix of the above chemical formula 1.

According to the manufacturing method of the present invention, high-purity relugolix can be manufactured economically with a high yield.

Figure 1 is an X-ray powder diffraction diagram of the 2HBr salt of the compound of chemical formula 9.

Figure 2 is an X-ray powder diffraction diagram of the compound of chemical formula 1.

Hereinafter, the present invention will be described more specifically by examples. It will be apparent to those skilled in the art that these examples are only for the purpose of explaining the present invention and that the scope of the present invention is not limited to these examples.

Example 1: Preparation of a compound of chemical formula 4

Methyl chloroformate (124 g) as a compound of formula 3 was added dropwise to a solution of the compound of formula 2 (200 g) in toluene (600 mL) at 90 to 100°C, and the reaction mixture was stirred until less than 1% of the compound of formula 2 remained (HPLC). The reaction mixture was cooled to 60 to 70°C, and ethanol was added dropwise (1800 mL). The reaction mixture was cooled to 0 to 10°C and stirred at that temperature for 1 hour. The reaction mixture was filtered, and the cake was washed with 1000 mL of ethanol. The washed reaction product was dried under vacuum to obtain 232.5 g of the compound of formula 4 (yield: 97.8%, purity: 96.87%).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.46 (t, J = 7.1 Hz, 3H), 2.46 (s, 3H), 3.91 (s, 3H), 4.43 (q, J = 7.1 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 8.31 (d, J = 8.8 Hz, 2H), 10.73 (s, 1H).

Example 2: Preparation of compound of chemical formula 6

To a solution of the compound of formula 4 (55.4 g) in DMF (277-388 mL) were added 2-(chloromethyl)-1,3-difluorobenzene (27.2 g), KI (27.76 g), and K ₂ CO ₃ (25.22 g) as the compound of formula 5, and the reaction mixture was stirred at 20-30 °C for 20-22 hours. Ethyl acetate (EtOAc, 443 mL) and water (554 mL) were added, and the layers were separated. The aqueous layer was further extracted with ethyl acetate (443 mL). The organic extracts were combined, washed with water (443 mL × 2), and the organic layer was concentrated under vacuum to 166 mL. It was then cooled to 20-30 °C. Heptane (166 mL) was added at 20-30 °C and stirred for 1 hour. The reaction mixture was filtered, and the solid was washed with 110 mL of heptane/ethyl acetate (1:1, v/v). The solid was collected and dried under vacuum to obtain 63 g of the compound of formula 6 (yield: 85%, purity: 99.88%).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.47 (t, J = 7.6 Hz, 3H), 2.46 (s, 3H), 3.76 (s, 3H), 4.30 (q, J = 7.6 Hz, 2H), 5.02 (s, 2H), 6.87-6.93 (m, 2H), 7.29-7.33 (m, 1H), 7.56 (d, J = 8.8 Hz, 2H), 8.30 (d, J = 8.8 Hz, 2H).

Example 3: Preparation of a compound of chemical formula 7

N-bromosuccinimide (NBS, 108.2 g) and azobisisobutyronitrile (AIBN, 6.66 g) were added to a solution of the compound of chemical formula 6 (198.8 g) in ethyl acetate (1600 mL) and acetonitrile (200 mL), and the reaction mixture was heated to 70 to 75°C and stirred for 5 hours. 5% hydrochloric acid (aqueous solution, 600 mL), 5% sodium carbonate (aqueous solution, 600 mL), and water (600 mL) were added to the reaction mixture, and the layers were separated. The obtained organic layer was used in the subsequent step without a separate separation and purification process.

Example 4: Preparation of a compound of chemical formula 8

Triethylamine (120 g) was added to a solution of dimethylamine hydrogen chloride (132 g) in acetonitrile (MeCN, 660 mL), and the reaction mixture was cooled to 0 to 5°C. The organic layer obtained in Example 3 was added dropwise to the reaction mixture at 0 to 5°C, and the mixture was stirred for 14 hours. The reaction mixture was filtered and concentrated under vacuum. MTBE (1320 mL) was added to the concentrated organic residue, and water (1320 mL) was further added, and the mixture was stirred for 10 minutes. The organic layer was separated, and 2 M HCl (aqueous solution, 260 mL) was added to the organic layer, and the layers were separated. NaHCO ₃ (9%, aqueous solution, 1320 mL) was added to the aqueous layer, and then ethyl acetate (1320 mL) was added, and the mixture was stirred for 10 minutes. The layers were separated, and the organic layer was dried under vacuum to obtain 202.84 g of the compound of chemical formula 8. (Yield: 93.8%, purity: 95.92%).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 8.29 - 8.19 (m, 2H), 7.69 - 7.61 (m, 2H), 7.32 - 7.19 (m, 1H), 6.92 - 6.80 (m, 2H), 5.09 - 4.95 (m, 2H), 5.03 (s, 2H), 4.24 (q, J = 5.6 Hz, 2H), 3.81 (s, 3H), 3.71 (brs, 3H), 3.50 (s, 2H), 2.03 (s, 6H), 1.31 (t, J = 5.6 Hz, 3H).

Example 5: Preparation of a compound of chemical formula 9 and its 2HBr salt

To the compound of chemical formula 8 (230.06 g) was added 4 M hydrochloric acid (HCl aqueous solution, 1380 mL) and stirred for 10 minutes. Iron (Fe, 3.4 eq.) was added and stirred for 12 hours. 4 M NaOH (aqueous solution, 1750 mL) was added to the reaction mixture to adjust the pH to 8–9, the reaction mixture was filtered through Celite, and the Celite was washed with ethyl acetate (460 mL). Ethyl acetate (1150 mL) was added to the filtrate, the layers were separated, and the organic layer was dried under vacuum to obtain 190.0 g of the compound of chemical formula 9 (yield: 87.5%, purity: 96.61%).

To the compound of chemical formula 9 (190.0 g) was added ethyl acetate (1900 mL), followed by adding HBr solution (48% aqueous solution, 2.5 eq.) and stirring for 10 minutes. Then, isopropyl alcohol (950 mL) was added and stirred for 7 hours, and the reaction mixture was cooled to 0°C and stirred for 1 hour. The reaction mixture was filtered, and the solid was washed with isopropyl alcohol (570 mL) and dried under vacuum to obtain 249.4 g of the 2HBr salt of the compound of chemical formula 9 (yield: 96.2%, purity: 99.345%).

¹ H NMR (400 MHz, DMSO, d ₆ ) δ ppm: 7.49 - 7.37 (m, 1H), 7.07 (t, J = 8.0 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 5.40 (s, 2H), 4.92 (s, 2H), 4.13 (q, J = 7.2 Hz, 2H), 3.61 (s, 3H), 3.39 (s, 2H), 1.94 (s, 6H), 1.23 (t, J = 7.2 Hz 3H).

X-ray powder diffraction analysis of the 2HBr salt of the compound of the above chemical formula 9 was performed, and the results are shown in Table 1 and Figure 1 below.

The characteristic peaks that appear in the X-ray powder diffraction diagram of Fig. 1 are shown in Table 1 below, where '2θ' represents the diffraction angle and 'I/I ₀ ' represents the relative intensity of the peak. The diffraction angle has a deviation range of ±0.2°.

Through the above X-ray powder diffraction analysis, it was confirmed that the 2HBr salt of the compound of chemical formula 9 obtained above was in crystalline form.

Diffraction angle (2θ) I/I _o (%) 1 8.3 10.7 2 8.9 29.1 3 9.1 22.9 4 10.8 72.6 5 11.7 16.4 6 12.1 83.1 7 12.8 52.2 8 13.7 6.2 9 14.2 31.0 10 14.9 13.0 11 15.3 38.8 12 16.5 16.1 13 17.0 18.6 14 17.8 70.7 15 17.9 38.6 16 19.1 82.5 17 19.5 99.8 18 20.4 34.1 19 20.7 19.3 20 21.3 72.5 21 21.5 40.5 22 21.8 8.1 23 22.3 16.5 24 23.3 51.6 25 24.0 24.7 26 24.4 100 27 25.1 19.8 28 25.5 21.4 29 25.7 21.2 30 26.5 91.2 31 17.2 33.3 32 27.5 30.5 33 28.9 13.4 34 29.6 20.2 35 30.3 27.5 36 30.8 13.3 37 31.5 15.7 38 32.2 12.9 39 33.3 25.2 40 33.4 14.7 41 35.3 10.7 42 37.3 12.1 43 37.7 18.2 44 38.5 15.1

Example 6: Preparation of a compound of chemical formula 10

To a solution of methoxy ammonium chloride (MOAc) (1.5 eq.) in dichloromethane (DCM, 180 mL) was added triethylamine (Et ₃ N, 1.5 eq.), the mixture was filled with nitrogen at 20 to 30 °C, carbodiimide (CDI, 1.4 eq.) was added, and the reaction mixture was stirred at 20 to 30 °C for 2 hours. Then, 2HBr salt (45.2 g) of the compound of formula 9 was added and stirred for 7 hours. Water (226 mL) was added to the reaction mixture, and the layers were separated, and the organic layer was washed again with water (226 mL). The organic layer was set aside, the aqueous layers were combined, and extracted with dichloromethane (DCM, 226 mL). After combining the organic extracts, concentration was performed to obtain 37.6 g of the compound of chemical formula 10 (yield: 96%, purity: 98.813%).

¹ H NMR (400 MHz, CD ₃ Cl) δ ppm: 7.61 (s, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.25 - 7.21 (m, 1H), 6.96 - 6.72 (m, 2H), 5.02 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 4.12 (p, J = 7.0 Hz, 1H), 3.81 (s, 4H), 3.72 (dd, J = 31.4, 11.2 Hz, 3H), 3.50 (s, 2H), 2.04 (d, J = 9.6 Hz, 7H), 1.65 (s, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 1H).

Example 7: Preparation of a compound of chemical formula 11

Potassium hydroxide (KOH, 30.22 g) was added to a solution of 56 g of the compound of chemical formula 10 in water (H ₂ O, 170 mL) and ethanol (EtOH, 170 mL), and the reaction mixture was heated to 10 to 20 °C and stirred for 17 hours. The reaction mixture was concentrated in vacuo to remove ethanol, water was added, and then extracted with isopropyl acetate (IPAc, × 3). After separating the layers, the pH of the aqueous layer was adjusted to 5 to 6 using 1 N hydrochloric acid. The aqueous layer was extracted with dichloromethane (DCM, 448 mL × 3), the organic extracts were combined, and then water (280 mL) was added to precipitate the desired compound of chemical formula 11. The entire mixture was filtered, and the solid was dried to obtain 33.9 g of the compound of chemical formula 11 (yield: 63%, purity: 93.80%).

¹ H NMR (400 MHz, DMSO, d ₆ ) δ ppm: 9.90 (s, 1H), 9.36 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.45 - 7.37 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.08 - 7.02 (m, 2H), 4.94 (brs, 2H), 3.90 (s, 2H), 3.90 (s, 2H), 3.65 (d, J = 13.1 Hz, 3H), 3.64 (s, 3H), 3.58 (s, 3H), 2.41 (s, 6H).

Example 8: Preparation of compound of chemical formula 13

N,N-diisopropylethylamine (DIPEA, 3 eq.) and the compound of formula 12 (1.5 eq.) were added to a solution of 33.9 g of the compound of formula 11 in N,N-dimethylacetamide (DMAc, 100 mL), and the reaction mixture was heated to 40 to 50 °C. Then, a 50% T4P solution (EtOAc, 2 eq.) was slowly added at the same temperature, and the mixture was stirred for 3 hours. To adjust the pH of the reaction mixture to 8 to 9, a 10% aqueous potassium carbonate (K ₂ CO ₃ ) solution was added, and the mixture was extracted twice with ethyl acetate (EtOAc). After separating the layers, the combined organic extracts were washed twice with water, and the organic layer was concentrated to 200 mL. After filtering the concentrated mixture, the solid was dried under vacuum to obtain 32.3 g of the compound of chemical formula 13 (yield: 79.7%, purity: 92.98%).

^1H NMR (400 MHz, DMSO, d ₆ ) δ ppm: 13.97 (s, 1H), 9.66 (s, 1H), 9.11 (s, 1H), 8.36 (d, J = 8 Hz, 2H), 7.72 (d, J = 8 Hz, 2H), 7.28 (d, J = 8) Hz, 4H), 7.21 (d, J = 8 Hz, 4H), 6.96 - 6.97 (t, J = 6 Hz, 2H), 4.87 (s,2H), 4.09 (s,3H), 3.64 (s, 4H), 3.53 (s, 2H), 2.11 (s, 6H).

Example 9: Preparation of the compound of chemical formula 1

To a solution of 32.3 g of the compound of chemical formula 13 in methanol (MeOH, 130 mL) was added a 30% sodium methoxide (MeONa) methanol solution (1.5 eq.), and the reaction mixture was stirred at 20 to 30°C for 2 hours. 2 M hydrochloric acid (HCl) in ethyl acetate (EtOAc) was added to the reaction mixture to adjust the pH to 3 to 4. Then, a 10% potassium carbonate (K ₂ CO ₃ ) aqueous solution was added to adjust the pH to 8 to 9. The reaction mixture was concentrated to remove the organic solvent, and dichloromethane (DCM, 160 mL) was added to the aqueous residue. Then, the organic layer was separated. The organic layer was washed twice with water (160 mL), and the combined organic extracts were concentrated. Ethyl acetate (EtOAc, 33 mL) was added to the organic concentrate, and the mixture was stirred at 15 to 25°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated and purified by chromatography to obtain 19.9 g of the compound of chemical formula 1 (yield: 64.8%, purity: 98.95%).

¹ H NMR (400 MHz, DMSO, d ₆ ) δ ppm: 2.06 (s, 6H), 3.54 (s, 1H), 3.65 (s, 4H), 4.11 (s, 3H), 5.30 (dd, J ₁ = 36 Hz, J ₂ = 16 Hz 2H), 7.13 - 7.19 (m, 2H), 7.45 - 7.51 (m, 2H), 7.54 (d, J = 8 Hz, 2H), 7.74 (d, J = 8 Hz, 2H), 7.77 (d, J = 8 Hz, 2H), 9.10 (s, 1H), 9.65 (s, 1H).

¹³ C NMR (400 MHz, DMSO, d ₆ ) δ: 41.34, 44.94, 53.21, 55.41, 64.43, 110.73, 110.91, 111.08, 112.25, 112.49, 115.08, 120.00, 125.96, 130.39, 131.57, 132.12, 132.32, 133.13, 140.10, 149.87, 150.54, 153.16, 157.36, 158.31, 160.22, 160.29, 162.70, 162.77, 165.42.

X-ray powder diffraction analysis of the compound of the above chemical formula 1 was performed, and the results are shown in Table 2 and Figure 2 below.

The characteristic peaks that appeared in the X-ray powder diffraction diagram of Fig. 2 are shown in Table 2 below, where '2θ' represents the diffraction angle and 'I/I ₀ ' represents the relative intensity of the peak. The diffraction angle has a deviation range of ±0.2°.

Through the above X-ray powder diffraction analysis, it was confirmed that the obtained compound of chemical formula 1 was in crystalline form.

Diffraction angle (2θ) Relative Strength [%] 1 7.5 3.7 2 9.0 55.9 3 10.1 34.4 4 10.3 7.4 5 11.5 15.6 6 12.2 41.0 7 12.5 8.9 8 13.3 10.9 9 13.5 4.0 10 15.0 16.1 11 15.9 2.0 12 16.7 100 13 17.5 59.1 14 18.2 8.2 15 18.9 15.6 16 19.5 18.5 17 20.2 11.9 18 20.8 1.7 19 21.5 9.6 20 22.1 23.4 21 22.4 44.8 22 22.9 43.1 23 23.1 18.5 24 23.7 13.6 25 24.5 8.5 26 25.1 3.6 27 25.4 2.7 28 25.8 2.3 29 26.4 4.6 30 26.8 13.0 31 27.6 23.0 32 28.0 3.7 33 28.4 3.1 34 29.1 16.9 35 29.8 12.3 36 30.4 2.6 37 31.2 2.4 38 31.5 2.0 39 33.0 6.7 40 34.2 5.8 41 34.9 5.3 42 35.4 2.3 43 35.6 15.0 44 36.7 2.3 45 37.5 2.2 46 38.2 2.4 47 38.5 1.1

Example 10: Purification of the compound of formula 1

The compound of chemical formula 1 obtained in the above Example 9 was placed in a container, 40 mL of dimethyl sulfoxide (DMSO) was added, and stirred at 40°C to completely dissolve. Then, activated carbon (×0.05) was added, and the mixture was stirred at the same temperature for an additional 30 minutes, and then the activated carbon was removed through filtration. The filtered solution was cooled to 35°C, and the seed compound of Form I (crystalline form prepared in Example 8 of U.S. Patent No. 10,464,945) was added, the temperature was raised to 50°C, and stirred for 2 hours. Thereafter, the temperature was lowered to 35°C again, reheated to 50°C, and 40 mL of ethanol was added. The mixture was cooled to 40°C, the seed compound of Form I was added, and cooled again to 35°C. The mixture was then stirred for 1 hour, the temperature was lowered to 20°C, and stirred for another hour. Finally, the mixture was filtered, washed with 40 mL of ethanol, and dried using a vacuum dryer at 50°C to obtain 16.0 g of the compound of chemical formula 1 (yield: 80%, purity: 99.86%).

Claims (18)

(i) a step of obtaining a compound of the following chemical formula 4 by subjecting a compound of the following chemical formula 2 to an amide bond reaction with a compound of the following chemical formula 3; (ii) a step of subjecting a compound of chemical formula 4 below to an alkylation reaction with a compound of chemical formula 5 below to obtain a compound of chemical formula 6 below; (iii) a step of obtaining a compound of chemical formula 7 by subjecting a compound of chemical formula 6 to a bromide reaction; (iv) a step of obtaining a compound of chemical formula 8 by subjecting the bromide of the compound of chemical formula 7 below to a substitution reaction with a dimethylamine salt; (v) a step of reducing the nitro group of the compound of the following chemical formula 8 and reacting it with HBr to obtain an HBr salt of the compound of the following chemical formula 9; (vi) a step of reacting the HBr salt of the compound of the following chemical formula 9 in the presence of a carbonylating agent and methoxy ammonium chloride and a base to obtain a compound of the following chemical formula 10; (vii) a step of subjecting a compound of chemical formula 10 below to an ester hydrolysis reaction to obtain a compound of chemical formula 11 below; (viii) a step of subjecting a compound of the following chemical formula 11 to a dehydration condensation reaction with a compound of the following chemical formula 12 in the presence of a coupling agent and a base to obtain a compound of the following chemical formula 13; and (ix) A method for producing relugolix of the following chemical formula 1, comprising the step of subjecting a compound of the following chemical formula 13 to an ester hydrolysis reaction in the presence of a base, followed by a cyclization reaction: [Chemical formula 2]

[Chemical Formula 3]

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical formula 6]

[Chemical formula 7]

[Chemical formula 8]

[Chemical formula 9]

[Chemical Formula 10]

[Chemical Formula 11]

[Chemical Formula 12]

[Chemical Formula 13]

[Chemical Formula 1]

In the above formula, R ¹ is a halogen atom or a hydrogen atom, R ² is a halogen atom, a tosylate group, a mesylate group, or a nitrobenzenesulfonate group. A manufacturing method in claim 1, wherein the alkylation reaction in step (ii) is performed in the presence of a base and a catalyst. A manufacturing method in claim 2, wherein the base is potassium carbonate and the catalyst is potassium iodide. A manufacturing method in which, in step (iii), the bromide reaction is performed in the presence of a radical generating reagent using a bromide reagent. A manufacturing method in claim 4, wherein the bromide reagent is N-bromosuccinimide and the radical generating reagent is azobisisobutyronitrile. A manufacturing method in claim 1, wherein in step (iv), the dimethylamine salt is at least one of dimethylamine hydrogen chloride, dimethylamine hydrogen bromide and dimethylamine hydrogen iodide. A manufacturing method in claim 1, wherein the substitution reaction in step (iv) is performed in the presence of a base. A manufacturing method in claim 7, wherein the base is triethylamine. A manufacturing method in claim 1, wherein in step (v), the reduction reaction is performed using a metal as a reducing agent in the presence of an acid. A manufacturing method in claim 1, wherein the carbonylating agent in step (vi) is carbonyldiimidazole (CDI). A manufacturing method in claim 1, wherein in step (vi), the base is triethylamine. A manufacturing method in claim 1, wherein the ester hydrolysis reaction in step (vii) is performed in the presence of a base. A manufacturing method in claim 12, wherein the base is potassium hydroxide. A manufacturing method in claim 1, wherein in step (viii), the coupling agent is 1,3,5,2,4,6-Trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxide (T4P). A manufacturing method in claim 1, wherein in step (viii), the base is N,N-diisopropylethylamine (DIPEA). A manufacturing method in claim 1, wherein in step (ix), the base is sodium methoxide. (i) a step of obtaining a compound of the following chemical formula 4 by subjecting a compound of the following chemical formula 2 to an amide bond reaction with a compound of the following chemical formula 3; (ii) a step of subjecting a compound of chemical formula 4 below to an alkylation reaction with a compound of chemical formula 5 below to obtain a compound of chemical formula 6 below; (iii) a step of obtaining a compound of chemical formula 7 by subjecting a compound of chemical formula 6 to a bromide reaction; (iv) a step of obtaining a compound of the following chemical formula 8 by substitution reaction of the bromide of the compound of the following chemical formula 7 with a dimethylamine salt; and (v) A method for producing an HBr salt of a compound of the following chemical formula 9, comprising the step of reducing a nitro group of a compound of the following chemical formula 8 and reacting it with HBr: [Chemical formula 2]

[Chemical Formula 3]

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical formula 6]

[Chemical formula 7]

[Chemical formula 8]

[Chemical formula 9]

In the above formula, R ¹ is a halogen atom or a hydrogen atom, R ² is a halogen atom, a tosylate group, a mesylate group, or a nitrobenzenesulfonate group. HBr salt of the compound of formula 9 below: [Chemical formula 9]

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