Method for preparing relugolix

Abstract

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

Description

Method of manufacturing relugolix

[0001] The present invention relates to a method for manufacturing relugolix, and more particularly, to a method for manufacturing high-purity relugolix economically with a high yield.

[0002] 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 Orgovyx, a prostate cancer treatment drug. ® ) is the active pharmaceutical ingredient (API).

[0003] [Chemical Formula 1]

[0004]

[0005] 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.

[0006] [Reaction Formula 1]

[0007]

[0008] One object of the present invention is to provide a method for economically producing high-purity relugolix with high yield.

[0009] 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:

[0010] (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;

[0011] (ii) a step of subjecting a compound of the following chemical formula 4 to an alkylation reaction with a compound of the following chemical formula 5 to obtain a compound of the following chemical formula 6;

[0012] (iii) a step of obtaining a compound of the following chemical formula 7 by subjecting the compound of the following chemical formula 6 to a bromide reaction;

[0013] (iv) a step of obtaining a compound of the following chemical formula 8 by subjecting the bromide of the compound of the following chemical formula 7 to a substitution reaction with a dimethylamine salt;

[0014] (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;

[0015] (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;

[0016] (vii) a step of subjecting a compound of the following chemical formula 10 to an ester hydrolysis reaction to obtain a compound of the following chemical formula 11;

[0017] (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

[0018] (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.

[0019] [Chemical Formula 1]

[0020]

[0021] [Chemical Formula 2]

[0022]

[0023] [Chemical Formula 3]

[0024]

[0025] [Chemical Formula 4]

[0026]

[0027] [Chemical Formula 5]

[0028]

[0029] [Chemical Formula 6]

[0030]

[0031] [Chemical Formula 7]

[0032]

[0033] [Chemical Formula 8]

[0034]

[0035] [Chemical Formula 9]

[0036]

[0037] [Chemical Formula 10]

[0038]

[0039] [Chemical Formula 11]

[0040]

[0041] [Chemical Formula 12]

[0042]

[0043] [Chemical Formula 13]

[0044]

[0045] In the above formula,

[0046] R 1 is a halogen atom or a hydrogen atom,

[0047] R 2 is a halogen atom, a tosylate group, a mesylate group, or a nitrobenzenesulfonate group.

[0048]

[0049] 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 as needed.

[0050] [Reaction Formula 2]

[0051]

[0052]

[0053] Step 1: Preparation of the compound of chemical formula 4

[0054] 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.

[0055] Examples of the compound of the above chemical formula 3 include methyl haloformate or methyl hydrogen carbonate.

[0056] As the above methyl haloformate, methyl chloroformate, methyl bromoformate, methyl iodoformate, methyl fluoroformate, etc. can be used, and methyl chloroformate is particularly preferred.

[0057] 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 chemical formula 2.

[0058] The above amide bond reaction can be performed in the presence or absence of a base.

[0059] The above base is not particularly limited, and any known base can be used.

[0060] The above amide coupling reaction can be performed in the presence or absence of a coupling reagent.

[0061] Toluene, hexane, heptane, pentane, benzene, cyclohexane, diethyl ether, etc. can be used as the reaction solvent, and toluene is particularly preferred.

[0062] The reaction temperature may be about 0 to 200°C, preferably 90 to 110°C.

[0063] The reaction time may be from 1 to 24 hours, preferably from 1 to 4 hours.

[0064]

[0065] Step 2: Preparation of the compound of chemical formula 6

[0066] The compound of chemical formula 6 can be prepared by alkylating the compound of chemical formula 4 with the compound of chemical formula 5.

[0067] As the compound of the above chemical formula 5, 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, 2,6-difluorobenzyl 4-nitrobenzenesulfonic acid, etc. can be used.

[0068] The above alkylation reaction can be carried out in the presence or absence of a base.

[0069] The above base is not particularly limited, and any known base can be used.

[0070] 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.

[0071] The above alkylation reaction can be carried out in the presence or absence of a catalyst.

[0072] 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.

[0073] The reaction is carried out in the presence of a solvent. There are no particular restrictions on the type of reaction solvent as long as the reaction proceeds.

[0074] For example, DMF, DMC, NMP, DMSO, THF, etc. can be used as the reaction solvent, and DMF is preferably used.

[0075] The reaction temperature may be 0 to 100°C, preferably 20 to 30°C.

[0076] The reaction time is generally 1 to 48 hours, preferably 18 to 24 hours.

[0077]

[0078] Step 3: Preparation of the compound of chemical formula 7

[0079] The compound of chemical formula 7 can be prepared by bromiding the compound of chemical formula 6.

[0080] The above bromide reaction can be performed using a bromide reagent.

[0081] As the above bromide reagent, for example, N-bromosuccinimide (NBS) can be used.

[0082] The above bromide reagent can be used in an amount of 1 to 5 moles per mole of the compound of chemical formula 6.

[0083] Preferably, the bromide reaction can be performed in the presence of a catalytic amount of a radical generating reagent.

[0084] As the radical generating reagent, for example, azobisisobutyronitrile (AIBN) can be used.

[0085] The above radical generating reagent can be used in an amount of 0.1 to 0.3 moles per 1 mole of the compound of chemical formula 6.

[0086] 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.

[0087] The reaction temperature may be 0°C to reflux temperature, and preferably 70 to 80°C.

[0088] Reaction times may range from 3 to 48 hours.

[0089]

[0090] Step 4: Preparation of the compound of chemical formula 8

[0091] The compound of chemical formula 8 can be prepared by substitution reaction of the bromide of the compound of chemical formula 7 with a dimethylamine salt.

[0092] The above substitution reaction may be an SN2 substitution reaction.

[0093] 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.

[0094] 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.

[0095] The above substitution reaction can be carried out in the presence or absence of a base.

[0096] The above base may be an organic base or an inorganic base.

[0097] Examples of the organic bases include triethylamine, tributylamine, diisopropylethylamine, pyridine, etc., and these can be used alone or in combination of two or more.

[0098] 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.

[0099] In particular, it is preferable to use triethylamine as the base.

[0100] The above base can be used in an amount of 4 to 10 moles per mole of the compound of chemical formula 7.

[0101] Dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, chloroform, etc. can be used as reaction solvents.

[0102] The reaction temperature may be from -10°C to reflux temperature, and preferably from 0 to room temperature.

[0103] Reaction times can range from 10 minutes to 30 hours.

[0104]

[0105] Step 5: Preparation of the compound of chemical formula 9 and its HBr salt

[0106] The compound of chemical formula 9 can be prepared by reducing the nitro group of the compound of chemical formula 8.

[0107] The above reduction reaction can be performed using a metal as a reducing agent in the presence of an acid.

[0108] The metal used may be iron (Fe), tin (Sn), zinc (Zn), copper (Cu), or nickel (Ni), and preferably iron (Fe).

[0109] 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.

[0110] The above acid can be hydrochloric acid, sulfuric acid, acetic acid, formic acid, phosphoric acid, nitric acid, etc., and hydrochloric acid can be preferably used.

[0111] Water, methanol, ethanol, acetic acid, dioxane, toluene, hydrochloric acid, etc. can be used as a reaction solvent, and water is preferred.

[0112] The reaction temperature may be 0°C to reflux temperature, and preferably room temperature.

[0113] The reaction time may generally be from 1 to 120 hours, preferably from 6 to 14 hours.

[0114] The HBr salt of the compound of formula 9 can be prepared by reacting the compound of formula 9 with HBr.

[0115] 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.

[0116] The 2HBr salt of the compound of the above chemical formula 9 may be in a crystal form.

[0117] Although the compound of chemical formula 9 has a sticky characteristic, the 2HBr salt of the compound of chemical formula 9 is in crystalline form, so it is easy to handle during the process and has high purity, which is also advantageous in terms of purity and yield of relugolix manufactured using it.

[0118]

[0119] Step 6: Preparation of the compound of chemical formula 10

[0120] 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.

[0121] The above carbonylating agent may be carbonyldiimidazole (CDI).

[0122] 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.

[0123] 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.

[0124] The base may include triethylamine, diisopropylethylamine, tributylamine, pyridine, etc., and these may be used alone or in combination of two or more. In particular, the base may be triethylamine.

[0125] The above base can be used in an amount of 1 to 5 moles, preferably 1 to 2 moles, per mole of the compound of chemical formula 9 or its HBr salt.

[0126] Dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, etc. can be used as reaction solvents.

[0127] The reaction temperature may be 0°C to reflux temperature, and preferably room temperature.

[0128] The reaction time may be from 10 minutes to 24 hours, preferably from 10 to 16 hours.

[0129]

[0130] Step 7: Preparation of the compound of chemical formula 11

[0131] The compound of chemical formula 11 can be prepared by ester hydrolysis reaction of the compound of chemical formula 10.

[0132] The above ester hydrolysis reaction can be carried out in the presence of a base.

[0133] The base may include sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., and these may be used alone or in combination of two or more. In particular, the base may be potassium hydroxide.

[0134] 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.

[0135] 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 a mixed solvent of ethanol and water is preferably used.

[0136] The reaction temperature may be 0°C to reflux temperature, and preferably room temperature.

[0137] The reaction time may be from 30 minutes to 36 hours, preferably from 12 to 24 hours.

[0138]

[0139] Step 8: Preparation of the compound of chemical formula 13

[0140] The compound of chemical formula 13 can be prepared by 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.

[0141] The coupling agent is 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 hydrochloride. One or more selected from the group consisting of (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, EDC·HCl) can be used, and preferably T4P can be used.

[0142] The above base is not particularly limited, and any known base can be used.

[0143] For example, the base may include 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).

[0144] 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 chemical formula 11.

[0145] The above coupling agent and base can be used in amounts of 1 to 3 moles and 1 to 5 moles, respectively, per 1 mole of the compound of chemical formula 11.

[0146] The type of reaction solvent is not particularly limited as long as the reaction proceeds.

[0147] For example, the reaction solvents include dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, etc.

[0148] The reaction temperature may be from 0°C to reflux temperature, and preferably from 0°C to room temperature.

[0149] Reaction times can range from 10 minutes to 36 hours.

[0150]

[0151] Step 9: Preparation of Relugolix of Chemical Formula 1

[0152] 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.

[0153] The above base may be an organic base or an inorganic base.

[0154] Examples of the organic base include sodium methoxide, sodium ethoxide, potassium t-butoxide, etc. These may be used alone or in combination of two or more.

[0155] 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.

[0156] In particular, it is preferable to use sodium methoxide as the base.

[0157] Methanol, ethanol, acetonitrile, tetrahydrofuran, water, etc. can be used as reaction solvents.

[0158] The reaction temperature may be from 0°C to reflux temperature, and preferably from 20°C to 30°C.

[0159] Response times can range from 30 minutes to 24 hours.

[0160] The compound of the above chemical formula 1 may be in crystalline form.

[0161]

[0162] 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 method according to one embodiment of the present invention is

[0163] (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;

[0164] (ii) a step of subjecting a compound of the following chemical formula 4 to an alkylation reaction with a compound of the following chemical formula 5 to obtain a compound of the following chemical formula 6;

[0165] (iii) a step of obtaining a compound of the following chemical formula 7 by subjecting the compound of the following chemical formula 6 to a bromide reaction;

[0166] (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

[0167] (v) a step of reducing the nitro group of the compound of the following chemical formula 8 and reacting it with HBr.

[0168] [Chemical Formula 2]

[0169]

[0170] [Chemical Formula 3]

[0171]

[0172] [Chemical Formula 4]

[0173]

[0174] [Chemical Formula 5]

[0175]

[0176] [Chemical Formula 6]

[0177]

[0178] [Chemical Formula 7]

[0179]

[0180] [Chemical Formula 8]

[0181]

[0182] [Chemical Formula 9]

[0183]

[0184]

[0185] 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 thereof is omitted.

[0186]

[0187] 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.

[0188] [Chemical Formula 9]

[0189]

[0190]

[0191] 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.

[0192] According to the manufacturing method of the present invention, high-purity relugolix can be manufactured economically with high yield.

[0193] Figure 1 is an X-ray powder diffraction diagram of the 2HBr salt of the compound of chemical formula 9.

[0194] Figure 2 is an X-ray powder diffraction diagram of the compound of chemical formula 1.

[0195] Hereinafter, the present invention will be described in more detail by way of examples. These examples are provided solely to illustrate the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

[0196]

[0197] Example 1: Preparation of a compound of chemical formula 4

[0198] To a solution of the compound of formula 2 (200 g) in toluene (600 mL), methyl chloroformate (124 g) as the compound of formula 3 was added dropwise 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 (1800 mL) was added dropwise. 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%).

[0199] 1 H NMR (400 MHz, CDCl3) 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).

[0200]

[0201] Example 2: Preparation of a compound of chemical formula 6

[0202] 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 K2CO3 (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 combined organic extracts were 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%).

[0203] 1 H NMR (400 MHz, CDCl3) 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).

[0204]

[0205] Example 3: Preparation of a compound of chemical formula 7

[0206] To a solution of the compound of chemical formula 6 (198.8 g) in ethyl acetate (1600 mL) and acetonitrile (200 mL), N-bromosuccinimide (NBS, 108.2 g) and azobisisobutyronitrile (AIBN, 6.66 g) were added, 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.

[0207]

[0208] Example 4: Preparation of a compound of chemical formula 8

[0209] 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, followed by additional water (1320 mL) and 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. NaHCO3 (9%, aqueous solution, 1320 mL) was added to the aqueous layer, followed by ethyl acetate (1320 mL) and 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%).

[0210] 1H NMR (400 MHz, CDCl3) 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).

[0211]

[0212] Example 5: Preparation of a compound of chemical formula 9 and its 2HBr salt

[0213] 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, and the reaction mixture was filtered through Celite, which was then 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%).

[0214] To the compound of chemical formula 9 (190.0 g) was added ethyl acetate (1900 mL), followed by the addition of HBr solution (48% aqueous solution, 2.5 eq.) and stirring for 10 minutes. Subsequently, isopropyl alcohol (950 mL) was added and stirred for 7 hours, after which 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%).

[0215] 1 H NMR (400 MHz, DMSO,d6) 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).

[0216] 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.

[0217] The characteristic peaks appearing in the X-ray powder diffraction diagram of Fig. 1 are shown in Table 1 below, where '2θ' represents the diffraction angle and 'I / I0' represents the relative intensity of the peak. The diffraction angle has a deviation range of ±0.2°.

[0218] 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.

[0219] Diffraction angle (2θ)I / I o(%)18.310.728.929.139.122.9410.872.6511.716.4612.183.1712.852.2813.76.2914.231.01014.913.01115.338.81216.516.11317.018.61417.870.71517.938.61619.182.51719.599.81820.434.11920.719.32021.372.52121.540.52221.88.12322. 316.52423.351.62524.024.72624.41002725.119.82825.521.42925.721.23026.591.23117.233.33227.530.53328.913.43429.620.23530.327.53630.813.33731.515.73832.212.93933.325.24033.414.74135.310.74237.312.14337.718.24438.515.1

[0220]

[0221] Example 6: Preparation of a compound of chemical formula 10

[0222] To a solution of methoxy ammonium chloride (MOAc) (1.5 eq.) in dichloromethane (DCM, 180 mL) was added triethylamine (Et3N, 1.5 eq.), and carbodiimide (CDI, 1.4 eq.) was added under nitrogen at 20 to 30°C, 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 the mixture was stirred for 7 hours. Water (226 mL) was added to the reaction mixture, 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 the mixture was extracted with dichloromethane (DCM, 226 mL). After combining the organic extracts, they were concentrated to obtain 37.6 g of the compound of chemical formula 10 (yield: 96%, purity: 98.813%).

[0223] 1H NMR (400 MHz, CD3Cl) 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).

[0224]

[0225] Example 7: Preparation of a compound of chemical formula 11

[0226] Potassium hydroxide (KOH, 30.22 g) was added to a solution of 56 g of the compound of chemical formula 10 in water (H2O, 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, followed by the addition of water and extraction 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%).

[0227] 1H NMR (400 MHz, DMSO,d6) 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).

[0228]

[0229] Example 8: Preparation of a compound of chemical formula 13

[0230] To a solution of 33.9 g of the compound of formula 11 in N,N-dimethylacetamide (DMAc, 100 mL) were added N,N-diisopropylethylamine (DIPEA, 3 eq.) and the compound of formula 12 (1.5 eq.), 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 stirred for 3 hours. To adjust the pH of the reaction mixture to 8 to 9, a 10% aqueous potassium carbonate (K2CO3) 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%).

[0231] 1H NMR (400 MHz, DMSO,d6) 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).

[0232]

[0233] Example 9: Preparation of the compound of chemical formula 1

[0234] To a solution of 32.3 g of compound of 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% aqueous potassium carbonate (K2CO3) 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. 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%).

[0235] 1H NMR (400 MHz, DMSO,d6) δ ppm: 2.06 (s, 6H), 3.54 (s, 1H), 3.65 (s, 4H), 4.11 (s, 3H), 5.30 (dd,J1= 36 Hz,J2= 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).

[0236] 13 C NMR (400 MHz, DMSO,d6) 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.

[0237]

[0238] 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.

[0239] The characteristic peaks appearing in the X-ray powder diffraction diagram of Fig. 2 are shown in Table 2 below, where '2θ' represents the diffraction angle and 'I / I0' represents the relative intensity of the peak. The diffraction angle has a deviation range of ±0.2°.

[0240] Through the above X-ray powder diffraction analysis, it was confirmed that the obtained compound of chemical formula 1 was in crystalline form.

[0241] Diffraction angle (2θ) Relative intensity [%] 17.53.7 29.05 5.93 10.134.44 10.37.45 11.5 15.66 12.24 1.07 12.58.98 13.3 10.99 13.54.01 015.016.111 15.92.01 216.7100 1317.55 9.114 18.28.21 518.915.6 16 19.518.51 720.21 1.918 20.81.7 19 21.59.6 20 22.123.42 122.44 4.8 2222.94 3.123 23.118.52 423 .713.62524.58.52625.13.62725.42.72825.82.32926.44.63026.813.03127.623.03228.03.73328.43.13429.116.93529.812.33630.42.63731.22.43831.52.03933.06.74034.25.84134.95.34235.42.34335.615.04436.72.34537.52.24638.22.44738.51.1

[0242]

[0243] Example 10: Purification of the compound of chemical formula 1

[0244] The compound of formula 1 obtained in Example 9 was placed in a container, 40 mL of dimethyl sulfoxide (DMSO) was added, and the mixture was stirred at 40°C to completely dissolve. Activated carbon (×0.05) was then added, and the mixture was stirred at the same temperature for an additional 30 minutes. The activated carbon was then removed by 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, and the temperature was raised to 50°C and stirred for 2 hours. The temperature was then lowered to 35°C, 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 1 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

1. (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.

2. A manufacturing method in which the alkylation reaction in step (ii) of paragraph 1 is performed in the presence of a base and a catalyst.

3. A manufacturing method in the second paragraph, wherein the base is potassium carbonate and the catalyst is potassium iodide.

4. 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.

5. A manufacturing method in claim 4, wherein the bromide reagent is N-bromosuccinimide and the radical generating reagent is azobisisobutyronitrile.

6. A manufacturing method in the first paragraph, wherein in step (iv), the dimethylamine salt is at least one of dimethylamine hydrogen chloride, dimethylamine hydrogen bromide and dimethylamine hydrogen iodide.

7. A manufacturing method in which, in step (iv), the substitution reaction is performed in the presence of a base.

8. A manufacturing method in claim 7, wherein the base is triethylamine.

9. A manufacturing method in which, in step (v), the reduction reaction is performed using a metal as a reducing agent in the presence of an acid.

10. A manufacturing method in claim 1, wherein the carbonylating agent in step (vi) is carbonyldiimidazole (CDI).

11. A manufacturing method in the first paragraph, wherein the base in step (vi) is triethylamine.

12. A manufacturing method in which the ester hydrolysis reaction in step (vii) of paragraph 1 is performed in the presence of a base.

13. A manufacturing method in claim 12, wherein the base is potassium hydroxide.

14. A manufacturing method in the first aspect, wherein in step (viii), the coupling agent is 1,3,5,2,4,6-Trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxide (1,3,5,2,4,6-Trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxide, T4P).

15. A manufacturing method in the first paragraph, wherein the base in step (viii) is N,N-diisopropylethylamine (DIPEA).

16. A manufacturing method in the first paragraph, wherein the base in step (ix) is sodium methoxide. 17.(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.

18. HBr salt of the compound of the following chemical formula 9: [Chemical formula 9]

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