Process for preparing endocrine-like quinolones from alkyl 3-(3-alkoxyphenyl)amino)-2-(4-(4-alkoxy)phenoxy)phenyl)but-2-enoates

Abstract

A novel, scalable synthetic method for preparing endokinin-like quinolone compounds of formula (I), wherein R is H, Cl, or F, and R is C1-C2 alkyl, comprising reacting a compound of formula 8 with acetate in acid to produce a compound of formula (I), wherein R is H, Cl, or F, preferably F, and R is C1-C2 alkyl, preferably C1 alkyl. [Case 1] TIFF2025538731000075.tif66144

Description

[Background technology]

[0001] U.S. Pat. No. 8,598,354 discloses endokine-like quinolone compounds with antiparasitic or anti-infective activity, including 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (ELQ-316) (see Figure 4, Sheet 23). [ka] McConnell et al. (ACS Infect. Dis. 2018, 4, 1574-1584) disclose additional endokine-like quinolone compounds, including 7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (see Table 1, compound 7B). [ka] WO / 2021 / 231335 discloses synthetic methods and novel intermediates that enable industrial scale-up production in the preparation of 3-arylendoquinolone (ELQ) compounds, including ELQ-316.

[0002] Hammers et al. describe the use of (diacetoxyiodo)benzene (also known as phenyliodine(III) diacetate; PhI(OAc)2) and trimethyl orthoformate (TMOF) in methanol for the oxidative 1,2-aryl migration of ketones to the corresponding α-methyl esters (Org. Biomol. Chem. 2021, 19, 2213-2223). [ka] Attempts to carry out the oxidative rearrangement of intermediate 3 to compound 4 in the presence of iodic acid and sulfuric acid as described by Krishnacharya G. Akamanchi and coworkers (ARKIVOC 2011 (v) 67-75) or in the presence of iodine in trimethyl orthoformate as described by Yamauchi et al. (J. Org. Chem. 1988, 53, 4858-4859) failed to produce the desired product 4.

[0003] Pou et al. have disclosed synthetic routes to endokine-like quinolone compounds, such as ELQ-300, ELQ-316, and other antiparasitic quinolones (Org. Process Res. Dev. 2021, 25, 1841-1852). Specifically, Pou discloses another process for producing compounds similar to compound 4, which involves the use of a metal (copper) at a high temperature of 160 °C. However, the reported yields are only moderate, ranging from 60% to 70%. Furthermore, Pou describes the use of acetic anhydride to introduce an acetyl group into compound 4, which results in a mixture of compound 5 and compound 5a. This mixture must then be treated with an acid (paratoluenesulfonic acid, TsOH) to convert 5a back to 5. This is an additional step, and it is not easy to remove TsOH from the product, which must be carried forward to the next step. [ka] Vaswani et al. (Org. Lett. 2014, 16, 4114-4117) disclose the acylation of aryl α-methyl esters using lithium bis(trimethylsilyl)amide (LiHMDS) and 1-(1H-imidazol-1-yl)ethanone at low temperature.

[0004] Atkins et al. (Org. Proc. Res. Dev. 1997, 1, 185-197) disclose a ring-closure reaction using POCl3 at low temperature.

[0005] WO2021231335 discloses novel intermediates useful in the synthesis of endokinin-like quinolone compounds. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 8,598,354 [Patent Document 2] WO / 2021 / 231335 [Patent Document 3] WO2021231335 [Non-patent literature]

[0007] [Non-Patent Document 1] ACS Infect. Dis. 2018, 4 ,1574-1584 [Non-patent document 2] Org. Biomol. Chem. 2021, 19, 2213-2223 [Non-patent document 3] ARKIVOC 2011 (v) 67-75 [Non-patent document 4] Org. Chem.1988, 53, 4858-4859 [Non-Patent Document 5] Org. Process Res. Dev. 2021, 25, 1841-1852 [Non-patent document 6] Org. Lett. 2014, 16, 4114-4117 [Non-Patent Document 7] Org. Proc. Res. Dev. 1997, 1, 185-197 Summary of the Invention

[0008] One embodiment of the present invention is a compound of formula (I) [ka] wherein the process comprises preparing a compound of formula 8 [ka] with acetate in an acid to produce a compound of formula (I) wherein R is H, Cl or F, preferably F, and R is C1-C2 alkyl, preferably C1 alkyl. DETAILED DESCRIPTION OF THE INVENTION

[0009] Formula (I) [ka] [During the ceremony, R2 is C1-C2 alkyl, preferably C1 alkyl; R is H, Cl or F; and R1 is C1-C2 alkyl. A novel, scalable synthetic method for preparing endokinin-like quinolone compounds represented by the formula: wherein the synthetic method avoids the use of metal catalysts (e.g., copper) and harsh reaction conditions, and allows the final compound to be isolated in extremely high purity (>99%) without traces of residual metal. Scheme 1 is a representative example where R is F and R is methyl.

[0010] Scheme 1 [ka] We have found that the use of copper can be avoided by reacting 4-fluoroacetophenone (compound 1) with p-trifluoromethoxyphenol (compound 2) in the presence of a base at 100–140°C. This temperature range is lower than that of other known similar reactions, which is a significant advantage when implementing this process on an industrial scale. The resulting diaryl ether acetophenone (compound 3) was obtained in nearly quantitative yield, and then the ester intermediate (compound 4) underwent oxidative rearrangement in high yield and purity. This novel process made it possible to isolate compound 4 without traces of residual metal. Avoiding the use of copper in the synthesis of active pharmaceutical ingredients (APIs) is advantageous. This process is applicable to large-scale / industrial use.

[0011] We also found that the ester (compound 4) could be conveniently converted to the ketoester (compound 5) in a single step by using a base and acetylimidazole as the alkylating agent and carefully quenching the reaction mixture at low temperature (<10 °C). This new process enabled us to isolate the desired ketoester (compound 5) in high yield and purity. Under these new reaction conditions, the formation of the by-product 5a, as reported in the literature, was not observed.

[0012] Furthermore, it was confirmed that the condensation / ring-closure reaction in the presence of phosphorus oxychloride (POCl3) under mild reaction conditions (80 °C) enabled the isolation of the chloroquinoline intermediate (compound 8) in high yield (approximately 75%) and high purity (>99%). This intermediate (compound 8) was then converted to 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one in quantitative yield in the presence of sodium acetate in acetic acid. This compound was isolated in extremely high purity (>99%) without traces of residual metal.

[0013] AcOH is acetic acid; AcONa is sodium acetate; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; LiHMDS is lithium bis(trimethylsilyl)amide or lithium hexamethyldisilazane; LTMP is lithium tetramethylpiperidide; LDA is lithium diisopropylamide; MeOH is methanol; NMP is N-methyl-2-pyrrolidone; PCl3 is phosphorus trichloride; PCl5 is phosphorus pentachloride; PhI(OAc)2 is (diacetoxyiodo)benzene or phenyliodonium diacetate; POCl3 is phosphorus oxychloride; THF is tetrahydrofuran; TMOF is trimethyl orthoformate.

[0014] Residual metals in pharmaceuticals with no therapeutic value are considered contaminants, and their levels are strictly controlled by various regulatory agencies worldwide (ICH Guideline Q3D(R2) for elemental impurities). "Substantially free" means not present in a number or amount greater than that which could be expected to result from, consistent with, normal handling and good cultural practices used in the manufacture and marketing of the commercial product. With respect to residual metals (e.g., copper) in parenterally administered active pharmaceutical ingredients (APIs), it means that the residual metal in the API composition is less than 300 ppm.

[0015] One embodiment of the present invention is a compound of formula 4 [ka] wherein R1 is C1-C2 alkyl, preferably C1 alkyl. wherein the process comprises: formula 3 [ka] with phenyliodonium diacetate (PhI(OAc)2) and orthoformate to produce a compound of formula 4.

[0016] In another embodiment of the invention, the orthoformate is trimethyl orthoformate or triethyl orthoformate, preferably trimethyl orthoformate (TMOF).

[0017] In another embodiment of the present invention, the reaction is carried out in an alcohol.

[0018] In another embodiment of the invention, the alcohol is methanol, ethanol, n-propanol or isopropanol, preferably methanol.

[0019] In another embodiment of the present invention, the compound of formula 3 is [ka] The compound represented by formula 2 [ka] to produce a compound represented by formula 3, wherein the reaction temperature is about 100°C to about 170°C, about 100°C to about 150°C, about 125°C to about 150°C, about 130°C to about 150°C, about 100°C to about 145°C, about 125°C to about 145°C, or about 100°C to about 140°C, and preferably about 135°C to about 145°C.

[0020] In another embodiment, the temperature is about 140°C.

[0021] In another embodiment of the invention, the reaction further comprises a base.

[0022] In another embodiment of the present invention, the base is potassium carbonate, sodium carbonate or cesium carbonate, preferably potassium carbonate.

[0023] In another embodiment of the present invention, the base is sodium carbonate.

[0024] In another embodiment of the invention, the base is cesium carbonate.

[0025] In another embodiment of the invention, the reaction further comprises a solvent.

[0026] In another embodiment of the invention, the solvent is N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO), preferably DMF.

[0027] In another embodiment of the invention, the solvent is NMP.

[0028] In another embodiment of the invention, the solvent is DMSO.

[0029] In an alternative embodiment of the present invention, the process comprises reacting a compound of formula 4 to form a compound of formula (I): [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. The method further comprises producing a compound represented by the formula:

[0030] In another embodiment of the present invention, R is Cl and R is C alkyl.

[0031] In another embodiment of the present invention, R is F and R2 is C1 alkyl.

[0032] In another embodiment of the present invention, R is H and R2 is C1 alkyl.

[0033] In another embodiment of the present invention, the compound of formula (I) is substantially free of residual metals.

[0034] Another embodiment of the present invention is a compound of formula 4 [ka] It is a compound represented by the formula:

[0035] One embodiment of the present invention is a compound of formula 5 [ka] wherein R1 is C1-C2 alkyl, preferably C1 alkyl. wherein the process comprises preparing a compound of formula 4 [ka] with a base and then with an alkylating agent to produce a compound of formula 5.

[0036] In another embodiment of the present invention, the base is lithium bis(trimethylsilyl)amide (LiHMDS), lithium tetramethylpiperidide (LTMP) or lithium diisopropylamide (LDA), preferably LiHMDS.

[0037] In another embodiment of the invention, the base is LTMP.

[0038] In another embodiment of the invention, the base is LDA.

[0039] In another embodiment of the invention, the alkylating agent is acetylimidazole.

[0040] In another embodiment of the present invention, the process is quenched at a temperature of about 0°C to less than about 20°C, preferably less than about 10°C.

[0041] In another embodiment of the invention, the process is quenched at a temperature of about 0°C to about 20°C, or at a temperature of about 0°C to about 10°C, or at a temperature of about 10°C to about 20°C.

[0042] In an alternative embodiment of the present invention, the process comprises reacting a compound of formula 5 to form a compound of formula (I): [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. The method further comprises producing a compound represented by the formula:

[0043] In another embodiment of the present invention, R is Cl and R is C alkyl.

[0044] In another embodiment of the present invention, R is F and R2 is C1 alkyl.

[0045] In another embodiment of the present invention, R is H and R2 is C1 alkyl.

[0046] Another embodiment of the present invention is a compound of formula 5 [ka] It is a compound represented by the formula:

[0047] One embodiment of the present invention is a compound of formula 7 [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. wherein the process comprises preparing a compound of formula 5 [ka] The compound represented by formula 6 [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. with a compound of formula 7 to form a compound of formula 7.

[0048] In another embodiment of the present invention, a solvent is used in the process.

[0049] In another embodiment of the present invention, the solvent is an aprotic non-polar solvent such as cyclohexane, toluene, heptane, xylene or mixtures thereof, preferably cyclohexane.

[0050] In another embodiment of the invention, the solvent is heptane.

[0051] In another embodiment of the invention, the solvent is toluene.

[0052] In another embodiment of the present invention, the temperature of the process is about 50°C to about 140°C, about 60°C to about 130°C, about 70°C to about 120°C, about 80°C to about 120°C, about 85°C to about 110°C, and preferably about 90°C to about 110°C.

[0053] In another embodiment, the temperature is about 110°C.

[0054] In an alternative embodiment of the present invention, the process comprises reacting a compound of formula 7 with phosphorus oxychloride (POCl), phosphorus trichloride (PCl), or phosphorus pentachloride (PCl), preferably with POCl, to give a compound of formula 8 [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. The method further comprises producing a compound represented by the formula:

[0055] In another embodiment of the present invention, the temperature of the process is about 50°C to about 140°C, about 60°C to about 130°C, about 70°C to about 120°C, about 80°C to about 120°C, about 85°C to about 110°C, and preferably about 90°C to about 110°C.

[0056] In another embodiment, the temperature is about 100°C.

[0057] In an alternative embodiment of the present invention, the process comprises reacting a compound of formula 8 to form a compound of formula (I): [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. The method further comprises producing a compound represented by the formula:

[0058] In another embodiment of the present invention, R is Cl and R is C alkyl.

[0059] In another embodiment of the present invention, R is F and R2 is C1 alkyl.

[0060] In another embodiment of the present invention, R is H and R2 is C1 alkyl.

[0061] In another embodiment, the process of forming a compound of formula (I) from a compound of formula 8 is carried out in situ from the process of forming a compound of formula 8 from a compound of formula 7.

[0062] Another embodiment of the present invention is a compound of formula 7 [ka] It is a compound represented by the formula:

[0063] One embodiment of the present invention is a compound of formula (I) [ka] wherein the process comprises preparing a compound of formula 8 [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. with acetate in an acid to produce a compound of formula (I).

[0064] In another embodiment of the present invention, R is Cl and R is C alkyl.

[0065] In another embodiment of the present invention, R is F and R2 is C1 alkyl.

[0066] In another embodiment of the present invention, R is H and R2 is C1 alkyl.

[0067] In another embodiment of the present invention, the acetate salt is potassium acetate or sodium acetate, preferably sodium acetate.

[0068] In another embodiment of the invention, the acetate salt is potassium acetate.

[0069] In another embodiment of the present invention, the acid is acetic acid or a C1-C4 aliphatic acid, preferably acetic acid.

[0070] In another embodiment of the present invention, the acid is a C1-C4 aliphatic acid.

[0071] In another embodiment of the present invention, the process for forming a compound of formula (I) from a compound of formula 8 comprises the step of reacting a compound of formula 7 [ka] The process is carried out in situ from the formation of a compound of formula 8 from a compound of formula

[0072] An alternative embodiment of the present invention is a compound of formula (I) [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. wherein the preparation comprises: (i) Equation 1 [ka] The compound represented by Equation 2 [ka] and reacting the compound represented by formula 3 [ka] (wherein the reaction temperature is about 100°C to about 170°C); (ii) Reacting a compound of formula 3 with phenyliodonium diacetate (PhI(OAc)2) and orthoformate to give a compound of formula 4 [ka] producing a compound represented by the formula: (iii) reacting a compound of formula 4 with a base and then with an alkylating agent to give a compound of formula 5 [ka] and (iv) reacting a compound of formula 5 with a compound of formula 6 to produce a compound of formula (I); Contains:

[0073] An alternative embodiment of the present invention is a compound of formula (I) [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. wherein the preparation comprises: (i) Equation 1 [ka] The compound represented by formula 2 [ka] and reacting the compound represented by formula 3 [ka] (wherein the reaction temperature is about 100°C to about 170°C); (ii) Reacting a compound of formula 3 with phenyliodonium diacetate (PhI(OAc)2) and orthoformate to give a compound of formula 4 [ka] producing a compound represented by the formula: (iii) reacting a compound of formula 4 with a base and then with an alkylating agent to give a compound of formula 5 [ka] producing a compound represented by the formula: (iv) Reacting the compound represented by formula 5 with a compound represented by formula 6 [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. and reacting the compound represented by formula 7 [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. producing a compound represented by the formula: (v) reacting a compound of formula 7 to form a compound of formula 8 [ka] and (vi) reacting a compound of formula 8 to form a compound of formula (I); Contains:

[0074] An alternative embodiment of the present invention is a compound of formula (I) [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. wherein the preparation comprises: (i) Equation 1 [ka] The compound represented by formula 2 [ka] and reacting the compound represented by formula 3 [ka] (wherein the reaction temperature is about 100°C to about 170°C); (ii) Reacting a compound of formula 3 with phenyliodonium diacetate (PhI(OAc)2) and orthoformate to give a compound of formula 4 [ka] producing a compound represented by the formula: (iii) reacting a compound of formula 4 with a base and then with an alkylating agent to give a compound of formula 5 [ka] producing a compound represented by the formula: (iv) Reacting the compound represented by formula 5 with a compound represented by formula 6 [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. and reacting the compound represented by formula 7 [ka] wherein R is H, Cl or F, preferably F, and R is C-C alkyl, preferably C alkyl. producing a compound represented by the formula: (v) reacting a compound of formula 7 to form a compound of formula 8 [ka] and (vi) reacting a compound of formula 8 with acetate in an acid to produce a compound of formula (I); Contains:

[0075] In an alternative embodiment, intermediate compounds 3, 4, 5 and 7 are carried on to the subsequent reaction step in the form of concentrated solutions without being completely dried.

[0076] In an alternative embodiment, intermediate compound 3 is carried on to the subsequent reaction step in the form of a concentrated solution without being completely dried.

[0077] In an alternative embodiment, intermediate compound 4 is carried on to the subsequent reaction step in the form of a concentrated solution without being completely dried.

[0078] In an alternative embodiment, intermediate compound 5 is carried on to the subsequent reaction step in the form of a concentrated solution without being completely dried.

[0079] In an alternative embodiment, intermediate compound 7 is carried on to the subsequent reaction step in the form of a concentrated solution without being completely dried. [Example]

[0080] HPLC method: Method A Agilent Technologies UHPLC / MSD 6130 B Series 1290 (which consists of a binary pump G7120A (including a degasser), a well-plate sampler G4226A, a column oven G1316B, a diode array detector G4212A, and a mass detector G6130B quadrupole LC / MS (with an ESI source)); Column: Waters XP, 2.1 × 50 mm Xbridge BEH C18 2.5μ, T = 40°C; Eluent A: acetonitrile containing 0.05% (vol / vol) formic acid; Eluent B: water containing 0.05% (vol / vol) formic acid; Flow rate: 0.8mL / min; Gradient: 2 → 100% eluent A 1.2 min, 0.5 min 100% eluent A; Implementation time: 2.2 minutes; Detection: ESI / MS, positive and negative ion scan: 100-1000 m / z; UV 254nm and 210nm.

[0081] Example 1: Preparation of methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (Compound 4) Step 1: Preparation of 1-(4-(4-(trifluoromethoxy)phenoxy)phenyl)ethan-1-one (compound 3) [ka] To a solution of 1-(4-fluorophenyl)ethan-1-one (17.70 mL, 143 mmol) and 4-(trifluoromethoxy)phenol (20.84 mL, 158 mmol) in N,N-dimethylformamide (400 mL) was added potassium carbonate (39.6 g, 287 mmol). The resulting mixture was heated to 140 °C and stirred at this temperature for 16 h. The reaction mixture was then brought to room temperature, diluted with water (1 L), and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were washed with 1 N aqueous hydrochloric acid (500 mL), dried, and concentrated under reduced pressure to give a brown oil. The resulting oil was dissolved in dichloromethane (1 L), filtered through a short pad of silica gel, and the filtrate was concentrated under reduced pressure to give the desired product as a brown oil (43.6 g, 140 mmol), which was carried on directly to Step 2.

[0082] NMR 1H NMR (300 MHz, methanol-d3) δ (ppm): 8.04 - 8.01 (m, 2H); 7.35 (d, J = 8.4 Hz, 2H); 7.20 - 7.15 (m, 2H); 7.08 - 7.04 (m, 2H); 2.58 (s, 3H) 13 C NMR (75 MHz, methanol-d3) δ (ppm): 197.7; 161.6; 154.4; 145.4; 132.2; 130.6; 122.8; 121.0; 117.2; 25.2 UPLC / MS (Method A): Rt = 1.23 min Step 2: Preparation of methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (compound 4) [ka] The crude product from Step 1 (43.6 g, 140 mmol) was dissolved in methanol (430 mL), trimethoxymethane (127 mL, 1161 mmol) was added, and the temperature of the resulting mixture was adjusted to 10 °C. Concentrated sulfuric acid (64.8 mL, 1161 mL) and phenyl iodine(III) diacetate (50.1 g, 152 mmol) were added sequentially while maintaining the temperature of the reaction mixture between 10 and 16 °C. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 90 minutes. The temperature was then adjusted to 5 °C, and water (500 mL) was added. The volume of the resulting mixture was reduced under reduced pressure (distilled volume approximately 70 mL), water (1 L) was added, and the pH was adjusted to 7 by adding sodium bicarbonate. The aqueous solution was extracted with dichloromethane (2 x 300 mL) and the combined organic layers were dried and concentrated under reduced pressure to give the desired product (71.3 g, 63 wt%) in the presence of iodobenzene (37 wt%).

[0083] 1 H NMR (600 MHz, dichloromethane-d2) δ (ppm): 7.33 - 7.28 (m, 2H); 7.24 (dd, J = 0.7, 9.0 Hz, 2H); 7.07 - 7.04 (m, 2H); 7.03 - 7.00 (m, 2H); 3.72 (s, 3H); 3.65 (s, 1H). 13 C NMR (75 MHz, methanol-d3) δ (ppm): 171.9; 155.9; 144.4; 130.8; 129.8; 122.6; 121.4; 119.6; 118.9; 51.9; 40.1 UPLC / MS (Method A): Rt = 1.26 min; m / z 325. Example 2: Preparation of 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (Compound 8) [ka] Step 1: Preparation of methyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)butanoate (compound 5) [ka] Methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (20.0 g, 63% by weight, 38.6 mmol) from Step 2 of Example 1 and 1-(1H-imidazol-1-yl)ethan-1-one (5.1 g, 46.3 mmol) were placed under a nitrogen atmosphere and dissolved in a mixture of dry tetrahydrofuran (200 mL) and dry N,N-dimethylacetamide (20 mL). The resulting solution was brought to −30°C, and a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (93 mL, 93 mmol) was added, maintaining the temperature between −31 and −28°C. After the addition was complete (approximately 20 minutes), the mixture was stirred at −30 to −25°C for 1 hour. The cooling was removed, and saturated aqueous ammonium chloride (100 mL) was slowly added to the reaction mixture, causing the temperature to rise to −1°C. The mixture was allowed to reach room temperature and stirred for 30 minutes. After dilution with water (200 mL), the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed successively with 2N aqueous hydrochloric acid (200 mL), brine (200 mL), and concentrated under reduced pressure to give the desired product as a brown oil (18.5 g), which was carried on directly to the next step.

[0084] UPLC / MS (Method A): Rt = 1.16, 1.23, 1.26 and 1.36 min; m / z 367. Step 2: Preparation of methyl 3-((4-fluoro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate (compound 7) [ka] The crude product isolated from step 1 (18.5 g, 38.7 mmol) was dissolved in cyclohexane (150 mL), 4-fluoro-3-methoxyaniline (5.46 g, 38.7 mmol) was added, and the resulting mixture was refluxed (about 110° C.) for 17 hours while removing the water that formed. After 17 hours of reaction time, the reaction mixture was concentrated under reduced pressure to give the desired product as a brown oil (22.9 g), which was carried on directly to the next step.

[0085] Step 3: Preparation of 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (compound 8) [ka] To the crude product isolated from Step 2 (51.2 g, 72.9 mmol) was added phosphoryl trichloride (50 mL, 536 mmol), and the resulting mixture was heated to 100° C. for 2 hours. The temperature of the reaction mixture was lowered to 5° C., dichloromethane (50 mL) was added, and water (500 mL) was added slowly with vigorous stirring while maintaining the temperature below 15° C. The reaction mixture was extracted with dichloromethane (300 mL), and the organic layer was collected, washed sequentially with saturated aqueous sodium bicarbonate (250 mL) and water (250 mL), and concentrated under reduced pressure. The resulting residue was triturated with ethanol (200 mL) at 45° C. for 20 minutes. The formed suspension was filtered, the wet cake was rinsed with ethanol (150 mL), and the resulting solid was dried under reduced pressure at 40° C. to give the desired product as a white solid (29.3 g, 60.7 mmol).

[0086] NMR 1 H NMR (300 MHz, dimethyl sulfoxide-d6) δ (ppm): 7.89 (d, J = 6.0 Hz, 1H); 7.66 (d, J = 4.2 Hz, 1H); 7.45 (d, J = 4.2 Hz, 2H); 7.41 - 7.39 (m, 2H); 7.24 - 7.23 (m, 2H); 7.20 - 7.18 (m, 2H); 4.04 (s, 3H); 2.40 (s, 3H). 13 C NMR (75 MHz, dimethyl sulfoxide-d6) δ (ppm): 158.2; 156.7; 155.6; 153.3; 151.6; 151.1; 151.0; 145.7; 144.5; 139.5; 139.4; 132.1; 123.6; 121.4; 120.9; 119.8; 119.4; 119.2; 110.6; 109.1; 108.9; 57.0; 25.4 19 F NMR (282 MHz, dimethyl sulfoxide-d6) δ (ppm): -57.1; -131.1 UPLC / MS (Method A): Rt = 1.45 min; m / z 325. Example 3 Preparation of 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (Compound ELQ-316) [ka] 4-Chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (28 g, 58.0 mmol) was dissolved in acetic acid (300 mL), sodium acetate (9.52 g, 116 mmol) was added, and the resulting mixture was reacted at 120 °C for 16 hours. The resulting suspension was brought to room temperature, diluted with water (300 mL), and filtered. The wet cake was washed successively with water (250 mL) and acetone (2 × 125 mL), and the resulting solid was dried under reduced pressure at 40 °C to give the desired product as a white solid (23.1 g, 50 mmol).

[0087] NMR 1 H NMR (300 MHz, N,N-dimethylformamide-d7) δ (ppm): 7.83 (d, J = 11.5 Hz, 1H); 7.49 (d, J = 8.8 Hz, 1H); 7.42 - 7.40 (m, 2H); 7.27 - 7.24 (m, 2H); 7.22 (d, J = 6.9 Hz, 1H); 7.15 - 7.13 (m, 2H); 4.05 (s, 3H); 2.36 (s, 3H). 13 C NMR (75 MHz, N,N-dimethylformamide-d7) δ (ppm): 174.4; 156.5; 155.3; 151.5; 151.4; 150.3; 148.7; 146.5; 144.2; 137.6; 132.3; 123.2; 121.5; 119.9; 118.5; 110.4; 110.3; 56.1; 18.6 19 F NMR (282 MHz, N,N-dimethylformamide-d7) δ (ppm): -57.2; -140.7 UPLC / MS (Method A): Rt = 1.13 min; m / z 460. Example 4: Preparation of 4,6-dichloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline [ka] Step 1: Preparation of methyl 3-((4-chloro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate [ka] The crude product isolated from Step 1 of Example 2 (2.0 g, 5.43 mmol) was dissolved in cyclohexane (15 mL), 4-chloro-3-methoxyaniline (0.87 g, 5.43 mmol) was added, and the resulting mixture was refluxed (approximately 110° C.) for 24 hours while removing the resulting water. Heating was removed and the reaction mixture was concentrated under reduced pressure to give the desired product as a brown oil (2.9 g), which was carried on directly to the next step.

[0088] Step 2: Preparation of 4,6-dichloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline [ka] To the crude product isolated from Step 1 (2.9 g) was added phosphoryl trichloride (10.6 mL, 114 mmol), and the resulting mixture was heated to 100° C. and reacted for 135 minutes. The temperature of the reaction mixture was lowered to 5° C., dichloromethane (50 mL) was added, and water (100 mL) was added slowly with vigorous stirring while maintaining the temperature below 15° C. The reaction mixture was extracted with dichloromethane (25 mL), and the organic layer was collected, washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and water (50 mL), and concentrated under reduced pressure. The resulting residue was triturated with ethanol (10 mL) at 45° C. for 20 minutes. The formed suspension was filtered, the wet cake was washed with ethanol (10 mL), and the resulting solid was dried under reduced pressure at 40° C. to afford the desired product as a white solid (1.3 g, 2.49 mmol).

[0089] NMR 1H NMR (300 MHz, dimethyl sulfoxide-d6) δ (ppm): 8.18 (s, 1H); 7.63 (s, 1H); 7.47-7.45 (m, 2H); 7.42-7.40 (m, 2H); 7.24-7.23 (m, 2H); 7.20-7.19 (m, 2H); 4.05 (s, 3H); 2.41 (s, 3H). 13 C NMR (75 MHz, dimethyl sulfoxide-d6) δ (ppm): 159.4; 156.7; 156.4; 155.6; 147.7; 144.5; 139.1; 132.5; 132.1; 131.8; 124.9; 124.6; 123.6; 121.4; 119.8; 119.2; 109.4; 57.3; 25.6 19 F NMR (282 MHz, dimethyl sulfoxide-d6) δ (ppm): -57.1 UPLC / MS (Method A): Rt = 1.50 min; m / z 494. Example 5: Preparation of 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one [ka] 4,6-Dichloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (1 g, 2.02 mmol) was dissolved in acetic acid (10 mL), sodium acetate (0.33 g, 4.05 mmol) was added, and the resulting mixture was reacted at 120° C. for 17 hours. The resulting suspension was brought to room temperature, diluted with water (15 mL), and filtered. The wet cake was rinsed with water (10 mL), and the resulting solid was dried under reduced pressure at 40° C. to afford the desired product as a white solid (0.9 g, 1.74 mmol).

[0090] UPLC / MS (Method A): Rt = 1.17 min; m / z 476. Example 6: Alternative preparation of 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (compound ELQ-316) [ka] Step 1: Preparation of 1-(4-(4-(trifluoromethoxy)phenoxy)phenyl)ethan-1-one (compound 3) [ka] To a solution of 1-(4-fluorophenyl)ethan-1-one (88 mL, 717 mmol) and 4-(trifluoromethoxy)phenol (99 mL, 752 mmol) in N,N-dimethylformamide (1000 mL) was added potassium carbonate (198 g, 1.433 mol). The resulting mixture was heated to 137 °C and stirred at this temperature for 20 hours. The reaction mixture was then brought to room temperature, diluted with water (2.5 L), and extracted with methyl tert-butyl ether (1 L). The organic layer was washed with 1 N aqueous hydrochloric acid (500 mL) and saturated aqueous sodium chloride (500 mL), dried, and concentrated under reduced pressure to give the desired product as a brown oil (218 g, 707 mmol), which was carried on directly to Step 2.

[0091] Step 2: Preparation of methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (compound 4) [ka] The crude product from Step 1 (218 g, 707 mmol) was dissolved in methanol (1740 mL), trimethoxymethane (618 mL, 5652 mmol) was added, and the temperature of the resulting mixture was adjusted to 5°C. Concentrated sulfuric acid (315 mL, 5652 mmol) and phenyl iodine(III) diacetate (244 g, 742 mmol) were added sequentially with stirring, while maintaining the temperature of the reaction mixture between 6 and 15°C. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 75 minutes. The temperature was then adjusted to 9°C, and cold water (3.5 L) was added. The resulting mixture was extracted with methyl tert-butyl ether (2 L), and the organic layer was washed sequentially with saturated aqueous sodium bicarbonate (1 L) and saturated aqueous sodium chloride (1 L). The organic layer was first concentrated at 45°C, and then the pressure was gradually reduced to 3 mbar while the temperature was increased to 60°C. Approximately 95 g of iodobenzene was distilled off to give the desired product (272 g, 80 wt%) in the presence of iodobenzene (8 wt%).

[0092] Step 3: Preparation of methyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)butanoate (compound 5) [ka] Methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (272 g, 80 wt%, 706 mmol) from Step 2 and 1-(1H-imidazol-1-yl)ethan-1-one (90 g, 804 mmol) were placed under a nitrogen atmosphere and dissolved in a mixture of dry tetrahydrofuran (2.4 L) and dry N,N-dimethylacetamide (440 mL). The resulting solution was brought to −36°C, and a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1609 mL, 1609 mmol) was added while maintaining the temperature between −36 and −28°C. After the addition was complete, the mixture was stirred at −30 to −28°C for 1 hour. The cooling was removed, and saturated aqueous ammonium chloride (1.5 L) was slowly added to the reaction mixture, causing the temperature to rise to −1°C. The mixture was allowed to warm to room temperature and stirred for 1 hour. After dilution with water (1 L), the mixture was extracted with cyclohexane (550 mL). The organic layer was washed sequentially with 1 N aqueous hydrochloric acid (1 L), brine (2 L), and concentrated under reduced pressure to a volume of approximately 650 mL, which was carried on directly to the next step.

[0093] Step 4: Preparation of methyl 3-((4-fluoro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate (compound 7) [ka] The concentrated product solution from step 3 (225 g, 610 mmol) in cyclohexane (approximately 650 mL) was diluted with cyclohexane (1 L), 4-fluoro-3-methoxyaniline (90 g, 610 mmol) was added, and the resulting mixture was refluxed (approximately 100° C.) for 20 hours while removing the water that formed. After the 20-hour reaction time, the reaction mixture was cooled to 50° C., filtered through Celite 545, and concentrated under reduced pressure to a volume of approximately 400 mL. This was carried on directly to the next step.

[0094] Step 5: Preparation of 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (compound 8) [ka] To a concentrated solution of methyl 3-((4-fluoro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate (264 g, 537 mmol) from Step 4 in cyclohexane (approximately 400 mL) was added phosphoryl trichloride (253 mL, 2685 mmol), and the mixture was heated at 100°C until all cyclohexane had distilled off (approximately 35 min), then stirred at 100°C for an additional 2 h. The reaction mixture was cooled to ambient temperature, dichloromethane (800 mL) was added, and the mixture was slowly added to ice-cold water (2 L) with vigorous stirring, maintaining the temperature between 5°C and 15°C. The phases were allowed to settle, and the aqueous layer was extracted with dichloromethane (500 mL). The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate (1.5 L) and water (1.5 L) and concentrated under reduced pressure. The resulting residue was triturated with ethanol (500 mL) for 20 minutes at 45° C. The formed suspension was filtered, the wet cake was rinsed with ethanol (150 mL), and the resulting solid was dried under reduced pressure at 40° C. to afford the desired product as a white solid (177.5 g, 371 mmol).

[0095] Step 6: Preparation of 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (compound ELQ-316) [ka] 4-Chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (177.5 g, 371 mmol) was dissolved in acetic acid (1775 mL), sodium acetate (60.9 g, 743 mmol) was added, and the resulting mixture was reacted at 120° C. for 16 hours. The resulting suspension was brought to room temperature, diluted with water (1775 mL), and filtered. The wet cake was rinsed sequentially with water (1 L) and acetone (2×500 mL), and the resulting solid was dried under reduced pressure at 40° C. to afford the desired product as a white solid (150 g, 326 mmol).

[0096] Example 7: Preparation of 7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-quinolin-4(1H)-one Steps 1 to 3 of Example 6 were reproduced, and Steps 4 and 5 of Example 6 were carried out using 3-methoxyaniline instead of 4-fluoro-3-methoxyaniline to give the desired 4-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline.

[0097] Step 6: Preparation of 7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one [ka] 4-Chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (3.7 g, 7.72 mmol) was dissolved in acetic acid (37 mL), sodium acetate (1.27 g, 15.5 mmol) was added, and the resulting mixture was reacted at 120° C. for 17 hours. The reaction mixture was cooled to 65° C., poured into water (200 mL), and stirred for 15 minutes. The resulting suspension was filtered and rinsed with water (50 mL). The wet filter cake was poured into acetone (80 mL) and stirred at ambient temperature for 20 minutes. The suspension was filtered and washed with acetone (20 mL). The filter cake was dried under reduced pressure at 40° C. to give the desired product as a white solid (2.9 g, 6.50 mmol).

[0098] 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ (ppm): 11.49 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 9.1 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 6.94 - 6.86 (m, 2H), 3.86 (s, 3H), 2.22 (s, 3H). 13C NMR (151 MHz, dimethyl sulfoxide-d6) δ (ppm): 174.6, 161.6, 155.9, 154.6, 146.2, 143.6, 141.0, 131.9, 127.3, 123.4, 121.0, 119.8, 119.7, 119.3, 118.7, 118.4, 112.8, 98.5, 55.4, 18.9. 19 F NMR (565 MHz, dimethyl sulfoxide-d6) δ (ppm): -57.2. UPLC / MS (Method A): Rt = 1.12 min, m / z 442.

Claims

1. Formula (I) 【Chemistry 1】 A process for preparing a compound of formula 8 【Chemistry 2】 with acetate in acid to produce a compound of formula (I) ２ is C １ -C ２ Alkyl, preferably C １ alkyl] process.

2. 2. The process of claim 1, wherein the acetate is potassium acetate or sodium acetate, preferably sodium acetate.

3. The acid is acetic acid or １ -C ４ The process according to any one of claims 1 to 2, wherein the acid is an aliphatic acid, preferably acetic acid.

4. The process for forming a compound of formula (I) from a compound of formula 8 is 【Transformation 3】 4. The process of any one of claims 1 to 3, carried out in situ from the process of forming a compound of formula 8 from a compound of formula

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