Method for preparing oxopolyoctane-like quinolones from 3-(3-alkoxyphenyl) amino)-2-(4-(4-alkoxy) phenoxy) phenyl) butyl-2-olefine acid alkyl ester

Abstract

A novel scalable synthesis for the preparation of an oxopolyoxin-like quinolone compound of formula (I) wherein R is H, Cl or F, preferably F, and R2 is C1-C2 alkyl, preferably C1 alkyl, where the synthesis comprises a process for the preparation of a compound of formula (4) wherein R1 is C1-C2 alkyl, preferably C1 alkyl. # imgabs0 #

Description

Background Art

[0001] U.S. Patent No. 8,598,354 discloses endochin-like quinolone compounds having anti-parasitic or anti-infective activity, which include 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (ELQ-316) (see Figure 4, Table 23).

[0002]

[0003] McConnell et al., (ACS Infect. Dis. 2018, 4, 1574-1584) disclose additional endochin-like quinolone compounds, which include 7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (see Table 1, Compound 7B).

[0004]

[0005] WO / 2021 / 231335 discloses a synthetic method and novel intermediates for preparing 3-aryl endochin-like quinolone (ELQ) compounds including ELQ-316 that can be produced on an industrial scale.

[0006] Hammers et al. describe the generation of the corresponding α-methyl ester by oxidative 1,2-aryl migration of a ketone using (diacetoxyiodo)benzene (also known as phenyl iodide(III) diacetate, PhI(OAc)2) and trimethyl orthoformate (TMOF) in methanol (Org. Biomol. Chem. 2021, 19, 2213–2223).

[0007]

[0008] Attempts at the oxidative rearrangement of Intermediate 3 to Compound 4 as described by Krishnacharya G. Akamanchi and co-workers in ARKIVOC 2011(v)67-75 in the presence of iodic acid and sulfuric acid, or as described by Yamauchi et al. in J. Org. Chem. 1988, 53, 4858-4859 in the presence of a solution of iodine in trimethyl orthoformate, failed to produce the desired product 4.

[0009] Pou et al. disclosed the synthetic routes of endoperoxide-like quinolone compounds (such as ELQ-300, ELQ-316, and other anti-parasitic quinolones) (Org. Process Res. Dev. 2021, 25, 1841-1852). Specifically, Pou disclosed a method for preparing compounds similar to compound 4, which involved using a metal (copper) at an elevated temperature of 160 °C. However, the reported yields remained moderate, at 60%-70%. In addition, Pou described introducing an acetyl group onto compound 4 using acetic anhydride, which formed a mixture of compound 5 and compound 5a. This mixture needed to be treated with an acid (p-toluenesulfonic acid, TsOH) to convert 5a back to 5. This was an additional step, and it was not easy to remove TsOH from the product, so it had to be left in the next step.

[0010]

[0011] Vaswani et al. (Org. Lett. 2014, 16, 4114–4117) disclosed the acylation of aryl α-methyl esters using lithium bis(trimethylsilyl)amide (LiHMDS) and 1-(1H-imidazol-1-yl)ethanone at low temperature.

[0012] Atkins et al. (Org. ProC. Res. Dev. 1997, 1, 185-197) disclosed a ring-closing reaction using POCl3 at low temperature.

[0013] WO2021231335 disclosed novel intermediates that can be used in the synthesis of endoperoxide-like quinolone compounds. Summary of the Invention

[0014] One embodiment of the present invention is a method for preparing a compound of formula 4

[0015]

[0016] wherein R1 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0017] The method comprises reacting a compound of formula 3

[0018]

[0019] with phenyl iodide diacetate (PhI(OAc)2) and a formate ester to produce the compound of formula 4. Detailed Description of the Invention

[0020] A novel scalable synthesis of an endoperoxide-like quinolone compound of formula (I)

[0021]

[0022] wherein R2 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0023] wherein R is H, Cl or F, and R1 is a C1-C2 alkyl group, which avoids the use of any metal catalysis (such as copper) and harsh reaction conditions, and allows the final compound to be separated with very high purity (>99%), and there is no trace of residual metal. Scheme 1 is representative, wherein R is F and R2 is methyl.

[0024] Scheme 1

[0025]

[0026] It has been 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 to 140 °C. This temperature range is lower than other known similar reactions and is a significant advantage when using this method on an industrial scale. The resulting diarylether acetophenone (Compound 3) is obtained in almost quantitative yield and is subsequently oxidized and rearranged to obtain the ester intermediate (Compound 4) in high yield and purity. This novel method allows the separation of Compound (Compound 4) in the absence of any trace of residual metal. In the synthesis of active pharmaceutical ingredients (APIs), avoiding the use of copper is advantageous. This method is suitable for large-scale / industrial use.

[0027] It has also been found that the ester (Compound 4) can be conveniently converted to the keto-ester (Compound 5) in one step by using a base and acetyl imidazole as an alkylating agent and carefully quenching the reaction mixture at low temperature (<10 °C). This novel method allows the separation of the target keto-ester (Compound 5) in high yield and high purity. Under these new reaction conditions, the formation of by-product 5a as reported in the literature was not observed.

[0028] In addition, it has also been determined that the condensation / ring-closing reaction carried out in the presence of phosphorus oxychloride (POCl3) under mild reaction conditions (80 °C) allows the separation of the chloroquinoline intermediate (Compound 8) in high yield (about 75%) and very high purity (>99%). This intermediate (Compound 8) is subsequently 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 an acetic acid solution of sodium acetate. This compound is separated with very high purity (>99%) and in the absence of any trace of residual metal.

[0029] AcOH is acetic acid.

[0030] AcONa is sodium acetate.

[0031] DMF is N,N-dimethylformamide.

[0032] DMSO is dimethyl sulfoxide.

[0033] LiHMDS is lithium bis(trimethylsilyl)amide or lithium hexamethyldisilazide.

[0034] LTMP is lithium tetramethylpiperidide.

[0035] LDA is lithium diisopropylamide.

[0036] MeOH is methanol.

[0037] NMP is N-methyl-2-pyrrolidone.

[0038] PCl3 is phosphorus trichloride.

[0039] PCl5 is phosphorus pentachloride.

[0040] PhI(OAc)2 is (diacetoxyiodo)benzene or phenyliodine diacetate.

[0041] POCl3 is phosphorus oxychloride.

[0042] THF is tetrahydrofuran.

[0043] TMOF is trimethyl orthoformate.

[0044] Residual metals in drugs that have no therapeutic value are considered contaminants, and their levels are strictly controlled by regulatory agencies around the world (ICH guideline Q3D(R2) on elemental impurities). Substantially free means that it is not present in amounts exceeding those that can be expected to arise during the production and sale of the article and that are consistent with normal practices and good manufacturing practice. For residual metals in parenteral active pharmaceutical ingredients (APIs), such as copper, it means that the residual metal in the API composition is less than 300 ppm.

[0045] One embodiment of the present invention is a method for preparing a compound of formula 4

[0046]

[0047] wherein R1 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0048] The method comprises reacting a compound of formula 3

[0049]

[0050] with phenyliodine diacetate (PhI(OAc)2) and an orthoformate to produce a compound of formula 4.

[0051] In another embodiment of the present invention, the orthoformate is trimethyl orthoformate or triethyl orthoformate, preferably trimethyl orthoformate (TMOF).

[0052] In another embodiment of the present invention, the reaction is carried out in an alcohol.

[0053] In another embodiment of the present invention, the alcohol is methanol, ethanol, n-propanol or isopropanol, preferably methanol.

[0054] In another embodiment of the present invention, the compound of formula 3 is produced by reacting the compound of formula 1

[0055]

[0056] with the compound of formula 2

[0057]

[0058] The reaction is carried out to produce the compound of 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, about 100 °C to about 140 °C, preferably about 135 °C to about 145 °C.

[0059] In another embodiment, the temperature is about 140 °C.

[0060] In another embodiment of the present invention, the reaction further includes a base.

[0061] In another embodiment of the present invention, the base is potassium carbonate, sodium carbonate or cesium carbonate, preferably potassium carbonate.

[0062] In another embodiment of the present invention, the base is sodium carbonate.

[0063] In another embodiment of the present invention, the base is cesium carbonate.

[0064] In another embodiment of the present invention, the reaction further includes a solvent.

[0065] In another embodiment of the present invention, the solvent is N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO), preferably DMF.

[0066] In another embodiment of the present invention, the solvent is NMP.

[0067] In another embodiment of the present invention, the solvent is DMSO.

[0068] In other embodiments of the present invention, the method further comprises reacting a compound of formula 4 to produce a compound of formula (I).

[0069]

[0070] Wherein R is H, Cl or F, preferably F, and R2 is C1-C2 alkyl, preferably C1 alkyl.

[0071] In another embodiment of the present invention, R is Cl and R2 is C1 alkyl.

[0072] In another embodiment of the present invention, R is F and R2 is C1 alkyl.

[0073] In another embodiment of the present invention, R is H and R2 is C1 alkyl.

[0074] In another embodiment of the present invention, the compound of formula (I) is substantially free of residual metals.

[0075] Another embodiment of the present invention is a compound of formula 4

[0076]

[0077] One embodiment of the present invention is a method for preparing a compound of formula 5

[0078]

[0079] Wherein R1 is C1-C2 alkyl, preferably C1 alkyl,

[0080] The method comprises reacting a compound of formula 4

[0081]

[0082] With a base and then with an alkylating agent to produce a compound of formula 5.

[0083] In another embodiment of the present invention, the base is lithium bis(trimethylsilyl)amide (LiHMDS), lithium tetramethylpiperidide (LTMP) or lithium diisopropylamide (LDA), preferably LiHMDS.

[0084] In another embodiment of the present invention, the base is LTMP.

[0085] In another embodiment of the present invention, the base is LDA.

[0086] In another embodiment of the present invention, the alkylating agent is acetylimidazole.

[0087] In another embodiment of the present invention, the method is quenched at a temperature of less than about 0 °C to about 20 °C, preferably less than about 10 °C.

[0088] In another embodiment of the present invention, the method is quenched at a temperature of about 0 °C to about 20 °C, or about 0 °C to about 10 °C or about 0 °C to about 20 °C.

[0089] In other embodiments of the present invention, the method further comprises reacting a compound of formula 5 to form a compound of formula (I)

[0090]

[0091] wherein R is H, Cl or F, preferably F, and R2 is C1-C2 alkyl, preferably C1 alkyl.

[0092] In another embodiment of the present invention, R is Cl and R2 is C1 alkyl.

[0093] In another embodiment of the present invention, R is F and R2 is C1 alkyl.

[0094] In another embodiment of the present invention, R is H and R2 is C1 alkyl.

[0095] Another embodiment of the present invention is a compound of formula 5

[0096]

[0097] One embodiment of the present invention is a method for preparing a compound of formula 7

[0098]

[0099] wherein R is H, Cl or F, preferably F, and R1 is C1-C2 alkyl, preferably C1 alkyl,

[0100] The method comprises reacting a compound of formula 5

[0101]

[0102] with a compound of formula 6

[0103]

[0104] wherein R is H, Cl or F, preferably F, and R2 is C1-C2 alkyl, preferably C1 alkyl.

[0105] to produce a compound of formula 7.

[0106] In another embodiment of the present invention, a solvent is used in the method.

[0107] In another embodiment of the present invention, the solvent is a non-polar aprotic solvent, such as cyclohexane, toluene, heptane, xylene or a mixture thereof, preferably cyclohexane.

[0108] In another embodiment of the present invention, the solvent is heptane.

[0109] In another embodiment of the present invention, the solvent is toluene.

[0110] In another embodiment of the present invention, the temperature of the method 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, preferably about 90°C to about 110°C.

[0111] In another embodiment, the temperature is about 110°C.

[0112] In other embodiments of the present invention, the method further comprises reacting the compound of formula 7 with phosphorus oxychloride (POCl3), phosphorus trichloride (PCl3) or phosphorus pentachloride (PCl5), preferably POCl3, to produce the compound of formula 8

[0113]

[0114] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group.

[0115] In another embodiment of the present invention, the temperature of the method 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, preferably about 90°C to about 110°C.

[0116] In another embodiment, the temperature is about 100°C.

[0117] In other embodiments of the present invention, the method further comprises reacting the compound of formula 8 to produce the compound of formula (I)

[0118]

[0119] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group.

[0120] In another embodiment of the present invention, R is Cl and R2 is a C1 alkyl group.

[0121] In another embodiment of the present invention, R is F and R2 is a C1 alkyl group.

[0122] In another embodiment of the present invention, R is H and R2 is a C1 alkyl group.

[0123] In another embodiment, the method for forming a compound of formula (I) from a compound of formula 8 is carried out in situ with respect to the method for forming a compound of formula 8 from a compound of formula 7.

[0124] Another embodiment of the invention is a compound of formula 7

[0125]

[0126] One embodiment of the invention is a method for preparing a compound of formula (I)

[0127]

[0128] which comprises reacting a compound of formula 8

[0129]

[0130] with an acidic solution of acetate to produce a compound of formula (I), wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group.

[0131] In another embodiment of the invention, R is Cl and R2 is a C1 alkyl group.

[0132] In another embodiment of the invention, R is F and R2 is a C1 alkyl group.

[0133] In another embodiment of the invention, R is H and R2 is a C1 alkyl group.

[0134] In another embodiment of the invention, the acetate is potassium acetate or sodium acetate, preferably sodium acetate.

[0135] In another embodiment of the invention, the acetate is potassium acetate.

[0136] In another embodiment of the invention, the acid is acetic acid or a C1-C4 aliphatic acid, preferably acetic acid.

[0137] In another embodiment of the invention, the acid is a C1-C4 aliphatic acid.

[0138] In another embodiment of the invention, the method for forming a compound of formula (I) from a compound of formula 8 is carried out in situ with respect to the method for forming a compound of formula 8 from a compound of formula 7

[0139]

[0140] to form a compound of formula 8.

[0141] Other embodiments of the invention are to generate a compound of formula (I)

[0142]

[0143] Wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0144] This embodiment includes

[0145] i) Reacting a compound of formula 1

[0146]

[0147] with a compound of formula 2

[0148]

[0149] to produce a compound of formula 3,

[0150]

[0151] wherein the temperature of the reaction is from about 100 °C to about 170 °C;

[0152] ii) Reacting the compound of formula 3 with phenyl iodide diacetate (PhI(OAc)2) and orthoformate to form a compound of formula 4

[0153]

[0154] iii) Reacting the compound of formula 4 with a base and then with an alkylating agent to form a compound of formula 5

[0155]

[0156] iv) Reacting the compound of formula 5 with a compound of formula 6 to form a compound of formula (I).

[0157] Other embodiments of the present invention are for producing a compound of formula (I)

[0158]

[0159] Wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0160] This embodiment includes

[0161] i) Reacting a compound of formula 1

[0162]

[0163] with a compound of formula 2

[0164]

[0165] The compound of formula 3,

[0166]

[0167] wherein the temperature of the reaction is from about 100 °C to about 170 °C;

[0168] ii) Reacting the compound of formula 3 with phenyl iodide diacetate (PhI(OAc)2) and orthoformate to form the compound of formula 4

[0169]

[0170] iii) Reacting the compound of formula 4 with a base and then with an alkylating agent to form the compound of formula 5

[0171]

[0172] iv) Reacting the compound of formula 5 with the compound of formula 6

[0173]

[0174] wherein R is H, Cl or F, preferably F, and R2 is C1-C2 alkyl, preferably C1 alkyl.

[0175] To produce the compound of formula 7

[0176]

[0177] wherein R is H, Cl or F, preferably F, and R1 is C1-C2 alkyl, preferably C1 alkyl;

[0178] v) Reacting the compound of formula 7 to form the compound of formula 8

[0179] and

[0180] vi) Reacting the compound of formula 8 to form the compound of formula (I).

[0181] Other embodiments of the present invention are for producing the compound of formula (I)

[0182]

[0183] wherein R is H, Cl or F, preferably F, and R2 is C1-C2 alkyl, preferably C1 alkyl,

[0184] This embodiment includes

[0185] i) The compound of formula 1

[0186]

[0187] React with the compound of formula 2

[0188]

[0189] to produce the compound of formula 3,

[0190]

[0191] wherein the temperature of the reaction is from about 100 °C to about 170 °C;

[0192] ii) React the compound of formula 3 with phenyl iodide diacetate (PhI(OAc)2) and orthoformate to form the compound of formula 4

[0193]

[0194] iii) React the compound of formula 4 with a base and then with an alkylating agent to form the compound of formula 5

[0195]

[0196] iv) React the compound of formula 5 with the compound of formula 6

[0197]

[0198] wherein R is H, Cl or F, preferably F, and R2 is C1-C2 alkyl, preferably C1 alkyl.

[0199] to produce the compound of formula 7

[0200]

[0201] wherein R is H, Cl or F, preferably F, and R1 is C1-C2 alkyl, preferably C1 alkyl,;

[0202] v) React the compound of formula 7 to form the compound of formula 8

[0203]

[0204] vi) React the compound of formula 8 with an acidic solution of acetate to form the compound of formula (I).

[0205] In other embodiments, the intermediate compounds 3, 4, 5 and 7 enter the subsequent reaction steps as concentrated solutions without complete drying.

[0206] In other embodiments, the intermediate compound 3 enters the subsequent reaction steps as a concentrated solution without complete drying.

[0207] In other embodiments, intermediate compound 4 enters the subsequent reaction step as a concentrated solution without complete drying.

[0208] In other embodiments, intermediate compound 5 enters the subsequent reaction step as a concentrated solution without complete drying.

[0209] In other embodiments, intermediate compound 7 enters the subsequent reaction step as a concentrated solution without complete drying.

[0210] Examples

[0211] HPLC method:

[0212] Method A

[0213] Agilent Technologies UHPLC / MSD 6130B Series 1290 includes a binary pump G7120A with a degasser, a plate sampler G4226A, a column oven G1316B, a diode array detector G4212A, and a mass detector G6130B quadrupole LC / MS with an ESI source.

[0214] Column: Waters XP, 2.1x 50mm Xbridge BEH C18 2.5μ, T = 40 °C;

[0215] Eluent: A: Acetonitrile containing 0.05% (v / v) formic acid.

[0216] B: Water containing 0.05% formic acid (v / v);

[0217] Flow rate: 0.8 mL / min;

[0218] Gradient: From 2 to 100% eluent A for 1.2 min, 0.5 min of 100% eluent A;

[0219] Run time: 2.2 min;

[0220] Detection: ESI / MS, positive and negative ion scans: 100 - 1000 m / z;

[0221] UV at 254 and 210 nm.

[0222] Example 1: Preparation of methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (Compound 4)

[0223] Step 1: Preparation of 1-(4-(4-(trifluoromethoxy)phenoxy)phenyl)ethan-1-one (Compound 3)

[0224]

[0225] Potassium carbonate (39.6 g, 287 mmol) was added 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). The resulting mixture was heated to 140 °C and stirred at this temperature for 16 h. Subsequently, the reaction mixture was allowed to reach room temperature, diluted with water (1 L) and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were washed with aqueous 1 N hydrochloric acid (500 mL), dried and concentrated under reduced pressure to give a brown oil. The oil obtained was dissolved in dichloromethane (1 L), filtered through a short silica gel plate, and the filtrate was concentrated under reduced pressure to give the desired product as a brown oil (43.6 g, 140 mmol), which was used directly in Step 2.

[0226] NMR

[0227] 1 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)

[0228] 13 13C 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

[0229] UPLC / MS (Method A): Rt = 1.23 min.

[0230] Step 2: Preparation of methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (Compound 4)

[0231]

[0232] The crude product obtained 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 phenyliodine(III) diacetate (50.1 g, 152 mmol) were added successively while maintaining the temperature of the reaction mixture between 10 and 16 °C. After the addition was complete, the reaction mixture was allowed to reach room temperature and stirred for 90 min. Subsequently, the temperature was adjusted to 5 °C and water (500 mL) was added. The volume of the resulting mixture was reduced under reduced pressure (fraction volume approximately 70 mL), water (1 L) was added, and the pH was set to 7 by adding sodium bicarbonate. The aqueous solution was extracted with dichloromethane (2 × 300 mL), and the combined organic layers were dried in the presence of iodobenzene (37 wt%) and concentrated under reduced pressure to give the desired product (71.3 g, 63 wt%).

[0233] 1 1H 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)

[0234] 13 13C 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

[0235] UPLC / MS (Method A): Rt = 1.26 min; m / z 325.

[0236] Example 2: Preparation of 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (Compound 8)

[0237]

[0238] Step 1: Preparation of methyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)butanoate (Compound 5)

[0239]

[0240] Methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (20.0 g, 63 wt%, 38.6 mmol) obtained 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 temperature of the resulting solution was set to -30 °C, and a solution of 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (93 mL, 93 mmol) was added while maintaining the temperature between -31 and -28 °C. After the addition was complete (ca. 20 min), the resulting mixture was stirred at -30 to -25 °C for 1 h. Cooling was stopped, and saturated aqueous ammonium chloride (100 mL) was slowly added to the reaction mixture, which caused the temperature to increase to -1 °C. The mixture was allowed to reach room temperature and stirred for 30 min. After dilution with water (200 mL), the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed successively with aqueous 2 N hydrochloric acid (200 mL) and with brine (200 mL) and concentrated under reduced pressure to give the desired product as a brown oil (18.5 g), which was used directly in the next step.

[0241] UPLC / MS (Method A): Rt = 1.16, 1.23, 1.26 and 1.36 min; m / z 367.

[0242] Step 2: Preparation of methyl 3-((4-fluoro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate (Compound 7)

[0243]

[0244] 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 (at ca. 110 °C) for 17 h while removing the water formed. After 17 h 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 used directly in the next step.

[0245] Step 3: Preparation of 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (Compound 8)

[0246]

[0247] Phosphorus trichloride (50 mL, 536 mmol) was added to the crude product separated from Step 2 (51.2 g, 72.9 mmol), and the resulting mixture was heated at 100 °C for 2 h. The temperature of the reaction mixture was lowered to 5 °C, dichloromethane (50 mL) was added, and water (500 mL) was slowly added with vigorous stirring while maintaining the temperature below 15 °C. The reaction mixture was extracted with dichloromethane (300 mL), the organic layer was collected, washed successively with aqueous saturated sodium bicarbonate (250 mL) and water (250 mL), and concentrated under reduced pressure. The residue obtained was triturated with ethanol (200 mL) at 45 °C for 20 min. The resulting suspension was filtered, the wet cake was washed with ethanol (150 mL), and the solid obtained was dried under reduced pressure at 40 °C to give the desired product as a white solid (29.3 g, 60.7 mmol).

[0248] NMR

[0249] 1 1H 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)

[0250] 13 13C 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

[0251] 19 19F NMR (282 MHz, dimethyl sulfoxide-d6) δ (ppm): -57.1; -131.1

[0252] UPLC / MS (Method A): Rt = 1.45 min; m / z 325.

[0253] Example 3: Preparation of 6-Fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (Compound ELQ-316)

[0254]

[0255] Dissolve 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (28 g, 58.0 mmol) in acetic acid (300 mL), add sodium acetate (9.52 g, 116 mmol), and react the resulting mixture at 120 °C for 16 h. Allow the obtained suspension to reach room temperature, dilute with water (300 mL) and filter. Wash the wet filter cake successively with water (250 mL) and with acetone (2 × 125 mL), and dry the obtained solid under reduced pressure at 40 °C to obtain the desired product as a white solid (23.1 g, 50 mmol).

[0256] NMR

[0257] 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)

[0258] 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

[0259] 19 F NMR (282 MHz, N,N-dimethylformamide-d7) δ (ppm): -57.2; -140.7

[0260] UPLC / MS (Method A): Rt = 1.13 min; m / z 460.

[0261] Example 4: Preparation of 4,6-dichloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline

[0262]

[0263] Step 1: Preparation of methyl 3-((4-chloro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate

[0264]

[0265] The crude product (2.0 g, 5.43 mmol) separated in Step 1 of Example 2 was dissolved in cyclohexane (15 mL), 4-chloro-3-methoxyaniline (0.87 g, 5.43 mmol) was added, and the resulting mixture was refluxed (at about 110 °C) for 24 h while removing the water formed. Heating was stopped, and the reaction mixture was concentrated under reduced pressure to obtain the desired product (2.9 g) as a brown oil, which was directly used in the next step.

[0266] Step 2: Preparation of 4,6-dichloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline

[0267]

[0268] Phosphorus trichloride (10.6 mL, 114 mmol) was added to the crude product (2.9 g) separated in Step 1, and the resulting mixture was heated to react at 100 °C for 135 min. The temperature of the reaction mixture was lowered to 5 °C, dichloromethane (50 mL) was added, and water (100 mL) was slowly added with vigorous stirring while maintaining the temperature below 15 °C. The reaction mixture was extracted with dichloromethane (25 mL), the organic layer was collected, washed successively with aqueous saturated sodium bicarbonate (50 mL) and water (50 mL), and concentrated under reduced pressure. The obtained residue was triturated with ethanol (10 mL) at 45 °C for 20 min. The formed suspension was filtered, the wet filter cake was washed with ethanol (10 mL), and the obtained solid was dried under reduced pressure at 40 °C to obtain the desired product (1.3 g, 2.49 mmol) as a white solid.

[0269] NMR

[0270] 1 H 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)

[0271] 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

[0272] 19 19F NMR (282 MHz, DMSO-d6) δ (ppm): -57.1

[0273] UPLC / MS (Method A): Rt = 1.50 min; m / z 494.

[0274] Example 5: Preparation of 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one

[0275]

[0276] 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 h. The resulting suspension was allowed to reach room temperature, diluted with water (15 mL) and filtered. The wet filter cake was washed with water (10 mL) and the obtained solid was dried under reduced pressure at 40 °C to give the desired product as a white solid (0.9 g, 1.74 mmol).

[0277] UPLC / MS (Method A): Rt = 1.17 min; m / z 476.

[0278] Example 6: Alternative Preparation of 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (Compound ELQ-316)

[0279]

[0280] Step 1: Preparation of 1-(4-(4-(trifluoromethoxy)phenoxy)phenyl)ethan-1-one (Compound 3)

[0281]

[0282] Potassium carbonate (198 g, 1.433 mol) was added 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). The resulting mixture was heated to 137 °C and stirred at this temperature for 20 h. Subsequently, the reaction mixture was allowed to reach room temperature, diluted with water (2.5 L), and extracted with methyl tert-butyl ether (1 L). The organic layer was washed with aqueous 1 N hydrochloric acid (500 mL) and aqueous saturated 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 used directly in Step 2.

[0283] Step 2: Preparation of methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (Compound 4)

[0284]

[0285] The crude product obtained 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 phenyliodine(III) diacetate (244 g, 742 mmol) were added successively with stirring while maintaining the temperature of the reaction mixture between 6 and 15 °C. After the addition was complete, the reaction mixture was allowed to reach room temperature and stirred for 75 min. Subsequently, the temperature was 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 successively with aqueous saturated sodium bicarbonate (1 L) and aqueous saturated 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 raised to 60 °C. Approximately 95 g of iodobenzene was distilled off in the presence of iodobenzene (8 wt.%) to give the desired product (272 g, 80 wt%).

[0286] Step 3: Preparation of methyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)butanoate (Compound 5)

[0287]

[0288] Methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (272 g, 80 wt%, 706 mmol) obtained 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 temperature of the resulting solution was set to -36 °C and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1609 mL, 1609 mmol, 1 M) was added while maintaining the temperature between -36 and -28 °C. After the addition was complete, the resulting mixture was stirred between -30 and -28 °C for 1 h. Cooling was stopped and aqueous saturated ammonium chloride (1.5 L) was slowly added to the reaction mixture, which caused the temperature to increase to -1 °C. The mixture was allowed to reach room temperature and stirred for 1 h. After dilution with water (1 L), the mixture was extracted with cyclohexane (550 mL). The organic layer was washed successively with aqueous 1 N hydrochloric acid (1 L) and with brine (2 L) and concentrated under reduced pressure to a volume of approximately 650 mL, which was used directly in the next step.

[0289] Step 4: Preparation of methyl 3-((4-fluoro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate (Compound 7)

[0290]

[0291] The solution of the concentrated product from Step 3 (225 g, 610 mmol) in cyclohexane (approx. 650 mL) was diluted with cyclohexane (1 L), 4-fluoro-3-methoxyaniline (90 g, 610 mmol) was added, and the resulting mixture was refluxed (at approximately 100 °C) for 20 h while removing the water formed. After 20 h of 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, which was used directly in the next step.

[0292] Step 5: Preparation of 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (Compound 8)

[0293]

[0294] 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) in cyclohexane (ca. 400 mL) was added phosphorus trichloride (253 mL, 2685 mmol), and the resulting mixture was heated at 100 °C until all of the cyclohexane was distilled off (ca. 35 min), and then stirred for an additional 2 h at 100 °C. The temperature of the reaction mixture was lowered to room temperature, dichloromethane (800 mL) was added, and the resulting mixture was slowly added to ice water (2 L) with vigorous stirring while maintaining the temperature between 5 °C and 15 °C. Phase separation was allowed, and the aqueous layer was extracted with dichloromethane (500 mL). The combined organic layers were washed successively with saturated aqueous sodium bicarbonate (1.5 L) and with water (1.5 L) and concentrated under reduced pressure. The residue obtained was triturated with ethanol (500 mL) at 45 °C for 20 min. The resulting suspension was filtered, the wet cake was washed with ethanol (150 mL), and the solid obtained was dried under reduced pressure at 40 °C to give the desired product as a white solid (177.5 g, 371 mmol).

[0295] Step 6: Preparation of 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (Compound ELQ-316)

[0296]

[0297] 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 h. The resulting suspension was allowed to reach room temperature, diluted with water (1775 mL) and filtered. The wet cake was washed successively with water (1 L) and with acetone (2 × 500 mL), and the solid obtained was dried under reduced pressure at 40 °C to give the desired product as a white solid (150 g, 326 mmol).

[0298] Example 7: Preparation of 7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)-quinolin-4(1H)-one

[0299] 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 obtain the desired 4-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline.

[0300] Step 6: Preparation of 7-Methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one

[0301]

[0302] Dissolve 4-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (3.7 g, 7.72 mmol) in acetic acid (37 mL), add sodium acetate (1.27 g, 15.5 mmol), and react the resulting mixture at 120 °C for 17 h. Cool the reaction mixture to 65 °C, add water (200 mL) and stir for 15 min. Filter the obtained suspension and wash with water (50 mL). Add the wet cake to acetone (80 mL) and stir at room temperature for 20 min. Filter the suspension and wash with acetone (20 mL). Dry the cake under reduced pressure at 40 °C to obtain the desired product as a white solid (2.9 g, 6.50 mmol).

[0303] 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).

[0304] 13 C 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.

[0305] 19 F NMR (565 MHz, dimethyl sulfoxide-d6) δ (ppm): -57.2.

[0306] UPLC / MS (Method A): Rt = 1.12 min, m / z 442.

Claims

1. A method for preparing a compound of formula 4 wherein R1 is a C1-C2 alkyl group, preferably a C1 alkyl group, the method comprising reacting a compound of formula 3 with phenyl iodide diacetate (PhI(OAc)2) and an orthoformate to produce the compound of formula 4.

2. The method according to claim 1, wherein the orthoformate is trimethyl orthoformate or triethyl orthoformate, preferably trimethyl orthoformate (TMOF).

3. The method according to any one of claims 1-2, wherein the reaction is carried out in an alcohol.

4. The method according to any one of claims 1-3, wherein the alcohol is methanol, ethanol, n-propanol or isopropanol, preferably methanol.

5. The method according to any one of claims 1-4, wherein the compound of formula 3 is produced by reacting a compound of formula 1 with a compound of formula 2 to produce the compound of formula 3, wherein the temperature of the reaction is from about 100 °C to about 150 °C, preferably from about 135 °C to about 145 °C.

6. The method according to claim 4, wherein the reaction further comprises a base.

7. The method according to claim 6, wherein the base is potassium carbonate, sodium carbonate or cesium carbonate, preferably potassium carbonate.

8. The method according to any one of claims 5-7, wherein the reaction further comprises a solvent.

9. The method according to claim 8, wherein the solvent is dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO), preferably DMF.

10. The method according to claim 1, which further comprises reacting the compound of formula 4 to produce a compound of formula (I) wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group, 11. The method according to any one of claims 1-10, wherein the compound of formula (I) is substantially free of residual metals.

12. A compound of formula 4

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