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

Abstract

There is provided a novel scalable synthesis for the preparation of an oxopolyoxin-like quinolone compound of formula (I) wherein R is H, Cl or F, and R2 is a C1-C2 alkyl group wherein the synthesis comprises reacting a compound of formula (8) with an acetate in an acid 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 C1-C2 alkyl group. # imgabs0 #

Description

Background Art

[0001] U.S. Patent No. 8,598,354 discloses endochin-like quinolone compounds having anti-parasitic 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, Table 23).

[0002]

[0003] McConnell et al., (ACS Infect. Dis. 2018, 4, 1574-1584) disclose additional endochin-like quinolone compounds, including 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 synthetic methods and new intermediates for preparing 3-aryl endochin-like quinolone (ELQ) compounds, including ELQ-316, which are suitable for industrial-scale production.

[0006] Hammers et al. described (diacetoxyiodo)benzene (also known as phenyl(III) diacetate, PhI(OAc)2) and trimethyl orthoformate (TMOF) in methanol for the 1,2-aryl migration of ketone oxidation to the corresponding α-methyl ester (Org. Biomol. Chem. 2021, 19, 2213-2223).

[0007]

[0008] As described by Krishnacharya G. Akamanchi and his colleagues 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 iodine in trimethyl orthoformate, an attempt was made to oxidatively rearrange intermediate 3 to compound 4; the desired product 4 was not produced.

[0009] Pou et al. disclosed many cinchonoquinolone compounds such as ELQ-300, ELQ-316 and other antiparasitic quinolones (Org. Process Res. Dev. 2021, 25, 1841-1852). Specifically, Pou disclosed another method for preparing compounds similar to compound 4, which involves using a metal (copper) at an elevated temperature of 160 °C. However, it was reported that the yield remained moderate, 60%-70%. In addition, Pou described the use of acetic anhydride to introduce an acetyl group onto compound 4, thereby obtaining a mixture of compounds 5 and 5a. This mixture needed to be treated with an acid (p-toluenesulfonic acid, TsOH) to convert 5a back to 5. This is an additional step and it is not easy to remove TsOH from the product that has to be carried forward in the next step.

[0010]

[0011] Vaswani et al. (Org. Lett. 2014, 16, 4114-4117) disclosed the use of lithium bis(trimethylsilyl)amide (LiHMDS) and 1-(1H-imidazol-1-yl)ethanone for the acylation of aryl α-methyl esters 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 for the synthesis of cinchonoquinolone compounds. Summary of the Invention

[0014] One embodiment of the present invention is a method for preparing a compound of formula (I),

[0015]

[0016] The method includes reacting a compound of formula 8

[0017]

[0018] with an acetate in an acid to produce a compound of formula (I), wherein R is H, Cl or F, preferably F, and wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl, preferably C1 alkyl. Detailed Description

[0019] A novel scalable synthesis for preparing a cinchonoquinolone compound of formula (I)

[0020]

[0021] wherein R2 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0022] wherein R is H, Cl or F, and R1 is a C1-C2 alkyl group, which avoids the use of any metal catalyst (such as copper) and harsh reaction conditions and allows the final compound to be isolated in very high purity (>99%) and in the absence of any trace of residual metal. Scheme 1 is representative, where R is F and R2 is methyl.

[0023] Scheme 1

[0024]

[0025] It has been found that the use of copper can be avoided by reacting 4-fluoroacetophenone (Compound 1) with p-trifluoromethylphenol (Compound 2) in the presence of a base at 100 °C to 140 °C. This temperature range is lower than other known similar reactions and has significant advantages when this method is operated on an industrial scale. The resulting diarylether acetophenone (Compound 3) is obtained in almost quantitative yield and then undergoes oxidative rearrangement to give the ester intermediate (Compound 4) in high yield and purity. This novel method allows the isolation of Compound (Compound 4) in the absence of any trace of residual metal. Avoiding the use of copper in the synthesis of active pharmaceutical ingredients (APIs) is advantageous. This method is suitable for large-scale / industrial use.

[0026] It has also been found that by using a base and acetylimidazole as an alkylating agent and by carefully quenching the reaction mixture at low temperature (<10 °C), the ester (Compound 4) can be conveniently converted into the keto-ester (Compound 5) in one step. This novel method allows the isolation of the target keto-ester (Compound 5) in high yield and high purity. As reported in the literature, the formation of by-product 5a was not observed under these novel reaction conditions.

[0027] In addition, it has been determined that the condensation / ring closure reaction carried out in the presence of phosphorus oxychloride (POCl3) under mild reaction conditions (80 °C) allows the isolation of the chloroquinoline intermediate (Compound 8) in high yield (~75%) and very high purity (>99%). Then, in the presence of sodium acetate in acetic acid, this intermediate (Compound 8) is converted to 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one in quantitative yield. This compound is isolated in very high purity (>99%) and in the absence of any trace of residual metal.

[0028] AcOH is acetic acid.

[0029] AcONa is sodium acetate.

[0030] DMF is N,N-dimethylformamide.

[0031] DMSO is dimethyl sulfoxide.

[0032] LiHMDS is lithium bis(trimethylsilyl)amide or lithium hexamethyldisilazide.

[0033] LTMP is lithium tetramethylpiperidide.

[0034] LDA is lithium diisopropylamide.

[0035] MeOH is methanol.

[0036] NMP is N-methyl-2-pyrrolidone.

[0037] PCl3 is phosphorus trichloride.

[0038] PCl5 is phosphorus pentachloride.

[0039] PhI(OAc)2 is (diacetoxyiodo)benzene or iodobenzene diacetate.

[0040] POCl3 is phosphorus oxychloride.

[0041] THF is tetrahydrofuran.

[0042] TMOF is trimethyl orthoformate.

[0043] Residual metals in drugs that have no therapeutic value are considered contaminants, and their levels are strictly controlled by various regulatory agencies worldwide (ICH guideline Q3D(R2) on elemental impurities). "Substantially free" means that their content or quantity does not exceed the quantity or amount that would be expected to arise from normal processing and good manufacturing practices employed in the production and sale of the article, and is consistent therewith. For residual metals in parenterally administered active pharmaceutical ingredients (APIs), such as copper, it means less than 300 ppm of residual metal in the API composition.

[0044] One embodiment of the present invention is a method for preparing a compound of formula 4

[0045]

[0046] wherein R1 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0047] The method comprises reacting a compound of formula 3

[0048]

[0049] with iodobenzene diacetate PhI(OAc)2 and an orthoformate to produce a compound of formula 4.

[0050] In another embodiment of the present invention, the orthoformate is trimethyl orthoformate or triethyl orthoformate, preferably trimethyl orthoformate (TMOF).

[0051] In another embodiment of the present invention, the reaction is carried out in an alcohol.

[0052] In another embodiment of the present invention, the alcohol is methanol, ethanol, n-propanol or isopropanol, preferably methanol.

[0053] In another embodiment of the present invention, the compound of formula 3 is obtained by reacting the compound of formula 1

[0054] with the compound of formula 2

[0055]

[0056] to produce the compound of formula 3, wherein the temperature of the reaction is between about 100 °C and about 170 °C, between about 100 °C and about 150 °C, between about 125 °C and about 150 °C, between about 130 °C and about 150 °C, between about 100 °C and about 145 °C, between about 125 °C and about 145 °C, between about 100 °C and about 140 °C, preferably about 135 °C to about 145 °C.

[0057] In another example, the temperature is about 140 °C.

[0058] In another embodiment of the present invention, the reaction further comprises a base.

[0059] In another embodiment of the present invention, the base is potassium carbonate, sodium carbonate or cesium carbonate, preferably potassium carbonate.

[0060] In another embodiment of the present invention, the base is sodium carbonate.

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

[0062] In another embodiment of the present invention, the reaction further comprises a solvent.

[0063] 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.

[0064] In another embodiment of the present invention, the solvent is NMP.

[0065] In another embodiment of the present invention, the solvent is DMSO.

[0066] In an alternative embodiment of the present invention, the method further comprises reacting a compound of formula 4 to produce a compound of formula (I).

[0067]

[0068] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group.

[0069] In another embodiment of the present invention, R is Cl and R2 is a C1 alkyl group.

[0070] In another embodiment of the present invention, R is F and R2 is a C1 alkyl group.

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

[0072] In another embodiment of the present invention, the compound of formula (I) is substantially free of residual metals.

[0073] Another embodiment of the present invention is a compound of formula 4

[0074]

[0075] One embodiment of the present invention is a method for preparing a compound of formula 5

[0076]

[0077] wherein R1 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0078] The method comprises reacting a compound of formula 4

[0079]

[0080] with a base and then with an alkylating agent to produce a compound of formula 5.

[0081] In another embodiment of the present invention, the base is lithium bis(trimethylsilyl)amide (LiHMDS), lithium tetramethylpiperidide (LTMP) or lithium diisopropylamide (LDA), preferably LiHMDS.

[0082] In another embodiment of the present invention, the base is LTMP.

[0083] In another embodiment of the present invention, the base is LDA.

[0084] In another embodiment of the present invention, the alkylating agent is acetyl imidazole.

[0085] In another embodiment of the present invention, the method is quenched at a temperature below about 0 °C to about 20 °C, preferably below about 10 °C.

[0086] In another embodiment of the present invention, the method is quenched at a temperature between about 0 °C and about 20 °C, or between about 0 °C and about 10 °C, or between about 10 °C and about 20 °C.

[0087] In an alternative embodiment of the present invention, the method further comprises reacting a compound of formula 5 to produce a compound of formula (I)

[0088]

[0089] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group.

[0090] In another embodiment of the present invention, R is Cl and R2 is a C1 alkyl group.

[0091] In another embodiment of the present invention, R is F and R2 is a C1 alkyl group.

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

[0093] Another embodiment of the present invention is a compound of formula 5

[0094]

[0095] One embodiment of the present invention is a method for preparing a compound of formula 7

[0096]

[0097] wherein R is H, Cl or F, preferably F, and R1 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0098] The method comprises reacting a compound of formula 5

[0099]

[0100] with a compound of formula 6

[0101]

[0102] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0103] to obtain a compound of formula 7.

[0104] In another embodiment of the present invention, a solvent is used in the method.

[0105] In another embodiment of the present invention, the solvent is an aprotic non-polar solvent such as cyclohexane, toluene, heptane, xylene or a mixture thereof, preferably cyclohexane.

[0106] In another embodiment of the present invention, the solvent is heptane.

[0107] In another embodiment of the present invention, the solvent is toluene.

[0108] In another embodiment of the present invention, the temperature of the method is from about 50 °C to about 140 °C, from about 60 °C to about 130 °C, from about 70 °C to about 120 °C, from about 80 °C to about 120 °C, from about 85 °C to about 110 °C, preferably from about 90 °C to about 110 °C.

[0109] In another embodiment, the temperature is about 110 °C.

[0110] In an alternative embodiment of the present invention, the method further comprises reacting a compound of formula 7 with phosphorus oxychloride (POCl3), phosphorus trichloride (PCl3) or phosphorus pentachloride (PCl5), preferably POCl3, to produce a compound of formula 8

[0111]

[0112] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group.

[0113] In another embodiment of the present invention, the temperature of the method is from about 50 °C to about 140 °C, from about 60 °C to about 130 °C, from about 70 °C to about 120 °C, from about 80 °C to about 120 °C, from about 85 °C to about 110 °C, preferably from about 90 °C to about 110 °C.

[0114] In another embodiment, the temperature is about 100 °C.

[0115] In an alternative embodiment of the present invention, the method further comprises reacting a compound of formula 8 to produce a compound of formula (I)

[0116]

[0117] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group.

[0118] In another embodiment of the present invention, R is Cl and R2 is a C1 alkyl group.

[0119] In another embodiment of the present invention, R is F and R2 is a C1 alkyl group.

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

[0121] 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.

[0122] Another embodiment of the present invention is a compound of formula 7

[0123]

[0124] One embodiment of the present invention is a method for preparing a compound of formula (I)

[0125]

[0126] The method comprises reacting a compound of formula 8

[0127]

[0128] with an acetate in an acid 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.

[0129] In another embodiment of the present invention, R is Cl and R2 is a C1 alkyl group.

[0130] In another embodiment of the present invention, R is F and R2 is a C1 alkyl group.

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

[0132] In another embodiment of the present invention, the acetate is potassium acetate or sodium acetate, preferably sodium acetate.

[0133] In another embodiment of the present invention, the acetate is potassium acetate.

[0134] In another embodiment of the present invention, the acid is acetic acid or a C1-C4 aliphatic acid, preferably acetic acid.

[0135] In another embodiment of the present invention, the acid is a C1-C4 aliphatic acid.

[0136] In another embodiment of the present 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

[0137]

[0138] An alternative embodiment of the present invention is to prepare a compound of formula (I)

[0139]

[0140] Wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0141] comprising

[0142] i) reacting a compound of formula 1

[0143]

[0144] with a compound of formula 2

[0145]

[0146] to produce a compound of formula 3

[0147]

[0148] wherein the temperature of the reaction is between about 100 °C and about 170 °C;

[0149] ii) reacting the compound of formula 3 with iodobenzene diacetate (PhI(OAc)2) and a formate to produce a compound of formula 4

[0150]

[0151] iii) reacting the compound of formula 4 with a base and then with an alkylating agent to produce a compound of formula 5

[0152] and

[0153] iv) reacting the compound of formula 5 with a compound of formula 6 to produce the compound of formula (I).

[0154] An alternative embodiment of the present invention is to prepare a compound of formula (I)

[0155]

[0156] Wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0157] which comprises

[0158] i) reacting a compound of formula 1

[0159]

[0160] with a compound of formula 2

[0161]

[0162] The compound of formula 3,

[0163]

[0164] wherein the temperature of the reaction is between about 100 °C and about 170 °C;

[0165] ii) Reacting the compound of formula 3 with iodobenzene diacetate (PhI(OAc)2) and orthoformate to produce the compound of formula 4

[0166]

[0167] iii) Reacting the compound of formula 4 with a base and then with an alkylating agent to produce the compound of formula 5

[0168]

[0169] iv) Reacting the compound of formula 5 with the compound of formula 6

[0170]

[0171] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0172] to obtain the compound of formula 7

[0173]

[0174] wherein R is H, Cl or F, preferably F, and R1 is a C1-C2 alkyl group, preferably a C1 alkyl group;

[0175] v) Reacting the compound of formula 7 to produce the compound of formula 8

[0176] and

[0177] vi) Reacting the compound of formula 8 to produce the compound of formula (I).

[0178] An alternative embodiment of the present invention is to prepare the compound of formula (I)

[0179]

[0180] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0181] which comprises

[0182] i) Reacting the compound of formula 1

[0183]

[0184] React with the compound of formula 2

[0185]

[0186] to produce the compound of formula 3,

[0187]

[0188] wherein the temperature of the reaction is between about 100 °C and about 170 °C;

[0189] ii) React the compound of formula 3 with iodobenzene diacetate (PhI(OAc)2) and orthoformate to produce the compound of formula 4

[0190]

[0191] iii) React the compound of formula 4 with a base and then with an alkylating agent to produce the compound of formula 5

[0192]

[0193] iv) React the compound of formula 5 with the compound of formula 6

[0194]

[0195] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0196] to obtain the compound of formula 7

[0197]

[0198] wherein R is H, Cl or F, preferably F, and R1 is a C1-C2 alkyl group, preferably a C1 alkyl group;

[0199] v) React the compound of formula 7 to produce the compound of formula 8

[0200]

[0201] vi) React the compound of formula 8 with an acetate in an acid to produce the compound of formula (I).

[0202] In an alternative embodiment, the intermediate compounds 3, 4, 5 and 7 are subjected to subsequent reaction steps in a concentrated solution without complete drying.

[0203] In an alternative embodiment, the intermediate compound 3 is subjected to subsequent reaction steps in a concentrated solution without complete drying.

[0204] In an alternative embodiment, the intermediate compound 4 is subjected to subsequent reaction steps in a concentrated solution without complete drying.

[0205] In an alternative embodiment, the subsequent reaction steps of intermediate compound 5 are carried out in a concentrated solution without complete drying.

[0206] In an alternative embodiment, the subsequent reaction steps of intermediate compound 7 are carried out in a concentrated solution without complete drying.

[0207] Embodiment

[0208] HPLC method:

[0209] Method A

[0210] Agilent Technologies UHPLC / MSD 6130B Series 1290 consisting of a binary pump G7120A, including 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.

[0211] Column: Waters XP, 2.1x50mm Xbridge BEH C18 2.5μ, T = 40 °C;

[0212] Eluent: A: Acetonitrile with 0.05% (vol. / vol.) formic acid.

[0213] B: Water containing 0.05% formic acid (vol. / vol.);

[0214] Flow rate: 0.8 mL / min;

[0215] Gradient: From 2 to 100% eluent A for 1.2 min, 0.5 min at 100% eluent A;

[0216] Run time: 2.2 min;

[0217] Detection: ESI / MS, positive and negative ion scans: 100 - 1000 m / z;

[0218] At 254 and 210 nm.

[0219] Example 1: Preparation of methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (Compound 4)

[0220] Step 1: Preparation of 1-(4-(4-(trifluoromethoxy)phenoxy)phenyl)ethan-1-one (Compound 3)

[0221]

[0222] 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. Then 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 1 N aqueous hydrochloric acid solution (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 silica gel pad 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.

[0223] NMR

[0224] 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)

[0225] 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

[0226] UPLC / MS (Method A): Rt = 1.23 min.

[0227] Step 2: Preparation of methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (Compound 4)

[0228]

[0229] 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 phenyl(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 brought to room temperature and stirred for 90 minutes. Then the temperature was adjusted to 5 °C and water (500 mL) was added. The volume of the resulting mixture was reduced under reduced pressure (distilled volume ~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), 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.%).

[0230] 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)

[0231] 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

[0232] UPLC / MS (Method A): Rt = 1.26 min; m / z 325.

[0233] Example 2: Preparation of 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (Compound 8)

[0234]

[0235] Step 1: Preparation of methyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)butanoate (Compound 5)

[0236]

[0237] 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 anhydrous tetrahydrofuran (200 mL) and anhydrous N,N-dimethylacetamide (20 mL). The temperature of the resulting solution was set to -30 °C and a 1 M solution of 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 (about 20 min), the resulting mixture was stirred at -30 to -25 °C for 1 h. Cooling was stopped and saturated aqueous ammonium chloride solution (100 mL) was slowly added to the reaction mixture, which caused the temperature to rise to -1 °C. The mixture was brought to 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 2 N aqueous hydrochloric acid solution (200 mL) and 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.

[0238] UPLC / MS (Method A): Rt = 1.16, 1.23, 1.26 and 1.36 min; m / z 367.

[0239] Step 2: Preparation of methyl 3-((4-fluoro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate (Compound 7)

[0240]

[0241] The crude product separated 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 about 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.

[0242] Step 3: Preparation of 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (Compound 8)

[0243]

[0244] To the crude product separated from Step 2 (51.2 g, 72.9 mmol), phosphorus oxychloride (50 mL, 536 mmol) was added 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 saturated aqueous 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 rinsed 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).

[0245] NMR

[0246] 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)

[0247] 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

[0248] 19 19F NMR (282 MHz, dimethyl sulfoxide-d6) δ (ppm): -57.1; -131.1 UPLC / MS (Method A): Rt = 1.45 min; m / z 325.

[0249] Example 3: Preparation of 6-Fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (Compound ELQ-316)

[0250]

[0251] 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. Let the resulting suspension reach room temperature, dilute with water (300 mL) and filter. Wash the wet filter cake successively with water (250 mL) and acetone (2125 mL), and dry the resulting solid under reduced pressure at 40 °C to obtain the desired product, which is a white solid (23.1 g, 50 mmol).

[0252] NMR

[0253] 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)

[0254] 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

[0255] 19 F NMR (282 MHz, N,N-dimethylformamide-d7) δ (ppm): -57.2; -140.7

[0256] UPLC / MS (Method A): Rt = 1.13 min; m / z 460..

[0257] Example 4: Preparation of 4,6-dichloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline

[0258]

[0259] Step 1: Preparation of methyl 3-((4-chloro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate

[0260]

[0261] 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, which was a brown oil (2.9 g), and it was directly used in the next step.

[0262] Step 2: Preparation of 4,6-dichloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline

[0263]

[0264] Phosphorus oxychloride (10.6 mL, 114 mmol) was added to the crude product (2.9 g) separated in Step 1, and the resulting mixture was heated 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 saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL), and concentrated under reduced pressure. The residue obtained was triturated with ethanol (10 mL) at 45 °C for 20 min. The resulting suspension was filtered, the wet cake was rinsed with ethanol (10 mL), and the obtained solid was dried under reduced pressure at 40 °C to obtain the desired product, which was a white solid (1.3 g, 2.49 mmol).

[0265] NMR

[0266] 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)

[0267] 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

[0268] 19 19F NMR (282 MHz, DMSO-d6) δ (ppm): -57.1

[0269] UPLC / MS (Method A): Rt = 1.50 min; m / z 494.

[0270] Example 5: Preparation of 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one

[0271]

[0272] 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 brought to 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).

[0273] UPLC / MS (Method A): Rt = 1.17 min; m / z 476.

[0274] Example 6: Alternative Preparation of 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (Compound ELQ-316)

[0275]

[0276] Step 1: Preparation of 1-(4-(4-(trifluoromethoxy)phenoxy)phenyl)ethan-1-one (Compound 3)

[0277]

[0278] 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. Then 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 1 N aqueous hydrochloric acid solution (500 mL) and saturated aqueous sodium chloride solution (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.

[0279] Step 2: Preparation of methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (Compound 4)

[0280]

[0281] 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 minutes. Then 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 saturated aqueous sodium bicarbonate solution (1 L) and saturated aqueous sodium chloride solution (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. In the presence of iodobenzene (8 wt.%), about 95 g of iodobenzene was distilled off to give the desired product (272 g, 80 wt.%).

[0282] Step 3: Preparation of methyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)butanoate (Compound 5)

[0283]

[0284] 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 anhydrous tetrahydrofuran (2.4 L) and anhydrous N,N-dimethylacetamide (440 mL). The temperature of the resulting solution was set 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 resulting mixture was stirred at -30 to -28 °C for 1 h. Cooling was stopped and a saturated aqueous ammonium chloride solution (1.5 L) was slowly added to the reaction mixture, causing the temperature to rise to -1 °C. The mixture was brought to 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 1 N aqueous hydrochloric acid solution (1 L) and brine (2 L), and concentrated under reduced pressure to a volume of approximately 650 mL, which was used directly in the next step.

[0285] Step 4: Preparation of methyl 3-((4-fluoro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate (Compound 7)

[0286]

[0287] The concentrated product solution (225 g, 610 mmol) in cyclohexane (~650 mL) from Step 3 was diluted with cyclohexane (1 L), 4-fluoro-3-methoxyaniline (90 g, 610 mmol) was added, and the resulting mixture was refluxed (at about 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.

[0288] Step 5: Preparation of 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (Compound 8)

[0289]

[0290] 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) obtained from Step 4 in cyclohexane (~400 mL), phosphorus oxychloride (253 mL, 2685 mmol) was added, and the resulting mixture was heated at 100 °C until all cyclohexane was distilled off (ca. 35), and then stirred at 100 °C for an additional 2 h. The temperature of the reaction mixture was lowered to ambient temperature, dichloromethane (800 mL) was added and the resulting mixture was slowly added to ice-cold water (2 L) with vigorous stirring while 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 successively with saturated aqueous sodium bicarbonate (1.5 L) and 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 rinsed 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). Step 6: Preparation of 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (Compound ELQ-316)

[0291]

[0292] 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 brought to room temperature, diluted with water (1775 mL) and filtered. The wet cake was rinsed successively with water (1 L) and acetone (2500 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).

[0293] Example 7: Preparation of 7-methoxy-2-methyl-3-(4-(4(trifluoromethoxy)phenoxy)phenyl)-quinolin-4(1H)-one

[0294] Steps 1 to 3 of Example 6 were repeated, 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.

[0295] Step 6: Preparation of 7-Methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one

[0296]

[0297] 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 allow the resulting mixture to react at 120 °C for 17 h. Cool the reaction mixture to 65 °C, absorb it in water (200 mL) and stir for 15 min. Filter the resulting suspension and wash with water (50 mL). Absorb the wet filter cake in acetone (80 mL) and stir at ambient temperature for 20 minutes. Filter the suspension and wash with acetone (20 mL). Dry the filter cake under reduced pressure at 40 °C to obtain the desired product as a white solid (2.9 g, 6.50 mmol).

[0298] 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).

[0299] 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.

[0300] 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. A method for preparing a compound of formula (I) The method comprises reacting a compound of formula 8 R2 with an acetate in an acid to produce the 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.

2. The method according to claim 1, wherein the acetate is potassium acetate or sodium acetate, preferably sodium acetate.

3. The method according to any one of claims 1-2, wherein the acid is acetic acid or a C1-C4 aliphatic acid, preferably acetic acid.

4. The method according to any one of claims 1-3, wherein the method of forming the compound of formula (I) from the compound of formula 8 is carried out in situ with respect to the method of forming the compound of formula 8 from the compound of formula 7

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