Process for preparation of oxopolyoctane-like quinolones from 3-(3-alkoxyphenyl) amino)-2-(4-(4-alkoxy) phenoxy) phenyl) but-2-enoic acid alkyl esters

Abstract

A novel amplifiable synthesis for the preparation of an oxdoxine-like quinolone compound of formula (I) in which R is H, Cl or F, and R2 is C1-C2 alkyl, where the synthesis comprises a process for the preparation of a compound of formula (7), where R is H, Cl or F, and R1 is C1-C2 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, including 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (ELQ-316) (see Figure 4, page 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 a synthetic method and novel intermediates for preparing 3-aryl endochin-like quinolone (ELQ) compounds including ELQ-316, which are suitable for industrial scale-up production.

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

[0007]

[0008] Attempts to perform 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 co-workers in ARKIVOC 2011(v)67-75, or in the presence of a solution of iodine in trimethyl orthoformate, as described by Yamauchi et al. in J. Org. Chem. 1988, 53, 4858-4859, failed to produce the desired product 4.

[0009] Pou et al. disclosed the synthetic routes of a number of oxazine-like quinolone 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, the reported yields remained moderate, at 60%-70%. In addition, Pou described introducing an acetyl group onto compound 4 using acetic anhydride, which forms a mixture of compound 5 and compound 5a. This mixture needs to be treated with an acid (p-toluenesulfonic acid, TsOH) to convert compound 5a back to compound 5. This is an additional step, and it is not easy to remove TsOH from the product, which has to be carried over to 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 oxazine-like quinolone compounds. Summary of the Invention

[0014] One embodiment of the present invention is a method for preparing a compound of formula 7

[0015]

[0016] wherein R is H, Cl, or F, preferably F, and R1 is a C1-C2 alkyl group, preferably a C1 alkyl group, and the method comprises reacting a compound of formula 5

[0017]

[0018] with a compound of formula 6

[0019]

[0020] wherein R is H, Cl, or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0021] to produce a compound of formula 7. Detailed Description

[0022] A novel scalable synthesis for the preparation of endoxifen-like quinolone compounds of formula (I)

[0023]

[0024] wherein R2 is C1-C2 alkyl, preferably C1 alkyl,

[0025] wherein R is H, Cl or F, and R1 is C1-C2 alkyl, which avoids the use of any metal catalysis (such as copper) and harsh reaction conditions, and allows the final compound to be isolated with very high purity (>99%) and without any trace of residual metal. Scheme 1 is representative, wherein R is F and R2 is methyl.

[0026] Scheme 1

[0027]

[0028] 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 this is a significant advantage when used on an industrial scale. The resulting diaryl ether acetophenone (Compound 3) is obtained in almost quantitative yield and subsequently 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. In the synthesis of active pharmaceutical ingredients (APIs), it is advantageous to avoid the use of copper. This method is suitable for large-scale / industrial use.

[0029] It has also been found that the ester (Compound 4) can be conveniently converted in one step to the keto-ester (Compound 5) by using a base and acetyl imidazole as the alkylating reagent and by carefully quenching the reaction mixture at low temperature (<10 °C). This novel method allows the isolation 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.

[0030] Furthermore, 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 (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 isolated in very high purity (>99%) and in the absence of any trace of residual metal.

[0031] AcOH is acetic acid.

[0032] AcONa is sodium acetate.

[0033] DMF is N,N-dimethylformamide.

[0034] DMSO is dimethyl sulfoxide.

[0035] LiHMDS is lithium bis(trimethylsilyl)amide or lithium hexamethyldisilazide.

[0036] LTMP is lithium tetramethylpiperidide.

[0037] LDA is lithium diisopropylamide.

[0038] MeOH is methanol.

[0039] NMP is N-methyl-2-pyrrolidone.

[0040] PCl3 is phosphorus trichloride.

[0041] PCl5 is phosphorus pentachloride.

[0042] PhI(OAc)2 is (diacetoxyiodo)benzene or phenyliodine diacetate.

[0043] POCl3 is phosphorus oxychloride.

[0044] THF is tetrahydrofuran.

[0045] TMOF is trimethyl orthoformate.

[0046] Residual metals in the drug that have no therapeutic value are considered contaminants, and their levels are strictly controlled by various regulatory agencies around the world (ICH guideline Q3D(R2) on elemental impurities). Substantially free means that they are not present in amounts or quantities exceeding those that can be expected to arise from normal processing and good manufacturing practices in the production and sale of the commodity and are 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.

[0047] One embodiment of the present invention is a method for preparing a compound of formula 4

[0048]

[0049] wherein R1 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0050] The method comprises reacting a compound of formula 3

[0051]

[0052] React with phenyl iodide diacetate (PhI(OAc)2) and orthoformate to produce the compound of Formula 4.

[0053] In another embodiment of the present invention, the orthoformate is trimethyl orthoformate or triethyl orthoformate, preferably trimethyl orthoformate (TMOF).

[0054] In another embodiment of the present invention, the reaction is carried out in an alcohol.

[0055] In another embodiment of the present invention, the alcohol is methanol, ethanol, n-propanol or isopropanol, preferably methanol.

[0056] In another embodiment of the present invention, the compound of Formula 3 is prepared by reacting the compound of Formula 1

[0057]

[0058] with the compound of Formula 2

[0059]

[0060] to produce the compound of Formula 3, wherein the temperature of the reaction 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.

[0061] In another embodiment, the temperature is about 140 °C.

[0062] In another embodiment of the present invention, the reaction further includes a base.

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

[0064] In another embodiment of the present invention, the base is sodium carbonate.

[0065] In another embodiment of the present invention, the base is cesium carbonate.

[0066] In another embodiment of the present invention, the reaction further includes a solvent.

[0067] 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.

[0068] In another embodiment of the present invention, the solvent is NMP.

[0069] In another embodiment of the present invention, the solvent is DMSO.

[0070] 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)

[0071]

[0072] wherein R is H, Cl or F, preferably F, and R2 is C1-C2 alkyl, preferably C1 alkyl.

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

[0074] In another embodiment of the present invention, R is F and R2 is C1 alkyl.

[0075] In another embodiment of the present invention, R is H and R2 is C1 alkyl.

[0076] In another embodiment of the present invention, the compound of formula (I) is substantially free of residual metals.

[0077] Another embodiment of the present invention is a compound of formula 4

[0078]

[0079] One embodiment of the present invention is a method for preparing a compound of formula 5

[0080]

[0081] wherein R1 is C1-C2 alkyl, preferably C1 alkyl,

[0082] The method comprises reacting a compound of formula 4

[0083]

[0084] with a base and subsequently with an alkylating agent to produce a compound of formula 5.

[0085] In another embodiment of the present invention, the base is lithium bis(trimethylsilyl)amide (LiHMDS), lithium tetramethylpiperidide (LTMP) or lithium diisopropylamide (LDA), preferably LiHMDS.

[0086] In another embodiment of the present invention, the base is LTMP.

[0087] In another embodiment of the present invention, the base is LDA.

[0088] In another embodiment of the present invention, the alkylating agent is acetylimidazole.

[0089] 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.

[0090] 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.

[0091] 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)

[0092]

[0093] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group.

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

[0095] In another embodiment of the present invention, R is F and R2 is a C1 alkyl group.

[0096] In another embodiment of the present invention, R is H and R2 is a C1 alkyl group.

[0097] Another embodiment of the present invention is a compound of formula 5

[0098]

[0099] One embodiment of the present invention is a method for preparing a compound of formula 7

[0100]

[0101] wherein R is H, Cl or F, preferably F, and R1 is a C1-C2 alkyl group, preferably a C1 alkyl group, the method comprising reacting a compound of formula 5

[0102]

[0103] with a compound of formula 6

[0104]

[0105] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group,

[0106] to produce a compound of formula 7.

[0107] In another embodiment of the present invention, a solvent is used in the method.

[0108] 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.

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

[0110] In another embodiment of the present invention, the solvent is toluene.

[0111] In another embodiment of the present invention, the temperature of the method is between about 50 °C and about 140 °C, between about 60 °C and about 130 °C, between about 70 °C and about 120 °C, between about 80 °C and about 120 °C, between about 85 °C and about 110 °C, preferably between about 90 °C and about 110 °C.

[0112] In another embodiment, the temperature is about 110 °C.

[0113] 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

[0114]

[0115] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group.

[0116] In another embodiment of the present invention, the temperature of the method is between about 50 °C and about 140 °C, between about 60 °C and about 130 °C, between about 70 °C and about 120 °C, between about 80 °C and about 120 °C, between about 85 °C and about 110 °C, preferably between about 90 °C and about 110 °C.

[0117] In another embodiment, the temperature is about 100 °C.

[0118] 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)

[0119]

[0120] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group.

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

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

[0123] In another embodiment of the present invention, R is H and R2 is a C1 alkyl group.

[0124] In another embodiment, the process of forming the compound of formula (I) from the compound of formula 8 is carried out in situ with the process of forming the compound of formula 8 from the compound of formula 7.

[0125] Another embodiment of the present invention is the compound of formula 7

[0126]

[0127] One embodiment of the present invention is a method for preparing a compound of formula (I)

[0128]

[0129] which comprises reacting a compound of formula 8

[0130]

[0131] 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.

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

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

[0134] In another embodiment of the present invention, R is H and R2 is a C1 alkyl group.

[0135] In another embodiment of the present invention, the acetate is potassium acetate or sodium acetate, preferably sodium acetate.

[0136] In another embodiment of the present invention, the acetate is potassium acetate.

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

[0138] In another embodiment of the present invention, the acid is a C1-C4 aliphatic acid.

[0139] In another embodiment of the present invention, the process of forming the compound of formula (I) from the compound of formula 8 is carried out in situ with the process of forming the compound of formula 8 from the compound of formula 7

[0140]

[0141] An alternative embodiment of the present invention is a method for producing 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, and the method comprises

[0144] i) reacting a compound of formula 1

[0145]

[0146] with a compound of formula 2

[0147]

[0148] to produce a compound of formula 3,

[0149]

[0150] wherein the temperature of the reaction is from about 100 °C to about 170 °C;

[0151] ii) reacting the compound of formula 3 with phenyl iododiacetate (PhI(OAc)2) and orthoformate to produce a compound of formula 4

[0152]

[0153] iii) reacting the compound of formula 4 with a base and then with an alkylating agent to produce a compound of formula 5

[0154] and

[0155] iv) reacting the compound of formula 5 with a compound of formula 6 to produce a compound of formula (I).

[0156] An alternative embodiment of the present invention is a method for producing a compound of formula (I)

[0157]

[0158] Wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group, and the method comprises

[0159] i) reacting a compound of formula 1

[0160]

[0161] with a compound of formula 2

[0162]

[0163] to produce a compound of formula 3,

[0164]

[0165] wherein the reaction temperature is from about 100 °C to about 170 °C;

[0166] ii) Reacting a compound of Formula 3 with phenyl iodide diacetate (PhI(OAc)2) and orthoformate to produce a compound of Formula 4

[0167]

[0168] iii) Reacting a compound of Formula 4 with a base and then with an alkylating agent to produce a compound of Formula 5

[0169]

[0170] iv) Reacting a compound of Formula 5 with a compound of Formula 6

[0171]

[0172] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group, to produce a 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; v) Reacting a compound of Formula 7 to produce a compound of Formula 8 and

[0175] vi) Reacting a compound of Formula 8 to produce a compound of Formula (I).

[0176] An alternative embodiment of the present invention is a method for producing a compound of Formula (I)

[0177] wherein R is H, Cl or F, preferably F, and R2 is a C1-C2 alkyl group, preferably a C1 alkyl group, the method comprising

[0178] i) Reacting a compound of Formula 1

[0179]

[0180] with a compound of Formula 2

[0181]

[0182] to produce a compound of Formula 3,

[0183]

[0184] wherein the reaction temperature is from about 100 °C to about 170 °C;

[0185] ii) React the compound of formula 3 with phenyl iodide diacetate (PhI(OAc)2) and orthoformate to produce the compound of formula 4

[0186]

[0187] iii) React the compound of formula 4 with a base, and then with an alkylating agent to produce the compound of formula 5

[0188]

[0189] iv) React the compound of formula 5 with the compound of formula 6

[0190]

[0191] wherein R is H, Cl or F, preferably F, and R2 is C1-C2 alkyl, preferably C1 alkyl, to produce the compound of formula 7

[0192]

[0193] wherein R is H, Cl or F, preferably F, and R1 is C1-C2 alkyl, preferably C1 alkyl;

[0194] v) React the compound of formula 7 to produce the compound of formula 8

[0195]

[0196] vi) React the compound of formula 8 with acetate in acid to produce the compound of formula (I).

[0197] In an alternative embodiment, the intermediate compounds 3, 4, 5 and 7 are carried out to the subsequent reaction steps in a concentrated solution without complete drying.

[0198] In an alternative embodiment, the intermediate compound 3 is carried out to the subsequent reaction steps in a concentrated solution without complete drying.

[0199] In an alternative embodiment, the intermediate compound 4 is carried out to the subsequent reaction steps in a concentrated solution without complete drying.

[0200] In an alternative embodiment, the intermediate compound 5 is carried out to the subsequent reaction steps in a concentrated solution without complete drying.

[0201] In an alternative embodiment, the intermediate compound 7 is carried out to the subsequent reaction steps in a concentrated solution without complete drying.

[0202] Examples

[0203] HPLC method:

[0204] Method A

[0205] Agilent Technologies UHPLC / MSD 6130B Series 1290, including binary pump G7120A with degasser, plate sampler G4226A, column oven G1316B, diode array detector G4212A, and mass detector G6130B quadrupole LC / MS with ESI source.

[0206] Column: Waters XP, 2.1x 50mm Xbridge BEH C18 2.5μ, T = 40°C;

[0207] Eluent A: Acetonitrile containing 0.05% (v / v) formic acid.

[0208] Eluent B: Water containing 0.05% (v / v) formic acid;

[0209] Flow rate: 0.8 mL / min;

[0210] Gradient: 2 to 100% eluent A for 1.2 min, 100% eluent A for 0.5 min;

[0211] Run time: 2.2 min;

[0212] Detection: ESI / MS, positive and negative ion scans: 100 - 1000 m / z;

[0213] UV at 254 and 210 nm.

[0214] Example 1: Preparation of methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (Compound 4)

[0215] Step 1: Preparation of 1-(4-(4-(trifluoromethoxy)phenoxy)phenyl)ethan-1-one (Compound 3)

[0216]

[0217] 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 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.

[0218] NMR

[0219] 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)

[0220] 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

[0221] UPLC / MS (Method A): Rt = 1.23 min.

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

[0223]

[0224] 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 (distilled 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 and concentrated under reduced pressure to obtain the desired product (71.3 g, 63 wt%) in the presence of iodobenzene (37 wt%).

[0225] 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)

[0226] 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

[0227] UPLC / MS (Method A): Rt = 1.26 min; m / z 325.

[0228] Example 2: Preparation of 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (Compound 8)

[0229]

[0230] Step 1: Preparation of methyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)butanoate (Compound 5)

[0231]

[0232] Methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (20.0 g, 63 wt%, 38.6 mmol) obtained in 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 completion of the addition (about 20 min), the resulting mixture was stirred at -30 to -25 °C for 1 h. Cooling was stopped, and a 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 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 2 N aqueous hydrochloric acid solution (200 mL) and brine (200 mL) and concentrated under reduced pressure to obtain the desired product as a brown oil (18.5 g), which was used directly in the next step.

[0233] UPLC / MS (Method A): Rt = 1.16, 1.23, 1.26, and 1.36 min; m / z 367.

[0234] Step 2: Preparation of methyl 3-((4-fluoro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate (Compound 7)

[0235]

[0236] The crude product (18.5 g, 38.7 mmol) isolated in Step 1 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 obtain the desired product as a brown oil (22.9 g), which was used directly in the next step.

[0237] Step 3: Preparation of 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (Compound 8)

[0238]

[0239] To the crude product separated in 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 obtained residue was triturated with ethanol (200 mL) at 45 °C for 20 min. The formed suspension was filtered, the wet filter cake was washed with ethanol (150 mL), and the obtained solid was dried under reduced pressure at 40 °C to obtain the desired product (29.3 g, 60.7 mmol) as a white solid.

[0240] NMR

[0241] 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)

[0242] 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

[0243] 19 19F NMR (282 MHz, dimethyl sulfoxide-d6) δ (ppm): -57.1; -131.1

[0244] UPLC / MS (Method A): Rt = 1.45 min; m / z 325.

[0245] Example 3: Preparation of 6-Fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (Compound ELQ-316)

[0246]

[0247] 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 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).

[0248] NMR

[0249] 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)

[0250] 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

[0251] 19 F NMR (282 MHz, N,N-dimethylformamide-d7) δ (ppm): -57.2; -140.7

[0252] UPLC / MS (Method A): Rt = 1.13 min; m / z 460.

[0253] Example 4: Preparation of 4,6-dichloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline

[0254]

[0255] Step 1: Preparation of methyl 3-((4-chloro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate

[0256]

[0257] 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.

[0258] Step 2: Preparation of 4,6-dichloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline

[0259]

[0260] 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 (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.

[0261] NMR

[0262] 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)

[0263] 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

[0264] 19 F NMR (282 MHz, DMSO-d6) δ (ppm): -57.1

[0265] UPLC / MS (Method A): Rt = 1.50 min; m / z 494.

[0266] Example 5: Preparation of 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one

[0267]

[0268] 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).

[0269] UPLC / MS (Method A): Rt = 1.17 min; m / z 476.

[0270] Example 6: Alternative Preparation of 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (Compound ELQ-316)

[0271]

[0272] Step 1: Preparation of 1-(4-(4-(trifluoromethoxy)phenoxy)phenyl)ethan-1-one (Compound 3)

[0273]

[0274] 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 1 N aqueous hydrochloric acid solution (500 mL) and saturated aqueous sodium chloride solution (500 mL), dried, and concentrated under reduced pressure to obtain the desired product as a brown oil (218 g, 707 mmol), which was used directly in Step 2.

[0275] Step 2: Preparation of methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (Compound 4)

[0276]

[0277] The crude product obtained in 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(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 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. Approximately 95 g of iodobenzene was distilled off to obtain the desired product (272 g, 80 wt%) in the presence of iodobenzene (8 wt%).

[0278] Step 3: Preparation of methyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)butanoate (Compound 5)

[0279]

[0280] Methyl 2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)acetate (272 g, 80 wt%, 706 mmol) obtained in 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 completion of the addition, the resulting mixture was stirred at between -30 and -28 °C for 1 h. Cooling was stopped and saturated aqueous ammonium chloride solution (1.5 L) was slowly added to the reaction mixture, which caused the temperature to rise 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 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.

[0281] Step 4: Preparation of methyl 3-((4-fluoro-3-methoxyphenyl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-2-enoate (Compound 7)

[0282]

[0283] 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.

[0284] Step 5: Preparation of 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (Compound 8)

[0285]

[0286] 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 in Step 4 in cyclohexane (ca. 400 mL) was added phosphorus oxychloride (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 was 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 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 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).

[0287] Step 6: Preparation of 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (Compound ELQ-316)

[0288]

[0289] 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 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).

[0290] Example 7: Preparation of 7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one

[0291] 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 obtain the desired 4-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline.

[0292] Step 6: Preparation of 7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one

[0293]

[0294] 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, dissolve it in water (200 mL) and stir for 15 min. Filter the obtained suspension and wash with water (50 mL). Dissolve the wet filter cake in acetone (80 mL) and stir at ambient temperature for 20 min. 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).

[0295] 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).

[0296] 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.

[0297] 19 F NMR (565 MHz, dimethyl sulfoxide-d6) δ (ppm): -57.2.

[0298] UPLC / MS (Method A): Rt = 1.12 min, m / z 442.

Claims

1. A method for preparing a compound of formula 7 wherein R is H, Cl or F, preferably F, and R1 is C1-C2 alkyl, preferably C1 alkyl, The method comprises reacting a compound of formula 5 with a compound of formula 6 wherein R is H, Cl or F, preferably F, and R2 is C1-C2 alkyl, preferably C1 alkyl, to produce the compound of formula 7.

2. The method according to claim 1, further comprising reacting the compound of formula 7 with phosphorus oxychloride (POCl3), phosphorus trichloride (PCl3) or phosphorus pentachloride (PCl5), preferably POCl3, to produce a compound of formula 8 wherein R is H, Cl or F, preferably F, and R2 is C1-C2 alkyl, preferably C1 alkyl.

3. The method according to claim 2, wherein a solvent is used in the method.

4. The method according to claim 3, wherein the solvent is an aprotic nonpolar solvent such as cyclohexane, toluene, heptane, xylene or a mixture thereof, preferably cyclohexane.

5. The method according to any one of claims 1-4, wherein the temperature of the method is between about 80 °C and about 120 °C, preferably between about 85 °C and about 115 °C.

6. The method according to any one of claims 2-5, further comprising reacting the compound of formula 8 to produce a compound of formula (I) wherein R is H, Cl or F, preferably F, and R2 is C1-C2 alkyl, preferably C1 alkyl.

7. The method according to claim 6, wherein the temperature of the method is between about 80 °C and about 120 °C, preferably between about 90 °C and about 110 °C.

8. The method according to any one of claims 6 or 7, wherein the process of forming the compound of formula 8 from the compound of formula 7 is carried out in situ with the process of forming the compound of formula 7 from the compound of formula 5.

9. A compound of formula 7

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