PROCESS FOR THE PREPARATION OF (2R)-2-[4-(7-BROMO-2- QUINOLYLOXY)PHENOXY]PROPANOIC ACID

BACKGROUND OF THE INVENTION This invention relates to a process for preparing (2R)-2-{4-[(7-bromoquinolin-2- yl)oxy]phenoxy} propionic acid and its pharmaceutically acceptable salts. This compound, which has the structure of Formula (I):

is described in, for example, U.S. Patent No. 6,867,219. This compound is known and is particularly useful as an antitumor agent.

U.S. Patent No. 6,867,219 describes a general method of synthesis which is difficult to transpose to the industrial scale for production in large quantities. This method of synthesis entails obtaining (2R)-2-{4-[(7-bromoquinolin-2-yl)oxy]phenoxy}propionic acid in 5 steps, which include reacting oxalyl chloride and ethylvinyl ether to prepare 3-ethoxy acryloyl chloride, which is next reacted with a substituted aniline (i.e. 3-bromoaniline). A non- regioselective ring closure is performed in sulfuric or hydrochloric acid, and the resulting regio-isomeric mixture (7-bromo-2-hydroxyquinoline and 5-bromo-2-hydroxyquinoline) is carried forward in a chlorination step using phosphorous oxychloride. The resulting 7- substituted intermediate is purified via fractional crystallization and chromatography and

reacted with chiral 2-(4-hydroxyphenoxy) propionic acid with sodium hydride or potassium carbonate to afford the (2R)-2-{4-[(7-bromoquinolin-2-yl)oxy]phenoxy}propionic acid.

The present invention has made it possible to optimize the synthesis of (2R)-2-[4-(7- bromo-2-quinolyloxy)phenoxy]propanoic acid for industrial use by avoiding: the distillation of 3-ethoxy acryloyl chloride; the formation of the undesired 5-bromoquinolin-2-ol, which, in the preparation described above, had been carried forward to the next step due to its insolubility; and the tedious chromatography used to obtain the pure 7-bromo-2- chloroquinoline.

BRIEF SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for producing (2R)-2-{4-[(7- bromoquinolin-2-yl)oxy]phenoxy}propionic acid and salts thereof, of high purity and in a relatively high yield suitable for use on an industrial scale and which furthermore avoids the necessity of chromatographic separations.

The present invention is also directed to synthetic intermediates, for example Formulae (III) and (IV) given below, that are useful in the preparation of the (2R)-2-{4-[(7- bromoquinolin-2-yl)oxy]phenoxy}propionic acid and salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and Abbreviations

As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

DCM dichloromethane

DMF N,N-dimethylformamide

NMP N-methylpyrrolidone

DMSO dimethylsulfoxide

EtOH ethanol g gram

HCl hydrochloric acid

HOAc acetic acid

HPLC high performance liquid chromatography t-BuOK potassium tert-butoxide

L liter ml milliliter

MTBE tert-buty\ methyl ether

Kg kilogram

TEA triethylamine

THF tetrahydrofuran

As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

The term "USP purified water" refers to water meeting the standards of the United States Pharmacopoeia (USP) for purified water.

According to the present invention, a process for preparing the (2R)-2-[4-(7-bromo-2- quinolyloxy)phenoxy]propanoic acid according to Formula (I) and the intermediates that are useful for preparing such compounds is outlined in Reaction Scheme 1 :

Scheme 1:

A process of the invention for preparing (2R)-2-[4-(7-bromo-2- quinolyloxy)phenoxy]propanoic acid, or a pharmaceutically acceptable salt thereof, comprises: a) reacting 4-bromo- 1 -fluoro-2-nitrobenzene with trimethyl phosphonoacetate in the presence of a first metal alkoxide to provide the intermediate methyl 2-(4-bromo-2- nitrophenyl)-2-(dimethoxy phosphoryl) acetate; b) converting methyl 2-(4-bromo-2-nitrophenyl)-2-(dimethoxy phosphoryl) acetate to dimethyl 4-bromo-2-nitro-benzylphosphonate in the presence of 1,2 -propylene glycol and a second metal alkoxide, which can be the same or different from the metal alkoxide used in step a; c) converting dimethyl 4-bromo-2-nitro-benzylphosphonate to ethyl 3-(4-bromo-2- nitrophenyl)acrylate in the presence of ethyl glycoxalate and an amine in the presence of an inert solvent; d) reducing ethyl 3-(4-bromo-2-nitrophenyl)acrylate with a reducing agent to give ethyl 3-(2-amino-4-bromophenyl)acrylate; e) converting ethyl 3-(2-amino-4-bromophenyl)acrylate to 7-bromo-2- hydroxyquinoline in the presence of a base; f) reacting 7-bromo-2-hydroxyquinoline with a chlorinating agent to provide 7- bromo-2-chloroquinoline; g) reacting 7-bromo-2-chloroquinoline with R-(+)-2-(4-hydroxy-phenoxy) propionic acid in the presence of a base and a high-boiling solvent to provide (2R)-2-{4-[(7- bromoquinolin-2-yl)oxy]phenoxy} propionic acid; and h) optionally reacting (2R)-2-{4-[(7-bromoquinolin-2-yl)oxy]phenoxy {propionic acid with a stoichiometric amount or an excess of a salt-forming inorganic or organic base in a solvent.

A preferred aspect of the invention is the process of preparing dimethyl 4-bromo-2- nitro-benzylphosphonate from methyl 2-(4-bromo-2-nitrophenyl)-2-(dimethoxy phosphoiyl) acetate in the presence of 1,2 -propylene glycol and a metal alkoxide, such as potassium t- butoxide or sodium t-butoxide.

Another preferred aspect of the invention is the process for preparing 7-bromo-2- hydroxyquinoline from ethyl 3-(4-bromo-2-nitrophenyl)acrylate by first reducing the nitro

group of ethyl 3-(4-bromo-2-nitrophenyl)acrylate with sodium thionite in the presence of DMF and water, followed by the cyclization of ethyl 3-(2-amino-4-bromophenyl)acrylate to 7-bromoquinoline-2-ol in the presence of a base, such as piperidine and morpholine. This process is outlined in Reaction Scheme 2:

Scheme 2:

(V) Na ₂ S ₂ O ₄ ZH ₂ O (VI) (VII)

For Reaction Schemes 1 and 2:

Step a entails the preparation of methyl 2-(4-bromo-2-nitrophenyl)-2-(dimethoxy phosphoryl) acetate by combining 4-bromo- 1 -fluoro 2-nitrobenzene with trimethyl phosphonoacetate in the presence of metal alkoxide, such as sodium ethoxide or, preferably, potassium tert-butoxide, in an ethereal solvent such as tetrahydrofiiran, diethyl ether, t- butylmethylether, and the like. Preferably, the ethereal solvent is tetrahydrofuran. The reaction is preferably performed at temperatures between about -2O ⁰ C and about 4O ⁰ C. In Step b, methyl 2-(4-bromo-2-nitrophenyl)-2-(dimethoxy phosphoryl) acetate is converted to dimethyl 4-bromo-2-nitro-benzylphosphonate in the presence of 1 ,2 -propylene glycol and a metal alkoxide, preferably potassium tert-butoxide, in an inert aprotic solvent, such as tetrahydrofuran and the like (see generally, Aneja et al., Tett. Lett. Vol. 24, No.43, 4641-4644 (1983)). In a preferred aspect of the invention, the reaction equipment is covered, such as with aluminum foil, or otherwise performed in order to avoid light (see e.g., Okamoto et al., J. Chem. Soc, Chem. Commun., (20) 1516 (1986)). The reaction is preferably performed at temperatures between about 5O ⁰ C and about 80 ⁰ C.

Ethyl 3-(4-bromo-2-nitrophenyl)acrylate is prepared from dimethyl 4-bromo-2-nitro- benzylphosphonate in step c by a Wittig-Horner reaction using ethylglyoxalate and an amine, such as triethylamine, in the presence of an inert solvent, such as toluene, at temperatures preferably between about 5O ⁰ C and 80 ⁰ C.

The reduction of the nitro group of ethyl 3-(4-bromo-2-nitrophenyl)acrylate in step d may be carried out using techniques well known in the art. The preferred reducing agent for carrying out this reduction is iron powder in an alcoholic solvent, such as ethanol, methanol and isopropanol and an acid, such as glacial acetic acid and hydrochloric acid. The technique

of catalytic hydrogenation using a catalyst such as platinum on carbon, platinum on alumina, platinum on carbon doped with vanadium and the like, under a pressure of between about 20 to about 2000 psi of hydrogen is also preferred. A particularly preferred reducing agent is sodium thionite (also called sodium hydrosulfite), which is reacted with ethyl 3-(4-bromo-2- nitrophenyl)acrylate in the presence of water and a polar solvent, such as DMF, DMSO and NMP.

Step e involves the ring closure of ethyl 3-(2-amino-4-bromophenyl)acrylate to 7- bromo-2-hydroxyquinoline via treatment with a base, such as piperidine or morpholine, in an inert solvent, such as benzene, xylene, toluene, and the like. This reaction is preferably performed at temperatures between about 80 ⁰ C and the reflux temperature of the mixture.

To prepare 7-bromo-2-chloroquinoline in step f, 7-bromo-2-hydroxyquinoline is reacted with a chlorinating agent, such as thionyl chloride or phosphorus oxychloride, in the presence of DMF and in an inert aprotic solvent, such as dichloromethane, toluene, xylene and the like. In step g, 7-bromo-2-chloroquinoline is reacted with R-(+)-2-(4-hydroxy-phenoxy) propionic acid at elevated temperatures, for example between about 100°C to 150°C, in the presence of a base, for example potassium carbonate, sodium carbonate and cesium carbonate, and a high-boiling polar solvent, such as NMP, DMF, DMSO and the like, to provide (2R)-2- {4-[(7-bromoquinolin-2-yl)oxy]phenoxy}propionic acid. Pharmaceutically acceptable salts of R-(+)-2-(4-hydroxy-phenoxy) propionic acid can be formed with metal or organic counterions, and include, but are not limited to, alkali metal salts such as sodium or potassium; alkaline earth metal salts such as magnesium or calcium; and ammonium or tetraalkyl ammonium. A pharmaceutically acceptable salt can be obtained using standard procedures well known in the art, such as by reacting the compound of Formula (I) with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic base in a suitable solvent or various combinations of solvents. For example, sodium and potassium salts can be made by dissolving the compound of Formula (I) in ethanol and adding about 1.1 equivalents of sodium hydroxide or potassium hydroxide, and allowing the salt to form. The following examples present typical syntheses as described in Schemes 1 and 2.

These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way.

Example 1

Preparation of Compound of Formula (III): Methyl (4-bromo-2- nitrophenyl)(dimethoxyphosphoryl)acetate

To an inerted reactor equipped with a mechanical stirrer, condenser, thermometer and dropping funnel, was charged trimethyl phosphonoacetate (TPA) (9.74 kg, 53.48 mole, 2.50 equiv.) in anhydrous THF (27.60 Kg) and was cooled to -5 to -9°C with rapid stirring at 500 rpm. While maintaining the temperature, 20 % potassium tert-butoxide (/-BuOK) in THF (29.96 Kg, 53.48 mole, 2.5 equiv.) was slowly added over a period of 3 hours. The resulting mixture was stirred for 1 hour at a temperature between -5 and -9 ⁰ C to obtain a white slurry (potassium salt of TPA). The white slurry was added to 4-bromo-l-fluoro 2-nitrobenzene ("BFN") (4.7 Kg, 23.5 mole, 1 equiv.) in THF (4.17 Kg) while maintaining the temperature between -5 and -1O ⁰ C. The reaction mixture was slowly allowed to reach room temperature overnight unassisted.

After 18 hours of reaction time, HPLC indicated reaction completion. The reaction was quenched with a solution of ammonium chloride (5.028 Kg) in water (16.6 L), while maintaining the temperature between 20 and 25 ⁰ C. The pH was adjusted to pH 4 by adding concentrated HCl (2600 ml). A gold colored solution was observed. The layers were partitioned, and the THF layer was set aside for concentration. The aqueous layer was extracted one time with MTBE (17.39 Kg). The combined organic layers were concentrated, the concentrate weighing 13.166 Kg. The residue was dissolved in MTBE (23.5 L) and washed with saturated aqueous sodium bicarbonate (2.6 L) to adjust to pH ~4. The MTBE layer was washed with water (9.4 L x 2), and the MTBE layer was then concentrated to yield 7.876 Kg of residue. Yield: 7.876 Kg, 87.7% NMR: Compatible with structure

In an alternative work-up, the product is extracted with toluene, and the organic layer is washed with water, dried and concentrated to obtain a 50% W/W concentration. The toluene solution is incorporated into the following step.

Example 2 Preparation of Compound of Formula (IV): Dimethyl (4-bromo-2-nitro-benzyl)phosphonate

A reactor equipped with a reflux condenser, a temperature probe and an addition funnel was flushed with nitrogen and wrapped with styrofoam and aluminum foil to avoid light in the reaction. The reactor was charged with 1 ,2-propylene glycol (24.132 L) followed by a rapid addition of 20% potassium tert-butoxide (/-BuOK) in THF (2.953 Kg, 3.274 L, 5.26 mole, 0.5 equiv) maintaining the temperature of the reaction between 20 and 25°C. This mixture was heated to 60 to 65°C and held at this range for 30 minutes.

In a separate reactor, a mixture of methyl (4-bromo-2- nitrophenyl)(dimethoxyphosphoryl)acetate (4.222 Kg, 10.52 mole) was mixed with 1,2- propylene glycol (4.022 L). The mixture was warmed to 30 to 35°C for loading to the addition funnel. The mixture was added as quickly as possible to the reactor which was heated to 60 to 65 ⁰ C. The addition was complete in less than 30 minutes, and the temperature of the reaction was maintained between 60 and 65 ⁰ C. After 30 minutes, the reactor was cooled with a wet-ice/acetone bath.

A 1:1 mixture of ice:water (48.264 L) was placed in the second reactor, with stirring at 600 rpm. The content of the first reactor was then transferred to the second reactor. The pH was adjusted to pH 3-4 using concentrated HCl (400 ml). The aqueous layer was extracted with MTBE (3 x 14.881 Kg, 20 L). The combined organic layers were washed with water (2 x 8.044 L). The organic later was concentrated to a residue using a rotovap, maintaining the temperature of the bath at 30 to 45°C to give 3.299 Kg of desired product. Yield: 3.290 Kg, 96.48%

NMR: Compatible with structure

Example 3 Preparation of Compound of Formula (V): Ethyl 3-(4-bromo-2-nitrophenyl)acrylate A reactor equipped with a reflux condenser, a temperature probe and an addition runnel was flushed with nitrogen and charged with dimethyl (4-bromo-2-nitro- benzyl)phosphonate (4.96 Kg, 14.47 moles) together with toluene (24.8 L) and ethyl glyoxalate (9.102 L, 9.375 g, 45.95 mole, 3 equiv., 50% toluene solution). This was followed by an addition of triethylamine (6400 ml, 4.646 Kg, 46.0 mole, 3 equiv.) maintaining the temperature below 60 ⁰ C. This mixture was heated to 60 to 65°C and stirred for 10 to 15 hours at this temperature.

The reaction mixture was cooled to 20 to 25°C, and water (37.2 L) was added to the reactor, maintaining the internal temperature between 20 to 25 ⁰ C. The pH of the mixture was

adjusted to pH 3 to 4 using 6N HCl (3.3 L) maintaining the internal temperature at 20 to 3O ⁰ C. The layers were separated, and the aqueous phase was extracted twice with 37.2 L of toluene. The combined organic layers were washed with water (24.8 L). The organic layer was concentrated to a residue using a rotovap. The remaining solvent was removed as an azeotrope with ethanol, maintaining the temperature of the bath between 40 to 50 ⁰ C to give 4.010 Kg of desired product.

Example 4 Preparation of Compound of Formula (VI): Ethyl-3-(2-amino-4-bromophenyl)acrylate An inerted reactor equipped with a mechanical stirrer, a reflux condenser, a temperature probe and an addition funnel, was charged with iron powder (0.71 Kg, 12.73 mole, 3.8 equiv.) and ethyl alcohol (9.470 Kg) followed by glacial acetic acid (0.048 Kg). The reaction mixture was stirred at 400 to 500 rpm and heated to 55°C. This temperature was maintained for 30 minutes. In a separate vessel, ethyl 3-(4-bromo-2-nitrophenyl)acrylate (0.998 Kg, 3.33 mole) was charged and dissolved in glacial acetic acid (1.754 Kg) at 25 ⁰ C. This solution was added to the reactor containing the iron powder via an addition pump. After the addition of -20% of the solution of ethyl 3-(4-bromo-2-nitrophenyl)acrylate, a broad exotherm set in. The addition was resumed after the maximum temperature (70 to 75 ⁰ C) was reached, resuming the addition at such a rate that the temperature did not exceed 75°C. The reaction was maintained at 65 ⁰ C for 30 minutes. .

The mixture was filtered at 55°C through a layer of Celite 545 to yield a gold colored liquid. The filter cake was rinsed with ethyl alcohol (0.998 Kg). The collected liquid was charged into a 1OL reactor and a distillation apparatus was set up to allow a solvent exchange of ethyl alcohol and acetic acid to toluene at atmospheric pressure. The final volume of toluene added was equal to 5 times the volume of the product.

Yield: 93.94% of mixture (59.16% ethyl-3-(2-amino-4-bromophenyi)acrylate and 34.69 % of 7-bromo-2-hydroxyquinoIine) Example 5

Preparation of Compound of Formula (VII): 7-Bromo-2-hydroxyquinoline

An inerted reactor equipped with mechanical stirrer, reflux condenser, and a temperature probe was charged with ethyl-3-(2-arnino-4-bromophenyl)acrylate mixture (3.33 moles) as described in Example 4, in 5 volumes of toluene, followed by the addition of

piperidine ( 1.548 Kg, 18.03 mole). The reaction mixture was stirred at 500 rpm and gradually heated to reflux. This temperature was maintained for 16 hours. The mixture was allowed to cool to room temperature when precipitate of the desired product was observed. The mixture was filtered through a 10 micron polylpropylene filter to yield a light colored solid. The crude dry cake of 7-bromo-2-hydroxyquinoline was charged back to the reactor followed by deionized water (7.065 Kg). The mixture was heated to reflux with stirring for one hour. The reactor was cooled to 20 to 25°C. The product was collected using a 10 micron polypropylene filter. The product was washed with deionized water (2 x 2.826 Kg). The wet cake was dried in vacuum oven at 40°C to obtain 514 g of the desired product. Yield: 68.8%

NMR: Compatible with structure

Example 6 Preparation of Compound of Formula (VIII): 7-Bromo-2-chloroquinoline An inerted reactor equipped with a mechanical stirrer, a reflux condenser, an addition funnel and caustic scrubber was charged with 7-bromo-2-hydroxyquinoline (1.22 Kg, 5.45 mole), dichloromethane (9.706 Kg), and dimethylformamide (0.276 Kg) followed by a slow addition of thionyl chloride (0.973 Kg, 8.17 mole, 1.5 equiv.). The reaction mixture was then gradually heated to reflux. The reflux was continued until solution is achieved (about 2 hours). The reaction mixture was then cooled to 20 to 25°C, and USP purified water (3.663 Kg) was added and stirred. Then to the reactor was gradually added with stirring a solution of potassium carbonate (0.828 Kg) in USP purified water (0.828 Kg). After 15 minutes, the stirring was stopped and the layers were allowed to separate. The pH of aqueous layer was confirmed greater than 7. The dichloromethane solution was separated and washed with USP purified water (3.663 Kg). USP purified water (7.326 Kg) was then added to the dichloromethane solution, and the dichloromethane was distilled off until the product precipitated out of the aqueous layer. The reactor was cooled to 20 to 25°C. The product was filtered and washed USP purified water (2 x 1.22 Kg). The product was dried in a vacuum oven at 40 to 5O ⁰ C to obtain 1.154 Kg of desired product. Yield: 78.8%

NMR: Compatible with product

Example 7

Preparation of Compound of Formula (I): (2R)-2-{4-[(7-Bromoquinolin-2- yl)oxy]phenoxy}propionic acid

An inerted rector equipped with a mechanical stirrer, a reflux condenser and a temperature probe was charged with 7-bromo-2-chloroquinoline (0.9225 Kg, 3.81 mole), of R-(+)-2-(4-hydroxy-phenoxy) propionic acid (0.721 Kg, 3.81 mole), potassium carbonate (1.319 Kg, 9.48 mole, 2.5 equiv.), and anhydrous dimethylformamide (4.254 Kg) with stirring at 200-300 rpm. The reaction mixture was then heated to 130 to 140°C over a period of 1 hour. A temperature of 130 to 14O ⁰ C was maintained for a period of 15 hours. The reaction mixture was cooled to 15 to 20 ⁰ C when it became thick. The reactor was then charged with USP purified water (13.84 Kg) and treated slowly by addition of concentrated HCl (834.7 g). At the end of the addition of HCl, a precipitate was observed, and the pH of the mixture was between pH 3 to 4. The solid was extracted with ethyl acetate (8 L), and the ethyl acetate extract was washed with USP purified water (2 x 2L), followed by two washes with 10% citric acid solution. The ethyl acetate solution was then treated with 100 g of Darco G-60 charcoal and stirred for 30 minutes at 22°C and filtered through a 10 micron polypropylene filter. The ethyl acetate extract thus obtained was distilled off at reduced (100 mm Hg) pressure. After !4 of the volume of ethyl acetate had distilled out, 6 L of isopropyl alcohol were added and the distillation was continued until another Vi volume of ethyl acetate distilled off. 4 Kg of USP purified water were then added slowly, and cooling was applied at

10°C/hour to reach a final temperature of 22°C. The product crystallized out of the solution. The product was filtered through a polypropylene filter. The wet cake was dried in an isolator at 4O ⁰ C in a vacuum oven. The final yield of desired product was 0.753 Kg. A manual sieving was performed though a polyethylene sieve. Yield: 50%

Example 8

Alternative preparation of 7-bromo-2-hydroxyquinoline from ethyl 3-(4-bromo-2- nitrophenyl)acrylate A one liter reactor was charged with ethyl 3-(4-bromo-2-nitrophenyl)acrylate (72.0 g,

0.24 mole) in DMF (360 ml) followed by sodium dithionite (125 g, 0.72 mol) and water (125 ml) with stirring. In 15 minutes, the reaction temperature rose to 54 °C and then started dropping. After one hour, TLC showed complete reduction to ethyl-3-(2-amino-4-

bromophenyl)acrylate. The reaction mixture was gradually heated to 130 ⁰ C over 50 minutes. The pot temperature reached 109 ⁰ C. The temperature was maintained at 130 ⁰ C for three hours, and then reduced to 90 ⁰ C pot temperature. Piperidine (72 ml) was added slowly, and the circulator oil bath was reheated to 12O ⁰ C for three hours; the pot temperature rose to 103 ⁰ C. At the end of three hours, the heating circulator oil bath was allowed to cool 20 degrees/hour overnight with stirring.

On the following day, the reaction mixture was drained from the reactor to a one liter flask and then gradually added to 1500 ml of water. A solid separated after allowing the mixture to stand for one hour. The solid was filtered off and dried in a vacuum oven at 55°C overnight to give 28.3 g of 7-bromoquinoline-2-ol. The solid was further purified by stirring with toluene (100 ml) for 15 minutes, filtered, washed with toluene (50 ml), and dried to give 24.1 g of desired product.

Example 9 Alternative preparation of Ethyl-3-(2-amino-4-bromophenyl)acrylate

A hydrogenation apparatus was charged with 3-(4-bromo-2-nitrophenyl)acrylate (200 mg), ethanol (2 ml) and 20 mg of platinum/vanadium on charcoal (Type F4, Degussa). The apparatus was degassed several times with nitrogen and then pressurized with hydrogen (P = 5 bar). The mixture was stirred at 500 rpm for 24 hours. After HPLC monitoring, the reaction was found to be complete. Filtration of the catalyst and evaporation of the solvent yielded 150 mg of an oil. Yield: 83%