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WO2009002955A1 - Procédé pour la préparation d'acide (2r)-2-[4-(7-bromo-2-quinoléyloxy)phénoxy]propanoïque - Google Patents

Procédé pour la préparation d'acide (2r)-2-[4-(7-bromo-2-quinoléyloxy)phénoxy]propanoïque Download PDF

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Publication number
WO2009002955A1
WO2009002955A1 PCT/US2008/067968 US2008067968W WO2009002955A1 WO 2009002955 A1 WO2009002955 A1 WO 2009002955A1 US 2008067968 W US2008067968 W US 2008067968W WO 2009002955 A1 WO2009002955 A1 WO 2009002955A1
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WO
WIPO (PCT)
Prior art keywords
bromo
ethyl
nitrophenyl
acrylate
phenoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2008/067968
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English (en)
Inventor
Dinubhai H. Shah
Philippe Lienard
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Sanofi Aventis US LLC
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Sanofi Aventis US LLC
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Filing date
Publication date
Application filed by Sanofi Aventis US LLC filed Critical Sanofi Aventis US LLC
Publication of WO2009002955A1 publication Critical patent/WO2009002955A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids

Definitions

  • 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):
  • 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.
  • 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.
  • 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.
  • USP purified water refers to water meeting the standards of the United States Pharmacopoeia (USP) for purified water.
  • 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-
  • 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.
  • 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.
  • a base such as piperidine and morpholine
  • 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.
  • the ethereal solvent is tetrahydrofuran.
  • the reaction is preferably performed at temperatures between about -2O 0 C and about 4O 0 C.
  • 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)).
  • a metal alkoxide preferably potassium tert-butoxide
  • 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.
  • sodium thionite also called sodium hydrosulfite
  • 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.
  • a base such as piperidine or morpholine
  • 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.
  • step f 7-bromo-2-chloroquinoline 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.
  • a chlorinating agent such as thionyl chloride or phosphorus oxychloride
  • 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.
  • a base for example potassium carbonate, sodium carbonate and cesium carbonate
  • a high-boiling polar solvent such as NMP, DMF, DMSO and the like
  • 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.
  • 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.
  • TPA trimethyl phosphonoacetate
  • 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.
  • /-BuOK potassium tert-butoxide
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé applicable sur le plan industriel pour préparer de l'acide (2R)-2-[4-(7-bromo-2-quinoléyloxy)phénoxy] propanoïque et des sels de celui-ci.
PCT/US2008/067968 2007-06-27 2008-06-24 Procédé pour la préparation d'acide (2r)-2-[4-(7-bromo-2-quinoléyloxy)phénoxy]propanoïque Ceased WO2009002955A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US94646607P 2007-06-27 2007-06-27
US60/946,466 2007-06-27
US4722108P 2008-04-23 2008-04-23
US61/047,221 2008-04-23

Publications (1)

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WO2009002955A1 true WO2009002955A1 (fr) 2008-12-31

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PCT/US2008/067968 Ceased WO2009002955A1 (fr) 2007-06-27 2008-06-24 Procédé pour la préparation d'acide (2r)-2-[4-(7-bromo-2-quinoléyloxy)phénoxy]propanoïque

Country Status (5)

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AR (1) AR067161A1 (fr)
CL (1) CL2008001900A1 (fr)
TW (1) TW200918505A (fr)
UY (1) UY31191A1 (fr)
WO (1) WO2009002955A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030144321A1 (en) * 2001-07-31 2003-07-31 Horwitz Jerome P. Antitumor agents
WO2004081008A1 (fr) * 2003-03-14 2004-09-23 Astrazeneca Ab Triazolones fusionnees et utilisations de celles-ci

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030144321A1 (en) * 2001-07-31 2003-07-31 Horwitz Jerome P. Antitumor agents
WO2004081008A1 (fr) * 2003-03-14 2004-09-23 Astrazeneca Ab Triazolones fusionnees et utilisations de celles-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KENNEDY G ET AL: "The Preparation of Heterobiaryl Phosphonates via the Stille Coupling Reaction", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, vol. 37, no. 42, 14 October 1996 (1996-10-14), pages 7611 - 7614, XP004068861, ISSN: 0040-4039 *

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TW200918505A (en) 2009-05-01
UY31191A1 (es) 2009-01-30
AR067161A1 (es) 2009-09-30

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