WO2015145163A1 - Procédé de fabrication de s-(+)-flurbiprofène - Google Patents

Procédé de fabrication de s-(+)-flurbiprofène Download PDF

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Publication number
WO2015145163A1
WO2015145163A1 PCT/GB2015/050920 GB2015050920W WO2015145163A1 WO 2015145163 A1 WO2015145163 A1 WO 2015145163A1 GB 2015050920 W GB2015050920 W GB 2015050920W WO 2015145163 A1 WO2015145163 A1 WO 2015145163A1
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WO
WIPO (PCT)
Prior art keywords
flurbiprofen
salt
solvent
process according
water
Prior art date
Application number
PCT/GB2015/050920
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English (en)
Inventor
Gary Reid
Original Assignee
Aesica Pharmaceuticals Limited
Priority date (The priority date 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 date listed.)
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Publication date
Application filed by Aesica Pharmaceuticals Limited filed Critical Aesica Pharmaceuticals Limited
Publication of WO2015145163A1 publication Critical patent/WO2015145163A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment

Definitions

  • the present invention relates to a novel process for the manufacture of S-(+)- flurbiprofen, and salts thereof.
  • the process of the present invention also provides S-(+)-flurbiprofen, and salts thereof, with a surprisingly low methyl ester content.
  • Non-steroidal anti-inflammatory drug compounds are generally used to treat, inter alia, inflammation and pain, for example, caused by arthritis.
  • One such drug compound is flurbiprofen, 2-(2-fluoro-4-biphenylyl) propionic acid.
  • NSAIDs such as flurbiprofen, are generally chiral and are often supplied as a racemate.
  • the separate enantiomers of flurbiprofen i.e. S-(+)-flurbiprofen and R-(-)-flurbiprofen are therapeutically useful in their own right.
  • the (unpublished) large scale manufacture of S-(+)-flurbiprofen, and salts thereof, consists of four discreet manufacturing stages, generally described as stages 1 A, IB, 2 and 3 :
  • Stage 1A manufactures and isolates R-(-)-flurbiprofen enantiomer from racemic flurbiprofen sodium salt, leaving mother liquors enriched in S-(+)-flurbiprofen.
  • Isolation of the R-(-)-flurbiprofen enantiomer is accomplished by removing the sodium from racemic flurbiprofen sodium salt via a hydrochloric acid wash to produce racemic flurbiprofen (free acid) as an intermediate and resolving this intermediate with R-phenylethylamine (R-PEA) to form the R-(-)-flurbiprofen R-PEA salt.
  • R-PEA R-phenylethylamine
  • Stage IB isolates S-(+)-flurbiprofen/ S-PEA salt which is accomplished by a hydrochloric acid wash of the mother liquors from Stage 1A, to produce a solution enriched in S-(+)-flurbiprofen (free acid).
  • the solution enriched in S-(+)-flurbiprofen (free acid) intermediate is resolved with S-phenylethylamine (S-PEA) to form the S- (+)-flurbiprofen/ S-PEA salt.
  • Stage 2 isolates and purifies S-(+)-flurbiprofen which is accomplished by a hydrochloric acid wash of the S-(+)-flurbiprofen/ S-PEA salt, washing crystallising and drying the S-(+)-flurbiprofen (free acid).
  • Stage 3 is a further purification stage, which is essentially a repeat of stage 2.
  • the mother liquors resulting from Stage 1 of the process generally comprise a solution enriched in S-(+)-flurbiprofen in a mixture of a non-polar, water immiscible, solvent and a polar, water miscible, solvent.
  • the polar, water miscible, solvent will have a lower boiling point than the non-polar, water immiscible, solvent, therefore the two solvents may be separated by distillation.
  • the non-polar, water immiscible, solvent is toluene and the polar, water miscible, solvent is methanol. It has now been found that the non-polar, water immiscible, solvent, and the polar, water miscible, solvent can be separated without the need for distillation, for example, by means of an aqueous wash.
  • the S-(+)-flurbiprofen is crystallised and/ or isolated as the free acid by treating the aforementioned solution rich in S-(+)- flurbiprofen, with an acidic aqueous wash; transforming any S-(+)-flurbiprofen to the free acid and then crystallising the S-(+)-flurbiprofen.
  • the acidic aqueous wash may comprise a wash with aqueous hydrochloric acid.
  • suitable acids e.g. mineral acids
  • the concentration of the aqueous acid may be varied, in particular, the washes may be checked to ensure that they meet an end point, i.e. pH of ⁇ 1.
  • the S-(+)-flurbiprofen can be crystallised and/ or isolated as S- phenylethylamine (S-PEA) salt, for example, by directly resolving the solution enriched in S-(+)-flurbiprofen, with S-phenylethylamine (S-PEA) to form the S-(+)- flurbiprofen/ S-PEA salt.
  • Isolation of the S-(+)-flurbiprofen/ S-PEA salt may still include an acid wash step, for example in order to remove any unreacted R- phenylethylamine (R-PEA).
  • the water immiscible solvent may comprise, for example, long chain alcohols, hexane, cyclohexane, chloroform, tetrachloroethylene, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, a petroleum solvent or an aromatic solvent, such as toluene.
  • the water immiscible solvent comprises toluene.
  • the water miscible solvent may be an alcohol, e.g. an alkyl CI to CIO alcohol, preferably an alkyl CI to 6 alcohol, for example, methanol, ethanol, n-propanol or iso- propanol.
  • the water miscible solvent comprises methanol.
  • the ratio of the water immiscible solvent to the water miscible solvent may vary depending, inter alia, upon the nature of the solvents. Thus, for example ratio of water immiscible solvent: water miscible solvent may be from about 2: 1 to about 7: 1 w/w, preferably from about 3 : 1 to about 6: 1, more preferably from about 4: 1 to about 5: 1, e.g. about 4.5: 1 w/w.
  • the solvent mixture desirably comprises a solvent in which at least one component of the mixture is methanol.
  • the mixture may comprise methanol and a water immiscible solvent, such as a hydrocarbon solvent as hereinbefore defined.
  • the most preferred solvent mixture is toluene and methanol, for example, solvent mixture of toluene and methanol in a ratio of about 4.5: 1 w/w.
  • Step (iv) may optionally include an acid wash.
  • the process may optionally include a racemisation step to obtain racemic flurbiprofen as a precursor for step (i).
  • the process is also advantageous in that, inter alia, it produces S-(+)-flurbiprofen, or a salt thereof, in which the methyl ester impurity content is reduced.
  • S-(+)-flurbiprofen, or a salt thereof, with a surprisingly low amount of methyl (2-(2- fluoro-4-biphenylyl)) propionate impurity is novel per se. Therefore, according to a further aspect of the invention there is provided S-(+)-flurbiprofen, or a salt thereof, wherein the amount of methyl (2-(2-fluoro-4-biphenylyl)) propionate is 0.05% w/w or less when measured by HPLC.
  • the amount of methyl (2-(2-fluoro-4- biphenylyl)) propionate present may be less than about 0.045%), 0.04%, 0.035%), 0.03%, 0.025%, 0.02%, 0.015%, 0.01%, by weight or may be undetectable when measured by HPLC.
  • Methods of determination of the amount of methyl (2-(2-fluoro- 4-biphenylyl)) propionate present are generally known to the person skilled in the art. An example of such a method is described in Example 2 herein.
  • the amount of methyl (2-(2-fluoro-4-biphenylyl)) propionate present described herein can be construed as measured according to the analytical technique of Example 2 herein.
  • a pharmaceutical composition comprising S-(+)-flurbiprofen, or a salt thereof, as the active ingredient, manufactured according the process hereinbefore described.
  • a pharmaceutical composition comprising S-(+)-flurbiprofen, or a salt thereof, as the active ingredient, wherein the amount of methyl (2-(2-fluoro-4-biphenylyl)) propionate is 0.05% w/w or less when measured by HPLC measurement as hereinbefore described.
  • Base addition salts may be produced by reacting with free bases in known manner.
  • a pharmaceutically acceptable salt is any salt of (S)-(+)-2-(2-fluoro-4-biphenylyl) propionic acid that is suitable for administration to an animal or human.
  • a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into SFP or salt.
  • a salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions.
  • salts shall mean “pharmaceutically acceptable salts” and refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which are not biologically or otherwise undesirable.
  • esters shall mean “pharmaceutically acceptable esters”.
  • Salts are desirably pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent (S)-(+)-2-(2-fluoro-4-biphenylyl) propionic acid, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the (S)-(+)-2-(2-fluoro-4- biphenylyl) propionic acid.
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • salts include ammonium or amino acid salts which are water soluble thereby being preferred.
  • Complex salts with basic amino acids can be used directly and mixed salts with neutral or acidic amino acids are previously converted into the alkali metal, alkaline earth metal or ammonium salts.
  • a preferred amino acid is lysine.
  • Amino acid salts may comprise an essential amino acid, such as, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and tyrosine; or a non-essential amino acid, such as, alanine, arginine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, asparagines and selenocysteine.
  • the salt may comprise an amino sugar, such as meglumine.
  • Figure 1 is a "block diagram" of the process of the invention.
  • FIG. 2(a) to (d) illustrates the synthetic process scheme.
  • the R-(-)-flurbiprofen/R-l -phenylethylamine salt can be used for the manufacture of R-(-)-flurbiprofen.
  • Approximately 4200 kg of mother liquor from the filtration of R-(-)-flurbiprofen/R-l- phenylethylamine salt is concentrated by distillation to remove methanol and approximately 725 kg of toluene is added.
  • Approximately 97 kg of 36 % hydrochloric acid in approximately 968 kg of water is added and the mixture is heated to above 55°C and the aqueous phase containing R-1 -phenylethylamine hydrochloride is separated off and retained for R-1 -phenylethylamine recovery.
  • the hydrochloric acid wash is repeated.
  • the organic phase, containing flurbiprofen enriched in S-(+)- flurbiprofen is washed at least once with approximately 968 kg of water at above 55°C, and dried by azeotropic distillation of toluene. Approximately 891 kg of methanol is added, followed by approximately 2127 kg of toluene. Approximately 187 kg of S-l -phenylethylamine, fresh or recovered, in approximately 396 kg of toluene is added at approximately 63 °C.
  • Crystallisation of S-(+)-flurbiprofen/S-l- phenylethylamine salt is brought about by heating and then cooling the mixture to not less than 0°C.
  • the crystals are isolated by filtration, washed with approximately 300 kg of toluene and optionally dried under vacuum. Yield: approximately 45 to 65% of theory.
  • the R-(-)-flurbiprofen/R-l-phenylethylamine salt can be used for the manufacture of R-(-)-flurbiprofen. Approximately 840 kg of water is added to approximately 4200 kg of mother liquor from the filtration of R-(-)-flurbiprofen/R-l-phenylethylamine salt. After agitation and settling at approximately 65°C, the aqueous phase is discarded. This washing is repeated once more.
  • the concentration of the solution is adjusted by addition or distillation of toluene and crystallisation is brought about by cooling the solution to not less than -10 °C.
  • the crystals are isolated by filtration, washed with approximately 253 kg of heptane, and dried under vacuum at not more than 65°C.
  • the filtrate from stages 1 and 2 is retained and is concentrated by distillation to give a mass of approximately 2750 kg; the active flurbiprofen content of which will be approximately 544kg.
  • This mixture is acidified by addition of approximately 110 kg of 36 % hydrochloric acid in approximately 313 kg of water, and separated at above 55°C, the aqueous phase containing S-(-)-l-phenylethylamine hydrochloride is separated off and retained for S-(-)-l-phenylethylamine recovery.
  • the batch is again acidified by addition of approximately 110 kg of 36 % hydrochloric acid, in approximately 313 kg of water, and separated at above 55°C, the aqueous phase containing S-(-)-l-phenylethylamine hydrochloride is separated off and retained for S- (-)-l-phenylethylamine recovery.
  • the batch is washed with approximately 616 kg of water, and separated at above 55°C.
  • the organic phase is dried by azeotropic distillation of toluene. Approximately 247 kg of methanol and approximately 50 kg of concentrated sulphuric acid is charged and the mixture heated at reflux. The water layer formed during the reaction is separated off.
  • the aqueous solution containing S-(-)-l-phenylethylamine hydrochloride, retained in the racemisation process, is basified by addition of approximately 1 molar equivalent of caustic soda solution and approximately 135 kg of toluene is added to extract the S- (-)-l-phenylethylamine.
  • the aqueous phase is separated off and the toluene solution of S-(-)-l-phenylethylamine is retained for recycle in Stage 1.
  • (S)-(+)-flurbiprofen was selectively isolated from racemic sodium flurbiprofen dihydrate, by modifying the method disclosed in International application No. WO 2008/095186, which is incorporated herein by reference. The quality of material obtained via this method was then examined.
  • Sodium flurbiprofen dihydrate (200. Og) was dissolved in toluene (370 mL) and hydrochloric acid (37%, 80 mL in 133 mL H 2 0), and the mixture was heated to 60°C for 30 mins. The aqueous layer was then removed, and the organic layer was washed with hot water (108 mL). Methanol (94 mL) was then added and mixture heated to 60°C.
  • Acetonitrile, water and trifluoroacetic acid are HPLC grade materials. Mobile phase.
  • A Add 1 ml of trifluoroacetic acid to 450ml of Acetonitrile, add 550ml of water and mix. Filter and degas using a suitable technique.
  • Detector Ultraviolet, wavelength set at 254 nm.
  • Phenylethylamine is given a response factor of 0 so that if any is detected it will not interfere with quantification of S-(+)-flurbiprofen and related impurities.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de S-(+)-flurbiprofène, ou d'un sel de celui-ci, qui comprend les étapes consistant à : (i) traiter une solution riche en S-(+)flurbiprofène, ou en sel de ce dernier, avec un agent de lavage aqueux; ladite solution comprenant un mélange d'un solvant non miscible dans l'eau et d'un solvant miscible dans l'eau; et (ii) à cristalliser et/ou isoler le S-(+)-flurbiprofène, ou un sel de ce dernier.
PCT/GB2015/050920 2014-03-26 2015-03-26 Procédé de fabrication de s-(+)-flurbiprofène WO2015145163A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1405456.3A GB201405456D0 (en) 2014-03-26 2014-03-26 Process for the manufacture of S-(+)-Flurbiprofen
GB1405456.3 2014-03-26

Publications (1)

Publication Number Publication Date
WO2015145163A1 true WO2015145163A1 (fr) 2015-10-01

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113651689A (zh) * 2021-08-27 2021-11-16 上海博悦生物科技有限公司 S-氟比洛芬钠新晶型及其制备方法
CN113956160A (zh) * 2021-12-23 2022-01-21 北京茗泽中和药物研究有限公司 一种氟比洛芬杂质f的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991006295A1 (fr) * 1989-11-06 1991-05-16 Sepracor, Inc. Composition analgesique contenant du s(+) flurbiprofene optiquement pur
WO1994012460A1 (fr) * 1992-12-02 1994-06-09 The Boots Company Plc Procede de preparation d'enantiomeres sensiblement purs d'acides phenylpropioniques
WO2008095186A1 (fr) 2007-02-01 2008-08-07 Myriad Genetics, Inc. Préparations de matières médicamenteuses, compositions pharmaceutiques et formes pharmaceutiques
WO2010001103A1 (fr) 2008-06-30 2010-01-07 Aesica Pharmaceuticals Limited Procédé de production d'un acide 2-aryl-propionique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991006295A1 (fr) * 1989-11-06 1991-05-16 Sepracor, Inc. Composition analgesique contenant du s(+) flurbiprofene optiquement pur
WO1994012460A1 (fr) * 1992-12-02 1994-06-09 The Boots Company Plc Procede de preparation d'enantiomeres sensiblement purs d'acides phenylpropioniques
US5599969A (en) 1992-12-02 1997-02-04 The Boots Company Plc Process of resolving phenylpropionic acids using α-methylbenzylamine
WO2008095186A1 (fr) 2007-02-01 2008-08-07 Myriad Genetics, Inc. Préparations de matières médicamenteuses, compositions pharmaceutiques et formes pharmaceutiques
WO2010001103A1 (fr) 2008-06-30 2010-01-07 Aesica Pharmaceuticals Limited Procédé de production d'un acide 2-aryl-propionique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
STAHL; WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113651689A (zh) * 2021-08-27 2021-11-16 上海博悦生物科技有限公司 S-氟比洛芬钠新晶型及其制备方法
CN113956160A (zh) * 2021-12-23 2022-01-21 北京茗泽中和药物研究有限公司 一种氟比洛芬杂质f的制备方法

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