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Title:
PROCESS FOR THE MANUFACTURE OF S-(+)-FLURBIPROFEN
Document Type and Number:
WIPO Patent Application WO/2015/145163
Kind Code:
A1
Abstract:
There is described a process for the preparation of S-(+)-flurbiprofen, or a salt thereof, which comprises the steps of: (i) treating a solution rich in S-(+)-flurbiprofen, or a salt thereof, with an aqueous wash; said solution comprising a mixture of a water immiscible solvent and a water miscible solvent; and (ii) crystallising and/ or isolating the S-(+)-flurbiprofen, or a salt thereof.

Inventors:
REID GARY (GB)
Application Number:
PCT/GB2015/050920
Publication Date:
October 01, 2015
Filing Date:
March 26, 2015
Export Citation:
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Assignee:
AESICA PHARMACEUTICALS LTD (GB)
International Classes:
C07C51/43; C07C51/48; C07C57/58
Domestic Patent References:
WO1991006295A11991-05-16
WO1994012460A11994-06-09
WO2010001103A12010-01-07
WO2008095186A12008-08-07
Foreign References:
US5599969A1997-02-04
Other References:
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
STAHL; WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
Attorney, Agent or Firm:
GILHOLM, Stephen Philip (Buzzard OfficeThe Hawk Creative Business Park,Easingwold, York North Yorkshire YO61 3FE, GB)
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Claims:
Claims

1. A process for the preparation of S-(+)-flurbiprofen, or a salt thereof, which comprises the steps of:

(i) treating a solution rich in S-(+)-flurbiprofen, or a salt thereof, with an aqueous wash; said solution comprising a mixture of a water immiscible solvent and a water miscible solvent; and

(ii) crystallising and/ or isolating the S-(+)-flurbiprofen, or a salt thereof.

2. A process according to claim 1 wherein the S-(+)-flurbiprofen is crystallised and/ or isolated as the free acid.

3. A process according to claim 2 wherein the S-(+)-flurbiprofen is transformed to the free acid by treating a solution of S-(+)-flurbiprofen, including any S-(+)- flurbiprofen salt, with an acidic aqueous wash.

4. A process according to claims 2 or 3 wherein the acid is a mineral acid.

5. A process according to any one of claims 2 to 4 wherein the acid is an aqueous hydrochloric acid.

6. A process according to claim 1 wherein the S-(+)-flurbiprofen is crystallised and/ or isolated as the S-phenylethylamine (S-PEA) salt.

7. A process according to claim 6 wherein the solution enriched in S-(+)- flurbiprofen is resolved with S-phenylethylamine (S-PEA) to form the S-(+)- flurbiprofen salt.

8. A process according to any one of the preceding claims wherein the water immiscible solvent comprises a long chain alcohol, hexane, cyclohexane, chloroform, tetrachloroethylene, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, a petroleum solvent or an aromatic solvent.

9. A process according to any one of the preceding claims wherein the water immiscible solvent comprises an aromatic solvent.

10. A process according to any one of the preceding claims wherein the water immiscible solvent comprises toluene.

11. A process according to any one of the preceding claims wherein the water miscible solvent comprises an alcohol. 12. A process according to any one of the preceding claims wherein the water miscible solvent comprises methanol, ethanol, n-propanol or iso-propanol.

13. A process according to any one of the preceding claims wherein the water miscible solvent comprises methanol.

14. A process according to any one of the preceding claims wherein the ratio of the water immiscible solvent to the water miscible solvent is from about 2: 1 to about 7: 1 w/w.

15. A process according to any one of the preceding claims wherein the solvent mixture is toluene and methanol.

16. A process according to any one of the preceding claims wherein the solvent mixture is toluene and methanol in a ratio of about 4.5: 1 w/w.

17. A process for the preparation of S-(+)-flurbiprofen, or a salt thereof, which comprises the steps of:

(i) separating S-(+)-flurbiprofen, or a salt thereof, from racemic or non- racemic flurbiprofen, in a solvent mixture comprising a water immiscible solvent and a water miscible solvent;

(ii) optionally isolating any R-(-)-flurbiprofen present, in the solvent mixture;

(iii) removing the water miscible solvent from the solvent mixture by washing the solvent mixture with water and separating the water/water miscible solvent from the water immiscible solvent; and optionally resolving the S-(+)- flurbiprofen with a chiral resolving agent;

(iv) isolating the S-(+)-flurbiprofen from the water immiscible solvent, and optionally converting the separated S-(+)-flurbiprofen to a salt; and (v) optionally purifying the S-(+)-flurbiprofen, or a salt thereof.

18. A process according to claim 17 which includes a racemisation step to obtain racemic flurbiprofen as a precursor for step (i).

19. A process according to claims 17 or 18 for the manufacture of S-(+)- flurbiprofen, or a salt thereof, wherein the amount of methyl (2-(2-fluoro-4- biphenylyl)) propionate is 0.5% w/w or less when measured by HPLC. 20. 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.

21. S-(+)-flurbiprofen, or a salt thereof, according to claim 20 wherein the S-(+)- flurbiprofen is prepared by the process of claim 17.

22. A pharmaceutical composition comprising S-(+)-flurbiprofen, or a salt thereof, according to claim 20, as the active ingredient, manufactured by the process of claim 17. 23. 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.

24. A process, (S)-(+)-flurbiprofen, or a salt or ester thereof, or a pharmaceutical composition as hereinbefore described with reference to the accompanying examples and figures.

Description:
PROCESS FOR THE MANUFACTURE OF S-(+)-FLURBIPROFEN

Field of the Invention

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. Background of the Invention

Non-steroidal anti-inflammatory drug compounds (NSAIDs) 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. However, the separate enantiomers of flurbiprofen, i.e. S-(+)-flurbiprofen and R-(-)-flurbiprofen are therapeutically useful in their own right.

R-Flurbiprofen

S-Flurbiprofen

In addition, there is renewed interest in S-(+)-flurbiprofen, and salts thereof, as a therapeutically active agent.

US Patent No. 5,599,969, the Hardy patent, describes the manufacture of S-(+)- flurbiprofen or R-(-)-flurbiprofen by conversion of the unwanted enantiomer into the methyl ester, allowing subsequent resolution of the racemate and enabling a higher yield of the desired enantiomer to be achieved.

International Patent application No. WO 2010/001103 describes a process for the manufacture of a racemic 2-aryl propionic acid compound which comprises reacting the S- or R- enantiomer of the corresponding 2-aryl propionic acid compound with a base.

Summary of the Invention

The synthetic chemistry for the preparation of S-(+)-flurbiprofen can be described schematically as follows:

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

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.

Stage IB

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

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

Stage 3 is a further purification stage, which is essentially a repeat of stage 2.

This process can be represented schematically as illustrated in Figures 1 and 2(a) to (d) herein.

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.

Usually, 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. In one example 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.

Thus, according to a first aspect of the present invention there is provided a process for the preparation of S-(+)-flurbiprofen, or a salt thereof, which comprises the steps of:

(i) treating a solution rich in S-(+)-flurbiprofen, or a salt thereof, with an aqueous wash; said solution comprising a mixture of a water immiscible solvent and a water miscible solvent; and

(ii) crystallising and/ or isolating the S-(+)-flurbiprofen, or a salt thereof.

According to a further aspect of the invention 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. Thus, for example, the acidic aqueous wash may comprise a wash with aqueous hydrochloric acid. It will be understood by the person skilled in the art that other suitable acids, e.g. mineral acids, may be used. Furthermore, it will also be understood that 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.

Alternatively, 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. Preferably 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. Preferably 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. Thus, 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. According to a yet further aspect of the invention there is provided a process for the preparation of S-(+)-flurbiprofen, or a salt thereof, which comprises the steps of:

(i) separating S-(+)-flurbiprofen, or a salt thereof, from racemic or non- racemic flurbiprofen, in a solvent mixture comprising a water immiscible solvent and a water miscible solvent;

(ii) optionally isolating any R-(-)-flurbiprofen present, in the solvent mixture;

(iii) removing the water miscible solvent from the solvent mixture by washing the solvent mixture with water and separating the water/water miscible solvent from the water immiscible solvent; and optionally resolving the S-(+)- flurbiprofen with a chiral resolving agent;

(iv) isolating the S-(+)-flurbiprofen from the water immiscible solvent, and optionally converting the separated S-(+)-flurbiprofen to a salt; and

(v) optionally purifying the S-(+)-flurbiprofen, or a salt thereof.

Step (iv) may optionally include an acid wash.

According to this aspect of the invention 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. Thus, according to a yet further aspect of the invention there is provided a process for the manufacture of S-(+)-flurbiprofen, or a salt thereof, as hereinbefore described, wherein the amount of methyl (2-(2-fluoro-4-biphenylyl)) propionate is 0.5% w/w or less when measured by HPLC.

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.

According to this aspect of the invention 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.

Thus, according to a further aspect of the invention there is provided a pharmaceutical composition comprising S-(+)-flurbiprofen, or a salt thereof, as the active ingredient, manufactured according the process hereinbefore described. Thus, according to this aspect of the invention there is provided 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.

As used herein, the term "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. Similarly, the "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. Generally, 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. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley- VCH, Weinheim, Germany, 2002). Other 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. Other methods also known for medicaments, in which the active material is adsorbed onto aluminium oxide gels, can also be carried out with the flurbiprofen according to the present invention. The (S)-(+)-flurbiprofen salts produced can then be further worked up in the manner described hereinbefore. Preferably, the flurbiprofen salts are prepared indirectly by adding the bases required for the salt formation. 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. Alternatively, the salt may comprise an amino sugar, such as meglumine. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims. The invention will now be described by way of example only and with reference to the accompanying figures in which:

Figure 1 is a "block diagram" of the process of the invention; and

Figures 2(a) to (d) illustrates the synthetic process scheme.

Example 1

1.1 Stage 1: S-(+)-Flurbiprofen S-l-Phenylethylamine salt (MeOH Distillation)

Approximately 944 kg of sodium flurbiprofen dihydrate is suspended in approximately 1737 kg of toluene, and acidified by addition of approximately 375 kg of 36 % hydrochloric acid, in approximately 625 kg of water. The mixture is heated to above 55°C and the aqueous phase is separated off. The organic phase is washed with approximately 500 kg of water, leaving a solution of flurbiprofen in toluene. Approximately 383 kg of methanol is added to the flurbiprofen solution in toluene, prepared as above or from the racemisation process, and approximately 190 kg of R- 1 -phenylethylamine, fresh or recovered, in approximately 405 kg of toluene, is added at approximately 63 °C. Crystallisation of R-(-)-flurbiprofen/R-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 270 kg of toluene, and optionally dried under vacuum. 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.

1.2 Stage 1: S-(+)-Flurbiprofen S-l-Phenylethylamine salt (MeOH Wash)

Approximately 944 kg of sodium flurbiprofen dihydrate is suspended in approximately 1737 kg of toluene, and acidified by addition of approximately 375 kg of 36 % hydrochloric acid, in approximately 625 kg of water. The mixture is heated to above 55°C and the aqueous phase is separated off. The organic phase is washed with approximately 500 kg of water, leaving a solution of flurbiprofen in toluene.

Approximately 383 kg of methanol is added to the flurbiprofen solution in toluene, prepared as above or from the racemisation process, and approximately 190 kg of R- 1-phenylethylamine, fresh or recovered, in approximately 405 kg of toluene, is added at approximately 63 °C. Crystallisation of R-(-)-flurbiprofen/R-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 270 kg of toluene, and optionally dried under vacuum. 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. 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-l-phenylethylamine hydrochloride is separated off and retained for R-l-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.

1.3 Stage 2: S-(+)-Flurbiprofen

Approximately 337 kg of S-(+)-flurbiprofen/S-l-phenylethylamine salt is suspended in approximately 317 kg of water and approximately 843 kg of toluene and acidified by the addition of approximately 179 kg of 36 % hydrochloric acid. The mixture is heated to above 55 °C and the aqueous phase containing S-l-phenylethylamine hydrochloride is separated off and retained for S-l-phenylethylamine recovery. The organic phase is further washed with approximately 42 kg of 36 % hydrochloric acid in approximately 421 kg of water, and separated at above 55 °C. The organic phase is washed at least once with approximately 421 kg of water, and separated at above 55°C. 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.

Yield: approximately 60 to 85 % of theory.

1.4 Stage 3: S-(+)-Flurbiprofen

Further purification is carried out as follows: Approximately 180 kg of S-(+)- flurbiprofen stage 2 is suspended in approximately 254 kg of water and approximately 675 kg of toluene acidified by addition of approximately 143 kg of 36 % hydrochloric acid. The mixture is heated to above 55°C and the aqueous phase is separated off. The organic phase is further washed with approximately 34 kg of 36 % hydrochloric acid in approximately338 kg of water, and separated at above 55°C. The organic phase is washed at least once with approximately 338 kg of water, and separated at above 55°C. The solution is dried by azeotropic distillation of toluene. Crystallisation is effected 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. Yield: approximately 60 to 85% of theory.

1.5 Racemisation

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 reaction is repeated at reflux by charging approximately 59 kg of methanol and approximately 25 kg of concentrated sulphuric acid. The water layer formed during the reaction is separated off. The batch is washed with approximately 616 kg of water, and separated at above 55°C. Residual water is removed by distillation. Approximately 500 kg of methanol and approximately 120 kg of caustic soda are added and the mixture is heated to reflux to bring about racemisation and saponification of the methyl ester. This mixture is acidified by addition of approximately 163 kg of 36 % hydrochloric acid in approximately 313 kg of water, and separated at above 55°C, leaving a solution of racemic flurbiprofen in toluene. 1.6 Recovery of S-(-)-l-lphenylethylamine hydrochloride

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.

Method for Preparing (S)-(+)-2-(2-Fluoro-4-Biphenylyl) Propionic Acid

(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. (S)-(+)-l-phenylethylamine (35.2g) in toluene (71.5 mL) was added dropwise over 30 mins. The solution was stirred at 60°C for 30 mins, then warmed to 68°C and held for 30 mins. The solution was cooled to 50°C, then further cooled to 3°C and held for 1 hour. Crystals of (S)-(+)-flurbiprofen-(S)-(-)-l-phenylethylamine were isolated, washed with cold toluene (53 mL) and dried on a vacuum filter overnight. The crystals of (S)-(+)-flurbiprofen-(S)-(-)-a-methylbenzylamine (49.4g) were returned to the vessel and suspended in methanol (125 mL) and toluene (500 mL). The mixture was warmed to 70°C, stirred for 15 mins, then cooled to 55°C and stirred for 30 mins. The solution was then warmed to 60°C for 30 mins, slowly cooled to 50°C, then further cooled to 3°C and stirred for 1 hour. Crystals of (S)-(+)- flurbiprofen-(S)-(-)-l-phenylethylamine were isolated, washed with cold toluene (53 mL) and dried on a vacuum filter overnight.

The crystals of (S)-(+)-flurbiprofen-(S)-(-)-l-phenylethylamine (38.4 g) were dissolved in deionised water (38 mL), toluene (160 mL) and aqueous hydrochloric acid (37%, 16 mL), and stirred at 60°C for 30 mins. The resulting solution was transferred hot to a separating funnel and the aqueous layer was removed. The organic layer was washed with water (50 mL) and aqueous hydrochloric acid (37%, 2 mL), then further water (2 x 50 mL). The organic layer was then heated to partially remove the solvent and reduce the volume to approx.100 mL. The resulting solution was then cooled to 30°C, and stirred for 30 mins. The solution was slowly cooled to 0°C, and the resulting crystals stirred for 1 hr. The crystalline (S)-(+)-flurbiprofen was then filtered, washed with cold ^-heptane (40 mL) and dried overnight under vacuum at 60°C.

Yield 19.9 g (12.5%). Example 2

Determination of Methyl (2-(2-fluoro-4-biphenylyl)) propionate (BTS-43986) Content by HPLC

Reagents:

Acetonitrile, water and trifluoroacetic acid. These 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.

B Add 1 ml of trifluoroacetic acid to 800ml of Acetonitrile, add 200ml of water and mix. Filter and degas using a suitable technique.

Sample Solvent:

Add 450ml acetonitrile to a 1 litre flask and dilute to volume with water and mix. Filter and degas using a suitable technique.

Test mixture:

Dissolve 5mg of BTS 43986 in 200ml acetonitrile and mix. To 1.0 ml of this solution add about 50mg of S-(+)-flurbiprofen reference standard and dilute to 100.0 ml using sample solvent. Example 2.1

Preparation of sample solution: (Prepare in duplicate)

Dissolve 50 mg (± 5 mg) of sample into a 100 ml volumetric flask and dilute to volume with sample solvent.

System Suitability test solution:

Transfer 1.0ml of Sample Solution (prep 1) to a 200ml volumetric flask and dilute to volume with sample solvent. Detectability Solution:

Transfer 5.0ml of the System Suitability test solution to a 25ml volumetric flask and dilute to volume with sample solvent.

The chromatographic conditions are as follows:

Column: Zorbax Eclipse XDB C18 4.6 x 150mm 5μιη

Flow rate: 1.0 ml/min.

Detector: Ultraviolet, wavelength set at 254 nm.

Temperature: 40°C.

Run Time: 40 minutes

Volume injected: 5 μΐ. Gradient:

At the start of any analysis condition the column with 2 injections of blank solvent. Following analysis to clean the column flush with 100% B for 30 minutes.

Inject a sequence as follows:

System suitability.

1. The blank injection should be free from interfering peaks 2. Confirm the peak area of S-(+)-flurbiprofen in the Detectability Solution is equivalent to 14-26% of that of the S-(+)-flurbiprofen peak area in the System Suitability Test Solution.

Determination of Related Substance Content ofS(+) Flurbiprofen:

Measure the areas of the flurbiprofen peak and of each related substance peak and calculate the percentage of each as follows:

area of related substance peak x f x 100

% impurity

corrected total area of all peaks

Where f is the correction factor specific to each impurity. Report result to 2dp.

The correction factors of the impurities and their retention times relative to S-(+)- flurbiprofen are given below.

Note: 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.

0424P.WO.Spec(4)