IE64689B1 - Process for converting [R(-)]-2-(3-benzoylphenyl)propionic acid into the S(+) isomer - Google Patents
Process for converting [R(-)]-2-(3-benzoylphenyl)propionic acid into the S(+) isomerInfo
- Publication number
- IE64689B1 IE64689B1 IE291791A IE291791A IE64689B1 IE 64689 B1 IE64689 B1 IE 64689B1 IE 291791 A IE291791 A IE 291791A IE 291791 A IE291791 A IE 291791A IE 64689 B1 IE64689 B1 IE 64689B1
- Authority
- IE
- Ireland
- Prior art keywords
- ketoprofen
- process according
- base
- mole
- carried out
- Prior art date
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Classifications
-
- 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
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Detergent Compositions (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Process for transforming (benzoyl-3 phenyl)-2 propionic-R(-) acid into an S(+) isomer through the action of a base either in situ during the splitting of racemic ketoprofen or on the crystallization mother liquor of a (benzoyl-3 phenyl)-2 propionic-S(+) acid salt.
Description
The present invention relates to a process for converting [R(-)]-2-(3-benzoylphenyl)propionic acid into the S(+) isomer. 2-(3-Benzoylphenyl)propionic acid (referred to herein by its ordinary name ketoprofen) exhibits particularly useful anti-inflammatory, analgesic and/or antipyretic properties. Ketoprofen, in the racemic form, consists of an equimolar mixture of S(+) and R(-) enantiomers.
Whereas in animals no substantial differences exist between racemic ketoprofen and the S(+) isomer, [S(+)]~ ketoprofen, it has been shown in humans that [S(+)]~ ketoprofen constitutes the active form of ketoprofen and that the R(-) isomer is not converted into the S(+) isomer. It is therefore particularly advantageous to be able to obtain [S(+)]-ketoprofen practically free from the R(-) isomer.
[S(+)]-Ketoprofen may be obtained by resolution of racemic ketoprofen either by physico-chemical methods (high-performance liquid chromatography with a chiral phase) or by formation of a salt with an optically active base.
These processes result in the separation of the S(+) isomer and the R(-) isomer, the latter having no inherent usefulness. It is therefore particularly important to be able to have available a process which makes it possible to convert [R(-))-ketoprofen into [S(+)]ketoprofen.
It has now been found, and that is what constitutes the subject of the present invention, that [R(-)]~ ketoprofen may be converted into [S(+)]-ketoprofen by treating the [R(-)]-ketoprofen with a base, preferably either in situ during resolution of the racemic ketoprofen using in particular the resolving agent as the converting agent, or in the crystallization mother liquors, before or after removing the chiral base, by treatment with a strong base. Sodium hydroxide may be used as strong base.
The process may be implemented in situ using, as resolving agent, a chiral base like cinchonidine and, as solvent, a ketone such as methyl isobutyl ketone or an alcohol such as ethanol. It is advantageous to use methyl isobutyl ketone which makes it possible to carry out the procedure at high temperatures. To obtain an improved yield, it is particularly advantageous to induce crystallisation of the preponderant desired salt (cinchonidine salt of [S(+)]-ketoprofen) by concentrating the solution under reduced pressure.
Generally, one mole of cinchonidine is used per mole of ketoprofen.
Generally, the concentration procedure under 25 reduced pressure is controlled so that the boiling temperature is constant and close to 100°C during the entire duration of concentration. The crystals of the [S(+)]-ketoprofen salt which are formed are separated by filtration at a high temperature.
The conversion may also be achieved independently of crystallisation, from crystallisation mother liquors after eliminating the chiral base used as resolving agent and using an achiral base such as sodium hydroxide.
In order to implement the process using crystallisation mother liquors, the resolution of racemic ketoprofen is first carried out using 0.5 to l mole of cinchonidine per mole of ketoprofen. After separation of the cinchonidine salt of ketoprofen (mainly [S(+)]ketoprofen) by filtration, the mother liquors are treated with an aqueous solution of a strong inorganic base such as sodium hydroxide, after liberation and separation of the cinchonidine (or other resolving agent) either as the base or as a salt. Ketoprofen (mainly [R(—)]-ketoprofen), in the form of the sodium salt, remains in the basic aqueous solution which is heated at a temperature generally above 100°C, preferably close to 110°C, while the variation of the optical titre is monitored as a function of time, the optical titre being expressed by the relationship 100 x R/(R+S). The conversion is characterised by a progressive decrease of the optical titre to 50 % when racemisation is complete.
The following Examples illustrate the invention.
Example 1 - Resolution - Racemisation Racemic ketoprofen (26.5 g, 0.104 mole), cinchonidine (31 g, 0.105 mole) and methyl isobutyl ketone (120.6 g or 151 cc, 1.204 mole) are introduced into a reactor (250 cc). The mixture is heated, with stirring, at 100®C and then the mixture is Concentrated under reduced pressure by setting the pressure so that the boiling point remains constant and equal to 100°C. Methyl isobutyl ketone (97.2 g) is distilled off in 8 hours. The mixture is stirred overnight at 100°C, and then for 45 minutes at 45°C. The reaction mixture is then poured onto a thermostated filter at 100°C. The filtration cake is washed with methyl isobutyl ketone (70 cc) at 20°C and dried. The ketoprofen salt (19 g) thus obtained has an optical titre (S/R+S) of 88.3 %. The yield is 58.6 «.
Evaluation of ketoprofen gives the following results: Ketoprofen (g) Optical titre (R/S) Ketoprofen S(+) (g) R(-) (g) Isolated product 8.80 11.7/88.3 7.77 1.03 Mother liquors 8.40 54.7/45.3 3.8 4.6 Washings 9.30 50.2/49.8 4.6 4.7 Example 2 - Racemisation using sodium hydroxide Racemic ketoprofen (10.4 g, 0.041 mole), cinchonidine (6 g, 0.020 mole) and methyl isobutyl ketone (28.9 g or 36 cc, 0.288 mole) are introduced into a reactor. The mixture is heated at 75°C, maintained at this temperature until complete dissolution occurs and then rapidly cooled to 70°C. Crystallisation is started using a few crystals of cinchonidine salt of [S(+))-ketoprofen. The slurry obtained is cooled over 6 hours from 70°C to 1O°C at a rate of about -1O"C per hour. The slurry is filtered at a temperature close to 20°C. The filtration cake is washed with methyl isobutyl ketone (15 g). A salt (7.3 g) is thus obtained whose composition is as follows: - cinchonidine salt of [S(+)]-ketoprofen: 5.9 g (0.011 mole) - cinchonidine salt of [R(-)]-ketoprofen: 1.4 g (0.002 mole).
The yield is 53.6 %.
The filtrates have the following composition: - [S(+)]-ketoprofen : 2.5 g (0.010 mole) [R(-)]-ketoprofen : 4.5 g (0.018 mole) - cinchonidine : 2.1 g (0.007 mole). % (w/w) aqueous sodium hydroxide (22.1 g, or 0.055 mole) is added, at room temperature, to the combined filtrates whose mass is 53 g.
Cinchonidine remains in the organic phase whereas ketoprofen, in the form of the sodium salt, remains in the agueous phase. The aqueous phase is extracted with methyl isobutyl ketone (32 g, or 40 cc) and then refluxed for 24 hours at 110-115®C. Variation of the optical titre as a function of time is determined. The results are presented in the following table: 15 Time (hours) Optical titre expressed as ketoprofen 100 x R/(R+S) 0.0 2.3 4.6 21.5 64.8 59.6 56.8 50.9 20 ExamDle 3 - Racemisation using sodium hydroxide There is introduced into an enamelled reactor (300 litres) a filtrate (175 litres, 145.3 kg) from the resolution of racemic ketoprofen using cinchonidine in ethanol whose composition is as follows: - cinchonidine salt of ketoprofen: 23.07 kg (42.04 moles) [optical purity of ketoprofen (S/S+R) close to 30 %] - ethanol: 155 litres (122.23 kg) The ethanol solution is concentrated under reduced pressure (80 mm Hg; 10.7 kPa) at 30°C until a thick mass is obtained to which toluene (57.7 litres, 50 kg) is added. More solvent (20 litres) is then distilled off.
Distilled water (42 litres) and 9.8 N hydrochloric acid (18.5 litres) are added to the toluenecontaining solution heated at 50°C by a water-steam mixture in a double jacket. The mixture is vigorously stirred until the temperature of the reaction mixture again reaches 50°C. After stopping the stirring and decanting, the lower, agueous phase is separated and the organic phase is washed with 1 N hydrochloric acid.
Distilled water (35 litres) and 9.8 N hydrochloric acid (3.1 litres) are added to the organic phase maintained at 50"C. The mixture is vigorously stirred for 10 minutes. After decanting, the agueous phase is combined with the previously separated agueous phases.
The organic phase is washed with distilled water (35 litres) containing 9.8 N hydrochloric acid (1.5 litres) and then with distilled water (30 litres). The washings are discarded. The toluene-containing solution is added to a solution (16.5 litres) of 10 N sodium hydroxide (21.9 kg, 165 moles) in distilled water (16 litres). The mixture is vigorously stirred and then heated to 100°C (superheated steam in the double jacket)i The reaction mixture is maintained under reflux for 12 hours. After cooling and decanting, the reaction mixture consists of 3 phases: 1) a milky bottom phase (11.9 kg) which is separated and removed, 2) a slightly yellow middle phase (39 kg) which contains the sodium salt of ketoprofen, 3) a colourless toluene-containing top phase.
Analysis of the middle phase by chiral HPLC shows that the optical titre (S/S+R) is 50 % : the racemisation is complete.
Toluene (20 litres) and 9.8 N hydrochloric acid (13 litres) are added to the middle phase heated to 50°C. The mixture is vigorously stirred. After decanting, the aqueous phase is exhaustively extracted with toluene (20 litres). The toluene-containing phases are combined and then concentrated by distillation of toluene (29 litres) under reduced pressure (80 mm Hg; 10.7 kPa) at 42°C. Cyclohexane is added to the concentrated toluenecontaining solution heated to 70°C so that the cyclohexane:toluene ratio is 6:4 (w/w), that is 23 litres of cyclohexane. The mixture is cooled to 60°C and recrystallisation is then started by adding racemic ketoprofen (50 g).
After cooling to a temperature close to 15°C, the slurry is filtered and the residue is then washed (2 x) with a mixture of toluene (3.5 litres) and cyclohexane (6 litres). A filtration cake is thus obtained which contains 9.76 kg of dry ketoprofen and which is used as it is in a new resolution procedure.
The ketoprofen assay, determined by nonchiral HPLC, is 100 %. ΐ
Claims (21)
1. A process for converting [R(-)]ketoprofen into [S(+)]-ketoprofen which comprises treating [R(-)]-ketoprofen with a base. 5
2. Process according to claim 1, wherein the conversion of [R(-)]-ketoprofen into [S(+)]-ketoprofen is carried out in situ during the resolution of racemic ketoprofen.
3. Process according to claim 1, wherein the 10 [R(-))-ketoprofen used is contained in the crystallisation mother liquors from which a salt of [S(+)]-ketoprofen with a chiral base has been separated.
4. Process according to claim 2, wherein a chiral base is used as converting agent and as resolving 15 agent.
5. Process according to claim 4, wherein the chiral base is cinchonidine.
6. Process according to claim 2, 4 or 5 wherein one mole of base is used per mole of racemic 20 ketoprofen.
7. Process according to any one of claims 2 and 4 to 6, wherein a ketone or an.alcohol is used as solvent.
8. Process according to claim 7, wherein the 25 solvent used is methyl isobutyl ketone or ethanol.
9. Process according to any one of claims 2 and 4 to 8, wherein the conversion is carried out at a temperature close to 100 e C.
10. Process according to claim 3, wherein the conversion is carried out with a strong base, before or 5 after elimination of the chiral base used as resolving agent.
11. Process according to claim 10, wherein the strong base used is sodium hydroxide.
12. Process according to claim 10 or 11, 10 wherein a molar excess of the strong base is used relative to the ketoprofen present in the mother liquors.
13. Process according to any one of claims 3 and 10 to 12, wherein the mother liquors used have been obtained from resolution of racemic ketoprofen using a 15 chiral base in an organic solvent.
14. Process according to claim 13, wherein a ketone or an alcohol is used as solvent.
15. Process according to claim 14, wherein the solvent used is methyl ethyl ketone or ethanol. 20
16. Process according to any one of claims 3 and 10 to 15, wherein the chiral base used is cinchonidine.
17. Process according to any one of claims 3 and 10 to 16, wherein 0.5 mole of chiral base is used per mole of ketoprofen. 25
18. Process according to any one of claims 3 and 10 to 17 which is carried out at a temperature above 100’C. ι
19. Process according to claim 18 which is carried out at a temperature beween 110°C and 115°C. >
20. Process according to claim 1 5 substantially as described in any one of the Examples.
21. [S(+)]-Ketoprofen when obtained by the process of any of the preceding claims. Dated this the 16th day of August, 1991 F. R. KELLY & CO.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9010460A FR2665897B1 (en) | 1990-08-20 | 1990-08-20 | PROCESS FOR THE CONVERSION OF ACID (BENZOYL-3 PHENYL) -2 PROPIONIC-R (-) TO THE S (+) ISOMER. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE912917A1 IE912917A1 (en) | 1992-02-26 |
| IE64689B1 true IE64689B1 (en) | 1995-08-23 |
Family
ID=9399732
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE291791A IE64689B1 (en) | 1990-08-20 | 1991-08-16 | Process for converting [R(-)]-2-(3-benzoylphenyl)propionic acid into the S(+) isomer |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0544740B1 (en) |
| JP (1) | JP3100059B2 (en) |
| AT (1) | ATE108172T1 (en) |
| AU (1) | AU8445691A (en) |
| CA (1) | CA2089558A1 (en) |
| CS (1) | CS256791A3 (en) |
| DE (1) | DE69102767T2 (en) |
| DK (1) | DK0544740T3 (en) |
| ES (1) | ES2056657T3 (en) |
| FI (1) | FI101880B1 (en) |
| FR (1) | FR2665897B1 (en) |
| HU (1) | HUT63373A (en) |
| IE (1) | IE64689B1 (en) |
| NO (1) | NO179001C (en) |
| NZ (1) | NZ239435A (en) |
| PL (1) | PL297972A1 (en) |
| PT (1) | PT98726B (en) |
| WO (1) | WO1992003404A1 (en) |
| ZA (1) | ZA916496B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010327A (en) * | 2009-09-07 | 2011-04-13 | 浙江九洲药业股份有限公司 | Splitting method of (+/-)-2-(3-benzoyl)-phenylpropionic acid |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5162576A (en) * | 1991-04-15 | 1992-11-10 | Ethyl Corporation | Resolution of ketoprofen |
| WO1996023759A1 (en) * | 1995-01-31 | 1996-08-08 | Nagase & Company, Ltd. | Method of racemizing optically active carboxylic acids |
| US6459878B1 (en) | 1999-09-30 | 2002-10-01 | Canon Kabushiki Kaisha | Heating assembly, image-forming apparatus, and process for producing silicone rubber sponge and roller |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1201726A (en) * | 1959-06-20 | 1960-01-05 | Process for obtaining flavonic derivatives from the leaves of certain plants | |
| IT1175941B (en) * | 1984-02-16 | 1987-08-12 | Stabil Bioterapico Farmachim | MONO, BI AND TRI-SUBSTITUTED ALUMINUM SALTS OF ARYL-ALCANOIC ACIDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US4831147A (en) * | 1988-07-05 | 1989-05-16 | The Dow Chemical Company | Resolution of enantiomers of herbicidal 2-(4-aryloxyphenoxy) propionates by chiral two-phase extraction |
| DE3824353A1 (en) * | 1988-07-19 | 1990-01-25 | Paz Arzneimittelentwicklung | METHOD FOR SEPARATING MIXED ENANTIOMER ARYLPROPIONIC ACIDS |
-
1990
- 1990-08-20 FR FR9010460A patent/FR2665897B1/en not_active Expired - Fee Related
-
1991
- 1991-08-16 IE IE291791A patent/IE64689B1/en not_active IP Right Cessation
- 1991-08-16 ZA ZA916496A patent/ZA916496B/en unknown
- 1991-08-16 NZ NZ239435A patent/NZ239435A/en unknown
- 1991-08-19 AT AT91914913T patent/ATE108172T1/en not_active IP Right Cessation
- 1991-08-19 ES ES91914913T patent/ES2056657T3/en not_active Expired - Lifetime
- 1991-08-19 EP EP91914913A patent/EP0544740B1/en not_active Expired - Lifetime
- 1991-08-19 AU AU84456/91A patent/AU8445691A/en not_active Abandoned
- 1991-08-19 CS CS912567A patent/CS256791A3/en unknown
- 1991-08-19 WO PCT/FR1991/000670 patent/WO1992003404A1/en active IP Right Grant
- 1991-08-19 HU HU93469A patent/HUT63373A/en unknown
- 1991-08-19 CA CA002089558A patent/CA2089558A1/en not_active Abandoned
- 1991-08-19 JP JP03514356A patent/JP3100059B2/en not_active Expired - Fee Related
- 1991-08-19 DE DE69102767T patent/DE69102767T2/en not_active Expired - Fee Related
- 1991-08-19 DK DK91914913.8T patent/DK0544740T3/en active
- 1991-08-19 PL PL29797291A patent/PL297972A1/en unknown
- 1991-08-20 PT PT98726A patent/PT98726B/en not_active IP Right Cessation
-
1993
- 1993-02-16 NO NO930546A patent/NO179001C/en not_active IP Right Cessation
- 1993-02-19 FI FI930751A patent/FI101880B1/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010327A (en) * | 2009-09-07 | 2011-04-13 | 浙江九洲药业股份有限公司 | Splitting method of (+/-)-2-(3-benzoyl)-phenylpropionic acid |
| CN102010327B (en) * | 2009-09-07 | 2013-04-10 | 浙江九洲药业股份有限公司 | Splitting method of (+/-)-2-(3-benzoyl)-phenylpropionic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| CS256791A3 (en) | 1992-03-18 |
| NZ239435A (en) | 1993-04-28 |
| CA2089558A1 (en) | 1992-02-21 |
| DE69102767D1 (en) | 1994-08-11 |
| ZA916496B (en) | 1992-05-27 |
| PT98726A (en) | 1992-07-31 |
| PL297972A1 (en) | 1993-11-02 |
| FI101880B (en) | 1998-09-15 |
| HU9300469D0 (en) | 1993-05-28 |
| JP3100059B2 (en) | 2000-10-16 |
| NO179001B (en) | 1996-04-09 |
| EP0544740B1 (en) | 1994-07-06 |
| PT98726B (en) | 1999-01-29 |
| ES2056657T3 (en) | 1994-10-01 |
| NO930546L (en) | 1993-02-16 |
| AU8445691A (en) | 1992-03-17 |
| FR2665897B1 (en) | 1994-03-18 |
| DE69102767T2 (en) | 1994-10-27 |
| NO179001C (en) | 1996-07-17 |
| EP0544740A1 (en) | 1993-06-09 |
| FI930751A (en) | 1993-02-19 |
| WO1992003404A1 (en) | 1992-03-05 |
| HUT63373A (en) | 1993-08-30 |
| FR2665897A1 (en) | 1992-02-21 |
| FI101880B1 (en) | 1998-09-15 |
| FI930751A0 (en) | 1993-02-19 |
| NO930546D0 (en) | 1993-02-16 |
| IE912917A1 (en) | 1992-02-26 |
| JPH06501683A (en) | 1994-02-24 |
| DK0544740T3 (en) | 1994-08-22 |
| ATE108172T1 (en) | 1994-07-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |