NO179001B - Process for converting 2 (3-benzoylphenyl) R (-) propionic acid into an S (+) isomer - Google Patents
Process for converting 2 (3-benzoylphenyl) R (-) propionic acid into an S (+) isomer Download PDFInfo
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- NO179001B NO179001B NO930546A NO930546A NO179001B NO 179001 B NO179001 B NO 179001B NO 930546 A NO930546 A NO 930546A NO 930546 A NO930546 A NO 930546A NO 179001 B NO179001 B NO 179001B
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- ketoprofen
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- cinchonidine
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 230000008569 process Effects 0.000 title claims abstract description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 title claims description 7
- -1 3-benzoylphenyl Chemical group 0.000 title claims description 5
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 238000002425 crystallisation Methods 0.000 claims abstract description 9
- 230000008025 crystallization Effects 0.000 claims abstract description 9
- 238000011065 in-situ storage Methods 0.000 claims abstract description 4
- 230000009471 action Effects 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- DKYWVDODHFEZIM-NSHDSACASA-N dexketoprofen Chemical compound OC(=O)[C@@H](C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-NSHDSACASA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical group C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 claims description 14
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 14
- DKYWVDODHFEZIM-LLVKDONJSA-N (2r)-2-(3-benzoylphenyl)propanoic acid Chemical compound OC(=O)[C@H](C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-LLVKDONJSA-N 0.000 claims description 12
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical group CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 12
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 12
- 238000003776 cleavage reaction Methods 0.000 claims description 9
- 230000007017 scission Effects 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 241000283986 Lepus Species 0.000 claims 1
- 239000012452 mother liquor Substances 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract 2
- 230000001131 transforming effect Effects 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 31
- 229960000991 ketoprofen Drugs 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000003287 optical effect Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000011197 physicochemical method Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- OAPDLBHLMVYMCW-UHFFFAOYSA-M sodium;2-(3-benzoylphenyl)propanoate Chemical compound [Na+].[O-]C(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 OAPDLBHLMVYMCW-UHFFFAOYSA-M 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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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
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
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- 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)
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- Agricultural Chemicals And Associated Chemicals (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Foreliggende oppfinnelse angår en fremgangsmåte for omdanning av 2(3-benzoylfenyl) R(-)propionsyre til en S(+)isomer. The present invention relates to a method for converting 2(3-benzoylphenyl) R(-)propionic acid into an S(+) isomer.
2(3-benzoylfenyl)propionsyre (eller ketoprofen) oppviser spesielt interessante anti-inflammatoriske, analgetiske og/eller antipyretiske egenskaper. 2(3-benzoylphenyl)propionic acid (or ketoprofen) exhibits particularly interesting anti-inflammatory, analgesic and/or antipyretic properties.
Ketoprofen i racemisk form består av en ekvimolar blanding av S(+)- og R(-)enantiomerene. Ketoprofen in racemic form consists of an equimolar mixture of the S(+) and R(-) enantiomers.
Mens det på dyr ikke foreligger signifikante forskjeller mellom racemisk ketoprofen og S(+)isomeren (S(+)ketoprofen), er det på mennesker v-ist at S( +)ketoprofen utgjør den aktive form av ketoprofen og at R(-)isomeren ikke omdannes til S(+)-isomeren. While in animals there are no significant differences between racemic ketoprofen and the S(+)isomer (S(+)ketoprofen), in humans it has been shown that S(+)ketoprofen constitutes the active form of ketoprofen and that R(-) isomer is not converted to the S(+) isomer.
Det er spesielt fordelaktig å kunne disponere S(+)ketoprofen praktisk talt fri for R(-)isomeren. It is particularly advantageous to be able to dispose of S(+)ketoprofen practically free of the R(-)isomer.
S(+)ketoprofen kan oppnås ved spalting av racemisk ketoprofen enten ved hjelp av fysikokjemiske metoder (høy-ytelses væskekromatografi med en chiral fase) eller" ved dannelse av et salt med en optisk aktiv base. S(+)ketoprofen can be obtained by cleavage of racemic ketoprofen either by physicochemical methods (high-performance liquid chromatography with a chiral phase) or by forming a salt with an optically active base.
Disse prosesser fører til oppnåelse av S(+)isomeren og R(-)-isomeren der den sistnevnte ikke har noen egen nytte. Det er således av betydning å kunne disponere en prosess som tillater å omdanne R(-)ketoprofen til S(+)ketoprofen. These processes lead to the attainment of the S(+) isomer and the R(-) isomer where the latter has no benefit of its own. It is therefore important to be able to dispose of a process that allows R(-)ketoprofen to be converted into S(+)ketoprofen.
Det er nu funnet, en fremgangsmåte for omdanning av 2(3-benzylfenyl) R(-)propionsyre eller R(- )ketoprofen til S(+)isomeren, og denne fremgangsmåte karakteriseres ved at man behandler R(-)ketoprofen med en base ved en temperatur A method for converting 2(3-benzylphenyl) R(-)propionic acid or R(-)ketoprofen to the S(+) isomer has now been found, and this method is characterized by treating R(-)ketoprofen with a base at a temperature
>100°C. >100°C.
I en utførelsesform av oppfinnelsen skjer omdanningen av R(-) ketoprofen til S(+)ketoprofen in situ under spaltingen av racemisk ketoprofen ved hjelp av en chiral base som benyttes som middel for omdanning og spalting, idet man arbeider i et organisk oppløsningsmiddel valgt blant ketoner og alkoholer ved en temperatur nær 100°C. In one embodiment of the invention, the conversion of R(-)ketoprofen to S(+)ketoprofen takes place in situ during the cleavage of racemic ketoprofen by means of a chiral base which is used as a means of conversion and cleavage, working in an organic solvent selected from ketones and alcohols at a temperature close to 100°C.
Fortrinnsvis anvendes kinkonidin som chiral base og metylisobutylketon eller etanol som oppløsningsmiddel. Preferably, cinchonidine is used as chiral base and methyl isobutyl ketone or ethanol as solvent.
I en annen utførelsesform av oppfinnelsen skjer omdanningen av R(-)ketoprofen til S(+)ketoprofen i moderlutene fra krystallisering av et salt av S(+)ketoprofen, oppnådd ved innvirkning av en chiral base på racemisk ketoprofen idet man arbeider i et organisk oppløsningsmiddel valgt blant ketoner og alkoholer, ved hjelp av et overskudd av en sterk base, etter frisetting og separering av den chirale base, ved en temperatur over 100°C. In another embodiment of the invention, the conversion of R(-)ketoprofen to S(+)ketoprofen in the mother liquors takes place from crystallization of a salt of S(+)ketoprofen, obtained by the action of a chiral base on racemic ketoprofen while working in an organic solvent selected from ketones and alcohols, using an excess of a strong base, after release and separation of the chiral base, at a temperature above 100°C.
Som base benyttes fortrinnsvis NaOE i vandig oppløsning, som chiral base benyttes fortrinnsvis kinkonidin og som oppløs-ningsmiddel benyttes fortrinnsvis metylisobutylketon eller etanol. NaOE in aqueous solution is preferably used as base, cinchonidine is preferably used as chiral base and methyl isobutyl ketone or ethanol is preferably used as solvent.
Som nevnt kan fremgangsmåten ifølge oppfinnelsen gjennomføres in situ ved som spaltingsmiddel å benytte en chiral base som kinkonidin og som oppløsningsmiddel å benytte et keton som metylisobutylketon eller en alkohol som etanol. Det er fordelaktig å benytte metylisobutylketon som tillater å arbeide ved høyere temperaturer. For å oppnå et forbedret utbytte er det spesielt fordelaktig å fremtvinge krystallisering av det ønskede overveiende salt (kinkonidinsalt med S(+)ketoprofen) ved konsentrering av oppløsningen under redusert trykk. As mentioned, the method according to the invention can be carried out in situ by using a chiral base such as cinchonidine as a cleavage agent and using a ketone such as methyl isobutyl ketone or an alcohol such as ethanol as a solvent. It is advantageous to use methyl isobutyl ketone which allows working at higher temperatures. In order to obtain an improved yield, it is particularly advantageous to force crystallization of the desired predominant salt (quinconidine salt with S(+)ketoprofen) by concentrating the solution under reduced pressure.
Generelt benytter man 1 mol kinkonidin/mol ketoprofen. In general, 1 mol cinchonidine/mol ketoprofen is used.
Generelt blir konsentreringen under redusert trykk regulert på en slik måte at koketemperaturen er konstant og nær 100°C under hele konsentreringens varighet. Saltkrystallene av S( + ) ketoprofen som dannes, separeres ved varmfiltrering. In general, the concentration under reduced pressure is regulated in such a way that the boiling temperature is constant and close to 100°C during the entire duration of the concentration. The salt crystals of S( + ) ketoprofen that are formed are separated by hot filtration.
Omdanningen kan som nevnt også realiseres uavhengig av krystalliseringen fra krystalliseringsmoderluten efter å ha fjernet den chirale base som ble benyttet som spaltingsmiddel ved å anvende en achiral base som natriumhydroksyd. As mentioned, the conversion can also be realized independently of the crystallization from the crystallization mother liquor after removing the chiral base that was used as a splitting agent by using an achiral base such as sodium hydroxide.
For gjennomføringen av fremgangsmåten på krystalliseringsmoderluten gjennomføres så spaltingen av racemisk ketoprofen ved å benytte 0,5 til 1 mol kinkonidin/mol ketoprofen. Efter separering ved filtrering av kinkonidinsaltet med ketoprofen (overveiende S(+)ketoprofen), blir moderluten behandlet med en vandig oppløsning av en sterk mineralbase som natriumhydroksyd efter frigjøring og separering av kinkonidin enten i form av base eller i form av salt. Ketoprofenet (overveiende R(-)ketoprofen) i form av natriumsaltet forblir i basis vandig oppløsning og oppvarmes til en temperatur generelt over 100°C, fortrinnsvis nær 110"C idet man følger utviklingen av den optiske titer som en funksjon av tiden der den optiske titer uttrykkes ved forholdet 100 x R/(R+S). Omdanningen karakteriseres ved en progressiv "reduksjon av den optiske titer. For carrying out the process on the crystallization mother liquor, the cleavage of racemic ketoprofen is then carried out by using 0.5 to 1 mol of cinchonidine/mol of ketoprofen. After separation by filtration of the cinchonidine salt with ketoprofen (predominantly S(+)ketoprofen), the mother liquor is treated with an aqueous solution of a strong mineral base such as sodium hydroxide after release and separation of cinchonidine either in the form of a base or in the form of a salt. The ketoprofen (predominantly R(-)ketoprofen) in the form of the sodium salt remains in base aqueous solution and is heated to a temperature generally above 100°C, preferably close to 110°C, following the development of the optical titer as a function of time in which the optical titer is expressed by the ratio 100 x R/(R+S). The transformation is characterized by a progressive "reduction of the optical titer.
De følgende eksempler skal illustrere oppfinnelsen i praksis. The following examples shall illustrate the invention in practice.
Eksempel 1 - Spalting - Racemisering. Example 1 - Cleavage - Racemisation.
Til en 250 cm<5> reaktor innføres 26,5 g racemisk ketoprofen (0,104 mol), 31 g kinkonidin (0,105 mol) og 120 g vann (eller 151 cm<5>) metylisobutylketon (1,204). Blandingen oppvarmes under opprøring til 100°C hvorefter blandingen konsentreres under redusert trykk ved å regulere trykket på en slik måte at koketemperaturen forblir konstant og lik 100°C. Man destillerer 97,2 g metylisobutylketon i 8 timer. Man omrører over natten ved 100° C, 45 minutter ved 45 °C og heller så reaksjonsblandingen på et filter, termostatert til 100°C. Filterkaken vaskes med 70 cm<3> metylisobutylketon ved 20°C og tørkes. Man oppnår på denne måte 19 g ketoprofensalt hvis optiske titer (S/R+S) er 88,3 %. 26.5 g of racemic ketoprofen (0.104 mol), 31 g of cinchonidine (0.105 mol) and 120 g of water (or 151 cm<5>) methyl isobutyl ketone (1.204) are introduced into a 250 cm<5> reactor. The mixture is heated under agitation to 100°C after which the mixture is concentrated under reduced pressure by regulating the pressure in such a way that the boiling temperature remains constant and equal to 100°C. 97.2 g of methyl isobutyl ketone is distilled for 8 hours. Stir overnight at 100°C, 45 minutes at 45°C and pour the reaction mixture onto a filter, thermostated at 100°C. The filter cake is washed with 70 cm<3> of methyl isobutyl ketone at 20°C and dried. In this way, 19 g of ketoprofen salt are obtained whose optical titer (S/R+S) is 88.3%.
Utbyttet er 58,6 %. Balansen på ketoprofen fører til de følgende resultater: The yield is 58.6%. The balance of ketoprofen leads to the following results:
Eksempel 2 - Racemisering med natriumhydroksyd. Example 2 - Racemization with sodium hydroxide.
Til en reaktor innføres 10,4 g racemisk ketoprofen (0,041 mol), 6 g kinkonidin (0,020 mol) og 28,9 g (eller 36 cm<5>) metylisobutylketon (0,288 mol). Blandingen oppvarmes til 75"C og holdes så ved denne temperatur inntil oppløsningen er total hvorefter man gjennomfører en hurtig avkjøling til 70°C. Man aksellererer krystalliseringen med noen S(+)-ketoprofenkinkonidinsaltkrystaller. Den oppnådde buljong avkjøles i 6 timer fra 70 til 10°C i en hastighet av ca. 10"C/t. Buljongen filtreres ved en temperatur nær 20°C. Filterkaken vaskes med 15 g metylisobutylketon. Man oppnår på denne måte 7,3 g av et salt hvis sammensetning er som følger: 10.4 g of racemic ketoprofen (0.041 mol), 6 g of cinchonidine (0.020 mol) and 28.9 g (or 36 cm<5>) of methyl isobutyl ketone (0.288 mol) are introduced into a reactor. The mixture is heated to 75°C and then kept at this temperature until the solution is complete, after which a rapid cooling to 70°C is carried out. The crystallization is accelerated with some S(+)-ketoprofen quinconidine salt crystals. The obtained broth is cooled for 6 hours from 70 to 10 °C at a rate of about 10"C/h. The broth is filtered at a temperature close to 20°C. The filter cake is washed with 15 g of methyl isobutyl ketone. In this way, 7.3 g of a salt whose composition is as follows is obtained:
- S(+)ketoprofen.kinkonidinsalt: 5,9 g (0,011 mol) - S(+)ketoprofen.quinconidine salt: 5.9 g (0.011 mol)
- R(-)ketoprofen.kinkonidinsalt: 1,4 g (0,002 mol). - R(-)ketoprofen.quinconidine salt: 1.4 g (0.002 mol).
Utbyttet er 53,6 %. The yield is 53.6%.
Filtratene har følgende sammensetning: The filtrates have the following composition:
- S(+)ketoprofen: 2,5 g (0,010 mol) - S(+)ketoprofen: 2.5 g (0.010 mol)
- R(-)ketoprofen: 4,5 g (0,018 mol) - R(-)ketoprofen: 4.5 g (0.018 mol)
- kinkonidin: 2,1 g (0,007 mol). - cinchonidine: 2.1 g (0.007 mol).
Til reaksjonsblandingen hvis vekt er 53 g settes, ved omgivelsestemperatur, 22,1 g 10 vekt-^-ig vandig natriumhydroksyd, det vil si 0,055 mol. To the reaction mixture whose weight is 53 g, at ambient temperature, 22.1 g of 10 wt-^-ig aqueous sodium hydroxide, i.e. 0.055 mol, is added.
Kinkonidinet forblir i den organiske fase mens ketoprofenet i form av natriumsaltet forblir i den vandige fase. Den vandige fase ekstraheres med 32 g eller 40 cm<5> metylisobutylketon og oppvarmes så til tilbakeløp i 24 timer ved 110 til 115°C. Man bestemmer utviklingen av den optiske titer som en funksjon av tiden. Resultatene er sammenfattet i den følgende tabell: The cinchonidine remains in the organic phase while the ketoprofen in the form of the sodium salt remains in the aqueous phase. The aqueous phase is extracted with 32 g or 40 cm<5> of methyl isobutyl ketone and then heated to reflux for 24 hours at 110 to 115°C. One determines the development of the optical titer as a function of time. The results are summarized in the following table:
Eksempel 3 - Racemisering med natriumhydroksyd. Example 3 - Racemization with sodium hydroxide.
Til en emaljert 300 liters reaktor settes 175 liter eller 145,3 kg av et filtrat efter spalting av racemisk ketoprofen med kinkonidin i etanol og der sammensetningen er som følger: ketoprofensalt med kinkonidin: 23,07 kg (42,04 mol) To an enamelled 300 liter reactor, add 175 liters or 145.3 kg of a filtrate after cleavage of racemic ketoprofen with cinchonidine in ethanol and where the composition is as follows: ketoprofen salt with cinchonidine: 23.07 kg (42.04 mol)
[optisk renhet for ketoprofen (S/S+R) nær 30 [optical purity for ketoprofen (S/S+R) close to 30
- etanol: 155 liter (122,23 kg) - ethanol: 155 liters (122.23 kg)
Den etanoliske oppløsning konsentreres under redusert trykk (80 mm Hg; 10,7 kPa) ved 30°C inntil man har oppnådd en tykk masse hvortil det settes 57,7 liter eller 50 kg toluen hvorefter man så destillerer av ytterligere 20 liter oppløsnings-middel . The ethanolic solution is concentrated under reduced pressure (80 mm Hg; 10.7 kPa) at 30°C until a thick mass has been obtained to which 57.7 liters or 50 kg of toluene are added, after which a further 20 liters of solvent are distilled .
Til toluenoppløsningen, oppvarmet til 50°C ved hjelp av en vann/damp-blanding i en dobbelt-kappe, settes 42 liter destillert vann og 18,5 liter 9,8 N saltsyre. Man omrører energisk inntil reaksjonstemperaturen på ny når 50°C. Efter ferdig omrøring og dekantering blir den undre vandige fase separert og den organiske fase vasket med IN saltsyre. Til den organiske fase, holdt ved 50°C, settes 35 liter destillert vann og 3,1 1 9,8 N saltsyre. Man omrører energisk i 10 minutter. Efter dekantering blir den vandige fase forent med de tidligere separerte vandige faser. 42 liters of distilled water and 18.5 liters of 9.8 N hydrochloric acid are added to the toluene solution, heated to 50°C using a water/steam mixture in a double jacket. Stir vigorously until the reaction temperature reaches 50°C again. After complete stirring and decanting, the lower aqueous phase is separated and the organic phase is washed with IN hydrochloric acid. 35 liters of distilled water and 3.1 1 9.8 N hydrochloric acid are added to the organic phase, kept at 50°C. Stir vigorously for 10 minutes. After decantation, the aqueous phase is combined with the previously separated aqueous phases.
Den organiske fase vaskes med 35 liter destillert vann-inneholdende 1,5 liter 9,8 N saltsyre og så med 30 liter destillert vann. Vaskevannet kasseres. The organic phase is washed with 35 liters of distilled water containing 1.5 liters of 9.8 N hydrochloric acid and then with 30 liters of distilled water. The wash water is discarded.
Til en oppløsning av 16,5 liter 10 N natriumhydroksyd (21,9 kg; 165 mol) i 16 liter destillert vann, setter man den ovenfor angitte toluenoppløsning. Man omrører heftig og oppvarmer så til 100° C (fri damp i en dobbeltkappe). Man holder reaksjonsblandingen under tilbakeløp i 12 timer. The above-mentioned toluene solution is added to a solution of 16.5 liters of 10 N sodium hydroxide (21.9 kg; 165 mol) in 16 liters of distilled water. Stir vigorously and then heat to 100° C (free steam in a double jacket). The reaction mixture is kept under reflux for 12 hours.
Efter avkjøling og dekantering består reaksjonsblandingen av tre faser: 1) en melkeaktig nedre fase på 11,9 kg som separeres og kasseres, 2) en lett gul midlere fase på 39 kg som inneholder ketoprofen natriumsaltet, og After cooling and decanting, the reaction mixture consists of three phases: 1) a milky lower phase of 11.9 kg which is separated and discarded, 2) a light yellow middle phase of 39 kg containing the ketoprofen sodium salt, and
3) en farveløs øvre toluenfase. 3) a colorless upper toluene phase.
En analyse av den midtre fase ved hjelp av chiral HPLC viser at den optiske titer (S/S+R) er 50 racemiseringen er total. An analysis of the middle phase by chiral HPLC shows that the optical titer (S/S+R) is 50. The racemization is total.
Til den midtre fase, oppvarmet til 50°C, settes 20 liter toluen og 13 liter 9,8 N saltsyre. Man omrører heftig. Efter dekantering blir den vandige fase behandlet med 20 liter toluen. 20 liters of toluene and 13 liters of 9.8 N hydrochloric acid are added to the middle phase, heated to 50°C. Stir vigorously. After decantation, the aqueous phase is treated with 20 liters of toluene.
Toluenfasen forenes og konsentreres ved destillering av 29 liter toluen ved 80 mm Hg eller 10,7 kPa og 42°C. The toluene phase is combined and concentrated by distilling 29 liters of toluene at 80 mm Hg or 10.7 kPa and 42°C.
Til den konsentrerte toluenoppløsning, oppvarmet til 70°C, settes cykloheksan på en slik måte at forholdet cykloheksan:-toluen er 6:4 på vekt-basis, det vil si 23 liter cykloheksan. To the concentrated toluene solution, heated to 70°C, cyclohexane is added in such a way that the ratio cyclohexane:-toluene is 6:4 on a weight basis, that is, 23 liters of cyclohexane.
Man avkjøler til 60° C og understøtter krystalliseringen ved tilsetning av 50 g racemisk ketoprofen. Efter avkjøling til en temperatur nær 15°C blir buljongen filtrert og så vasket 2 ganger med en blanding av 3,5 liter toluen og 6 liter cykloheksan . It is cooled to 60° C and the crystallization is supported by the addition of 50 g of racemic ketoprofen. After cooling to a temperature close to 15°C, the broth is filtered and then washed twice with a mixture of 3.5 liters of toluene and 6 liters of cyclohexane.
Man oppnår således en filterkake som representerer 9,76 kg tørr ketoprofen og benyttes. som sådan ved en ny spaltings-operasj on. A filter cake is thus obtained which represents 9.76 kg of dry ketoprofen and is used. as such by a new splitting operation.
Ketoprofenrenheten, bestemt ved ikke-chiral HPLC, er 100 %. Ketoprofen purity, determined by non-chiral HPLC, is 100%.
Claims (8)
Applications Claiming Priority (2)
| 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. |
| PCT/FR1991/000670 WO1992003404A1 (en) | 1990-08-20 | 1991-08-19 | Process for transforming (benzoyl-3 phenyl)-2 propionic acid into an s(+) isomer |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO930546D0 NO930546D0 (en) | 1993-02-16 |
| NO930546L NO930546L (en) | 1993-02-16 |
| NO179001B true NO179001B (en) | 1996-04-09 |
| NO179001C NO179001C (en) | 1996-07-17 |
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ID=9399732
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO930546A NO179001C (en) | 1990-08-20 | 1993-02-16 | Process for converting 2 (3-benzoylphenyl) R (-) propionic acid into an 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) | FI101880B (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) |
Families Citing this family (4)
| 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 |
| 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 |
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|---|---|---|---|---|
| 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 NZ NZ239435A patent/NZ239435A/en unknown
- 1991-08-16 ZA ZA916496A patent/ZA916496B/en unknown
- 1991-08-16 IE IE291791A patent/IE64689B1/en not_active IP Right Cessation
- 1991-08-19 PL PL29797291A patent/PL297972A1/en unknown
- 1991-08-19 HU HU93469A patent/HUT63373A/en unknown
- 1991-08-19 AU AU84456/91A patent/AU8445691A/en not_active Abandoned
- 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 CA CA002089558A patent/CA2089558A1/en not_active Abandoned
- 1991-08-19 DE DE69102767T patent/DE69102767T2/en not_active Expired - Fee Related
- 1991-08-19 JP JP03514356A patent/JP3100059B2/en not_active Expired - Fee Related
- 1991-08-19 WO PCT/FR1991/000670 patent/WO1992003404A1/en active IP Right Grant
- 1991-08-19 DK DK91914913.8T patent/DK0544740T3/en active
- 1991-08-19 EP EP91914913A patent/EP0544740B1/en not_active Expired - Lifetime
- 1991-08-19 CS CS912567A patent/CS256791A3/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/FI101880B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CA2089558A1 (en) | 1992-02-21 |
| NZ239435A (en) | 1993-04-28 |
| ES2056657T3 (en) | 1994-10-01 |
| NO930546D0 (en) | 1993-02-16 |
| PT98726B (en) | 1999-01-29 |
| EP0544740A1 (en) | 1993-06-09 |
| FI101880B1 (en) | 1998-09-15 |
| FR2665897A1 (en) | 1992-02-21 |
| CS256791A3 (en) | 1992-03-18 |
| NO930546L (en) | 1993-02-16 |
| JP3100059B2 (en) | 2000-10-16 |
| IE912917A1 (en) | 1992-02-26 |
| DE69102767D1 (en) | 1994-08-11 |
| FR2665897B1 (en) | 1994-03-18 |
| FI101880B (en) | 1998-09-15 |
| FI930751A0 (en) | 1993-02-19 |
| JPH06501683A (en) | 1994-02-24 |
| DK0544740T3 (en) | 1994-08-22 |
| ZA916496B (en) | 1992-05-27 |
| AU8445691A (en) | 1992-03-17 |
| HU9300469D0 (en) | 1993-05-28 |
| PL297972A1 (en) | 1993-11-02 |
| EP0544740B1 (en) | 1994-07-06 |
| ATE108172T1 (en) | 1994-07-15 |
| NO179001C (en) | 1996-07-17 |
| FI930751A (en) | 1993-02-19 |
| PT98726A (en) | 1992-07-31 |
| IE64689B1 (en) | 1995-08-23 |
| HUT63373A (en) | 1993-08-30 |
| WO1992003404A1 (en) | 1992-03-05 |
| DE69102767T2 (en) | 1994-10-27 |
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