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WO1994006747A1 - Resolution de cetoprofene - Google Patents

Resolution de cetoprofene Download PDF

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Publication number
WO1994006747A1
WO1994006747A1 PCT/US1992/007997 US9207997W WO9406747A1 WO 1994006747 A1 WO1994006747 A1 WO 1994006747A1 US 9207997 W US9207997 W US 9207997W WO 9406747 A1 WO9406747 A1 WO 9406747A1
Authority
WO
WIPO (PCT)
Prior art keywords
salt
ketoprofen
propionic acid
alcohol
cinchonidine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1992/007997
Other languages
English (en)
Inventor
Thanikavelu Manimaran
Alicia A. Potter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ethyl Corp
Original Assignee
Ethyl Corp
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.)
Filing date
Publication date
Application filed by Ethyl Corp filed Critical Ethyl Corp
Priority to JP6508029A priority Critical patent/JPH07505165A/ja
Priority to PCT/US1992/007997 priority patent/WO1994006747A1/fr
Priority to EP92920678A priority patent/EP0613456A1/fr
Publication of WO1994006747A1 publication Critical patent/WO1994006747A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • 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

Definitions

  • the invention relates to a process for resolution of mixtures of enantiomeric arylpropionic acids and for obtaining one of the enantiomeric forms of the acids, in which the mixture is converted with a chiral base in an inert solvent to a diastereoisomeric salt and the desired acid enantiomer is separated therefrom.
  • Chromatographic separation has been carried out using a variety of substrates.
  • the object of the present invention is to provide an efficient and practical process for the separation of a racemic mixture of ketoprofen [(j-_)- ⁇ :-(3-benzoyl- phenyl)propionic acid] into its individual enantiomeric forms, particularly the S( + ) form.
  • ketoproten-cinchonidine salt forms from a solution of an aliphatic ester and alkyl alcohol.
  • the diastereomeric forms of the salt are readily separated and further purified in a single recrystallization.
  • the separated salt is easily hydrolyzed to afford the highly pure (S)-( + )-ketoprofen without the need for any further recrystallization.
  • aliphatic ester means an ester of the formula RC(O)OR 1 , where R and R ⁇ are the same or different and are to C 12 linear or branched alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, neopentyl, hexyl, nonyl, dodecyl and the like.
  • R and R t are the same or different and are to C 6 linear or branched alkyl.
  • Most preferred are the to C 6 linear or branched alkyl esters of acetic acid.
  • a particularly preferred aliphatic ester is ethyl acetate.
  • Alkyl alcohol means the C t to C 12 linear or branched alkyl alcohols such as methanol, ethanol, n-propanol, n-butanol, n-hexanol, 2-ethylhexanol, nonan-1-ol and the like.
  • the alkyl group is a to C 6 linear or branched alkyl. Particularly preferred is methanol.
  • racemic ketoprofen obtained commercially, is dissolved in a solvent mixture of an aliphatic ester and alkyl alcohol. The solution is heated to from 30 ° C to 70 ° C, preferably 50-60 ° C, and cinchonidine is added. Typically for best results, an equal equivalent weight of cinchonidine to ketoprofen is used in this reaction. However, it should be understood that more than an equivalent weight of cinchonidine can be used, facilitating the complete reaction of the ketoprofen.
  • the solvent system ratios are critical to achieving the highly pure material isolated from the present process.
  • the (volumetric) amount of aliphatic ester should be from 2 to 20 times the amount of alkyl alcohol, preferably 15 times, most preferably 7 to 12 times such amount.
  • the ratio of salt to solvent is in the range of 1:0.2 to 1:100, preferably 1:0.6 to 1:15 (w/v).
  • the diaster ⁇ eomeric salt is separated from the optionally cooled reaction solution.
  • a single recrystallization (from ethyl acetate/methanol) produces a sufficiently pure salt for further (hydrolysis) treatment. While further recrystallizations are possible, they are not needed since the optical purity of the diasteromeric salt is very high, typically over 95%.
  • the diastereomeric salt is cleaved with dilute hydrochloric and the S( + )ketoprofen separated.
  • Cinchonidine (155 g; 0.53 mol) was added to a solution of 151 g (0.59 mol) of racemic ketoprofen and 2.8 L of ethyl acetate under vigorous stirring at 50-60 ° C. The mixture was diluted with 280 mL of methanol, cooled to 35 ° C, then seeded with 98% enantiomerically pure S-salt to induce crystallization.
  • Parenthetical data are for samples prepared with purified MBA.

Landscapes

  • 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)

Abstract

Procédé permettant de dissoudre de l'acide (±)-α-(-benzoylphényle)propionique qui consiste: i) à convertir ledit acide propionique à l'aide de (-)-cinchonidine en un solvant comprenant un mélange d'ester aliphatique et un alcool d'alkyle; ii) à séparer le sel diastéréomère du produit de conversion; iii) à purifier ledit sel diastéréomère séparé par une recristallisation unique; et (iv) à isoler l'acide (+)-α-(3-benzoylphényle)propionique sans aucune nouvelle recristallisation.
PCT/US1992/007997 1992-09-21 1992-09-21 Resolution de cetoprofene Ceased WO1994006747A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP6508029A JPH07505165A (ja) 1992-09-21 1992-09-21 ケトプロフェンの分離
PCT/US1992/007997 WO1994006747A1 (fr) 1992-09-21 1992-09-21 Resolution de cetoprofene
EP92920678A EP0613456A1 (fr) 1992-09-21 1992-09-21 Resolution de cetoprofene

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1992/007997 WO1994006747A1 (fr) 1992-09-21 1992-09-21 Resolution de cetoprofene

Publications (1)

Publication Number Publication Date
WO1994006747A1 true WO1994006747A1 (fr) 1994-03-31

Family

ID=22231391

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/007997 Ceased WO1994006747A1 (fr) 1992-09-21 1992-09-21 Resolution de cetoprofene

Country Status (3)

Country Link
EP (1) EP0613456A1 (fr)
JP (1) JPH07505165A (fr)
WO (1) WO1994006747A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705900A (en) * 1970-03-09 1972-12-12 Lilly Co Eli Isomer resolution
EP0362476A2 (fr) * 1988-07-19 1990-04-11 Paz Arzneimittel- Entwicklungsgesellschaft Mbh Procédé de dédoublement de mélanges d'acides arylpropioniques enatiomères
WO1992018455A1 (fr) * 1991-04-15 1992-10-29 Ethyl Corporation Resolution de ketoprofene

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705900A (en) * 1970-03-09 1972-12-12 Lilly Co Eli Isomer resolution
EP0362476A2 (fr) * 1988-07-19 1990-04-11 Paz Arzneimittel- Entwicklungsgesellschaft Mbh Procédé de dédoublement de mélanges d'acides arylpropioniques enatiomères
WO1992018455A1 (fr) * 1991-04-15 1992-10-29 Ethyl Corporation Resolution de ketoprofene

Also Published As

Publication number Publication date
EP0613456A1 (fr) 1994-09-07
JPH07505165A (ja) 1995-06-08

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