WO1996023759A1 - Procede de racemisation d'acides carboxyliques a activite optique - Google Patents

Procede de racemisation d'acides carboxyliques a activite optique Download PDF

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Publication number
WO1996023759A1
WO1996023759A1 PCT/JP1996/000176 JP9600176W WO9623759A1 WO 1996023759 A1 WO1996023759 A1 WO 1996023759A1 JP 9600176 W JP9600176 W JP 9600176W WO 9623759 A1 WO9623759 A1 WO 9623759A1
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WO
WIPO (PCT)
Prior art keywords
carboxylic acid
optically active
water
formula
equivalents
Prior art date
Application number
PCT/JP1996/000176
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English (en)
Japanese (ja)
Inventor
Kazutoshi Toyoda
Shunji Kamiyama
Original Assignee
Nagase & Company, Ltd.
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 Nagase & Company, Ltd. filed Critical Nagase & Company, Ltd.
Priority to JP52340996A priority Critical patent/JP3784411B2/ja
Publication of WO1996023759A1 publication Critical patent/WO1996023759A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification

Definitions

  • the present invention relates to a method for racemizing an optically active carboxylic acid. More specifically, the present invention relates to a method for racemizing a carboxylic acid represented by the following formula (1), which reacts quickly at a low temperature.
  • R 3 is water * atom, lower alkyl, phenyl or benzoyl, and R ⁇ is a hydrogen atom or a halogen atom
  • R 5 is a hydrogen atom or lower alkoxy
  • the compound represented by is used as a medicinal substance having an action such as anti-inflammatory and antipyretic or antipyretic or an intermediate thereof.
  • a compound of formula (1) in which is 3-benzoylphenyl and R 2 is methyl, ie, 2- (3-benzoylphenyl) brobionic acid is called ketobrofuune and is 41-isobutylfuel;
  • the compound of formula (1) in which R 2 is methyl, ie, 2- (4-isobutylphenyl) propionic acid, is called ibubrofin and is used as an anti-inflammatory and antipyretic agent.
  • These compounds have an asymmetric sequence, and have (-)-integral and (+)-isomer.
  • only one of the optically active substances exhibits pharmacological activity.
  • the other optically active substance having no or low pharmacological activity is converted into an optically active substance having high pharmacological activity. Will be needed. For this purpose, it is common to first racemize the former optically active substance, and then to separate the latter optically active substance having high pharmacological activity from this racemic substance.
  • a method of racemizing such a compound a method of heating at a high S in a solvent in the presence of a base is generally used.
  • a method of racemizing ketobloxin a method of heating to 100 to 200 in a solvent, particularly water, in the presence of an organic amine or an inorganic basic compound is known.
  • the flat method requires more than 8 hours at 150 reaction temperatures to complete the reaction, and usually requires pressurization.
  • Bertrand et al. The method requires 12 hours at a reaction temperature of 100 ° C or higher.
  • the method of Manimaran et al. Requires a reaction time of 15 hours at a high flow temperature.
  • the known methods have disadvantages such as a high reaction temperature, a long reaction time, and a need for pressurization in some cases, and the material may be damaged in a general-purpose reactor. .
  • the present inventors have proposed a method of converting an optically active form of the compound represented by the above formula (1) into a racemic form which does not have such a drawback, that is, a reaction temperature is low, a reaction time is short, and a severe reaction
  • a reaction temperature is low
  • a reaction time is short
  • a severe reaction An attempt was made to develop a practical racemization method that does not require conditions and thus allows the use of a general purpose reactor, applicable to industrial manufacturing processes.
  • R 3 is a hydrogen atom, lower alkyl, phenyl or benzoyl, and R 4 is a random atom or a halogen atom
  • R 5 is a hydrogen atom or lower alkoxy
  • R 2 is lower alkyl
  • a racemization method for an optically active carboxylic acid represented by the formula: wherein the carboxylic acid is added with 0.5 to 9.0 equivalents of water with respect to the carboxylic acid in the presence of an inorganic base to form a 40 to 50 9 provides a method characterized by heating.
  • lower alkyl means a carbon or straight or branched alkyl having 1 to 6 atoms, for example, methyl, ethyl, n-propyl, isopropyl, butyl, etc. , Isobutyl, n-pentyl, neopentyl, n-hexyl and the like.
  • the lower alkyl is often a direct- or branched-chain alkyl having 1 to 4 carbon atoms.
  • Halogen atoms include fluorine, chlorine, bromine and iodine.
  • the lower alkyne refers to an alkoxy in which the alkyl moiety is a straight-chain or branched lower alkyl having 1 to 6 carbon atoms.
  • the alkoxy is often an alkoxy moiety in which the alkyl moiety comprises a straight or branched chain alkyl having 1 to 4 carbon atoms.
  • Such lower alkyls are as described above, and thus lower alkoxy includes methoxy, ethoxyquin, n-bromoxy, isopropoxy, n-butoxy, ⁇ -pentyloquin, n-hexyloxy, etc. It is.
  • the optically active haponic acid represented by the above formula (1) can be efficiently racemized, but it is preferable to racemize a specific group of carboxylic acids. Specifically, it is preferred to racemize the carboxylic acid of formula (1) wherein R 2 is methyl. Further, is a carboxylic acid of the formula (1) in which is 3-benzoylphenyl, 4-isobutylphenyl, 2-fluoro-4-biphenyl or 6-methoxy-12-naphthyl, and R 2 is methyl. Racemization is preferred. It is also preferred to racemize the carboxylic acid of formula (1) wherein R 2 is isopropyl.
  • preferred carboxylic acids to be racemized according to the method of the present invention include the previously mentioned 2- (3-benzoylphenyl) propionic acid [ketobrophene] and 2- (4-isobutylphenyl) propionate.
  • the optically active carboxylic acid used in the method of the present invention is usually one containing a large amount of the other optically active substance after one optically active substance is separated from (earth) rubonic acid. Therefore, the optical purity may be high or it may be relatively low. Carboxylic acids of any optical purity can be used in the present method. Further, an optically active carboxylic acid derived from another source may be used.
  • the (earth) unit of the carboxylic acid represented by the above K formula (1) can be obtained from commercial products, or can be produced according to the method described in the literature. 3-1 2 8 3 7 French Patent No. 1.546.4878, Japanese Patent Publication No. 63-230652, U.S. Patent No. 3.904.682, U.S. Patent No. 4. No. 09/1977, U.S. Pat. No. 3.755.427, French patent M5 737, Masmoto et al. (Bioscience Biotechnology & Biochemistry, vol. 59, p. 720 ( 1 995)).
  • the racemization reaction can be performed as follows. That is, a mixture of the optically active carboxylic acid, the inorganic group and water is heated and stirred. If desired, a suitable solvent may be added to the mixture to cause a reaction. After the reaction is completed, cool the reaction solution and acidify it to pH 1 or less with an appropriate acid (hydrochloric acid, sulfuric acid, etc.). Next, the mixture is extracted with an organic solvent immiscible with water (toluene, ethyl acetate, etc.), the organic layer is washed with water, dried, and the solvent is distilled off under reduced pressure to obtain a racemized carboxylic acid.
  • the amount of water used in the present method is in the range of 0.5 to 9.0 equivalents, preferably 0.5 to 6.0 equivalents to the optically active carboxylic acid, according to the results of Examples described later. And more preferably 1.0 to 4.5 equivalents.
  • alkali metal or hydroxide of earth metal can be used as the inorganic base.
  • Preferred bases are sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide, especially sodium hydroxide and potassium hydroxide.
  • the amount of the inorganic base to be used is 0.5 equivalent or more, preferably 1.0 to 2.0 equivalent, more preferably 1.5 to 2.0 equivalent based on the optically active carboxylic acid.
  • a suitable solvent can be added to the reaction mixture.
  • the addition of a solvent is preferable from the viewpoint of operability, for example, the fluidity of the entire reaction system is improved.
  • the solvent to be added is not particularly limited as long as it is inert to the reaction mixture, and may be, for example, methyl alcohol, ethyl alcohol, or isopropyl alcohol.
  • Alcohols such as alcohol, ethers such as methyl-t-butyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; aliphatic hydrocarbons such as hexane, heptane, and octane; aromatic hydrocarbons such as benzene, toluene, and xylene Hydrogens or a mixed solvent thereof 0
  • Preferred solvents are non-polar solvents, selected from aliphatic hydrocarbons or aromatic hydrocarbons.
  • Preferred aliphatic hydrocarbons are selected from the group consisting of hexane, heptane and octane, and preferred aromatic hydrocarbons are selected from the group consisting of benzene, toluene and xylene.
  • a polar solvent such as a lower alcohol.
  • Particularly preferred alcohol in the present invention is methyl alcohol.
  • the reaction temperature may be between 40 and 99, at which temperature the reaction is usually completed within a few 10 minutes to 8 hours.
  • wZw% represents wt% by weight
  • wZv% represents wt / vol%
  • optical purity of the optically active carboxylic acid was measured by a high-performance liquid chromatography method (hereinafter abbreviated as HPLC) under the following analytical conditions.
  • HPLC high-performance liquid chromatography method
  • Buffer solution 1 OmM NaPB (1 ⁇ phosphate buffer + lmM
  • Table 1 shows the results of experiments performed under the same reaction conditions as above S, but with the water equivalent to KET changed.
  • racemization was performed in the same manner as in Example 1 except that heating was performed at a temperature of 80 for 60 minutes. Was.
  • the optical purity of the obtained white crystal (5. Og) was measured, it was 0% e.e. NMR and IR were consistent with the starting compound. That is, it was found that racemization was completely achieved with a recovery rate of 100%.
  • Racemization was carried out in the same manner as in Example 2 except that 7XC 1.5 g. 83.3 mmol, water ZIBU-30w% (3.43 mol nomole ratio) was used and heating was performed at a temperature of 80 for 50 minutes. When the optical purity of the obtained white crystal (5. Og) was measured, it was 0% e. NMR and IR were consistent with the starting compound. That is, it was found that racemization was completely achieved with a recovery rate of 100%.
  • Example 8 Racemization of 1-phenyl-2-methylbutanoic acid Instead of (1-) 1-2- (3-benzoylphenyl) propionic acid of Example 1, (1-) 1-2- (95% ee) 95% using phenyl-3-methylbutanoic acid The mixture was heated at ° C for 8 hours, and a racemization reaction was performed in the same manner. When the optical purity of the obtained white quartz (5. Og) was measured, it was 0% ee. NMR and IR were consistent with the starting compound. That is, it was found that racemization was completely achieved with a recovery rate of 100%.
  • an optically active carboxylic acid can be racemized at a low temperature in a short time. That is, the present method is a practical and efficient racemization method applicable to industrial manufacturing processes, which does not require harsh reaction conditions and thus enables the use of a general-purpose reactor.

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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)

Abstract

Procédé de racémisation d'acides carboxyliques à activité optique à basse température et en un temps réduit consistant à ajouter de 0,5 à 9,0 équivalents d'eau à un équivalent d'un acide carboxylique donné à activité optique en présence d'une base non organique puis à chauffer le mélange résultant entre 40 et 99 °C. Ce procédé pratique et efficace de racémisation s'applique à des productions industrielles car il permet, en évitant des conditions 'lourdes' de réaction, d'utiliser des réacteurs polyvalents.
PCT/JP1996/000176 1995-01-31 1996-01-31 Procede de racemisation d'acides carboxyliques a activite optique WO1996023759A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP52340996A JP3784411B2 (ja) 1995-01-31 1996-01-31 光学活性なカルボン酸のラセミ化法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1368895 1995-01-31
JP7/13688 1995-01-31

Publications (1)

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WO1996023759A1 true WO1996023759A1 (fr) 1996-08-08

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WO (1) WO1996023759A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006049211A1 (fr) * 2004-11-02 2006-05-11 National University Corporation University Of Toyama Acide 2 aryl-2-fluoroalcanoique, son ester et methodes servant a preparer ces derniers
US7214820B2 (en) 2003-01-23 2007-05-08 Nagase & Co., Ltd. Process for producing optically active flurbiprofen
WO2010001103A1 (fr) * 2008-06-30 2010-01-07 Aesica Pharmaceuticals Limited Procédé de production d'un acide 2-aryl-propionique

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100978776B1 (ko) 2008-04-11 2010-08-30 주식회사 엔지켐 광학활성 이부프로펜의 라세미화방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0469356A (ja) * 1990-07-09 1992-03-04 Nissan Chem Ind Ltd ２―（３―ベンゾイル）フェニルプロピオン酸のラセミ化法
US5162576A (en) * 1991-04-15 1992-11-10 Ethyl Corporation Resolution of ketoprofen
JPH06501683A (ja) * 1990-08-20 1994-02-24 ローン―プーラン・ロレ・ソシエテ・アノニム ［ｒ（−）］―２―（３―ベンゾイルフエニル）プロピオン酸をそのｓ（＋）異性体に変換する方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0469356A (ja) * 1990-07-09 1992-03-04 Nissan Chem Ind Ltd ２―（３―ベンゾイル）フェニルプロピオン酸のラセミ化法
JPH06501683A (ja) * 1990-08-20 1994-02-24 ローン―プーラン・ロレ・ソシエテ・アノニム ［ｒ（−）］―２―（３―ベンゾイルフエニル）プロピオン酸をそのｓ（＋）異性体に変換する方法
US5162576A (en) * 1991-04-15 1992-11-10 Ethyl Corporation Resolution of ketoprofen

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7214820B2 (en) 2003-01-23 2007-05-08 Nagase & Co., Ltd. Process for producing optically active flurbiprofen
WO2006049211A1 (fr) * 2004-11-02 2006-05-11 National University Corporation University Of Toyama Acide 2 aryl-2-fluoroalcanoique, son ester et methodes servant a preparer ces derniers
JPWO2006049211A1 (ja) * 2004-11-02 2008-05-29 国立大学法人富山大学 ２−アリール−２−フルオロアルカン酸及びそのエステル並びにそれらの製造方法
WO2010001103A1 (fr) * 2008-06-30 2010-01-07 Aesica Pharmaceuticals Limited Procédé de production d'un acide 2-aryl-propionique
GB2477218A (en) * 2008-06-30 2011-07-27 Aesica Pharmaceuticals Ltd Process for the manufacture of racemic 2-aryl-propionic acid

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Publication number Publication date
JP3784411B2 (ja) 2006-06-14

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