WO2002012221A1 - Procede de resolution optique de l'acide (±)-6-hydroxy-2,5,7,8,-tetramethyle de coumarone-2-carboxylique - Google Patents

Procede de resolution optique de l'acide (±)-6-hydroxy-2,5,7,8,-tetramethyle de coumarone-2-carboxylique Download PDF

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Publication number
WO2002012221A1
WO2002012221A1 PCT/JP2001/005111 JP0105111W WO0212221A1 WO 2002012221 A1 WO2002012221 A1 WO 2002012221A1 JP 0105111 W JP0105111 W JP 0105111W WO 0212221 A1 WO0212221 A1 WO 0212221A1
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WIPO (PCT)
Prior art keywords
hydroxy
tetramethylchroman
acid
carboxylic acid
optical resolution
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PCT/JP2001/005111
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English (en)
Japanese (ja)
Inventor
Hideki Matsuda
Masahiro Torihara
Yoshin Tamai
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Kuraray Co., Ltd.
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Application filed by Kuraray Co., Ltd. filed Critical Kuraray Co., Ltd.
Publication of WO2002012221A1 publication Critical patent/WO2002012221A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/66—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Definitions

  • the present invention relates to a method for resolving (6-)-2-hydroxy-2,5,7,8-tetramethylchroman-12-carboxylic acid.
  • the optically active 6-hydroxy-2,5,7,8-tetramethylchroman-l-monocarboxylic acid obtained by the present invention is useful as a synthetic intermediate for an optically active vitamin E derivative [for example, Herbe et al. Chika Kimi Power Acta (He1Vetica Chimica Acta), 64 volumes, see page 1158 (1992) L Background technology
  • the method of synthesizing optically active 6-hydroxy-2,5,7,8-tetramethylchroman-12-carboxylic acid is as follows: 1 (Sat) _6-hydroxy 2,2,5,7,8-tetramethylchromane A method for asymmetric hydrolysis of 2-carboxylic acid esters using enzymes (see US Pat. No. 5,348,973), a method for converting an optically active acylproline derivative into a halolacton [Chemistry Letters (See Chemistry Letters), p. 465 (1989)], 3 A method of reacting an organotitanium compound with an optically active pyruvate (European Patent No. 0173314) And Japanese Patent Application Laid-Open No. Sho 61-66028) are known.
  • the method (2) has a problem that the operation of isolating and purifying the target substance after the asymmetric hydrolysis and the operation of separating and removing the enzyme are complicated. In the method, it is difficult to easily obtain an optically active substance or an organic titanium compound as a starting material. Therefore, These methods are not industrially advantageous for producing optically active 6-hydroxy-2,5,7,8-tetramethylchroman-12-carboxylic acid.
  • (Sat) 1-hydroxy-2,5,7,8-tetramethylchromano and -2 mono-rubric acid can be optically resolved by using an optically active ⁇ -phenylethylamine (US Patent No.
  • optically active ⁇ -benzyl- ⁇ ; -phenylethylamine acts on (sat) 16-hydroxy-1,2,5,7,8-tetramethylchroman1 / 2-carboxylic acid in tetrahydrofuran. Then, after distilling off the solvent, crystallization is carried out with a mixed solvent of ethanol and getyl ether.Therefore, different solvents are used for the reaction and crystallization, and the operation is complicated. . In the latter case, there is a problem that an expensive optically active amine is used, although the separation efficiency is high.
  • an object of the present invention is to provide a simple and efficient method for resolving (sat) 1-6-hydroxy-1,2,5,7,8-tetramethylchroman-2-carboxylic acid to obtain optically active 6-hydroxy-2,2 It is an object of the present invention to provide a method for obtaining 5,7,8-tetramethylchroman-l-carboxylic acid with high optical purity. Disclosure of the invention
  • the present invention relates to (Sat) 1-hydroxy-1,2,5,7,8-tetramethylchroman-12-carboxylic acid [hereinafter sometimes abbreviated as (Sat) monochromancarboxylic acid].
  • (Sat) monochromancarboxylic acid By reacting optically active a-phenylethylamine in a solvent consisting of propanol and / or methyl isobutyl ketone, and cooling the resulting reaction mixture, (+)-or (1-) 16-hydroxy-2, 5, 7, 8 —tetramethylchroman-1 2 (Sat) monochromancarboxylic acid characterized in that crystals of a diastereomer salt corresponding to monobasic rubonic acid [hereinafter, this may be abbreviated as (+)-or (-) monochromancarboxylic acid] are deposited. This is an optical resolution method of (+)-or (-) monochromancarboxylic acid.
  • the diastereomer salt is further separated, treated with a basic metal compound, and the obtained (+)-or (1-)-chroman force is reacted with an acid on the metal salt of rubonic acid to obtain the diastereomer salt.
  • (+) — Or (1) Includes the optical resolution method described above to obtain chromancarboxylic acids.
  • the present invention further encompasses the above-mentioned optical resolution method in which the diastereomer salt is separated and treated with an acid to obtain the (+)-or (1) monochromancarboxylic acid.
  • an optically active ⁇ -phenylethylamine is used as a resolving agent.
  • the amount of the optically active polyphenylethylamine used is not particularly limited. However, from the viewpoint that (Chroma) monochromancarboxylic acid can be efficiently separated with high purity, Is preferably in the range of 0.3 to 1.5 equivalents, more preferably in the range of 0.4 to 1.0 equivalents.
  • 2-propanol and / or methyl isobutyl ketone are used as a reaction solvent and a crystallization solvent.
  • the amount of the solvent used varies depending on the type of the solvent, the crystallization temperature, etc., but is preferably in the range of 1 to 100 times by weight, more preferably in the range of 2 to 10 times by weight, based on (sat) -chromancarboxylic acid. It is good.
  • the present invention is implemented, for example, by the following method.
  • (Earth) One chroman carboxylic acid, optically active ⁇ -phenylethylamine and a solvent are mixed and dissolved by heating if necessary, then the reaction mixture is cooled and (+) — or (I) -Chroman carboxylic acid and ⁇ -phenylethylamino
  • the salt is made supersaturated, and a sparingly soluble diastereomer salt is precipitated and separated.
  • methods for separating diastereomeric salts methods such as filtration and centrifugation are used.
  • the reaction temperature varies depending on the type of the solvent used, but is preferably in the range of 0 to 150 ° C, more preferably in the range of 20 to 100 ° C.
  • the crystallization temperature varies depending on the amount of the solvent used, the type of the solvent, the reaction temperature and the like, but is preferably in the range of 150 to 50 ° C, more preferably in the range of 130 to 30 ° C.
  • the resulting diastereomer salt is treated with an aqueous solution of a basic metal compound such as sodium hydroxide, hydroxylic acid, sodium methoxide, etc. to give (+)-or (-)-phenylphenylamine And (+)-or (+)-a metal salt of chromancarboxylic acid, and the mixture is extracted with an organic solvent such as hexane, toluene, ethyl acetate, methylene chloride, and the like. Or (1) Recover 1-phenylethylamine.
  • a basic metal compound such as sodium hydroxide, hydroxylic acid, sodium methoxide, etc.
  • an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, and mono-toluenesulfonic acid is allowed to act on the aqueous layer containing the metal salt of (-)-or (+)-chromancarboxylic acid.
  • an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, and mono-toluenesulfonic acid is allowed to act on the aqueous layer containing the metal salt of (-)-or (+)-chromancarboxylic acid.
  • Precipitate chromancarboxylic acid Precipitate chromancarboxylic acid.
  • the diastereomer salt is first treated with the above-mentioned acid to precipitate (+)-or (-1) monochromancarboxylic acid, and then (1-)-or (+)-hyphenyl.
  • the above-mentioned basic metal compound is allowed to act on the aqueous layer containing the ethylamine salt to release optically active ⁇ -phenylethylamine, and an organic solvent is added to the mixture to extract the optically active ⁇ -phenylethylamine.
  • the phenylethylamine may be recovered.
  • (Sat) monochromancarboxylic acid used as a raw material in the present invention is, for example, a reaction of 4-acetoxy-2,3,5-trimethylphenol with formaldehydes and methyl acrylate in the presence of secondary amine and acid. Then, the compound can be easily and inexpensively synthesized by hydrolysis (see US Pat. No. 5,495,026 and Japanese Patent Application Laid-Open No. 7-9738). No. 0).
  • (+ )-A monophenylethylamine salt was obtained.
  • (+)-chromancarboxylic acid or (-) monochromancarboxylic acid having high optical purity can be obtained by simply and efficiently subjecting (earth) -chromancarboxylic acid to optical resolution.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de résolution optique de l'acide (±)-6-hydroxy-2,5,7,8-tétraméthyle de coumarone-2-carboxylique en acides (+)- et (-)-6-hydroxy-2,5,7,8-tétraméthyle de coumarone-2-carboxyliques, qui se caractérise par la réaction de l'acide (±)-6-hydroxy-2,5,7,8-tétraméthyle de coumarone-2-carboxylique avec α-phényléthylamine optiquement active dans un solvant constitué de 2-propanol et/ou méthyle isobutyle cétone, et le refroidissement du mélange de réaction obtenu de façon à déposer des cristaux d'un sel diastéréomère correspondant à l'acide (+)- ou (-)-6-hydroxy-2,5,7,8-tétraméthyle de coumarone-2-carboxylique.
PCT/JP2001/005111 2000-08-03 2001-06-15 Procede de resolution optique de l'acide (±)-6-hydroxy-2,5,7,8,-tetramethyle de coumarone-2-carboxylique WO2002012221A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-235670 2000-08-03
JP2000235670 2000-08-03

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WO2002012221A1 true WO2002012221A1 (fr) 2002-02-14

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006306809A (ja) * 2005-04-28 2006-11-09 Mitsubishi Gas Chem Co Inc Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸及びその製造方法
JP2006306808A (ja) * 2005-04-28 2006-11-09 Mitsubishi Gas Chem Co Inc ６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸及びその製造方法
WO2008050829A1 (fr) 2006-10-26 2008-05-02 Mitsubishi Gas Chemical Company, Inc. Procédé de fabrication de l'acide s -(-)-6-hydroxy-2,5,7,8-tétraméthylchromane-2-carboxylique et produit obtenu par le procédé
WO2010050499A1 (fr) * 2008-10-29 2010-05-06 三菱瓦斯化学株式会社 Procédé de production d'un acide carboxylique organique optiquement actif
WO2016100576A1 (fr) * 2014-12-16 2016-06-23 Edison Pharmaceuticals, Inc. Procédés de résolution chirale du trolox
US10251847B2 (en) 2014-12-16 2019-04-09 Bioelectron Technology Corporation Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
EP4108658A4 (fr) * 2020-02-21 2024-05-22 Sumitomo Pharma Co Ltd Intermediaire de trolox optiquement résolu et son procédé de production

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947473A (en) * 1972-12-22 1976-03-30 Hoffman-La Roche Inc. Antioxidant chroman compounds
GB1456827A (en) * 1972-12-22 1976-11-24 Hoffmann La Roche Chromane derivatives
US4003919A (en) * 1973-11-19 1977-01-18 Hoffmann-La Roche Inc. Antioxidant chroman compounds
US4026907A (en) * 1973-11-19 1977-05-31 Hoffmann-La Roche Inc. Antioxidant chroman compounds
JPH1180149A (ja) * 1997-09-11 1999-03-26 Kuraray Co Ltd （±）−クロマンカルボン酸の光学分割法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947473A (en) * 1972-12-22 1976-03-30 Hoffman-La Roche Inc. Antioxidant chroman compounds
GB1456827A (en) * 1972-12-22 1976-11-24 Hoffmann La Roche Chromane derivatives
US4003919A (en) * 1973-11-19 1977-01-18 Hoffmann-La Roche Inc. Antioxidant chroman compounds
US4026907A (en) * 1973-11-19 1977-05-31 Hoffmann-La Roche Inc. Antioxidant chroman compounds
JPH1180149A (ja) * 1997-09-11 1999-03-26 Kuraray Co Ltd （±）−クロマンカルボン酸の光学分割法

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006306808A (ja) * 2005-04-28 2006-11-09 Mitsubishi Gas Chem Co Inc ６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸及びその製造方法
JP2006306809A (ja) * 2005-04-28 2006-11-09 Mitsubishi Gas Chem Co Inc Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸及びその製造方法
US8080676B2 (en) 2006-10-26 2011-12-20 Mitsubishi Gas Chemical Company, Inc. Method of producing S-(−)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid and product obtained by the method
WO2008050829A1 (fr) 2006-10-26 2008-05-02 Mitsubishi Gas Chemical Company, Inc. Procédé de fabrication de l'acide s -(-)-6-hydroxy-2,5,7,8-tétraméthylchromane-2-carboxylique et produit obtenu par le procédé
JP5598330B2 (ja) * 2008-10-29 2014-10-01 三菱瓦斯化学株式会社 光学活性有機カルボン酸の製造方法
CN102203047A (zh) * 2008-10-29 2011-09-28 三菱瓦斯化学株式会社 光学活性有机羧酸的制造方法
WO2010050499A1 (fr) * 2008-10-29 2010-05-06 三菱瓦斯化学株式会社 Procédé de production d'un acide carboxylique organique optiquement actif
WO2016100576A1 (fr) * 2014-12-16 2016-06-23 Edison Pharmaceuticals, Inc. Procédés de résolution chirale du trolox
US10251847B2 (en) 2014-12-16 2019-04-09 Bioelectron Technology Corporation Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
US10751302B2 (en) 2014-12-16 2020-08-25 Ptc Therapeutics, Inc. Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
US11304914B2 (en) 2014-12-16 2022-04-19 Ptc Therapeutics, Inc. Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
US11938101B2 (en) 2014-12-16 2024-03-26 Ptc Therapeutics, Inc. Polymorphic forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
EP4108658A4 (fr) * 2020-02-21 2024-05-22 Sumitomo Pharma Co Ltd Intermediaire de trolox optiquement résolu et son procédé de production

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