WO2006014015A1 - Procédé pour la production d'aminodiols insaturés - Google Patents

Procédé pour la production d'aminodiols insaturés Download PDF

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Publication number
WO2006014015A1
WO2006014015A1 PCT/JP2005/014615 JP2005014615W WO2006014015A1 WO 2006014015 A1 WO2006014015 A1 WO 2006014015A1 JP 2005014615 W JP2005014615 W JP 2005014615W WO 2006014015 A1 WO2006014015 A1 WO 2006014015A1
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WO
WIPO (PCT)
Prior art keywords
unsaturated
aminodiols
group
general formula
alkyl group
Prior art date
Application number
PCT/JP2005/014615
Other languages
English (en)
Japanese (ja)
Inventor
Shigeo Katsumura
Original Assignee
Chemicrea Inc.
Kwansei Gakuin Educational Foundation
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 Chemicrea Inc., Kwansei Gakuin Educational Foundation filed Critical Chemicrea Inc.
Publication of WO2006014015A1 publication Critical patent/WO2006014015A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms

Definitions

  • the present invention relates to a method for producing unsaturated aminodiols utilizing a metathesis reaction.
  • Unsaturated aminodiols are sphingosine derivatives and are useful as synthetic raw materials such as sphingomyelin which are effective for drug delivery systems.
  • methods for producing unsaturated aminodiols include synthesis methods using sugar as a raw material, methods using Sharpless asymmetric epoxidation, methods using Garner aldehyde, and methods using asymmetric aldol reactions.
  • methods using Sharpless asymmetric epoxidation methods using Garner aldehyde
  • methods using asymmetric aldol reactions for example, Natsuo Katsumura, Toshikazu Hakogi, “Protein Nucleic Acid Enzyme”, Vol.47, No.4, 526-536 (2002)), all of which have complicated processes and stereoselectivity. I have a bad problem.
  • the present invention utilizes a metathesis reaction to provide an unsaturated aminodioic acid conveniently and inexpensively.
  • the object of the present invention is to provide a method for producing sulfids. Disclosure of the invention
  • the method for producing the unsaturated aminodiols of the present invention comprises the following general formula (I)
  • R 1 is a hydrogen atom or hydroxyl protecting group
  • R 2 is a hydrogen atom or amino protecting group, and and each independently represent a lower alkyl group or an oxo group
  • 5 represents a lower alkyl group.
  • the metathesis catalyst is preferably a ruthenium carbene complex.
  • the ruthenium carbene complex has the following general formula (IV):
  • R 7 and R 8 are an alkyl group or an aryl group, R 9 is a phosphine ligand, and X is a halogen atom).
  • unsaturated aminodiols and olefins are reacted in the presence of a metathesis catalyst, so that they are simpler, more versatile and more reactive than conventional reaction steps. Since the selectivity (EZZ selectivity) is good, it is possible to produce unsaturated aminodiols which are target compounds in high yield.
  • unsaturated aminodiols, olefins and metathesis catalysts used in the method for producing unsaturated aminodiols of the present invention are relatively inexpensive, it is possible to produce unsaturated aminodiols at low cost. Therefore, it is possible to economically provide synthetic raw materials such as sphingomyelin that are effective for drug delivery systems.
  • Preferred embodiments for carrying out the invention are relatively inexpensive, it is possible to produce unsaturated aminodiols at low cost. Therefore, it is possible to economically provide synthetic raw materials such as sphingomyelin that are effective for drug delivery systems.
  • R 1 is a hydrogen atom or hydroxyl protecting group
  • R 2 is a hydrogen atom or amino protecting group
  • R 3 and R 4 are each independently a lower alkyl group or an oxo group
  • R 5 represents a lower alkyl group.
  • an unsaturated aminodiol represented by the following general formula (II):
  • the lower alkyl group is an alkyl group having 1 to 5 carbon atoms which may be branched, and includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a t-butyl group. Examples thereof include a group and a pentyl group.
  • a C1-C20 alkyl group is a C1-C20 alkyl group which may have a substituent which does not participate in reaction.
  • hydroxyl protecting groups include silyl protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylpropylsilyl, methoxymethyl, tetrahydro
  • silyl protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylpropylsilyl, methoxymethyl, tetrahydro
  • ether-based protecting groups such as pyrael and ethoxyethyl
  • ester-based protecting groups such as acetyleno and benzoyl.
  • protecting groups for amino groups include silyl-based protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylpropyl, and the like, and strong rubamate-based protecting groups such as t-butoxycarbol and benzylcarpyl, acetyl and benzoyl. And ester-based protecting groups such as
  • the production method of the present invention is carried out in the presence of a metathesis catalyst, and as a metathesis catalyst, a ruthenium carbene complex is preferred from the viewpoint of reaction efficiency, even among existing metathesis catalysts. ,.
  • ruthenium carbene complex As a ruthenium carbene complex, a force that allows an existing ruthenium carbene complex to be suitably used.
  • R 7 and R 8 are alkyl groups or aryl groups, R 9 is a phosphine ligand, and X is a halogen atom). It is preferable in terms of ease of use.
  • the alkyl group is an alkyl group having 1 to 20 carbon atoms that may have a substituent that does not participate in the reaction, and the aryl group may have a substituent that does not participate in the reaction. Examples thereof include a good phenyl group, naphthyl group, furan group, pyrrole group, and thiophene group.
  • the phosphine ligand is a phosphine ligand substituted with the alkyl group or aryl group.
  • a halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • hydrocarbon solvents such as benzene, toluene, xylene, hexane, and cyclohexane
  • ether solvents such as tetrahydrofuran, dimethoxyethane, and dioxane
  • halogenated solvents such as dichloromethane, chloroform, and dichloroethane. can do.
  • the reaction temperature can be appropriately selected from the temperature range of 0 ° C to 150 ° C. Force The reaction temperature and the economic point of view are preferably in the range of room temperature to 80 ° C.
  • Tetrahydropyraninoreprono ⁇ quinoleanol Tetrahydropyranyl propargyl ether: 0.656 g, 4.68 mmol
  • THF 29.8 ml
  • 1.6 N hexane solution 2.80 ml, 4.47 mmol
  • n-butyllithium n-butyllithium
  • (4S) -3-Benzyl-2-oxo-oxazolidine-4-carponic acid methyl ester (above 1) ((4S) -3_Benzyl-2-Ox0-oxazolidine- 4- carboxylic acid methyl ester: l.OOg, 4.25mmol ) was added dropwise to a THF solution and stirred for 10 minutes. 1N-HC1 and jetyl ether were added dropwise to the reaction mixture, and the mixture was extracted with jetyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • reaction mixture was concentrated under reduced pressure, separated and purified by silica gel chromatography (9% -17% ethyl acetate dissolved in hexane), and (4S, l'R, 2'E) -4- [l -(t-Ptyldimethylsilyloxy) -hexadec_ 2 -enyl] -oxazolidin-2-one (above 8) ((4S, l'R, 2, E)-4- [1-(tert- Buty Dimethyl-dimethyl-silyloxy) -hexadec_2-enyl] -oxazolidin-2-one: 56mg, 69%, E form only).
  • the method for producing unsaturated aminodiols of the present invention is simpler and more versatile than conventional reaction steps in which unsaturated aminodiols and olefins are reacted in the presence of a metathesis catalyst.
  • the reactivity is high and the stereoselectivity ( ⁇ / ⁇ selectivity) is good, it is possible to produce unsaturated aminodiols that are target compounds in a high yield. Therefore, it is possible to economically provide synthetic raw materials such as sphingomyelin effective for drug delivery systems.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

On peut produire grâce à des moyens faciles et ordinaires des aminodiols insaturés utiles comme matière première dans la synthèse de sphingomyéline efficace pour des systèmes de relargage de médicaments ou similaires, en faisant réagir un aminodiol insaturé représenté par la formule générale (I) : avec une oléfine représentée par la formule générale (II) : en présence d'un catalyseur de métathèse.
PCT/JP2005/014615 2004-08-04 2005-08-03 Procédé pour la production d'aminodiols insaturés WO2006014015A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004-228055 2004-08-04
JP2004228055A JP2006045112A (ja) 2004-08-04 2004-08-04 不飽和アミノジオール類の製造方法

Publications (1)

Publication Number Publication Date
WO2006014015A1 true WO2006014015A1 (fr) 2006-02-09

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2005/014615 WO2006014015A1 (fr) 2004-08-04 2005-08-03 Procédé pour la production d'aminodiols insaturés

Country Status (2)

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JP (1) JP2006045112A (fr)
WO (1) WO2006014015A1 (fr)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GRUBBS RH ET AL: "Recent advances in olefin metathesis and its application in organic synthesis.", TETRAHEDRON., vol. 54, no. 18, 30 April 1998 (1998-04-30), pages 4413 - 4450, XP004122044 *
TORSELL S ET AL: "A practical synthesis of D-erythro-sphingosine using a cross-metathesis approach.", ORGANIC & BIOMOLECULAR CHEMISTRY., vol. 2, no. 11, 2004, pages 1643 - 1646, XP008056624 *

Also Published As

Publication number Publication date
JP2006045112A (ja) 2006-02-16

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