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WO2006014006A1 - Procédé servant à produire des aminodiols insaturés - Google Patents

Procédé servant à produire des aminodiols insaturés Download PDF

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Publication number
WO2006014006A1
WO2006014006A1 PCT/JP2005/014602 JP2005014602W WO2006014006A1 WO 2006014006 A1 WO2006014006 A1 WO 2006014006A1 JP 2005014602 W JP2005014602 W JP 2005014602W WO 2006014006 A1 WO2006014006 A1 WO 2006014006A1
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WO
WIPO (PCT)
Prior art keywords
nmr
unsaturated
aminodiols
mmol
group
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/JP2005/014602
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English (en)
Japanese (ja)
Inventor
Shigeo Katsumura
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.)
Kwansei Gakuin Educational Foundation
Chemicrea Inc
Original Assignee
Kwansei Gakuin Educational Foundation
Chemicrea Inc
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 Kwansei Gakuin Educational Foundation, Chemicrea Inc filed Critical Kwansei Gakuin Educational Foundation
Publication of WO2006014006A1 publication Critical patent/WO2006014006A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2265—Carbenes or carbynes, i.e.(image)
    • B01J31/2278—Complexes comprising two carbene ligands differing from each other, e.g. Grubbs second generation catalysts
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2265—Carbenes or carbynes, i.e.(image)
    • B01J31/2269—Heterocyclic carbenes
    • B01J31/2273—Heterocyclic carbenes with only nitrogen as heteroatomic ring members, e.g. 1,3-diarylimidazoline-2-ylidenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/113—Esters of phosphoric acids with unsaturated acyclic alcohols
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/50—Redistribution or isomerisation reactions of C-C, C=C or C-C triple bonds
    • B01J2231/54—Metathesis reactions, e.g. olefin metathesis
    • B01J2231/543—Metathesis reactions, e.g. olefin metathesis alkene metathesis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/821—Ruthenium

Definitions

  • the present invention relates to a method for producing unsaturated aminodiols utilizing a metathesis reaction.
  • Unsaturated aminodiols are swinging conductors and are useful as synthetic raw materials such as sphingomyelin, which are effective in 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, methods using asymmetric aldol reactions, and the like.
  • Reported for example, Natsuo Katsumura, Toshikazu Hakogi, “Protein Nucleic Acid Enzyme”, Vol.147, No.4, 526-536 (2002)). I have bad problems, and I have a problem.
  • the method for producing the unsaturated aminodiols of the present invention has the following general formula (I)
  • R 1 and R 4 are a hydrogen atom or a protecting group for a hydroxyl group
  • R 3 is a protecting group for a hydrogen atom or an amino group
  • R 5 is a hydrogen atom or a lower alkyl group.
  • the metathesis catalyst is 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. Therefore, the stereoselection is simpler, versatile and more reactive than conventional reaction steps. Because of its excellent properties (EZZ selectivity), it is possible to produce unsaturated aminodiols, which are target compounds, in high yield and yield.
  • unsaturated amino diols, olefins and metathesis catalysts used in the method for producing unsaturated amino diols of the present invention are relatively inexpensive, so that unsaturated amino diols can be produced at low cost. Yes, it is possible to economically provide synthetic raw materials such as sphingomyelin that are effective for drug delivery systems. Preferred for carrying out the invention U, embodiment
  • R 1 and R 4 are a hydrogen atom or a protecting group for a hydroxyl group
  • R 3 is a protecting group for a hydrogen atom or an amino group
  • R 5 is a hydrogen atom or a lower alkyl group.
  • R is the same as defined above for R 3 , R 4 and R 6 ), and is characterized by producing an unsaturated aminodiol.
  • Examples of the lower alkyl group include branched, ole, and alkenoquinole groups having 1 to 5 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a petit / le group, sec- Examples include a butyl group, a t-butyl group, and a pentyl group.
  • hydroxyl protecting groups include silyl protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, and triisopropylpropylsilyl, ether protecting groups such as methoxymethyl, tetrahydrovinylanol, and ethoxyethyl, and ester-based groups such as acetyl and benzoyl. Protecting groups can be listed.
  • protecting groups for amino groups include silyl protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropynolesilyl, trubate protecting groups such as t, butoxycarbonyl, and benzylcarbonyl, and esters such as acetyl and benzoyl.
  • System protecting groups can be opened.
  • 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 preferable from the viewpoint of reaction efficiency, among the forces in which various existing metathesis catalysts are suitably used.
  • ruthenium carbene complex an existing ruthenium carbene complex is preferably used, but the following general formula (IV)
  • R 7 and R 8 are an anoalkyl group or an aryl group, R 9 is a phosphine ligand, and X is a halogen atom). It is preferable in terms of ease.
  • the alkyl group does not participate in the reaction! /, Has a substituent! /, Mayore, carbon number
  • the aryl group includes, for example, a phenyl group, a naphthyl group, a furan group, a pyrrole group, and a thiophene group, which may have a substituent not involved in the reaction .
  • 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, cyclohexane, tetrahydrofuran, dimethoxyethane, dioxane, etc.
  • halogenated solvents such as ether solvents, dichloromethane, chloroform, dichloroethane and the like.
  • the reaction temperature is 0 ° C, and the power in the temperature range of 150 ° C can be selected as appropriate.
  • the reaction speed is very economical.
  • the temperature is room temperature, and the range of 80 ° C is preferred. .
  • Tetrahydropyraninoreprono Gizoleate 7 Tetrahydropyranyl propargyl ether; 0.656g, 4.68mmol
  • THF 29.8ml
  • 1.6N hexane solution of n-butyllithium (2.80ml, 4.47mmol) was added dropwise and stirred at the same temperature for 15 minutes. One hundred of this solution. Cooled below C.
  • reaction mixture was concentrated under reduced pressure, separated and purified by silica gel chromatography (9% to 25% ethyl acetate dissolved in hexane), and (2S, 3R, 4E) -2-butylene Xyloxycarbonylamino-3- (t-butyldimethylsilyloxy) -4-octadecene-1-ol (above 12) ((2S, 3R, 4E) -2-tert-Butyloxycarbonylamino-3- (tert-butyi- dimethy ⁇ silyloxy) _4-octadecene-l_ol: 12mg, 18%, E form only).
  • reaction mixture was filtered, acidified with 2N hydrochloric acid, and extracted with ethyl acetate.
  • the organic layer was washed successively with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, 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% to 25% ethyl acetate dissolved in hexane), and (2S, 3R, 4E)-2 -t-butylo Xyloxycarbonylamino-t-butyldimethinoresilyloxy-4-dodecene-3-ol (19 above) (71 mg, 55%) was obtained.
  • IR, 3 ⁇ 4 NMR, and 13 C NMR data for (2S, 3R, 4E) -2-t-ptyloxycarboxylamino-1-1-1-butyldimethylenosilylyl-4-dodecene-3-ol are shown below. Show.
  • reaction mixture was concentrated in vacuo, and purified by silica gel chromatography i (hexane to 2 0% to 33% of the acetic acid Echiru what was ⁇ to) by the separation 'Purification, (2S, 3R, 4E) - 2- 1 - Puchiruo Xyloxycarbonylamino-1-t-butyldimethylsilyloxy-14- (4 '-(7'- Nitrobenzofurazal) amino) -4-tetradecene-3-ol (21) (55 mg, 57%) was obtained.
  • reaction mixture was concentrated under reduced pressure and then subjected to silica gel chromatography (17% -3% in hexane). 3% of that dissolved acetic acid Echiru) by the separation 'Purification, (2 S, 3 R, 4E) -2-t- Petit / Reokishika Ruponiruamino - 1-t-butyldimethylsilyl O carboxymethyl-4-tetradecene - 3 , 14-diol (22 above) (54 mg, 75%).
  • the method for producing unsaturated aminodiols of the present invention reacts unsaturated aminodiols and olefins in the presence of a metathesis catalyst, and thus is simpler, versatile and reactive than conventional reaction steps.
  • High stereoselectivity ( ⁇ / ⁇ selectivity) makes it possible to produce unsaturated aminodiols that are target compounds in high yields.
  • synthetic raw materials such as sphingomyelin that are effective for drug delivery systems and the like.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

En faisant réagir des aminodiols insaturés représentés par la formule générale (I) ci-dessous avec des oléfines représentées par la formule générale (II) ci-dessous en présence d'un catalyseur de métathèse, on peut produire d'une façon simple par un procédé extrêmement souple des aminodiols insaturés qui sont utiles comme matière première pour synthétiser de la sphingomyéline ou une substance similaire efficace pour des systèmes de relargage de médicaments ou similaires.
PCT/JP2005/014602 2004-08-04 2005-08-03 Procédé servant à produire des aminodiols insaturés Ceased WO2006014006A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2004228054 2004-08-04
JP2004-228054 2004-08-04
JP2005024062A JP4825947B2 (ja) 2004-08-04 2005-01-31 不飽和アミノジオール類の製造方法
JP2005-024062 2005-01-31

Publications (1)

Publication Number Publication Date
WO2006014006A1 true WO2006014006A1 (fr) 2006-02-09

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PCT/JP2005/014602 Ceased WO2006014006A1 (fr) 2004-08-04 2005-08-03 Procédé servant à produire des aminodiols insaturés

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JP (1) JP4825947B2 (fr)
WO (1) WO2006014006A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006128657A1 (fr) * 2005-05-31 2006-12-07 Novartis Ag Sphingolipides
US9643915B2 (en) 2013-03-15 2017-05-09 Cerenis Therapeutics Holding Sa Methods for the synthesis of sphingomyelins and dihydrosphingomyelins
US9708354B2 (en) 2013-03-15 2017-07-18 Cerenis Therapeutics Holding Sa Methods for the synthesis of sphingomyelins and dihydrosphingomyelins

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HASEGAWA H. ET AL: "Cross Metathesis Route in Sphingomyelin Systhesis", CHEMISTRY LETTERS, vol. 33, no. 12, 5 December 2004 (2004-12-05), pages 1592 - 1593, XP002999815 *
HASEGAWA H. ET AL: "Cross-Metathesis ni yoru Sphingo Shishitsu Goseiho", THE CHEMICAL SOCIETY OF JAPAN KOEN YOKOSHU, vol. 85, no. 2, 11 March 2005 (2005-03-11), pages 875, XP002999816 *
TORSSELL S. ET AL: "A practical synthesis of D-erythro-sphingosine using a cross-metathesis approach", ORG.BIOMOL.CHEM., vol. 2, 7 June 2004 (2004-06-07), pages 1643 - 1646, XP008056624 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006128657A1 (fr) * 2005-05-31 2006-12-07 Novartis Ag Sphingolipides
US9643915B2 (en) 2013-03-15 2017-05-09 Cerenis Therapeutics Holding Sa Methods for the synthesis of sphingomyelins and dihydrosphingomyelins
US9708354B2 (en) 2013-03-15 2017-07-18 Cerenis Therapeutics Holding Sa Methods for the synthesis of sphingomyelins and dihydrosphingomyelins

Also Published As

Publication number Publication date
JP2006070017A (ja) 2006-03-16
JP4825947B2 (ja) 2011-11-30

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