WO2002088105A1 - Procede de production d'un compose d'oxirane - Google Patents

Procede de production d'un compose d'oxirane Download PDF

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Publication number
WO2002088105A1
WO2002088105A1 PCT/JP2002/003986 JP0203986W WO02088105A1 WO 2002088105 A1 WO2002088105 A1 WO 2002088105A1 JP 0203986 W JP0203986 W JP 0203986W WO 02088105 A1 WO02088105 A1 WO 02088105A1
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group
compound
general formula
represented
same
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PCT/JP2002/003986
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English (en)
Japanese (ja)
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Manabu Sasyou
Toshihiko Naito
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Eisai Co., Ltd.
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Priority to JP2002585405A priority Critical patent/JPWO2002088105A1/ja
Publication of WO2002088105A1 publication Critical patent/WO2002088105A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/24—Synthesis of the oxirane ring by splitting off HAL—Y from compounds containing the radical HAL—C—C—OY
    • C07D301/26—Y being hydrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a lipid A (Lipid A) analog (lipid A) useful for prevention and treatment of endotoxin exposure including infectious disease (sepsis), septicemia (septicemia), endotoxemia and various forms of septic shock.
  • the present invention relates to a novel method for producing an oxysilane compound which is important as a side chain synthesis intermediate of E5564). Background art
  • E5564 a lipid A. analog disclosed in U.S. Patent Nos. 5,750,664 and 5,935,938, is a compound represented by the following structural formula:
  • LPS lipopolysaccharide
  • Lipid A is thought to play a central role in the toxicity exhibited by this bacterial lipopolysaccharide molecule.It has a structure in which diphosphorylated disaccharides are acylated by long-chain fatty acids. I have.
  • E5564 is a compound that has been developed as an analog to suppress the toxicity of lipid A. As shown in the above formula, E5564 has four side chains from diphosphorylated disaccharide. It has a rugged structure.
  • the fourth side chain from the right (hereinafter referred to as the “fourth side chain”), a 3-methoxydecanol derivative, is a side chain having a characteristic structure.
  • the present inventors have found an industrially advantageous method for producing a 3-methoxydeoxyl derivative from (S)-(2-benzyloxystyl) oxylan and have filed a patent application ( Japanese Patent Application No. 200 1-1 23 95 1).
  • An object of the present invention is to provide an excellent method for synthesizing (S)-(2-benzyloxyshethyl) oxysilane, which solves the above problems.
  • Another object of the present invention is to provide a method for producing highly pure (S)-(2-benzyloxystyl) oxylan which has an excellent total yield and does not require purification using a column, in addition to the above objects.
  • An object of the present invention is to provide an industrially very useful method.
  • the present inventors have found that the novel production method satisfies these conditions and is industrially very useful. That is, the present inventors have found the following ⁇ 1> to ⁇ 11>. ⁇
  • the compound (4) represented by the general formula (4) [wherein PG 1 represents a protecting group for a hydroxyl group] is a compound represented by the general formula (5) , R 3 and R 4 each represent a C 1 _6 alkyl group which may be the same or different, and PG 1 has the same definition as described above.)
  • the compound (5) is reacted with a compound represented by the formula Y—X wherein X represents a halogen atom and Y represents a C 2-11 acyl group. And each symbol has the same definition as described above.]
  • a compound (6) and / or a general formula (7) [Wherein each symbol has the same definition as above], and then the leaving group of these compounds (6) and Z or compound (7) is eliminated.
  • a protecting group is introduced into the compound (2) represented by the general formula (2), wherein R 1 and R 2 each represent a C 1 _6 alkyl group which may be the same or different, and Wherein R 1 and R 2 have the same definition as described above, and PG 1 represents a hydroxyl-protecting group.
  • R 3 and R 4 are the same or different may be C 1 one alkyl group of the compound (4), PG 1 Has the same definition as described above.
  • a protecting group is introduced into the compound (1) represented by the general formula (1) to form a compound represented by the general formula (2) wherein R 1 and R 2 may be the same or different and each is a C 16 alkyl group.
  • R 1 and R 2 may be the same or different and each is a C 16 alkyl group.
  • R 3 and R 4 are the same or different may be C 1 _ 6 alkyl group of the compound (4), PG 1 Has the same definition as described above.
  • ⁇ 7> The method according to any one of ⁇ 1> to ⁇ 6>, wherein X is a bromine atom.
  • ⁇ 8> The method according to any one of ⁇ 1> to ⁇ 7>, wherein ⁇ is an acetyl group.
  • ⁇ 9> The method according to any one of ⁇ 1> to ⁇ 8>, wherein PG 1 is a benzyl group.
  • R ⁇ 3 > and R ⁇ 4 > are methyl groups. the method of.
  • a C 1-6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, for example, a methyl group, an ethyl group, an n-propyl group, i -Propinole, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, neopentyl, 1-methylol Butyl, 2-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, i-hexyl, 1-methylpentyl, 2-methylpentyl, 3- Methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-d
  • the C 2-11 acyl group means a C 2-11 aliphatic acyl group, a C 7-11 aromatic acyl group, and a C 1-10 alkyl group, a C 2-10 alkenyl group or Above C A 2- to 10-alkyl group having a carbonyl group bonded to the terminal thereof; and a C6-10 aryl group having a terminal carbonyl group or the above C2-7 aliphatic acyl group at the terminal thereof.
  • a group derived by removing one hydrogen atom and corresponding thereto is bonded, and specifically, for example, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a vivaloyl group, and a hexanoyl group
  • Octanoyl group acryloyl group, methacryloyl group, methacrylonitrile group, benzoyl group, o-tonoleoyl group, m-tonoleoyl group, P-toluoyl group, cinnamoyl group, 1-naphthoyl group, 2-naphthoyl group, etc.
  • hydroxyl-protecting group examples include, but are not particularly limited to, any group that is generally known as a hydroxyl-protecting group in organic synthesis. Examples thereof include a trimethylsilyl group and a t-butyl group.
  • a lower alkylsilyl group such as a dimethylsilyl group; a lower alkoxymethyl group such as a methoxymethyl group and a 2-methoxyethoxymethyl group; for example, a tetrahydroviranyl group; for example, a benzyl group, a P-methoxybenzyl group, and 2,4;
  • Aralkyl groups such as -dimethyloxybenzyl group, 0-nitrobenzyl group, p-nitrobenzyl group, and trityl group; for example, acyl groups such as formyl group and acetyl group; for example, t-butoxy force / repotinole group, Lower alkoxycarbonyl groups such as 2-odo
  • Elimination of these protecting groups can be carried out by a conventional method such as hydrolysis or reduction depending on the type of the protecting group used.
  • the halogen atom specifically refers to, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • the leaving group may be any group that is generally known as a leaving group in organic synthesis, and is not particularly limited. Examples thereof include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; Substituted or unsubstituted acetoxy groups such as trifluoroacetoxy group; substitution of methanesulfonolenoxy group, trifluoromethanesulfoninoleoxy group, benzenesnolephoninolexy group, p-toluenesolephoninoleoxy group, etc.
  • a halogen atom such as a chlorine atom, a bromine atom and an iodine atom
  • Substituted or unsubstituted acetoxy groups such as trifluoroacetoxy group
  • a Suruhoniruo alkoxy group more preferably a bromine atom, an iodine atom, Asetokishi group, methanesulfonic sulfo two / Reokishi group, p - toluene sulfonyl Nino les group.
  • the type of the salt is not particularly limited, but specific examples thereof include, for example, hydrofluoric acid, hydrochloride, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate
  • Addition salts of inorganic acids such as, hydrobromide and hydroiodide
  • organic carboxylic acids such as acetate, maleate, fumarate, oxalate, lactate, tartrate, trifluoroacetate
  • Addition salts methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, hydroxymethanesulfonate, hydroxyxetane snorefonate, benzenesnolefonate, tonoleensnolefonate, taurine salt, etc.
  • Addition salts of organic sulfonic acids trimethylamine salts, triethylamine salts, pyridin salts, proline salts, picoline salts, dicyclohexylamine salts, N, N '— Giben
  • Addition salts of amines such as diethylenediamine salt, N-methyldalcamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) methane salt and phenylbenzylamine salt; sodium salt,
  • Addition salts of alkali metals such as potassium salts; addition salts of alkaline earth metals such as magnesium salts and calcium salts; addition of amino acids such as arginine, lysine, serine, glycine, aspartate and glutamate Salts and the like can be mentioned.
  • the production method of the present invention can be carried out by the following method.
  • each symbol represents the same group as defined above.
  • Step 1 is a step of introducing a protecting group into the diol.
  • a dialkoxyalkyl such as dimethoxypropane, dimethoxypentane, dimethoxyheptane, ethoxypropane, diethoxypentane or diethoxyheptane, or a ketone such as acetone, getylketone or diisopropylketone is acidified.
  • a compound of formula (2) can be obtained.
  • the acid catalyst is not particularly limited.
  • hydrochloric acid, hydrogen bromide, hydrogen fluoride, sulfuric acid, phosphoric acid, boron trifluoride getyl ether complex, p-toluenesulfonate, pyridinium p-toluenesulfonate, (1S ) _ (+) - 10-camphorsulfonic acid, and the like may be used triphenylmethyl salts such TrC10 4.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • dimethylformamide, tetrahydrofuran, acetonitrile, ethyl acetate, getyl ether, t- Butyl methyl ether, toluene, chloroform, methylene chloride, or benzene chloride, or a mixed solvent thereof can be used.
  • -Incubate at 20 ° C to 100 ° C for several hours to tens of hours.
  • Step 2 is a step of introducing a protecting group into a hydroxyl group.
  • the alcohol compound of formula (2) is reacted with a reagent such as benzyl chloride, methoxymethyl chloride, benzyloxymethyl chloride, or p-methoxybenzyloxymethyl chloride in the presence of a base, usually in the presence of a base.
  • a reagent such as benzyl chloride, methoxymethyl chloride, benzyloxymethyl chloride, or p-methoxybenzyloxymethyl chloride in the presence of a base, usually in the presence of a base.
  • the compound represented by (3) can be obtained.
  • Bases include n-butyllithium, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, carbon dioxide, carbon dioxide, potassium t-butoxide, lithium disopropylamide, lithium Hexamethyldisilazane, sodium hexamethyldisilazane, or the like can be used.
  • the reaction can be performed at 0 to 100 ° C. in a non-protonic solvent such as tetrahydrofuran, getinoleatenole, t-butynolemethinoleatele, or dioxane, or a mixed solvent thereof.
  • the reaction time is usually several hours.
  • Step 3 is a step of deprotecting the protecting group of the diol.
  • PG 1 is not deprotected.
  • an acetal-based protecting group it can be deprotected with an acid such as hydrochloric acid.
  • the reaction can be performed in a solvent such as methanol, ethanol, propanol, butanol, acetonitrile, toluene, or dimethylformamide, or a mixed solvent thereof.
  • the reaction can be performed at 0 to 100 ° C for several hours to tens of hours.
  • Step 4 is a step of converting 1,2-diol to a cyclic orthoester.
  • the compound represented by the formula (4) is converted to trimethyl orthoacetate, trimethyl orthopropionate, trimethyl orthobutyrate, trimethyl orthovalerate, trimethyl orthobenzoate, trimethyl orthoacetate, triethyl orthopropionate in the presence of an acid catalyst.
  • the compound represented by the formula (5) can be obtained by reacting with orthoesters such as triethyl orthobutyrate, triethyl orthovalerate, and triethyl orthobenzoate.
  • the acid catalyst is not particularly limited.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • the solvent examples include dimethylformamide, tetrahydrofuran, acetonitrile, ethyl acetate, diethylenoethenol, t-butynolemethynoleethenol, and tonolone.
  • Chlorophonolem, methylene chloride, or benzene chloride, or a mixed solvent thereof can be used.
  • the reaction is usually performed at 0 ° C to 100 ° C for several tens of minutes to several hours.
  • Step 5 is a step of opening the cyclic orthoester and introducing a leaving group.
  • an acyl halide represented by the general formula Y—X wherein each symbol has the same meaning as described above
  • the compounds represented by the formulas (6) and ( The compound represented by 7) can be obtained.
  • the acyl halide acetyl chloride, acetyl chloride, acetyl chloride, acetyl chloride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, benzoyl chloride, benzoyl bromide, benzoyl iodide, etc.
  • the solvent is not particularly limited as long as it does not participate in the reaction.For example, dimethylformamide, tetrahydrofuran, acetonitrile, ethyl acetate, getyl ether, t-butyl methine ether, toluene, chloroform, chloride, etc. Methylene, benzene chloride, or a mixed solvent thereof can be used.
  • the reaction is usually performed at 0 ° C to 100 ° C for tens of minutes to several hours.
  • Step 6 is a step of a ring-closing reaction of the oxysilane.
  • the oxysilane compound represented by the formula (8) can be obtained.
  • the base potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, carbon dioxide lime, hydrogen carbonate lime, or the like can be used.
  • the solvent is not particularly limited as long as it does not participate in the reaction. For example, methanol can be used.
  • the reaction is usually performed at 0 ° C to 100 ° C for several tens of minutes to several hours.
  • Steps 4 to 6 can be applied to the next reaction without isolating each target compound.
  • X is preferably a bromine atom and the like
  • Y is preferably an acetyl group and the like
  • PG] is preferably a benzyl group and the like
  • R 3 and R 4 are preferably a methyl group and the like
  • R 1 and R 2 are preferably an ethyl group. Therefore, the method of the present invention can be implemented by the following scheme.
  • Ts is a p-toluenesulfonyl group
  • Bn is a benzyl group
  • TBAI is tetra-n-butylammonium hydroxide
  • PPTS is pyridyl-dimethyl P-toluenesulfonate
  • Ac is acetyl Each means a group.
  • the solvent that can be used in the present invention is not particularly limited as long as it does not inhibit the reaction, and may be any solvent that is generally used in organic synthesis.
  • the solvent include methanol and ethanol. , Lower alcohols such as propanol and butanol, polyalcohols such as ethylene glycol and glycerin, ketones such as acetone, methinoolethylene ketone, ethynoleketone and cyclohexanone, getyl ether, isopropyl ether, tetrahydrofuran, and dioxy.
  • Ethers such as sun, 2-methoxyethanol and 1,2-dimethoxetane, trinitols such as acetonitrile and propionitrile, and esters such as methyl acetate, ethyl acetate, isopropyl acetate, petitinole acetate, and ginolephthalate.
  • the bases that can be used in the present invention are those that do not inhibit the reaction, and are not particularly limited as long as they are generally known as bases in organic synthesis.
  • bases in organic synthesis for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydride, potassium hydride, potassium t-butoxide, pyridine, dimethylaminopyridine, trimethylamine, triethylamine, N, N-diisopropylethyl N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylaniline, 1,8-diazabicik mouth [5,4,0] pendene-7-ene (DBU), pyridine , 4-dimethylaminoviridine, picoline, lutidine, quinoline, isoquinoline, sodium hydroxide, hydroxylated water, hydroxylated Lithium, heptyl lithium, sodium methylate, Kariumumechi acrylate, etc. Natoriumu or force
  • purification can be performed by a usual treatment method, for example, by column chromatography using silica gel or an adsorption resin, or by recrystallization from a suitable solvent.
  • benzyl bromide a solution of 25.5 g (0.149 mol) in tetrahydrofuran (50 ml), tetra-n-butylammonium iodide: 5.3 g (0.014 mol) And heated again at 70 ° C for 2 hours. Under ice-cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate (250 ml). The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and n-hexane (250 ml) was added to the residue. After filtration of the insolubles, the solvent was distilled off to obtain 40.8 g (quant.) Of the title compound.
  • (S)-(2-benzyloxystyl) oxysilane () is converted to the following (3R) -3-methoxy-1-decanol (4) or (3R) -3-methoxydecanyl methanesulfur Fornate (5) , Used by guiding.
  • Reference Example 1 Method for producing (3R) -3- 3-methoxydecanyl methanesulfonate
  • (3R) _1-benzyloxydecane-3-ol A solution of 1.80 g (6.8 mmol) in tetrahydrofuran (2 ml) was mixed with potassium hydroxide: 895 mg (13.6 s ol), and lodomethane: 0.55 ml ( 8.8 mmol) and stirred for 4 days. Water was added to the reaction solution, extracted with n-hexane, and the extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate.
  • Ice-cooled (3R) -3- 3-methoxy-1-decanol 1.90 g (10.1 acetyl) of tetrahydrofuran (20 ml) in solution of triethylamine: 1.60 ml (11.5 glutanol) ), And then 0.80 ml (10.3 tmol) of methanesulfonyl chloride was added, followed by stirring for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml). The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate.
  • E5564 (R) -3-Methoxy-1-decanol (4) and (3R) -3-methoxydecanyl methanesulfonate (5) thus obtained can be used for the production of E5564 by the following method.
  • This E5564 can be produced, for example, by a method represented by the following scheme, as disclosed in US Pat. Nos. 5,750,664, 5,935,938, and JP-T-11-506793.
  • E5564 can be similarly produced by using the following formula synthesized in the present application instead of

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Abstract

L'invention se rapporte à un procédé de production d'un dérivé d'oxirane plus avantageux en termes industriels. Ce procédé, consistant à produire un composé (8) représenté par la formule générale (8) (dans laquelle PG1 représente un groupe de protection d'hydroxyle), son sel, ou un hydrate du groupe ou du sel, est caractérisé par l'élimination de groupes partant d'un composé (6) représenté par la formule générale (6) (dans laquelle X représente un halogéno ; Y représente un alcyle C¿2-11 ?; et PG?1¿ est défini comme ci-dessus) et/ou un composé (7) représenté par la formule générale (7) (dans laquelle les symboles sont tels que définis ci-dessus).
PCT/JP2002/003986 2001-04-27 2002-04-22 Procede de production d'un compose d'oxirane WO2002088105A1 (fr)

Priority Applications (1)

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JP2002585405A JPWO2002088105A1 (ja) 2001-04-27 2002-04-22 オキシラン化合物の製造方法

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JP2001-131120 2001-04-27

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5726677A (en) * 1980-07-25 1982-02-12 Sagami Chem Res Center Preparation of oxirane compound
US5072002A (en) * 1989-07-18 1991-12-10 The Governors Of The University Of Alberta Synthesis of cholesterol-lowering agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5726677A (en) * 1980-07-25 1982-02-12 Sagami Chem Res Center Preparation of oxirane compound
US5072002A (en) * 1989-07-18 1991-12-10 The Governors Of The University Of Alberta Synthesis of cholesterol-lowering agents

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FRICK J.A. ET AL.: "An efficient synthesis of enantiomerically pure (R)-(2-Benzyloxyethyl)oxirane from (S)-aspartic acid", SYNTHESIS, 1992, pages 621 - 623, XP002147517 *
VAN DER EYCKEN E. ET AL.: "L-(S)-erythrulose: the synthesis of (R)-1,2,4-butanetriol and some related C4 chirons", TETRAHEDRON LETTERS, 1987, pages 4759 - 4760, XP002955018 *

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