WO2003031455A1 - Composes dihydroxycyclohexane optiquement actifs et procede de production de composes hydroxyethylenedihydroxycyclohexane optiquement actifs - Google Patents

Composes dihydroxycyclohexane optiquement actifs et procede de production de composes hydroxyethylenedihydroxycyclohexane optiquement actifs Download PDF

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WO2003031455A1
WO2003031455A1 PCT/JP2002/010216 JP0210216W WO03031455A1 WO 2003031455 A1 WO2003031455 A1 WO 2003031455A1 JP 0210216 W JP0210216 W JP 0210216W WO 03031455 A1 WO03031455 A1 WO 03031455A1
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group
compound
optically active
reaction
substituted
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PCT/JP2002/010216
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Japanese (ja)
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Fumie Sato
Sentaro Okamoto
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Nissan Chemical Industries, Ltd.
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Priority to JP2003534437A priority Critical patent/JP4126555B2/ja
Publication of WO2003031455A1 publication Critical patent/WO2003031455A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • 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
    • 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
    • C07F7/22—Tin compounds
    • 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 an optically active dioxycyclohexane compound, and the use of the compound.
  • the present invention relates to a method for producing an optically active hydroxyethylenedioxycyclohexane compound which is an important intermediate in the synthesis of 19-nor-monoactive vitamin D derivatives.
  • activated vitamin D 3 (1, 2 5- dihydroxy cholecalciferol sheet Hue port one Le) is calcium transport capacity in the small intestine, strong physiological activity such as bone mineral mobilization ability, important physiological functions of the human for its It is known to play a role.
  • T BS represents a t-butyldimethylsilyl group.
  • Bn represents a benzyl group
  • TBS represents a t-butyldimethylsilyl group
  • MPM represents a p-methoxyphenylmethyl group
  • TBDPS represents a t-butyldiphenylsilyl group.
  • any of the production methods described in the above scheme 1 has problems such as a long number of steps from the starting material and a low total yield of all the steps, and thus a more practical production method.
  • the development of is desired.
  • the present invention has been made in view of the above circumstances, and provides a key intermediate that can be efficiently converted to an A-ring partial precursor, which is an important intermediate when producing a 19-nor-monoactive vitamin D derivative.
  • An object of the present invention is to provide an optically active dioxycyclohexane compound and a method for efficiently producing an optically active hydroxyethylenedioxycyclohexane compound which is an A-ring partial precursor using the compound.
  • the present inventors have conducted intensive studies in order to achieve the above object, and as a result, the optically active dioxycyclohexane compounds represented by the general formulas (1) and (2) 9 In addition to finding that it can be an important key intermediate for the A-ring partial precursor in the production of 1-nor monoactive vitamin D derivatives, hydroxymethylation of this compound leads to the optically active hydroxyethylenediamine, the A-ring partial precursor.
  • the present inventors have found that an oxycyclohexane compound can be efficiently produced, and have completed the present invention.
  • R represents a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group.
  • X and ⁇ represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the terminal.
  • R 'and R ⁇ independently represent a substituted alkyl group, a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group.
  • X and Y represent a hydrogen atom, a hydroxyl-protecting group or Represents a solid phase having a protecting group at the terminal.
  • R represents a halogen atom, a substituted silyl group, a substituted boron group, or a substituted tin group.
  • X and Y represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the terminal.
  • X and ⁇ represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the terminal.
  • a method for producing an optically active hydroxyethylenedioxycyclohexane compound comprising obtaining a compound represented by
  • the substituent R represents a halogen atom, a substituted silyl group, a substituted hydrogen group or a substituted tin group.
  • the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Examples of the substituted silyl group include a trisubstituted silyl group substituted by three groups selected from an alkyl group and a phenyl group (the phenyl group may be substituted with an alkoxy group). Specifically, trimethylsilyl, triethylsilyl, triisopropylsilyl, acetylethylsilyl, dimethylisopropylsilyl, t-butyldimethylsilyl, texyldimethylsilyl, diphenylmethylsilyl, t-butyldiphenylsilyl, t-butyl Examples thereof include dimethoxyphenylsilyl and triphenylsilyl.
  • substituted boron group examples include a dialkylboron group (for example, dimethylboron, methylboron, di-n-butylboron, etc.), a diarylboron group (for example, diphenylboron, etc.), dialkoxy And a boron group (for example, diisopropoxyboron, ethylenedioxyboron, tetramethylethylenedioxyboron, etc.).
  • dialkylboron group for example, dimethylboron, methylboron, di-n-butylboron, etc.
  • diarylboron group for example, diphenylboron, etc.
  • dialkoxy And a boron group for example, diisopropoxyboron, ethylenedioxyboron, tetramethylethylenedioxyboron, etc.
  • substituted tin group examples include a trialkyltin group (for example, trimethyltin, triethyltin, tri_n-propyltin, tri-n-butyltin, tri-c-hexyltin, etc.), a triaryltin group (for example, , Trifenyltin, etc.).
  • a trialkyltin group for example, trimethyltin, triethyltin, tri_n-propyltin, tri-n-butyltin, tri-c-hexyltin, etc.
  • a triaryltin group for example, Trifenyltin, etc.
  • a halogen atom trimethylsilyl, tetramethylethylenedioxyboron, or tri-n-butyltin is preferably used, more preferably a halogen atom, particularly a bromine atom.
  • the substituents R ′ and R ⁇ independently represent a substituted alkyl group, a halogen atom, a substituted silyl group, a substituted boron group, or a substituted tin group, wherein a halogen atom, a substituted silyl group, As the group, the substituted boron group, and the substituted tin group, those similar to the above can be used.
  • Examples of the substituted alkyl group include a linear, branched or cyclic C 1-6 alkyl group (the alkyl group may be optionally substituted with a halogen atom).
  • the alkyl group may be optionally substituted with a halogen atom.
  • the substituents R ′ and R ⁇ it is preferable to use both a halogen atom, one of which is methyl and the other is a halogen atom, one of which is ethyl, the other is a halogen atom, one is n-butyl and the other is a halogen atom, More preferably, both have a halogen atom, and particularly, both have a bromine atom.
  • the substituents X and Y represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the terminal.
  • hydroxyl-protecting group examples include, for example, Cl to 7-acyl groups (for example, formyl, acetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, propionyl, vivalyl, tigloyl)
  • An arylcarbonyl group for example, benzoyl, benzoylformyl, benzoylpropionyl, phenylpropionyl and the like
  • a C1-4 alkoxyl group for example, methoxycarbonyl, Ethoxycarbonyl, n_propoxyl-proponyl, i-propoxyl-lponyl, n-butoxycarbonyl, i-butoxyl-carponyl, t-butoxyl-carponyl, t-amyloxycarbonyl, vinyloxyl-loxyl-pon
  • a C1-4 alkylaminocarboyl group for example, methylcarbamoyl, ethylcarbamoyl, n-propylcaprolumyl and the like), an arylaminocarboxyl group (for example, phenylcarbamoyl and the like)
  • Trialkylsilyl groups for example, trimethylsilyl, triethylsilyl, triisopropylsilyl, getylisopropylsilyl, dimethylisopropylsilyl, di-t-butylmethylsilyl, isopropyldimethylsilyl, tert-butylsilyl) Dimethylsilyl, texyldimethylsilyl, etc.
  • trialkylarylsilyl group for example, diphenylmethylsilyl, t-butyldiphenylsilyl, t-butyldimethoxyphenylsilyl, triphenyl
  • Examples of the solid phase having a hydroxyl-protecting group at the terminal include a liponyl group resin terminal, a liponyloxy group resin terminal, a liponylamino group resin terminal, and a silyl group resin terminal.
  • Examples of the resin used include polystyrene resin, PEG-polystyrene resin, PGA resin and the like. Among these, it is preferable to use, as the substituents X and Y, a Cl to 7 acyl group, a Cl to 4 alkoxycarbonyl group, a trialkylsilyl group, a trialkylarylsilyl group, a silyl group resin terminal, and the like. Preferred are a trialkylsilyl group, a trialkylarylsilyl group, and a silyl group resin terminal.
  • the substituents X and Y may be the same or different from each other.
  • T BS represents a t-butyldimethylsilyl group.
  • the optically active cyclohexenone compound which is the starting material, is epoxidized to form a cyclohexenoxide compound A, and then a bromethylene conversion reaction is performed on the ketone to form a bromomethylenecyclohexenoxide compound, and finally the epoxide is reduced. It can be produced by silylating the resulting hydroxyl group.
  • the oxidizing agent for the first epoxidation reaction is not particularly limited, and includes, for example, peracids such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, hydrogen peroxide, oxygen and the like. Preferably, it is hydrogen peroxide.
  • the amount of the oxidizing agent to be used is usually in the range of 0.8 to 50 times by mole, and particularly preferably in the range of 1.0 to 20 times by mole, relative to the substrate.
  • the reaction solvent is not particularly limited as long as it is stable under the reaction conditions, and is inert and does not hinder the reaction.
  • the following solvents can be used.
  • water e.g., water, alcohols (eg, methanol, ethanol, propanol, butanol, octanol, etc.), cellosolves (eg, methoxyethanol, ethoxyethanol, etc.), aprotic polar organic solvents (eg, For example, dimethylformamide, dimethylsulfoxide, dimethylacetamide, tetramethylperyl, sulfolane, N-methylpyrrolidone, N, N_dimethylimidazolidinone, etc., ethers (eg, getyl ether, diisopropyl ether, t Butyl methyl ether, tetrahydrofuran, dioxane, etc.), aliphatic hydrocarbons (for example, pentane, hexane, c-hexane, octane, decane, decalin, petroleum ether, etc.), aromatic hydrocarbons (benzene, Black mouth
  • the reaction temperature can usually be from 100 ° C. to the boiling point of the solvent used, but is preferably in the range of 150 ° C. to 50 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • a reaction for introducing bromethylene into a ketone for example, a Wittig reaction using bromomethyl triphenylphosphonium bromide, or a Homon-Emmons reaction using, for example, diisopropyl bromomethyl phosphonate
  • a Wittig reaction using bromomethyltriphenylphosphonium bromide for example, a Wittig reaction using bromomethyltriphenylphosphonium bromide.
  • the amount of bromomethyltriphenylphosphonium bromide to be used is usually in the range of 0.8 to 20 mol times, especially 1.0 to 5.0 mol times, relative to the substrate. preferable.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than ketone solvents can be used.
  • the reaction temperature can be generally from —100 ° C. to the boiling point of the solvent to be used, but is preferably in the range of —50 to 50 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • the reducing agent for the epoxide is not particularly limited, and examples thereof include diisobutylaluminum hydride, sodium borohydride, aluminum hydride, bismethoxyethoxyaluminum hydride, and the like. Or diisobutylaluminum hydride.
  • the amount of the reducing agent to be used is generally in the range of 0.5 to 20 times by mole, particularly preferably in the range of 1.0 to 10 times by mole, relative to the substrate.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than water, ketones and esters can be used.
  • the reaction temperature can usually be from ⁇ 100 to the boiling point of the solvent used, but is preferably in the range of 180 to 50 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • a pure hydroxyl compound can be isolated by performing purification by a conventional method such as silica gel column chromatography.
  • the protective agent for protecting the hydroxyl group of the hydroxyl compound obtained as described above is not particularly limited, and examples thereof include an acylating agent, an oxypropylating agent, an aminocarbonylating agent, and a silylating agent. And the like, and preferably a silylating agent.
  • Such a silylating agent is not particularly limited, and includes, for example, trimethylsilyl chloride, t-butyldimethylsilyl chloride, diphenylt-butylsilyl chloride and the like.
  • the amount of the silylating agent to be used is usually in the range of 0.5 to 20 mol times, particularly preferably in the range of 1.0 to 10 mol times with respect to the substrate.
  • a base may be allowed to coexist in the reaction system.
  • a base include getylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, DBU, and N-methylmorpholine.
  • Amines such as N, N-N-dimethylaniline, pyridines such as pyridine, methylethylpyridine, lutidine, pyridines such as 4-N, N-dimethylaminopyridine, imidazole and pyrazole, and preferably imidazole. It is one le.
  • the amount of the base to be used is generally in the range of 0.5 to 20 mol times, preferably in the range of 1.0 to 10 mol times, based on the substrate.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than water and alcohols can be used.
  • the reaction temperature can usually be from 100 ° C. to the boiling point of the solvent used, but is preferably in the range of 150 ° C. to 50 ° C.
  • reaction time is usually 0.1 to 1000 hours.
  • desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product.
  • T BS represents a t-butyldimethylsilyl group.
  • Et represents an ethyl group.
  • 3 represents a solid support.
  • T BS represents a t-butyldimethylsilyl group.
  • the compound can be produced by using the compound obtained above as a raw material, lithifying the compound, and then treating the compound with a borating agent.
  • lithiation agent include n-butyllithium, s-butyllithium, t-butyllithium and the like.
  • the amount of the lithiating agent to be used is usually in the range of 0.5 to 20 mole times, particularly preferably in the range of 1.0 to 10 mole times with respect to the substrate.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than water, alcohols, ketones, and esters can be used.
  • the reaction temperature can be generally from 100 ° C. to the boiling point of the solvent used, but is preferably from 180 ° C. to 0 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • the lithiated compound is not isolated, but a boron compound is directly added to the reaction system to obtain a boron compound. Further, the compound I can be synthesized by treating the obtained boron compound with pinacol.
  • the boronating agent is not particularly limited, and includes, for example, trimethoxypolan, triethoxypolan, triisopropoxypolan and the like.
  • the amount of the boronating agent used is usually in the range of 0.5 to 20 mole times, particularly preferably in the range of 1.0 to 10 mole times with respect to the substrate.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction, and the solvent used for lithiation can be used as it is.
  • the reaction temperature can be usually from —100 ° C. to the boiling point of the solvent to be used, but is preferably in the range of —80 to 50 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • pure compound ⁇ can be isolated by performing purification by a conventional method such as silica gel column chromatography.
  • TBS represents a t-butyldimethylsilyl group
  • Me represents a methyl group.
  • Examples of the lithiating agent include the same reagents as described above.
  • the amount of the lithiating agent used is usually in the range of 0.5 to 20 moles per mole of the substrate.
  • a range of 1.0 to 10 mole times is preferable.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than water, alcohols, ketones, and esters can be used.
  • the reaction temperature can usually be from ⁇ 100 ° C. to the boiling point of the solvent used, but is preferably in the range of ⁇ 80 to 0 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • the lithiated compound is not isolated but is silylated by adding a silylating agent to the reaction system.
  • the silylating agent is not particularly restricted but includes, for example, chlorotrimethylsilane, chlorotri-n-butylsilane, bromotri-n-butylethylsilane, chlorotri-n-octylsilane, bromotri-n-octylsilane, chlorotriphenylsilane, bromotriphenylsilane, etc. Is mentioned.
  • the amount of the silylating agent to be used is usually in the range of 0.5 to 20 mol times, particularly preferably in the range of 1.0 to 10 mol times with respect to the substrate.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction, and the solvent used for lithiation can be used as it is.
  • the reaction temperature can be usually from 110 ° C. to the boiling point of the solvent used, but is preferably in the range of ⁇ 80 to 50.
  • the reaction time is usually 0.1 to 1000 hours.
  • pure compound A can be isolated by performing purification by a conventional method such as silica gel column chromatography.
  • optically active cyclohexenone compound used as a starting material for producing the optically active dioxycyclohexane compound represented by the general formula (1) is, as shown in Scheme 5, Tetrahedron Letters, 38, 8299 (1997) , J. Am. Chem. Soc., 121,
  • T BS represents a t-butyldimethylsilyl group.
  • the optically active chlorohydrin ester is iodinated to give an eodohydrin form 10, and then the hydroxyl group is silylated to give a siloxy form 11, and further reacted with a vinyl Grignard reagent to form a homoallyl ether form 12. And finally by cyclization with Ti.
  • T BS represents a t-butyldimethylsilyl group.
  • the optically active cyclohexenone compound which is the starting material, is epoxidized to give a cyclohexenonoxide A, and then the ketone is subjected to dibromomethylene conversion reaction to give a dibromomethylenecyclohexenoxide 13. It can be produced by reducing epoxides and silylating hydroxyl groups.
  • the same oxidizing agent as the compound represented by the general formula (1) can be used.
  • the amount of the oxidizing agent to be used is usually in the range of 0.850 times by mole, particularly preferably in the range of 1.020 times by mole relative to the substrate.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction, and the above-mentioned solvents can be used.
  • the reaction temperature can be generally from 100 ° C. to the boiling point of the solvent used, but is preferably in the range of 150 ° C.
  • the reaction time is usually 0.1100 hours.
  • pure cyclohexenonoxide A can be isolated by purification by a conventional method such as silica gel column chromatography.
  • the reaction for introducing dibromomethylene into a ketone is not particularly limited, and examples thereof include a Wittig reaction using carbon tetrachloride and triphenylphosphine.
  • the amount of carbon tetrachloride to be used is usually in the range of 0.8 to 20 times by mole, particularly preferably in the range of 1.0 to 5.0 times by mole, relative to the substrate.
  • the amount of triphenylphosphine used is usually in the range of 0.8 to 20 mole times, particularly preferably in the range of 1.0 to 5.0 mole times, relative to the substrate.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than ketones can be used.
  • the reaction temperature can be usually from 110 Ot to the boiling point of the solvent used, but is preferably in the range of -50 to 50 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • pure dibromomethylenecyclohexenoxide 13 can be isolated by purification by a conventional method such as silica gel column chromatography.
  • Compound 14 is obtained by reducing the compound and silylating the hydroxyl group.
  • examples of the epoxide reducing agent include the same ones as described above, and it is particularly preferable to use diisobutylaluminum hydride.
  • the amount of the reducing agent to be used is generally in the range of 0.5 to 20 mol times, preferably in the range of 1.0 to 10 mol times, relative to the substrate.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than water, ketones and esters can be used.
  • the reaction temperature can be generally from 10 ° C. to the boiling point of the solvent used, but is preferably in the range of ⁇ 80 ° C. to 50 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product.
  • a pure hydroxyl form can be isolated by performing purification by a conventional method such as silica gel gel chromatography.
  • Examples of the protecting agent for protecting the hydroxyl group include the same as described above, but it is preferable to use a silylating agent.
  • the type and amount of the silylating agent, the type and amount of the base used as the reaction accelerator, and the reaction conditions are the same as described above.
  • the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product.
  • pure compound 14 can be isolated by performing purification by a conventional method such as silica gel column chromatography.
  • the compound can be produced by subjecting the optically active dioxycyclohexane compound represented by the general formula (1) obtained above to a hydroxymethylation reaction.
  • lithiation agents include n-butyllithium and s Monobutyl lithium, t-butyl lithium and the like.
  • the amount of the lithiating agent to be used is usually in the range of 0.5 to 20 mol times, particularly preferably in the range of 1.0 to 0 mol times, relative to the substrate.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than water, alcohols, ketones, and esters can be used.
  • the reaction temperature can be generally from —100 to the boiling point of the solvent to be used, but is preferably in the range of 180 to 0 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • the lithiated compound is not isolated, and formaldehyde is added to the reaction system as it is, followed by hydroxymethyl irrigation.
  • the amount of formaldehyde to be used is usually in the range of 0.5 to 20 moles, preferably 1.0 to 10 moles per mole of the substrate.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction, and the solvent used for lithiation can be used as it is.
  • the reaction temperature can usually be from -10 to the boiling point of the solvent used, but is preferably in the range of 180 to 50 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • purification can be performed by a conventional method such as silica gel column chromatography.
  • TBS represents a t-butyldimethylsilyl group.
  • TBS represents a t-butyldimethylsilyl group.
  • reaction solution was concentrated under reduced pressure, and ethyl ether (2 mL) and hexane (40 mL) were added to the obtained residue, and the precipitated crystals were filtered through celite.
  • TBS represents a t-butyldimethylsilyl group.
  • TBS represents a t_butyldimethylsilyl group.
  • Triisopropoxypolane (2.0 MZ Jetyl ether solution, 0.6 mL, 1.2 mmo 1) was added at —78 ° C, and the reaction solution was warmed to room temperature over 4 hours, and then saturated An aqueous ammonia solution (8 mL) and ethyl acetate (8 mL) were added. Subsequently, the mixture was extracted twice with ethyl acetate (6 mL), and the organic layer was concentrated under reduced pressure.
  • chlorotrimethylsilane (76 L, 0.6 mmo 1) was added at ⁇ 78 ° C., the reaction solution was heated to room temperature over 3 hours, and a saturated aqueous solution of ammonium chloride (4 mL) was added.
  • TBS represents a t-butyldimethylsilyl group.
  • reaction solution was diluted with hexane (30 mL) and filtered through celite.
  • TBS represents a t-butyldimethylsilyl group.
  • diisobutylaluminum hydride (0.96MZ) was added to a solution of the crude product of 1-dibromomethylene-15-siloxy-2,3-epoxycycline hexane obtained in Example 6 in hexane (5 mL). Hexane solution, 2.08 mL, 2.0 mm o 1) was added, and the mixture was stirred at 0 ° C for 1 hour. Water (0.36 mL) was carefully added to the reaction solution at 0 ° C., followed by stirring for 30 minutes. Sodium fluoride (lg) and celite (lg) were added, and the mixture was filtered through celite.
  • TBS represents a t-butyldimethylsilyl group.
  • TBS represents a t-butyldimethylsilyl group.
  • Bu represents an n_butyl group.
  • chlorotri-n-butyltin (0.434 mL, 1.2 mmo 1) was added at _78 ° C, and the reaction solution was heated to room temperature over 3 hours.
  • TBS represents a t-butyldimethylsilyl group.
  • Et represents an ethyl group. 3 indicates a solid support
  • the reaction solution was filtered under argon, and the obtained resin was washed three times with methylene chloride (2 OmL) and further three times with THF (2 OmL), and then dried under reduced pressure.
  • Loading of the obtained resin was determined to be 0.738 mmolZg by decomposing the resin with monopyridine hydrofluorate and then analyzing the resulting alcohol form by 1 HNMR.
  • the bromomethylenecyclohexanediol was 0.1063 mmol, and the loading of the resin was calculated to be 0.738 mmolZg.
  • a compound By using a compound, it can be produced relatively easily and efficiently.

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Abstract

Composés dihydroxycyclohexane optiquement actifs de formule générale (1) et (2) ou leurs énantiomères. Dans lesdites formules, R représente halogéno, silyle substitué ou un groupe bore ou étain substitué, R et R'' représentent chacun indépendamment alkyle substitué, halogéno, silyle substitué ou un groupe bore ou étain substitué et X et Y représentent chacun hydrogène, un groupe protecteur hydroxy ou une phase solide possédant ledit groupe protecteur à sa terminaison.
PCT/JP2002/010216 2001-10-05 2002-10-01 Composes dihydroxycyclohexane optiquement actifs et procede de production de composes hydroxyethylenedihydroxycyclohexane optiquement actifs WO2003031455A1 (fr)

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JP2003534437A JP4126555B2 (ja) 2001-10-05 2002-10-01 光学活性ジオキシシクロヘキサン化合物および光学活性ヒドロキシエチレンジオキシシクロヘキサン化合物の製造方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074480A1 (fr) * 2002-03-05 2003-09-12 Nissan Chemical Industries, Ltd. Compose halovinylidenemethylenecyclohexane, compose borovinylidenemethylenecyclohexane et procede permettant de produire un derive de vitamine d a partir desdits composes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HILPERT H. ET AL.: "Novel versatile approach to an enantiopure 19-nor, des-C,D vitamin D3 derivative", TETRAHEDRON, vol. 57, no. 4, 21 January 2001 (2001-01-21), pages 681 - 694, XP004314669 *
TAKESHI HANAZAWA ET AL.: "Novel synthetic approach to 19-nor-1alpha, 25-dihydroxyvitamin D3 and its derivatives by Suzuki-Miyaura coupling in solution and on solid support", ORGANIC LETTERS, vol. 3, no. 24, 29 November 2001 (2001-11-29), pages 3975 - 3977, XP002961704 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074480A1 (fr) * 2002-03-05 2003-09-12 Nissan Chemical Industries, Ltd. Compose halovinylidenemethylenecyclohexane, compose borovinylidenemethylenecyclohexane et procede permettant de produire un derive de vitamine d a partir desdits composes

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JPWO2003031455A1 (ja) 2005-01-20

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