WO2003031402A1 - Procede de preparation de derives de 19-norvitamine d - Google Patents

Procede de preparation de derives de 19-norvitamine d Download PDF

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Publication number
WO2003031402A1
WO2003031402A1 PCT/JP2002/010217 JP0210217W WO03031402A1 WO 2003031402 A1 WO2003031402 A1 WO 2003031402A1 JP 0210217 W JP0210217 W JP 0210217W WO 03031402 A1 WO03031402 A1 WO 03031402A1
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group
alkyl
alkoxy
hydroxyl
halogen atom
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PCT/JP2002/010217
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English (en)
Japanese (ja)
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Fumie Sato
Sentaro Okamoto
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Nissan Chemical Industries, Ltd.
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Publication of WO2003031402A1 publication Critical patent/WO2003031402A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • 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
    • 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
    • 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 novel method for producing a 19-nor-vitamin D derivative.
  • Activated vitamin D 3 (1,25-dihydroxycholecalciferol) has strong physiological activities such as calcium transport ability and bone mineral mobilization ability in the small intestine, and is known to play an important role in human physiological functions. Have been.
  • the present invention has been made in view of the above circumstances, and an object of the present invention is to provide an efficient and useful method for producing a 19-nor-monoactive vitamin D derivative.
  • the present inventors have conducted intensive studies to achieve the above object, and as a result, using an optically active boron vinylidenecyclohexane compound represented by the following general formula (1) (an enantiomer thereof) as a raw material, —The inventors have found that a nor-active vitamin D derivative can be efficiently produced, and have completed the present invention.
  • W represents a hydrogen atom, a halogen atom or a C 1-6 alkyl group (the alkyl group may be optionally substituted with a halogen atom).
  • R a and R b are each other, C L ⁇ 6 alkyl group, C L ⁇ 6 alkoxy group, Ariru group, a Ariru Okishi group or a hydroxyl group, or, C 2 to 3 by bonding R a and R b Represents an alkylenedioxy group (the C2-3 alkylenedioxy group may be optionally substituted with a C1-4 alkyl group).
  • X 1 and X 2 independently represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the terminal.
  • Ha represents a halogen atom.
  • Z is a Cl-26 alkyl group, a C2-26 alkenyl group, a C2-26 alkynyl group (the alkyl group, alkenyl group and alkynyl group are a halogen atom, a hydroxyl group, a nitro group, a cyano group, a Cl-10 Coxy group (The alkoxy group is a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C1-6 alkoxy group, a C1-6 alkoxycarbonyl group, a C1-6 alkylcarbo group.
  • a Cl 6 alkoxycarbonyl group a C 16 alkyl group optionally substituted with a alkyl group or a substituted silyloxy group ⁇ aryl group, furyl group ,
  • a phenyl group, a pyrenyl group or a phenyl group are each a C 16 alkyl group, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C 16 alkoxy group, A C 16 alkoxycarbonyl group, a C 16 alkyl group or a substituted silyloxy group.
  • R 4 is a hydrogen atom or a C 16 alkyl group ⁇ the alkyl group is a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C10 alkoxy group (the alkoxy group is a halogen atom, a hydroxyl group, a nitro group , A cyano group, a C16 alkoxy group, a C16 alkoxycarbonyl group, a C16 alkyl radical or a substituted silyloxy group, which may be optionally substituted), a C16 alkoxycarbonyl group, a C16 Which may be arbitrarily substituted with a 16-alkyl group or a substituted silyloxy group.
  • R 5 is C 1 18 alkyl group, C2 18 alkenyl, or C2 l 8 alkynyl group ⁇ said alkyl group, alkenyl group and alkynyl group is a halogen atom, a hydroxyl group, a nitro group, Shiano group, C l 10 alkoxy group (said alkoxy The group may be a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C16 alkoxy group, a C16 alkoxycarbonyl group, a C16 alkyl group Optionally substituted with a substituted silyloxy group), a C 1-6 alkoxycarbonyl group, a C 1-6 alkyl group, optionally substituted with a substituted silyloxy group ⁇ .
  • R 6 is a Cl-9 alkyl group, a C2-9 alkenyl group or a C2-9 alkynyl group (the alkyl, alkenyl and alkynyl groups are a halogen atom, a hydroxyl group, a nitro group, a cyano group, Cl-10 alkoxy group (The alkoxy group is a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C1-6 alkoxy group, a C1-6 alkoxycarbonyl group, a C1-6 alkylcarbonyloxy group or a substituted silyloxy group.
  • a C1-6 alkoxycarbonyl group, a C1-6 alkylcarboxyloxy group or a substituted silyloxy group ⁇ A group represented by or
  • R 5 is a C 1-18 alkyl group, C 2-18 alkenyl group or C 2-18 alkynyl group (the alkyl group, alkenyl group and alkynyl group are a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C l-10 alkoxy group (the alkoxy group may be a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C1-6 alkoxy group, a C1-6 alkoxycarbonyl group, a C1-6 alkyl group or a substituted silyloxy group.
  • a C 1-6 alkoxycarbonyl group, a C 1-6 alkylcarbonyl group or a substituted silyloxy group optionally substituted with a C 1-6 alkoxycarbonyl group, a C 1-6 alkylcarbonyl group or a substituted silyloxy group ⁇ .
  • R 6 is a Cl-9 alkyl group, a C2-9 alkenyl group or a C2-9 alkynyl group (the alkyl, alkenyl and alkynyl groups are a halogen atom, a hydroxyl group, a nitro group, a cyano group, Cl-10 alkoxy group (the alkoxy group is a halogen atom, a hydroxyl group, a nitro group, a cyano group, a Cl-6 alkoxy group, a Cl-6 alkoxycarbonyl group, a C1-6 alkyl carbonyl group or a substituted silyloxy group.
  • M 1 represents a hydrogen atom, a hydroxyl group or a substituted silyloxy group.
  • M 2 represents a hydrogen atom or a C 1-6 alkyl group] [3] [5]
  • the Z is
  • M 1 represents a hydrogen atom, a hydroxyl group or a substituted silyloxy group.
  • n is normal, “i” is iso, “s” is secondary, ⁇ t J is Yuichi Shari, “c” is cyclo, and “o” is Means Ortho.
  • halogen atom in the present invention examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the C1-6 alkyl group may be linear, branched or cyclic, for example, methyl, ethyl, n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl , T-butyl, c-butyl, n-pentyl, 1-methyl_n-butyl, 2-methyl_n-butyl, 3-methyl-n-butyl, 1,1-dimethyl-n-propyl, c-pentyl, 2-methyl- c-butyl, n-hexyl, 1-methyl-n-pentyl, 2-methyl-n-pentyl, 1,1-dimethyl-n-butyl, 1-ethyl-n-butyl, 1,1,2-trimethyl-n— Propyl, c-hexyl, 1-methyl-c-pentyl, 1-ethyl-c-butyl, 1,2-dimethyl-
  • the C1-9 alkyl group may be linear, branched or cyclic.
  • n-heptyl, n-octyl, n-nonyl, etc. Can be mentioned.
  • the C1-18 alkyl group may be linear, branched or cyclic.
  • the C 1-26 alkyl group may be linear, branched or cyclic, and includes, for example, n-nonadecyl, n-eicosyl and the like in addition to the substituents mentioned above for the C 1-9 alkyl group.
  • alkyl group having each carbon number may include a monocyclic or condensed polycyclic hydrocarbon group in the middle of the alkyl chain.
  • hydrocarbon group include a group represented by the following formula.
  • the C2-9 alkenyl group may be straight-chained, branched or cyclic, for example, ethenyl, n-propenyl, i-propenyl, c-propenyl, n-butenyl, i-butenyl, s-butenyl, t-butenyl, c-butenyl, n-pentenyl, 1-methyl-n-butenyl, 2-methyl-n-butenyl, 3-methyl-n-butenyl, 1,1-dimethyl_n-propenyl, c-1 Pentenyl, 2-methyl-c-butenyl, n-hexenyl, 1-methyl-n-pentenyl, 2-methyl-n-pentenyl, 1,1-dimethyl-n-butenyl, 1-ethyl-n-butenyl, 1 , 1,2-Trimethyl_n-propenyl, c-hexenyl, 1-methyl-c-
  • the C 2-18 alkenyl group may be straight-chain, branched or cyclic.
  • the C2-26 alkenyl group may be linear, branched or cyclic, and includes, for example, n-nonadecenyl, n-eicosenyl and the like in addition to the substituents mentioned above for the C2-1-8 alkenyl group. .
  • the alkenyl group may have two or more double bonds, and may include a monocyclic or condensed polycyclic hydrocarbon group in the middle of the alkenyl chain. And the above-mentioned hydrocarbon groups.
  • the C 2-9 alkynyl group may be straight-chain, branched or cyclic and includes, for example, ethynyl, n-propyl, i-propynyl, c-propynyl, n-butynyl, i-butynyl, s-butynyl, t-butynyl C-butynyl, n-pentynyl, 1-methyl-n-butynyl, 2-methyl-n-butynyl, 3-methyl-n-butynyl, 1,1-dimethyl-n-propynyl, c-pentynyl, 2-methyl-c Butynyl, n-hexynyl, 1_methyl-n_pentynyl, 2-methyl_n-pentynyl, 1,1_dimethyl-n-butynyl, 1-ethyl-n-butynyl, 1,1,2-trimethyl-n
  • the C 2-18 alkynyl group may be linear, branched or cyclic.
  • substituents listed above for the C 2-9 alkynyl group n-decynyl, n- ndenyl, n-dodecynyl , N-tridecyl, n-tetradecynyl, n-pentadecynyl, n-hexadecynyl, n-hepdecynyl, n-octadecynyl and the like.
  • the C2-26 alkynyl group may be linear, branched or cyclic, and includes, for example, n-nonadecynyl, n-eicosinyl and the like in addition to the substituents mentioned above for the C2-1-8 alkynyl group. .
  • the alkynyl group may have two or more triple bonds, and may include a monocyclic or condensed polycyclic hydrocarbon group in the middle of the alkynyl chain.
  • Examples of the hydrocarbon group include the hydrocarbon groups described above.
  • the C1-6 alkoxy group may be linear, branched or cyclic and includes, for example, methoxy, ethoxy, n-propoxy, i-propoxy, c-propoxy, n-butoxy, i-butoxy, s- Butoxy, t-butoxy, c-butoxy, n-pentyloxy, n-hexyloxy, c-hexyloxy and the like.
  • the C 1-10 alkoxy group may be straight-chain, branched or cyclic.
  • substituents listed above for the C 1-6 alkoxy group for example, n-heptyloxy, n-octyloxy , N-nonyloxy, n-decyloxy and the like
  • the C 1-4 alkoxyl radical may be linear, branched or cyclic, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, s-butoxycarbonyl. , T-butoxycarbonyl and the like.
  • the C1-6 alkoxycarbonyl group may be linear, branched or cyclic.
  • substituents mentioned above for the C1-4 alkoxy group for example, n-pentyloxycarbonyl, n-hexyloxycarbonyl And the like.
  • the C 1-6 alkyl radicalyloxy group may be straight-chain, branched or cyclic, for example, methylcarbonyloxy, ethylcarponyloxy, n-propoxypropyloxy, i-propylponyloxy, n-butyl. Examples thereof include carbonyloxy, s-butyl carbonyl, tert-butyl carbonyl, n-pentyl carbonyl, n-hexyl carbonyl and the like.
  • aryl groups include phenyl, naphthyl, p-tolyl and the like.
  • aryloxy group examples include phenoxy, naphthoxy, p-tolyloxy and the like.
  • Examples of the C2-3 alkylenedioxy group include ethylenedioxy, tetramethylethylenedioxy, propylenedioxy, and 2,2-dimethylpropylenedioxy.
  • hydroxyl-protecting group examples include, for example, a Cl to 7 acyl group (for example, formyl, acetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, propionyl, vivaloy) Benzyl, thiogyl and the like), aryl propyl group (for example, benzoyl, benzoylformyl, benzoylpropionyl, phenylpropionyl, etc.), C1-4 alkoxycarbonyl group (for example, methoxycarbonyl) , Ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, t-butoxycarbonyl, t-amyloxycarbonyl, bieroxycarbonyl, aryl
  • 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, and PGA resin.
  • substituted silyloxy group examples include a trialkylsilyloxy group (for example, trimethylsilyloxy, triethylsilyloxy, triisopropylsilyloxy, t-butylmethylsilyloxy, isopropyldimethylsilyloxy, t-butyldimethyl Silyloxy, texyldimethylsilyloxy, etc.), Alkylalkylsilyloxy group (for example, diphenylmethylsilyloxy, t-butyldiphenylsilyloxy, t-butyldimethoxyphenylsilyloxy, triphenylsilyloxy, etc.) and the like. .
  • a trialkylsilyloxy group for example, trimethylsilyloxy, triethylsilyloxy, triisopropylsilyloxy, t-butylmethylsilyloxy, isopropyldimethylsilyloxy, t-buty
  • R a and R b are as described above, independently of one another, C L ⁇ 6 alkyl group, C L ⁇ 6 alkoxy group, ⁇ Li Ichiru group, a Ariruokishi group or a hydroxyl group, also, R a and by bonding R b represents a C. 2 to 3 alkylenedioxy O alkoxy group (the C 2 to 3 alkylene Njiokishi group may be optionally substituted with C 1 to 4 alkyl group), in particular, R a It is preferable to use a C2-3 alkylenedioxy group in which Rb and Rb are bonded. For example, it is preferable to use a tetramethylethylenedioxy group or a 2,2-dimethylpropylenedioxy group.
  • substituents X 1 and X 2 it is preferable to use a Cl to 7 acyl group, a Cl to 4 alkoxycarbonyl group, 1, a lialkylsilyl group, a trialkylarylsilyl group, a silyl group resin terminal, or the like. Particularly preferred are a trialkylsilyl group, a trialkylarylsilyl group, a silyl group resin terminal and the like.
  • the substituents X 1 and X 2 may be the same or different from each other.
  • the substituent Z is, as described above, a straight-chain, branched or cyclic C 1-26 alkyl group, C 2-26 alkenyl group, C 2-26 It represents an alkynyl group, an aryl group, a furyl group, a chenyl group or a pyrrole group.
  • alkyl groups, alkenyl groups and alkynyl groups are halogen atoms, hydroxyl groups, nitro groups, cyano groups, Cl-10 alkoxy groups (wherein the alkoxy groups are halogen atoms, ⁇ ⁇ ⁇ ⁇ acid groups, nitro groups, cyano groups).
  • a C 1-6 alkoxy group, a C 1-6 alkoxycarbonyl group, a C 1-6 alkyl group or a substituted silyloxy group, a C 1-6 alkoxycarbonyl group It may be arbitrarily substituted with a 1 to 6 alkylcarbonyloxy group or a substituted silyloxy group.
  • the aryl group, the furyl group, the phenyl group, the phenyl group and the pyrrole group may be located at any positions, and may be any of the following: C1-6 alkyl, halogen, hydroxyl, nitro, cyano, C1-6 alkoxy, C1-6 It may be arbitrarily substituted with a 6 alkoxycarbonyl group, a Cl-6 alkyl group, or a substituted silyloxy group.
  • R 4 is a hydrogen atom or a C 1-6 alkyl group ⁇ the alkyl group, alkenyl group and alkynyl group are a halogen atom, a hydroxyl group, a nitro group, a cyano group, a Cl-10 alkoxy group (the alkoxy group is Optionally substituted with a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C1-6 alkoxy group, a C1-6 alkoxycarbonyl group, a C1-6 alkyl group, a luponyloxy group, or a substituted silyloxy group ), which may be arbitrarily substituted with a C1-6 alkoxycarbonyl group, a C1-6 alkylcarbonyloxy group, or a substituted silyloxy group ⁇ .
  • R 5 is a C18 alkyl group, C2-18 alkenyl group, or C2-18 alkynyl group (the alkyl group, the alkenyl group and the alkynyl group are a halogen atom, a hydroxyl group, a nitro group, a cyano group, l-10 alkoxy group (the alkoxy group is a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C1-6 alkoxy group, a C1-6 alkoxycarponyl group, a C1-6 alkyl carbonyl group or a substituted silyloxy group.
  • R 6 is a C1-9 alkyl group, a C2-9 alkenyl group, or a C2-9 alkynyl group (the alkyl group, the alkenyl group and the alkynyl group are a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C1 to 10 alkoxy group (The alkoxy group is a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C1-6 alkoxy group, a C1-6 alkoxy group.
  • M 1 represents a hydrogen atom, a hydroxyl group or a substituted silyl group.
  • M 2 represents a hydrogen atom or a C 1-6 alkyl group.
  • the reaction solvent used in the production method according to the present invention is not particularly limited as long as it is stable under the reaction conditions, and it is inert and does not hinder the reaction. Can be used.
  • ком ⁇ онентs for example, methanol, ethanol, propanol, and ethanol
  • cellosolves for example, methoxyethanol and ethoxyethanol
  • aprotic polar organic solvents for example, dimethylformamide, dimethylsulfoxide, dimethylacetamide, tetramethylperyl, sulfolane, N-methylpyrrolidone, N, N-dimethylimidazolidinone, etc.
  • ethers for example, 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 for example, pentane, hexane, c-hexane, octane
  • solvents are appropriately selected according to the easiness of the reaction, and can be used alone or in combination of two or more. If necessary, water may be removed with a suitable dehydrating agent or desiccant to use as a non-aqueous solvent.
  • T B S represents a t-butyldimethylsilyl group.
  • optically active cyclohexenone compound ⁇ ⁇ which is the starting material, is epoxidized.
  • bromethylene conversion reaction to ketone To form a bromethylenecyclohexenoxide form A, further reduce the epoxide to form a hydroxyl form _, silylize the hydroxyl group to form a disiloxy form, and finally replace the bromine atom with boron. it can.
  • Examples of the oxidizing agent for the first epoxidation reaction include peracids such as peracetic acid, perbenzoic acid, and m-chloroperbenzoic acid, hydrogen peroxide, oxygen, and the like, and preferably, 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 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 from 150 ° C. to 50 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • a pure xenon oxide can be isolated by performing purification by a conventional method such as sie gel gel ram chromatography.
  • examples of the reaction for introducing bromethylene into a ketone include a Wittig reaction using bromomethyl triphenylphosphonium bromide, and a Horner-Emmons reaction using, for example, diisopropyl bromomethyl phosphonate.
  • a Wittig reaction using bromomethyltriphenylphosphonium bromide is preferred.
  • 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 water and ketones can be used.
  • the reaction temperature can be generally from 10 ° C. to the boiling point of the solvent used, but is preferably from 150 ° C. to 50 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • pure bromethylenecyclohexenoxide 3 can be isolated by purification by a conventional method such as silica gel column chromatography.
  • Examples of the reducing agent include diisobutylaluminum hydride, sodium borohydride, lithium aluminum hydride, bismethoxyethoxyminium sodium hydride, and the like.
  • diisobutylaluminum hydride is used. It is.
  • 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 is usually from ⁇ 10 ° C. to the boiling point of the solvent used, but is preferably from 180 ° C. 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.
  • Examples of the protective agent for protecting the hydroxyl group of the hydroxyl compound A obtained as described above include an acylating agent, an oxycarbonyl compound, an aminocarbonylating agent, a silylating agent, and the like. It is preferable to use an agent.
  • silylating agent examples include trimethylsilyl chloride, t-butyldimethylsilyl chloride, diphenylt-butylsilyl chloride and the like.
  • the amount of the silylating agent to be used is generally 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, tree n-propylamine, tree n-butylamine, DBU, N-methylmorpholine, Amines such as N, N_dimethylaniline; pyridines such as pyridine, methylethylpyridine, lutidine; pyridines such as 4-N, N-dimethylaminopyridine; imidazole and pyrazole; and preferably imidazole It is.
  • 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, alcohols and cellosolves can be used.
  • the reaction temperature can be generally from 100 ° C. to the boiling point of the solvent used, but is preferably from 150 ° C. to 50 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • a pure disiloxy compound can be isolated by performing purification by a conventional method such as silica gel column chromatography.
  • the target compound can be produced by substituting halogen in the obtained disiloxy compound with boron.
  • lithiating agent examples 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 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. Among the above-mentioned solvents, solvents other than water, alcohols, cellosolves, ketones, halogenated hydrocarbons and esters can be used. it can.
  • the reaction temperature can be usually from —100 to the boiling point of the solvent to be used, but is preferably in the range of 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.
  • the compound can be synthesized by treating the obtained boron compound with pinacol.
  • the boronating agent is not particularly limited, and includes, for example, trimethoxyporan, triethoxyporan, triisopropoxypolane 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 generally from 10 ° C. to the boiling point of the solvent used, but is preferably from 180 ° C. to 50 ° C.
  • 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.
  • Et represents an ethyl group
  • TBS represents a t-butyldimethylsilyl group
  • 5 Pr represents an isopropyl group.
  • the optically active chlorohydrin ester is iodinated to form a hydrido compound 10, then the hydroxyl group is silylated to form a siloxy compound 11, and further reacted with vinyl Grignard to form a homoallyl ether compound 12, and finally It can be produced by cyclizing with Ti.
  • TM S represents a trimethylsilyl group.
  • the compound represented by the general formula (3) can be produced by reacting the optically active vinylidenecyclohexane compound represented by the general formula (1) with a compound represented by the general formula (2),
  • compound 14 can be produced by reacting compound 13 obtained above with compound 13.
  • TBS represents a t-butyldimethylsilyl group
  • TMS represents a trimethylsilyl group
  • compound 16 can be produced by reacting compound 6 obtained above with compound 16.
  • TBS represents a t-butyldimethylsilyl group
  • TES represents a triethylsilyl group.
  • the amount of the halide to be used is usually in the range of 0.5 to 2.0 mol times based on the substrate.
  • a palladium catalyst or a nickel catalyst is required in order to progress the reaction between the compound represented by the general formula (1) and the compound represented by the general formula (2).
  • a valent palladium complex or a nickel complex is preferred, and a tertiary phosphine or a zero-valent complex having a tertiary phosphite as a ligand is particularly preferred.
  • a suitable precursor that can be easily converted to a zero-valent complex in the reaction system can also be used.
  • a tertiary phosphine or tertiary phosphite is mixed with a tertiary phosphine or tertiary phosphite to form a tertiary phosphine or tertiary phosphite as a ligand. It can also generate low-valent complexes.
  • Tertiary phosphines and tertiary phosphites used as ligands include triphenylphosphine, diphenylmethylphosphine, phenyldimethylphosphine, 1,2-bis (diphenylphosphino) ethane, and 1,3-bis ( Diphenylphosphine) propane, 1,4-bis (diphenylphosphino) butane, 1,1, —bis (diphenylphosphino) phenoctene, trimethylphosphite, triethylphosphite, triphenylphosphite And the like.
  • a complex containing a mixture of two or more types can also be suitably used.
  • complexes that do not contain tertiary phosphine or tertiary phosphite include bis (benzylideneacetone) palladium, palladium acetate, palladium chloride, nickel acetate, nickel chloride and the like.
  • Examples of the phosphine or phosphite complex include dimethylpis (triphenylphosphine) palladium, dimethylbis (diphenylphosphine) palladium, (ethylene) bis (triphenylphosphine) palladium, and tetrakis (triphenylphosphine) palladium.
  • the amount of the palladium catalyst or nickel catalyst used may be a so-called catalytic amount, and generally, 20 mol% or less based on the substrate is sufficient.
  • 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 usually from 100 ° C to the boiling point of the solvent used, but is preferably from 30 ° C to 50 ° C.
  • the reaction time is usually 0.1 to 1000 hours.
  • a pure compound 19-nor-vitamin D derivative can be isolated by performing purification by a conventional method such as a silica gel gel column chromatography.
  • a conventional method such as a silica gel gel column chromatography.
  • TBS represents a t-butyldimethylsilyl group.
  • Optically active 5-siloxy-1-cyclohexenone II (6.14 g, 27. 2 mmo 1) and 35% hydrogen peroxide (23.6 mL, 272 mmo 1) in methanol (2 1 OmL) was cooled to ⁇ 78 ° C., and a 3M aqueous solution of sodium hydroxide (4.8 mL, 14.4 mmol) was added to the mixture at ⁇ 178 ° C.
  • reaction solution was concentrated to about half the volume under reduced pressure, the solution was extracted three times with methylene chloride (15 OmL), and the organic layer was dried over anhydrous magnesium sulfate.
  • TBS represents a t_butyldimethylsilyl group.
  • optically active 5-siloxy-2,3-epoxycyclohexanone (4.84 g, 2 Ommo 1) was added, and the reaction was warmed to room temperature over 30 minutes.
  • reaction solution was concentrated under reduced pressure, hexane (200 mL) was added to the obtained residue, and the precipitated crystals were filtered through celite.
  • TBS represents t-butyldimethylsilyl group.
  • diisobutylaluminum hydride 1.0 M hexane solution, 26. OmL, 26.0 mm o 1
  • TBS represents a t-butyldimethylsilyl group.
  • TBS represents a t-butyldimethylsilyl group.
  • TBS represents a t-butyldimethylsilyl group
  • TMS represents a trimethylsilyl group
  • optically active boron vinylidenecyclohexane compound A (191 mg, 0.40 mmo 1) obtained in Reference Example and a 3 M aqueous potassium hydroxide solution (0.106 mL) were added to the HF (0.3 mL) solution, A solution of compound 13 (106 mg, 0.25 mmo 1) and palladium chloride 'diphenylphosphinophene-mouth complex (11.8 mg, 0.016 mmo 1) in THF (0.5 mL) was added at room temperature. After stirring at room temperature for 8 hours as it was, the temperature was raised to 40 and further stirred for 12 hours.
  • reaction solution was cooled, ether (1 OmL) was added, and the mixture was washed with 1M hydrochloric acid (5 mL), and further washed with saturated saline.
  • the organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product obtained was purified by silica gel column chromatography, and the coupled product was purified.
  • the obtained coupling product 14 was dissolved in THF (1 mL), 30% hydrofluoric acid (2 drops) was added thereto, and the mixture was stirred at room temperature for 3 hours.
  • a 19-nor monovitamin D derivative can be relatively easily and efficiently produced by using an optically active boron vinylidenecyclohexane compound as a raw material.

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Abstract

Procédé de préparation de dérivés de 19-norvitamine D de formule générale (3) dans laquelle W représente hydrogène, halogéno, ou analogue, Z représente alkyle C1-C26 ou analogue et X1 et X2 représentent chacun indépendamment hydrogène, un groupe protecteur hydroxyle ou une phase solide possédant un tel groupe protecteur à sa terminaison, qui consiste à faire réagir un composé borylvinylidène-cyclohexane optiquement actif de formule générale (1), ou un énantiomère dudit composé, formule dans laquelle W, X1 et X2 sont tels que définis ci-dessus et Ra et Rb représentent chacun indépendamment alkyle C1-6 ou analogue, ou bien Ra et Rb peuvent être réunis pour former un akylènedioxy C2-3 ou analogue, avec un composé de formule générale Hal Z dans laquelle Hal représente halogéno et Z est tel que défini ci-dessus.
PCT/JP2002/010217 2001-10-05 2002-10-01 Procede de preparation de derives de 19-norvitamine d WO2003031402A1 (fr)

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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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