WO2001023337A1 - Nouveaux procedes de synthese de 1d-chiro-inositol et intermediaires - Google Patents

Nouveaux procedes de synthese de 1d-chiro-inositol et intermediaires Download PDF

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WO2001023337A1
WO2001023337A1 PCT/JP2000/006826 JP0006826W WO0123337A1 WO 2001023337 A1 WO2001023337 A1 WO 2001023337A1 JP 0006826 W JP0006826 W JP 0006826W WO 0123337 A1 WO0123337 A1 WO 0123337A1
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group
general formula
compound
formula
inositol
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WO2001023337A9 (fr
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Toshiaki Miake
Yoshiaki Takahashi
Tomohisa Takita
Tomio Takeuchi
Kaoru Chiba
Nobuhiro Ito
Sumio Umezawa
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Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
Hokko Chemical Industry Co., Ltd.
UMEZAWA, Miyoko
WADACHI, Asako
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Publication of WO2001023337A1 publication Critical patent/WO2001023337A1/fr
Publication of WO2001023337A9 publication Critical patent/WO2001023337A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/56—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by isomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
    • C07C29/10—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes
    • C07C29/103—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes of cyclic ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/128—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by alcoholysis
    • C07C29/1285—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by alcoholysis of esters of organic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • 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

  • 1D-kilo-inositol (1D-chiro-Inositol) can be used as a raw material of inexpensive myo-inositol (myo-inositol). It relates to a new synthesis method that can be easily and efficiently manufactured.
  • the ID-kilo-inositol compound represented by is one of nine types of inositol stereoisomers, and a typical example of the production method is as follows (a ) To (d) are known.
  • (1R) _ (+)-A camphor is used to convert the myo-nositol represented by the formula (1R) _ (+)-force
  • the hydroxyl groups at the 2nd and 3rd positions of the myo-inosintone are (1R) — (+)-force Protected by one 1,1-disubstituted methylidene group induced by the dissociation of two methoxy groups in the acetal moiety from the dimethyl acetate potential Myo-inositol protected derivative, that is, the following formula (C)
  • An object of the present invention is to provide a novel method for synthesizing 1D-kilo-inositol that can meet the demand. Disclosure of the invention
  • the 1D-2,3-di-0-aceta / Rayidai-myo-no-shitonore represented by the above formula (C) is Dichloromethane in a solvent consisting of lysine alone or in the presence of an organic base such as pyridine or trianolekylamin which acts as an acid binder.
  • 1D-2,3-di-0-acetalization of the above formula (C) In myo-inositol, the 2- and 3-hydroxyl groups are derived from the dimethylacetal of (1R)-(+)-force. Derived 1,1-disubstituted methylidene groups that are protected in the form of acetals with difunctional hydroxysilyl protecting groups of the type Hydroxylsyl groups at positions 2 and 3 of inositol are generally derived from optically active ketones or aldehydes.
  • the 1-hydroxyl group of 1D—2,3-di-O-acetyl-methyl-phosphate is a trif / rhelo-metanes-norrefonic acid
  • various sulfonylating agents other than anhydrides can be used to selectively sulfonylate.
  • Inositol has three remaining free hydroxyl groups at positions 4, 5, and 6, and these three hydroxy groups are sugars. Of sugar in the chemistry of It was also found that the monofunctional hydroxy group, which is commonly used for protecting the xyl group, can be easily capped with the hydroxyl group for protecting the hydroxy group.
  • R 3 is a lower alkyl group, ⁇ -trino, mouth- (lower) alkyl group, aryl group, preferably phenyl group, or lower alkyl group Or a phenyl group substituted with a methoxy group, or an alanolequinol group or, preferably, a benzyl group).
  • the 1,1-disubstituted methylidene group having R 1 and R 2 and R 3 have the same meanings as described above, and R 4 is a monofunctional amino group.
  • An anoyl group as a protecting group for hydroxy preferably Represents an acetyl group, an aryl group, or, preferably, a benzoyl group.
  • M represents an aluminum metal atom, preferably lithium or sodium or a lithium atom
  • R 5 represents a lower alkyl group. Or a phenyl group which may be substituted with an aryl group or, preferably, a lower alkyl group) in a non-reactive polar organic solvent. And thereby react with heat, thereby inverting the configuration at position 1 of the protected myo-inositol derivative of the general formula (IV).
  • sheet group - 0- S0 2 removal and Anore force R 3 Roh I Noreoki Shimotoma other ⁇ b a Noreoki sheet group - 0- CO- by that performs substitution reactions, the following general formula (VI)
  • a difunctional hydroxy-protecting group having a 1,1-disubstituted methylidene group represented by the above formula (a) can be obtained.
  • a method for synthesizing ID-kilo-inositol characterized by comprising a fifth step of producing the 1D-kilo-inositol. Provided.
  • the 2,3-acetal of myo-inositol of the general formula (I) used as a starting compound in the first step of the first method of the present invention is a myo-inositol.
  • (D) (LR)-(+)-forced dimethyl ether is obtained.
  • the myo-inositol is suspended in dimethylsulfonamide or N, N-dimethylhonolemamide, and the suspension is added to the suspension.
  • (1R)-(+)-camphor'dimethylaceteneol is converted to 2 mol ratio per 1 mole of myo-inositoid or Add a slight excess, then add a catalytic amount of acid, for example, sulfuric acid, hydrogen chloride or p-toluenesulfonic acid, and heat the reaction mixture to 50-90 ° C.
  • the reaction can be carried out under agitation at a temperature for 2-5 hours.
  • An organic base for example, sodium methoxide, triethylamine, is added to the obtained reaction solution containing an acetylated derivative of myo-inositol. D and neutralized, and the neutralized reaction solution is concentrated by distilling off the solvent to obtain the desired IDS '3-di-O-aceta-Rui-Dani of the formula (la)
  • Mixtures of myo-inositol and undesired resin or other bis-0-acetonolated myo-inositol derivatives can be used as syrups. can get.
  • a suitable organic solvent preferably methanol, acetone, or a mixture of methanol and methanol.
  • the (1R) _ (+)-camphor-substituted methylidene group in the compound of the above formula (la) is bonded to the 2nd and 3rd hydroxyl groups located in the cis configuration with each other. It is relatively stable to acids as compared to those which bind to adjacent hydroxyl groups located in a trans configuration with each other.
  • the 1,2-disubstituted methylidene group represented by the formula (1) is a difunctional, pendant, hydroxyl-protecting group for the methyl group of (1R)-(+)-camphor. / 1,1-disubstituted methylidene group derived from / rarecetal, and not only (1) to (XV i) It can also be a 1,1-disubstituted methylidene-type group derived from the optically active ketones or the phenolic dimethinophenol acetates mentioned. You.
  • a non-protonic organic solvent without reactive hydrogen for example, Jiklo Rome In a chlorinated hydrocarbon such as tan, 1D-mino-inositol-2,3-acetal of the general formula (I) is dissolved.
  • a non-protonic organic solvent without reactive hydrogen for example, Jiklo Rome In a chlorinated hydrocarbon such as tan, 1D-mino-inositol-2,3-acetal of the general formula (I) is dissolved.
  • the organic sulfonic acid anhydride of the general formula (II) or the organic sulfonic acid halide of the general formula (II) is dissolved.
  • the resulting reaction mixture is stirred under cooling and cooled to a temperature in the range of -50 ° C or room temperature, preferably -40 ° C or 0 ° C, of the formula (I).
  • a reaction is carried out to selectively convert the 1-hydroxyl group of the compound to an organic sulfonylation with the snorolenylating agent of the formula (II) or (I ⁇ ).
  • the sulfonic anhydride of the formula (II) is used as the above organic snollenylating agent, this is the 1D-myo-inosinose of the formula (I). -2,3-Acetanore per mole of one mole ratio or slightly more.
  • the 1D miolino of the formula (I) can be used.
  • Nore scan le phon anhydride (II) is a lower ⁇ Norre mosquitoes down, is rather than the preferred (c ⁇ c 6!) ⁇ Noreka down, Oh Ru Les, is ⁇ door Li Ha Russia (low grade) Anore mosquitoes down, preferred to rather than the ⁇ - door Li off Norre O ports ( C 1 -C 6 ) It can be a snolefonic anhydride derived from the snolefonic acid phenol of the phenol.
  • sulfonic anhydride of the formula (II) examples include methansnorephonic acid, ethanesnolephonic acid and trifnorolelomethansnorephonic anhydride. That Ru have use was or like correct c and scan le phon anhydride of formula (II), aromatic scan Honoré phon It can be an acid anhydride.
  • aromatic sulfonic acid anhydride examples include benzenesnolefonic acid, p-tonolenesulfonate or P-ditrovenzens-norefonic acid It is preferable to use
  • the reaction solution is distilled under reduced pressure to remove the solvent, and a residue of the desired formula (III) as a residue is obtained.
  • 1-0-Organic sulfonation products can be separated.
  • the reaction solution is immediately used in the method of the present invention. It is convenient to work in two processes.
  • the second step of the first method of the present invention can be carried out as follows.
  • the reaction solution obtained in the first step is commonly used for protecting the hydroxyl group of a sugar by sugar chemistry.
  • Monofunctional hydroxy protecting groups such as (C 2 -C 6 ) phenolic, especially acetyl, or benzoyl groups
  • a hydroxylating group-protecting acylating agent having a non-hydroxyl group is added as a hydroxyl-protecting group-introducing agent, and 1- of the formula (III) is added.
  • the acylation reaction that protects all of the hydroxyl groups is carried out in a conventional manner according to the conventional hydroxyl group protection method of sugar chemistry.
  • the silation reaction can be terminated by stirring the reaction mixture at room temperature or elevated temperature for 1 to 10 hours.
  • the group-introducing agent (acylating agent) include (C 2 to C 6 ) anorecanyl 'chloride, bromide or chloride, for example, acetinol chloride. Li de, can in profile Pio two Honoré click b Li de a to use this and force s, or (c 2 ⁇ c 6) ⁇ Noreka phosphate anhydride, ⁇ you can acetic anhydride used, for example.
  • an aromatic carboxylic acid for example, chloride or anhydride of benzoic acid can be used as the agent for introducing a protecting group for a hydroxyl group (acylating agent).
  • ID-1-0-organo-sulfonyl-myo-inositol of the formula (III) 4th, 5th and 6th position of 2,3 acetals
  • the resulting 1D—1—0 organic phenolic compound of formula (IV) 2,3—G—0—Acetallich—4,5
  • reaction solution is diluted with an organic solvent immiscible with water, for example, a chlorophore, and the organic layer is separated, and further diluted with a dilute aqueous solution of hydrogen sulfate.
  • Dilute aqueous solution of sodium bicarbonate Washing successively with water and further drying and concentrating under reduced pressure, the compound of formula (IV) can be obtained as syrups or crystals.
  • the third step of the first method of the present invention can be carried out as follows. That is, the compound of the formula (IV) obtained from the second step is obtained by reacting a non-reactive, polar organic compound. Solvents, for example, N, N-dimethylformamide (DMF), dimethylsulfoxymide (DMS0) And dissolving it in a solution of the formula (1), and adding the alkali metal carboxylate of the formula (V) to the resulting solution. The obtained reaction mixture is stirred while being heated, and reacted at a temperature of 40 ° C. and 180 ° C. for 120 hours.
  • Solvents for example, N, N-dimethylformamide (DMF), dimethylsulfoxymide (DMS0)
  • alkali metal olevonate of the formula (V) a lithium salt or a sodium salt of (C 2 C 6 ) alkanoic acid or potassium Salts, especially lithium acetate, sodium acetate, potassium acetate, lithium propionate, etc. can be used.
  • an aromatic carboxylic acid for example, an alkali metal salt of benzoic acid or p-methylbenzoic acid is used. Can be used. Lithium benzoate is preferred.
  • the potassium olevonate of the formula (V) is used in an excess amount of 210 mol per 1 mole of the compound of the formula (IV).
  • the reaction in the third step in Tsu by in rows cormorants this position 1 Organic scan Honoré e d Noreoki sheet group of a compound of formula (IV) - 0- S0 2 R 3 is in desorption formula (V Olenoic acid or phenolic group of olevones Sheet group - 0_C0- R 5 in location-out place et been Ru substitution reaction proceeds, the 1-position of 1D- 6-0 Anoreka Roh Lee Honoré or the ⁇ port configuration is inverted formula (VI) 1,2,0,0,0,0,0,1,3,5,3,0,0,0,0,0,3,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0
  • the obtained residue is extracted with a water-immiscible organic solvent, for example, toluene, ethyl acetate, dimethyl ether, or cross-linked form, and the obtained extract is washed with water. After drying, and further concentrating, the compound of the formula (VI) can be obtained.
  • a water-immiscible organic solvent for example, toluene, ethyl acetate, dimethyl ether, or cross-linked form
  • the fourth step of the first method of the present invention can be carried out as follows. That is, in the fourth step, the acyl group R 4 for protecting the 3-, 4-, and 5-hydroxyl groups of the compound of the formula (VI) obtained in the third step is obtained. The elimination and the elimination of the acyl group -CO- bonded to the 6-hydroxyl group are performed in a conventional manner according to the deprotection method commonly used in sugar chemistry. In order to carry out the deprotection reaction of the fourth step, first, the compound of the formula (VI) is dissolved in a suitable organic solvent such as methanol, for example, anhydrous methanol, and the solution is dissolved.
  • a suitable organic solvent such as methanol, for example, anhydrous methanol
  • the 1- and 2-hydroxyl groups of the compound of the formula (VII) are protected from the compound of the formula (VII) in the form of acetals.
  • the following equation (a) The elimination of the 1,1-disubstituted methylidene group is carried out according to the deprotection method commonly used in sugar chemistry.
  • the compound of formula (V11) is treated with an acid. For example, when the compound of the formula (VII) is dissolved in 50% aqueous acetic acid and heated at 50 ° C to 100 ° C for 30 minutes to 1 hour, deacetylation is performed.
  • 1st and 2nd positions of the hydroxy group of the compound of formula (V11) As described above, de-centering generates 1D-kilo-inositol of formula (A).
  • the reaction solution containing the generated 1D-kilo-inositol is concentrated, the obtained residue is extracted with water, and the obtained aqueous extract is extracted with ethyl ether or hexane. After washing with, for example, a concentrate, 1D-kilo-inositol with high optical purity can be obtained as a colorless solid by concentrating.
  • the reaction solution of the above deacetal reaction is concentrated to dryness, dimethyl ether and water are added to the residue, and the mixture is stirred. An aqueous solution of rosinositol can also be obtained.
  • the high-purity 1D-kilo-inositol obtained in this way has a melting point of 238 ° C in conformity with the physical properties of a commercially available ID-kilo-inositol. C and specific rotation [c] D 25 + 65 ° (c 1, water).
  • the resulting 1D-kilo-inositol product can be further purified by crystallization from a suitable solvent, for example, a hydrated methanol solvent. .
  • the first method of the present invention is carried out starting from 1D-2,3-di-0-acetalized-myo-inositol compound of the formula (la). Therefore, the preferred implementation of the first method of the present invention is represented by the following formula (Ia)
  • R 3a represents a trifluorophenol methynole group or a p-methylphenyl group or a methyl group.
  • Acetic anhydride, acetinolechloride, benzoic anhydride or benzoyl chloride as an acylating agent for introducing a protecting group
  • R 3a has the same meaning as described above, and R 4a represents a monofunctional hydroxyl-protecting group which is an acetyl group or a benzyl group.
  • the reaction of um or sodium or cadmium in an organic solvent, preferably N, N-dimethylformamide, is carried out at an elevated temperature.
  • R 4a has the same meaning as above, and R 5a is a phenyl group or a methyl group.
  • an acyl group ie, an acetyl group or a benzo group protecting the 3-, 4-, and 5-hydroxyl groups of the compound of the general formula (VIb).
  • I Norre group an al beauty to the 6-position of the human mud key ⁇ sill group attached to the sill based on (- CO- R 5a) and desorption, and in Tsu by the Re this the following formula (V 11 a)
  • the first method of the present invention is a method for preparing a 1D-2,3-di-0-acetalized compound represented by the above formula (la) as a starting compound of the first step.
  • the method is performed using Myo-nositol, each method of the first step, the second step, the third step, the fourth step, and the fifth step of the present invention is individually performed. This is a new method.
  • the group represented by is derived from an optically active ketone or aldehyde, or is a dimethyl ester of the ketone or aldehyde.
  • 2 methoxy groups in the acetate part A difunctional hydroxyl-protecting group of the type of a 1,1-disubstituted methylidene group derived from the dissociation of a mino-inositol.
  • R 3 is a lower alkyl group, ⁇ -trino, mouth- (lower) phenolic alkyl group, aryl group, preferably phenyl group, or lower group.
  • R 3 is a lower anoalkyl group, ⁇ -trino, Mouth- (lower) anoalkyl groups, aryl groups, preferably phenyl groups, or phenyl groups substituted with lower alkyl groups or methoxy groups, etc. Or an aralkyl group, or preferably a benzyl group).
  • the 1,1-disubstituted methylidene group having R 1 and R 2 and R 3 have the same meaning as described above, and R 4 is monofunctional. Represents a phenol group or a hydroxyl group as a hydroxyl-protecting group].
  • a method for producing -0-aceta-i-rui-dori 4,5,6-tri 0_asino-re-mo-inositol is provided.
  • R 4 is a monofunctional hydroxyl-protecting group, which is a phenyl group, a phenyl group, or a phenyl group, preferably a benzyl group, which is substituted with a nitrogen group.
  • V The following general formula (V) is added to the noise control.
  • M represents an aluminum metal atom, particularly lithium or sodium or a lithium atom
  • R 5 represents a lower alkyl group or an aryl group. Or a substituted or unsubstituted alkyl group, preferably a lower alkyl group, which represents a non-protonic polar organic solvent.
  • the reaction is carried out under heating in an atmosphere, whereby the protected organic derivative of the general formula (IV) undergoes the inversion of the configuration at the 1-position of the protected myo-inositol derivative.
  • the 1,1-disubstituted methylidene group having R 1 and R 2 and R 4 and R 5 have the same meanings as described above.
  • R 4 is a monofunctional hydroxy group.
  • R 5 represents a lower alkyl group or an aryl group, preferably a lower alkyl group.
  • 1D-6-0 Anore force or aloin-1,2, -di—0—Acetanore 3, 4, 5—tri-l-oxyl-hydroxyl-protecting hydroxy-protecting group R 4 and alkano-inole group ⁇ b a Honoré group - C0-R 5 this whether Ru Naru Luo the Ru is a compound or et desorption by Ri general formula deprotected (VI), the following equation
  • the group represented by is derived from an optically active ketone or aldehyde, or is a dimethyl ether of the ketone or aldehyde.
  • a difunctional hydroxyl protecting group of the type 1,1-disubstituted methylidene group induced by the dissociation of two methoxy groups in the acetal moiety The 1D-1,2-di-0-acetonolization-kilo-inositol force represented by the following formulas: 1- and 2-position hydroxy groups
  • a hydroxy-protecting group of the 1,1-disubstituted methylidene group type protected in the form of an acetal is removed by acid treatment.
  • the following equation (A) A method for producing the ID-kilo-inositol is provided.
  • the present inventors have set forth a special purpose for developing a new method that can produce 1D-kilo-inositol with a new route different from the first method of the present invention.
  • the research was advanced.
  • the 1D-1-0 organic organophosphorus of the above-mentioned general formula (IV) obtained as an intermediate by the first method of the present invention, 2,3 Di-0-acetonolide 4—5, 6—triol 0-nore-force or non-reactive polar organic solvent
  • the myo-inositol compound of the general formula (IV) 0 - 1 of organic scan Honoré e d Noreo key sheet group a sheet Honoré derivatives - 0- S0 2 to cause the elimination of R 3, the configuration of Banre ,, human mud key sill groups Re this
  • the reaction solution containing the compounds of the formulas (Villa) to (Vllld) thus produced is washed with water, dried and concentrated, and the resulting syrup is subjected to removal of impurities.
  • the compounds of formula (Villa), compounds of formula (VI lib), compounds of formula (VIIIc) and compounds of formula (Vllld) Or a mixture of the following, or a compound of formula (Villa), a compound of formula (Vlllb), a compound of formula (VIIIc) and a compound of Z or formula (VIIId) It was found that a mixture could be collected.
  • the group represented by is derived from an optically active ketone or aldehyde, or a dimethyl ether alcohol of the ketone or aldehyde.
  • R 3 is a lower alkyl group, ⁇ -trihalo- (lower) alkynole group, aryl group, preferably phenyl Or a phenyl group substituted by a lower phenol or dinitro group, or a phenyl group, preferably a benzyl group.
  • R 4 represents an anorecanol or an aryl group as a monofunctional hydroxyl-protecting group.
  • Seat-0 - ⁇ 1 of organic sulfo Niruoki sheet group Le derivative - 0- S0 2 to cause the elimination of R 3, along with this, the following general configuration arsenide mud key Sill group is inverted Expression (Villa)
  • the 1,1-disubstituted methylidene group having R 1 and R 2 and R 4 have the same meanings as described above.
  • 2-di-0-acetor norei-4, 5, 6-tri-0-nore or no-no-no-no-no-no-no-no Or a mixture of the product obtained in the first step, which produces one of the two, and the product obtained in the first step in a low-altitude aluminum alloy.
  • R 3 is a lower alkyl group, a ⁇ tri-mouth- (lower) phenol group, a aryl group, preferably a phenyl group, or a lower group.
  • 4 is an alkanoinole group as a monofunctional hydroxyl protecting group, preferably an acetyl or aryl group, preferably a benzoyl group 1D—1 1—0—organic phosphoric acid 1,2,3-di-1 0—aceta / rayid — 4,5,6—tri 1 0— Add a folder or a folder.
  • R 4 has the same meaning as described above] represented by the formula: 1D-1,2-di-O-aceta-norai-dori-4,5,6-tri--0-
  • the mixture of the products of the one step is treated with a metal alloy in a lower metal alloy, whereby the compound of formula (V11Ia-1) is obtained.
  • the nositol derivative is treated with an acid to obtain a compound having the general formula (Vila), thereby obtaining a difunctional hydroxyl group having the form of a carbonyl-substituted methylidene group.
  • a method for synthesizing 1D-kilo-inositol characterized by comprising a third step of producing the ID-kilo-inositol.
  • the compound of the general formula (IV) used as a starting compound in the first step of the seventh process of the present invention is a compound of the second process of the first process of the present invention. It is a product obtained in the process.
  • the first step of the seventh method of the present invention can be carried out as follows. That is, the compound of the formula (IV) obtained from the second step of the first method of the present invention is replaced with the seventh book.
  • a suitable non-reactive and polar organic solvent for example N, N-dimethylhonoleamide (DMF), dimethylsulfonexamide (DMSO) Or hexamethylphosphoric triamide (HMPA), and the resulting solution is added to an anorecalic metal fuzzy ridge, preferably a fluoride. Power the stream.
  • the obtained reaction mixture is stirred while being heated, and reacted at a temperature of 100 ° C to 180 ° C for 1 to 20 hours.
  • lithium, sodium, or power fluoride can be used as the alkali metal futsudani.
  • the excess metal fluoride is used in an excess of an equimolar ratio to a molar ratio of 10 per 1 mole of the compound of formula (IV).
  • the 1D chloroinositol derivative of the formula (Villa) and the formula (Vlllb) Is generated.
  • the phenol compound bonded to the hydroxy group of the compound of the formula (Villa) and the formula (Vlllb) A reaction that causes an acyl transfer, in which the amino group or aryl group R 4 is transferred to a free hydroxy group, also proceeds.
  • the compound of the formula (VIIIa) and the compound of the formula (VI lib) are produced, and in some cases, In other words, one or both of the compound of the formula (VIIIc) and the compound of the formula (Vllld) are produced.
  • the compound of the formula (Villa), the compound of the formula (Vlllb), the compound of the formula (VIIIc), and the compound of the formula (Vllld), which are mixed and contained in the reaction solution, are mutually chromatographed. No technology has yet been found that can be used to separate the mixture, but if it is used as an intermediate in the second step of the seventh method of the present invention, it does not interfere with the mixture at all. There is no.
  • the seventh step of the seventh method of the present invention the above-mentioned mixture obtained in the first step in the preceding step is treated with a metal hydroxide in a low-grade alcohol.
  • the compound of the formula (Villa), the compound of the formula (Vlllb) and the compound of the formula (VIIIc) and / or the compound of the formula Z or (VIIId) are combined with the alkanol group.
  • the royole group R 4 can be eliminated and thus the 10-1,2_di-0-aceta-nore-chloro-inositol phenol of the general formula (VII) can be formed.
  • the second step can be performed in exactly the same manner as the fourth step of the first method of the present invention.
  • the third step can be performed in exactly the same manner as the fifth step of the first method of the present invention.
  • the group is derived from an optically active ketone or aldehyde, or is derived from the dimethyl acetate of the ketone or aldehyde.
  • R 3 is a lower alkyl group, ⁇ -trihalo- (lower) alkylene group, arylene group, preferably phenyl group, or lower phenolic or lower alkyl group.
  • a ninth compound of the general formula (IV) according to the present invention has the following general formula (IVb)
  • R 3a represents a trifluoromethyl group, a p-methyl group or a methyl group
  • R 43 represents an acetyl group or a benzoyl group.
  • the 1,1-disubstituted methylidene group having R 1 and R 2 and R 4 and R 5 have the same meanings as described above.
  • 1D 6—0 Fan force or noise—1,2 di-acetated -3,4,5-tri-0-protection-Kyro-ino A seat will be provided.
  • the novel product produced by the 7th method of the present invention is represented by the following general formula (Villa)
  • myo-inositol is treated with a suitable polar organic solvent, preferably dimethyl sulfoxide (DMS0) or N, N-dimethyl honolem. Suspended in an organic solvent of amide (DMF), and trimethylethyl formate, which acts as a dehydrating agent, is added to this suspension. An excess amount of 3 to 15 moles per mole and lower alkyl alcohol, preferably methanol, is added to one mole of myo-inositol. Add an excess amount of 5 to 20 moles per day and add a catalytic amount of acid, for example, sulfuric acid, hydrogen chloride, or p-toluenesulfonic acid. The reaction mixture can be subjected to the reaction with stirring at a temperature in the range of 50 to 100 ° C for 4 to 20 hours.
  • a suitable polar organic solvent preferably dimethyl sulfoxide (DMS0) or N, N-dimethyl honolem.
  • DMF organic solvent
  • the obtained acetate derivative of myo-inositol was converted to An organic base, such as sodium methoxide and triethylamine, is added to the reaction mixture containing [] to neutralize it, and the neutralized reaction solution is distilled off.
  • the desired compound of formula (la) 1D—2,3 di—0-acetonolone is not desired, and undesired other excessively
  • a mixture of acetylated myo-inositol derivatives is obtained as a syrup.
  • a suitable organic solvent preferably methanol, acetate, or a mixture of chlorophenol and methanol. Dissolve in a mixture of ethanol and methanol, add a small amount of water and a catalytic amount of p-toluenes-nolefonic acid to the solution, and stir at room temperature for 5 to 20 hours.
  • the desired compound of formula (la), ID-2,3-di-0-acetalized-my-inositol, is relatively stable, but not excessively.
  • a mixture of acetylated myo-inositol derivatives has a trans configuration derived from camphor, which is relatively unstable to acids.
  • the acetal-type protecting group is eliminated, and a suspension-like reaction solution is obtained. Hexane is mixed with this reaction solution, the generated precipitate is collected by filtration, and the obtained solid is washed with water and dried to obtain a compound of the formula (la) and its isomers.
  • a mixture of the compounds of the formulas (IXa), (IXb) and (IXc) is obtained. By crystallizing this mixture from hydrated methanol, the compound of the formula (la) can be obtained as crystals of high optical purity.
  • the step of preparing the (1R)-(+)-force and the (1R) (+)-force dimethinoreacetanol is omitted.
  • -It is possible to introduce a difunctional hydroxyl-protecting group in the form of a methyl-substituted methylene group into a myo-inositol, even with the use of a nucleic acid. And it became.
  • the suspension reaction solution thus obtained contains the desired compound (1) of the above formula (la).
  • 1.5 L of hexane was added to the reaction solution, and the resulting precipitate was collected by filtration to obtain a solid (24.1 g). This was further washed well with water (80 mL ⁇ 4) and dried to obtain 16.7 g of the above crude product of the title compound (1).
  • reaction solution A small amount of water was added to the obtained reaction solution to decompose excess reagent. Thereafter, the reaction solution was diluted with a black hole home. The organic layer was separated, washed successively with a 5% aqueous solution of sodium hydrogen sulfate, a 5% aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The dried solution was concentrated to obtain 705 mg of crude compound (2) as a colorless solid (crude yield: 99%, purity of compound (2): 60%).
  • the solid was found to be compound (2) and 1, 4 —Di—0— A mixture of trifonole and methanocene form and anhydro form.
  • the ratio of each component compound was about 60:16:24. .
  • the daggered compound (2) is an unstable substance that partially decomposes in the gel gel chromatographic graph and decomposes in a few days even when stored in a freezer. I did.
  • TMS trimethyl norecilane
  • the obtained chloroform layer was washed successively with a 5% aqueous solution of sodium hydrogen sulfate, a 5% aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. .
  • the dried solution was concentrated to give 1.79 g of the title compound (3) of the formula (IVc) in the form of colorless crystals (crude yield 98%).
  • the solid compound (5) obtained in the previous step (4a) was suspended in 1.5 mL of a 50% acetic acid aqueous solution. The resulting suspension was heated and stirred at 80 ° C for 30 minutes to deacetate compound (5). The reaction solution was concentrated, and further azeotroped with toluene. The obtained residue was extracted with water, and the extract was washed with ethyl ether, concentrated, and then concentrated as a colorless solid to give the title 1D-kilo-inositol. 10.2 mg was obtained (yield 95%). 1 obtained in this way D-kilo-inositol was identical in physical properties with the pure commercial product.
  • the obtained reaction solution was concentrated, and the obtained residue was extracted with a black hole home.
  • the organic layer composed of the clonorolem extract was washed with water and dried over anhydrous sodium sulfate.
  • the syrup obtained by the further concentration is purified by a gel gel chromatograph (development system), the formula (V 53 nig of the compound (4) of the title (Ic) was obtained (58% yield from the compound (1)).
  • the compound (4) obtained in the previous step (3) was converted to a sodium salt with sodium methoxide in the same manner as in the methods (4a) and (4b) of Example 1.
  • the target 1D-kilo-inositol was obtained.
  • B z represents a benzoquinone group. The same applies hereinafter.).
  • the compound (5) obtained in the previous step is then treated with a 50% aqueous acetic acid solution in the same manner as in Examples 1 and (4b) to deacetate the compound (5).
  • a 50% aqueous acetic acid solution in the same manner as in Examples 1 and (4b) to deacetate the compound (5).
  • the obtained reaction solution was post-treated in the same manner as the post-treatment in Example 1, (4b), the desired 1D-kilo-inositol was obtained as a colorless solid. I was taken.
  • the homogeneous reaction solution containing the produced 1D-kilo-inositol was concentrated, and further azeotroped with toluene.
  • the obtained residue is extracted with water, and the aqueous extract is washed with ethyl ether, concentrated and concentrated to give a colorless solid, 1D-kilo-inositol You got 15.2 rags. 95% yield.
  • the physical properties of the thus obtained 1D-kilo-inositol match those of a commercially available 1D-kilo-inositol.
  • the compound (10) of the formula (VI e) obtained in the preceding step (1) is treated for deprotection in the same manner as in the methods of Examples 4, (2) and (3). As a result, the desired 1D-kilo-inositol was obtained.
  • the reaction solution was concentrated, and the obtained residue was extracted with a black hole home.
  • the organic layer (cloth mouth extract) was washed successively with a 5% aqueous solution of sodium hydrogen carbonate and water, then dried over anhydrous sodium sulfate and concentrated.
  • a novel method for the synthesis of 1D-kilo-inositol according to the present invention is an inexpensive myo-inositol.
  • 1D-2,3-di-0-acetanol conversion-mio which can be easily prepared as a pure substance with high strength and high purity
  • Starting from phenol-inositol it is possible to produce 1D-chloro-inositol of high optical purity in high yield through virtually five reaction steps. enable .
  • Each reaction step of the present method can be carried out simply and can efficiently produce a desired product of each step.
  • the method for synthesizing 1D-kilo-inositol according to the present invention is an industrial method capable of producing ID-kilo-inositol with high optical purity with high efficiency. It is useful.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)

Abstract

L'invention concerne un procédé de synthèse de 1d-chiro-inositol mettant en oeuvre plusieurs séries de conversions (I)→(III)→(IV)→(VI)→(A), ainsi qu'un autre procédé destiné à cette synthèse et mettant en oeuvre à la fois un composé (VIIIa), obtenu par traitement d'un composé (IV) avec un fluorure de métal alcalin, et un composé dérivé du composé (VIIIa) par transfert acyle.
PCT/JP2000/006826 1999-09-30 2000-10-02 Nouveaux procedes de synthese de 1d-chiro-inositol et intermediaires WO2001023337A1 (fr)

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JP28006899 1999-09-30
JP11/280068 1999-09-30
JP2000/300346 2000-09-29
JP2000300346A JP2001163810A (ja) 1999-09-30 2000-09-29 １ｄ−キロ−イノシトールの新規合成方法および中間体

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7521481B2 (en) 2003-02-27 2009-04-21 Mclaurin Joanne Methods of preventing, treating and diagnosing disorders of protein aggregation

Citations (3)

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Publication number Priority date Publication date Assignee Title
JPS4939982B1 (fr) * 1970-02-24 1974-10-30
WO1994007897A1 (fr) * 1992-10-05 1994-04-14 Virginia Tech Intellectual Properties, Inc. Syntheses de d-chiro-3-inosose et (+)-d-chiro-inositol
US5463142A (en) * 1994-11-10 1995-10-31 Abbott Laboratories Method for the preparation of D-chiro-inositol

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Publication number Priority date Publication date Assignee Title
JPS4939982B1 (fr) * 1970-02-24 1974-10-30
WO1994007897A1 (fr) * 1992-10-05 1994-04-14 Virginia Tech Intellectual Properties, Inc. Syntheses de d-chiro-3-inosose et (+)-d-chiro-inositol
US5463142A (en) * 1994-11-10 1995-10-31 Abbott Laboratories Method for the preparation of D-chiro-inositol

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MARTIN MANDEL ET AL.: "General synthesis of inositols by hydrolysis of conduritol epoxides obtained biocatalytically from halogenobenzens", J. CHEM. SOC. PERKIN TRANS. 1, 1993, pages 741 - 742, XP002933381 *
SEIICHIRO OGAWA ET AL.: "Inositol derivatives. 11.", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 52, no. 4, 1979, pages 1095 - 1101, XP002933379 *
TETSUO SUAMI ET AL.: "Inositol derivatives. V.", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 45, no. 12, 1972, pages 3660 - 3667, XP002933378 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7521481B2 (en) 2003-02-27 2009-04-21 Mclaurin Joanne Methods of preventing, treating and diagnosing disorders of protein aggregation
US9833420B2 (en) 2003-02-27 2017-12-05 JoAnne McLaurin Methods of preventing, treating, and diagnosing disorders of protein aggregation

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