WO2005040099A1 - Procedes destines a produire un derive d'acide (2r,3r)-2-(amino protege)-3-hydroxypropionique 3-substitue et produit intermediaire associe - Google Patents

Procedes destines a produire un derive d'acide (2r,3r)-2-(amino protege)-3-hydroxypropionique 3-substitue et produit intermediaire associe Download PDF

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WO2005040099A1
WO2005040099A1 PCT/JP2004/016070 JP2004016070W WO2005040099A1 WO 2005040099 A1 WO2005040099 A1 WO 2005040099A1 JP 2004016070 W JP2004016070 W JP 2004016070W WO 2005040099 A1 WO2005040099 A1 WO 2005040099A1
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group
acid
substituted
salt
substituted mono
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PCT/JP2004/016070
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Japanese (ja)
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Hiroki Tanaka
Kazuyoshi Nishikawa
Ryota Hamasaki
Hirofumi Oda
Toshinori Okano
Takanori Nakajima
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Ono Pharmaceutical Co., Ltd.
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Priority to JP2005515044A priority Critical patent/JPWO2005040099A1/ja
Publication of WO2005040099A1 publication Critical patent/WO2005040099A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • 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
    • 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 is useful as a raw material for a pharmaceutical product.
  • the present invention relates to an intermediate compound.
  • (2R, 3R) _2-protected amino-3-hydroxypropionic acid derivatives are useful intermediates as pharmaceuticals.
  • (2R, 3R) -2- (N-t-butynoleoxycanolepodinole) amino-3-cyclohexyl-3-hydroxypropionic acid is disclosed in Japanese Unexamined Patent Publication No. 2003-55358 as a raw material for an anti-AIDS drug.
  • (2S, 3R) -2,3-epoxy-13-cyclohexylpropionic acid is opened with benzylamine and then hydrogenolyzed to give (2R, 3R) -2-amino-3 Cyclohexyl-3-hydroxypropionic acid is converted to t-butyloxycarbonyl (2R, 3R) -2- (N-t-butyloxycarbonyl) amino-3-cyclohexyl-3-hydroxypropionic acid Is described.
  • (2R, 3R) —2-amino-13-cyclohexyl-13-hydroxypropionic acid is disclosed in Japanese Patent Application Laid-Open No. 06-165693.
  • -D-erythrocin aldolase is allowed to act on D-Ellis Michiru-A method for producing hydroxyamino acids is known.
  • the present invention relates to 3-substituted- (2R, 3R) -12-protected amino-13-hydroxypropionic acid derivatives, especially (2R, 3R) -12- (N-t-p-tinoleoxycanololeponic acid).
  • 3-Substituted mono-trans-2-propenoic acid is treated with hydrogen peroxide in the presence of tungstic acid or a salt thereof to give 3-substituted mono (2S *, 3R *)-1,2,3-epoxy Propionic acid and then
  • a salt using an optically active amine selected from the group consisting of a salt and optical resolution characterized in that it is a 3-substituted mono (2S, 3R) -1,2,3-epoxypropionic acid conjugate.
  • a method for producing a salt with an optically active amine 3. 3-substituted (2S, 3R) -12,3-epoxypropionic acid and ammonia to open the epoxy group and then subject to a reaction to introduce a protecting group, Process for producing 3-substituted mono (2R, 3R) -2-protected amino-3-hydroxypropionic acid derivatives,
  • a salt with an optically active amine selected from the group consisting of:
  • the epoxy group is opened by reacting with an optically active amine selected from
  • R 1 represents a cyclic group which may have a substituent or an aliphatic hydrocarbon group which may have a substituent
  • R 2 is a protected amino group
  • R -1-phenylethylamino
  • R 1- (4-methylphenyl) ethylamino
  • S -N, N-dimethyl-1-phenylphenylamino
  • R 1--4-methylphenyl) ethylamino
  • S -N, N-dimethyl-1-phenylphenyla
  • the compound represented by the formula (1) is a compound of the formula: Production method
  • R 1 represents a cyclic group which may have a substituent or an aliphatic hydrocarbon group which may have a substituent
  • R 2 is a protected amino group
  • R -1-phenylethylamino, (R)-1-(4-methylphenyl) ethylamino, (S) -N, N-dimethyl-1- 1-phenylethylamino, (+) Cis-1-N-benzinole-1- (hydroxymethinole) -cyclohexynoleamino, (R) _i3-methylphenylethylamino, (R) —N-benzyl-11-phenylethylamino, (1 R , 2 S) — 1,2-diphenylethanol 2-amino group or (R) — 1- (1-naphthyl) ethylamino group.)
  • Tri-substituted mono-trans-2-propenoic acid is treated with hydrogen peroxide in the presence of tungstic acid or a salt thereof to give 3-substituted mono (2S *, 3R *)-1,2,3-epoxypropion. After acidification and, if necessary, esterification, it was optically resolved by chromatography to give a 3-substituted mono (2R, 3S) -1,2,3-epoxypropionic acid derivative, and then using ammonia, Production of 3-substituted mono (2S, 3S) —2-protected amino-1-hydroxypropionic acid derivatives, characterized by opening the epoxy group and then subjecting it to a reaction for introducing a protecting group.
  • Substituent at the 3-position is 1-methylethyl, 1-ethylpropyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclopentene-4-yl, tetrahydropyran-1
  • the present invention also relates to the production method according to any one of the above 1-3, 9-: L1, 15-17, which is
  • the substituent at the 3-position of the present invention may be any substituent, and is particularly limited. Not determined. For example, there may be mentioned a cyclic group which may have a substituent or a substituent which may have a substituent !, and an aliphatic hydrocarbon group.
  • examples of the “cyclic group” in the “optionally substituted cyclic group” include a carbocyclic ring and a heterocyclic ring.
  • Examples of the carbocycle include a C3-15 monocyclic, bicyclic or tricyclic carbocyclic ring, a spiro-bonded bicyclic carbocyclic ring or a bridged bicyclic carbocyclic ring.
  • a C3-I5 monocyclic, bicyclic or tricyclic carbocyclic ring includes a C3-I5 monocyclic, bicyclic or tricyclic carbocyclic unsaturated carbocyclic ring, part or all of which is Includes saturated carbocycles.
  • a 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ring containing 1 to 5 heteroatoms selected from oxygen, nitrogen and Z or sulfur atoms includes oxygen, nitrogen and 3- to 15-membered monocyclic, bicyclic or tricyclic unsaturated heterocyclic ring containing 1 to 5 heteroatoms selected from sulfur atoms and / or partially or wholly saturated heterocyclic ring Rings are included.
  • aliphatic hydrocarbon group in the “aliphatic hydrocarbon group optionally having substituent (s)
  • a “linear or branched aliphatic hydrocarbon group” may be mentioned.
  • Examples of the “linear or branched aliphatic hydrocarbon group” include a “linear or branched alkyl group, alkenyl group or alkynyl group”.
  • linear or branched alkyl group examples include methyl, ethyl, propyl, isopropynole, butyl, isoptinole, sec-butyl, tert-butynole, pentynole, isopentinole, neopentynole, 1-ethynolepropino And straight-chain or branched C 1-10 alkyl groups such as ⁇ , hexinole, heptyl, octyl, nonyl, and decyl.
  • linear or branched alkenyl group examples include, in order, etheninole, propeninole, puteninole, butadheninole, penteninole, pentagenole, hexeninole, hexeninole, hepteninole, heptageninole, otatenyl, And linear or branched C 2-10 alkenyl groups such as nonenyl, nonenyl, nonyl, decyl and decadenyl groups.
  • linear or branched alkynyl group examples include, for example, ethynyl, propynyl, butynyl, butadiynyl, pentul, pentadiynyl, hexyl, hexazinyl, heptininole, heptadininole, octininole, octininole And a linear or branched C 2-10 alkynyl group such as, nonyl, nonazinyl, desynyl, decadinyl group and the like.
  • An optionally substituted heterocyclic group (f) an optionally substituted hydroxyl group, (g) an optionally substituted thiol group, (h) an optionally substituted diamino group, (i) an optionally substituted May be a rubamoyl group, (j) place Optionally substituted sulfamoyl group, (k) carboxy group, (1) alkoxycarbyl group (for example, Cl-6 anoreoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and the like) ), (m) sulfo group (one S0 3 H), (n) sulfino group, (o) a phosphono group, (p) nits port group, (q) Okiso group, (r) Chiokiso group, (s) Shiano group, (t) Amiji amino group, (u) imino group, (V) - B (OH ) 2 group, (w) (For example,
  • C 1 to 6 alkyl sulfonyl groups such Echirusuruhoniru
  • aa ⁇ reel sulfonyl group (e.g., such as C 6 to 10 ⁇ reel sulfonyl groups such Fuenirusuru Honiru)
  • bb an acyl group (for example, a C1-6 alkanol group such as formyl, acetyl, propanol, pivaloyl, etc., for example, a C6-10 arylcarboyl group such as benzoyl), and the like; May have 1 to 5 substitutions at substitutable positions.
  • alkyl group in the “optionally substituted alkyl group” as a substituent examples include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutynole, sec-butyl, tert-butynole, pentyl, isopentyl, neopentyl And a straight-chain or branched C1-10 alkyl group such as hexyl, heptyl, octyl, noel, decyl and the like.
  • examples of the alkyl-substituting group include a hydroxyl group, an amino group, a carboxy group, a nitro group, a mono- or di-C 1-6 alkylamino group (for example, methinoleamino, ethynoleamino, propylamino, dimethylamino, getylamino, etc.), C l-6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, hexyloxy, etc.), Cl-6 alkylcarbonyloxy groups (e.g., acetoxy, ethylcarboxy) And the like, a phenyl group and a halogen atom (for example, fluorine, chlorine, bromine, iodine), etc., and one to four of these optional substituents may be substituted at substitutable positions.
  • a phenyl group and a halogen atom for example, fluorine, chlorine, bromine, i
  • alkenyl group in the “optionally substituted alkenyl group” as a substituent include, for example, ethenyl, propenyl, buteninole, ptageninole, pentenenole, pentageninole, hexenenole, hexenenole, Examples thereof include linear or branched C2-10 alkenyl groups such as hepteninole, heptageninole, octeninole, octageninole, nonenyl, nonagel, decenyl and decadienyl groups.
  • the substituent of the alkenyl group has the same meaning as the substituent in the aforementioned “optionally substituted alkyl group”.
  • the “alkynyl group” in the “optionally substituted alkynyl group” as a substituent include, for example, ethynyl, probel, butul, butadiinole, pentininole, pentadiinole, hexinole, hexazinyl, heptininyl, heptinin Examples thereof include a linear or branched C 2-10 alkyl group such as nyl, heptadinyl, otatur, octadinyl, noninyl, nonazinyl, decynyl, decadinyl and the like.
  • the substituent of the alkynyl group has the same meaning as the substituent in the aforementioned “optionally substituted alkyl group”.
  • the carbon ring in the “optionally substituted carbocyclic group” as the substituent is the same as the carbon ring in the “cyclic group” in the aforementioned “optionally substituted cyclic group”.
  • Examples of the carbocyclic substituent include, for example, a linear or branched C 1-10 alkyl group (having the same meaning as the alkyl group in the aforementioned “optionally substituted alkyl group”).
  • a linear or branched C 2-10 alkyl group (having the same meaning as the alkenyl group in the above-mentioned “optionally substituted alkenyl group”); A 2- to 10-alkynyl group (having the same meaning as the alkynyl group in the above-mentioned “optionally substituted alkynyl group”), a hydroxyl group, a C1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, iso- Propoxy, butoxy, isoptyloki , Tert-butoxy, pentynoleoxy, hexyloxy, etc.), thiol group, C1-6 alkylthio group (for example, methylthio, ethylthio, propylthio, isopropinorethio, butylthio, isobutinorethio, tert-butinorethio, pentylthio, Xylthio etc.), amino group
  • these optional substituents may be substituted 1-5 at substitutable position.
  • the heterocyclic ring in the “optionally substituted heterocyclic group” as the substituent is the same as the heterocyclic ring in the “cyclic group” in the aforementioned “optionally substituted cyclic group”. Indicates meaning.
  • the substituent of the complex ring has the same meaning as the substituent in the aforementioned “carbocyclic group optionally having substituent (s)”.
  • Examples of the “substituent” in the “optionally substituted hydroxyl group”, the “optionally substituted thiol group” and the “optionally substituted diamino group” include (i) An optionally substituted alkyl group (having the same meaning as described above), (ii) an optionally substituted alkenyl group (having the same meaning as described above), and (iii) even a substituted alkenyl group.
  • a good alkynyl group (having the same meaning as described above), (iv) a carbocyclic group optionally having a substituent (having the same meaning as described above), and (V) a group having a substituent.
  • an acyl group for example, C 1-6 alkanol such as formyl, acetyl, propanol, bivaloyl, butanol, pentanoyl, hexanoyl, etc.
  • an acyl group for example, C 1-6 alkanol such as formyl, acetyl, propanol, bivaloyl, butanol, pentanoyl, hexanoyl, etc.
  • an isomer thereof for example, a C 6-10 aromatic carbocyclic carbonyl such as benzoyl
  • yii an optionally substituted carbamoyl group (the same as those described below) Means the same.
  • alkylsulfonyl group for example, C1-6 alkylsulfonyl group such as methinolesulfonyl, ethylsulfonyl, etc.
  • arylsulfonyl group for example, C6 such as phenylsulfonyl, etc.
  • Examples of the “optionally substituted force rubamoyl group” as a substituent include an unsubstituted force rubamoyl group, N-mono-Cl to 6-anolekyl force lubamoinole (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N-propyl carbamoyl, N-isopropyl carbamoyl, N-butyl carbamoyl, N-isobutyl carbamoyl, N- (tert-butyl) rubamoyl, N-pentylcarbamoyl, N_hexylcarbamoyl, etc.), N-phenylcarbamoyl, etc.
  • N-mono-Cl to 6-anolekyl force lubamoinole for example, N-methylcarbamoyl, N-ethylcarbamoyl, N-propyl carbamoyl,
  • N, N—Diphenylcanorebamoyl etc.
  • N—G C 6-10 arylcarbamoyl, N—C 6-10 aryl, N—C 1-6 Alkyl Lubamoyl e.g., N-Feninole N-Methinolecanole Bamoinole, N-Feninole N-Echinodia Lubamoyl, N-Feniru N-Propyl N-propyl Lubamoyl, N-Phenylcarbamoyl, N —Phenyl-N-pentylcarbamoyl, N-phenyl-N-hexylcarbamoyl and the like).
  • N-Feninole N-Methinolecanole Bamoinole N-Feninole N-Echinodia Lubamoyl
  • N-Feniru N-Propyl N-propyl Lubamoyl N-Phenylcarbamoyl
  • Examples of the “optionally substituted sulfamoyl group” as a substituent include an unsubstituted sulfamoyl group, N-mono-C 1-6 alkylsulfamoyl (eg, N-methylsulfamoyl, N-ethinolesulfa Moyl, N-propynoles-no-famoinole, N-isopropylsulfamoyl, N-butylsulfamoynole, N-isobutylinoresulfamoyl, N- (tert-butyl) -snorefamoinole, N-pentinolesnole Famoyl, N-hexylsulfamoyl, etc.), N-Feninoresnoreff N—Mono C 6-: L 0 Arinoresulfamoyl, N, N—Di C 1-6
  • N-getylsulfamoyl N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, N, N-dipentylsulfamoyl, N, N-dihexinolesnorefamoyl, N-methyl- N-diethylsulfamoyl, N, N-diphenylsulfamoyl, etc.
  • N6-diaryl sulfamoyl, N-C6-10 aryl-N-C1-6 alkyl sulfa Moir for example, N-Feninole-N-Methinoles-no-Famoyl, N-Fenix-Lou N-Echinores-no-Refamoine, N-Feninole N-propinoles-no-Famenole, N-Feninole N-butinoresnorefamoinole, N-phenyl-N-pentylsnorefamoyl, N-phenyl-N-hexylsulfoylmoyl, and the like.
  • Moir for example, N-Feninole-N-Methinoles-no-Famoyl, N-Fenix-Lou N-Echinores-no-Refamoine, N-Feninole N-propinoles-no-
  • the substituent at the 3-position is preferably a 3- to 8-membered member containing 1 to 5 heteroatoms selected from C3 to C8 monocyclic carbocycles, oxygen atoms, nitrogen atoms and / or sulfur atoms.
  • a monocyclic heterocycle a linear or branched C 1-10 alkyl group, more preferably a 1-methyl ⁇ ethyl group, a 1-ethylpropyl group, a cyclopentyl group, a cyclohexyl A cyclohexyl group, a 1-cyclopentene-4-yl group and a tetrahydropyran-14-yl group, and most preferably a cyclohexynole group.
  • the protecting group for the amino group of the present invention is not particularly limited, and may be any protecting group.
  • an acetyl group a benzoyl group, a benzyloxycarbonyl group, a t-butoxycarbonyl group, an aryloxycarbonyl (A11oc) group, and a methyl-1- (4-biphenyl) ethoxy group Carboninole (B poc) group, trifluoroacetyl group, 9-fluorenyl methoxycarbol group, Benzyl, p-methoxybenzyl, benzyloxymethyl (BOM), and 2- (trimethinoresilyl) ethoxymethyl (SEM), more preferably benzyloxycarbonyl.
  • t-butoxycarbyl group most preferably, t-butoxycarbonyl group.
  • the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the alkylthio group, the alkylene group, the alkenylene group and the alkynylene group include straight-chain and branched-chain ones.
  • isomers in double bonds, rings, and condensed rings, isomers due to the presence of asymmetric carbon (R, S, a , j8 configuration, enantiomers, diastereomers), Optically active form with optical activity (D, L, d, 1 form), polar form by chromatographic separation (high polar form, low polar form), equilibrium compound, rotamer, any ratio of these And racemic mixtures are all included in the present invention.
  • the symbol indicates that the symbol is connected to the other side of the paper (that is, ⁇ -configuration), and ⁇ indicates the front of the paper (that is, J3-configuration). ), ⁇ Indicates ⁇ -configuration,] 3-configuration or a mixture thereof, and ⁇ indicates a mixture of ⁇ -configuration and / 3-configuration. .
  • the 3-substituted mono-trans-1-propenoic acid which is a starting material of the production method of the present invention is known per se or can be produced by a known method.
  • trans-1,3-cyclohexyl-2-propenoic acid is prepared by reacting 1,2,3,6-tetrahydrobenzaldehyde in the presence of a palladium-based catalyst.
  • hexahydrobenzaldehyde and react it with malonic acid according to the method described in J. Chem. Soc., 26 (1928).
  • Tri-substituted mono-trans-2-propenoic acid derivatives are treated with hydrogen peroxide in the presence of tungstic acid or a salt thereof to give 3-substituted- (2S *, 3R *)-1,2,3-epoxypropion It can be an acid.
  • the tungstate include alkali metal salts of tungsten acid such as sodium tungstate and tungstic lithium, tungstic acid, and the like, and sodium tungstate dihydrate is preferable.
  • the amount is preferably 0.05 to: L0 mol times, and most preferably 0.1 to 0.3 mol times, relative to the 3-substituted mono-trans-2-propenoic acid.
  • the desired product can be obtained by oxidizing the mixture with hydrogen peroxide.
  • Hydrogen peroxide may be added as generally available aqueous hydrogen peroxide.
  • the reaction is preferably performed in the presence of a solvent that is miscible with water, such as methanol, ethanol, or acetone, at an arbitrary ratio. Most preferred is methanol. In the case of methanol, the concentration of methanol in the solvent is 10 to 60 mass. /. A degree is preferred.
  • the reaction temperature is preferably in the range of 30 to 60 ° C, and most preferably around 40 ° C. ⁇ during the reaction may be 3.0 to 6.5, but a preferable result is obtained in the range of 4.0 to 6.0. Outside the above range of ⁇ ⁇ and temperature, the reaction rate decreases or reaction by-products increase.
  • the reaction time can be appropriately set and is usually 10 to 30 hours. For example, if the reaction time is around 40 ° C., the reaction is completed in about 15 hours.
  • the optical resolution of 3-substituted mono (2S *, 3R *)-1,2,3-epoxypropionic acid or a salt thereof includes, for example, a chromatographic method, a microorganism capable of asymmetric identification such as lipase, and the like.
  • a method using a hydrolase using an enzyme, a method for producing a salt with an optically active amine and performing fractional crystallization, a method for reacting with an appropriate optically active amine and then performing a fractional crystallization can be applied.
  • optical resolution by chromatography can be carried out using a usual packing material for optical resolution or a commercially available column, but for efficient production, it is preferable to carry out simulated moving bed chromatography.
  • This method is known from JP-A-6-170111, JP-A-6-239767, JP-A-7-89950 and the like.
  • fillers for optical resolution include optically active polymer compounds such as polysaccharide derivatives (senorelose, amylose, 1,4-chitosan, chitin, j3-1,4-mannan, ⁇ -1,4-xylan, inulin,- 1,3-glucan, ⁇ -1,3-glucan ester or olebamate), polyatalylate derivative, polyamide derivative supported on silica gel, or polymer itself granulated, and has optical resolution
  • a low molecular weight compound for example, a compound in which a silica gel or a cyclodextrin derivative is supported on silica gel can be used, and a commercially available product can be appropriately selected and used.
  • CHIRALCEL OD registered trademark
  • CHIRALCEL OJ registered trademark
  • CHIRALCEL OF registered trademark
  • CHIRALPAKAS registered trademark
  • CHIRALPAKAD registered trademark
  • the average particle size of the filler varies depending on the type of optical isomer to be separated, the volume flow rate of the solvent flowing through the simulated moving bed, and the like. Preferably it is 5 to 75 / zm. To minimize the pressure drop in the simulated moving bed, it is desirable to adjust the average particle size of the filler to 15 to 75 ⁇ m. Pseudo-movement when the average particle size of the filler is in the above range ⁇ Pressure loss on the floor can be reduced, for example, it can be suppressed to 1 O kgf Zcm 2 or less. On the other hand, the larger the average particle size of the filler, the lower the theoretical number of adsorption plates.
  • the average particle size of the filler is usually 1 to 50 m, only considering that a practical number of theoretical adsorption plates is achieved.
  • the desorbing liquid supplied to the desorbing liquid inlet include alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as hexane, and organic solvents such as acetate nitrile, for example, aqueous copper sulfate and perchlorine.
  • An aqueous solution containing a salt such as an aqueous acid salt solution can be used. Which elimination solution is preferable is appropriately determined depending on the type of the compound to be subjected to optical resolution.
  • the 3-substituted mono (2S *, 3R *)-2,3-epoxypropionic acid is known in consideration of the solubility in the solvent and the amount that can be loaded on the column. It is preferable to convert to 3-substituted mono (2S *, 3R *)-2,3_epoxypropionate by the above method.
  • the esterification is performed, for example, in JP-A-55-8577, JP-A-11-269166, 4th edition Experimental Chemistry Lecture 22 Organic Synthesis IV-Acid 'Amino Acid' Peptide I, p.44, published November 30, 1992 This is carried out by a usual method described in, for example, The Chemical Society of Japan, published by Maruzen Co., Ltd., etc. After optical resolution, it can be deesterified by a usual method described in, for example, JP-A-9-59229. The most favorable result is obtained with the methyl ester.
  • the optimal conditions for separation by simulated moving bed chromatography can be determined as appropriate according to known methods.
  • Sample concentration 110 to 250 gZl, step time: 0.75 to 15 minutes, number of columns: 3 to 20, columns Inside diameter::! It is preferable to carry out in the range of 100100 cm.
  • the flow rates of the feed, extrastrat, roughinite, eruient, and recycling are appropriately adjusted according to the above conditions and the pressure resistance of the apparatus.
  • FIG. 1 shows an example of a simulated moving bed chromatography apparatus used in the present invention.
  • a separation by chromatography not only a method using a normal solvent but also a supercritical fluid chromatography using a supercritical fluid as a medium, and a supercritical fluid-simulated moving bed chromatography can be used.
  • the 3-substituted mono (2S *, 3R *)-2,3-epoxypropionate ester is treated with a hydrolase to give the 3-substituted mono (2S, 3R) -2,3- It is also possible to obtain 3-substituted mono (2S, 3R) -1,2,3-epoxypropionic acid by hydrolyzing epoxypropionic acid ester.
  • the enzyme used in the present invention is obtained from 3-substituted- (2S *, 3R *) — 2,3-epoxypropionate to 3-substituted- (2S, 3R) -1,2,3-epoxypropionic acid
  • Commercially available hydrolases lipase, protease, etc. derived from microorganisms, plants or animals, enzymes derived from microorganisms of various preserved strains, and enzymes derived from microorganisms newly isolated from nature can be used.
  • (2R, 3S) A commercially available product used to hydrolyze 1,3-cyclohexyl 2,3-epoxypropionate and obtain the remaining (2S, 3R) _3-cyclohexyl 2,3-epoxypropionate
  • the hydrolase include pancreatic lipase (derived from pig glands) manufactured by Biocatalysts Ltd., lipase L (derived from genus Candida) manufactured by Amano Enzym, pu leather (derived from genus Bacillus), and protease N (Derived from the genus Bacillus) and Immobilized Lipase manufactured by Toyobo.
  • the hydrolysis of the 3-substituted mono (2S *, 3R *)-2,3-epoxypropionate in the present invention can be carried out as follows. That is, 3-substituted- (2S *, 3R *)-2,3-epoxypropionate, which is a substrate for the enzymatic reaction, is added to the reaction medium, dissolved or suspended, and the enzyme is added as a catalyst.
  • a reaction medium for example, ion-exchanged water or a buffer can be used.
  • the substrate concentration in the reaction solution is 0 ::! There is no particular limitation on the range of from about 70% by mass to about 70% by mass, but preferably 0.5 to 20% by mass in consideration of the solubility and conversion of the substrate.
  • a hydrophilic organic solvent such as acetonitrile or dimethyl sulfoxide is added to the system to improve the solubility of the substrate. You can also.
  • a hydrophobic organic solvent such as hexane or toluene into the system and react as two phases of an aqueous system and an organic solvent.
  • the reaction can be carried out at a temperature of 5 to 80 ° C, preferably 10 to 60 ° C, in consideration of the optimum temperature of the enzyme and the stability of the substrate.
  • the pH of the reaction solution can be in the range of 2.0 to 10.0, preferably 6.0 to 9.0 in consideration of the optimum pH of the enzyme and the stability of the substrate. If the pH fluctuates with the progress of the reaction, it is desirable to add an appropriate neutralizing agent and maintain the optimum pH.
  • Separation and purification of the product from the reaction-terminated liquid can be carried out by combining known methods such as separation using an ion exchange resin, crystallization, distillation, and solvent extraction.
  • a method by solvent extraction can be performed as follows.
  • a common organic solvent near neutral such as ethyl acetate, hexane, and toluene , Dimethyl ether, methylene chloride, chlorophonolem, etc.
  • a strong acid such as hydrochloric acid is added to adjust the pH to about 2.0, and extraction and separation can be performed by performing the same general extraction operation as described above.
  • extraction and separation can be performed by performing the same general extraction operation as described above.
  • the same general extraction procedure as above should be used for extraction and separation near neutrality. can do.
  • 3-substituted mono (2S *, 3R *)-2,3-epoxypropionic acid forms a salt with an optically active amine
  • 3-substituted mono (2S, 3R) -1,2,3- It is also possible to carry out fractional crystallization as a salt of epoxypropionic acid with an optically active amine.
  • optically active amines include (R) -1-phenylethylamine, (R) -1- (4-methylphenyl) ethylamine, and (+)-cis-N-benzyl—2- (hydroxymethyl) -cyclo.
  • the amount of optically active amine required for fractional crystallization is 0.5-1.5 with respect to (R) -1 -fuunerethylamine, 3-substituted mono (2S *, 3R *)-1,2,3-epoxypropionic acid. It is preferable to use the compound in a molar ratio.
  • Solvents for fractional crystallization include alcohols such as methanol, ethanol, propanol and isopropanol; ethers such as getyl ether, diisopropyl ether and t-butyl methyl ether; and esters such as methyl acetate and ethyl acetate.
  • alcohols such as methanol, ethanol, propanol and isopropanol
  • ethers such as getyl ether, diisopropyl ether and t-butyl methyl ether
  • esters such as methyl acetate and ethyl acetate.
  • (R) -1-1- (1-naphthyl) ethylamine ethyl acetate is preferable, and the crystallization yield is increased by adding a poor solvent such as t-butyl methyl ether. You can also.
  • the crystallization temperature is preferably in the range of 120 to 50 ° C, more preferably in the range of 0 to 10 ° C.
  • the crystallization time is 5 to 30 hours. For example, in the case of (R) -1-1 (1-naphthyl) ethylamine, 15 hours at 0 ° C.
  • Seed crystals can be used for crystallization, and the crystallization time can be shortened by adding seed crystals.
  • As the seed crystal it is preferable to use a salt of the same optically active amine as that used for fractional crystallization with a 3-substituted- (2S, 3R) -2,3-epoxypropionic acid derivative.
  • the diastereoselection of the isolated 3-substituted mono (2S, 3R) -2,3-epoxypropionic acid salt with the optically active amine is carried out again by fractional crystallization using the above solvent. Performance can be improved. For example, 6 0 0 /od.e of (2 S, 3 R) - improved to 99.2% de by performing 3-cyclohexane Kishiru 2, re-Pi fractional crystallization of 3-epoxy propionate..
  • the optically active amine used for the resolution was the filtrate obtained after the salt isolation.
  • the 3-substituted mono (2S, 3R) -1,2-epoxypropionic acid was converted to the optically active amine by the 3-substituted monoamine.
  • (2 S, 3R) — 2,3-Epoxypropionic acid derivative can be easily recovered after isolation.
  • t-butyloxycarbonitrile is prepared by mixing a base such as sodium hydroxide, potassium hydroxide, triethylamine, dimethylaminopyridine, etc. in a mixed solvent of water and an organic solvent miscible with water. This is done by the presence of lucarbonate. The reaction is usually completed in 20 to 40 ° (5 to 25 hours).
  • a base such as sodium hydroxide, potassium hydroxide, triethylamine, dimethylaminopyridine, etc.
  • 3-substituted mono (2S *, 3R *)-1,2,3-epoxypropionic acid reacts with an optically active amine to open the epoxy group, thereby obtaining a 3-substituted 1-2-protected amino.
  • the 3-substituted mono (2R, 3R) -2-protected amino-3-hydroxypropionic acid derivative can be fractionally crystallized.
  • optically active amines include (R) -1-phenylethylamine, (R) -1- (4-methylphenyl) ethylamine, and (S) —N, N-dimethyl-1-phenylethylamine.
  • a preferred example is (R) -1-phenyl Ethiluamine is preferably used.
  • Derivatization of the salt may be performed, for example, using an ether-based solvent such as tetrahydrofuran, dioxane, dimethoxyethane, or dimethyl ether; an alcohol-based solvent such as methanol, ethanol, or isopropyl alcohol; or a benzene-based solvent such as benzene or toluene.
  • the reaction is carried out using 1 to 3 equivalents of a base in an amide solvent such as dimethylformamide, water, acetic acid, ethyl acetate or the like, or a mixed solvent thereof.
  • the base used is, for example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, or a tertiary amine such as triethylamine or pyridine.
  • the optically active amine used for the ring opening reaction may be used as a base.
  • the amount of the optically active amine used is 1.5 to 8 equivalents, more preferably 2 to 6 equivalents.
  • the optically active amine used for the derivatization of the salt is not used as a base itself, it is added in an amount of 0.5 to 5 equivalents, more preferably 1 to 3 equivalents to the substrate.
  • the reaction is usually completed in 60 to 120 ° (more preferably 90 to L 0 ° C) in 8 to 24 hours.
  • the crystallization of the 3-substituted mono (2R, 3R) -12-protected amino-13-hydroxypropionic acid derivative is carried out by distilling off the solvent from the above reaction product and adding a basic aqueous solution. .
  • the pH of the basic aqueous solution can be appropriately adjusted with an aqueous hydrochloric acid solution or the like, but is preferably adjusted to 9 to 12, more preferably 10.5 to 11.5.
  • the 3-substituted mono (2R, 3R) -12-protected amino-3-hydroxypropionic acid derivative obtained above is obtained by using the protective 'Groups'in' Organic Synthesis, John 'Willie' and 'Sands' Published, p.
  • ether solvents such as tetrahydrofuran, dioxane, dimethyloxetane and getyl ether
  • alcohol solvents such as methanol, ethanol and isopropyl alcohol
  • benzene solvents such as benzene and toluene
  • dimethylformamide and the like Amide solvents, water, acetic acid, ethyl acetate, etc., or a mixed solvent thereof in the presence of a catalyst such as palladium-carbon, palladium-black, palladium, palladium hydroxide, platinum-carbon, platinum dioxide, nickel, ruthenium chloride, etc.
  • the reaction is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid or the like, in a hydrogen atmosphere at normal pressure or under pressure.
  • the reaction is usually completed at 20 to 60 ° C for 2 to 20 hours.
  • 3-Substituted (2R, 3R) -12-protected amino-13-hydroxypropionic acid can be separated and purified by chromatographic separation, filtration, concentration, crystallization, recrystallization, or a combination of these. And the like.
  • the structure of the purified product can be confirmed by known methods such as —NMR spectrum, 13 C—NMR spectrum, mass spectrum, and elemental analysis. Optical purity can be determined by HPLC analysis using an optical resolution column. Can be.
  • FIG. 1 is a schematic explanatory view showing a simulated moving bed type chromatographic separation method of the present invention using a simulated moving bed having eight unit columns.
  • 1 to 8 are unit columns
  • a to E are first to fifth rotary valves
  • 7 a to 7 h are solenoid valves
  • 13 is a desorbing liquid supply line
  • 14 is an eta structure extraction line
  • 15 is A liquid supply line containing an optical isomer mixture
  • 16 is a raffinate extraction line
  • 17 is a circulation channel
  • 18 is a circulation pump
  • 19 is a desorbed liquid supply line (at the time of recycling).
  • a 40% aqueous solution of sodium thiosulfate was added dropwise at 20 ° C or lower until hydrogen peroxide was completely decomposed. After the decomposition of hydrogen peroxide, methanol was distilled off under reduced pressure. After methanol was distilled off, concentrated hydrochloric acid was added to adjust the pH of the reaction solution to 2.0 to 3.0. After adding 676 g of t-butyl methyl ether, the mixture was stirred for 30 minutes or more, and then allowed to stand. After separating the lower layer water with a separating funnel, the upper layer was filtered. The filtrate was concentrated under reduced pressure to obtain 131 g (81%) of pale yellow oily (2S *, 3R *)-13-cyclohexyl-2,3-epoxypropionic acid.
  • the reaction was carried out at 50 ° C. necessary for dissolving (2 S *, 3 R *) — 3-cyclohexyl 2,3-epoxypropionic acid for 15 hours while maintaining the pH at 4.5 to 5.0. After completion of the reaction, 45 g of ethyl acetate was added, and the lower layer water was separated using a separating funnel. By concentrating the obtained upper layer, (2 S *, 3 R *) — 3-cyclohexyl 9.0 g of pale yellow oily residue containing 2.99 g (27%) of 3-epoxypropionic acid was obtained. The major by-product was cypress hexane carboxylic acid.
  • (2S *, 3R *) _ 3-Cyclohexyl 2,3-epoxypropionic acid sodium salt 150g was dissolved in methanol 1500mL, sulfuric acid 53.6g was added, and it stirred at 30-40 degreeC for 5 hours. After completion of the reaction, the reaction mixture was cooled to 3 ° C, and the pH was adjusted to 7.0 to 7.5 by adding a 5% aqueous sodium hydrogen carbonate solution. The methanol was distilled off by reducing the pressure of the mixture at an external temperature of 30 to 40 ° C. to 80 Torr. 50 OmL of water was added thereto, and the mixture was extracted twice with 1200 mL of t-butyl methyl ether. The organic layer thus obtained was concentrated to obtain 134 g of the desired methyl (2S *, 3R *) _ 3-cyclohexyl 2,3-epoxypropionate.
  • Table 1 shows the optical purity and productivity of the front component (Raffinate) and the rear component (Extract; target isomer) obtained as a result of operation of the small simulated moving bed type chromatograph preparative separation apparatus.
  • Example 4 Optical Resolution of Benzyl (2S *, 3R *)-1,3-Cyclohexyl-1,2,3-epoxypropionate (2S *, 3R *) — 3-cyclohexyl 2,3-epoxypropionate was synthesized in the same manner as in Example 3 using the same small simulated moving bed chromatographic apparatus as in Example 3. The optical resolution of the oil was performed.
  • Table 1 shows the optical purity and productivity of the front component (Raffinate) and the rear component (Extract; target isomer) obtained as a result of operation of the small simulated moving bed type chromatograph preparative separation apparatus.
  • the desired compound (2S, 3R)-3-hexylhexyl 2,3-epoxypropionate benzyl under the optimal operating conditions can be converted to a target optical purity of 98% ee or more. Obtained with optical purity.
  • the productivity at that time is 0.77 kg-enan./kg-csp/ day 7c
  • Example 5 Optical resolution of (2S *, 3R *)-13-cyclohexyl 2,3-epoxypropionate using hydrolase to give (2S, 3R) -3-cyclohexanol Production of 1,2,3-epoxypropionic acid or its esteranol
  • (2 S *, 3R *) 3-Cycoxyhexyl 2,3-epoxypropionate as a substrate by kinetic optical resolution in hydrolysis reaction
  • (2 S, 3 R) 3-Cyclohexyl
  • Example 7 Optical Resolution of 2-Amino-3-cyclohexyl 2-Hydroxypropionic Acid Derivative ((2S *, 3R *)-13-cyclohexyl-1-2,3-epoxypropion) By the ring-opening reaction of the acid) At room temperature, 5.00 g (purity: 90.6wt%) of (2S *, 3R *)-3-cyclohexyl-1,2,3-epoxypropionic acid and 14.6mL of 2N-NaOH aqueous solution were dropped into a 5 OmL three-necked flask at room temperature. did.
  • the three-necked flask was rinsed with 1 OmL of deionized water.
  • the pH of this stirred solution was adjusted to 3.0-4.0.
  • the mixture was further stirred at room temperature for 30 minutes.
  • the slurry solution was filtered and rinsed with 5 OmL of deionized water.
  • the residue was taken out and stirred in a 10 OmL beaker with 5 OmL of deionized water for 1 hour to completely remove the hydrochloride salt of (R) -11-phenylethylamine.
  • the stirred mixture was filtered and rinsed twice with deionized water Z acetone (25 mL / 25 mL).
  • the wet crystals were dried under vacuum at 50 to 60 ° C, and 2-((1R)-1-phenylinoletinamino) 1-3-cyclohexinole-3-hydroxypropionic acid 5.61 g (71%) as white crystals with a slight brown coloration.
  • Retention time required component (R, R, R), 13.5 min., Unnecessary component (S, S, R), 15.1 mm.
  • the diastereo ratio of the target product was determined by HP LC analysis under the following conditions.
  • Oxycanoleboninole) Amino_3-cyclohexynole-13-hydroxypropionic acid is useful as a raw material for pharmaceuticals (eg, anti-AIDS drug).

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Abstract

L'invention concerne des procédés destinés à produire efficacement un dérivé d'acide (2R,3R)-2-(amino protégé)-3-hydroxypropionique 3-substitué à partir d'un acide (2S*,3R*)-2,3-époxypropionique 3-substitué. Ces procédés sont représentés par les nombres (1) à (3). Le procédé (1) consiste à convertir l'acide (2S*,3R*)-2,3-époxypropionique 3-substitué en un sel à l'aide d'une amine optiquement active et à soumettre ce sel à une résolution optique, à une ouverture de cycle époxy avec de l'ammoniac, puis à une réaction destinée à introduire un groupe protecteur. Le procédé (2) consiste à faire réagir l'acide (2S*,3R*)-2,3-époxypropionique 3-substitué avec une amine optiquement active en vue d'ouvrir le cycle époxy et à soumettre cet acide à une résolution optique, à une réaction d'élimination de groupe protecteur, puis à une réaction destinée à introduire un groupe protecteur. Le procédé (3) consiste à estérifier l'acide (2S*,3R*)-2,3-époxypropionique 3-substitué et à soumettre l'ester à une résolution optique par chromatographie sur lit mobile simulé, à une ouverture de cycle époxy avec de l'ammoniac, puis à une réaction destinée à introduire un groupe protecteur.
PCT/JP2004/016070 2003-10-23 2004-10-22 Procedes destines a produire un derive d'acide (2r,3r)-2-(amino protege)-3-hydroxypropionique 3-substitue et produit intermediaire associe WO2005040099A1 (fr)

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JP2007191400A (ja) * 2006-01-17 2007-08-02 Sumitomo Chemical Co Ltd 光学活性（ｓ）−２−メチル−６−オキソヘプタン酸の製造方法
JP2008546761A (ja) * 2005-06-23 2008-12-25 ハンミ ファーム． シーオー．， エルティーディー． クロピドグレルの製造方法及びこの方法に用いられる中間体

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JP2007191400A (ja) * 2006-01-17 2007-08-02 Sumitomo Chemical Co Ltd 光学活性（ｓ）−２−メチル−６−オキソヘプタン酸の製造方法

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