WO2007040272A1 - Procédé pour la production d'un dérivé de d-(4-aminométhyl)phénylalanine - Google Patents

Procédé pour la production d'un dérivé de d-(4-aminométhyl)phénylalanine Download PDF

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WO2007040272A1
WO2007040272A1 PCT/JP2006/320070 JP2006320070W WO2007040272A1 WO 2007040272 A1 WO2007040272 A1 WO 2007040272A1 JP 2006320070 W JP2006320070 W JP 2006320070W WO 2007040272 A1 WO2007040272 A1 WO 2007040272A1
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chemical
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Takahiro Ohishi
Yoshinori Hirai
Satohiro Yanagisawa
Makoto Ueda
Nobuo Nagashima
Hirokazu Nanba
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Kaneka Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring

Definitions

  • the present invention is a method for producing a D- (4 aminomethyl) phenylalanine derivative useful as a pharmaceutical intermediate, and an intermediate of a D- (4 aminomethyl) ferrolanine derivative.
  • the present invention relates to a process for producing 4-aminomethyl) benzyl] hydantoin.
  • Patent Document 1 WO2002076964
  • An object of the present invention is to make it possible to easily and industrially advantageously produce a D- (4aminomethyl) ferrolanine derivative and a synthetic intermediate 5-[(4aminomethyl) benzyl] hydantoin derivative. Is to provide a practical way.
  • R 3 and R 4 are a hydrogen atom, an optionally substituted C1-C20 alkyl group, a substituted group, and a C6-C20 aryl group or It has a substituent! /, May! / Represents a C 7 to C 20 aralkyl group, which may be the same or different from each other, and may be joined together to form a ring
  • R 1 may have a substituent, C1-C20 alkyl group, and has a substituent. Moyo! /, Having a C6-C20 aryl group or substituent! /, May! /, A C7-C20 aralkyl group.
  • R 3 and R 4 are the same as above. It is related with the method characterized by performing hydrolysis of the ester site
  • the present invention provides a method for producing a compound represented by the above formula (3), comprising the general formula (1);
  • the present invention relates to a method comprising reacting a compound represented by the formula: wherein R 2 represents a leaving group, and R 3 and R 4 are the same as above.
  • the present invention provides a compound of the general formula (9);
  • the present invention relates to a method comprising reacting a compound represented by the formula (wherein R 3 and R 4 are the same as described above) and hydantoin.
  • the present invention relates to a method for producing the compound represented by the formula (4), wherein the olefin moiety of the compound represented by the formula (9) is reduced. .
  • the present invention provides a compound of the general formula (10);
  • R 3 and R 4 are the same as described above, R 6 represents a hydrogen atom, an alkali metal or an alkaline earth metal).
  • the present invention relates to a method characterized in that D is stereoselectively hydrolyzed with a hydantoinase.
  • the present invention provides a compound of the general formula (11);
  • R 7 represents a hydrogen atom or a protecting group for an amino group
  • R 7 is a method for producing a D— (4 aminomethyl) ferrolanine derivative represented by the formula (10).
  • the present invention relates to a method characterized by carrying out rubamoi, and protecting an amino group as necessary.
  • the present invention provides a compound represented by the formula (4), the general formula (12);
  • R 3 and R 4 are the same as above.
  • R 8 has a hydrogen atom, an alkali metal, an alkaline earth metal, or a substituent, but may have a C1-C20 alkyl group or a substituent. Or a C6 to C20 aryl group or a C7 to C20 aralkyl group optionally having a substituent), a compound represented by the formula (10) A compound represented by the formula (9), a general formula (13);
  • a D- (4-aminomethyl) phenylalanine derivative useful as a pharmaceutical intermediate can be produced conveniently and industrially advantageously.
  • “may have a substituent” means that it may be substituted by another atom or substituent.
  • the “substituent” of an alkyl group, aryl group, or aralkyl group is not particularly limited as long as it does not adversely affect the reaction. Specifically, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, a nitro group Amino group, cyano group, carboxyl group, halogen atom and the like.
  • a 5 — [(4 aminomethyl) benzyl] hydantoin derivative represented by [0038] is used as an important intermediate to produce a D— (4 aminomethyl) phenylalanine derivative. There are two methods.
  • R 1 may have a substituent, and may have a C1-C20 alkyl group or a substituent! / Alternatively, it may be a C6 to C20 aryl group or a substituent, which may represent a C7 to C20 aralkyl group.
  • the C1-C20 alkyl group which may have a substituent is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, and an n-butyl group. Examples thereof include a til group, isobutyl group, t-butyl group, cyclobutyl group, n pentyl group, cyclopentyl group, n-hexyl group, cyclohexyl group, n-octyl group, and n-decyl group.
  • the C6 to C20 aryl group is not particularly limited, and examples thereof include a phenyl group, a p-methylphenol group, and a p-methoxyphenol group. Group, p-type phenyl group, naphthyl group and the like.
  • the C7 to C20 aralkyl group is not particularly limited, and examples thereof include a benzyl group, a p-hydroxybenzyl group, a p-methoxybenzyl group, and a p-trobenzyl group.
  • a benzyl group a p-hydroxybenzyl group, a p-methoxybenzyl group, and a p-trobenzyl group.
  • R 1 is preferably a C1-C20 alkyl group, more preferably a C1-C4 alkyl group, more preferably a methyl group or an ethyl group, particularly preferably an ethyl group.
  • Compound (1) is a compound represented by the general formula (5) described in, for example, J. Am. Chem. So, 29, 2003 (1964); [0052] [Chemical 39]
  • R 1 is as described above.
  • Compound (5) may be used by purchasing a commercially available product.
  • compound (5) can be easily obtained by allowing potassium cyanate to act on an aminomalonic acid diester.
  • the cyclization reaction of compound (5) is performed in the presence of a suitable base.
  • a suitable base include organic lithium compounds such as methyllithium, n-butyllithium, t-butyllithium, and ferric lithium; n Grignards such as butylmagnesium chloride, t-butylmagnesium mouthmid, and methylmagnesium bromide.
  • Alkali metal amides such as lithium amide, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkaline earth such as magnesium diisopropylamide Metal amides; sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium methoxide, lithium ethoxide
  • Alkali metal alkoxides such as lithium tert-butoxide, potassium methoxide, potassium ethoxide and potassium tert-butoxide; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Hydrogenation such as calcium hydride Alkaline earth metals; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and cesium hydroxide; Alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and barium hydroxide; Lithium carbonate, Examples include alkali metal carbonates such as potassium carbonate and sodium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate; tertiary amines such as triethylamine and diisopropylethylamine. .
  • an alkali is used in order to allow the reaction to proceed smoothly and from an economical viewpoint.
  • metal alkoxide, alkali metal hydride, alkaline earth metal hydride is preferred, more preferred is alkali metal alkoxide, and particularly preferred is lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide. , Potassium metoxide, and potassium t-butoxide.
  • the amount of the base used is not particularly limited, but is preferably 1 to 5 times the molar amount relative to the compound (5), and more preferably 1 to 1.5 times the molar amount from the economical viewpoint. preferable.
  • reaction solvent examples include chloroalkanes such as dichloromethane, chloroform, and dichloroethane; benzene and substituted benzenes such as toluene; ethers such as jetyl ether, tetrahydrofuran, and 1,4 dioxane; methanol Alcohols such as ethanol, isopropanol, and t-butanol; and aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone, and hexamethylphosphoric triamide.
  • chloroalkanes such as dichloromethane, chloroform, and dichloroethane
  • benzene and substituted benzenes such as toluene
  • ethers such as jetyl ether, tetrahydrofuran, and 1,4 dioxane
  • methanol Alcohols such as ethanol, isopropanol, and t-butanol
  • the concentration of the compound (5) is not particularly limited as long as the reaction proceeds smoothly, but is usually about 50 wZv% or less, preferably 20 wZv% or less.
  • the reaction temperature is not particularly limited as long as the reaction proceeds smoothly, but it is preferably selected from a range of 78 ° C. or higher and lower than the boiling point of the solvent used. ° C.
  • the reaction time is not particularly limited, and it may be carried out until the disappearance of compound (5), which is a raw material, is observed, but the 30 minutes force is usually about 48 hours.
  • the compound (1) may be isolated and subjected to the next step or may be used as it is as a solution of the compound (1) without being isolated.
  • the key-on of the compound (1) is the compound (1) in which the carbon to which —COOR 1 is bonded is a key-on.
  • the compound represented by the above formula (2) (hereinafter referred to as the compound (2)) is, for example, the general formula (6);
  • R 2 and R 5 represent a leaving group and may be the same or different from each other.
  • the leaving group is not particularly limited as long as it can react with the compound represented by the above formula (7) (hereinafter referred to as compound (7)).
  • Halogen atoms such as iodine atoms; acyloxy groups such as acetoxy groups and benzoyloxy groups; substituted sulfo-loxy groups such as methanesulfonyloxy groups and trifluoromethanesulfo-oxyl groups; substituted phosphoryls such as diphenylphosphoryloxy groups
  • An oxy group can be mentioned.
  • a substituted sulfonyloxy group or a halogen atom is more preferably a halogen atom, and further preferably a bromine atom or a chlorine atom.
  • the compound (6) a commercially available product can be preferably used, but it may be newly prepared and used.
  • R 3 and R 4 may have a hydrogen atom or a substituent! /, Or may have a C1-C20 alkyl group or a substituent.
  • R 3 and R 4 joined together to form a ring include, for example, a nitrogen-containing monocycle And those that form a bicyclic heterocyclic group such as azetidinyl group, pyrrolidinyl group, piperidyl group, morpholin-4-yl group, thiomorpholine-4-yl group, piperidyl-1-yl group, piperazine- 1-yl group, 1, 2, 3, 6-tetrahydropyrido- 1-yl group, 2, 3, 4, 5-tetrahydropyridyl-um group, decahydroquinolyl group, decahydroisoquinolyl Group, tetrahydroisoquinolyl group, octahydro-1H—isoindolyl group, cycloalkyl-spiropiperidyl group, 3 azabicyclo [3. 1. 0] hexyl group, 7 azabicyclo [2.2.1] butane 7— And the like.
  • These groups may be unsubstituted or substituted by halogen atoms, C1-C4 alkyl groups, hydroxy groups, C1-C4 alkoxy groups, trifluoromethyl groups, difluoromethyl groups, difluorophenol groups, etc. May be substituted.
  • Preferred are 2,6 cis-dimethyl-1-piperidyl group and 7-azabicyclo [2.2.1] hept-7-yl group, and more preferred are 2,6 cis-dimethyl-1piperidyl group.
  • a commercially available product can be preferably used, but it may be newly prepared and used.
  • R 2 , R 3 and R 4 in the compound (2) are as described in the compounds (6) and (7).
  • R 2 is a halogen atom
  • R 3 and R 4 are combined to form a piperidyl group that is unsubstituted or has a substituent at positions 2 and 6; That is, the general formula (13);
  • the compound represented by formula (1) is a novel compound that has been confirmed by the present inventors to be useful in the production of the compound (4), and thus the D- (4 aminomethyl) ferrolanine derivative.
  • X represents a halogen atom, and specifically represents fluorine, chlorine, bromine or iodine.
  • X is a chlorine atom.
  • R 9 and R 1Q represent a hydrogen atom or a C1-C4 alkyl group, and may be the same or different from each other.
  • R 9 and R 1Q are both methyl groups.
  • the reaction for obtaining the compound (2) from the compound (6) and the compound (7) is carried out in the presence of a suitable base.
  • a suitable base examples include organic lithium compounds, Grignard compounds, alkali metal amides, alkaline earth metal amides, alkali metal alkoxides, alkali metal hydrides, alkaline earth metal hydrides, alkali metal hydroxides, alkalis.
  • An earth metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, or a tertiary amine can be used. Specific examples include those described above.
  • alkali metal carbonates or alkali metal hydrogen carbonates are more preferable from the viewpoint of allowing the reaction to proceed smoothly and from an economical viewpoint, and potassium carbonate, sodium carbonate, hydrogen carbonate is more preferable. Potassium and sodium bicarbonate.
  • the amount of the base used is not particularly limited, but is preferably 1 to 5 times the molar amount relative to the compound (8), and more preferably 1 to 1.5 times the molar amount from the economical viewpoint.
  • reaction solvent examples include chloroalkanes, substituted benzenes, ethers, alcohols, aprotic polar solvents, and water. Specific examples include those mentioned above.
  • the above solvents may be used alone or in combination of two or more, and the mixing ratio is not particularly limited. From the viewpoint of the solubility of the base used, a mixed solvent system with water is preferred over an organic solvent alone, and a mixed solvent of toluene and water is particularly preferred.
  • phase transfer catalyst is used in order to facilitate the reaction.
  • the phase transfer catalyst is not particularly limited as long as the reaction proceeds smoothly.
  • quaternary ammonium salts such as tetra-n-butylammonium halide and tetrabenzil ammonia-halide; tetrafluorophospho- Umharide Any quaternary phospho-um salt; crown ethers such as 18-crown 6 and the like, preferably a quaternary ammonium salt.
  • the amount of the phase transfer catalyst to be used is not particularly limited, but is preferably 0.01 to 1 times the molar amount relative to the compound (7), and more preferably from the economic viewpoint. 0. About twice the molar amount.
  • the reaction may not proceed smoothly due to its low leaving ability.
  • iodine ions are generated in the reaction system.
  • the reaction can proceed smoothly by adding the compound to be used and making the leaving group an iodine atom in the system.
  • the iodine ion source is not particularly limited, but alkali metal iodides such as potassium iodide, sodium iodide and lithium iodide; alkaline earth metal iodides such as magnesium iodide and calcium iodide; Ammonium salts such as tetra-n-butylammonium iodide are preferable, and potassium iodide and sodium iodide are preferable.
  • the amount of the compound that generates iodine ions in the system is not particularly limited, but is preferably 0.01 to 1 times the molar amount relative to compound (7), more preferably 0.01 to 0. About twice the molar amount.
  • the concentration of the compound (7) is not particularly limited as long as the reaction proceeds smoothly, but is usually about 50 wZv% or less, preferably 20 wZv% or less.
  • the reaction temperature is not particularly limited as long as the reaction proceeds smoothly, but it is preferably selected from a range of 78 ° C or higher and lower than the boiling point of the solvent used. ° C.
  • the reaction time is not particularly limited, and it may be carried out until the disappearance of compound (7), which is a raw material, is observed, but the 30 minutes force is usually about 48 hours.
  • the molar ratio of the amounts used of compound (6) and compound (7) is not particularly limited as long as the reaction proceeds smoothly and compound (2) is obtained in good yield.
  • the amount of compound (6) used relative to compound (7) 1. It is preferable that the amount is 5 to 50 times the molar amount, and the economic viewpoint power is more preferably 1.5 to 20 times the molar amount.
  • the pH of the aqueous layer is made acidic and the compound (2) is dissolved in the aqueous layer. Then, excess compound (6) can be removed by washing with an organic solvent such as toluene.
  • the pH of the water layer is generated There is no particular limitation as long as it is a pH at which compound (2) is soluble in the aqueous layer, but it is preferably 0 to 5, particularly preferably about 0 to 2.
  • the washing solvent is not particularly limited as long as it is a solvent in which compound (6) can be dissolved, but is preferably toluene.
  • the pH of the aqueous layer is made alkaline, and then the compound (2) can be extracted from the aqueous layer with an appropriate organic solvent.
  • the pH at this time is not particularly limited as long as it is a pH at which the compound (2) can be extracted, but is preferably 8 to 14, particularly preferably about 10 to 14.
  • the extraction solvent is not particularly limited as long as it is a solvent capable of extracting the compound (2), but is preferably ethyl acetate, methylene chloride, and toluene, and more preferably has an economical viewpoint.
  • the extracted compound (2) may be concentrated as it is and used in the next step without any particular purification, or may be purified by a method such as crystallization.
  • a 5-alkoxycarboru- 5-[(4 aminomethyl) benzyl] hydantoin derivative represented by the following formula can be obtained.
  • R 3 and R 4 are as described above.
  • Compound (3) may be optically active or racemic.
  • the compound (3) is a novel compound that has been confirmed by the present inventors to be useful in the production of the compound (4), and thus the D- (4 aminomethyl) phenolan derivative.
  • the reaction may be carried out using the isolated compound (1) or by cyclization reaction of compound (5).
  • the anion of the compound (1) to be produced can be used as it is without being isolated.
  • the compound (1) may be generated with a base such as hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, tertiary amine. it can.
  • a base such as hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, tertiary amine.
  • the reaction can be carried out by adding the compound (2) to the reaction solution following the cyclization reaction of the compound (5).
  • the cyclization reaction of compound (5) is as already described.
  • the reaction solvent the cyclization reaction solvent of compound (5) may be used as it is, or a solvent may be newly added to form a mixed solvent of two or more.
  • the mole ratio of the charged amount can be defined as the molar ratio of compound (2) and compound (5) to be subjected to the cyclization reaction.
  • compound (5) is 0.5 to LO molar amount relative to compound (2), particularly preferably about 1 to 1.5 molar amount.
  • the concentration of the compound (2) is not particularly limited as long as the reaction proceeds smoothly, but is usually about 50 wZv% or less, preferably 20 wZv% or less.
  • the reaction temperature is not particularly limited as long as the reaction proceeds smoothly, but it is preferably selected from a range of 78 ° C or higher and lower than the boiling point of the solvent used. ° C.
  • the reaction time is not particularly limited, and it may be carried out until the disappearance of compound (2), which is a raw material, is observed, but the 30 minutes force is usually about 48 hours.
  • the compound represented by [0100] is a novel compound that has been confirmed by the present inventors to be useful as a pharmaceutical intermediate in the production of D- (4 aminomethyl) phenylalanine derivatives.
  • R 4 is the same as hydrogen or R 1 described above, preferably a hydrogen atom or an ethyl group.
  • R 3 and R 4 are as described above.
  • Compound (4) is a novel compound that has been confirmed by the present inventors to be useful in the production of D- (4-aminomethyl) phenolanine derivatives.
  • the ester hydrolysis reaction of the compound (3) will be described.
  • the reaction can be carried out by adding a base and adjusting to an appropriate pH.
  • the compound (3) may be used as a solution of the solvent and water used in the synthesis, or in the case where the reaction does not proceed smoothly after the addition of the base due to the two-phase system, the compound (3 )), Concentrate the solution and remove the solvent to make an aqueous solution.
  • Examples of the base to be used include alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, and the like, specifically as described above. .
  • Alkali metal hydroxide is preferable. These may be used alone or in combination of two or more. These may be directly added or added as an aqueous solution.
  • the concentration of the aqueous solution is not particularly limited, but if the concentration is too low, a large amount of aqueous solution is required to adjust to the following pH, which is not realistic when considering scale-up.
  • the yield of the compound (4) by crystallization which will be described later, may decrease the crystallization yield, it is preferable to select 10 wt% or more within the saturation concentration range of the base used.
  • the pH of the reaction solution is not particularly limited as long as the reaction proceeds smoothly, but is preferably 8 to 14, particularly preferably 10 to 14.
  • the reaction temperature is not particularly limited as long as the reaction proceeds smoothly. However, it is preferable to select from the range of 78 ° C or higher and lower than the boiling point of the solvent used.
  • the reaction time is not particularly limited and may be carried out until the disappearance of the compound (3) is observed, but is usually about 5 minutes to 24 hours.
  • the compound (15) can be obtained by acidifying the pH of the reaction solution.
  • R 3 and R 4 are as described above.
  • Decarboxylation can be performed by adding an acid to the above reaction solution to adjust to an appropriate pH and then heating, but after making the pH acidic, the resulting carboxylic acid can be isolated and used for strength.
  • the pH of the reaction solution is not particularly limited as long as decarboxylation proceeds, but it is preferably 0 to 6, particularly preferably about 0 to 3.
  • the acid to be used is not particularly limited as long as pH can be adjusted to a suitable range.
  • formic acid, hydrochloric acid, sulfuric acid, acetic acid, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid examples include p-toluenesulfonic acid, and hydrochloric acid, sulfuric acid, and acetic acid are preferable. These acids may be added as they are without forming an aqueous solution, or may be added as an aqueous solution.
  • the concentration is too low, a large amount of aqueous solution is required, which is not practical when considering scale-up. Further, it is preferable to use the compound as it is because it may cause a decrease in the crystallization yield in the acquisition of the compound (4) by crystallization described later.
  • the reaction temperature is not particularly limited as long as the reaction proceeds smoothly, but preferably selected from the range of the boiling point of the solvent used from 0 ° C. : LOO ° C.
  • the reaction time is not particularly limited and may be carried out until the disappearance of the compound (15) is observed, but it is usually about 5 minutes to 24 hours.
  • the resulting compound (4) can be isolated and purified by crystallization.
  • a crystallization method in the case where the solvent is removed in advance after the synthesis of the compound (3) and ester hydrolysis and decarboxylation are carried out in an aqueous solvent will be described.
  • Compound (4) can be obtained as crystals by adjusting the pH of the reaction solution to a suitable range by adding an appropriate base after the decarboxylation reaction.
  • the preferred pH range here is not particularly limited as long as it is the pH at which the crystals of compound (4) are deposited, but is preferably 7 to: L 1 and particularly preferably. It is preferably 8-10.
  • Examples of the base to be used include alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, and the like, specifically as described above. .
  • Alkali metal hydroxides are preferable, and sodium hydroxide and potassium hydroxide are particularly preferable. These may be used alone or in combination of two or more. These may be added to the reaction solution as they are, or may be added as an aqueous solution. Considering the scale-up, there is a concern that when the base is added as it is, it takes time to dissolve the base, and the pH locally deviates significantly from the above-mentioned suitable range force, or local abnormal heat generation occurs. Therefore, it is preferable to add as an aqueous solution.
  • the concentration of these aqueous base solutions is not particularly limited, but if the concentration is too low, a large amount of aqueous solution is required to adjust to the above-mentioned pH. It ’s not realistic. Further, in obtaining the compound (4), the crystallization yield may be lowered. Therefore, it is preferable to select from the range of 10 wt% or more and the saturation concentration of the base used.
  • the base is added at the reaction temperature at which the decarboxylation is carried out.
  • the compound (4) crystals can be obtained by cooling.
  • the cooling temperature is not particularly limited as long as it is cooled to a temperature at which the crystals of compound (4) can be obtained with good yield, but preferably 5 to 40 ° C, more preferably 0 to 20 ° C.
  • the compound (4) crystals are precipitated by cooling, not only the compound (4) but also impurities are precipitated, and a sufficient purification effect may not be obtained.
  • precipitation of impurities can be suppressed by adding an organic solvent before cooling.
  • the organic solvent to be added is not particularly limited as long as it can be uniformly mixed with water. Examples of the organic solvent include the aforementioned alcohols, dimethylformamide, dimethyl sulfoxide, and the like, preferably methanol, ethanol, and isopropanol. is there.
  • the amount of the organic solvent that can be uniformly mixed with water is not particularly limited as long as it provides a sufficient purification effect and does not cause an extreme decrease in crystallization yield. Although not preferably, it is preferably 5 to: LOOvZv%, particularly preferably 10 to 7 with respect to the reaction solution. OvZv%.
  • compound (8) The compound represented by the above formula (8) (hereinafter referred to as compound (8)) is obtained by reductive amination with a compound (7) of terephthalaldehyde.
  • R 3 and R 4 are as described above.
  • the compound represented by the present invention is a novel compound that has been confirmed by the present inventors to be useful in the production of the compound (4), and in turn, the D- (4 aminomethyl) phenolanine derivative. .
  • R 9 and R 1Q are as described above.
  • reaction proceeds by simply mixing compound (7) and terephthalaldehyde in the presence of an appropriate reducing agent in an organic solvent.
  • the reaction solvent include chloroalkanes, substituted benzenes, ethers, alcohols, aprotic polar solvents, and the like. Specific examples are those mentioned above.
  • the above solvents may be used alone or in combination of two or more, and the mixing ratio is not particularly limited. In the above solvent, tetrahydrofuran, methanol, ethanol and dichloromethane are preferred.
  • the reducing agent to be used is not particularly limited as long as the compound (8) can be obtained in good yield selectively without reduction of the remaining formyl group.
  • sodium triacetoxyhydrogen hydride examples thereof include fluorine compounds such as sodium cyanoborohydride, picoline borane and pyridine borane, and metal catalysts such as palladium carbon, Raney nickel and platinum oxide.
  • the molar ratio of the amount of each reagent used is not particularly limited as long as the compound (8) can be obtained in a high yield, but an excessive amount of the compound (7) with respect to terephthalaldehyde is present. Existence If present, there is a concern that a large amount of the compound into which 2 mol of the compound (7) is introduced is produced as a by-product. Therefore, the amount of the compound (7) used is preferably 0.8 to 1.5 times the molar amount relative to terephthalaldehyde, particularly preferably 0.9 to 1.1 times the molar amount.
  • the amount of the reducing agent used is not particularly limited.
  • sodium triacetoxyborohydride when sodium triacetoxyborohydride is used as the reducing agent, it is 0.8 to 2.0 times that of terephthalaldehyde.
  • the molar amount is particularly preferably 0.9 to 1.5 times the molar amount.
  • Commercially available sodium triacetoxyborohydride can be used, or sodium borohydride and acetic acid can be prepared by the method described above.
  • the concentration of terephthalaldehyde is not particularly limited as long as the reaction proceeds smoothly, but is usually about 50 wZv% or less, and preferably 20 wZv% or less.
  • the reaction temperature is not particularly limited as long as the reaction proceeds smoothly, but is preferably selected from a range of 78 ° C or higher and lower than the boiling point of the solvent used. 0 to: LOO ° C.
  • the reaction time is not particularly limited, but is usually about 5 to 24 hours until the disappearance of terephthalaldehyde, a raw material, is observed.
  • the compound (8) After completion of the reaction, water is added to stop the reaction, and an appropriate acid is added to make the pH of the aqueous layer acidic, whereby the compound (8) can be dissolved in the aqueous layer.
  • the compound (8) can be extracted with an organic solvent by washing with an appropriate organic solvent to remove impurities insoluble in water and making the pH of the aqueous layer alkaline by adding an appropriate base. .
  • the extracted compound (8) may be used in the next step without being purified, or may be purified by a method such as column chromatography.
  • the acid to be added after the termination of the reaction is not particularly limited, and examples thereof include acetic acid, formic acid, hydrochloric acid, sulfuric acid and the like, preferably hydrochloric acid and sulfuric acid.
  • the pH range is not particularly limited as long as compound (8) can be dissolved in the aqueous layer, but is preferably 0 to 5, particularly preferably 0 to 3.
  • Examples of the organic solvent used for washing include ethyl acetate, toluene, benzene, dichloromethane, jetyl ether, hexane, and the like. Ethyl acetate or toluene is preferable.
  • Examples of the base for making the pH of the layer alkaline include sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate and the like, preferably water Acid sodium or potassium hydroxide.
  • the pH range after the addition of the base is not particularly limited as long as the compound (8) can be extracted into the extraction solvent, but is preferably 7 to 14, particularly preferably 9 to The range is 14.
  • the compound (9) is a novel compound which has been confirmed by the present inventors to be useful in the production of the compound (4), and thus the D- (4 aminomethyl) furanalanine derivative. It is.
  • the reaction proceeds by mixing compound (8) and hydantoin in the presence of a base in an appropriate reaction solvent.
  • the solvent to be used is not particularly limited, and examples thereof include chloroalkanes, substituted benzenes, ethers, alcohols, aprotic polar solvents, and water. Specific examples include those described above.
  • the above solvents may be used alone or in combination of two or more, and the mixing ratio is not particularly limited. Of the above solvents, water and alcohols are preferred as the solvent for allowing the reaction to proceed more smoothly, and water, methanol, and ethanol are particularly preferred.
  • Examples of the base to be used include, for example, the aforementioned alkali metal hydroxides; alkaline earth metal waters Examples include acid salts; alkali metal carbonates; alkali metal hydrogen carbonates; tertiary amines; and amino alcohols such as ethanolamine and isopropanolamine. Of the above-mentioned bases, soprono V-luamine is particularly preferred in order to facilitate the reaction.
  • the amount of the base to be used is not particularly limited, but is preferably 0.01 to 10-fold molar amount, particularly preferably 0.1 to 5-fold molar amount relative to compound (8).
  • the amount of hydantoin used with respect to compound (8) is not particularly limited as long as compound (9) can be obtained in good yield, but is preferably 0.8 relative to compound (8).
  • the molar amount is about 5 times, particularly preferably about 1 to 3 times the molar amount.
  • the concentration of compound (8) is not particularly limited as long as the reaction proceeds smoothly, but is usually about 50 wZv% or less, preferably 20 wZv% or less.
  • the reaction temperature is not particularly limited as long as the reaction proceeds smoothly, but is preferably selected from the range of 0 ° C or higher and lower than the boiling point of the solvent used. 60-120 ° C.
  • the reaction time is not particularly limited, and may be carried out until the disappearance of the starting compound (8) is observed, but is usually about 5 minutes to 24 hours.
  • Examples of the reducing agent used include metal catalysts such as palladium carbon, Raney nickel, and platinum oxide.
  • metal catalysts such as palladium carbon, Raney nickel, and platinum oxide.
  • both hydrogenation using hydrogen gas or hydrogen transfer type in which a hydrogen source such as formic acid is added to the reaction system can be carried out.
  • a hydrogen source such as formic acid
  • side reactions such as reductive elimination of the amine moiety are likely to occur.
  • acid platinum, ethylenediamine, triethyl Palladium carbon poisoned with amines such as amine is preferred, and platinum oxide is particularly preferred.
  • the amount of the catalyst used is preferably 0.1 to 50 wtZwt%, particularly preferably 0.5 to 20 wtZwt% with respect to compound (9).
  • the reaction is carried out in an appropriate solvent.
  • the solvent used include the aforementioned chloroalkanes, substituted benzenes, ethers, alcohols, aprotic polar solvents, water and the like.
  • the above solvents may be used alone or in combination of two or more, and the mixing ratio is not particularly limited.
  • water, alcohols and ethers are preferred as the solvent for allowing the reaction to proceed more smoothly, and water, methanol, ethanol and tetrahydrofuran are particularly preferred.
  • the catalytic metal is activated by the addition of an acid, and may give good results.
  • the acid to be added include hydrochloric acid, sulfuric acid, acetic acid, formic acid, nitric acid and the like, and hydrochloric acid and sulfuric acid are preferable.
  • the acid concentration is preferably 0.1 to 6 mol%, more preferably about 0.5 to 3 mol%.
  • the reaction temperature is not particularly limited as long as the reaction proceeds smoothly, but is preferably selected from the range of 78 ° C or higher and lower than the boiling point of the solvent used. 0 to 100 ° C.
  • the reaction time is not particularly limited and may be carried out until the disappearance of the starting compound (9) is observed, but it is usually about 5 minutes to 24 hours.
  • Compound (4) can be obtained as crystals by adding an appropriate base and adjusting the pH to a suitable range after completion of the reaction.
  • the crystallization method of compound (4) has already been explained.
  • R 6 is a hydrogen atom, an alkali metal, or an alkaline earth metal, preferably a hydrogen atom, sodium, potassium, or sodium. Is calcium. When hydrolysis is carried out under basic conditions, R 6 becomes an alkali metal or alkaline earth metal.
  • the compound (10) is a novel compound that has been confirmed by the present inventors to be useful in the production of a D- (4 aminomethyl) ferrolanine derivative.
  • Examples of the D-selective hydrolysis method include a hydrolysis method using hydantoinase.
  • the hydantoinase is an enzyme having an activity of hydrolyzing a 5-substituted hydantoin derivative to produce an N-strength rubamoyl amino acid derivative.
  • hydantoinase used in the present invention those derived from animals, plants and microorganisms can be used, but those derived from microorganisms are preferred for industrial use.
  • the microorganism can be used as long as it has the ability to produce the enzyme. For example, the following known microorganisms having the ability to produce the enzyme can be mentioned.
  • Hydantoinases that catalyze D-form selective hydrolysis include bacteria belonging to the genus Acetobacter, Achromobacter, Aerobacter, and Agrobatateru.
  • a hydantoinase derived from a microorganism belonging to the genus Agrobacterium, Bacillus, Pseudomonas or Rhizobium, more preferably Examples include hydantoinases derived from microorganisms belonging to the genus Agrobacterium, Bacillus or Pseudomonas.
  • a transformed microorganism In order to obtain hydantoinase efficiently, a transformed microorganism can be used.
  • a method for producing a transformed microorganism is, for example, as described in WO96Z20275. Strain ability to show lyase activity After cloning the hydantoinase gene, a recombinant plasmid with an appropriate vector is prepared and used to transform an appropriate host fungus.
  • the host and vector the host-vector system described in "Recombinant DNA Experiment Guide” (edited by Science and Technology Agency, Research and Development Bureau, Life Science Division: Revised March 22, 1996) can be used.
  • the hosts include the genus Escherichia, the genus Pseudomonas, the genus Flavobacterium, the genus Bacillus, the Serratia, the genus Corynebacterium, the Brevi The genus Brevibacterium, the genus Agrobacterium, the genus Acetobacter, the genus Gluconobacter, the genus Lactobacillus, the genus Streptococcus or the Streptococcus It is possible to use microorganisms belonging to the genus (Streptomyces).
  • a plasmid, phage or derivative thereof derived from a microorganism capable of autonomous replication in the above host can be used.
  • Escherichia coli as a host microorganism and a vector capable of autonomous replication in the microorganism as a vector.
  • vectors include pUC18, pUC19, pBR322, pACYC184, pSTV28, pSTV29, pSC101, pT7Blue, or pUCNT (described in WO94Z03613), or derivatives thereof.
  • These derivatives are modified promoters, terminators, enhancers, SD sequences, replication start sites (ori), and other genes involved in regulation, for the purpose of increasing enzyme production and stabilizing plasmids. Also refers to drug resistance, modified restriction enzyme sites in the cloning site, etc.
  • the hydantoinase produced by the above-mentioned microorganism can be used as the enzyme itself, and can also be used as a form of a microorganism having the enzyme activity or a processed product thereof.
  • the treated product of microorganisms means, for example, a crude extract, cultured cells, freeze-dried organisms, acetone-dried organisms, or disrupted products of these cells.
  • the hydantoinase or a processed product thereof may be used as the enzyme itself or as a fixed enzyme obtained by fixing with a known means in the form of cells. The fixation may be carried out by a cross-linking method, a covalent bonding method, a physical adsorption method, a comprehensive method, etc., which are well known to those skilled in the art.
  • a D- (4 aminomethyl) ferrolanine derivative can be obtained by using the compound (4) as a substrate and allowing the above-mentioned hydantoinase to act in an aqueous medium and stereoselectively hydrolyzing it. it can.
  • all of compound (4) can be converted to the corresponding compound (10) by the simultaneous stereoselective hydrolysis reaction with hydantoinase and chemical racemization of the substrate.
  • Compound (4) which is a substrate, promotes chemical racemization under high temperature and Z or high PH conditions.
  • the racemization of the substrate is hydantoin racema. It can also be performed using a lyase.
  • the reaction is performed in a dissolved or suspended state at a substrate concentration of preferably 0.1% or more and 90wZv% or less, more preferably 1% or more and 60wZv% or less.
  • the reaction temperature is preferably adjusted to an appropriate temperature of 10 ° C or more and 80 ° C or less, more preferably 30 ° C or more and 70 ° C or less, and the reaction pH is preferably pH 4 or more, 11 or less, More preferably, it may be allowed to stand for a while or stirred while maintaining the pH at 7 or more and 10 or less.
  • the aforementioned alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, and the like can be used.
  • the substrate may be added continuously! /.
  • the reaction is carried out in batch or continuous mode.
  • the reaction of the present invention may be performed using an immobilized enzyme, a membrane reactor, or the like.
  • aqueous medium examples include water, a buffer solution, an aqueous medium containing a water-soluble organic solvent such as ethanol, or an organic solvent that is difficult to dissolve in water, for example, ethyl acetate, butylacetate, toluene,
  • a suitable solvent such as a two-layer system with an aqueous medium containing an organic solvent such as black mouth form and n-xane can be used.
  • antioxidants, surfactants, coenzymes, metals, etc. can be added as necessary.
  • the metal ion is not particularly limited, and examples thereof include ions of manganese, cobalt, nickel, zinc, iron, magnesium, calcium, copper and the like, and preferably ions of manganese or cobalt. These metal ions may be used alone or in combination of two or more kinds of metal ions.
  • compound (10) is converted to compound (10) quantitatively by undergoing chemical racemization at the same time as D form is hydrolyzed by D form selective hydantoinase.
  • the resulting compound (10) can be isolated and purified by a conventional separation method, for example, a separation method such as extraction, concentration, crystallization, or force chromatography, or a combination thereof.
  • R 4 and R 6 are as described above.
  • R 7 represents a hydrogen atom or a protecting group for an amino group.
  • Examples of the protecting group for the amino group include a benzyl group, a trityl group, a formyl group, a acetyl group, a black acetyl group, a trichloroacetyl group, a trifluoroacetyl group, a benzoyl group, a phenylacetoxy group, a methoxycarbo- group.
  • benzyl group, trityl group, formyl group, acetyl group, chloroacetyl group, trichloroacetyl group, trifluoroacetyl group, benzoyl group are preferable in the above group.
  • the weak rubamoylation of compound (10) can be carried out by a known chemical method or an enzymatic method using decarbamoylase.
  • a decarbamoylase is an enzyme having an activity of hydrolyzing an N-strength rubamoyl amino acid derivative to produce an amino acid derivative.
  • the decarbamoylase used in the present invention can be derived from animals, plants, or microorganisms, but those derived from microorganisms are preferred for industrial use.
  • As a microorganism serving as an enzyme source any microorganism that has the ability to produce the enzyme can be used.
  • Achromobacter genus Aerobacter genus, Aeromonas (Aeromonas), Agrobacterium, Alcaligenes, Arthrobacter, Bacillus, B1 astobacter, Bradyrhizobium, Bradyrhizobium Brevibacterium, Comamonas, Flavobacterium, Moraxella, Paracoccus, Pseudomonas, Rhizobium, Rhizobium Examples include a decarbamoylase derived from a microorganism belonging to the genus (Serratia) or the genus Sporosarcina.
  • the genus Agrobacterium the blast pactor (Bla stobactei genus, comomamonas musci, ummonas musci Enzymes derived from microorganisms to which they belong are mentioned.
  • a transformed microorganism In order to efficiently obtain decarbamoylase, a transformed microorganism can be used.
  • a method for producing a transformed microorganism is the same as the above-mentioned hydantoinase, using a recombinant DNA technique known in the art, for example, as described in WO92Z10579. After that, a recombinant plasmid with an appropriate vector is prepared and used to transform an appropriate host fungus.
  • Transformed microorganisms obtained in this manner that produce D-selective decarbamoylase with high production include Agrobata terium sp. KNK712 (FERM BP— 1900 described in WO92Z10579. Decarbamoylase gene derived from Escherichia coli JM109 (pAD108) (FERM BP— 3184), Pseudomonas sp. KNK003A (FERM BP— 31 81) Escherichia coli JM109 (pPD304) (FERM BP—3183) and WO94Z03613-containing Agrobacterium sp.
  • Agrobata terium sp. KNK712 (FERM BP— 1900 described in WO92Z10579. Decarbamoylase gene derived from Escherichia coli JM109 (pAD108) (FERM BP— 3184), Pseudomonas sp. KNK003A (FERM BP—
  • Escherichia coli HB101 pNT4553
  • FERM BP-4368 Escherichia coli HB101 containing a decarbamoylase gene derived from K712 (FERM BP-1900). More preferred is Escherichia coli HB101 (pNT4553) (FERM BP-4368).
  • decarbamoylase by these transformed microorganisms or the production of decarbamoylase by a strain exhibiting the above-mentioned decarbamoylase activity, is carried out using a normal nutrient medium described in, for example, W094 Z03613. If necessary, treatment for inducing the enzyme can be performed.
  • the decarbamoylase produced by the above-mentioned microorganism can be used as the enzyme itself, and can also be used in the form of a microorganism having the enzyme activity or a processed product thereof.
  • the treated product of microorganisms means, for example, a crude extract, cultured cells, freeze-dried organisms, acetone-dried organisms, or disrupted products of these cells.
  • the hydantoinase or a processed product thereof may be used as the enzyme itself or as a fixed enzyme obtained by fixing with a known means as a cell.
  • immobilization use methods known to those skilled in the art, such as cross-linking, covalent bonding, physical adsorption, and entrapment.
  • the enzyme reaction of the present invention can be carried out by the following method.
  • the compound (10) is used as a substrate and the reaction is carried out in an aqueous medium in the presence of the aforementioned decarbamoylase.
  • the reaction is performed in a dissolved or suspended state at a substrate concentration of preferably 0.1% or more and 90wZv% or less, more preferably 1% or more and 60wZv% or less.
  • the reaction temperature is preferably adjusted to an appropriate temperature of 10 ° C or higher and 80 ° C or lower, more preferably 20 ° C or higher and 60 ° C or lower, and the reaction pH is preferably pH 4 or higher, 9 or lower, More preferably, it may be allowed to stand for a while or stirred while maintaining the pH at 5 or more and 8 or less.
  • the substrate may be added continuously.
  • the reaction can be carried out batchwise or continuously.
  • the reaction of the present invention may be performed using an immobilized enzyme, a membrane reactor, or the like.
  • aqueous medium examples include water, a buffer solution, an aqueous medium containing a water-soluble organic solvent such as ethanol, or an organic solvent that is difficult to dissolve in water, such as ethyl acetate, butylacetate, toluene, Two-phase with aqueous medium containing organic solvent such as black mouth form and n-xane Any suitable solvent such as a system can be used. Furthermore, antioxidants, surfactants, coenzymes, metals, etc. can be added as necessary.
  • compound (10) is hydrolyzed only by D-form by D-form selective decarbamoylase, and converted to a compound in which R 7 is a hydrogen atom in compound (11).
  • Isolation of the compound in which R 7 is a hydrogen atom in the obtained compound (11) can be performed by a conventional separation method, for example, a separation method such as extraction, concentration, crystallization, or column chromatography, or a combination thereof. It can be separated and purified by combining.
  • the enzymatic method and the chemical method are optimal for substrates that are not particularly limited as long as the weak rubamoyl reaction proceeds smoothly and gives the compound (11) with high yield. It is sufficient to select the method.
  • R 7 when R 7 is not a hydrogen atom but a protecting group for an amino group, it is necessary to protect the amino group.
  • the method for protecting the amino group is not particularly limited. For example, from the method described in “PROTECTIVE GROUPS in ORGANIC SYNTHESIS” (Theodora W. Greene and Peter GW Wuts, JOHN WILEY & SONS, INC.) may be carried out to select the best way to R 7. for example, in the case of R 7 is tert- butoxycarbonyl group under basic conditions, it may do it by reacting such dicarbonate di tert- butyl.
  • the isolation of the compound in which R 7 is an amino group-protecting group can be performed by a conventional separation method, for example, a separation method such as extraction, concentration, crystallization, or column chromatography, It can be separated and purified by combination.
  • Agrobacterium sp. KNK712 (FERM BP— 1900) was released on May 31, 1988, and Bacillus sp. KNK24 5 (FERM BP— 4863) was On November 2, 1994, Pseudomonas sp. KNK003A (FERM BP— 3181) was released on December 1, 1990, while Rhizobium sp.
  • This aqueous solution was stirred at 60 ° C for 2 hours to decarburize.
  • Cis-2,6 dimethylbiperidine (0.12 g, 1.04 mmol) and sodium triacetoxyborohydride (1.42 g, 6.37 mmol) were added, and the mixture was stirred at room temperature for 22 hours.
  • Water (30 mL) was added to the reaction solution, pH was adjusted to 1.2 using concentrated hydrochloric acid, and the mixture was washed twice with ethyl acetate (30 mL).
  • the organic layer was concentrated under reduced pressure to give a dark green oil (1.71 g).
  • Escherichia coli containing a decarbamoylase gene from Agrobataterium sp. KNK712 (FERM BP— 1900) with improved heat resistance by genetic modification
  • Example 8 D—4 — “(cis-1,2.6 dimethyl-1-piperidyl) methyl ⁇ -ferulanin
  • Escherichia coli HB 101 pAH1043 (FERM BP-4865) containing a hydantoinase gene derived from Agrobacterium sp. KNK712 (FERMBP— 1900) was used in the same manner as in Example 6. Culture was performed by the method.
  • Example 9 D—4 “(cis—2.6 dimethyl-1-piperidyl) methyl ⁇ phenylalanine A plasmid recovered from Escherichia coli HBl 01 pPHD301 (FERM BP-4866) containing a hydantoinase gene derived from Pseudomonas sp. KNK003A (FERM BP—318 1) A DNA primer (Primer—1: SEQ ID NO: 1 in the sequence listing) based on the base sequence of the hydantoinase gene derived from Pseudomonas sp.
  • a DNA primer (Primer-2: SEQ ID NO: 2 in the sequence listing) having a sequence that destroys the Ngl cleavage site located upstream of the Bglll cleavage site in the gene. PCR was performed using primers to obtain 0.4 kb fragment 1. Next, the same plasmid is made into a saddle type, the primer (Primer-3: SEQ ID NO: 3 in the sequence listing) reverse to the previous Bglll cleavage site, the sequence in which the Hindlll cleavage site is bound to the stop codon, and its sequence.
  • a DNA primer (Primer-4: SEQ ID NO: 4 in the sequence listing) with a sequence that destroys the Ndel cleavage site existing in the upstream was synthesized, and PCR was performed using these primers.
  • lkb fragment 2 Got.
  • a large amount of hydantoinase can be obtained by ligating the fragment 1 with Ndel and Bglll, fragment 2 with Bglll and Hindlll, the beta plasmid pUCNT (see WO94Z03613) with Ndel and Hindlll, and T4 DNA ligase.
  • a plasmid designed so that it could be expressed in The resulting plasmid was mixed with Escherichia coli HB101 competent cells and transformed to breed a transformed microorganism having hydantoinase activity.
  • Bacillus sp. KNK245 (FERM BP-4863) is cultured, collected, and then ultrasonically disrupted.
  • Immobilized hydantoinase was obtained by adding the anion-exchange resin, Duolite A-568, which is a carrier for immobilization, to adsorb the enzyme, and then cross-linking with dartalaldehyde.
  • Example 11 D—N—Boc—4 “(cis 1, 2.6 dimethyl 1 piperidyl) methyl ⁇ felurananine
  • DN-force rubermoyl 4 [(cis-2,6-dimethyl-1piperidyl) methyl] phenol (4.73 wt% aqueous solution, 82. 29 g, 11.7 mmol) to concentrated sulfuric acid (2.43 g, 23.5 mmol) was added and cooled in an ice bath. An aqueous sodium nitrite solution (11.7 wt%, 8.41 g, 14.4 mmol) was added dropwise over 1.5 hours under ice cooling, and the mixture was stirred at room temperature for 2.5 hours.
  • Aminomalonic acid jetyl hydrochloride 35. l lg, 0.17 mol is dissolved in water (44. Olg). Cooled to ° C. Potassium cyanate (33.2 wt% aqueous solution, 68.32 g, 0.25 mol) was added dropwise at 5-9 ° C. After stirring for 1 hour, the precipitate was filtered off, washed twice with cold water (40 mL), and dried at 35 ° C. for 18 hours to obtain a slightly brown solid (33. 79 g). The obtained light brown solid was subjected to HPLC analysis under the analysis conditions described in Example 2, and it was found that the title compound was obtained in a yield of 96.9 mol%.

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Abstract

L'invention concerne un procédé pour la production d'un dérivé de D-(4-aminométhyl)phénylalanine, lequel est utile comme intermédiaire pour la production d'un agent pharmaceutique. Le procédé comprend les étapes consistant à produire un dérivé de 5-[(4-aminométhyl)benzyl]hydantoïne et à hydrolyser le dérivé résultant avec de l'hydantoïnase d'une manière stéréosélective pour l'isomère D. Dans le procédé, on peut produire le dérivé de 5-[(4-aminométhyl)benzyl]hydantoïne par un procédé comprenant de faire réagir un dérivé de 5-alcoxycarbonylhydantoïne avec un dérivé d'halogénure de 4-aminométhylbenzyle pour produire un dérivé de 5-alcoxycarbonyl-5-[(4-aminométhyl)benzyl]hydantoïne, de soumettre le dérivé résultant à une hydrolyse de l'ester pour produire un acide carboxylique et de décarbonater ensuite l'acide carboxylique pour produire le dérivé souhaité. Autrement, on peut également produire le dérivé de 5-[(4-aminométhyl)benzyl]hydantoïne par un procédé comprenant de faire réagir de l'hydantoïne avec un dérivé de 4-aminométhylbenzaldéhyde pour produire un dérivé de 5-[(4-aminométhyl)benzylidène]hydantoïne et d'effectuer ensuite la réduction du dérivé résultant pour produire le dérivé souhaité. Le procédé peut produire le composé d'une manière simple et à l'échelle industrielle.
PCT/JP2006/320070 2005-10-06 2006-10-06 Procédé pour la production d'un dérivé de d-(4-aminométhyl)phénylalanine WO2007040272A1 (fr)

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JPS5511569A (en) * 1978-05-23 1980-01-26 Snam Progetti Manufacture of ddamino acid
JPS6183150A (ja) * 1984-08-17 1986-04-26 ストウフア−　ケミカル　カンパニ− 不飽和ヒダントインからのアミノ酸の製造法
JPS6284A (ja) * 1985-04-25 1987-01-06 ブリストル―マイアーズ　スクイブ　コムパニー イミダゾキノリン抗血栓性強心薬
WO1992010579A1 (fr) * 1990-12-07 1992-06-25 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha PROCEDE DE PRODUCTION DE D-α-AMINOACIDES
WO1994003613A1 (fr) * 1992-08-10 1994-02-17 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Adn codant pour la decarbamylase a thermostabilite accrue et utilisation de cet adn
WO1996020275A1 (fr) * 1994-12-28 1996-07-04 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha PROCEDE DE FABRICATION DE L'ACIDE D-N-CARBAMYLE-α-AMINE
WO2003033473A1 (fr) * 2001-10-10 2003-04-24 Kaneka Corporation Nouveau derive d'hydantoine a substitution en position 5 et son procede de production
WO2006101266A1 (fr) * 2005-03-23 2006-09-28 Ajinomoto Co., Inc. Procede de fabrication de phenylalanine hydroxymethyl-substituee et optiquement active

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5511569A (en) * 1978-05-23 1980-01-26 Snam Progetti Manufacture of ddamino acid
JPS6183150A (ja) * 1984-08-17 1986-04-26 ストウフア−　ケミカル　カンパニ− 不飽和ヒダントインからのアミノ酸の製造法
JPS6284A (ja) * 1985-04-25 1987-01-06 ブリストル―マイアーズ　スクイブ　コムパニー イミダゾキノリン抗血栓性強心薬
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