WO2007114125A1 - Procede de production d'adamantane hydroxylee en utilisant un microorganisme - Google Patents

Procede de production d'adamantane hydroxylee en utilisant un microorganisme Download PDF

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Publication number
WO2007114125A1
WO2007114125A1 PCT/JP2007/056542 JP2007056542W WO2007114125A1 WO 2007114125 A1 WO2007114125 A1 WO 2007114125A1 JP 2007056542 W JP2007056542 W JP 2007056542W WO 2007114125 A1 WO2007114125 A1 WO 2007114125A1
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Prior art keywords
adamantyl
monohydroxy
phthalimide
rhizoctonia
group
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PCT/JP2007/056542
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English (en)
Japanese (ja)
Inventor
Yuuichi Mitsuda
Kazuyuki Minagawa
Tomoyuki Ogawa
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Shionogi & Co., Ltd.
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Priority to JP2008508544A priority Critical patent/JPWO2007114125A1/ja
Publication of WO2007114125A1 publication Critical patent/WO2007114125A1/fr

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    • 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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi

Definitions

  • the present invention relates to a method for producing an amino protected form of monohydroxy-12-adamantanamine (eg, N- (monohydroxy-2-adamantyl) phthalimide derivative) using a microorganism.
  • monohydroxy-2-adamantanamine amine protector is a raw material of monohydroxy-2-adamantanamine, and monohydroxy-2-adamantanamine is useful as an intermediate for pharmaceuticals.
  • a method for producing an adamantane derivative hydroxide using a microorganism has been known for some time. For example, by using biotransformation of Beauveria sulfurescens, it is possible to produce adamantamine hydroxyammonium salt protected with benzylamide (Non-patent Document 1). In addition, it has been reported that an adamantane derivative protected with phthalimide can also produce a dihydroxy form by in vivo conversion of Sporotrichum sulfurescens (Non-patent Document 2).
  • Patent Document 1 JP 2006-63061
  • Patent Document 2 International Publication No. WO04Z056744 Pamphlet
  • Non-Patent Document 1 “Journal of Organic Chemistry”, 1992, 57 ⁇ , p.7209-7212
  • Non-Patent Document 2 "The Journal of Organic Chemistry” Organic Chemistry), 1968, 33 ⁇ , p.3201-3207
  • the problem to be solved by the present invention is that an amino protector of monohydroxy 2-adamantanamine, which is a raw material for monohydroxy-2-adamantanamine, which is useful as an intermediate for functional linseed drugs (for example, N — To provide a high-yield and stable production method using a microorganism of (monohydroxy-2-adamantyl) monophthalimide derivative).
  • the present inventors have intensively studied to achieve the above object.
  • the filamentous fungus isolated by the present inventors produces N- (monohydroxy-2-adamantyl) phthalimide derivative from N- (2-adamantyl) -phthalimide derivative. I found this for the first time.
  • N- (monohydroxy-2-adamantyl) phthalimide derivative was successfully produced in the medium, and the present invention was completed.
  • the present invention provides:
  • Filamentous fungi are genus Nakataea, Rhizoctonia, Caetumum (
  • the method according to (1) selected from the group of Chaetomium), The method according to (2) above, wherein the filamentous fungus is Nakataea sigmoidea Rhi zoctonia solani or 7 Chaotomium cochliodes.
  • N- (2-adamantyl) phthalimide derivative is a compound represented by the following formula:
  • N- (monohydroxy-2-adamantyl) phthalimide derivative is a compound represented by any one of the following formulae:
  • the method according to (1) comprising a step of culturing a filamentous fungus in a medium, and a step of separating the N- (monohydroxy-2-adamantyl) phthalimide derivative from the culture solution, (9)
  • A is a substituted or non-cyclic hydrocarbon group or a substituted or heterocyclic group
  • R 2 is a single bond or alkylene which may be substituted
  • X is a hydroxyl group, a halogen or a hydroxyl group derivative. is a leaving group wither
  • R 4 is is hydrogen or substituted, I also characterized by reacting a compound represented by alkyl as), formula ( ⁇ ):
  • the method for producing N- (monohydroxy-2-adamantyl) phthalimide derivatives of the present invention realizes stable production (supply) of N (monohydroxy-2-adamantyl) phthalimide derivatives. Hydroxy-2-adamantyl) It is possible to produce phthalimide derivatives efficiently and safely at low cost.
  • the microorganism of the present invention can be suitably used in the above-described method for producing N- (monohydroxy-2-adamantyl) -phthalimide derivatives.
  • the method for producing an N- (monohydroxy-2-adamantyl) -phthalimide derivative of the present invention comprises a yarn having the ability to produce N (monohydroxy-2-adamantyl) phthalimide derivative. Culturing the fungus in a medium, producing and accumulating N (monohydroxy-2-adamantyl) -phthalimide derivative in the medium, and collecting it.
  • the N- (2 adamantyl) phthalimide derivative is a compound that can be a starting material for the production method of the present invention.
  • other derivatives such as Partial force of benzene ring of phthaloyl group F, Cl, Br, I and other halogens, alkyls, hydroxys, alkoxys, nitros, aryls, arylalkyls, carboxys, esters, strong compounds such as rubermoyl
  • halogen such as F, Cl, Br, or I, halogen, alkyl, hydroxy, alkoxy, nitro, aryl, arylalkyl, carboxy, ester, rubamoyl, etc.
  • halogen such as F, Cl, Br, or I
  • halogen alkyl, hydroxy, alkoxy, nitro, aryl, arylalkyl, carboxy, ester, rubamoyl, etc.
  • the N- (monohydroxy-2-adamantyl) phthalimide derivative is a compound produced by the method of the present invention using an N- (2-adamantyl) phthalimide derivative as a starting material.
  • a particularly preferred embodiment is N— (5 hydroxy-12 adamantyl) monophthalimide or N— (6 hydroxy-12 adamantyl) monophthalimide.
  • Alkyl means a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • alkyl having 1 to 6 or 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl , Neopentyl, n-hexyl, isohexyl.
  • the alkyl part of alkoxy has the same meaning as the above alkyl.
  • Aryl means a monocyclic aromatic hydrocarbon group (eg phenyl) and a polycyclic aromatic hydrocarbon group. (Examples: 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, etc.).
  • Arylalkyl means the above alkyl substituted with the above aryl. The alkoxy moiety of the alkoxy carb is similar to the above alkyl.
  • Cyclic hydrocarbon group includes “cycloalkyl”, “cycloalkenyl”, and “aryl”.
  • Cycloalkyl '' means a cyclic saturated hydrocarbon group having 3 to 15 carbon atoms, such as cyclopropenole, cyclobutinole, cyclopentinole, cyclohexinole, cycloheptinole, cyclooctyl, bridged cyclic carbonization. Examples thereof include a hydrogen group and a spiro hydrocarbon group.
  • “Bridged cyclic hydrocarbon group” includes a group formed by removing one hydrogen atom having 5 to 8 carbon atoms in which two or more rings share two or more atoms. To do. Specifically, bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl, tricyclo [2.2 .1.0] heptyl and the like.
  • the “spiro hydrocarbon group” includes a group formed by removing one hydrogen from a ring force in which two hydrocarbon rings are formed by sharing one carbon atom. Specific examples include spiro [3.4] octyl.
  • “Cycloalkenyl” means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutene, cyclopentale, and cyclohexene.
  • Cycloalkenyl also includes bridging 4-nacyclic hydrocarbon groups and spiro hydrocarbon groups having unsaturated bonds in the ring.
  • Heterocyclic group includes “heteroaryl, heterocycle”.
  • Heteroaryl means a monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group.
  • a monocyclic aromatic heterocyclic group may contain from 1 to 4 oxygen atoms, sulfur atoms, and Z or nitrogen atoms in the ring. Means a group which may have a bond at the position.
  • the fused aromatic heterocyclic group is oxygen 1 to 4 5- to 8-membered aromatic rings which may contain from 1 to 4 atoms, sulfur atoms, and / or nitrogen atoms in the ring, or other 5- to 8-membered aromatic carbocycles or other 5 It means a group which has a bond at any substitutable position when it is condensed with an ⁇ 8-membered aromatic heterocyclic ring.
  • furyl eg 2 furyl, 3 furyl
  • chael eg 2 chael, 3 chael
  • pyrrolyl eg 1 pyrrolyl, 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl eg: 1 imidazolyl, 2 imidazolyl, 4 imidazolyl
  • pyrazolyl eg 1 pyrazolyl, 3-virazolyl, 4 pyrazolyl
  • triazolyl eg 1, 2, 4 triazole— 1-yl, 1, 2, 4-triazole
  • tetrazolyl eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl
  • oxazolyl eg 2-oxazolyl, 4-oxazolyl, 5— Oxazolyl
  • isoxazolyl eg: 3-isoxazolyl, 4 isoxazolyl, 5 iso
  • pyridyl e.g. 2 pyridyl, 3 pyridyl, 4 pyridyl
  • pyridazil e.g. 3-pyridazil, 4-pyridazil
  • Pyrimidyl eg,
  • Heterocycle '' includes 1 to 4 oxygen atoms, sulfur atoms, and Z or nitrogen atoms in the ring! /, Or a bond at any substitutable position! / , Even! Means a non-aromatic bicyclic group.
  • such a non-aromatic heterocyclic group may be further bridged with an alkyl chain having 1 to 4 carbon atoms !, and may be a cycloalkane (preferably a 5-6 membered ring! /,) Or benzene.
  • the ring may be condensed. If it is non-aromatic, it may be saturated or unsaturated.
  • Alkylene includes a divalent group of 1 to 6 consecutive methylenes, and specific examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene.
  • Examples of the “leaving group derived from a hydroxyl group” include one OMs, one OTs, one OTf, and one ONs.
  • Ms represents a methanesulfol group
  • Ts represents a para-toluenesulfol group
  • Tf represents a trifluoromethanesulfol group
  • Ns represents an ortho-trobenzenesulfol group.
  • N (monohydroxy-2-adamantyl) Any microorganism may be used as long as it is capable of producing a phthalimide derivative or a salt thereof.
  • Such microorganisms have, for example, the ability to produce N- (monohydroxy-2-adamantyl) -phthalimide derivatives and belong to the genus Nakataea, Rhizoctonia, and Chaetomium. The microorganism to which it belongs is listed.
  • Microorganisms having the ability to produce N (monohydroxy-2 adamantyl) phthalimide derivatives are obtained by culturing microorganisms in a suitable medium, preferably a liquid medium, and accumulating N- (monohydroxy-2 —Adamantyl) Searching can be done with or without phthalimide derivatives.
  • the detection of N— (monohydroxy-2-adamantyl) monophthalimide derivative in the medium is performed, for example, by HPLC using the N- (monohydroxy-2-adamantyl) monophthalimide derivative obtained by the present invention as a standard product. It can be carried out.
  • a specific example of the microorganism used in the present invention is the newly isolated RF-9402 strain as a microorganism having the ability to produce N- (monohydroxy-2-adamantyl) phthalimide derivatives.
  • This strain is a filamentous fungus belonging to the genus Rhizoctonia, and is an example of an N- (monohydroxy-2-adamantyl) monophthalimide derivative-producing bacterium that is most preferably used in the method of the present invention.
  • the strain is cultured under suitable conditions, it produces an N— (monohydroxy-2-adamantyl) phthalimide derivative outside the cell.
  • the present inventors have found that the RF-5733 strain belonging to the genus Chaetomium and the Na kataea RF-9475 strain have similar characteristics.
  • the RF-9402 strain grows vigorously on a potato dextrose agar medium, but does not form a clear colony and is partially felt or powdery.
  • the aerial mycelium is light brown to brown, with a width of 7-20 / ⁇ ⁇ , branched almost at right angles and constricted at the branch. It forms a brown sclerotia but no conidia or spores are seen.
  • the RF-5733 strain forms a subspherical to egg-shaped persevere that opens to the top on potato dextrose agar.
  • Persecia has two types of crests, one of which originates from the base and is thin and loosely wavy, while the other is straight at the bottom and spirals 3-5 times above.
  • the cyst is rod-shaped and contains 8 lemon-shaped ascospores. Ascospore size is 7.5-10. 0 X 6.5-5. O / zm.
  • the strain RF-9475 grows vigorously on potato dextrose agar and is accompanied by abundant aerial hyphae to form loose felt colonies.
  • the aerial mycelium is colorless and has a diameter of 1.0 to 2.
  • O ⁇ m and the vegetative mycelium in agar is brown and has a diameter of 2.0 to 5.
  • O / z m Formation of conidia nuclei and sexual reproductive organs is not observed on potato dextrose agar, corn meal agar, malt extract agar, etc.
  • Rhizoctonia sola-RF-9402 force Etomum 'cocliodes RF-5733, and Nakata Air Sigmoidea RF-9475, for example, preserved on a slant of potato dextrose agar, or supplemented with 10% glycerin It can be stably stored by freezing at -80 ° C or lower using potato dextrose broth as a protective agent.
  • RF-9402 strain, RF-5733 strain, and RF-9475 strain which are examples of N (monohydroxy-2 adamantyl) phthalimide derivative-producing bacteria
  • the bacteriological properties have changed significantly and are not immediately constant.
  • Fungi can be mutated by artificial or artificial means such as UV irradiation, X-ray irradiation, or mutagenic agents (eg, N-methinole N'-tro-N-trosoguanidine), which are commonly used. This is a well-known fact.
  • Such natural mutants and artificial mutants All strains belonging to filamentous fungi including different strains and capable of producing N- (monohydroxy-12-adamantyl) monophthalimide derivatives can be used in the present invention.
  • Filamentous fungi belonging to the genus Rhizoctonia include Rhizoctonia solani, Rhizoctonia aderholdii, Rhiz octonia aerea, Rhizoctonia alpina and the like.
  • the filamentous fungi belonging to the genus Etomyum are: Chetomium cochliodes, Chietomium funicola, Chaetomium inicum, Chaetomium olivac (Chaetomium olivac) ) And the like.
  • filamentous fungi belonging to the genus Nakataae include Nakataea curvularioides, Nakataea cylindrospora, Nak ataea fusispora, and the like.
  • an N- (monohydroxy-2 adamantyl) phthalimide derivative-producing bacterium belonging to a filamentous fungus is used in a medium suitable for the microorganism to be used, for example, a normal microorganism.
  • a nutrient source any medium containing a carbon source, a nitrogen source, and an inorganic salt that can be assimilated by the microorganisms used can be used even in a natural medium or a synthetic medium.
  • glucose, fructose, galactose, glycerol, soluble starch, glutamic acid, molasses, animal vegetable oil and the like can be used.
  • nitrogen source malt extract, corn steep liquor, meat extract, peptone, yeast extract, ammonium sulfate, sodium nitrate, urea and the like can be used.
  • inorganic salts capable of producing sodium, potassium, calcium, vitamins, magnesium, chlorine, sulfuric acid and other ions can be added to the medium.
  • inorganic substances and / or organic substances that help the growth of N- (monohydroxy-2-adamantyl) monophthalimide derivative-producing bacteria and promote the production of N- (monohydroxy-2-adamantyl) phthalimide derivatives.
  • the substance can be added appropriately.
  • inclusion agents such as hydroxypropyl mono- ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, methyl-13-cyclodextrin and the like can be mentioned.
  • Rhizoctonia sola -RF— 9402 force Etomum 'cocliodes RF — 5733, Nakataae' sigmoidea RF — 9475
  • ⁇ (Monohydroxy-2-adamantyl) A method for culturing a phthalimide derivative-producing bacterium is most suitably a culture method under aerobic conditions, particularly a deep liquid culture method under aeration. The temperature suitable for cultivation is 10-30 ° C. In most cases, it is better to cultivate at 15-30 ° C. Production of N- (monohydroxy-2-adamantyl) phthalimide derivatives reaches the maximum in 3 to 10 days of culture for both shaking culture and tank culture, depending on the type of culture medium and culture conditions used. .
  • N- (monohydroxy-2-adamantyl) phthalimide derivatives should be separated according to standard methods. Specifically, for example, N- (monohydroxy-2-adamantyl) -phthalimide derivative can be isolated from the medium by solvent extraction, ion exchange chromatography, activated carbon treatment, crystallization, membrane separation, and the like. it can.
  • the culture conditions for efficiently producing N- (monohydroxy-2adamantyl) phthalimide derivatives are the composition of the medium components, the culture temperature, the stirring speed, the pH, the aeration rate, the culture time of the seed mother, The inoculation amount, etc. is adjusted or selected as appropriate according to the type of production strain used and external conditions. If there is foaming in liquid culture, add antifoaming agents such as silicone oil, vegetable oil, and surfactants alone or in a mixture and mix appropriately in the medium.
  • N- (2 adamantyl) phthalimide derivative lOgZL or more can be added in the dissolved state in the presence of an inclusion agent.
  • the method shown in the examples is improved to 2% at the start of culture and on the second day of culture. Conversion rate exceeding 80% can be obtained by adding 8% to it can.
  • the filamentous fungus can be used for biotransformation as a whole fungal mycelium or in the form of an extract containing hydroxylase.
  • the extract means a product obtained by crushing and treating fungal cells, and containing a soluble enzyme.
  • the enzymes of the extract, in particular the hydroxylase can be stabilized in some cases, for example by adding the natural cofactors, koffers, salts of the enzyme.
  • the hydroxylated enzyme of the extract can be used in a fixed form.
  • a method for producing a monosaccharide from an amino protector of 2 adamantanamin by using a bacterium belonging to the genus Nakataea, Rhizoctonia, or Chaetomium, or an extract thereof. Also included is a method for producing an amino-protected form of hydroxy 2-adamantanamine.
  • microorganisms described above can be used as microorganisms belonging to any one of the genus Nakataea, Rhizoctonia, or Chaeto mium.
  • any compound can be used as long as it is a compound in which the amino group of adamantanamin is protected.
  • the adamantane part other than the hydroxylated part is replaced with halogen such as F, Cl, Br, I, alkyl, hydroxy, alkoxy, nitro, aryl, aryl alkyl, carboxy, ester, force rumoyl, etc. It may be.
  • N— (2-adamantyl) monophthalimide derivatives N- (2-adamantyl) -phthalimide, N-benzoyl-2-adamantanamine derivatives, N-benzoyl-2-adamantanamines, N-acetyl-2-adamantanamine derivatives, N Acetyl 2-adadamantanamin.
  • the monoamino-2-adamantanamine amine protector means a compound in which the above-mentioned 2-adamantanamine amine protector is monohydroxylated.
  • the amino-protected form of monohydroxy-2-adadamantamine, N- (monohydroxy-2-adamantyl) phthalimide derivative, obtained by the present invention can be easily converted to monohydroxy-2-adamantanamine by removing the protecting group. Can do.
  • the fermented 24-well multiplate culture solution is stirred and extracted with 1 ml of acetone per well, then transferred to a 96-well deep plate, centrifuged at 2500 rpm for 15 minutes, and the supernatant is reversed. Subjected to phase HPLC analysis.
  • P5 and P6 were identified as peaks presumed to have been given one hydroxyl group by ESI-MS for the sample in which a new peak was detected.
  • the following three strains were selected as strains that efficiently convert the substrate to 80% or more of these compounds.
  • the spore-incomplete fungus RF-9475 produces approximately equal amounts of both P5 and P6 compounds, while Rhizoctonia 'sora-RF-9402 and Ketomyum cochliodes RF-5733 produce more than 80% of the substrate. Convert to P5 and P6 respectively.
  • [0028] [Seed culture] Glucose 2.0%, Soybean Minore 0.5%, East Etastrata KDifco) 0.5%, Sodium Chloride 0.5%, Potassium Phosphate 0.5% Tap water (adjusted to PH7, diluted hydrochloric acid) 100 ml of the medium was dispensed into a 500 ml wide-mouth flask and sterilized at 121 ° C for 20 minutes. Helminthosporium sigmoideum RF-9475 was scraped from the agar slant culture and cultured at 28 ° C for 2 days at an amplitude of 70 mm and 180 rpm. .
  • Tap water 100 ml of a medium having a composition was dispensed into 50 500 ml wide-neck flasks and sterilized at 121 ° C for 20 minutes.
  • 2-Adamantane phthalimide lOOmg per flask was made into a DMS02ml solution and added aseptically, then 4ml of seed culture was inoculated and cultured at 28 ° C for 4 days at an amplitude of 70mm and 180 rpm.
  • 57.2% of the substrate was converted to P5 and 43.7% of the substrate was converted to P6.
  • the fermentation finished solution for 50 flasks was extracted with 3 L of ethyl acetate and then re-extracted with 1 L of n-butanol. Both extracts were combined and concentrated to dryness under reduced pressure to obtain 11.39 g of a crude extract.
  • the obtained crude extract (11.39 g) was dissolved in ethyl acetate using a medium pressure ram (inner diameter: 3 cm, length: 50 cm) filled with 200 g of silica gel (MS gel D-150-60A, manufactured by Asahi Glass Co., Ltd.) The effective fraction was concentrated to dryness to obtain 5. Olg crude extract.
  • the effective fraction was concentrated under reduced pressure, and 1.36 g and 1.02 g were obtained as purified products of 2-adamantanephthalimide-P5 and P6 by lyophilization, respectively.
  • Tap water 100 ml of the medium having the composition shown below was dispensed into a 500 ml wide-mouth flask and sterilized at 121 ° C. for 20 minutes.
  • the medium was inoculated with Rhizoctonia solani RF-9402 strain from an agar slope culture, and cultured at 28 ° C for 3 days at an amplitude of 70 mm and 180 rpm for 3 days.
  • the fermentation finished liquid for 3 flasks was extracted with 150 ml of n-butanol.
  • the extract was concentrated to dryness under reduced pressure to obtain 0.253 g of a crude extract.
  • the effective fraction was concentrated under reduced pressure and freeze-dried to obtain 65.4 mg of 2-adamantanphthalimide-P5 purified product.
  • Tap Water (adjusted to PH7, diluted hydrochloric acid) 1 medium 500ml flask with glucose and glucose 1.0%, CS L 2.0 50 ml of medium with the composition of% tap water (adjusted to PH 7.0, dilute caustic soda) was dispensed into one 500 ml wide mouth flask, and sterilized at 121 ° C for 20 minutes.
  • 2-Adamantanephthalimide lOmg per flask was made into a DMSO 0.2ml solution and aseptically added, then 5ml of the seed culture was inoculated and cultured at 28 ° C for 3 days at an amplitude of 70mm and 180 rpm.
  • As a result of reverse phase HPLC analysis 23.6% of the substrate was converted to P5 and 1.1% of the substrate was converted to P6.
  • the fermentation finished liquid for two flasks was extracted with 100 ml of n-butanol.
  • the extract was concentrated to dryness under reduced pressure to obtain 0.097 g of a crude extract.
  • the resulting crude extract (0.097 g) was chromatographed on a Unison US—C 18 (inner diameter 2 cm, length 15 cm) column with a gradient of acetonitrile / water 20-95% (20 minutes) at a flow rate of 15 ml / min. .
  • the effective fraction was concentrated under reduced pressure, and lyophilized to obtain 2.4 mg and 0.1 mg as purified products of 2-adamantanephthalimide-P 5 and P6, respectively.
  • Methylhydrazine (776 mg) was added to an ethanol solution (20 ml) of compound l (2.0 g), and the mixture was heated to reflux for 24 hours. After completion of the reaction, the solvent was distilled off, and the residue was diluted with 2N aqueous hydrochloric acid (30 ml). The aqueous layer was washed with ethyl acetate (50 ml X 2) and then concentrated to about 1/3 under reduced pressure. The precipitated crystals were collected by filtration and washed with isopropyl alcohol. The target product 2 (890 mg) was obtained as colorless crystals.
  • N (monohydroxy-2-adamantyl) phthalimide derivatives which are useful as an intermediate for pharmaceuticals.

Abstract

La présente invention concerne un procédé de production d'un dérivé de N-(monohydroxy-2-adamantyl)-phtalimide, ledit dérivé étant un composé utilisable en tant qu'intermédiaire pour la production à haut rendement et à bas coût d'une résine ou d'un produit pharmaceutique fonctionnel. Une moisissure isolée du sol et appartenant au genre Nakataea, Rhizoctonia ou Chaetomium peut produire dans un milieu de culture et avec un rendement élevé un dérivé de N-(monohydroxy-2-adamantyl)-phtalimide à partir d'un dérivé de N-(2-adamantyl)-phtalimide.
PCT/JP2007/056542 2006-03-31 2007-03-28 Procede de production d'adamantane hydroxylee en utilisant un microorganisme WO2007114125A1 (fr)

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WO2011078101A1 (fr) 2009-12-22 2011-06-30 塩野義製薬株式会社 Dérivé d'adamantanamine
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US8324265B2 (en) 2005-11-21 2012-12-04 Shionogi & Co., Ltd. Heterocyclic compounds having type I 11β hydroxysteroid dehydrogenase inhibitory activity
CN101754954B (zh) * 2007-05-18 2015-11-25 盐野义制药株式会社 具有11β-羟基类固醇脱氢酶Ⅰ型抑制活性的含氮杂环衍生物
WO2008142986A1 (fr) * 2007-05-18 2008-11-27 Shionogi & Co., Ltd. DÉRIVÉ HÉTÉROCYCLIQUE CONTENANT DE L'AZOTE POSSÉDANT UNE ACTIVITÉ INHIBITRICE SUR LA 11 β-HYDROXYSTÉROÏDE DÉSHYDROGÉNASE DE TYPE I
US8383622B2 (en) 2007-05-18 2013-02-26 Shionogi & Co., Ltd. Nitrogen-containing heterocyclic derivative having 11β-hydroxysteroid dehydrogenase type I inhibitory activity
US8614080B2 (en) 2007-09-27 2013-12-24 Shionogi & Co., Ltd. Method for producing hydroxylated adamantane using cytochrome P450
US8383381B2 (en) 2007-09-27 2013-02-26 Shjonogi & Co., Ltd. Method for producing hydroxylated adaivjantane using cytochrome P450
WO2009041470A1 (fr) * 2007-09-27 2009-04-02 Shionogi & Co., Ltd. Procédé de production d'adamantane hydroxylé utilisant le cytochrome p450
US8507493B2 (en) 2009-04-20 2013-08-13 Abbvie Inc. Amide and amidine derivatives and uses thereof
EP2243479A2 (fr) 2009-04-20 2010-10-27 Abbott Laboratories Nouvel amide et dérivés d'amidine et utilisations associées
WO2011078101A1 (fr) 2009-12-22 2011-06-30 塩野義製薬株式会社 Dérivé d'adamantanamine
US8796468B2 (en) 2009-12-22 2014-08-05 Shionogi & Co., Ltd. Adamantanamine derivative
US8901316B2 (en) 2010-08-09 2014-12-02 Shionogi & Co., Ltd. Process for preparing aminoadamantyl carbamate derivatives
WO2012124781A1 (fr) 2011-03-17 2012-09-20 塩野義製薬株式会社 Procédé pour produire un dérivé d'acide pyrazolecarboxylique

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