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WO2011010332A1 - Procédé de préparation de rel-(3r*,3as*,7as*)-3-benzyl-2-méthyl-2,3, 3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one ou de l'un de ses sels - Google Patents

Procédé de préparation de rel-(3r*,3as*,7as*)-3-benzyl-2-méthyl-2,3, 3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one ou de l'un de ses sels Download PDF

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Publication number
WO2011010332A1
WO2011010332A1 PCT/IT2009/000327 IT2009000327W WO2011010332A1 WO 2011010332 A1 WO2011010332 A1 WO 2011010332A1 IT 2009000327 W IT2009000327 W IT 2009000327W WO 2011010332 A1 WO2011010332 A1 WO 2011010332A1
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process according
btg
salt
dimer
phenylacetaldehyde
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English (en)
Inventor
Elio Napolitano
Simone Basagni
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Abiogen Pharma SRL
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Abiogen Pharma SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C07D213/20—Quaternary compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a process for preparing the compound rel-
  • the final product (1a), purified by chromatography, is obtained as an orange coloured oil from which the respective crystalline hydrochloride salt is obtained by an initial treatment with acetylchloride in methanol, removal of solvents under vacuum then recrystallization from acetone.
  • the object of the present invention is to provide BTG-1640 in a reproducible manner and in good yields and so enabling BTG-1640 to be prepared on an industrial scale.
  • phenylacetaldehyde (4) to N-methylhydroxylamine (5) in the form of a salt in the presence of an organic base selected from the group consisting of tertiary amines NR1R2R3 where R1 , R2, R3 independently from one another represent a C- 1 -C 4 alkyl group, alkali or alkaline earth metal (Ci-C 4 )alkoxides, alkali metal or alkaline earth metal (Ci-C 4 )carboxylates;
  • anhydrous polar solvent selected from the group consisting of C 1 -C 5 alcohols, formamide, dimethylformamide, dimethylsulphoxide, at a temperature within the range from O 0 C to 12O 0 C to provide, after removal of the solvent, a solid mixture of nitrone monomer (3) and dimer (10), wherein the nitrone to dimer ratio is within the range from 90:10 to 0:100
  • step d) reacting the solid mixture obtained in step d), wherein the nitrone to dimer ratio is within the range from 90:10 to 0:100, with cyclohexenone (2);
  • the process of the invention allows BTG-1640 to be obtained in the form of an oxalate salt or as a free base and, from this latter, BTG-1640 to be obtained in the form of a salt other than oxalate in hectogram amounts.
  • Step d) of the process of the invention allows a solid mixture of nitrone (3) and dimer (10) to be obtained which is particularly stable and easily storable.
  • Another aspect of the invention therefore concerns a solid mixture of a monomer
  • Said mixture, as produced, can be advantageously used to produce BTG-1640 by way of steps e), f), g) and optionally h).
  • Another aspect of the invention therefore concerns the use of the mixture for preparing BTG-1640 i.e. rel-(3R * ,3aS * ,7aS*)-3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one.
  • Said mixture can also be used for preparing the dimer (10) by actual crystallization of the mixture from a solvent, preferably toluene.
  • the invention therefore also concerns a process for preparing BTG-1640 which uses as the starting material the dimer (10) and consists of the following steps: e) reacting the dimer (10) with cyclohexenone (2);
  • a further aspect of the invention concerns the use of the dimer (10) for preparing
  • the process of the invention allows the oxalate salt of BTG-1640 to be obtained, which by way of optional step h) is converted into the BTG-1640 free base which can itself be salified into a salt of interest.
  • Another aspect of the invention concerns the tosylated salt of BTG-1640.
  • Phenylacetaldehyde used as a raw material in the process of the invention.
  • Phenylacetaldehyde which is used freshly distilled, is actually a known sensitizer and its handling should be if possible avoided.
  • Phenylacetaldehyde (4) is a commercially available product; however, the degree of purity of the commercial product is very variable due to the spontaneous polymerization process to which the substance is subject and which invariably is manifested even if the substance is stored at low temperature.
  • the present invention therefore also relates to a process for preparing phenylacetaldehyde which avoids the use of commercial distilled phenylacetaldehyde and which can be used as a step preceding the process of the invention for preparing BTG-1640, as the phenylacetaldehyde obtained therefrom appears spectroscopically indistinguishable from distilled commercial aldehyde.
  • the invention also relates to the chloride salt (8) of N-(1-methoxy-2- phenylethyl)pyridinium and the chloride salt (9) of 1-(2-phenyl-1-methoxyethyl)-4- aza-1-azoniabicyclo[2.2.2]octane.
  • the invention concerns a process for the preparation of BTG-1640, i.e. rel-
  • phenylacetaldehyde (4) to N-methylhydroxylamine (5) in the form of a salt in the presence of an organic base selected from the group consisting of tertiary amines NR1 R2R3 where R1 , R2, R3 independently from one another represent a Ci-C 4 alkyl group, alkali or alkaline earth metal (Ci-C 4 )alkoxides, alkali or alkaline earth metal (Ci-C 4 )carboxylates;
  • anhydrous polar solvent selected from the group consisting of Ci-C 5 alcohols, formamide, dimethylformamide, dimethylsulphoxide at a temperature within the range from O 0 C to 12O 0 C to provide, after removal of the solvent, a solid mixture of nitrone monomer (3) and dimer (10), wherein the nitrone to dimer ratio is within the range from 90:10 to 0:100
  • step d) reacting the solid mixture obtained in step d), wherein the nitrone to dimer ratio is within the range from 90:10 to 0:100, with cyclohexenone (2);
  • phenylacetaldehyde (4) is added to N-methylhydroxylamine in the form of a salt in the presence of an organic base selected from the group consisting of tertiary amines NR1R2R3 where R1 , R2, R3 independently from one another represent a CrC 4 alkyl group, alkali or alkaline earth metal (C- ⁇ -C 4 )alkoxides, alkali or alkaline earth metal (C-i-C 4 )carboxylates.
  • an organic base selected from the group consisting of tertiary amines NR1R2R3 where R1 , R2, R3 independently from one another represent a CrC 4 alkyl group, alkali or alkaline earth metal (C- ⁇ -C 4 )alkoxides, alkali or alkaline earth metal (C-i-C 4 )carboxylates.
  • said salt is the hydrochloride of N-methylhydroxylamine, more preferably in the presence of an organic base selected from pyridine and triethylamine.
  • an organic base selected from pyridine and triethylamine.
  • the molar ratio of N-methylhydroxylamine hydrochloride to phenylacetaldehyde used overall for the reaction is about 1.2.
  • the organic base used is triethylamine, preferably the molar ratio of triethylamine to phenylacetaldehyde used overall for the reaction is not less than about 1.2, and even is more preferably about 1.3.
  • the phenylacetaldehyde is preferably added ⁇ in portions to the N- methylhydroxylamine salt, such as to be always locally in a deficient amount relative to the N-methylhydroxylamine salt, thus advantageously avoiding the formation of reaction by-products.
  • Step d) takes place in the presence of an anhydrous polar solvent selected from the group consisting of C 1 -C 5 alcohols, formamide, dimethylformamide, dimethylsulphoxide at a temperature within the range from O 0 C to 12O 0 C.
  • an anhydrous polar solvent selected from the group consisting of C 1 -C 5 alcohols, formamide, dimethylformamide, dimethylsulphoxide at a temperature within the range from O 0 C to 12O 0 C.
  • said polar solvent is methanol.
  • the temperature of step d) is within the range from about 25 0 C to about 7O 0 C, but advantageously within the range from about 5O 0 C to about 7O 0 C, and even more preferably within the range from about 55 0 C to about 6O 0 C.
  • Step d) of adding phenylacetaldehyde (4) to N-methylhydroxylamine hydrochloride leads to the formation of a solid mixture of the dimer (10) and nitrone (3) in which the nitrone to dimer ratio is within the range from 90:10 and 0:100.
  • the mixture is separated after solvent removal, preferably by forced evaporation to dryness, thus advantageously completing the reaction and increasing its yield. Therefore step d) can lead to a mixture of the monomer nitrone (3) and dimer (10), or just the dimer alone (10).
  • said solid mixture comprises the nitrone (3) and dimer (10) in a ratio within the range from 90:10 to 20:80, more preferably from 80:20 to 20:80, and even more preferably about 50:50.
  • the invention hence concerns the various stereoisomeric forms which are all included in the present invention. They are:
  • the dimer can also be obtained from the solid mixture of monomer (3) and dimer (10) by recrystallization from a solvent.
  • Said solvent is preferably toluene.
  • the dimer (10) as the stable and storable form can be used for preparing BTG-
  • the invention therefore also concerns the use of the dimer (10) for preparing BTG- 1640, i.e. rel-(3R*,3aS*,7aS*)-3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a- octahydrobenzo[d]isoxazol-4-one.
  • the solid mixture of the monomer (3) and dimer (10) obtained in step d) also appears as an extremely stable and storable crystalline solid, in which the nitrone (3) to dimer (10) ratio is within the range from 90:10 to 1 :99, preferably from 90:10 to 20:80, more preferably from 80:20 to 20:80, and even more preferably said ratio is about 50:50.
  • Another aspect of the invention concerns a solid mixture of a monomer (3) of formula
  • Said mixture even more preferably comprises the dimer (10) and the nitrone (3) in a 1 :1 ratio (50:50 mixture).
  • step e is an essential element for the reaction with cyclohexenone (2) in step e) to give the final BTG-1640 product in high yields.
  • the invention also concerns the use of the mixture for preparing BTG-1640, i.e. rel-(3R*,3aS*,7aS*)-3-benzyl-2-methyl-2,3,3a,4,5,6 I 7,7a-octahydrobenzo-
  • the invention hence concerns the use of the aforementioned solid mixture for obtaining BTG-1640 by way of steps e), f), g) and optionally h) described earlier.
  • step e) the solid mixture, in a nitrone (3) to dimer (10) ratio of 90:10 to 0:100, reacts with cyclohexenone, preferably in a 20% excess.
  • Said reaction is advantageously carried out over a time period within the range from 8 to 24 hours, more preferably over 16 hours at a temperature within the range from 40° to 12O 0 C, more preferably at 8O 0 C.
  • BTG-1640 is obtained in yields within the range from 40 to 60%, preferably 50%.
  • the solid nitrone (3)/dimer (10) mixture is reacted with cyclohexenone (2) preferably in the presence of an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, MTBE, toluene, DMF, acetonitrile, an optionally halogenated hydrocarbon and benzene, more preferably toluene.
  • an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, MTBE, toluene, DMF, acetonitrile, an optionally halogenated hydrocarbon and benzene, more preferably toluene.
  • step e) If in the reaction step e) a solvent is used, and if said solvent is other than toluene, then the crude reaction product deriving from step e) is evaporated to dryness and retaken in a water-immiscible solvent, preferably toluene, after which it is subjected to a wash with water then to evaporation (step f), before being subjected to subsequent reaction step g).
  • a water-immiscible solvent preferably toluene
  • reaction solvent in step e) is toluene
  • the crude reaction product can be directly washed with water.
  • step g) the BTG-1640 can be separated from the organic phase evaporated to dryness of step f), by precipitation with oxalic acid preferably in a stoichiometric amount.
  • Said step g) of separation by precipitation preferably takes place in the presence of acetone as solvent at a temperature within the range from -25 0 C to 1O 0 C, preferably at about -2O 0 C.
  • Step g) of separating BTG-1640 by precipitation is carried out advantageously over a time period within the range from 6 to 12 hours, and preferably over about 8 hours.
  • the BTG-1640 oxalate salt (1c) obtained with a yield of about 27-32% relative to the starting monomer/dimer mixture or dimer alone, can be advantageously treated in step h), to free BTG-1640 free base (1a).
  • this freeing step of the base from the BTG-1640 oxalate salt (1c) is carried out with anhydrous sodium carbonate in acetone.
  • the mixture thus obtained can be filtered and evaporated to give BTG-1640 free base (1a) in a quantitative yield as a viscous oil which slowly solidifies.
  • the BTG-1640 free base (1a) can be reacted with an acid selected from the group consisting of hydrochloric acid, fumaric acid, p-toluenesulphonic acid, preferably added in a stoichiometric amount to give respectively, BTG-1640 hydrochloride (1b), BTG-1640 fumarate (1d), BTG-1640 p-toluenesulphonate (1e) in an approximately quantitative yield as summarized in scheme 2 below:
  • a further aspect of the invention concerns the salt (1e), i.e. rel-(3R*,3aS*,7aS*)-3- benzyl-2-methyI-2,3,3a,4,5,6,7,7a-octahycirobenzo[d]isoxazol-4-one p- toluenesulphonate, found to be a stable salt and suitable for use as a medicament.
  • a further aspect of the invention concerns a process for preparing phenylacetaldehyde which comprises the following steps:
  • reaction step a) the phenylacetaldehyde dimethyl acetal (6) is selected as the starting commercial compound for the synthesis.
  • phenylacetaldehyde can be obtained from its acetal by acid hydrolysis; this process however proved to be complicated in that the phenylacetaldehyde resulting from the hydrolysis was unstable in the acidic hydrolysis environment.
  • phenylacetaldehyde dimethyl acetal (6) reacts with acetyl chloride preferably in the absence of solvent and at room temperature.
  • chloroether (7) and methyl acetate are obtained quantitatively over a period of about 24 hours.
  • the reaction can be accelerated by operating either in the presence of a catalyst, preferably in the presence of a catalytic amount of a
  • Lewis acid more preferably ZnCI 2 , or AICI 3 , or at temperatures above room temperature.
  • step b) the chloroether (7) and methyl acetate mixture is reacted with pyridine or
  • Another aspect of the invention concerns the N-(1-methoxy-2- phenylethyOpyridinium, chloride salt of formula :
  • Step b) preferably takes place in the presence of acetone.
  • the salt (8) or (9) dissolved in water undergoes a slow hydrolysis thus producing methanol, pyridinium chloride (in the case of pyridine) or [2.2.2.]-1 ,8-diazabicyclooctane chloride (in the case of [2.2.2.]-1 ,8-diazabicyclooctane) and phenylacetaldehyde which is efficiently removed from the reaction environment by extracting with an organic solvent.
  • the organic solvent used in step c) is preferably a water- immiscible organic solvent having a boiling temperature not less than 5O 0 C; more preferably it is selected from the group consisting of hydrocarbons, ethers and esters, being even more preferably hexane or MTBE.
  • the reaction preferably proceeds for 24 hours, in an inert atmosphere, with heating of the water and organic solvent mixture at reflux, the purity of the aldehyde (4) which accumulates in the organic phase remaining high, probably by virtue of the not excessively acidic conditions of the reaction environment. Evaporation of the organic phase produces an aldehyde (4) which is spectrophotometrically (13C-1 H-NMR) indistinguishable from distilled commercial aldehyde.
  • phenylacetaldehyde (4) of step d) of the process of the invention is the product obtained from step c) of the process of the invention for producing phenylacetaldehyde.
  • phenylacetaldehyde (4) of step d) can be the phenylacetaldehyde of step c) of the process for preparing the phenylacetaldehyde after removing the organic extraction solvent.
  • phenylacetaldehyde (4) (47.58 g, 90% yield) usable for step d) of the process of the invention.
  • the combined hexane extracts containing phenylacetaldehyde (4) can be used as such for the phenylacetaldehyde addition in step d) of the process of the invention.
  • the process allowed a total amount of product equal to 30.75 g to be obtained, consisting of a monomer/dimer mixture having a composition of 65:35 (total yield of the process equal to about 83%).
  • the composition of the residue (337 g) was estimated by 1 H-NMR assuming a mixture of BTG- 1640, cyclohexenone, toluene and free phenylacetaldehyde.
  • the BTG-1640 content was 168 g (0.7 mol, 50% yield).
  • the material was dissolved in a solution of oxalic acid (30.5 g, 0.35 mol) in acetone (500 ml), seeded and left at -2O 0 C overnight.
  • the precipitate, collected by aspiration and washed with the minimum amount of acetone provided BTG-1640 oxalate (121.28 g, 31.2% yield; M. p. 123- 124°C (dec.)) as a colourless crystalline solid.
  • the reaction mixture diluted with toluene (100 ml) was washed with two 50 ml portions of water and evaporated under vacuum in the rotary evaporator (water bath temperature 7O 0 C; pressure 115 mmHg).
  • the composition of the residue (28 g), estimated by 1 H-NMR was identical to that obtained when starting from a monomer-dimer mixture.
  • the material was dissolved in a solution of oxalic acid (5.4 g, 0.06 mol) in acetone (70 ml), seeded and left at -2O 0 C overnight.
  • the precipitate collected by aspiration and washed with a minimal amount of acetone, furnished BTG-1640 oxalate (9 g, 25.7% yield; M. p. 123-124 0 C (dec.)) as a colourless crystalline solid.
  • 1 H-NMR (DMSOd ⁇ , 300 MHz) 1.70-1.93 (4H, superimposed multiplets), 2.18-2.36
  • the BTG-1640 free base without further treatments was used in the following preparations of the respective salts.

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Abstract

L'invention a pour objet un procédé de préparation de BTG-1640, c'est-à-dire la rel- (3R*,3aS*,7aS*)-3-benzyl-2-méthyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]- isoxazol-4-one ou l'un de ses sels, comprenant les étapes suivantes : d) l'addition de phénylacétaldéhyde (4) à de la N-méthylhydroxylamine (5) sous la forme d'un sel en présence d'une base organique choisie dans le groupe comprenant des amines tertiaires NR1R2R3, R1, R2, R3, indépendamment les uns des autres, représentant un groupe alkyle en C1 à C4, des alcoxydes (en C1 à C4) de métaux alcalins ou alcalinoterreux, des carboxylates (en C1 à C4) de métaux alcalins ou alcalinoterreux, et en présence d'un solvant polaire anhydre choisi dans le groupe comprenant des alcools en C1 à C5, le formamide, le diméthylformamide, le diméthylsulfoxyde, à une température située dans la plage de 0 °C à 120 °C pour fournir, après l'élimination du solvant, un mélange solide de nitrone monomère (3) et dimère (10), le rapport de la nitrone sur le dimère étant situé dans la plage de 90/10 à 0/100 ; e) la réaction du mélange solide obtenu dans l'étape d), le rapport de la nitrone sur le dimère étant situé dans la plage de 90/10 à 0/100, avec de la cyclohexénone (2) ; f) la soumission du produit réactionnel brut obtenu en e), ayant été éventuellement évaporé jusqu'à l'état sec et repris dans un solvant non miscible à l'eau, à au moins un lavage avec de l'eau suivi d'une évaporation de la phase organique jusqu'à l'état sec ; g) la séparation de BTG-1640 sous la forme d'un sel oxalate (1c) par une précipitation avec de l'acide oxalique ajouté à la phase organique dans l'état sec ; et h) la libération éventuelle de la base BTG-1640 à partir du sel oxalate.
PCT/IT2009/000327 2009-07-23 2009-07-23 Procédé de préparation de rel-(3r*,3as*,7as*)-3-benzyl-2-méthyl-2,3, 3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one ou de l'un de ses sels Ceased WO2011010332A1 (fr)

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PCT/IT2009/000327 WO2011010332A1 (fr) 2009-07-23 2009-07-23 Procédé de préparation de rel-(3r*,3as*,7as*)-3-benzyl-2-méthyl-2,3, 3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one ou de l'un de ses sels

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PCT/IT2009/000327 WO2011010332A1 (fr) 2009-07-23 2009-07-23 Procédé de préparation de rel-(3r*,3as*,7as*)-3-benzyl-2-méthyl-2,3, 3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one ou de l'un de ses sels

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN107746392A (zh) * 2017-12-05 2018-03-02 河南师范大学 一种含桥环结构的恶唑烷类化合物的制备方法

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WO1993017004A1 (fr) * 1992-02-19 1993-09-02 British Technology Group Ltd. Derives benzisoxazole et compositions pharmaceutiques les contenant
WO2008053325A1 (fr) * 2006-11-02 2008-05-08 Abiogen Pharma S.P.A. Sel de 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one

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Publication number Priority date Publication date Assignee Title
WO1993017004A1 (fr) * 1992-02-19 1993-09-02 British Technology Group Ltd. Derives benzisoxazole et compositions pharmaceutiques les contenant
WO2008053325A1 (fr) * 2006-11-02 2008-05-08 Abiogen Pharma S.P.A. Sel de 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one

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CN107746392A (zh) * 2017-12-05 2018-03-02 河南师范大学 一种含桥环结构的恶唑烷类化合物的制备方法
CN107746392B (zh) * 2017-12-05 2020-10-09 河南师范大学 一种含桥环结构的恶唑烷类化合物的制备方法

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