WO2016056475A1 - 3-アリールオキシキノリン誘導体の製造方法 - Google Patents
3-アリールオキシキノリン誘導体の製造方法 Download PDFInfo
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- WO2016056475A1 WO2016056475A1 PCT/JP2015/078019 JP2015078019W WO2016056475A1 WO 2016056475 A1 WO2016056475 A1 WO 2016056475A1 JP 2015078019 W JP2015078019 W JP 2015078019W WO 2016056475 A1 WO2016056475 A1 WO 2016056475A1
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- 0 *C(c(cccc1)c1N)=O Chemical compound *C(c(cccc1)c1N)=O 0.000 description 2
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
- A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
Definitions
- the present invention relates to a method for producing a 3-aryloxyquinoline derivative. More specifically, the present invention relates to a novel method for producing a 3-aryloxyquinoline derivative useful as an agricultural pharmaceutical intermediate.
- This application claims priority based on Japanese Patent Application No. 2014-206000 for which it applied to Japan on October 6, 2014, and uses the content here.
- Known methods for synthesizing asymmetric ether compounds include Ullmann ether synthesis and Chang Lam Evans coupling.
- 3-phenyloxyquinoline should be able to be synthesized by reacting 3-hydroxyquinoline with halobenzene in the presence of a copper catalyst.
- 3-hydroxyquinoline as a raw material has low solubility in a solvent, handling thereof is inconvenient.
- Non-Patent Document 1 discloses that 3-methoxyquinoline was produced by the reaction of 2-aminobenzaldehyde and 2-methoxyketones.
- An object of the present invention is to provide a novel method for producing a 3-aryloxyquinoline derivative useful as an agricultural pharmaceutical intermediate.
- a method for producing a 3-aryloxyquinoline derivative comprising reacting a 2-aminobenzaldehyde derivative and an ⁇ -aryloxyketone derivative in the presence of an acid or a base.
- a 3-aryloxyquinoline skeleton can be constructed at once using a 2-aminobenzaldehyde derivative and an ⁇ -aryloxyketone derivative, which are raw materials having good solubility in a solvent, It is suitable for mass production.
- the 3-aryloxyquinoline derivative obtained by the production method of the present invention is useful as an agricultural pharmaceutical intermediate.
- the method for producing a 3-aryloxyquinoline derivative according to the present invention includes reacting a 2-aminobenzaldehyde derivative and an ⁇ -aryloxyketone derivative in the presence of an acid or a base.
- a reaction is represented by, for example, the formula (1).
- R represents a hydrogen atom or an unsubstituted or substituted C1-6 alkyl group
- Ar represents an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted group
- R 1 represents a chemically acceptable organic group.
- the 2-aminobenzaldehyde derivative used in the present invention is a benzene derivative having at least an amino group at the 2-position of the benzene ring and at least a formyl group or a C1-6 alkylcarbonyl group at the 1-position of the benzene ring.
- Examples of the “C1-6 alkylcarbonyl group” include an acetyl group and a propionyl group.
- the 2-aminobenzaldehyde derivative used in the present invention may further have a substituent that does not inhibit the reaction at the 3, 4, 5 and / or 6 position of the benzene ring.
- substituents include the following. Halogeno groups such as fluoro, chloro, bromo and iodo groups; C1-6 such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group, n-hexyl group, etc.
- An alkyl group Vinyl group, 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, etc.
- a C2-6 alkenyl group of C2-6 alkynyl groups such as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group;
- a C3-8 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group; C6-10 aryl groups such as phenyl and naphthyl groups; C6-10 aryl C1-6 alkyl groups such as benzyl and phenethyl groups; 3-6 membered heterocyclyl group; 3-6 membered heterocyclyl C1-6 alkyl group;
- Hydroxyl group C1-6 alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group, t-butoxy group; C2-6 alkenyloxy groups such as vinyloxy group, allyloxy group, propenyloxy group, butenyloxy group; C2-6 alkynyloxy groups such as ethynyloxy group and propargyloxy group; C6-10 aryloxy groups such as phenoxy group and naphthoxy group; A C6-10 aryl C1-6 alkoxy group such as a benzyloxy group or a phenethyloxy group; A 3-6 membered heterocyclyloxy group; A 3-6 membered heterocyclyl C1-6 alkoxy group;
- C1-6 haloalkyl groups such as chloromethyl group, chloroethyl group, trifluoromethyl group, 1,2-dichloro-n-propyl group, 1-fluoro-n-butyl group, perfluoro-n-pentyl group;
- a C1-6 haloalkoxy group such as a trifluoromethoxy group, 2-chloro-n-propoxy group, 2,3-dichlorobutoxy group;
- Hydroxy C1-6 alkyl groups such as hydroxymethyl group, 2-hydroxyethyl group;
- a C1-6 alkoxy C1-6 alkyl group such as a methoxymethyl group, ethoxymethyl group, methoxyethyl group, 1-ethoxyethyl group, 2-ethoxyethyl group;
- C2-6 alkenyloxy C1-6 alkyl groups such as vinyloxymethyl group, allyloxymethyl group, propenyloxymethyl group, butenyloxymethyl group; Cyano group; nitro group.
- any hydrogen atom in the substituent may be substituted with a group having a different structure.
- examples of the “substituent” include a halogeno group, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 haloalkoxy group, a cyano group, and a nitro group.
- the “3- to 6-membered heterocyclyl group” is a group containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as constituent atoms of the ring.
- the heterocyclyl group may be monocyclic or polycyclic. In the polycyclic heterocyclyl group, if at least one ring is a hetero ring, the remaining ring may be a saturated alicyclic ring, an unsaturated alicyclic ring, or an aromatic ring.
- Examples of the “3- to 6-membered heterocyclyl group” include a 3- to 6-membered saturated heterocyclyl group, a 5- to 6-membered heteroaryl group, and a 5- to 6-membered partially unsaturated heterocyclyl group.
- Examples of the 3- to 6-membered saturated heterocyclyl group include aziridinyl group, epoxy group, pyrrolidinyl group, tetrahydrofuranyl group, thiazolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, dioxolanyl group and dioxanyl group.
- Examples of 5-membered heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, etc. Can do.
- Examples of the 6-membered heteroaryl group include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, and a triazinyl group.
- a substituent which can be present at the 3, 4, 5 or 6 position of the benzene ring is preferably a C1-6 alkyl group, a C1-6 haloalkyl group, a hydroxyl group, a C1-6 alkoxy group, A C1-6 haloalkoxy group, a hydroxy C1-6 alkyl group, a C1-6 alkoxy C1-6 alkyl group, a halogeno group, a cyano group, or a nitro group, more preferably a halogeno group.
- the ⁇ -aryloxyketone derivative used in the present invention is a ketone having a structure in which a 1-aryloxyalkyl group or 1-heteroaryloxyalkyl group and a chemically acceptable organic group are bonded by a carbonyl group.
- Examples of the ⁇ -aryloxyketone derivatives used in the present invention include compounds represented by the formula: Ar—O—CH 2 —C ( ⁇ O) —R 1 .
- Ar represents an unsubstituted or substituted C6-10 aryl group or an unsubstituted or substituted 5- to 6-membered heteroaryl group.
- R 1 represents a chemically acceptable organic group.
- the “C6-10 aryl group” may be monocyclic or polycyclic. In the polycyclic aryl group, if at least one ring is an aromatic ring, the remaining ring may be a saturated alicyclic ring, an unsaturated alicyclic ring, or an aromatic ring. Examples of the “C6-10 aryl group” include phenyl group, naphthyl group, azulenyl group, indenyl group, indanyl group, tetralinyl group and the like.
- the “5- to 6-membered heteroaryl group” is a group containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as constituent atoms of an aromatic ring.
- Examples of the 5-membered heteroaryl group include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl (for details, [1,2,3] triazolyl Or [1,2,4] triazolyl group), oxadiazolyl group (specifically, [1,2,4] oxadiazolyl group or [1,3,4] oxadiazolyl group), thiadiazolyl group, tetrazolyl group, etc. Can do.
- 6-membered heteroaryl group examples include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, and a triazinyl group.
- the substituent that can be present on Ar is not particularly limited as long as it does not inhibit the reaction of the present invention.
- the substituent include the same substituents that can be present at the 3, 4, 5, or 6 position of the benzene ring exemplified for the 2-aminobenzaldehyde derivative.
- the substituent that can be present on Ar is preferably a C1-6 alkyl group, a C1-6 haloalkyl group, a hydroxyl group, a C1-6 alkoxy group, a C1-6 halo.
- Ar is preferably a phenyl group which is unsubstituted or has a substituent.
- substituents that can be included in the phenyl group include ⁇ -phenoxy-acetone (1-phenoxypropan-2-one) having a hydroxy C1-6 alkyl group, a C1-6 alkoxy C1-6 alkyl group, or a halogeno group. preferable.
- R 1 is preferably an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl.
- C1-6 alkyl group “C2-6 alkenyl group”, “C2-6 alkynyl group”, “C3-8 cycloalkyl group”, “C6-10 aryl group”, and “3-6 members” in R 1
- heterocyclyl group examples include those already exemplified.
- C1-6 alkyl group C2-6 alkenyl group”, “C2-6 alkynyl group” in R 1
- substituents on “C1-6 alkyl group”, “C2-6 alkenyl group”, “C2-6 alkynyl group” in R 1 include C1-6 alkoxy group, halogeno group, cyano group, C3-8 cyclo Examples thereof include an alkyl group, a C6-10 aryl group, and a 3-6 membered heterocyclyl group.
- R 1 examples include a C1-6 alkyl group, a C1-6 haloalkyl group, a hydroxyl group, C1-6 alkoxy groups, C1-6 haloalkoxy groups, halogeno groups, cyano groups, nitro groups and the like can be mentioned.
- R 1 is preferably a C1-6 alkyl group.
- the acid used in the present invention may be either an organic acid or an inorganic acid.
- a Lewis acid examples include boron trifluoride, aluminum chloride, titanium tetrachloride, and tin tetrachloride.
- the base used in the present invention may be either an organic base or an inorganic base. In the present invention, a Lewis base can also be used. In the present invention, it is preferable to use an inorganic base. Examples of the inorganic base include alkali metal hydroxides and alkaline earth hydroxides. Of these, sodium hydroxide and potassium hydroxide are particularly preferred.
- the base or acid can be used as it is or after being dissolved in a solvent.
- the amount of the base or acid used is not particularly limited, but is preferably 0.1 to 5 mol, more preferably 1.0 to 4.0 mol, per 1 mol of the 2-aminobenzaldehyde derivative.
- a solvent can be used.
- the solvent that can be used in the present invention is not particularly limited as long as it does not inhibit the reaction.
- the solvent that can be used in the present invention is preferably a polar solvent, more preferably a protic polar solvent, further preferably an alcohol, particularly preferably a lower alcohol (alcohol having 1 to 5 carbon atoms such as methanol and ethanol). ).
- the amount of the solvent used is not particularly limited as long as it is an amount sufficient to dissolve each reaction substrate.
- the 2-aminobenzaldehyde derivative and the ⁇ -aryloxyketone derivative can be brought into a reaction state in the presence of a base or an acid
- the reaction between the 2-aminobenzaldehyde derivative and the ⁇ -aryloxyketone derivative is performed, for example, by dissolving the 2-aminobenzaldehyde derivative and the ⁇ -aryloxyketone derivative in a solvent, and then mixing this solution with a base or an acid. Or by dissolving the 2-aminobenzaldehyde derivative and the base or acid in a solvent and then mixing this solution with the ⁇ -aryloxyketone derivative.
- the reaction temperature is not particularly limited, but is not less than room temperature and not more than the boiling point of the solvent.
- Example 1 At room temperature, 100 mg (0.64 mmol) of 2-amino-3,4-difluorobenzaldehyde and 105 mg (0.70 mmol) of 1-phenoxypropan-2-one were dissolved in 10 ml of ethanol. To this solution, 100 mg (1.8 mmol) of potassium hydroxide was added and reacted at room temperature. Thereafter, the solvent was distilled off, neutralized with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The extracted solution was dehydrated with magnesium sulfate, filtered, and concentrated to obtain a crude product.
- Example 2 At room temperature, 150 mg (1.1 mmol) of 2-amino-4-fluorobenzaldehyde and 178 mg (1.2 mmol) of 1-phenoxypropan-2-one were dissolved in 10 ml of ethanol. To this solution, 120 mg (2.3 mmol) of potassium hydroxide was added and reacted at room temperature. Thereafter, the solvent was distilled off, neutralized with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The extracted solution was dehydrated with magnesium sulfate, filtered, and concentrated to obtain a crude product.
- Example 3 In a reaction vessel, 210 mg (1.51 mmol) of 2-amino-4-fluorobenzaldehyde, 340 mg of 1- (3-fluoro-2- (2-hydroxypropan-2-yl) phenoxy) propan-2-one (1. 51 mmol) and 1.5 ml of methanol were added and stirred at room temperature. To this solution was added 60 mg of 10% aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 6 hours. The solution was then added to a large amount of water and then extracted twice with ethyl acetate. The extracted solution was dehydrated with magnesium sulfate, filtered, and concentrated to obtain a crude product.
- a 3-aryloxyquinoline skeleton can be constructed at once using a 2-aminobenzaldehyde derivative and an ⁇ -aryloxyketone derivative, which are raw materials having good solubility in a solvent, It is suitable for mass production.
- the 3-aryloxyquinoline derivative obtained by the production method of the present invention is useful as an agricultural pharmaceutical intermediate.
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Abstract
Description
本願は、2014年10月6日に日本に出願された特願2014-206000号に基づき優先権を主張し、その内容をここに援用する。
〔1〕2-アミノベンツアルデヒド誘導体とα-アリールオキシケトン誘導体とを、酸または塩基の存在下に、反応させることを含む、3-アリールオキシキノリン誘導体の製造方法。
〔2〕前記反応を低級アルコール類から選ばれる少なくとも一つの溶媒中にて行う、〔1〕に記載の製造方法。
〔3〕1-(3-フルオロ-2-(2-ヒドロキシプロパン-2-イル)フェノキシ)プロパン-2-オン。
本発明に用いられる2-アミノベンツアルデヒド誘導体は、ベンゼン環の2位にアミノ基を、ベンゼン環の1位にホルミル基またはC1~6アルキルカルボニル基を、少なくとも有するベンゼン誘導体である。「C1~6アルキルカルボニル基」としては、アセチル基、プロピオニル基などを挙げることができる。
係る置換基としては、以下のようなものを挙げることができる。
フルオロ基、クロロ基、ブロモ基、イオド基などのハロゲノ基;
メチル基、エチル基、n-プロピル基、i-プロピル基、n-ブチル基、s-ブチル基、i-ブチル基、t-ブチル基、n-ペンチル基、n-ヘキシル基などのC1~6アルキル基;
ビニル基、1-プロペニル基、2-プロペニル基(アリル基)、1-ブテニル基、2-ブテニル基、3-ブテニル基、1-メチル-2-プロペニル基、2-メチル-2-プロペニル基などのC2~6アルケニル基;
エチニル基、1-プロピニル基、2-プロピニル基、1-ブチニル基、2-ブチニル基、3-ブチニル基、1-メチル-2-プロピニル基などのC2~6アルキニル基;
フェニル基、ナフチル基などのC6~10アリール基; ベンジル基、フェネチル基などのC6~10アリールC1~6アルキル基;
3~6員ヘテロシクリル基; 3~6員へテロシクリルC1~6アルキル基;
メトキシ基、エトキシ基、n-プロポキシ基、i-プロポキシ基、n-ブトキシ基、s-ブトキシ基、i-ブトキシ基、t-ブトキシ基などのC1~6アルコキシ基;
ビニルオキシ基、アリルオキシ基、プロペニルオキシ基、ブテニルオキシ基などのC2~6アルケニルオキシ基;
エチニルオキシ基、プロパルギルオキシ基などのC2~6アルキニルオキシ基;
フェノキシ基、ナフトキシ基などのC6~10アリールオキシ基;
ベンジルオキシ基、フェネチルオキシ基などのC6~10アリールC1~6アルコキシ基;
3~6員ヘテロシクリルオキシ基;
3~6員へテロシクリルC1~6アルコキシ基;
トリフルオロメトキシ基、2-クロロ-n-プロポキシ基、2,3-ジクロロブトキシ基などのC1~6ハロアルコキシ基;
メトキシメチル基、エトキシメチル基、メトキシエチル基、1-エトキシエチル基、2-エトキシエチル基などのC1~6アルコキシC1~6アルキル基;
ビニルオキシメチル基、アリルオキシメチル基、プロペニルオキシメチル基、ブテニルオキシメチル基などのC2~6アルケニルオキシC1~6アルキル基;
シアノ基;ニトロ基。
これらの「置換基」は、当該置換基中のいずれかの水素原子が、異なる構造の基で置換されていてもよい。その場合の「置換基」としては、ハロゲノ基、C1~6アルキル基、C1~6ハロアルキル基、C1~6アルコキシ基、C1~6ハロアルコキシ基、シアノ基、ニトロ基などを挙げることができる。
6員ヘテロアリール基としては、ピリジル基、ピラジニル基、ピリミジニル基、ピリダジニル基、トリアジニル基などを挙げることができる。
本発明に用いられるα-アリールオキシケトン誘導体は、1-アリールオキシアルキル基もしくは1-ヘテロアリールオキシアルキル基と化学的に許容される有機基とがカルボニル基で結合された構造を有するケトンである。本発明に用いられるα-アリールオキシケトン誘導体として、例えば、式:Ar-O-CH2-C(=O)-R1で表される化合物を挙げることができる。
式中、Arは、無置換のもしくは置換基を有するC6~10アリール基または無置換のもしくは置換基を有する5~6員ヘテロアリール基を示す。R1は、化学的に許容される有機基を示す。
「C6~10アリール基」としては、フェニル基、ナフチル基、アズレニル基、インデニル基、インダニル基、テトラリニル基などを挙げることができる。
6員ヘテロアリール基としては、ピリジル基、ピラジニル基、ピリミジニル基、ピリダジニル基、トリアジニル基などを挙げることができる。
本発明に用いられるα-アリールオキシケトン誘導体は、Ar上に有することができる置換基が、好ましくはC1~6アルキル基、C1~6ハロアルキル基、水酸基、C1~6アルコキシ基、C1~6ハロアルコキシ基、ヒドロキシC1~6アルキル基、C1~6アルコキシC1~6アルキル基、ハロゲノ基、シアノ基またはニトロ基である。
R1における「C3~8シクロアルキル基」、「C6~10アリール基」、および「3~6員ヘテロシクリル基」上の置換基としては、C1~6アルキル基、C1~6ハロアルキル基、水酸基、C1~6アルコキシ基、C1~6ハロアルコキシ基、ハロゲノ基、シアノ基、ニトロ基などを挙げることができる。
本発明に用いられるα-アリールオキシケトン誘導体は、R1が、好ましくはC1~6アルキル基である。
本発明に用いられる塩基は、有機塩基、無機塩基のいずれでもよい。本発明においてはルイス塩基を使用することもできる。本発明においては無機塩基を使用することが好ましい。無機塩基としては、アルカリ金属水酸化物、アルカリ土類水酸化物が挙げられる。これらのうち、水酸化ナトリウム、水酸化カリウムが特に好ましい。
塩基または酸は、そのままの状態で、または溶媒に溶解して、用いることができる。塩基または酸の使用量は、特に制限されないが、2-アミノベンツアルデヒド誘導体1モルに対して、好ましくは0.1~5モル、より好ましくは1.0~4.0モルである。
室温下、2-アミノ-3,4-ジフルオロベンツアルデヒド100mg(0.64mmol)と1-フェノキシプロパン-2-オン105mg(0.70mmol)とをエタノール10mlに溶解させた。この溶液に水酸化カリウム100mg(1.8mmol)を加え、室温下で反応させた。
その後、溶媒を留去し、1N塩酸水で中和し、酢酸エチルを用いて抽出した。抽出した溶液を硫酸マグネシウムにて脱水し、ろ過、濃縮により粗生成物を得た。得られた粗生成物をシリカゲルカラムクロマトグラフィー(展開溶媒;ヘキサン:酢酸エチル=4:1)にて精製を施すことにより目的物である7,8-ジフルオロ-2-メチル-3-フェノキシキノリン156mg(収率90%)を得た。
室温下、2-アミノ-4-フルオロベンツアルデヒド150mg(1.1mmol)と1-フェノキシプロパン-2-オン178mg(1.2mmol)とをエタノール10mlに溶解させた。この溶液に水酸化カリウム120mg(2.3mmol)を加え、室温下で反応させた。
その後、溶媒を留去し、1N塩酸水で中和し、酢酸エチルを用いて抽出した。抽出した溶液を硫酸マグネシウムにて脱水し、ろ過、濃縮により粗生成物を得た。得られた粗生成物をシリカゲルカラムクロマトグラフィー(展開溶媒;ヘキサン:酢酸エチル=4:1)にて精製を施すことにより目的物である7-フルオロ-2-メチル-3-フェノキシキノリン243mg(収率89%)を得た。
反応容器に、2-アミノ-4-フルオロベンツアルデヒド210mg(1.51mmol)、1-(3-フルオロ-2-(2-ヒドロキシプロパン-2-イル)フェノキシ)プロパン-2-オン340mg(1.51mmol)、およびメタノール1.5mlを加え、室温にて撹拌した。この溶液に10%水酸化ナトリウム水溶液60mgを加え、室温にて6時間撹拌した。
その後、溶液を多量の水に加え、次いで酢酸エチルにて2回抽出した。抽出した溶液を硫酸マグネシウムにて脱水し、ろ過、濃縮により粗生成物を得た。この生成物をシリカゲルカラムクロマトグラフィー(展開溶媒;酢酸エチル:ヘキサン=1:4 Rf値=0.25)にて精製を施すことにより目的物である2-(2-フルオロ-6-((7-フルオロ-2-メチルキノリン-3-イル)オキシ)フェニル)プロパン-2-オール370mg(収率:75.5%)を得た。
得られた化合物の1H-NMRを以下に示す。
400MHz1H-NMR(CDCl3):δ 7.69(2H, m)、7.27(1H, m)、7.15(1H, m)、6.89(1H, m)、6.52(1H, m)、4.05(1H, d)、2.73(3H, s)、1.78(6H, s)、1.77(1H, s).
400MHz1H-NMR(CDCl3):δ 7.14(1H, m)、6.73(1H, m)、6.56(1H, m)、5.35(1H, s)、4.73(2H, s)、2.26(3H, s)、1.71(6H, s).
Claims (3)
- 2-アミノベンツアルデヒド誘導体とα-アリールオキシケトン誘導体とを、酸または塩基の存在下に、反応させることを含む、3-アリールオキシキノリン誘導体の製造方法。
- 前記反応を低級アルコール類から選ばれる少なくとも一つの溶媒中にて行う、請求項1に記載の製造方法。
- 1-(3-フルオロ-2-(2-ヒドロキシプロパン-2-イル)フェノキシ)プロパン-2-オン。
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