WO2014065122A1 - Nouveau procédé pour synthétiser un dérivé de 3-hydroxyquinoléine - Google Patents

Nouveau procédé pour synthétiser un dérivé de 3-hydroxyquinoléine Download PDF

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WO2014065122A1
WO2014065122A1 PCT/JP2013/077490 JP2013077490W WO2014065122A1 WO 2014065122 A1 WO2014065122 A1 WO 2014065122A1 JP 2013077490 W JP2013077490 W JP 2013077490W WO 2014065122 A1 WO2014065122 A1 WO 2014065122A1
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group
substituted
unsubstituted
formula
haloalkyl
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PCT/JP2013/077490
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Japanese (ja)
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芳和 伊藤
山口　正男
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日本曹達株式会社
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins

Definitions

  • the present invention relates to a method suitable for producing a large amount of a 3-hydroxyquinoline derivative useful as an intermediate for producing agricultural pharmaceuticals on an industrial scale.
  • Non-patent Document 1 3-Hydroxyquinoline derivatives are useful as intermediates for the production of pharmaceuticals, agricultural chemicals and the like.
  • Patent Documents 1 to 4 As a method for synthesizing 3-hydroxyquinoline, a method using isatin is known (Non-patent Document 1).
  • the above method has the following problems. 1) Isatins have high crystallinity and are limited in reaction in the liquid phase. 2) Decarbonation must be performed at a high temperature, resulting in poor thermal efficiency.
  • An object of the present invention is to provide a method suitable for producing a large amount of 3-hydroxyquinoline derivatives useful as intermediates for production of agricultural medicines on an industrial scale.
  • a process for producing a 3-hydroxyquinoline derivative represented by formula (3) comprising a step of reacting an aniline compound represented by formula (1) with a halooxirane compound represented by formula (2).
  • each R 1 is independently a halogeno group, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, unsubstituted or substituted A C2-6 alkynyl group having a group, an unsubstituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted heterocyclic group, Unsubstituted or substituted C1-7 acyl group, C1-6 alkoxy group, C1-6 haloalkyl group, unsubstituted or substituted carboxyl group, unsubstituted or substituted aminocarbonyl group, A substituted or substituted hydroxyl group, an unsubstituted or substituted mercapto group, a substituted sulfonyl group, a cyano group, A nitro group.
  • n represents the number of R 1 and is an integer from 0 to 4.
  • Two adjacent R 1 on the benzene ring may be taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 5- to 7-membered ring.
  • R 2 is a hydrogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2 An alkynyl group, an unsubstituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted heterocyclic group, or a C1-6 A haloalkyl group;
  • R 3 is a hydrogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, A substituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted heterocyclic group, or a C
  • R 4 each independently represents an unsubstituted or substituted C1-6 alkyl group.
  • Two OR 4 may be taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 5- to 7-membered ring.
  • X represents a halogeno group.
  • R 1 to R 3 and n have the same meaning as described above. That is, in the formula (3), each R 1 independently represents a halogeno group, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted group.
  • a substituted C2-6 alkynyl group an unsubstituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted heterocycle Group, unsubstituted or substituted C1-7 acyl group, C1-6 alkoxy group, C1-6 haloalkyl group, unsubstituted or substituted carboxyl group, unsubstituted or substituted aminocarbonyl group An unsubstituted or substituted hydroxyl group, an unsubstituted or substituted mercapto group, a substituted sulfonyl group, A group or a nitro group.
  • n represents the number of R 1 and is an integer from 0 to 4.
  • Two adjacent R 1 on the benzene ring may be taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 5- to 7-membered ring.
  • R 2 represents a hydrogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, A substituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted heterocyclic group, or a C1-6 haloalkyl group is shown.
  • R 3 is a hydrogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, A substituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted heterocyclic group, or a C1-6 haloalkyl group is shown.
  • a process for producing an N-substituted aniline compound represented by formula (4) comprising a step of reacting an aniline compound represented by formula (1) with a halooxirane compound represented by formula (2) .
  • a process for producing a 3-hydroxyquinoline derivative represented by formula (3) comprising a step of reacting an N-substituted aniline compound represented by formula (4) in the presence of an acid.
  • R 1 to R 4 , X, and n have the same meaning as described above. That is, in formula (4), each R 1 independently represents a halogeno group, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted group.
  • a substituted C2-6 alkynyl group an unsubstituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted heterocycle Group, unsubstituted or substituted C1-7 acyl group, C1-6 alkoxy group, C1-6 haloalkyl group, unsubstituted or substituted carboxyl group, unsubstituted or substituted aminocarbonyl group An unsubstituted or substituted hydroxyl group, an unsubstituted or substituted mercapto group, a substituted sulfonyl group, A group or a nitro group.
  • n represents the number of R 1 and is an integer from 0 to 4.
  • Two adjacent R 1 on the benzene ring may be taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 5- to 7-membered ring.
  • R 2 represents a hydrogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, A substituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted heterocyclic group, or a C1-6 haloalkyl group is shown.
  • R 3 is a hydrogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, A substituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted heterocyclic group, or a C1-6 haloalkyl group is shown.
  • R 4 represents an unsubstituted or substituted C1-6 alkyl group. Two OR 4 may be taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 5- to 7-membered ring.
  • X represents a halogeno group.
  • a 3-hydroxyquinoline derivative useful as a production intermediate for agricultural medicine and the like can be obtained in a high yield under mild conditions.
  • the production method of the present invention is suitable for mass production on an industrial scale.
  • the method for producing a 3-hydroxyquinoline derivative represented by formula (3) according to the present invention comprises an aniline compound represented by formula (1) (
  • the reaction may be simply performed between the “aniline compound (1)” and the halooxirane compound represented by the formula (2) (hereinafter sometimes simply referred to as “halooxirane compound (2)”).
  • the method for producing a quinoline derivative (3) according to the present invention comprises an N-substituted aniline compound represented by the formula (4) (hereinafter sometimes simply referred to as “N-substituted aniline compound (4)”). And reacting in the presence of an acid.
  • the N-substituted aniline compound (4) can be obtained by the production method according to the present invention including the step of reacting the aniline compound (1) with the halooxirane compound (2).
  • the N-substituted aniline compound (4) according to the present invention is a novel compound useful as an intermediate for producing the quinoline derivative (3) according to the present invention.
  • the aniline compound (1) used in the present invention is represented by the formula (1).
  • each R 1 is independently a halogeno group, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, unsubstituted or substituted A C2-6 alkynyl group having a group, an unsubstituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted heterocyclic group, Unsubstituted or substituted C1-7 acyl group, C1-6 alkoxy group, C1-6 haloalkyl group, unsubstituted or substituted carboxyl group, unsubstituted or substituted aminocarbonyl group, A substituted or substituted hydroxyl group, an unsubstituted or substituted mercapto group, a substituted sulfonyl group, a cyano group, A nitro group.
  • R 1 examples that can be R 1 include a halogeno group, an unsubstituted or substituted C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a cyano group, and a nitro group. More preferable examples that can be R 1 include a halogeno group, an unsubstituted C1-6 alkyl group, and a C1-6 alkoxy group.
  • n represents the number of R 1 and is an integer from 0 to 4. Preferably, n is an integer from 0 to 2.
  • Two adjacent R 1 on the benzene ring may be combined with the carbon atom to which they are bonded to form an unsubstituted or substituted 5- to 7-membered ring.
  • the term “unsubstituted” means only a group serving as a mother nucleus. In the present specification, when there is no description of “having a substituent” and only the name of the group serving as a mother nucleus is used, it means “unsubstituted” unless otherwise specified.
  • the term “having a substituent” means that any hydrogen atom in the group serving as the mother nucleus is substituted with a group having the same or different structure from the mother nucleus.
  • the number of substituents may be one, or two or more. Two or more substituents may be the same or different. Terms such as “C1-6” indicate that the number of carbon atoms of the group serving as the mother nucleus is 1-6. This number of carbon atoms does not include the number of carbon atoms present in the substituent. For example, a butyl group having an ethoxy group as a substituent is classified as a C2 alkoxy C4 alkyl group.
  • the “substituent” is not particularly limited as long as it is chemically acceptable and has the effects of the present invention.
  • groups that can be “substituents” are shown below.
  • 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.
  • alkyl group 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 C3-6 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group;
  • a C4-8 cycloalkenyl group such as a 2-cyclopentenyl group, a 3-cyclohexenyl group, a 4-cyclooctenyl group;
  • a C6-10 aryl group such as a phenyl group or a naphthyl group;
  • a C7-11 aralkyl group such as a benzyl group or a phenethyl 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 1-naphthoxy group; A C7-11 aralkyloxy group such as a benzyloxy group or a phenethyloxy group;
  • a C1-7 acyl group such as a formyl group, an acetyl group, a propionyl group, a benzoyl group, a cyclohexylcarbonyl group; C1-7 acyloxy groups such as formyloxy group, acetyloxy group, propionyloxy group, benzoyloxy group, cyclohexylcarbonyloxy group;
  • a C1-6 alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, a t-butoxycarbonyl group; Carboxyl 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 C2-6 haloalkenyl group such as a 2-chloro-1-propenyl group and a 2-fluoro-1-butenyl group;
  • a C2-6 haloalkynyl group such as 4,4-dichloro-1-butynyl group, 4-fluoro-1-pentynyl group, 5-bromo-2-pentynyl group;
  • C6-10 haloaryl group such as 4-chlorophenyl group, 4-fluorophenyl group, 2,4-dichlorophenyl group;
  • a C1-6 haloalkoxy group such as a trifluoromethoxy group, 2-chloro-n-propoxy group, 2,
  • a C1-6 alkylamino group such as a methylamino group, a dimethylamino group, a diethylamino group; C6-10 arylamino groups such as anilino group and naphthylamino group; A C7-11 aralkylamino group such as a benzylamino group or a phenethylamino group; C1-7 acylamino groups such as formylamino group, acetylamino group, propanoylamino group, butyrylamino group, i-propylcarbonylamino group, benzoylamino group; A C1-6 alkoxycarbonylamino group such as a methoxycarbonylamino group, ethoxycarbonylamino group, n-propoxycarbonylamino group, i-propoxycarbonylamino group; An aminocarbonyl group having no substituent or a substituent such as an aminocarbonyl group,
  • a mercapto group such as methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, s-butylthio group, t-butylthio group;
  • a C6-10 arylthio group such as a phenylthio group or a naphthylthio group;
  • a heteroarylthio group such as a thiazolylthio group or a pyridylthio group;
  • a C7-11 aralkylthio group such as a benzylthio group or a phenethylthio group;
  • a C1-6 alkylsulfonyl group such as a methylsulfonyl group, an ethylsulfonyl group, a t-butylsulfonyl group;
  • 5-membered heteroaryl groups such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl;
  • a 6-membered heteroaryl group such as a pyridyl group, pyrazinyl group, pyrimidinyl group, pyridanidyl group, triazinyl group;
  • Saturated heterocyclic groups such as aziridinyl group, epoxy group, pyrrolidinyl group, tetrahydrofuranyl group, piperidyl group, piperazinyl group, morpholinyl group, dioxolane ring and dioxane ring;
  • Cyano group nitro group; A tri-C1-6 alkyl-substituted silyl group such as a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group; A triaryl-substituted silyl group such as a triphenylsilyl group;
  • At least one hydrogen atom therein may be substituted with a group having the same or different structure.
  • an alkyl group in which a hydrogen atom is substituted with an alkoxy group that is, an alkoxyalkyl group
  • preferable groups that can be “substituents” are halogeno groups, C1-6 alkyl groups, C3-6 cycloalkyl groups, C1-6 alkoxy groups, hydroxyl groups, C1-6 haloalkyl groups, C1. -6 haloalkoxy group, cyano group, or nitro group.
  • examples of the halogeno group include the same groups as those exemplified as the halogeno group in the above “substituent”.
  • a preferred example of the halogeno group is a fluoro group.
  • the unsubstituted C1-6 alkyl group may be the same as those exemplified as the C1-6 alkyl group in the above-mentioned “substituent”.
  • Preferable examples of the unsubstituted C1-6 alkyl group include a methyl group.
  • Specific examples of the C1-6 alkyl group having a substituent include the C1-6 haloalkyl group and the C7-11 aralkyl group in the above-mentioned “substituent”.
  • the unsubstituted C2-6 alkenyl group may be the same as those exemplified as the C2-6 alkenyl group in the above-mentioned “substituent”.
  • Specific examples of the C2-6 alkenyl group having a substituent include the C2-6 haloalkenyl group in the above-mentioned “substituent”.
  • examples of the unsubstituted C2-6 alkynyl group include the same groups as those exemplified as the C2-6 alkynyl group in the above-mentioned “substituent”.
  • Specific examples of the C2-6 alkynyl group having a substituent include the C2-6 haloalkynyl group in the above-mentioned “substituent”.
  • the unsubstituted C3-6 cycloalkyl group may be the same as those exemplified as the C3-6 cycloalkyl group in the above-mentioned “substituent”.
  • the unsubstituted C6-10 aryl group may be the same as those exemplified as the C6-10 aryl group in the above-mentioned “substituent”.
  • preferred groups that can be a substituent include halogeno group, C1-6 alkyl group, C3-6 cycloalkyl group, C1-6 alkoxy group, hydroxyl group, C1-6 haloalkyl group, C1-6 haloalkoxy group, cyano group, nitro group and the like can be mentioned.
  • examples of the unsubstituted heterocyclic group are the same as those exemplified as the 5-membered heteroaryl group, 6-membered heteroaryl group, and saturated heterocyclic group in the above-mentioned “substituent”. be able to.
  • preferred groups that can be a substituent include halogeno group, C1-6 alkyl group, C3-6 cycloalkyl group, C1-6 alkoxy group, hydroxyl group, C1-6 haloalkyl group, C1 ⁇ A 6-haloalkoxy group, a cyano group, a nitro group and the like can be mentioned.
  • the unsubstituted C1-7 acyl group may be the same as those exemplified as the C1-7 acyl group in the above-mentioned “substituent”.
  • Specific examples of the C1-7 acyl group having a substituent include the C1-7 haloacyl group in the above-mentioned “substituent”.
  • examples of the C1-6 alkoxy group include the same groups as those exemplified as the C1-6 alkoxy group in the above-mentioned “substituent”.
  • Preferable examples of the C1-6 alkoxy group include a methoxy group.
  • examples of the C1-6 haloalkyl group include the same groups as those exemplified as the C1-6 haloalkyl group in the above-mentioned “substituent”.
  • Preferable examples of the C1-6 haloalkyl group include a trifluoromethyl group.
  • Specific examples of the carboxyl group having a substituent in R 1 include the C1-6 alkoxycarbonyl group in the above-mentioned “substituent”.
  • the aminocarbonyl group having a substituent may be the same as those exemplified as the aminocarbonyl group having a substituent in the “substituent”.
  • the hydroxyl group having a substituent includes a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C6-10 aryloxy group, a C7-11 aralkyl group in the above-mentioned “substituent”.
  • Specific examples include an oxy group, a C1-7 acyloxy group, a C1-6 haloalkoxy group, a C2-6 haloalkenyloxy group, and the like.
  • mercapto group having a substituent in R 1 include the C1-6 alkylthio group, the C6-10 arylthio group, the heteroarylthio group, and the C7-11 aralkylthio group in the above-mentioned “substituent”. be able to.
  • the sulfonyl group having a substituent specifically includes a C1-6 alkylsulfonyl group, a C6-10 arylsulfonyl group, a heteroarylsulfonyl group, a C7-11 aralkylsulfonyl group, etc. in the above-mentioned “substituent”. Can be listed.
  • An unsubstituted or substituted 5- to 7-membered ring formed by combining two adjacent R 1 on the benzene ring with the carbon atom to which they are bonded includes an aromatic hydrocarbon ring such as a benzene ring; C5-7 cycloalkene ring such as cyclopentene ring, cyclohexene ring, cycloheptene ring; furan ring, thiophene ring, pyrrole ring, imidazole ring, pyrazole ring, thiazole ring, oxazole ring, isoxazole ring, pyridine ring, pyrazine ring, Aromatic 5- to 7-membered heterocycles such as a pyrimidine ring, pyridazine ring, azepine ring, and diazepine ring; And so on.
  • aniline compound (1) Specific examples of the aniline compound (1) are shown in Table 1. Incidentally, Table 1 in the (R 1) n is an aniline compound (1) in the (R 1) n. The substitution position of R 1 is the position of the number shown beside the benzene ring in formula (1).
  • the halooxirane compound (2) used in the present invention is represented by the formula (2).
  • R 2 is a hydrogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted group A C2-6 alkynyl group having an unsubstituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted heterocyclic group, or C1-6 haloalkyl group.
  • R 3 is a hydrogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, A substituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted heterocyclic group, or a C1-6 haloalkyl group is shown.
  • R 4 each independently represents an unsubstituted or substituted C1-6 alkyl group. Two OR 4 may be taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 5- to 7-membered ring.
  • X represents a halogeno group.
  • an unsubstituted or substituted C1-6 alkyl group an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, unsubstituted or Examples of the substituted C3-6 cycloalkyl group, unsubstituted or substituted C6-10 aryl group, unsubstituted or substituted heterocyclic group, and C1-6 haloalkyl group include the above R 1. The same thing as what was illustrated in can be mentioned.
  • R 2 include a hydrogen atom, an unsubstituted or substituted C1-6 alkyl group, a C1-6 haloalkyl group, an unsubstituted or substituted C6-10 aryl group. . Of these, unsubstituted C1-6 alkyl groups are more preferred. Preferable examples of the unsubstituted C1-6 alkyl group include a methyl group.
  • an unsubstituted or substituted C1-6 alkyl group an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, unsubstituted or Examples of the substituted C3-6 cycloalkyl group, unsubstituted or substituted C6-10 aryl group, unsubstituted or substituted heterocyclic group, and C1-6 haloalkyl group include the above R 1. The same thing as what was illustrated in can be mentioned.
  • R 3 Preferable examples that can be R 3 include a hydrogen atom, an unsubstituted or substituted C1-6 alkyl group, a C1-6 haloalkyl group, an unsubstituted or substituted C6-10 aryl group. . Of these, a hydrogen atom is more preferable.
  • Examples of the unsubstituted or substituted C1-6 alkyl group in R 4 are the same as those exemplified for R 1 above.
  • Preferable examples that can be R 4 include an unsubstituted C1-6 alkyl group.
  • Preferable examples of the unsubstituted C1-6 alkyl group include an ethyl group.
  • Examples of the unsubstituted or substituted 5- to 7-membered ring formed by two OR 4 together with the carbon atom to which they are bonded include a dioxolane ring and a dioxane ring.
  • the halogeno group may be the same as those exemplified as the halogeno group in the above-mentioned “substituent”.
  • a preferred example of the halogeno group is a chloro group.
  • the halooxirane compound (2) can be prepared by the method described in Non-Patent Document 2. Specific examples of the halooxirane compound (2) are shown in Table 2. Incidentally, X in Table 2, R 2, R 3, and R 4 X in a halo oxirane compound (2), R 2, R 3, and an R 4.
  • R 1 to R 4 , X, and n have the same meaning as described above.
  • R 1 to R 4 , X, and n have the same meaning as described above.
  • a symbol “ ⁇ ” indicating an unpaired electron is shown in order to emphasize that an unpaired electron exists in the nitrogen atom.
  • the N-substituted aniline compound (4) is useful as a reaction precursor for the quinoline derivative (3).
  • N-substituted aniline compound (4) Specific examples of the N-substituted aniline compound (4) are shown in Table 3.
  • Table 3 (R 1) n, R 2 , R 3, R 4, and X is the compound (4) in the (R 1) n, R 2 , R 3, R 4, and a X.
  • the substitution position of R 1 is the position of the number shown beside the benzene ring in formula (4).
  • the base used in the reaction described in scheme (1) is not particularly limited as long as it does not inhibit the reaction. Specifically, triethylamine, diethylamine, diisopropylamine, dicyclohexylamine, diisopropylethylamine, pyrrolidine, piperidine, 1,8-diazabicyclo [5,4,0] -7-undecene (DBU), pyridine, t-butylamine, cyclohexylamine Amine compounds such as sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium fluoride, cesium fluoride, sodium hydrogen carbonate, potassium hydrogen carbonate and other alkali metal salts; lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.
  • DBU 1,8-diazabicyclo [5,4,0] -7-undecene
  • Alkali metal hydroxides quaternary ammonium salts such as tetrabutylammonium fluoride and tetrabutylammonium hydroxide; potassium t-butoxide, sodium methoxide, sodium phenoxy And alkali metal alkoxides such as n-butyllithium; organometallic compounds such as n-butyllithium, ethylmagnesium chloride and diethylzinc;
  • bases can be used singly or in combination of two or more.
  • the base is used in an amount of 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of aniline compound (1).
  • a solvent can be used. In some cases, it may be solvent-free.
  • the solvent is not particularly limited as long as the reaction is not inhibited.
  • ether solvents such as tetrahydrofuran, 1,4-dioxane, diethyl ether, dimethoxyethane, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether; hydrocarbons such as benzene, toluene, heptane, hexane, cyclohexane
  • Solvents aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone; methanol, ethanol, isopropyl Alcohols such as alcohol, ethylene glycol and ethylene glycol monomethyl ether; amines such as
  • the volume (L) of the solvent used is preferably 1 L / kg to 100 L / kg, more preferably 3 L / kg to 30 L / kg with respect to the weight (kg) of the aniline compound (1).
  • the reaction is carried out with stirring.
  • the temperature during the reaction is a suitable temperature from the melting point of the solvent to the boiling point of the solvent, preferably a temperature in the range of ⁇ 80 ° C. to 150 ° C.
  • the reaction time can be appropriately set according to the reaction rate, but is preferably 3 to 50 hours, more preferably 6 to 24 hours.
  • the method for producing a 3-hydroxyquinoline derivative according to the present invention includes reacting an N-substituted aniline compound (4) in the presence of an acid as shown in Scheme (2).
  • a reaction for converting acetal to carbonyl proceeds, and the carbonyl compound represented by the formula (4 ′) (hereinafter, simply referred to as “carbonyl compound (4 ′)” may be used. ) Is generated.
  • the carbonyl carbon formed by the reaction is nucleophilic attacked by the electron-rich o-position carbon on the benzene ring activated by the lone pair of electrons derived from the amino group on the aniline ring, thereby closing the partially unsaturated pyridine ring.
  • the acid used in the reaction described in Scheme (2) is not particularly limited as long as it does not inhibit the reaction.
  • a protonic acid can be mentioned.
  • inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, fuming sulfuric acid, sulfane, phosphoric acid, boric acid; formic acid, acetic acid, citric acid, oxalic acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, Examples thereof include organic acids such as trifluoromethanesulfonic acid; cation exchange resins.
  • Protic acids may be used alone or in combination of two or more.
  • a Lewis acid that is physically stable can be used.
  • acids can be used alone or in combination of two or more.
  • acids in the case of a solution-like proton acid, it may be used as a solvent.
  • the acid is preferably used in an amount of 1 to 100 mol, more preferably 1 to 10 mol, per 1 mol of the N-substituted aniline compound (4).
  • a solvent can be used. In some cases, it may be solvent-free.
  • the solvent that can be used for the reaction is not particularly limited as long as the reaction is not inhibited.
  • ether solvents such as tetrahydrofuran, 1,4-dioxane, diethyl ether, dimethoxyethane, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether; hydrocarbons such as benzene, toluene, heptane, hexane, cyclohexane
  • Solvents aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone; methanol, ethanol, isopropyl Alcohols such as alcohol, ethylene glycol and ethylene glycol monomethyl
  • the volume (L) of the solvent used is preferably 1.0 L / kg to 100 L / kg, more preferably 3 L / kg to 30 L / kg with respect to the weight (kg) of the N-substituted aniline compound (4). .
  • the reaction is carried out with stirring.
  • the temperature during the reaction is an appropriate temperature between the melting point of the solvent and the boiling point of the solvent, preferably in the range of ⁇ 80 ° C. to 150 ° C.
  • the reaction time can be appropriately set according to the reaction rate, but is preferably 3 to 50 hours, more preferably 6 to 24 hours.
  • the 3-hydroxyquinoline derivative obtained by the production method according to the present invention is represented by the formula (3).
  • R 1 , R 2 , R 3 and n have the same meaning as described above.
  • Step 2 Preparation of 7,8-difluoro-2-methylquinolin-3-ol 2-Chloro-1,1-diethoxy-3- (2,3-difluorophenylamino) butan-2-ol 971 mg (3 mmol) was dissolved in 9 ml of ethanol. To this solution, 3 ml of 6N hydrochloric acid (equivalent to 18 mmol of hydrogen chloride) was added and refluxed for 3 hours. Then, it cooled to room temperature and adjusted pH to 7 with saturated sodium hydrogen carbonate solution. The resulting product was extracted with ethyl acetate. The organic phase was washed with water and then with saturated brine.
  • 6N hydrochloric acid equivalent to 18 mmol of hydrogen chloride
  • Step 1 Preparation of 7-fluoro-2-methylquinolin-3-ol (Step 1) Preparation of 2-chloro-1,1-diethoxy-3- (3-fluorophenylamino) butan-2-ol 3 -222 mg (2 mmol) of fluoroaniline was dissolved in 1 ml of toluene. To this solution, 3 ml of saturated aqueous sodium hydrogen carbonate (equivalent to 3.2 mmol of sodium bicarbonate) was added and stirred. To this was added 584 mg (3 mmol) of 2-chloro-2- (diethoxymethyl) -3-methyloxirane, and the mixture was stirred at room temperature for 24 hours.
  • Step 2 Preparation of 7-fluoro-2-methylquinolin-3-ol 483 mg (1.58 mmol) of 2-chloro-1,1-diethoxy-3- (3-fluorophenylamino) butan-2-ol was ethanol Dissolved in 4.8 ml. To this solution, 1.6 ml of 6N hydrochloric acid (equivalent to 9.6 mmol of hydrogen chloride) was added and refluxed for 3 hours. Then, it cooled to room temperature and adjusted pH to 7 with saturated sodium hydrogen carbonate solution. The resulting product was extracted with ethyl acetate. The organic phase was washed with water and then with saturated brine.
  • 6N hydrochloric acid equivalent to 9.6 mmol of hydrogen chloride
  • Example 5 Preparation of 7,8-difluoro-2-methylquinolin-3-ol 700 mg of 2-chloro-1,1-diethoxy-3- (2,3-difluorophenylamino) butan-2-ol (2 .13 mmol) was dissolved in 3 ml of toluene. To this solution, 470 mg (2.42 mmol) of p-toluenesulfonic acid monohydrate was added and refluxed for 2 hours. Then, it cooled to room temperature and washed the reaction solution with water. The organic layer was dried over magnesium sulfate and then the solvent was distilled off.
  • Step 1 Production of 2,7,8-trimethylquinolin-3-ol (Step 1) of 2-chloro-1,1-diethoxy-3- (2,3-dimethylphenylamino) butan-2-ol Production: To 12 ml of toluene containing 12.37 mmol of 2-chloro-2- (diethoxymethyl) -3-methyloxirane, 1.00 g (8.25 mmol) of 2,3-dimethylaniline, 0.83 g (9.87 mmol) of sodium bicarbonate, Then, 19 ml of water was sequentially added, followed by stirring at 40 to 50 ° C. for 4 hours.
  • Example 2 The same post treatment as in Step 1 was carried out, and 2.25 g (7.12 mmol, yield 86) of 2-chloro-1,1-diethoxy-3- (2,3-dimethylphenylamino) butan-2-ol %)was gotten.
  • the results of 1 H-NMR analysis of the obtained compound were as follows.
  • Step 2 Preparation of 2,7,8-trimethylquinolin-3-ol 2.20 g of 2-chloro-1,1-diethoxy-3- (2,3-dimethylphenylamino) butan-2-ol (6. 97 mmol) was dissolved in 20 ml of ethanol. To this solution, 10 ml of 6N hydrochloric acid (equivalent to 60 mmol of hydrogen chloride) was added and refluxed for 2 hours. Example 2 The same post-treatment as in Step 2 was carried out to obtain 1.14 g (6.09 mmol, yield 88%) of 2,7,8-trimethylquinolin-3-ol. Melting point 202-205 ° C The results of 1 H-NMR analysis of the obtained compound were as follows. 1 H-NMR (400 MHz, CDCl 3 ) ⁇ 7.35-7.10 (m, 3H), 4.77 (bs, 1H), 2.69 (s, 3H), 2.65 (s, 3H), 2.40 (s, 3H).
  • Step 1 Production of 8-methoxy-2-methylquinolin-3-ol (Step 1) Production of 2-chloro-1,1-diethoxy-3- (2-methoxyphenylamino) butan-2-ol 2 To 12 ml of toluene containing 12.15 mmol of -chloro-2- (diethoxymethyl) -3-methyloxirane, 1.00 g (8.12 mmol) of 2-methoxyaniline, 0.82 g (9.76 mmol) of sodium bicarbonate, and 19 ml of water were added. After the sequential addition, the mixture was stirred at 40 to 50 ° C. for 4 hours.
  • Example 2 The same post-treatment as in Step 1 was performed, and 2.04 g (6.42 mmol, yield 79%) of 2-chloro-1,1-diethoxy-3- (2-methoxyphenylamino) butan-2-ol was gotten.
  • the results of 1 H-NMR analysis of the obtained compound were as follows. 1 H-NMR (400 MHz, CDCl 3 ) ⁇ 6.85-6.55 (m, 4H), 4.81 (bs, 1H), 4.76 (s, 1H), 4.58 (bs, 1H), 3.85 (s, 3H), 3.80 -3.45 (m, 4H), 1.43 (d, 3H), 1.35-1.20 (m, 6H).
  • Step 2 Preparation of 8-methoxy-2-methylquinolin-3-ol 2-chloro-1,1-diethoxy-3- (2-methoxyphenylamino) butan-2-ol 2.00 g (6.29 mmol) was dissolved in 20 ml of ethanol. To this solution, 10 ml of 6N hydrochloric acid (equivalent to 60 mmol of hydrogen chloride) was added and refluxed for 2 hours.
  • Example 2 The same post-treatment as in Step 2 was carried out to obtain 1.16 g (6.13 mmol, yield 97%) of 8-methoxy-2-methylquinolin-3-ol. Melting point 222-225 ° C
  • the production method according to the present invention is a method suitable for producing a large amount of a 3-hydroxyquinoline derivative useful as an intermediate for producing agricultural medicines on an industrial scale.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Selon l'invention, on fait réagir un composé d'aniline tel que l'aniline, la 2,3-difluoroaniline ou la 3-fluoroaniline ; et un composé d'halogéno-oxirane tel que le 2-chloro-2-(diéthoxyméthyl)-3-méthyloxirane et analogues en présence d'une base, telle que le bicarbonate de sodium, pour obtenir un composé d'aniline N-substitué, tel que le 2-chloro-1,1-diéthoxy-3-(phénylamino)butan-2-ol, le 2-chloro-3-(2,3-difluoroamino)-1,1-diéthoxybutan-2-ol ou le 2-chloro-1,1-diéthoxy-3-(3-fluorophénylamino)butan-2-ol ; puis on fait réagir le composé d'aniline N-substitué en présence d'un acide tel que l'acide chlorhydrique pour obtenir un dérivé de 3-hydroxyquinoléine tel que le 2-methylquinoléin-3-ol, le 7,8-difluoro-2-méthylquinoléin-3-ol ou le 7-fluoro-2-méthylquinoléin-3-ol, le 5-fluoro-2-méthylquinolein-3-ol.
PCT/JP2013/077490 2012-10-22 2013-10-09 Nouveau procédé pour synthétiser un dérivé de 3-hydroxyquinoléine WO2014065122A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5414977A (en) * 1977-07-02 1979-02-03 Bayer Ag Production of quinoline derivative
WO2011081174A1 (fr) * 2010-01-04 2011-07-07 日本曹達株式会社 Compose heterocyclique contenant de l'azote et germicide agricole/horticole

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5414977A (en) * 1977-07-02 1979-02-03 Bayer Ag Production of quinoline derivative
WO2011081174A1 (fr) * 2010-01-04 2011-07-07 日本曹達株式会社 Compose heterocyclique contenant de l'azote et germicide agricole/horticole

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GUSEINOV, F. I. ET AL.: "Functionally substituted a-chlorooxiranes. Synthesis and rearrangement", ZHURNAL ORGANICHESKOI KHIMII, vol. 31, no. 8, 1995, pages 1131 - 1133 *

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