JPH04210974A - Production of aminoketones - Google Patents

Abstract

PURPOSE:To obtain a new aminoketones useful as a central muscle relaxant by reacting a secondary alcohol in the presence of hypohalides and pyridines and reacting the resultant product with amines in the presence of an aqueous solution of formaldehyde. CONSTITUTION:A compound expressed by formula I [R is formula II to formula VI (R3 is halogen, alkyl, benzyl, furyl, phenyl, etc.; R4 and R5 are phenyl or naphthyl; W is O or S); R1 is H, alkyl, benzyl, methoxy, etc.; R2 is H of alkyl] is reacted in the presence of a compound expressed by the formula M(O-X)n [M is alkali(earth) metal; n is 1 or 2] and compound expressed by the formula VII (Y and Z are H or alkyl) to provide ketones expressed by formula VIII. Then the resultant compound is reacted with amines expressed by the formula NHR6R7 (R6 and R7 are alkyl or mutually bonded to form 5-8 membered ring together with N) in the presence of formamide aqueous solution to provide the compound expressed by formula IX, e.g. 5-(2-piperidinomethylpropionyl)-3- phenylisoxazole.

Description

[Detailed description of the invention]

[00011

[Industrial Field of Application] The present invention relates to a method for producing aminoketones and intermediates thereof useful as central muscle relaxants. [0002] More specifically, the compound RC of general formula [I]
HOH-CHRIR2 is oxidized to produce a compound RCOCHRI R2 of the general formula [IV], and from this compound a compound RCo CRI R2CH2 of the general formula [VI] is produced.
The present invention relates to a method of manufacturing NR6R7. [0003] The meanings of R1R1, R2, R6, and R7 will be described later. [0004] Compounds of general formula [V I ] are novel compounds and are useful as central muscle relaxants. [0005] [Prior Art and its Problems] Heavy metals such as chromic acid are generally known as oxidizing agents in the method for producing ketones from secondary alcohols. [0006] However, heavy metals are biologically or otherwise harmful, and their use in pharmaceutical manufacturing methods is undesirable. [0007] As a method using another oxidizing agent that does not use heavy metals, for example, a method using a combination of sodium hypochlorite and a phase transfer catalyst (G, A, Lee et al.
etrahedron Letters, p. 1641, 1976) or a method using calcium hypochlorite in the presence of an acidic solvent such as acetic acid (S, D, Nwa
Tetrahedron Letters such as vkwa,
35, 1982), but these oxidation methods produce alcohols of general formula [IV] rather than alcohols of general formula [I].
] Ketones could not be produced. [0008] Further, as a method for producing aminoketones from ketones, for example, a method is known in which ketones are reacted with paraformaldehyde and amine hydrochlorides in an alcohol solvent in the presence of concentrated hydrochloric acid (Japanese Patent Application Laid-Open No. 119444/1982). However, in the aminoketones produced by this method, the amine moiety becomes a hydrochloride, so it is necessary to generate free aminoketones through a neutralization reaction with an appropriate alkaline agent, such as aqueous ammonia or aqueous sodium hydroxide solution. However, inconveniences such as increased manufacturing costs and complicated manufacturing processes are unavoidable. [0009]

[Means for Solving the Problems] The present invention has been made to solve the above-mentioned problems, and is directed to a compound having an excellent effect as a central muscle relaxant, that is, a compound of the general formula [VI
]CO R1 2 CH2 R6 7 [VI] In producing aminoketones represented by the formula [
I] RCHOHCHRI R2... Alcohols represented by [I] are represented by the general formula [II]M (0-X)
... Hypohalides represented by [II] and general formula [III]

0010

[Chemical formula 3] A reaction is carried out in the presence of a pyridine represented by the general formula [III] or an acid addition salt thereof to produce a ketone represented by the general formula [IV] R-Co-CHRI R2...[IV], Furthermore, the general formula [V]NHR6R7・
... [V] It is characterized by reacting the amines represented by these in the presence of an aqueous formaldehyde solution. [00111 That is, the production method of the present invention is based on the following reaction formula (1)
% formula % (2) ]

[4] M(0-X), ll and [II or acid addition salt thereof [III] Represented by an aqueous formaldehyde solution. (Each symbol will be explained below.) Alcohols As already stated, the alcohols used as starting materials in the production method of the present invention have the following general formula [I]RCHO
HCHRI R2...Represented by [I]. [0013] General formula % formula %]

[5] [] [0015] However, R3 is halogen; lower alkyl group;
Benzyl group; benzoyl group; pyridyl group; furyl group optionally substituted with lower alkyl group; thienyl group optionally substituted with lower alkyl group; halogen, lower alkoxy group, lower alkyl group, trifluoromethyl group, Represents a phenyl group which may be substituted with a cyano group, a nitro group, an amino group, a dimethylamino group, an acetamido group, a methanesulfonylamide group, an acetyl group or a lower alkoxycarbonyl group; or a naphthyl group. Further, R4 and R5 each independently represent a phenyl group or a lower alkyl group, and W represents an oxygen atom or a sulfur atom, respectively. [0016] R+ represents a hydrogen atom; a lower alkyl group; a benzyl group; a methoxy group; a phenyl group; an allyl group; a lower alkyl group substituted with a trifluoromethyl group or a lower alkoxy group; or a cyclopropylmethyl group. [0017] R2 each represents a hydrogen atom or a lower alkyl group, or R1 and R2 may be linked to form an alicyclic five- or six-membered ring. [0018] The lower alkyl group as R4 and R5 is preferably an alkyl group having 1 or 2 carbon atoms,
The lower alkyl group as R3 is preferably an alkyl group having 1 to 3 carbon atoms, and the lower alkyl group substituted with the furyl group or thienyl group as R3 is preferably an alkyl group having 1 to 3 carbon atoms.
-3 alkyl groups are preferred, and the alkoxy groups of the lower alkoxy group, lower alkyl group, and lower alkoxycarbonyl group substituted by the phenyl group as R3 are preferably those having 1 or 2 carbon atoms. [0019] Furthermore, as the lower alkyl group as R1, an alkyl group having 1 to 4 carbon atoms is preferable, and as the lower alkyl group substituted with a lower alkoxy group as R1,
A lower alkyl group having 1 or 2 carbon atoms substituted with an alkoxy group having 1 or 2 carbon atoms is preferred. [00201 Furthermore, the lower alkyl group as R2 is preferably an alkyl group having 1 or 2 carbon atoms. Hypohalides On the other hand, the hypohalides to be reacted with the alcohols of the above general formula [I] are of the following general formula [II]M (0-X
)...Represented by [II]. [00211 In the general formula [II], M represents an alkali metal or an alkaline earth metal. Examples of alkali metals include lithium, sodium, potassium,
Examples include cesium. [0022] Examples of alkaline earth metals include magnesium, calcium, strontium, barium, and the like. [0023] Group X represents a halogen atom, such as chlorine, bromine, and iodine. n represents 1 when M is an alkali metal, and represents 2 when M is an alkaline earth metal. Pyridines and their acid addition salts and alcohols of the above general formula [I] can be added to the alcohols of the above general formula [I].
The pyridine to be reacted with the hypohalide of [II] has the following general formula [III] [0024]

[0025] In the general formula [III], the groups Y and Z represent a hydrogen atom or a lower alkyl group.Specifically, such pyridines include [0026]

[Image Omitted] [Image Omitted] [0027] Furthermore, examples of acid addition salts of pyridines of general formula [III] include hydrochloric acid, hydrobromic acid, nitric acid,
Examples include addition salts with mineral acids such as sulfuric acid and phosphoric acid, and organic acids such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, acetic acid, and propionic acid. It may also be present with pyridines of formula [III]. Ketones Ketones produced from the above general formula [I] are represented by the following general formula [IV] R-CO-CHR+ R2...[IV]. [0028] In general formula [IV], R is [0029
]

[Chemical formula 8] represents or. [00301 However, R3 is halogen; lower alkyl group;
Benzyl group; benzoyl group; pyridyl group; furyl group optionally substituted with lower alkyl group; thienyl group optionally substituted with lower alkyl group; halogen, lower alkoxy group, lower alkyl group, trifluoromethyl group, Represents a phenyl group which may be substituted with a cyano group, a nitro group, an amino group, a dimethylamino group, an acetamido group, a methanesulfonylamide group, an acetyl group or a lower alkoxycarbonyl group; or a naphthyl group. Further, R4 and R5 each independently represent a phenyl group or a lower alkyl group, and W represents an oxygen atom or a sulfur atom, respectively. [0031] R+ represents a hydrogen atom; a lower alkyl group; a benzyl group; a methoxy group; a phenyl group; an allyl group; a lower alkyl group substituted with a trifluoromethyl group or a lower alkoxy group; or a cyclopropylmethyl group. [0032] R2 each represents a hydrogen atom or a lower alkyl group, or R1 and R2 may be linked to form an alicyclic five- or six-membered ring. [0033] The lower alkyl group as R4 and R5 is preferably an alkyl group having 1 or 2 carbon atoms,
The lower alkyl group as R3 is preferably an alkyl group having 1 to 3 carbon atoms, and the lower alkyl group substituted with the furyl group or thienyl group as R3 is preferably an alkyl group having 1 to 3 carbon atoms.
-3 alkyl groups are preferred, and the lower alkoxy group, lower alkyl group, and lower alkoxycarbonyl group substituted by the phenyl group as R3 preferably have 1 or 2 carbon atoms. [0034] Furthermore, as the lower alkyl group as R1, an alkyl group having 1 to 4 carbon atoms is preferable, and as the lower alkyl group substituted with a lower alkoxy group as R1,
A lower alkyl group having 1 or 2 carbon atoms substituted with an alkoxy group having 1 or 2 carbon atoms is preferred. [0035] Furthermore, the lower alkyl group as R2 is preferably an alkyl group having 1 or 2 carbon atoms. On the other hand, the amines to be reacted with the above general formula [IV] are represented by the following general formula [V] NHR6R7...[V]. [0036] In the general formula [V], groups R6 and R7
represents two types of groups: [0037] 1. Indicates a lower alkyl group, R6 and R
7 may be the same group or may be different groups from each other. [0038] 2. Re and R7 combine with each other,
Together with the nitrogen atom, it forms a 5- to 8-membered ring. This ring may have branches. [0039] The lower alkyl group of type 1 is:
Examples include methyl group, ethyl group, isopropyl group, and butyl group.

Furthermore, as type 2 5- to 8-membered rings, [00411

[Chemical Formula 9] Synthesis Reaction In the production method of the present invention, the alcohol of the above general formula [I] is mixed with the hypohalide [I] of the above general formula [II].
I] in the presence of pyridines of the above general formula [III] or acid addition salts thereof, to synthesize ketones of the above general formula [IV]. [0042] Furthermore, this ketone is represented by the above general formula [V]
The aminoketones of the general formula [VI] are synthesized by reacting the amines with the above in the presence of an aqueous formaldehyde solution. [0043] This synthesis reaction is represented by the reaction formula (1) and reaction formula (2) above. [0044] In the reaction formula (1), the general formula [IV]
The above general formula [II
] The hypohalides of formula [I] are usually used in a molar ratio of 0. It is used in a ratio of 5 to 20, preferably 1 to 5. [0045] These hypohalides of the general formula [II] can be used as an aqueous solution if necessary, and can be made to exist in the reaction solution by means such as dropping. [0046] Furthermore, the pyridine of the general formula [III] or its acid addition salt is usually used in a molar ratio of 0.01 to 10, preferably 0.1 to 5, to the alcohol of the general formula [I]. used in percentages. [0047] These pyridines of the general formula [III] or acid addition salts thereof may be mixed with water or acidic aqueous solutions such as acetic acid, hydrochloric acid, sulfuric acid, and phosphoric acid, alcohols such as methanol, ethanol, and isopropanol, Ethers such as dioxane, chloroform, dichloromethane, ■
, 2 dichloroethane, 1. 1. It can be used as a solution of halogenated hydrocarbons such as 2-trichloroethane, acetonitrile, dimethylformamide, etc., and made to exist in the reaction solution by dropping or the like. [0048] In addition, in the reaction, if necessary, hydrocarbons such as hexane, pentane, and cyclohexane, aromatic hydrocarbons such as benzene, toluene, and xylene, and alcohols such as methanol, ethanol, and isopropanol are used as reaction solvents. ethers such as tetrahydrofuran and dioxane, chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, 1. 1. 2-)
- halogenated hydrocarbons such as dichloroethane, esters such as methyl acetate, ethyl acetate, propyl acetate, and water;
Acetonitrile, dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, etc. can be used. [0049] The reaction is carried out by combining the alcohol of the general formula [I], the hypohalide of the general formula [II], and the pyridine of the general formula [III] or an acid addition salt thereof in the absence of a solvent or in the solvent. The temperature is usually between 150 and 50 degrees Celsius.
, preferably 0.5 to 4 in the temperature range of -30 to 40°C.
This is done by mixing and stirring for 8 hours. [00501] After the reaction is completed, the target ketones of general formula [IV] are separated by commonly used means such as solvent extraction. [00511 Furthermore, if necessary, purification means known per se such as recrystallization and chromatography may be appropriately employed. [0052] On the other hand, in the reaction formula (2), the general formula [
The amines of the general formula [V] used in the synthesis of the aminoketones of the general formula [IV] are usually in a molar ratio of 0.5 to 5, preferably 1 to the ketones of the general formula [IV].
It is used at a ratio of 1 to 2. [00531 Furthermore, the formaldehyde aqueous solution is usually used at a concentration of 5 to 50%, preferably 10 to 40%, and the molar ratio to the ketone of the general formula [IV] is usually 0.5 to 5, preferably 1. It is used at a ratio of 1 to 2. [0054] Further, in the reaction, alcohols such as methanol, ethanol, isopropanol, propatool, butanol, amyl alcohol, and isoamyl alcohol can be used as a reaction solvent if necessary. [0055] The reaction is carried out by converting the ketone of the general formula [IV] into -30 amines of the general formula [V] and in the presence of an aqueous formaldehyde solution without a solvent or in the solvent.
This is carried out by mixing and stirring for 0.5 to 24 hours at a temperature range of from -100°C to 100°C, preferably from -10 to 60°C. [0056] After the reaction is completed, the target aminoketones of the general formula [VI] are separated by commonly used means such as solvent extraction. [00571 Furthermore, purification means known per se, such as recrystallization and chromatography, may be employed as appropriate. [0058] According to the present invention, aminoketones of the general formula [VI], which are extremely useful as central muscle relaxants, can be produced by an industrially advantageous method. [0059] Furthermore, in this production method, when producing and using the alcohol of the general formula [I] as a starting material, if it can be produced using the hypohalide of the general formula [II], the general formula [ This production method has the advantage that the ketones of the general formula [IV], which are intermediates, can be produced in the same reaction vessel without isolating the alcohols of formula [I] from the reaction solution. [00601 The present invention will be explained in detail below using Examples. [00611

[Example] Reference example 15-(1-hydroxypropyl)3
-Phenyl isoxazole (compound of general formula [I])
Synthesis of; [0062] embedded image Benzaldoxime 2. 5g (20.7mmol
), ■-pentyn-3-ol2. Ig (25
,0 mmol) was dissolved in 12.5 ml of dichloromethane. [0063] 14.5 g of a 12.0% aqueous sodium hypochloride solution was added dropwise to this solution under water cooling. [0064] After completion of the dropwise addition, the reaction mixture was reacted at room temperature for 3 hours, and then the organic layer was extracted with dichloromethane. After washing with water, the organic layer was dried over anhydrous sodium sulfate. [0065] The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (chloroform elution) to obtain the target product, 5-(1-hydroxypropyl).
-3-Phenyl isoxazole was obtained as crystals. [0066] Yield 3. 3g (yield 78.7%
) Melting point 101-102°C NMR (δppm, CDC13) 1. 0 (
3H, t, J=8Hz) 1, 6-2. 2 (2H
, m) 3. 1 (LH, bs) 4゜9 (L
H, t, J=6Hz) 6. 5 (LH,s)
7. 3-7, 6 (3H, m) 7. 7
~7. 9 (2H,m) Reference Example 25-(1-hydroxybutyl)-3-phenylisoxazole (general formula [
Synthesis of compound I); [0067]

embedded image Benzaldoxime 5. 0g (41.3mmol
) and 1-hexyn-3-ol4. 5g (4
5.9 mmol) was dissolved in 25 ml of dichloromethane. [0068] 29.0 g of a 12.0% aqueous sodium hypochloride solution was added dropwise to this solution over 30 minutes while cooling with water. [0069] After the dropwise addition was completed, the reaction was continued at 20°C for 2 hours. [00701 After the reaction was completed, dichloromethane extraction was performed, and the organic layer was washed with water. [0071] After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. [0072] Purification of the residue by silica gel column chromatography (chloroform elution) yields the desired product 5
-(1-Hydroxybutyl)-3-phenylisoxazole was obtained as an oil. [0073] Yield 6. 5g (yield 72.5%
) NMR (δppm, CDC13) 0. 7～
1. 1 (3H, m) 1, 1-2. 1 (4
H, m) 3. 8 (LH, m) 4. 8(
LH, t, J=7Hz) 6.4 (LH, s)
7. 2-7゜5 (3H, m) 7. 5-7
．． 9 (2H,m)Example 15-propionyl-3-
Phenyl isoxazole (compound of general formula [IV])
Synthesis of; [0074]

embedded image 5-(i-hydroxypropyl)-3-phenylisoxazole 1. 0 g (5.0 mmol) was dissolved in 10 ml of dichloromethane. [0075] To this, 100 mg of pyridine hydrochloride (0
, 9 mmol 1), and further added 1.4 g (9.9 mmol) of calcium hypochloride,
Time reacted. [0076] After the reaction was completed, insoluble matter was filtered off, and the organic layer was washed with water. [0077] After drying the organic layer with anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain the desired 5-propionyl-3-phenylisoxazole as crystals. [0078] Yield 0. 9g (Yield 91.0%
) Melting point 111-112°C NMR (δppL CDC13) 1. 3 (3
H, t, J=8Hz) 3, 1 (2H, q, J
=8Hz) 7. 2 (3H,s) 7. 5
~8. 0 (5H, m) Example 2-1 Synthesis of 5-butyryl-3-phenylisoxazole (compound of general formula [IV]); [0079]

embedded image 4.4 g (20 mmol) of 5-'(1-hydroxybutyl)-3-phenylisoxazole was dissolved in 12.5 ml of dichloromethane. (00801 While stirring this solution, add 35.2 g of 12°7% sodium hypochlorite aqueous solution (6
0mm. l) was added dropwise. [0081] Next, a mixed solution (a solution of 0.48 g (6.1 mmol) of pyridine added to 1.0 ml of 6N hydrochloric acid) was added dropwise over 1 hour while maintaining the internal temperature at 20°C. [0082] After the reaction was completed, the organic layer was separated and washed successively with a 5% aqueous sodium bisulfite solution, water, and an IN aqueous hydrochloric acid solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain the desired 5-
Butyryl-3-phenylisoxazole was obtained as crystals. (0083) Yield 2.9g (Yield 66.5%
) Melting point 89-90°C NMR (δppm, CDC13) 1. 0
(3H, t, J=7Hz) 1, 5-2. 1 (
2H, m) 2. 0 (2H, t, J=7Hz
)7, 2 (IH,s) 7. 3-7. 6
(3H, m) 7. 6-8. 0 (2H, m
) Example 2-2 Synthesis of 5-butyryl-3-phenylisoxazole (compound of general formula [IV]); [0084]

embedded image Benzaldoxime 2. 5g (20.6mmol
) and 2.3 g of 1-hexyn-3-ol (22
, 9 mmol) was dissolved in 12.5 ml of dichloromethane. [0085] Under water cooling, 15.6 g of a 12% Na0Cl aqueous solution was added dropwise to this solution while maintaining the reaction temperature at 5°C. [0086] After that, stirring was continued for 3 hours at room temperature, and 5-(1
A reaction solution of -hydroxybutyl)-3-phenylisoxazole was obtained. [0087] Add 12% Na0C1 aqueous solution 39 to this solution.
．． Add 0.0 g of pyridine hydrochloride, and add 0.0 g of pyridine hydrochloride. 7g (6
, 1 mmol) in 3 ml of water at a reaction temperature of 15-20
It was added dropwise while keeping the temperature at °C. [0088] The reaction was further continued at the same temperature for 1 hour. [0089] After the reaction was completed, the organic layer was separated and washed successively with 5% aqueous sodium bisulfite solution, water, and IN aqueous hydrochloric acid solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain the desired 5-
Butyryl-3-phenylisoxazole was obtained as crystals.

Yield 2. 8g (yield 63.7%
) The melting point and NMR were consistent with that synthesized in Example 2-1. Examples 3 to 5 The same reaction as in Example 2-1 was carried out except that the alcohols shown in Table 1 were used in Example 2-1 to obtain the target substance of general formula [IV] shown in Table 1.
A compound of ketones was obtained. [0091]

[Table 1] Table Example 65-(2-piperidinomethylpropionyl)-
Synthesis of 3-phenylisoxazole (compound of general formula [VI]); [0092]

embedded image 5-propionyl-3-phenylisoxazole 2
°Og (10,0 mmol) and piperidine 1.
7g (20.0mmol) in 1 part ethyl alcohol
0 ml plus 1 ml of 37% formaldehyde aqueous solution under water cooling.
．． 63 ml (20.0 mmol) was added dropwise. After further stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. [0093] Dissolve the obtained residue in ethyl ether,
The organic layer was washed with water and then dried over anhydrous sodium sulfate. [0094] When the solvent is distilled off under reduced pressure, the desired 5(2
-piperidinomethylpropionyl)-3-phenylisoxazole was obtained as crystals. [0095] Yield 2. 3g (yield 78%) Melting point 114-116°C NMR (δppm, CDC13) 1. 3 (
3H, d, J=6Hz) 1, 5-1. 8 (6H
, m) 2. 3-3. 0 (6H, m)3, 5
~4. 0 (LH, m) 7. 2 (LH,s)
7. 5-7. 7 (3H, m) 7. 7-8
．． 0 (2H,m) Example 7 Synthesis of 5-(2-pyrrolidinomethylbutyryl)-3-phenylisoxazole (compound of general formula [VI]); [0096]

[Chemical formula 16] 200 g (0.93 mol) of 5-'(2-pyrrolidinomethylbutyryl)-3-phenylisoxazole and 110 ml (1.32 mol) of pyrrolidine were added to 400 ml of ethyl alcohol, and a mixture of 37% 120 ml (1.48 mol) of formaldehyde aqueous solution was added dropwise over 30 minutes. [0097] After further stirring at room temperature for 1.5 hours, the unreacted liquid was concentrated to dryness under reduced pressure. [0098] The obtained residue was dissolved in 1 liter of ethyl ether, washed with water, the organic layer was dried using anhydrous magnesium sulfate, the solvent was distilled off, and 5-(2-pyrrolidinomethylbutyryl)- 3-phenylisoxazole was obtained as colorless crystals. [0099] Yield 264g (yield 95.2%) Melting point 68-69°C NMR (δppm, CDC13) 0. 9 (
3H, t, J-7Hz) 1, 3-2. 0 (6H
, m) 7. 2 (IH,s) 7. 2~
7. 6 (3H, m) 7. 6-8. 0 (2
H, m) Example 8 Synthesis of 5-(2-piperidinomethylbutyryl)-3-phenylisoxazole (compound of general formula [VI]); [01001

[Chemical formula 17] 160 g of 5-butyryl-3-phenylisoxazole
(0.74 mol) and 103 ml of piperidine were added to 320 ml of ethyl alcohol, and 96 ml (1.18 mol) of a 37% formaldehyde aqueous solution was added dropwise over 30 minutes under water cooling. [0101] After stirring at room temperature for 1.5 hours, the solvent was distilled off. [0102] The obtained residue was dissolved in 800 ml of ethyl ether.
After washing with water, it was dried using anhydrous magnesium sulfate. [0103] The solvent was distilled off to obtain the desired 5-(2-piperidinomethylbutyryl)-3-phenylisoxazole as colorless crystals. [0104] Yield 223g (yield 96.0%) Melting point 83-84°C NMR (δppm, CDC13) 0. 8-1
．． 1 (3H, m) 1, 2-2. 0 (8H,
m) 3.4-3. 8 (LH, m)7, 1
(IH, S) 7. 3-7. 6 (3H, m)
7. 6-8. 0 (2H, m) Examples 9 to 16 For Examples 9 to 12, each amine HNR6R7 for introducing the -NR6R7 group shown in Table 2 was used instead of piperidine in Example 6 (NR6R7 corresponds to that shown in Table 2). The aminoketones shown in Table 2 were obtained in the same manner as in Example 6, except that the following aminoketones were used. [0105] Regarding Example 13, the aminoketone shown in Table 2 was obtained in the same manner as in Example 7 except that 2-methylpyrrolidine was used instead of pyrrolidine in Example 7. [0106] For Examples 14 to 16, Table 2 was carried out in the same manner as in Example 7 except that the ketones synthesized in Examples 3 to 4 were used instead of 5-butyryl-3-phenylisoxazole in Example 7. Each aminoketone shown in was obtained. [0107] Each of the obtained aminoketones (general formula [VI]
Table 2 shows the analysis results of the compound (compound). [0108] [Table 2] Table 2 [0109]

[Table 3] table 2 (continued)

Claims (1)

[Scope of Claims] [Claim 1] The following general formula [I] RCHOHCHRI R2 ... [I] [In the formula, R represents [Formula 1] and R3 is a halogen atom; a lower alkyl group; a benzyl group; benzoyl group; pyridyl group; furyl group optionally substituted with one or more lower alkyl groups; thienyl group optionally substituted with one or more lower alkyl groups; one or more halogen atoms, one or more lower alkoxy groups , a lower alkyl group, a trifluoromethyl group, a cyano group, a nitro group, an amino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a phenyl group optionally substituted with an acetyl group or a lower alkoxycarbonyl group, or naphthyl. R4 and R5 each independently represent a phenyl group or a lower alkyl group, W represents an oxygen atom or a sulfur atom, respectively), R1 is a hydrogen atom; a lower alkyl group; a benzyl group; a methoxy group; a phenyl group; an allyl group; group; lower alkyl group substituted with trifluoromethyl group or lower alkoxy group; It may form a ring or a six-membered ring. ] Alcohols represented by the following general formula [II] M (0-
X) ... [II] [Wherein, M represents an alkali metal or an alkaline earth metal, and X represents a halogen atom. n represents 1 when M is an alkali metal, and represents 2 when M is an alkaline earth metal. ] and the following general formula [ ] [2] [ [wherein Y and Z independently represent a hydrogen atom or a lower alkyl group. ] A method for producing ketones represented by the following general formula [] % formula % [] (R, R1 and R2 are the same as above), characterized in that the reaction is carried out in the presence of pyridines represented by pyridine or acid addition salts thereof . [Claim 2] The method of Claim 1, wherein R is a 5 (3R3 isoxazole) group. 3. The method according to claim 2, wherein R3 is a phenyl group. 4. The method according to claim 3, wherein R1 is a hydrogen atom and R2 is a lower alkyl group. 5. The method according to claim 1, wherein the hypohalide of general formula [II] is sodium hypochlorite. 6. The method according to claim 1, wherein the pyridine of general formula [III] or its acid addition salt is pyridine or pyridine hydrochloride. 7. The method according to claim 1, wherein the molar ratio of the hypohalide of general formula [II] to the alcohol of general formula [I] is 1 to 5. 8. The method according to claim 1, wherein the pyridine of general formula [III] or its acid addition salt is in a molar ratio of 0.1 to 5 with respect to the alcohol of general formula [I]. [Claim 9] The following general formula [V] may form a 5- to 8-membered ring together with the nitrogen atom, and the ring chain may further have one or more branches. ] The following general formula [VI] RCo is obtained by reacting amines represented by the following with ketones of general formula [IV] in the presence of an aqueous formaldehyde solution.
CRI R2CH2NR6R7...[VI](R,R
1, R2, R6, R7 are the same as above). 10. The method of claim 9, wherein R is a 5 (3Rs isoxazole) group. [Claim 11] Claim 10 wherein R3 is a phenyl group
the method of. [Claim 12] The method according to Clause 11, wherein R+ is a hydrogen atom and R2 is a lower alkyl group. 13. Aminos of general formula [V] are represented by general formula [
The method according to claim 9, wherein the molar ratio is 1 to 2 with respect to the ketone of [I]]. [Claim 14] Formaldehyde has the general formula [IV]
10. The method according to claim 9, wherein the molar ratio to the ketones is 1 to 2. 15. The method according to claim 9, wherein the ketone of general formula [IV] is obtained by the method according to claim 1. 16. 5-Butyryl-3-phenylisoxazole.