JPH10316630A - Amine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having an excellent antifungal activity. SOLUTION: This amine derivative is a compound of formula I [R<1> is a 1-4C alkyl; R<2> is a 1-4C alkyl or phenyl; R<3> is a 1-3C alkyl, a 1-5C acyl, a halogen, etc.; (k), (l), and (m) are each 1-4], e.g. trans-3'-[N-(4-tert-butylbenzyl)-N- methylaminomethyl]acetophenone. The compound of the formula I is obtained by condensing 0.1-10.0 mol, especially 1.0-2.5 mol secondary amine derivative of formula II with a halogenated compound of formula III (X is a halogen). This condensation reaction is performed by using a condensation reagent such as a tertiary organic amine such as triethylamine, and an inorganic base such as anhydrous potassium carbonate in the presence of a solvent e.g. N,N- dimethylformamide. This compound is excellent in antifungal activity and has a high usefulness as an antifungal agent, an antifungal composition containing the same, and a medicine, etc., containing the same as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel amine derivative having excellent antifungal activity.

[0002]

2. Description of the Related Art Superficial mycosis typified by athlete's foot has been increasing in number of patients due to westernization of life and increased wearing time of shoes. However, no reliable treatment or therapeutic agent has yet been found, and it is one of the unsurpassed diseases in modern times. In the past, a great deal of effort has been expended to find therapeutic agents, and many compounds have been screened for antifungal activity. In the clinical stage of, there were not many things that dropped out, and those that had satisfactory results were limited.

[0003]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a novel compound having excellent antifungal activity.

[0004]

Under such circumstances, the present inventors have conducted intensive studies and as a result, have found that the amine derivative represented by the following general formula (1) has an excellent antifungal activity, and Was completed.

That is, the present invention provides the following general formula (1)

[0006]

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[0007] [In the formula, R ¹ represents a linear, branched or cyclic alkyl group of 1 to 4 carbon atoms; R ² represents a linear alkyl group or a phenyl group having 1 to 4 carbon atoms; R ³ is Carbon number 1
3 straight-chain, branched-chain or cyclic alkyl group, a straight-chain, branched-chain or cyclic alkyl group having 1 to 5 carbon atoms, substituted by a hydroxyl group, having a straight-chain, branched-chain or cyclic structure having 1 to 5 carbon atoms acyl group, a straight-chain having 2 to 5 carbon atoms, shows a branched chain or cyclic alkenyl group or a halogen atom, m pieces of R ³ may be the same or different. K;
l and m each represent an integer of 1-4. And a salt thereof.

The present invention also provides a method for producing the amine derivative or a salt thereof.

[0009] The present invention also provides an antifungal agent comprising the amine derivative or a salt thereof.

The present invention also provides an antifungal composition containing the amine derivative or a salt thereof.

The present invention also provides a medicine containing the amine derivative or a salt thereof as an active ingredient.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The amine derivative of the present invention is represented by the general formula (1). In the formula, as the linear, branched or cyclic alkyl having 1 to 4 carbon atoms represented by R ¹ , for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, se
c-butyl group, isobutyl group, tert-butyl group, cyclobutyl group and the like. Of these, carbon number 1
To 3, especially a methyl group, an ethyl group, an isopropyl group and a cyclopropyl group.

R ² represents a linear alkyl group having 1 to 4 carbon atoms or a phenyl group, and a methyl group and a phenyl group are particularly preferable.

Among the groups represented by R ³ , straight-chain, branched-chain or cyclic alkyl groups having 1 to 3 carbon atoms include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl and the like. Of these,
A methyl group is preferred. Examples of the linear, branched or cyclic alkyl group having 1 to 5 carbon atoms substituted by a hydroxyl group include a 1-hydroxy-1-methylethyl group,
A 2-dimethyl-1-hydroxypropyl group is preferred.

As the acyl group having a linear, branched or cyclic structure having 1 to 5 carbon atoms, a formyl group or a C2 to C2 acyl group may be used.
And an alkanoyl group of 5, among which a formyl group, an acetyl group and a propionyl group are preferred. As a linear, branched or cyclic alkenyl group having 2 to 5 carbon atoms,
For example, a vinyl group, an isopropenyl group, 2-methyl-1-
Propenyl group, 1-ethylvinyl group, 1-methyl-1-
A propenyl group and a 1-isopropylvinyl group are preferred. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

R ³ is preferably methyl, 1-hydroxy-1-methylethyl, 1,2-dimethyl-1-hydroxypropyl, 1-hydroxypropyl, formyl, acetyl, propionyl, vinyl or the like. Groups, isopropenyl group, 2-methyl-1-propenyl group, 1-ethylvinyl group, 1-methyl-1-propenyl group, 1-isopropylvinyl group, fluorine atom and bromine atom are preferred. In addition, m R < ³ > may be the same or different.
Further, at least one of R ³ is a straight, branched or cyclic alkenyl group having 2 to 5 carbon atoms, particularly a vinyl group, an isopropenyl group, a 2-methyl-1-propenyl group, a 1-ethylvinyl group, -Methyl-1-propenyl group and 1-isopropylvinyl group are preferred.

K, l and m each represent an integer of 1 to 4, k is preferably 1, l is 1 and m is preferably 1 to 3.

Preferred examples of the amine derivative (1) include the following.

3 '-[N- (4-tert-butylbenzyl) -N-methylaminomethyl] acetophenone, N
-(4-tert-butylbenzyl) -N-methyl-
(3-isopropenylbenzyl) amine, N- (4-t
tert-butylbenzyl) -N-methyl- (3-bromobenzyl) amine, 3- [N- (4-tert-butylbenzyl) -N-methylaminomethyl] benzaldehyde, N- (4-tert-butylbenzyl) -N-methyl- (3-vinylbenzyl) amine, 3 '-[N- (4
-Tert-butylbenzyl) -N-cyclopropylaminomethyl] acetophenone, N- (4-tert-butylbenzyl) -N-cyclopropyl- (3-isopropenylbenzyl) amine, N- (4-tert-butylbenzyl) ) -N-methyl- (3-bromo-5-methylbenzyl) amine, 2- [3- {N- (4-tert-butylbenzyl) -N-methylaminomethyl} -5-methylphenyl] -2- Propanol, N- (4-tert
-Butylbenzyl) -N-methyl- (3-isopropenyl-5-methylbenzyl) amine, 2- [3- {N-
(4-tert-butylbenzyl) -N-methylaminomethyl {phenyl] -3-methyl-2-butanol, N
-(4-tert-butylbenzyl) -N-methyl-
[3- (1-isopropylvinyl) benzyl] amine,
1- [3- {N- (4-tert-butylbenzyl)-
N-methylaminomethyldiphenyl] -1-propanol, 3 '-[N- (4-tert-butylbenzyl)-
N-methylaminomethyl] propiophenone, N- (4
-Tert-butylbenzyl) -N-methyl- [3-
(1-ethylvinyl) benzyl] amine, cis-N-
(4-tert-butylbenzyl) -N-methyl- [3
-(1-methyl-1-propenyl) benzyl] amine,
N- (4-tert-butylbenzyl) -N-methyl-
(3-bromo-5-fluorobenzyl) amine, 2-
[3- {N- (4-tert-butylbenzyl) -N-
Methylaminomethyl {-5-fluorophenyl] -2-
Butanol, N- (4-tert-butylbenzyl)-
N-methyl- (3-fluoro-5-isopropenylbenzyl) amine, 3 '-[N-4- (1-methyl-1-phenylethyl) benzyl-N-methylaminomethyl] acetophenone, N-methyl-N -[4- (1-methyl-
1-phenylethyl) benzyl]-(3-isopropenylbenzyl) amine, N- (4-tert-butylbenzyl) -N-methyl- (2-bromobenzyl) amine,
2- [3- {N- (4-tert-butylbenzyl)-
N-methylaminomethyl {phenyl] -2-propanol, N- (4-tert-butylbenzyl) -N-methyl- (2-isopropenylbenzyl) amine, 3'-
[N- (4-tert-butylbenzyl) -N-isopropylaminomethyl] acetophenone, N- (4-te
rt-butylbenzyl) -N-isopropyl- (3-isopropenylbenzyl) amine, 3 ′-[N- (4-t
tert-butylbenzyl) -N-ethylaminomethyl]
Acetophenone, N- (4-tert-butylbenzyl) -N-ethyl- (3-isopropenylbenzyl) amine, N- (4-tert-butylbenzyl) -N-methyl- (3-bromo-2-methylbenzyl) ) Amine, 2
-[3- {N- (4-tert-butylbenzyl) -N
-Methylaminomethyl {-2-methylphenyl] -2-
Propanol, N- (4-tert-butylbenzyl)
-N-methyl- (3-isopropenyl-2-methylbenzyl) amine, N- (4-tert-butylbenzyl)
-N-methyl- (2-bromo-6-methylbenzyl) amine, 2- [2- {N- (4-tert-butylbenzyl) -N-methylaminomethyl} -3-methylphenyl] -2-propanol , N- (4-tert-butylbenzyl) -N-methyl- (2-isopropenyl-6-
Methylbenzyl) amine, N- (4-tert-butylbenzyl) -N-methyl- (3-bromo-4-methylbenzyl) amine, 2- [5- {N- (4-tert-butylbenzyl) -N -Methylaminomethyl {-2-methylphenyl] -2-propanol, N- (4-tert
-Butylbenzyl) -N-methyl- (3-isopropenyl-4-methylbenzyl) amine, N- (4-tert
-Butylbenzyl) -N-methyl- (3-bromo-4-
Fluorobenzyl) amine, 2- [5- {N- (4-t
tert-butylbenzyl) -N-methylaminomethyl
-2-fluorophenyl] -2-propanol, N-
(4-tert-butylbenzyl) -N-methyl- (4
-Fluoro-3-isopropenylbenzyl) amine, N
-(4-tert-butylbenzyl) -N-methyl-
(5-bromo-2-fluorobenzyl) amine, 2-
[3- {N- (4-tert-butylbenzyl) -N-
Methylaminomethyl {-4-fluorophenyl] -2-
Propanol, N- (4-tert-butylbenzyl)
-N-methyl- (2-fluoro-5-isopropenylbenzyl) amine, N- (3-bromo-5-methylbenzyl) -N-methyl- [4- (1-methyl-1-phenylethyl) benzyl] Amine, 2- [3-methyl-5-
[N-methyl-N- {4- (1-methyl-1-phenylethyl) benzyl} aminomethyl] phenyl] -2-propanol, N-methyl-N- [4- (1-methyl-1
-Phenylethyl) benzyl]-(3-isopropenyl-5-methylbenzyl) amine, N- (4-tert-
Butylbenzyl) -N-methyl- (3,5-dibromobenzyl) amine, 2- [3-bromo-5- {N- (4-
tert-butylbenzyl) -N-methylaminomethyl {phenyl] -2-propanol, N- (4-ter
t-butylbenzyl) -N-methyl- (3-bromo-5
-Isopropenylbenzyl) amine, 2- [3-isopropenyl-5- {N- (4-tert-butylbenzyl) -N-methylaminomethyl} phenyl] -2-propanol, N- (4-tert-butyl) Benzyl) -N
-Methyl- (3,5-bisisopropenylbenzyl) amine.

Among these, the following are more preferred. N- (4-tert-butylbenzyl) -N-methyl- (3-isopropenylbenzyl) amine, N- (4-tert-butylbenzyl) -N-methyl- (3-vinylbenzyl) amine, N
-(4-tert-butylbenzyl) -N-cyclopropyl- (3-isopropenylbenzyl) amine, N-
(4-tert-butylbenzyl) -N-methyl- (3
-Isopropenyl-5-methylbenzyl) amine, N-
(4-tert-butylbenzyl) -N-methyl- [3
-(1-isopropylvinyl) benzyl] amine, N-
(4-tert-butylbenzyl) -N-methyl- [3
-(1-ethylvinyl) benzyl] amine, cis-N-
(4-tert-butylbenzyl) -N-methyl- [3
-(1-methyl-1-propenyl) benzyl] amine,
N- (4-tert-butylbenzyl) -N-methyl-
(3-fluoro-5-isopropenylbenzyl) amine, N-methyl-N- [4- (1-methyl-1-phenylethyl) benzyl]-(3-isopropenylbenzyl) amine, N- (4-tert -Butylbenzyl)-
N-methyl- (2-isopropenylbenzyl) amine,
N- (4-tert-butylbenzyl) -N-isopropyl- (3-isopropenylbenzyl) amine, N-
(4-tert-butylbenzyl) -N-ethyl- (3
-Isopropenylbenzyl) amine, N- (4-ter
t-butylbenzyl) -N-methyl- (3-isopropenyl-2-methylbenzyl) amine, N- (4-ter
t-butylbenzyl) -N-methyl- (2-isopropenyl-6-methylbenzyl) amine, N- (4-ter
t-butylbenzyl) -N-methyl- (3-isopropenyl-4-methylbenzyl) amine, N- (4-ter
t-butylbenzyl) -N-methyl- (4-fluoro-
3-isopropenylbenzyl) amine, N- (4-te
rt-butylbenzyl) -N-methyl- (2-fluoro-5-isopropenylbenzyl) amine, N-methyl-
N- [4- (1-methyl-1-phenylethyl) benzyl]-(3-isopropenyl-5-methylbenzyl) amine, N- (4-tert-butylbenzyl) -N-methyl- (3-bromo -5-isopropenylbenzyl) amine, 2- [3-isopropenyl-5- {N- (4-t
tert-butylbenzyl) -N-methylaminomethyl
Phenyl] -2-propanol, N- (4-tert-
(Butylbenzyl) -N-methyl- (3,5-bisisopropenylbenzyl) amine.

The salt which can be used in the present invention is not particularly limited as long as it is physiologically acceptable. For example, mineral salts such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, citric acid and oxalic acid Preferred examples thereof include organic acid salts such as fumaric acid, maleic acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, and paratoluenesulfonic acid, and carbonates.
Of these, the hydrochloride is particularly preferred. These salts
It can be obtained according to a conventional method using the amine derivative (1) and an acid. For example, the amine derivative (1) and the acid may be mixed in a polar or non-polar solvent.

The compound (1) of the present invention also includes solvates such as hydrates.

The compound (1) of the present invention can be produced, for example, according to the reaction formula of the following method I or II.

[0024]

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Wherein R ¹ , R ² , R ³ , k, l and m
Represents the same meaning as described above, and X represents a halogen atom.

That is, the secondary amine derivative (2) or its salt is condensed with the halogenated compound (3) or its salt (method I), or the halogenated compound (4) or its salt is condensed with the secondary compound. The amine derivative (1) of the present invention can be obtained by condensing the amine derivative (5) or a salt thereof (method II). These condensation reactions can be performed, for example, using a condensing agent in the presence of a solvent.

In the method I or II, the ratio of the secondary amine derivative to the halogenated compound used as a raw material is such that the ratio of the secondary amine derivative to the halogenated compound is usually 0.1.
It is preferably from 1 to 10.0 mol, particularly preferably from 1.0 to 2.5 mol. As the condensing agent for the reaction, tertiary organic amines and inorganic bases are used, and specific examples include triethylamine, N, N-diisopropylethylamine, anhydrous potassium carbonate, anhydrous sodium carbonate and the like. These condensing agents are used usually in an amount of 0.1 to 30.0 mol, preferably 2.0 to 5.0 mol, based on the amount of the raw material.

The solvent used in the reaction is not particularly limited as long as it is a non-aqueous solvent capable of dissolving the two raw materials, and specific examples include N, N-dimethylformamide. The amount of the solvent used is preferably 5 to 100 times the amount of the reaction raw material. Further, these solvents can be used alone or in combination of two or more. The solvent may be selected in accordance with the physical properties of the raw material compound and the condensing agent.

The reaction temperature may be any temperature from room temperature to a temperature near the boiling point of the solvent, but preferably room temperature. The reaction time varies depending on various conditions, but usually requires 10 minutes to 30 days. As for the post-treatment and the purification method of the reaction, a general method, for example, quenching with water, solvent extraction, column chromatography, recrystallization and the like may be appropriately combined.

The compound (1) of the present invention can also be produced, for example, according to the reaction scheme of the following method III or IV.

[0031]

Embedded image

Wherein R ¹ , R ² , R ³ , k, l and m
Has the same meaning as above)

That is, the secondary amine derivative (2) or a salt thereof is condensed with the aldehyde derivative (6) (method
III) or the condensation of an aldehyde derivative (7) with a secondary amine derivative (5) or a salt thereof (Method IV)
Thereby, the amine derivative (1) of the present invention can be obtained. These condensation reactions can be performed, for example, by reacting an amine moiety and an aldehyde moiety, and then forming a tertiary amine moiety using a reducing agent.

In the method III or IV, the ratio of the secondary amine derivative and the aldehyde derivative used as the raw materials is as follows:
It is preferable that the amount of the secondary amine derivative is usually 0.1 to 10.0 mol, particularly 1.0 to 2.5 mol, based on the aldehyde derivative.

The solvent used in the reaction is not particularly limited as long as it is a non-aqueous solvent capable of dissolving the two raw materials, and specific examples include methanol. The amount of the solvent used is preferably 5 to 100 times the amount of the reaction raw material. Also, these solvents can be used alone,
It is also possible to use two or more kinds in combination. The solvent may be selected in accordance with the physical properties of the raw material compound and the condensing agent.

First, in the reaction of reacting a secondary amine derivative with an aldehyde derivative, an inorganic base such as potassium hydroxide or sodium hydroxide or triethylamine, N, N
-It is preferable to carry out the reaction after making it basic with an organic base such as diisopropylethylamine. The reaction temperature may be any temperature from room temperature to a temperature near the boiling point of the solvent, but room temperature is preferred. The reaction time varies depending on various conditions, but usually requires 10 minutes to 30 days.

Next, in order to make the reducing agent act, the reducing agent may be made to act as it is without isolating the intermediate obtained from the two raw materials. Examples of the reducing agent to be used include sodium cyanoborohydride and sodium borohydride. The amount of the reducing agent used may be used in accordance with the amount of the raw material used. The time during which the reducing agent is applied varies depending on various conditions, but it requires 10 minutes to 30 days.
As for the post-treatment and the purification method of the reaction, a general method, for example, quenching with water, solvent extraction, column chromatography, recrystallization and the like may be appropriately combined.

Further, before and after the steps of the methods I to IV, if necessary, a substituent conversion is carried out to obtain another amine derivative (1). Specific examples of the conversion of these substituents include halogenation using N-bromosuccinimide, phosphorus tribromide, and the like; conversion of a primary amino group to a secondary amino group using an alkyl halide; Wittig Conversion of a carbonyl group to a carbon-carbon double bond using a reaction, for example, conversion of a formyl group to a vinyl group, conversion of a formyl group to a 2-methyl-1-propenyl group, and conversion of an acetyl group to an isopropenyl group Conversion, conversion of an acetyl group to a 1-methyl-1-propenyl group, conversion of a propionyl group to a 1-ethylvinyl group, etc .; a halogen-metal exchange reaction between an aromatic halogen atom and n-butyllithium, followed by N Conversion to an acyl group, for example, a formyl group, characterized by the action of an acylating source such as N, N-dimethylformamide; an aromatic halogen atom a halogen-metal exchange reaction with n-butyllithium or the like, followed by the action of a ketone such as acetone or 3-methyl-2-butanone, and a 1-hydroxy-1-methylethyl group, 1,2-dimethyl Conversion to a 1-hydroxypropyl group or the like; construction of a carbon-carbon double bond characterized by a dehydration reaction using phosphorus oxychloride or the like, for example, conversion of a 1-hydroxy-1-methylethyl group to an isopropenyl group. Conversion of a 1,2-dimethyl-1-hydroxypropyl group to a 1-isopropylvinyl group; and the like.

The amine derivative (1) or a salt thereof of the present invention has excellent antifungal activity, and comprises an antifungal agent comprising the same, an antifungal composition containing the same, and a medicament containing the same as an active ingredient. High usefulness.

The antifungal composition of the present invention can be produced by blending one or more amine derivatives (1) or salts thereof. As the composition, any composition known to contain an antifungal agent can be used without particular limitation, for example, an external preparation for skin,
Pharmaceutical compositions such as external preparations for cleaning and disinfection, clothing such as socks and underwear, plastic products such as toothbrushes and ballpoint pens, and the like can be exemplified, and pharmaceutical compositions, especially external preparations for skin, are most preferred. The method for incorporating the amine derivative (1) of the present invention or a salt thereof into the composition may be performed according to a conventional technique. For example, in the case of a pharmaceutical composition, it may be emulsified or solubilized with other components, or may be mixed with a powder component and granulated. Also, clothing may be melt-mixed and spun in the stage of producing fibers, or it may be impregnated in clothing,
For plastic products, it is preferred to be melt mixed. Further, it is also possible to impregnate wood or the like in the sense of preventing mold.

The composition of the present invention contains an amine derivative (1)
Alternatively, in addition to the salt thereof, optional components usually contained in these compositions can be appropriately compounded as necessary. Such optional ingredients are not particularly limited, but in pharmaceutical compositions, excipients, coloring agents, flavoring agents, binders, disintegrants, coating agents, stabilizers, pH adjusters, sugar coatings, emulsification / dispersion・
Solubilizers and the like, among others, for skin external preparations, hydrocarbons such as liquid paraffin and petrolatum, esters such as gay wax and beeswax, triglycerides such as olive oil and tallow, higher alcohols such as cetanol and oleyl alcohol, Examples thereof include fatty acids such as stearic acid and oleic acid, polyhydric alcohols such as propylene glycol and glycerin, nonionic surfactants, anionic surfactants, cationic surfactants, and thickeners. In the case of clothing and plastics, plasticizers, crosslinking agents, coloring agents, antioxidants, ultraviolet absorbers and the like can be exemplified. The amount of the amine derivative or a salt thereof in the composition of the present invention is not particularly limited, but is 0.001 to 20% by weight, particularly 0.1% by weight in the whole composition.
It is preferably from 0.01 to 15% by weight, more preferably from 0.1 to 10% by weight.

[0042]

EXAMPLES Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

Reference Example 1 Production of 3'-bromomethylacetophenone: 5.00 g of 3'-methylacetophenone (70 ml of carbon tetrachloride)
7.3 mmol), 6.63 g of N-bromosuccinimide
(37.3 mmol) and 100 mg of benzoyl peroxide were mixed and refluxed for 1 hour. After allowing to cool to room temperature, the precipitated crystals were separated by filtration, the filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to obtain the desired compound. 0.08 g (yield 38.8%) was obtained.

¹ H-NMR (CDCl ₃ , ppm) 2.6
2 (3H, s), 4.53 (2H, s), 7.46 (1
H, t, J = 7.70 Hz), 7.64 (1H, d, J)
= 7.70 Hz), 7.89 (1H, d, J = 7.70)
Hz), 7.97 (1H, s)

Reference Example 2 Preparation of N- (4-tert-butylbenzyl) methylamine: 10.1 g (56.6 mmol) of p-tert-butylbenzoic acid and 100 ml of chloroform and thionyl chloride 2
0.2 g were mixed and refluxed for 5 hours. The solvent and excess thionyl chloride were distilled off under reduced pressure, the residue was dissolved in a small amount of methanol, and added dropwise to 17 ml of a 40% methylamine-methanol solution using an ice bath. After the dropwise addition, the mixture was taken out of the ice bath and stirred at room temperature for 48 hours. 100 ml of 2N hydrochloric acid was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained white crystals were dissolved in dichloromethane, washed with 1 L of a saturated aqueous solution of sodium hydrogen carbonate, and p-tert-
Butylbenzoic acid was removed. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and N-methyl-4-tert was removed.
8.15 g of -butylbenzoic acid amide as white crystals
(74.9% yield). Next, diethyl ether 11
0 ml, 8.15 g (42.6 mmol) of N-methyl-4-tert-butylbenzoic acid amide and 2.88 g (85.2 mmol) of lithium aluminum hydride were mixed and refluxed for 6 hours under a nitrogen atmosphere. After the reflux, the reaction solution was ice-cooled and water was added to decompose excess lithium aluminum hydride. The precipitated aluminum hydroxide was removed by filtration, the filtrate was extracted with diethyl ether, and the organic layer was washed with water and saturated saline, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure,
The resulting yellow oil was distilled under reduced pressure (115-118 ° C / 1
0 mmHg) to give the target compound as a yellow oil (3.6).
9 g (48.9% yield) was obtained.

¹ H-NMR (CDCl ₃ , ppm) 1.3
1 (9H, s), 2.45 (3H, s), 7.24 (2
H, d, J = 8.37 Hz), 7.35 (2H, d, J
= 8.37 Hz)

Reference Example 3 Production of N- (4-tert-butylbenzyl) methylamine (Part 2): p-tert-butyltoluene
8 g (0.10 mol) was dissolved in carbon tetrachloride, 17.8 g (0.10 mol) of N-bromosuccinimide and 200 mg of benzoyl peroxide were added, and the mixture was refluxed for 2 hours. After cooling, insolubles were removed by filtration, the residue was washed with carbon tetrachloride, and the filtrate was concentrated under reduced pressure. The residue was dissolved in n-hexane, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
22.7 g of t-butylbenzyl bromide (yield 100
% However, from the result of ¹ H-NMR, the product was found to be a mixture of target substance: raw material: dibromo compound = 10: 1: 1). 10.6 g (0.10 mol) of sodium carbonate was added to 200 ml of a 40% methylamine-methanol solution, and 22.7 g of p-tert-butylbenzylbromide was added in an ice bath.
A solution of (0.10 mol) in 20 ml of methanol was added dropwise.
Removed from the ice bath and stirred at room temperature for 41 hours. The methanol was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with 400 ml of ether. The ether layer was washed with 200 ml of 1N hydrochloric acid and 100 ml.
The mixture was extracted twice, and the aqueous layer was extracted with ethyl acetate. The aqueous layer was made alkaline with a 2N aqueous sodium hydroxide solution, and ether 40 was added.
Extracted with 0 ml. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 200: 1 → 100:
(1 → 20: 1) to give 9.51 g (yield 53.7%) of the target compound.

Example 1 3 '-[N- (4-tert-butylbenzyl) -N-
Preparation of methylaminomethyl] acetophenone (compound 1): N- (4-
tert-butylbenzyl) methylamine 1.25 g
(7.04 mmol) and 1.95 g of potassium carbonate (14.
1 mmol), and a solution prepared by dissolving 1.50 g (7.04 mmol) of 3'-bromomethylacetophenone in 10 ml of N, N-dimethylformamide was added dropwise while stirring in an ice bath. After the dropwise addition, the reaction mixture was taken out of an ice bath, stirred at room temperature for 1 hour, and poured into ice + a saturated aqueous solution of sodium hydrogen carbonate to stop the reaction. The mixture was extracted with 100 ml of ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform) to obtain 1.42 g (yield: 65.2%) of the target compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ , ppm) 1.3
1 (9H, s), 2.19 (3H, s), 2.61 (3
H, s), 3.51 (2H, s), 3.57 (2H,
s), 7.22 to 7.94 (8H, m),

Example 2 N- (4-tert-butylbenzyl) -N-methyl-
Production of (3-isopropenylbenzyl) amine (compound 2): 1.97 g (5.51 mmol) of methyltriphenylphosphonium bromide was suspended in 15 ml of tetrahydrofuran, and stirred under a nitrogen atmosphere at room temperature while stirring at 1.68.
3.9 ml of M n-butyllithium-n-hexane solution
(6.60 mmol) was added dropwise. After the reaction solution became dark red, it was cooled in an ice bath, and 1.42 g (4.59 mm) of Compound 1 was obtained.
ol) in 15 ml of tetrahydrofuran was added dropwise. After the dropwise addition, the reaction mixture was taken out of the ice bath, stirred at room temperature for 30 minutes, and poured into ice water to stop the reaction. Diethyl ether 10
The mixture was extracted with 0 ml, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1).
0: 1) to afford the target compound as a yellow oil in 0.1.
81 g (57.4% yield) was obtained.

¹ H-NMR (CDCl ₃ , ppm) 1.3
3 (9H, s), 2.16 (3H, s), 2.20 (3
H, s), 3.50 (2H, s), 3.52 (2H,
s), 5.08 (1H, s), 5.37 (1H, s),
7.24 to 7.46 (8H, m)

Example 3 N- (4-tert-butylbenzyl) -N-methyl-
Preparation of (3-isopropenylbenzyl) amine hydrochloride (compound 3): Dissolve 0.45 g (1.46 mmol) of compound 2 in 150 ml of diisopropyl ether, and stir at room temperature with a 4N hydrogen chloride-ethyl acetate solution (0.1 mL). 44ml
(1.75 mmol) was added dropwise. Stir at room temperature for 14 hours,
The precipitated white crystals were collected by filtration, washed with diisopropyl ether, and dried in a desiccator under reduced pressure to obtain 0.45 g (yield: 89.6%) of the target compound as white crystals.

IR (KBr tablet, cm ^-1 ) 2958, 29
04,2868,2678,2627,2597,25
62, 2528, 1461, 915, 717 m. p. 185.0-190.5 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.33 (9H,
s), 2.19 (3H, s), 2.58 (3H, d, J
= 4.32 Hz), 4.00 to 4.10 (2H, m),
4.20 to 4.30 (2H, m), 5.17 (1H,
s), 5.47 (1H, s), 7.39 to 7.56 (8
H, m), 7.74 (1H, s), 12.9 (1H, b
rs)

Reference Example 4 Production of 3-bromobenzyl bromide: carbon tetrachloride 200
25.33 g of m-bromotoluene (148.1 mmol
l), 26.36 g of N-bromosuccinimide (14
8.1 mmol) and 0.3 g of benzoyl peroxide.
The mixture was heated under reflux for 3 hours. After allowing to cool to room temperature, the precipitated crystals were separated by filtration, and the filtrate was concentrated under reduced pressure. 200 ml of hexane in the residue
Was added and left at room temperature for 15 hours, and the precipitated white crystals were separated by filtration. The filtrate was concentrated to give the target compound as a yellow oil.
1 g was obtained. ^{From the} result of ¹ H-NMR measurement, it was found that the target compound: raw material: dibromo compound was present at a ratio of 4.34: 1.03: 1.00. Modified yield 67.9%.

¹ H-NMR (CDCl ₃ , ppm) 4.4
3 (2H, s), 7.12 to 7.54 (4H, m)

Reference Example 5 Preparation of N- (3-bromobenzyl) methylamine: 40
19.2 g (100.5 mmol) of triethylamine was dissolved in 150 ml of a methylamine-methanol solution, and 25.1 g of 3-bromobenzyl bromide was stirred in an ice bath.
(100.5 mmol) dissolved in 40 ml of methanol was added dropwise. After the addition, the mixture was taken out of the ice bath and stirred at room temperature for 15 hours. Methanol and excess methylamine were distilled off under reduced pressure, and the residue was washed with ether-2N hydrochloric acid (100-100 ml).
Extracted. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and extracted with 100 ml of chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the target compound was converted into a yellow-orange oily substance (12.7 g).
(63.2% yield).

¹ H-NMR (CDCl ₃ , ppm) 2.4
4 (3H, s), 3.72 (2H, s), 7.16-
7.26 (2H, m), 7.36 to 7.40 (1H,
m), 7.49 (1H, s)

Example 4 N- (4-tert-butylbenzyl) -N-methyl-
Preparation of (3-bromobenzyl) amine (Compound 4):
2.00 g (10.0 mmol) of N- (3-bromobenzyl) methylamine in 20 ml of N, N-dimethylformamide
And 2.02 g (19.0 mmol) of sodium carbonate, and while stirring at room temperature, a solution of 2.16 g (9.52 mmol) of 4-tert-butylbenzylbromide dissolved in 15 ml of N, N-dimethylformamide was added dropwise. did. After stirring at room temperature for 30 minutes, the reaction was stopped by pouring into ice water. The mixture was extracted with 100 ml of ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain 2.26 g of the desired compound (yield: 6).
8.5%).

¹ H-NMR (CDCl ₃ , ppm) 1.3
2 (9H, s), 2.18 (3H, s), 3.47 (2
H, s), 3.57 (2H, s), 7.17 (1H,
t, J = 7.56 Hz), 7.26 to 7.38 (6H,
m), 7.53 (1H, s)

Example 5 Preparation of 3- [N- (4-tert-butylbenzyl) -N-methylaminomethyl] benzaldehyde (compound 5): 2.26 g of compound 4 in 25 ml of tetrahydrofuran
(6.53 mmol) was dissolved and cooled to -75 ° C with a dry ice-acetone solvent under a nitrogen atmosphere. To this, 1.
56M n-butyllithium-n-hexane solution 4.2
ml (6.53 mmol) was slowly added dropwise and stirred for 15 minutes. Then 0.95 g of N, N-dimethylformamide
(13.1 mmol) was added dropwise, and the temperature was slowly returned to room temperature.
The reaction was quenched by dropwise addition of a saturated aqueous ammonium chloride solution, and the mixture was extracted with 100 ml of ether. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain 0.59 g of the desired compound.
(30.6% yield).

¹ H-NMR (CDCl ₃ , ppm) 1.3
2 (9H, s), 2.20 (3H, s), 3.53 (2
H, s), 3.58 (2H, s), 7.29 (2H,
d, J = 8.37 Hz), 7.36 (2H, d, J =
8.37 Hz), 7.49 (1H, t, J = 7.56H)
z), 7.66 (1H, d, J = 7.56 Hz), 7.
77 (1H, d, J = 7.56 Hz), 7.94 (1
H, s), 10.0 (1H, s)

Example 6 N- (4-tert-butylbenzyl) -N-methyl-
Preparation of (3-vinylbenzyl) amine (compound 6): 1.57 M n-butyl was mixed with 20 ml of benzene mixed with 1.07 g (3.00 mmol) of methyltriphenylphosphonium bromide under a nitrogen atmosphere at room temperature while stirring. 1.9 ml (3.00 mmol) of a lithium-n-hexane solution was added dropwise. After stirring for 10 minutes, 0.59 g of compound 5
(2.00 mmol) in 15 ml of benzene was added dropwise and stirred at room temperature for 3 hours. The reaction was stopped by pouring into ice water, extracted with 100 ml of benzene, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to obtain 0.29 g (yield: 49.4%) of the target compound as a slightly yellow oil.

¹ H-NMR (CDCl ₃ , ppm) 1.3
1 (9H, s), 2.19 (3H, s), 3.44 (2
H, s), 3.50 (2H, s), 5.24 (1H, d
d, J = 10.8 Hz, 0.81 Hz), 5.76 (1
H, dd, J = 17.8 Hz, 0.81 Hz), 6.7
3 (1H, dd, J = 17.8 Hz, 10.8 Hz),
7.26 to 7.41 (8H, m)

Example 7 N- (4-tert-butylbenzyl) -N-methyl-
Preparation of (3-vinylbenzyl) amine hydrochloride (compound 7): 0.2 g of compound 6 in 70 ml of diisopropyl ether
9 g (9.88 × 10 ⁻¹ mmol) was dissolved and 0.25 ml of 4N hydrochloric acid-ethyl acetate solution (1 equivalent) was stirred at room temperature.
Was added dropwise. After stirring for 3 hours, the precipitated crystals were collected by filtration, washed with diisopropyl ether, and further dried in a desiccator under reduced pressure to give the target compound as white crystals in 0.2%.
9 g (89.0% yield) was obtained.

IR (KBr tablet, cm ^-1 ) 3462, 29
59, 2904, 2870, 2855, 2688, 26
32, 2561, 2543, 1485, 1463, 14
51, 1417, 1394, 1363, 1067 m. p. 210-212 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.27 (9H,
s), 2.57 (3H, d, J = 4.32 Hz);
99-4.10 (2H, m), 4.21-4.30 (2
H, m), 5.35 (1H, d, J = 10.8 Hz),
5.88 (1H, d, J = 17.8 Hz), 6.73
(1H, dd, J = 17.8 Hz, 10.8 Hz),
7.39 to 7.57 (7H, m), 7.69 (1H,
s), 12.9 (1H, brs)

Reference Example 6 Production of 3 '-(N-cyclopropylaminomethyl) acetophenone: 5.71 g (100 mmol) of cyclopropylamine and 1.0 mol of triethylamine in 50 ml of methanol.
Dissolve 1 g (10.0 mmol) and, with stirring in an ice bath, 2.13 g of 3'-bromomethylacetophenone (1
0.0 mmol) in 10 ml of methanol was added dropwise. After taking out of the ice bath and stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure. 100 ml of 2N hydrochloric acid was added to the residue, and the mixture was extracted with 100 ml of diethyl ether. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution, and then chloroform 1 was added.
Extracted with 00 ml. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
5: 1 → 0: 1) to give 0.66 g (yield 34.9%) of the target compound as a yellow oil.

¹ H-NMR (CDCl ₃ , ppm) 0.3
4 to 0.49 (4H, m), 2.11 to 2.19 (1
H, m), 2.61 (3H, s), 3.90 (2H,
s), 7.42 (1H, t, J = 7.70 Hz), 7.
53 (1H, d, J = 7.70 Hz), 7.84 (1
H, d, J = 7.70 Hz), 7.91 (1H, s)

Example 8 3 '-[N- (4-tert-butylbenzyl) -N-
Preparation of [cyclopropylaminomethyl] acetophenone (compound 8): 0.30 g (1.59 mmol) of 3 '-(N-cyclopropylaminomethyl) acetophenone and potassium carbonate in 15 ml of N, N-dimethylformamide.
31 g (2.27 mmol) were mixed and stirred at room temperature while stirring 0.29 g of 4-tert-butylbenzylbromide.
(1.51 mmol) in 5 ml of N, N-dimethylformamide
The solution dissolved in was added dropwise. After stirring for 1 hour at room temperature,
The reaction was stopped by pouring into ice + aqueous saturated sodium hydrogen carbonate solution. The mixture was extracted with 100 ml of ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 15: 1) to give 0.20 g of the desired compound as a colorless transparent oil (yield 39.5%). )Obtained.

¹ H-NMR (CDCl ₃ , ppm) 0.3
2 to 0.46 (4H, m), 1.32 (9H, s),
1.80 to 1.88 (1H, m), 2.60 (3H,
s), 3.66 (2H, s), 3.72 (2H, s),
7.11 to 7.41 (6H, m), 7.81 to 7.85
(2H, m)

Example 9 Preparation of N- (4-tert-butylbenzyl) -N-cyclopropyl- (3-isopropenylbenzyl) amine (compound 9): 0.32 g of methyltriphenylphosphonium bromide (8.94 × 10 ^-1 mmol), 1.56M
0.6 ml of n-butyllithium-n-hexane solution (8.
9 × 10 ⁻¹ mmol) and 0.20 g (5.96) of compound 8
× 10 ^-1 mmol) to obtain 0.07 g (yield 35.2%) of the target compound in the same manner as in Example 6.

¹ H-NMR (CDCl ₃ , ppm) 0.3
2 to 0.46 (4H, m), 1.32 (9H, s),
1.80 to 1.87 (1H, m), 2.17 (3H,
s), 3.66 (2H, s), 3.68 (2H, s),
5.08 (1H, s), 5.37 (1H, s), 7.1
9 to 7.37 (8H, m)

Example 10 Preparation of N- (4-tert-butylbenzyl) -N-cyclopropyl- (3-isopropenylbenzyl) amine hydrochloride (Compound 10) 0.07 g of Compound 9 (2.1
0 × 10 ^-1 mmol) and 4N hydrochloric acid - ethyl acetate solution with 0.05ml (2.0 × 10 ^-1 mmol), was prepared as in Example 7, 0.05 g of the desired compound as white crystals
(64.4% yield).

IR (KBr tablet, cm ^-1 ) 3424, 29
62,2869,2680,2599,2554,24
24, 2360, 2341, 1456, 1410, 13
65, 1038, 892.9 m. p. 133-136 ° C ¹ H-NMR (CDCl ₃ , ppm) 0.59-0.72
(4H, m), 1.28 (9H, s), 1.39-1.
49 (1H, m), 2.18 (3H, s), 4.10
4.36 (2H × 2, m), 5.16 (1H, s),
5.45 (1H, s), 7.28 to 7.56 (7H,
m), 7.71 (1H, s), 12.5 (1H, br)
s)

Reference Example 7 Production of 3-bromo-5-methylbenzyl bromide: 10.0 g of 5-bromo-m-xylene in 100 ml of benzene
(54.0 mmol), 9.63 N-bromosuccinimide
g (54.0 mmol) and 150 mg of benzoyl peroxide were mixed and heated under reflux for 2.5 hours. After returning to room temperature, the insolubles were removed by filtration, washed with benzene, and the filtrate was distilled off under reduced pressure. N-Hexane was added to the obtained residue, left for 30 minutes, and magnesium sulfate was added thereto and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 0 → 20: 1) to obtain 9.44 g (yield: 66.3%) of the target compound.

¹ H-NMR (CDCl ₃ , ppm) 2.3
1 (3H, s), 4.39 (2H, s), 7.12 (1
H, s), 7.26 (1H, s), 7.34 (1H,
s)

Reference Example 8 Preparation of N- (3-bromo-5-methylbenzyl) methylamine: 100 ml of a 40% methylamine-methanol solution
And 3.44 g (35.8 mmol) of 3-bromo-5-methylbenzylbromide dissolved in chloroform / methanol = 25 ml / 25 ml while stirring in an ice bath while dissolving 3.62 g (35.8 mmol) of triethylamine in water. Was added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 72 hours, and then the solvent was distilled off under reduced pressure. 100 ml of 2N hydrochloric acid was added to the residue, and the mixture was washed with 100 ml of ether. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and extracted with 100 ml of chloroform.
The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 10: 1).
5.58 g (yield: 72.8%) of the target compound was obtained as a pale yellow oil.

¹ H-NMR (CDCl ₃ , ppm) 2.3
2 (3H, s), 2.44 (3H, s), 3.68 (2
H, s), 7.06 (1H, s), 7.22 (1H,
s), 7.26 (1H, s)

Example 11 N- (4-tert-butylbenzyl) -N-methyl-
(3-Bromo-5-methylbenzyl) amine (Compound 1
Preparation of 1): N- (3-bromo-5-methylbenzyl)
Using 1.62 g (7.57 mmol) of methylamine, 1.15 g (10.8 mmol) of sodium carbonate and 1.64 g (7.21 mmol) of 4-tert-butylbenzylbromide, the target compound was obtained in the same manner as in Example 4. Was obtained as a white oil (yield 54.7%).

¹ H-NMR (CDCl ₃ , ppm) 1.3
2 (9H, s), 2.17 (3H, s), 2.32 (3
H, s), 3.43 (2H, s), 3.49 (2H,
s), 7.09 (1H, s), 7.20 (1H, s),
7.27 (2H, d, J = 6.48 Hz), 7.32
(1H, s), 7.36 (2H, d, J = 6.48H
z)

Example 12 2- [3- {N- (4-tert-butylbenzyl)-
N-methylaminomethyl {-5-methylphenyl] -2
Preparation of propanol (compound 12): 1.42 g (3.94 mmol) of compound 11 in 20 ml of tetrahydrofuran
Dissolve and stir at -75 ° C under nitrogen atmosphere.
56M n-butyllithium-n-hexane solution 2.5
ml (3.94 mmol) were added dropwise. After stirring for 15 minutes,
2 ml of acetone was added dropwise, the temperature was returned to room temperature over 2 hours, and a saturated aqueous solution of ammonium chloride was added dropwise to stop the reaction. The mixture was extracted with 100 ml of diethyl ether, and the organic layer was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 10: 1 → 4:
Purified in 1) to give 0.41 of the desired compound as a yellow oil.
g (30.6% yield).

¹ H-NMR (CDCl ₃ , ppm) 1.3
3 (9H, s), 1.58 (3H × 2, s), 2.22
(3H, s), 2.36 (3H, s), 3.48 (2
H, s), 3.50 (2H, s), 7.08 (1H,
s), 7.18 (1H, s), 7.26 to 7.36 (5
H, m)

Example 13 N- (4-tert-butylbenzyl) -N-methyl-
Preparation of (3-isopropenyl-5-methylbenzyl) amine (compound 13): Dissolve 0.40 g (1.18 mmol) of compound 12 in 20 ml of pyridine, and stir in an ice bath 1.81 g (11) of phosphorus oxychloride. .8 mmol) was added dropwise. After the dropwise addition, the mixture was taken out of the ice bath, stirred at room temperature for 30 minutes, and then heated and refluxed for 4 hours. After returning to room temperature, the mixture was poured into ice + a saturated aqueous solution of sodium hydrogen carbonate. After neutralization with sodium hydrogen carbonate, the mixture was extracted with 70 ml of chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 15: 1) to give the desired compound in 0.12%.
g (yield 31.6%).

¹ H-NMR (CDCl ₃ , ppm) 1.3
1 (9H, s), 2.15 (3H, s), 2.19 (3
H, s), 2.35 (3H, s), 3.49 (2H ×
2, s), 5.06 (1H, s), 5.36 (1H,
s), 7.11 (1H, s), 7.16 (1H, s),
7.26 to 7.60 (5H, m)

Example 14 N- (4-tert-butylbenzyl) -N-methyl-
Preparation of (3-isopropenyl-5-methylbenzyl) amine hydrochloride (Compound 14): 0.12 g of Compound 13
(3.73 × 10 ⁻¹ mmol) and 0.10 ml (4.00 × 10 ⁻¹ mmol) of a 4N hydrochloric acid-ethyl acetate solution were used to obtain the target compound as white crystals in the same manner as in Example 7. 10
g (74.9% yield).

IR (KBr tablet, cm ^-1 ) 3440, 29
62, 2921, 2869, 2694, 2625, 25
23, 1601, 1462, 1417, 1365 m. p. 156-159 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.33 (9H,
s), 2.17 (3H, s), 2.40 (3H, s),
2.57 (3H, d, J = 4.33 Hz), 3.96-
4.08 (2H, m), 4.19 to 4.26 (2H,
m), 5.14 (1H, s), 5.44 (1H, s),
7.30 to 7.55 (7H, m), 12.8 (1H, b
rs)

Example 15 2- [3- {N- (4-tert-butylbenzyl)-
N-methylaminomethyl {phenyl] -3-methyl-2
Preparation of -butanol (compound 15): Dissolve 2.00 g (5.78 mmol) of compound 4 in 20 ml of tetrahydrofuran and stir at -40 ° C under a nitrogen atmosphere at 1.56 M
3.7 ml of n-butyllithium-n-hexane solution
(5.8 mmol) was added dropwise. After the dropwise addition, the mixture was cooled to -75 ° C, and a solution of 2.00 g of 3-methyl-2-butanone dissolved in a small amount of tetrahydrofuran was added dropwise. The temperature was gradually returned to room temperature, and a saturated aqueous ammonium chloride solution was added dropwise to stop the reaction. The solution was extracted with 100 ml of diethyl ether, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain 0.86 g (yield: 43.3%) of the target compound as a brown oil. Obtained.

¹ H-NMR (CDCl ₃ , ppm) 0.8
0 (3H, d, J = 7.02 Hz), 0.89 (3H,
d, J = 7.02 Hz), 1.31 (9H, s), 1.
53 (3H, s), 1.98 to 2.11 (1H, m),
2.18 (3H, s), 3.47 (2H, s), 3.5
3 (2H, s), 7.26 to 7.42 (8H, m)

Example 16 N- (4-tert-butylbenzyl) -N-methyl-
Preparation of [3- (1-isopropylvinyl) benzyl] amine (compound 16): Compound 15 in 20 ml of pyridine
Was dissolved in 0.30 g (8.73 × 10 ⁻¹ mmol), and 1.34 g (8.73 mm) of phosphorus oxychloride was dissolved with stirring at room temperature.
ol) was added dropwise. After the dropwise addition, the mixture was heated and stirred at 100 ° C. for 6 hours, then allowed to cool to room temperature, and poured into ice + aqueous saturated sodium hydrogen carbonate aqueous solution. The mixture was extracted with 100 ml of chloroform, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain 0.19 g of the desired compound as a yellow oil (yield: 6).
4.9%).

¹ H-NMR (CDCl ₃ , ppm) 1.1
0 (3H × 2, d, J = 6.21 Hz), 1.28 (9
H, s), 2.20 (3H, s), 2.78 to 2.90.
(1H, m), 3.49 (2H, s), 3.52 (2
H, s), 5.03 (1H, s), 5.15 (1H,
s), 7.20 to 7.34 (8H, m).

Example 17 N- (4-tert-butylbenzyl) -N-methyl-
Production method of [3- (1-isopropylvinyl) benzyl] amine hydrochloride (compound 17): 0.19 g of compound 16
0.16 g (yield: 8) of the target compound as white crystals in the same manner as in Example 7 using 0.14 ml (1 equivalent) of 4N hydrochloric acid-ethyl acetate solution (5.66 × 10 ⁻¹ mmol).
0.7%).

IR (KBr tablet, cm ^-1 ) 3436, 29
63, 2925, 2906, 2883, 2870, 26
74, 2628, 2562, 1471, 1461, 14
19, 1405, 888.8 m. p. 177 to 179 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.08 to 1.14
(3H × 2, m), 1.33 (9H, s), 2.57
(3H, d, J = 4.86 Hz), 2.81 to 2.91
(1H, m), 4.01 to 4.08 (2H, m), 4.
20-4.30 (2H, m), 5.11 (1H, s),
5.21 (1H, s), 7.39 to 7.65 (8H,
m), 12.9 (1H, brs)

Example 18 1- [3- {N- (4-tert-butylbenzyl)-
Preparation of N-methylaminomethyldiphenyl] -1-propanol (compound 18): Dissolve 2.00 g (5.78 mmol) of compound 4 in 20 ml of tetrahydrofuran, and stir at −30 ° C. under a nitrogen atmosphere. 3.70 ml of a 56 M n-butyllithium-n-hexane solution (5.77)
mmol) was added dropwise. After stirring for 5 minutes, the mixture was cooled to -75 ° C. 1 ml of propionaldehyde is slowly dropped,
The temperature was returned to room temperature over 2 hours. The reaction was stopped by adding a saturated ammonium chloride aqueous solution dropwise, and diethyl ether 100 ml was added.
Extracted. The organic layer was washed with a saturated saline solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain 1.08 g of the target compound as a yellow oil (yield: 57.4%). Obtained.

¹ H-NMR (CDCl ₃ , ppm) 0.9
2 (3H, t, J = 7.02 Hz), 1.31 (9H,
s), 1.70 to 1.89 (2H, m), 2.18 (3
H, s), 3.49 (2H, s), 3.52 (2H,
s), 4.60 (1H, t, J = 6.48 Hz), 7.
21 to 7.35 (8H, m)

Example 19 3 '-[N- (4-tert-butylbenzyl) -N-
Methylaminomethyl] propiophenone (compound 19)
Preparation of: 2.89 g (7.68 mmol) of pyridinium dichromate was suspended in 30 ml of methylene chloride, and a solution prepared by dissolving 0.50 g (1.54 mmol) of compound 18 in 5 ml of methylene chloride was added dropwise with stirring at room temperature. did. After stirring for 4 hours, 30 ml of diethyl ether and 3 g of magnesium sulfate were added, and the mixture was further stirred for 10 minutes. Filter off insolubles,
The filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1).
0: 1) to give 0.19 g (yield 38.1%) of the target compound as a colorless transparent oil.

¹ H-NMR (CDCl ₃ , ppm) 1.2
3 (3H, t, J = 7.02 Hz), 1.31 (9H,
s), 2.19 (3H, s), 3.03 (2H, q, J
= 7.02 Hz), 3.51 (2H, s), 3.56
(2H, s), 7.30 to 7.44 (5H, m), 7.
58 (1H, d, J = 7.83 Hz), 7.84 (1
H, d, J = 7.83 Hz), 7.95 (1H, s)

Example 20 N- (4-tert-butylbenzyl) -N-methyl-
Production of [3- (1-ethylvinyl) benzyl] amine (compound 20): 0.18 g (4.94 × 10 ⁻¹ mmol) of methyltriphenylphosphonium bromide in 7 ml of benzene
And stirring at room temperature under a nitrogen atmosphere while mixing
0.32 ml of 6Mn-butyllithium-n-hexane solution
(5.00 × 10 ^-1 mmol) was added dropwise. After stirring for 5 minutes, 0.08 g (2.47 × 10 ⁻¹ mmol) of compound 19
Was dissolved in 5 ml of benzene, and the mixture was heated under reflux for 2 hours. After returning to room temperature, the reaction was stopped by pouring into ice water and extracted with 100 ml of benzene. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain 0.05 g (yield: 63%) of the target compound as a colorless transparent oil. Was.

¹ H-NMR (CDCl ₃ , ppm) 1.1
1 (3H, t, J = 7.56 Hz), 1.31 (9H,
s), 2.20 (3H, s), 2.53 (2H, q, J
= 7.56 Hz), 3.50 (2H, s), 3.52
(2H, s), 5.06 (1H, s), 5.29 (1
H, s), 7.26-7.36 (7H, m), 7.41.
(1H, s)

Example 21 N- (4-tert-butylbenzyl) -N-methyl-
Production of [3- (1-ethylvinyl) benzyl] amine hydrochloride (Compound 21): 0.09 g of Compound 20 (2.
80 × 10 ^-1 mmol), 4 N hydrochloric acid - ethyl acetate solution using 0.07 ml (1 eq), in the same manner as in Example 7, 0.07 g (yield 69.8 of the desired compound as white crystals
%)Obtained.

IR (KBr tablet, cm ^-1 ) 2964, 29
04,2886,2689,2677,2632,14
64m. p. 177-181 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.11 (3H,
t, J = 7.29 Hz), 1.33 (9H, s), 1.
57 (3H, s), 2.55 (2H, q, J = 7.29
Hz), 4.03 to 4.07 (2H, m), 4.22 to
4.25 (2H, m), 5.14 (1H, s), 5.3
7 (1H, s), 7.39 to 7.57 (7H, m),
7.64 (1H, s)

Example 22 Preparation of cis-N- (4-tert-butylbenzyl) -N-methyl- [3- (1-methyl-1-propenyl) benzyl] amine (compound 22) 1.58 g of phenylphosphonium bromide
(4.26 mmol) were mixed, and 2.7 ml (4.21 mmol) of a 1.56 M n-butyllithium-n-hexane solution was added dropwise with stirring at room temperature under a nitrogen atmosphere. After stirring for 5 minutes, a solution of 0.88 g (2.84 mmol) of compound 1 dissolved in 10 ml of benzene was added dropwise, and the mixture was heated under reflux for 3 hours. After returning to room temperature, the reaction was stopped by pouring into ice water and extracted with 100 ml of benzene. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 40: 1) to obtain 0.11 g (yield: 12.0%) of the target compound.

¹ H-NMR (CDCl ₃ , ppm) 1.3
1 (9H, s), 1.60 (3H, dq, J = 7.02
Hz, 1.49 Hz), 2.03 (3H, q, J = 1.
49Hz), 2.20 (3H, s), 3.50 (2H,
s), 3.52 (2H, s), 5.52 to 5.60 (1
H, m), 7.06-7.09 (1H, m), 7.20
~ 7.35 (7H, m)

Example 23 Preparation of cis-N- (4-tert-butylbenzyl) -N-methyl- [3- (1-methyl-1-propenyl) benzyl] amine hydrochloride (Compound 23) 0.19 g (3.41 × 10 ^-1 mmol) of 0.09 g of the target compound as white crystals was obtained in the same manner as in Example 7 using 0.08 ml (1 equivalent) of a 4 N hydrochloric acid-ethyl acetate solution.
(73.6% yield).

IR (KBr tablet, cm ^-1 ) 3458, 29
62, 2937, 2917, 2889, 2694, 26
77, 2633, 2566, 2548, 1461 m. p. 185-187 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.32 (9H,
s), 1.58 (3H, d, J = 7.02 Hz), 2.
04 (3H, s), 2.57 (3H, d, J = 7.83)
Hz), 4.00 to 4.09 (2H, m), 4.21 to
4.30 (2H, m), 5.58 to 5.65 (1H,
m), 7.26 to 7.65 (8H, m), 12.8 (1
H, brs)

Reference Example 9 Production of 3-bromo-5-fluorobenzoic acid: ether 1
1.97 g of magnesium (sharpened) and the amount of iodine catalyst were added to 50 ml. 1,3-dibromo-5 under a nitrogen atmosphere
A solution of 19.6 g of fluorobenzene in 20 ml of ether was added dropwise at a gentle reflux rate, and the mixture was heated under reflux for 3 hours. After cooling, crushed dry ice was added, and the mixture was stirred for 1 hour. The reaction was poured into water, acidified with hydrochloric acid and extracted with 200 ml of ether. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 100: 1) to obtain 9.37 g of the desired compound.
(55.4% yield).

¹ H-NMR (CDCl ₃ , ppm) 7.5
1 (1H, dt, J = 7.83 Hz, 2.30 Hz),
7.74 (1H, ddd, J = 8.91 Hz, 2.30
Hz, 1.35 Hz), 8.06 (1H, brs)

Reference Example 10 Production of 3-bromo-5-fluorobenzyl alcohol
1.68 g of sodium borohydride was added to 40 ml of diethylene glycol dimethyl ether, and 9.72 g of 3-bromo-5-fluorobenzoic acid was added to the solution while stirring at room temperature.
Added in batches. After the crystals were completely dissolved, a solution of 8.40 g of trifluoroborane ether complex in 10 ml of diethylene glycol dimethyl ether was added dropwise, and the mixture was stirred for 5 hours. The reaction solution was poured into ice water, extracted with 200 ml of ether, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 10: 1 →
5: 1) to give the desired compound (including diethylene glycol dimethyl ether). From the NMR measurement results, the yield of the target compound excluding diethylene glycol dimethyl ether was 7.70 g, and the yield was 84.6%.

¹ H-NMR (CDCl ₃ , ppm) 1.8
7 (1H, t, J = 5.94 Hz), 4.69 (2H,
d, J = 5.94 Hz), 7.04 (1H, brd),
7.16 (1H, dt, J = 7.83 Hz, 1.89H
z), 7.31 (1H, brs)

Reference Example 11 Production of 3-bromo-5-fluorobenzyl bromide: 18.3 ml of a 47% aqueous hydrogen bromide solution was stirred with 3.65 g of phosphorus tribromide so that the reaction temperature did not exceed 40 ° C. While adding. After dropwise adding a solution of 7.70 g of 3-bromo-5-fluorobenzyl alcohol in 6 ml of ethanol, the mixture was heated and refluxed on an oil bath for 5 hours. After cooling, pour the reaction solution into ice water
-Extracted with 150 ml of hexane. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 30: 1),
6.64 g of the desired product (66.0% yield).

¹ H-NMR (CDCl ₃ , ppm) 4.3
9 (2H, s), 7.06 (1H, dt, J = 8.91)
Hz, 1.89 Hz), 7.19 (1H, dt, J =
8.37 Hz, 1.89 Hz), 7.33 (1 H, br)
s)

Example 24 N- (4-tert-butylbenzyl) -N-methyl-
Preparation of (3-fluoro-5-isopropenylbenzyl) amine hydrochloride (Compound 27): Using 3-bromo-5-fluorobenzyl bromide and N- (4-tert-butylbenzyl) methylamine, Similarly, N
-(4-tert-butylbenzyl) -N-methyl-
(3-Bromo-5-fluorobenzyl) amine (Compound 24) was obtained. Then, using Compound 24 as a raw material, Example 1
In a similar manner to 2, 2- [3- {N- (4-tert-butylbenzyl) -N-methylaminomethyl} -5-fluorophenyl] -2-butanol (compound 25) was obtained. Next, N- (4-tert-butylbenzyl) -N-methyl- (3-fluoro-5-isopropenylbenzyl) was prepared in the same manner as in Example 13 using Compound 25 as a raw material.
The amine (compound 26) was obtained. Further, using Compound 26 as a raw material, Compound 27 was obtained in the same manner as in Example 3.

M. p. 181 to 183.5 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.33 (9H,
s), 2.17 (3H, s), 2.60 (3H, d, J
= 4.86 Hz), 4.00 (1H, dd, J = 12.
96Hz, 5.94Hz), 4.11 (1H, dd, J
= 13.23 Hz, 4.86 Hz), 4.20 to 4.3
0 (2H, m), 5.22 (1H, s), 5.53 (1
H, s), 7.19-7.29 (2H, m), 7.47.
(2H, d, J = 8.37 Hz), 7.53 (2H,
d, J = 8.37 Hz), 7.70 (1H, brs),
13.04 (1H, brs)

Reference Example 12 Production of 4- (1-methyl-1-phenylethyl) benzaldehyde: 3.93 g (20.0 mmol) of 2,2-diphenylpropane and 2.80 g of hexamethylenetetramine (20 ml in 35 ml of trifluoroacetic acid) And the mixture was heated under reflux for 16 hours. After returning to room temperature, the mixture was poured into ice water and stirred for 1 hour. The pH was adjusted to about 9 by adding potassium carbonate, and extracted with 100 ml of ether. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain 3.61 g (yield: 80.5%) of the target compound.

¹ H-NMR (CDCl ₃ , ppm) 1.7
1 (6H, s), 7.17 to 7.32 (5H, m),
7.40 (2H, d, J = 8.37 Hz), 7.79
(2H, d, J = 8.37 Hz), 9.98 (1H,
s)

Reference Example 13 Production of N- [4- (1-methyl-1-phenylethyl) benzyl] methylamine: 4- (1-methyl-1-phenyl) was dissolved in 40 ml of a 40% methylamine-methanol solution. Ethyl) benzaldehyde 3.61 g (16.1 mm
ol) and molecular sieves (4 Å)
About 5 particles were added, and the mixture was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was extracted with 100 ml of ether, and the organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (25 ml), sodium borohydride (0.70 g) was added, and the mixture was heated at 50 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and the residue was extracted with 100 ml of ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of ethanol, and an excess amount of a 4 N hydrochloric acid-ethyl acetate solution was added. The solvent was distilled off under reduced pressure, 100 ml of isopropyl ether was added to the residue, and the precipitated white crystals were collected by filtration. The crystals were returned to a free form with an aqueous sodium hydroxide solution, extracted with ether, and the organic layer was dried over anhydrous sodium sulfate.
2.49 g of the target compound as an orange oil (yield 64.
6%).

¹ H-NMR (CDCl ₃ , ppm) 1.6
8 (6H, s), 2.46 (3H, s), 3.71 (2
H, s), 7.08 to 7.29 (9H, m).

Example 25 3 '-[N-4- (1-methyl-1-phenylethyl)
Preparation of benzyl-N-methylaminomethyl] acetophenone (compound 28): 2.00 g (4.18 mmol) of N- [4- (1-methyl-1-phenylethyl) benzyl] methylamine in 20 ml of N, N-dimethylformamide
l) and 0.63 g (5.97 mmol) of sodium carbonate, and a solution obtained by dissolving 0.85 g (3.98 mmol) of 3'-bromomethylacetophenone in 5 ml of N, N-dimethylformamide was stirred at room temperature. It was dropped. After stirring at room temperature for 1 hour, the reaction was quenched by pouring into ice + a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with 100 ml of ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain 1.16 g (yield: 78.5%) of the target compound as a yellowish white oil. )Obtained.

¹ H-NMR (CDCl ₃ , ppm) 1.6
8 (4H, s), 2.19 (3H, s), 2.60 (3
H, s), 3.50 (2H, s), 3.56 (2H,
s), 7.14 to 7.29 (9H, m), 7.41 (1
H, t, J = 7.29 Hz), 7.59 (1H, d, J)
= 7.29 Hz), 7.83 (1H, d, J = 7.29)
Hz), 7.93 (1H, s)

Example 26 Preparation of N-methyl-N- [4- (1-methyl-1-phenylethyl) benzyl]-(3-isopropenylbenzyl) amine (compound 29): Methyltriphenylphosphonium in 20 ml of benzene 1.67 g of bromide (4.68
mmol) and stirring at room temperature under a nitrogen atmosphere.
2.9 ml (4.73 mmol) of a 1.63 M n-butyllithium-n-hexane solution were added dropwise. After stirring for 5 minutes, a solution of 1.16 g (3.12 mmol) of compound 28 in 5 ml of benzene was added dropwise, and the mixture was further stirred at room temperature overnight. The reaction was quenched by pouring into ice water, extracted with 100 ml of benzene, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 2).
0: 1) to give 0.44 g (yield 38.2%) of the target compound as a colorless transparent oil.

¹ H-NMR (CDCl ₃ , ppm) 1.6
7 (4H, s), 2.16 (3H, s), 2.19 (3
H, s), 3.48 (2H, s), 3.52 (2H,
s), 5.07 (1H, s), 5.37 (1H, s),
7.14 to 7.36 (12H, m), 7.36 (1H,
s)

Example 27 Preparation of N-methyl-N- [4- (1-methyl-1-phenylethyl) benzyl]-(3-isopropenylbenzyl) amine hydrochloride (Compound 30): Compound 2 as a starting material
9 0.44 g (1.19 mmol) of Example 4 using 0.30 ml (1.2 mmol) of 4N hydrochloric acid-ethyl acetate solution.
In the same manner as in the above, a hydrochloride was prepared. Further, recrystallization from isopropyl ether-ethanol gave 0.34 g (yield: 70.4%) of the target compound as white crystals.

IR (KBr tablet, cm ^-1 ) 3445, 29
72, 2942, 2669, 2625, 2560, 25
39, 1462, 797.9, 700.3 m. p. 168-170 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.69 (4H,
s), 2.18 (3H, s), 2.58 (3H, d, J
= 4.32 Hz), 3.98 to 4.08 (2H, m),
4.19 to 4.29 (2H, m), 5.16 (1H,
s), 5.46 (1H, s), 7.16 to 7.55 (1
2H, m), 7.73 (1H, s), 12.9 (1H,
brs)

Example 28 N- (4-tert-butylbenzyl) -N-methyl-
Production of (2-isopropenylbenzyl) amine hydrochloride (compound 34): 2-bromobenzyl bromide was obtained in the same manner as in Reference Example 3 using o-bromotoluene as a raw material. Then, using this and N- (4-tert-butylbenzyl) methylamine, N-
(4-tert-butylbenzyl) -N-methyl- (2
-Bromobenzyl) amine (Compound 31) was obtained. Then, using compound 31 as a raw material, 2
-[3- {N- (4-tert-butylbenzyl) -N
-Methylaminomethyldiphenyl] -2-propanol (Compound 32) was obtained. Further, N- (4-tert-butylbenzyl) -N-methyl- (2-isopropenylbenzyl) amine (Compound 33) was obtained in the same manner as in Example 13 using Compound 32 as a raw material. Finally, the target compound was obtained in the same manner as in Example 3 using Compound 33 as a raw material.

M. p. Once it became candy at 60-75 ° C, it liquefied at 130 ° C. ¹ H-NMR (CDCl ₃ , ppm) 1.32 (9H, s), 1.98 (3H, s), 2.5
2 (3H, d, J = 4.86 Hz), 4.06 (1H,
dd, J = 12.69 Hz, 5.40 Hz), 4.15
４4.27 (2H, m), 4.33 (1H, dd, J =
13.23 Hz, 4.86 Hz), 4.80 (1H,
s), 5.26 (1H, s), 7.20 (1H, dd,
J = 7.56 Hz, 1.62 Hz), 7.30 to 7.4
5 (2H, m), 7.44 (2H, d, J = 8.64H
z), 7.52 (2H, d, J = 8.64 Hz), 8.
21 (1H, dd, J = 7.56 Hz, 1.62H
z), 12.52 (1H, brs)

Example 29 Preparation of N- (4-tert-butylbenzyl) -N-isopropyl- (3-isopropenylbenzyl) amine hydrochloride (Compound 37): Starting from 3'-bromomethylacetophenone, 40% Using 3 ′-(N-isopropylaminomethyl) acetophenone in the same manner as in Reference Example 4 except that isopropylamine was used instead of the methylamine-methanol solution. Then, this was allowed to act on 4-tert-butylbenzyl bromide in the same manner as in Example 4, and 3 ′-[N- (4-tert-butylbenzyl)-
[N-isopropylaminomethyl] acetophenone (Compound 35) was obtained. Next, N- (4-tert-butylbenzyl) -N-isopropyl- (3-isopropenylbenzyl) amine (Compound 36) was obtained in the same manner as in Example 2 using Compound 35 as a raw material. Further, Compound 37 was obtained as a colorless transparent amorphous in the same manner as in Example 3 using Compound 36 as a raw material.

¹ H-NMR (CDCl ₃ , ppm) 1.3
0 (9H, s), 1.48 (3H, d, J = 7.56H
z), 1.51 (3H, d, J = 7.56 Hz);
18 (3H, s), 3.58 (1H, m), 3.91-
4.10 (2H, m), 4.11 to 4.21 (2H,
m), 5.14 (1H, s), 5.49 (1H, s),
7.36 (1H, t, J = 7.83 Hz), 7.42
(2H, d, J = 8.37 Hz), 7.49 (1H,
d, J = 7.83 Hz), 7.63-7.72 (1H,
m), 7.70 (2H, d, J = 8.37 Hz), 7.
95 (1H, s), 12.50 (1H, brs)

Example 30 N- (4-tert-butylbenzyl) -N-ethyl-
Preparation of (3-isopropenylbenzyl) amine hydrochloride (compound 40): Starting from 3′-bromomethylacetophenone, using ethylamine hydrochloride instead of a 40% methylamine-methanol solution in the presence of sodium hydroxide In the same manner as in Reference Example 4, 3 ′-(N-ethylaminomethyl) acetophenone was obtained. And this and 4-t
3 ′-[N- (4-tert-butylbenzyl) -N-ethylaminomethyl] acetophenone (compound 38) was obtained in the same manner as in Example 4 using tert-butylbenzyl bromide. Next, N- (4-tert-butylbenzyl) -N-ethyl- (3-isopropenylbenzyl) amine (Compound 39) was obtained in the same manner as in Example 2 using Compound 38 as a raw material. Further, Compound 40 was obtained in the same manner as in Example 3 using Compound 39 as a raw material.

M. p. 122-126 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.32 (9H,
s), 1.51 (3H, t, J = 7.29 Hz), 2.
19 (3H, s), 3.01 (2H, m), 4.02-
4.16 (2H, m), 4.18 to 4.30 (2H,
m), 5.16 (1H, s), 5.48 (1H, s),
7.41 (1H, t, J = 7.70 Hz), 7.46
(2H, d, J = 8.10 Hz), 7.50 to 7.65
(2H, m), 7.57 (2H, d, J = 8.10H
z), 7.80 (1H, s), 12.62 (1H, br)
s)

Example 31 N- (4-tert-butylbenzyl) -N-methyl-
Production of (3-isopropenyl-2-methylbenzyl) amine hydrochloride (Compound 44): 3-bromo-2 was obtained in the same manner as in Reference Example 6 using 3-bromo-o-xylene as a raw material.
-Methylbenzyl bromide was obtained with the by-product 2-bromo-6-methylbenzyl bromide. These were used as raw materials without purification, and N- (3-bromo-2-methylbenzyl) methylamine was obtained in the same manner as in Reference Example 7. Also, N- (2-
(Bromo-6-methylbenzyl) methylamine was also obtained. Next, using N- (3-bromo-2-methylbenzyl) methylamine and 4-tert-butylbenzylbromide, in the same manner as in Example 4, N- (4-tert-butylbenzyl) -N-methyl- ( 3-Bromo-2-methylbenzyl) amine (compound 41) was obtained. Then, using compound 41 as a starting material, in the same manner as in Example 12, 2-
[3- {N- (4-tert-butylbenzyl) -N-
Methylaminomethyl {-2-methylphenyl] -2-propanol (compound 42) was obtained. Further, using Compound 42 as a starting material, N- (4-ter
t-Butylbenzyl) -N-methyl- (3-isopropenyl-2-methylbenzyl) amine (Compound 43) was obtained. Finally, Compound 44 was obtained in the same manner as in Example 3 using Compound 43 as a raw material.

M. p. 207.5-210.5 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.33 (9H,
s), 2.00 (3H, s), 2.28 (3H, s),
2.63 (3H, d, J = 5.13 Hz), 4.01
(1H, dd, J = 12.83 Hz, 7.43 Hz),
4.15 to 4.38 (3H, m), 4.82 (1H,
s), 5.21 (1H, s), 7.17 (1H, dd,
J = 7.56 Hz, 1.08 Hz), 7.25 (1H,
t, 7.56 Hz), 7.47 (2H, d, J = 8.3)
757), 7.57 (2H, d, J = 8.37 Hz),
7.63 (1H, dd, J = 7.56 Hz, 1.08H
z), 12.40 (1H, brs)

Example 32 N- (4-tert-butylbenzyl) -N-methyl-
Preparation of (2-isopropenyl-6-methylbenzyl) amine hydrochloride (compound 48): N- (2-bromo-6-methylbenzyl) methylamine obtained in the intermediate step of Example 31 and 4-tert N- (4-tert-butylbenzyl) -N-methyl- (2-bromo-6-methylbenzyl) amine (Compound 45) was obtained in the same manner as in Example 4 using -butylbenzylbromide. Then, using compound 45 as a raw material, 2- [2
-{N- (4-tert-butylbenzyl) -N-methylaminomethyl} -3-methylphenyl] -2-propanol (Compound 46) was obtained. Further, using Compound 46 as a starting material, N- (4-tert-
(Butylbenzyl) -N-methyl- (2-isopropenyl-6-methylbenzyl) amine (Compound 47) was obtained.
Finally, Compound 48 was obtained in the same manner as in Example 3 using Compound 47 as a raw material.

M. p. 166-167.5 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.34 (9H,
s), 1.93 (3H, s), 2.50 (3H, s),
2.57 (3H, d, J = 4.59 Hz), 3.99
(1H, dd, J = 12.96 Hz, 6.48 Hz),
4.16 (1H, m), 4.25 (1H, m), 4.6
1 (1H, m), 4.82 (1H, s), 5.21 (1
H, s), 7.00 (1H, d, J = 7.29 Hz),
7.16 (1H, d, J = 7.29 Hz), 7.25
(1H, t, 7.29 Hz), 7.50 (2H, d, J
= 8.37 Hz), 7.68 (2H, d, J = 8.37)
Hz), 11.33 (1H, brs)

Example 33 N- (4-tert-butylbenzyl) -N-methyl-
Production of (3-isopropenyl-4-methylbenzyl) amine hydrochloride (Compound 52): 3-bromo-4-methylbenzoic acid was used as a starting material, and 3-bromo-4-methyl was prepared in the same manner as in Reference Example 9. Benzyl alcohol was obtained. And 3-
Using bromo-4-methylbenzyl alcohol as a raw material,
In the same manner as in Reference Example 10, 3-bromo-4-methylbenzyl bromide was obtained. Then, using 3-bromo-4-methylbenzyl bromide as a raw material, in the same manner as in Reference Example 7,
N- (3-Bromo-4-methylbenzyl) methylamine was obtained. Further, using this and 4-tert-butylbenzyl bromide, N- (4-te
rt-butylbenzyl) -N-methyl- (3-bromo-
4-Methylbenzyl) amine (compound 49) was obtained. Using compound 49 as a starting material, as in Example 12, 2-
[5- {N- (4-tert-butylbenzyl) -N-
Methylaminomethyl {-2-methylphenyl] -2-propanol (Compound 50) was obtained. Further, using Compound 50 as a starting material, N- (4-ter
t-Butylbenzyl) -N-methyl- (3-isopropenyl-4-methylbenzyl) amine (Compound 51) was obtained. Finally, Compound 52 was obtained in the same manner as in Example 3 using Compound 51 as a raw material.

M. p. 175-177 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.32 (9H,
s), 2.05 (3H, s), 2.33 (3H, s),
2.56 (3H, brs), 3.95 to 4.08 (2
H, m), 4.17-4.28 (2H, m), 4.86
(1H, s), 5.23 (1H, s), 7.20-7.
30 (2H, m), 7.46 (2H, d, J = 8.37)
Hz), 7.42 to 7.52 (1H, m), 7.53
(2H, d, J = 8.37 Hz), 12.72 (1H,
brs)

Example 34 N- (4-tert-butylbenzyl) -N-methyl-
Production of (4-fluoro-3-isopropenylbenzyl) amine hydrochloride (compound 56): 3-bromo-4-fluorotoluene was used as a starting material, and
Bromo-4-fluorobenzyl bromide was obtained. Then, using this as a raw material, N-
(3-Bromo-4-fluorobenzyl) methylamine was obtained. Then, using this and 4-tert-butylbenzyl bromide, N- (4-te
rt-butylbenzyl) -N-methyl- (3-bromo-
4-Fluorobenzyl) amine (compound 53) was obtained.
Further, using compound 53 as a raw material, in the same manner as in Example 12,
2- [5- {N- (4-tert-butylbenzyl)-
N-methylaminomethyl {-2-fluorophenyl]-
2-Propanol (compound 54) was obtained. Then, using Compound 54 as a raw material, N- (4
-Tert-Butylbenzyl) -N-methyl- (4-fluoro-3-isopropenylbenzyl) amine (Compound 55) was obtained. Finally, Compound 56 was obtained in the same manner as in Example 3 using Compound 55 as a raw material.

M. p. 209-212 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.33 (9H,
s), 2.17 (3H, s), 2.58 (3H, d, J
= 4.86 Hz), 3.98 (1H, dd, J = 13).
23Hz, 5.94Hz), 4.07 (1H, dd, J
= 13.23 Hz, 5.40 Hz), 4.24 (1H,
dd, J = 13.23 Hz, 4.05 Hz), 4.26
(1H, dd, J = 13.23 Hz, 4.05 Hz),
5.29 (1H, s), 5.32 (1H, s), 7.1
2 (1H, dd, J = 9.45 Hz, 8.37 Hz),
7.47 (2H, d, J = 8.64 Hz), 7.53
(2H, d, J = 8.64 Hz), 7.58 to 7.66
(2H, m), 12.87 (1H, brs)

Example 35 N- (4-tert-butylbenzyl) -N-methyl-
Production of (2-fluoro-5-isopropenylbenzyl) amine hydrochloride (compound 60): 5-bromo-2-fluorotoluene was used as a starting material, and
Bromo-2-fluorobenzyl bromide was obtained. Then, using this as a raw material, N-
(5-Bromo-2-fluorobenzyl) methylamine was obtained. Then, using this and 4-tert-butylbenzyl bromide, N- (4-te
rt-butylbenzyl) -N-methyl- (5-bromo-
2-Fluorobenzyl) amine (compound 57) was obtained.
Further, using compound 57 as a raw material, in the same manner as in Example 12,
2- [3- {N- (4-tert-butylbenzyl)-
N-methylaminomethyl {-4-fluorophenyl]-
2-Propanol (compound 58) was obtained. Then, using Compound 58 as a raw material, N- (4
-Tert-Butylbenzyl) -N-methyl- (2-fluoro-5-isopropenylbenzyl) amine (Compound 59) was obtained. Finally, Compound 60 was obtained in the same manner as in Example 3 using Compound 59 as a raw material.

M. p. 171.5-173 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.32 (9H,
s), 2.19 (3H, s), 2.59 (3H, d, J
= 4.59 Hz), 4.03 (1H, dd, J = 12.
96Hz, 5.67Hz), 4.21 (1H, dd, J
= 13.23 Hz, 5.67 Hz), 4.25 to 4.3.
5 (2H, m), 5.16 (1H, s), 5.49 (1
H, s), 7.09 (1H, t, J = 9.18 Hz),
7.47 (2H, d, J = 8.64 Hz), 7.50-
7.58 (1H, m), 7.56 (2H, d, J = 8.
64 Hz), 8.12 (1H, dd, J = 7.56H)
z, 2.43 Hz), 12.95 (1H, brs)

Example 36 Preparation of N- (3-bromo-5-methylbenzyl) -N-methyl- [4- (1-methyl-1-phenylethyl) benzyl] amine (Compound 61): N- (3 -Bromo-
11.0 g of 5-methylbenzyl) methylamine hydrochloride was dissolved in 30 ml of methanol, 800 mg of potassium hydroxide was added, and the mixture was stirred until dissolved. 4- (1-methyl-1-
8.96 g of phenylethyl) benzaldehyde were added,
After stirring for 15 minutes, sodium cyanoborohydride 9
A solution of 50 mg of methanol in 10 ml was added dropwise, and the mixture was further stirred for 30 minutes. After filtering the insoluble matter and washing with methanol, the filtrate was concentrated under reduced pressure. After adding water and extracting with 250 ml of ether, 150 ml of 1N hydrochloric acid was added to the organic layer and the mixture was stirred, and the precipitated crystals were collected by filtration and washed with water and ether. The filtrate was separated, the aqueous layer was combined with the previous crystals, made alkaline with sodium hydroxide and extracted with 250 ml of chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 30: 1) to obtain 7.60 g (yield: 45.0%) of the target compound. .

¹ H-NMR (CDCl ₃ , ppm) 1.6
8 (6H, s), 2.16 (3H, s), 2.31 (3
H, s), 3.42 (2H, s), 3.47 (2H,
s), 7.08 (1H, s), 7.10 to 7.29 (1
0H, m), 7.31 (1H, s)

Example 37 Preparation of N-methyl-N- [4- (1-methyl-1-phenylethyl) benzyl]-(3-isopropenyl-5-methylbenzyl) amine hydrochloride (Compound 64): Compound Using 61 as a raw material, 2- [3
-Methyl-5- [N-methyl-N- {4- (1-methyl-1-phenylethyl) benzyl} aminomethyl] phenyl] -2-propanol (Compound 62) was obtained. This was used as a raw material, and N
-Methyl-N- [4- (1-methyl-1-phenylethyl) benzyl]-(3-isopropenyl-5-methylbenzyl) amine (Compound 63) was obtained. Finally, compound 6
Compound 64 was obtained in the same manner as in Example 3 except that Compound 3 was used as a starting material.

M. p. 153 to 156 ° C ¹ H-NMR (CDCl ₃ , ppm) 1.69 (6H,
s), 2.16 (3H, s), 2.40 (3H, s),
2.57 (3H, d, J = 4.32 Hz), 3.95-
4.07 (2H, m), 4.16 to 4.27 (2H,
m), 5.13 (1H, s), 5.43 (1H, s),
7.14 to 7.36 (9H, m), 7.47 to 7.55
(3H, m), 12.82 (1H, brs)

Reference Example 14 Production of 3,5-dibromobenzyl bromide: benzene 2
27.0 g of 3,5-dibromotoluene (10 mL
8.0 mmol), 19.2 g of N-bromosuccinimide
(108.0 mmol) and 0.32 g of benzoyl peroxide
And heated to reflux for 2.5 hours. After returning to room temperature, the solvent was distilled off under reduced pressure, 200 ml of n-hexane was added to the residue, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 17.2 g of the desired compound (yield: 48.3).
%)Obtained.

¹ H-NMR (CDCl ₃ , ppm) 4.3
6 (2H, s), 7.47 (2H, d, J = 1.62H)
z), 7.60 (1H, t, J = 1.62 Hz)

Reference Example 15 Production of N- (3,5-dibromobenzyl) methylamine: 5.28 g (52.2 mmol) of triethylamine was dissolved in 100 ml of a 40% methylamine-methanol solution.
While stirring at room temperature, a solution of 17.2 g (52.2 mmol) of 3,5-dibromobenzyl bromide in 20 ml of N, N-dimethylformamide was added dropwise. After stirring at room temperature overnight, the solvent was distilled off under reduced pressure. 150 ml of 2N hydrochloric acid was added to the residue and extracted with 150 ml of diethyl ether to remove impurities. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution, and extracted with 100 ml of chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to give the target compound as an orange oil (11.3 g).
(77.7% yield).

¹ H-NMR (CDCl ₃ , ppm) 2.4
3 (3H, s), 3.70 (2H, s), 7.42 (2
H, s), 7.55 (1H, s)

Example 38 N- (4-tert-butylbenzyl) -N-methyl-
Preparation of (3,5-dibromobenzyl) amine (compound 65): N-N-dimethylformamide
4.38 g of (3,5-dibromobenzyl) methylamine
(15.7 mmol) and 2.37 g of sodium carbonate (2
2.4 mmol) and p-te
3.40 g of rt-butylbenzyl bromide (14.9 mm
ol) in 20 ml of N, N-dimethylformamide was added dropwise. After the dropwise addition, the mixture was heated and stirred at 50 ° C. for 100 minutes. After allowing to cool to room temperature, the mixture was poured into ice and a saturated aqueous solution of sodium hydrogen carbonate, and extracted with 100 ml of diethyl ether.
The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and extracted twice with 100 ml of 2N hydrochloric acid. The aqueous layer and the precipitated crystals were collected, made alkaline with an aqueous sodium hydroxide solution, and extracted with 100 ml of chloroform. The organic layer was washed with water and saturated saline and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 40: 1).
4.21 g of the target compound as a pale white oil (yield 6
6.4%).

¹ H-NMR (CDCl ₃ , ppm) 1.3
0 (9H, s), 2.18 (3H, s), 3.43 (2
H, s), 3.50 (2H, s), 7.26 (2H,
d, J = 7.83 Hz), 7.36 (2H, d, J =
7.83 Hz), 7.53 (2H, s), 7.56 (1
H, s)

Example 39 2- [3-bromo-5- {N- (4-tert-butylbenzyl) -N-methylaminomethyl} phenyl] -2
Preparation of propanol (compound 66): 4.21 g (9.90 mmol) of compound 65 in 40 ml of tetrahydrofuran
Is dissolved in a nitrogen atmosphere at −78 ° C. while stirring.
6.1 ml (9.94 mmol) of a 1.63 M n-butyllithium-n-hexane solution was added dropwise. After 10 minutes, 1.5 ml of acetone was added dropwise, and the temperature was gradually returned to room temperature. A saturated aqueous ammonium chloride solution was added dropwise, and water was further added, followed by extraction with 100 ml of diethyl ether. The organic layer was washed with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1 → 2: 1) to give 3.11 g of the desired compound as a pale yellow oil (yield). 77.7%).

¹ H-NMR (CDCl ₃ , ppm) 1.3
2 (9H, s), 1.57 (3H × 2, s), 2.19
(3H, s), 3.48 (2H × 2, s), 7.27
(2H, d, J = 8.37 Hz), 7.35 (2H,
d, J = 8.37 Hz), 7.39 (1H, s), 7.
42 (1H, s), 7.51 (1H, s)

Example 40 N- (4-tert-butylbenzyl) -N-methyl-
Preparation of (3-bromo-5-isopropenylbenzyl) amine (compound 67): Dissolve 3.11 g (7.69 mmol) of compound 66 in 50 ml of pyridine, and stir at room temperature with 11.8 g (76) of phosphorus oxychloride. .9 mmol) was added dropwise. After the dropwise addition, the mixture was heated and stirred at 120 ° C. for 3 hours. After returning to room temperature, the mixture was poured into ice water and alkalified by adding sodium hydroxide. The mixture was extracted with 150 ml of chloroform, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (n
-Hexane: ethyl acetate = 20: 1) to obtain 1.83 g of the desired compound as a pale yellow oil (yield: 61.6).
%)Obtained.

¹ H-NMR (CDCl ₃ , ppm) 1.3
2 (9H, s), 2.13 (3H, s), 2.19 (3
H, s), 3.48 (2H, s), 3.50 (2H,
s), 5.11 (1H, t, J = 1.35 Hz), 5.
37 (1H, s), 7.26 to 7.36 (5H, m),
7.44 (1H, s), 7.46 (1H, s)

Example 41 2- [3-isopropenyl-5- {N- (4-tert
-Butylbenzyl) -N-methylaminomethyl {phenyl] -2-propanol (compound 68): 0.80 g (2.0 g of compound 67) in 15 ml of tetrahydrofuran.
Under a nitrogen atmosphere, 1.3 ml (2.1 mmol) of a 1.63 M n-butyllithium-n-hexane solution was slowly added dropwise while stirring at -78 ° C. 10
After a minute, 0.5 ml of acetone was added dropwise, and the temperature was gradually returned to room temperature. The reaction was stopped by dropwise addition of a saturated aqueous ammonium chloride solution, and the mixture was extracted with 100 ml of diethyl ether. The organic layer was washed with a saturated saline solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 5: 1 → 2:
Purification was performed in 1) to obtain 0.28 g of the target compound (yield: 37.0).
%)Obtained.

¹ H-NMR (CDCl ₃ , ppm) 1.3
1 (9H, s), 1.60 (6H, s), 2.18 (3
H, s), 2.21 (3H, s), 3.48 (2H,
s), 3.54 (2H, s), 5.09 (1H, s),
5.38 (1H, s), 7.26-7.48 (7H,
m)

Example 42 N- (4-tert-butylbenzyl) -N-methyl-
Preparation of (3,5-bisisopropenylbenzyl) amine (compound 69): 0.2 of compound 68 in 15 ml of pyridine
8 g (7.66 × 10 ⁻¹ mmol) and phosphorous oxychloride 0.1 g.
59 g (3.83 mmol) was added dropwise, and the mixture was heated under reflux for 2 hours. After returning to room temperature, the mixture was poured into ice water and made weakly alkaline by adding sodium carbonate. The mixture was extracted with 50 ml of chloroform, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain 0.18 g (yield: 67.6%) of the target compound.

IR (Nujol, cm ^-1 ) 2964, 29
06,2870,2784,1591,1450,13
64,1269,1135,1111,1031,10
20,884.6 ¹ H-NMR (CDCl ₃ , ppm) 1.28 (9H,
s), 2.18 (3H × 2, s), 2.21 (3H,
s), 3.50 (2H, s), 3.54 (2H, s),
5.09 (1H, s), 5.38 (1H, s), 7.2
6 to 7.38 (6H, m), 7.43 (1H, m)

Example 43 In accordance with the following formulation, polystyrene spheres and Compound 3 were mixed and melt-molded to produce a toothbrush handle.

[Table 1] (Formulation) Polystyrene small spheres 99 parts by weight Compound 3 1 part by weight

Example 44 According to the following formulation, polystyrene spheres and compound 7 were mixed and melt-molded to produce a toothbrush handle.

[Table 2] (Formulation) Polystyrene globules 90 parts by weight Compound 7 10 parts by weight

Example 45 According to the following prescription, each prescription component was weighed and kneaded in a kneader to prepare an ointment for treating athlete's foot.

Table 3 (Formulation) Vaseline 99 parts by weight Compound 10 1 part by weight

Example 46 According to the following prescription, each prescription component was weighed and kneaded in a kneader to prepare an ointment for treating athlete's foot.

[Table 4] (Formulation) Water-absorbing ointment 99 parts by weight Compound 14 1 part by weight

Example 47 A solution was prepared by solubilizing the following ingredients with stirring.

(Formulation) Ethanol 92 parts by weight Methacrylic acid alkyl ester copolymer 2 parts by weight Compound 17 1 part by weight Propylene glycol 5 parts by weight

Example 48 A formulation was prepared by stirring and solubilizing the following ingredients.

(Formulation) Ethanol 92 parts by weight Methacrylic acid alkyl ester copolymer 2 parts by weight Compound 21 1 part by weight Propylene glycol 5 parts by weight

Test Example 1 Measurement of Antifungal Activity (Measurement of Minimum Inhibitory Concentration) The antifungal activity of the compound of the present invention on dermatophytes was examined. That is, the test filamentous strain was prepared in advance using a Sabouraud agar medium (manufactured by Nissui Pharmaceutical Co .;
%, Agar 1.5%, pH 5.9) on a slant medium at 27 ° C.
For 2 weeks to produce sufficient conidia. Then 0.0
Sterile physiological saline containing 5% by weight / volume Tween 80 was added, and the conidia were released and suspended while rubbing the surface with a platinum loop. The suspension is filtered through two layers of sterile gauze,
Agar and mycelial mass were removed. The filtrate was adjusted with the same physiological saline using a hemocytometer so that the concentration of conidia became 10 ⁵ cells / ml. On the other hand, compound 3,
7, 14, 21, 23, 27, 34, 40 and 52 were each taken in an amount of 10 mg, and 1 ml of dimethyl sulfoxide was added to make a stock solution.
A 2-fold dilution was prepared by adding 00 μl. The same operation was repeated to prepare 13-step diluted drug solutions of 10 to 0.0025 mg / ml (final concentration of test system: 100 to 0.025 μg / ml). 100 μl of various dilution solutions of the test drug were dispensed into a sterile petri dish. Then, a sterilized and dissolved Sabouraud agar medium (peptone 1.0%, glucose 4.0
%, Agar 1.5%, pH 5.9), and mixed well, followed by solidification. Next, 5 μl of the already prepared test bacterial solution was inoculated using a microplanter. Culture is 2
The test was performed at 7 ° C. for one week, and the minimum drug concentration (μg / ml) that clearly suppressed the visible growth was defined as the MIC value. Table 7 shows the results.

[0163]

[Table 7]

[0164]

The amine derivative (1) or a salt thereof of the present invention has excellent antifungal activity and is extremely useful as an antifungal agent, an antifungal composition, a medicament and the like.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 209/60 C07C 209/60 211/35 211/35 213/02 213/02 215/28 215/28 221/00 221/00 223/02 223/02 225/16 225/16 (72) Inventor Koji Yokoyama 560 Pola, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside the Tokazuka Research Laboratories (72) Inventor Hiroyuki Takimoto 560 Pola, Kashio-cho, Totsuka-ku, Yokohama, Kanagawa (72) Inventor Masayuki Yuasa, Inventor Masayuki Yuasa, 560 Pola, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture In-house Chemical Company, Ltd. (72) Inventor Yukio Kawazu, 560 Kashio-cho, Totsuka-ku, Yokohama, Kanagawa, Japan Inside Totsuka Laboratory Co., Ltd. (72) Inventor Toshimitsu Suzuki 560 Pola, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside the Totsuka Laboratory Co., Ltd. Inside Totsuka Research Laboratory

Claims (11)

[Claims] 1. The following general formula (1): [In the formula, R ¹ represents a linear, branched or cyclic alkyl group of 1 to 4 carbon atoms; R ² represents a linear alkyl group or a phenyl group having 1 to 4 carbon atoms; R ³ is C 1 -C Straight-chain, branched-chain or cyclic alkyl group having 1 to 5 carbon atoms, a straight-chain, branched-chain or cyclic alkyl group having 1 to 5 carbon atoms, an acyl group having a straight chain of 2-5 carbon atoms, shows a branched chain or cyclic alkenyl group or a halogen atom, m pieces of R ³
May be the same or different. K, l and m each represent an integer of 1-4. Or a salt thereof. 2. In the general formula (1), R ¹ is methyl, ethyl, isopropyl or cyclopropyl; R ² is methyl or phenyl; R ³ is methyl, 1-hydroxy -1-methylethyl group, 1,2
-Dimethyl-1-hydroxypropyl group, 1-hydroxypropyl group, formyl group, acetyl group, propionyl group, vinyl group, isopropenyl group, 2-methyl-1-propenyl group, 1-ethylvinyl group, 1-methyl-1 The amine derivative according to claim 1, which is a -propenyl group, a 1-isopropylvinyl group, a fluorine atom or a bromine atom, or a salt thereof. 3. 3 ′-[N- (4-tert-butylbenzyl) -N-methylaminomethyl] acetophenone,
N- (4-tert-butylbenzyl) -N-methyl-
(3-isopropenylbenzyl) amine, N- (4-t
tert-butylbenzyl) -N-methyl- (3-bromobenzyl) amine, 3- [N- (4-tert-butylbenzyl) -N-methylaminomethyl] benzaldehyde, N- (4-tert-butylbenzyl) -N-methyl- (3-vinylbenzyl) amine, 3 '-[N- (4
-Tert-butylbenzyl) -N-cyclopropylaminomethyl] acetophenone, N- (4-tert-butylbenzyl) -N-cyclopropyl- (3-isopropenylbenzyl) amine, N- (4-tert-butylbenzyl) ) -N-methyl- (3-bromo-5-methylbenzyl) amine, 2- [3- {N- (4-tert-butylbenzyl) -N-methylaminomethyl} -5-methylphenyl] -2- Propanol, N- (4-tert
-Butylbenzyl) -N-methyl- (3-isopropenyl-5-methylbenzyl) amine, 2- [3- {N-
(4-tert-butylbenzyl) -N-methylaminomethyl {phenyl] -3-methyl-2-butanol, N
-(4-tert-butylbenzyl) -N-methyl-
[3- (1-isopropylvinyl) benzyl] amine,
1- [3- {N- (4-tert-butylbenzyl)-
N-methylaminomethyldiphenyl] -1-propanol, 3 '-[N- (4-tert-butylbenzyl)-
N-methylaminomethyl] propiophenone, N- (4
-Tert-butylbenzyl) -N-methyl- [3-
(1-ethylvinyl) benzyl] amine, cis-N-
(4-tert-butylbenzyl) -N-methyl- [3
-(1-methyl-1-propenyl) benzyl] amine,
N- (4-tert-butylbenzyl) -N-methyl-
(3-bromo-5-fluorobenzyl) amine, 2-
[3- {N- (4-tert-butylbenzyl) -N-
Methylaminomethyl {-5-fluorophenyl] -2-
Butanol, N- (4-tert-butylbenzyl)-
N-methyl- (3-fluoro-5-isopropenylbenzyl) amine, 3 '-[N-4- (1-methyl-1-phenylethyl) benzyl-N-methylaminomethyl] acetophenone, N-methyl-N -[4- (1-methyl-
1-phenylethyl) benzyl]-(3-isopropenylbenzyl) amine, N- (4-tert-butylbenzyl) -N-methyl- (2-bromobenzyl) amine,
2- [3- {N- (4-tert-butylbenzyl)-
N-methylaminomethyl {phenyl] -2-propanol, N- (4-tert-butylbenzyl) -N-methyl- (2-isopropenylbenzyl) amine, 3'-
[N- (4-tert-butylbenzyl) -N-isopropylaminomethyl] acetophenone, N- (4-te
rt-butylbenzyl) -N-isopropyl- (3-isopropenylbenzyl) amine, 3 ′-[N- (4-t
tert-butylbenzyl) -N-ethylaminomethyl]
Acetophenone, N- (4-tert-butylbenzyl) -N-ethyl- (3-isopropenylbenzyl) amine, N- (4-tert-butylbenzyl) -N-methyl- (3-bromo-2-methylbenzyl) ) Amine, 2
-[3- {N- (4-tert-butylbenzyl) -N
-Methylaminomethyl {-2-methylphenyl] -2-
Propanol, N- (4-tert-butylbenzyl)
-N-methyl- (3-isopropenyl-2-methylbenzyl) amine, N- (4-tert-butylbenzyl)
-N-methyl- (2-bromo-6-methylbenzyl) amine, 2- [2- {N- (4-tert-butylbenzyl) -N-methylaminomethyl} -3-methylphenyl] -2-propanol , N- (4-tert-butylbenzyl) -N-methyl- (2-isopropenyl-6-
Methylbenzyl) amine, N- (4-tert-butylbenzyl) -N-methyl- (3-bromo-4-methylbenzyl) amine, 2- [5- {N- (4-tert-butylbenzyl) -N -Methylaminomethyl {-2-methylphenyl] -2-propanol, N- (4-tert
-Butylbenzyl) -N-methyl- (3-isopropenyl-4-methylbenzyl) amine, N- (4-tert
-Butylbenzyl) -N-methyl- (3-bromo-4-
Fluorobenzyl) amine, 2- [5- {N- (4-t
tert-butylbenzyl) -N-methylaminomethyl
-2-fluorophenyl] -2-propanol, N-
(4-tert-butylbenzyl) -N-methyl- (4
-Fluoro-3-isopropenylbenzyl) amine, N
-(4-tert-butylbenzyl) -N-methyl-
(5-bromo-2-fluorobenzyl) amine, 2-
[3- {N- (4-tert-butylbenzyl) -N-
Methylaminomethyl {-4-fluorophenyl] -2-
Propanol, N- (4-tert-butylbenzyl)
-N-methyl- (2-fluoro-5-isopropenylbenzyl) amine, N- (3-bromo-5-methylbenzyl) -N-methyl- [4- (1-methyl-1-phenylethyl) benzyl] Amine, 2- [3-methyl-5-
[N-methyl-N- {4- (1-methyl-1-phenylethyl) benzyl} aminomethyl] phenyl] -2-propanol, N-methyl-N- [4- (1-methyl-1
-Phenylethyl) benzyl]-(3-isopropenyl-5-methylbenzyl) amine, N- (4-tert-
Butylbenzyl) -N-methyl- (3,5-dibromobenzyl) amine, 2- [3-bromo-5- {N- (4-
tert-butylbenzyl) -N-methylaminomethyl {phenyl] -2-propanol, N- (4-ter
t-butylbenzyl) -N-methyl- (3-bromo-5
-Isopropenylbenzyl) amine, 2- [3-isopropenyl-5- {N- (4-tert-butylbenzyl) -N-methylaminomethyl} phenyl] -2-propanol, and N- (4-tert- Butylbenzyl)
The amine derivative according to claim 1, which is selected from -N-methyl- (3,5-bisisopropenylbenzyl) amine or a salt thereof. 4. The amine derivative or a salt thereof according to claim 1, wherein the salt is a hydrochloride. 5. The following general formula (2): [Wherein, R ¹ represents a linear, branched or cyclic alkyl group having 1 to 4 carbon atoms; R ³ is substituted by a linear, branched or cyclic alkyl group having 1 to ³ carbon atoms, or a hydroxyl group. A linear, branched or cyclic alkyl group having 1 to 5 carbon atoms,
Linear C1-5, branched chain or acyl group having a cyclic structure, a linear, branched or cyclic alkenyl group, or a halogen atom having 2 to 5 carbon atoms, m pieces of R ³ may be the same or different You may. K and m are each 1 to 4
Indicates an integer. And a salt thereof and a compound represented by the following general formula (3): [Wherein, R ² represents a linear alkyl group having 1 to 4 carbon atoms or a phenyl group; 1 represents an integer of 1 to 4; X represents a halogen atom. Wherein the compound represented by the general formula (1) or a salt thereof is condensed. (Wherein R ¹ , R ² , R ³ , k, l and m have the same meanings as described above) or a salt thereof. 6. The following general formula (4): [In the formula, R ³ represents a straight-chain, branched-chain or cyclic alkyl group having 1 to 3 carbon atoms,
Straight-chain, branched-chain or cyclic alkyl group having 1 to 5 carbon atoms
Represents an acyl group having a linear, branched or cyclic structure of from 5 to 5, a linear, branched or cyclic alkenyl group having from 2 to 5 carbon atoms or a halogen atom, and m R ^{3 s} may be the same or different . K and m each represent an integer of 1 to 4; X represents a halogen atom. Or a salt thereof, and a compound represented by the following general formula (5): [In the formula, R ¹ represents a linear, branched or cyclic alkyl group having 1 to 4 carbon atoms; R ² represents a linear alkyl group or a phenyl group having 1 to 4 carbon atoms; Indicates an integer. A compound represented by the general formula (1): (Wherein R ¹ , R ² , R ³ , k, l and m have the same meanings as described above) or a salt thereof. 7. The following general formula (2): [Wherein, R ¹ represents a linear, branched or cyclic alkyl group having 1 to 4 carbon atoms; R ³ is substituted by a linear, branched or cyclic alkyl group having 1 to ³ carbon atoms, or a hydroxyl group. A linear, branched or cyclic alkyl group having 1 to 5 carbon atoms,
Linear C1-5, branched chain or acyl group having a cyclic structure, a linear, branched or cyclic alkenyl group, or a halogen atom having 2 to 5 carbon atoms, m pieces of R ³ may be the same or different You may. K and m are each 1 to 4
Indicates an integer. And a salt thereof, and a compound represented by the following general formula (6): [Wherein, R ² represents a linear alkyl group having 1 to 4 carbon atoms or a phenyl group; l represents an integer of 1 to 4]. Wherein the compound represented by the general formula (1) or a salt thereof is condensed. (Wherein R ¹ , R ² , R ³ , k, l and m have the same meanings as described above) or a salt thereof. 8. The following general formula (7): [In the formula, R ³ represents a straight-chain, branched-chain or cyclic alkyl group having 1 to 3 carbon atoms,
Straight-chain, branched-chain or cyclic alkyl group having 1 to 5 carbon atoms
Represents an acyl group having a linear, branched or cyclic structure of from 5 to 5, a linear, branched or cyclic alkenyl group having from 2 to 5 carbon atoms or a halogen atom, and m R ^{3 s} may be the same or different . k and m each represent an integer of 1 to 4. And a salt thereof, and a compound represented by the following general formula (5): [In the formula, R ¹ represents a linear, branched or cyclic alkyl group having 1 to 4 carbon atoms; R ² represents a linear alkyl group or a phenyl group having 1 to 4 carbon atoms; Indicates an integer. Wherein the compound represented by the formula (1) or a salt thereof is condensed: (Wherein R ¹ , R ² , R ³ , k, l and m have the same meanings as described above) or a salt thereof. 9. An antifungal agent comprising the amine derivative according to claim 1 or a salt thereof. 10. An antifungal composition comprising the amine derivative according to claim 1 or a salt thereof. 11. A pharmaceutical comprising the amine derivative according to claim 1 or a salt thereof as an active ingredient.