WO2002096853A1 - Process for producing aralkylamine derivative - Google Patents

Abstract

An aromatic aldehyde derivative represented by the general formula (1): Ar-CHO (1) (wherein Ar represents an aromatic group) is reacted with trichlorosilane and a carbamate represented by the general formula (2): NH2COOR (2) (wherein R represents alkyl or aralkyl) to obtain an aralkyl derivative of the carbamate, the derivative being represented by the general formula Ar-CH2-B (wherein Ar and R have the same meanings as defined above and B represents hydrogen or -COOR). According to need, this derivative is subjected to a reaction for eliminating the protective group to obtain an aralkylamine derivative represented by the general formula Ar-CH2-NH2 (wherein Ar has the same meaning as defined above).

Description

 Description Method for producing aralkylamine derivative

Technical field

 The present invention relates to a novel method for producing an aralkylamine derivative. The aralkylamine derivative obtained according to the present invention is useful, for example, as an intermediate for producing a physiologically active substance such as a medicament, a pesticide and the like.

Background art

 Aralkylamine derivatives such as 3,5-bistrifluoromethylbenzylamine are known to be useful as intermediates for producing physiologically active substances such as pharmaceuticals and agricultural chemicals. ing.

 As a method for producing such an aralkylamine (eg, benzylamine) derivative represented by 3,5-bistrifluoromethylbenzylamine, 3,5-bis-trifluoromethyl is used. A method for catalytic hydrogenation of benzonitrile (Japanese Patent Laid-Open Publication No. 2000-256821), and a method for hydrogenating an oxime of 3,5-bistrifluoromethylbenzaldehyde by contact hydrogenation (Japanese Unexamined Patent Publication No. 2000-27369) is known.

Among them, the former method (Japanese Patent Application Laid-Open No. 2000-256628) discloses a method for synthesizing 3,5-bistrifluoromethylbenzonitrile as a raw material. Because of the low yield of cyanation of benzene, which is 3,5_bistrifluoromethylol, which is a crystalline form (WO98 / 37058), this raw material is used on an industrial scale. There were difficulties in procurement. In order to suppress the by-product of the dibenzylamine derivative in the catalytic hydrogenation reaction, in the former method, liquid ammonia is used. And uses a tetrahydrofuran solvent, which can explode when used on an industrial scale.

 On the other hand, in the latter method (Japanese Patent Application Laid-Open No. 2000-27369), hydrogen chloride gas is allowed to coexist in the reaction system, and the hydrogen pressure is 1.013 MPa (1 (0 atm). Therefore, when implementing any of these methods on an industrial scale, it was unavoidable to use special equipment and materials in view of the danger in their reactions.

 As described above, in the prior art, there has been no production method using a simple process for an aralkylamine derivative represented by 3,5-bistrifluoromethyl benzylamine. More specifically, with respect to aralkylamine derivatives, it is easy and safe to implement on an industrial scale (that is, no special equipment or materials are required on an industrial scale). Did not exist. Disclosure of the invention

 An object of the present invention is to provide a method for producing an aralkylamine derivative using a simple process.

 Another object of the present invention is to provide a method for producing an aralkylamine derivative which can be carried out on an industrial scale and is safe (that is, it does not require special equipment and materials even on an industrial scale). It is in.

As a result of the earnest study, the present inventors have conducted highly selective aromatization by subjecting an aromatic aldehyde derivative as a starting material to a reductive amination reaction using carpamide esters and trichlorosilane. Aralkyl carpamide derivatives and aralkyl carbamide derivatives are obtained. I found that. As a result of further research, the present inventors have found that an aralkylamine derivative can be produced with high purity by deprotecting the aralkylcarpamide derivative as required.

 The method for producing an aralkylamine derivative of the present invention is based on the above findings, and more specifically, the general formula (1)

 A r-C H O (1)

 (Wherein Ar represents an aromatic group) and an aromatic aldehyde derivative represented by the general formula (2) in the presence of trichlorosilane.

NH ₂ COOR (2)

 (Wherein, R represents an alkyl group or an aralkyl group).

A r-CH ₂ NH- B (3)

 (Wherein, Ar represents an aromatic group, B represents a hydrogen atom or a COOR group, and R represents an alkyl group or an aralkyl group).

 According to a preferred embodiment of the present invention, a compound represented by the following general formula (4)

 (In the formula, X represents an alkyl group or a halogen atom, 1 represents an integer of 0 to 5, m represents an integer of 0 to 5, m + 1 is 5 or less, and when m is 2 or more, X may be the same or different.) In the presence of trichlorosilane, the compound represented by the general formula (2) NH 2 COO (2)

(Where R represents an alkyl group or an aralkyl group) Reaction of rubamide ester with the general formula (5)

 (Wherein, B represents a hydrogen atom or a —CO 0 R group, R represents an alkyl group or an aralkyl group, X represents an alkyl group or a halogen atom, 1 represents an integer of 0 to 5, m Represents an integer of 0 to 5, m + 1 is 5 or less, and when m is 2 or more, X may be the same or different.

 In the method for producing an aralkylamine derivative of the present invention having the above structure, an aromatic aldehyde derivative as a starting material is generally easily available industrially in high yield. In addition, carpamidates and trichlorosilane, which are reaction reagents for the reductive amination reaction of the aromatic aldehyde derivative, are both commercially available. In addition, the N-benzylcarbamic acid ester derivative, which is one embodiment of the production intermediate in the production method of the present invention, is not only useful in the above-mentioned method for producing an aralkylamine derivative, but also a novel compound. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail. In the following description, “parts” and “%” representing quantitative ratios are based on mass unless otherwise specified.

 (Production method of aralkylamine derivative)

 In the method for producing an aralkyl derivative of the present invention, the above general formula (1)

 A r-C H O (1)

(Wherein, A r represents an aromatic group) In the body, in the presence of trichlorosilane, the general formula (2)

 NH 2 COOR (2)

 (Wherein, R represents an alkyl group or an aralkyl group).

A r ~ CH ₂ NH- B (3)

 (Wherein, Ar represents an aromatic group, B represents a hydrogen atom or a single COOR group, and R represents an alkyl group or an aralkyl group).

 (Aromatic group)

 In the present invention, in the presence of trichlorosilane, a reaction with the carpamide ester represented by the above general formula (2) is possible (preferably, this reaction involves steric hindrance and And / or the number of heteroatoms, the number and number of heteroatoms, the number of unsaturated bonds, the number of substituents, etc. are particularly limited as long as they are not substantially hindered by electronic effects. Not done. That is, the aromatic group Ar may be a polycyclic aromatic group or a monocyclic aromatic group. The aromatic group Ar may be a heterocyclic ring (for example, a complex ring containing at least one or more (preferably 1 to 3) hetero atoms selected from O, S, and N).

 As the aromatic group, those having a benzene ring as a ring to which an aldehyde group (that is, C—HO group of Ar—CHO) should be bonded are preferable.

(Polycyclic aromatic group)

 When the aromatic group Ar is a polycyclic aromatic group, specific examples of the group that can be used as the polycyclic aromatic group are listed below.

For example, naphthyl, biphenyl, pyridylphenyl, bipyridyl, ceylpheninole, furanylphenyl, indolyl Group, quinolyl group, benzofuranyl group, benzimidazolyl group, benzothiazolyl group, benzochenyl group, benzoxazolyl group, phthalazinyl group, quinazolinyl group and the like.

 The polycyclic aromatic group Ar is preferably a benzene nucleus and a saturated or unsaturated carbocyclic or heterocyclic ring bonded or condensed to the benzene ring from the viewpoint of availability. The saturated or unsaturated carbocyclic or heterocyclic ring bonded or condensed to the benzene ring is preferably a 3- to 8-membered ring (more preferably: a to 7-membered ring). Ar — From the viewpoint of the reactivity of the CHO aldehyde group, a saturated or unsaturated carbocyclic or heterocyclic ring bonded or fused to a benzene ring has an electron-withdrawing effect on the benzene ring. It is preferred that

 (Monocyclic aromatic group)

 When the aromatic group Ar is a monocyclic aromatic group, specific examples of the group that can be used as the monocyclic aromatic group are listed below.

 For example, a phenyl group, a pyrrolyl group, a pyridyl group, a virazyl group, a pyrimidinyl group, a triazidinyl group, a chenyl group, a furanyl group, an oxazolyl group, a thiazolyl group, which may have a substituent. The monocyclic aromatic group Ar is preferably a group based on a benzene nucleus from the viewpoint of availability. From the viewpoint of the reactivity of the aldehyde group of Ar—CHO, for example, the substituent bonded to the benzene ring preferably has an electron-withdrawing effect on the benzene ring.

 In the present invention, the monocyclic aromatic group Ar is particularly represented by the following general formula (4) from the viewpoint of providing an intermediate suitable for a physiologically active substance such as a medicine, a pesticide and the like. Is preferred.

 (Method for producing benzylamine derivative)

In the method for producing a benzylamine derivative according to one embodiment of the present invention, The above general formula (4)

 (In the formula, X represents an alkyl group or a halogen atom, 1 represents an integer of 0 to 5, m represents an integer of 0 to 5, m + 1 is 5 or less, and when m is 2 or more, X may be the same or different) to the benzaldehyde derivative represented by the general formula (2) NH 2 COOR (2) in the presence of trichlorosilane.

 (Wherein, R represents an alkyl group or an aralkyl group) by reacting the rubamide ester with the above-mentioned general formula (5)

 (In the formula, B represents a hydrogen atom or one COOR group, R represents an alkyl group or an aralkyl group, X represents an alkyl group or a halogen atom, 1 represents an integer of 0 to 5, and m represents 0 And m + 1 is 5 or less, and when m is 2 or more, X may be the same or different.), Thereby obtaining a benzylamine derivative represented by the following formula:

 (Representative mode)

 Representative embodiments of the present invention for obtaining the above benzylamine derivative are shown in the following [1] to [4].

 [1] General formula (4)

 (In the formula, X represents an alkyl group or a halogen atom, 1 represents an integer of 0 to 5, m represents an integer of 0 to 5, m + 1 is 5 or less, and m is 2 or more. , X may be the same or different)

In the presence of an acid, trichlorosilane and a benzaldehyde derivative represented by the general formula (2)

NH 2 COOR (2) (Wherein R represents an alkyl group or an aralkyl group) by reacting with a carbamide ester represented by the general formula (5a):

 (In the formula, R represents an alkyl group or an aralkyl group, X represents an alkyl group or a halogen atom, 1 represents an integer of 0 to 5, m represents an integer of 0 to 5, m + 1 represents 5 X is the same or different when m is 2 or more.)

After producing the N-benzylcarbamide derivative represented by

The deprotection reaction is performed by the general formula (6)

 (In the formula, X represents an alkyl group or a halogen atom, 1 represents an integer of 0 to 5, m represents an integer of 0 to 5, m + 1 is 5 or less, and when m is 2 or more, X may be the same or different)

The aspect which obtains the benzylamine derivative represented by these.

[2] General formula (4) (4)

(In the formula, X represents an alkyl group or a halogen atom, 1 represents an integer of 0 to 5, m represents an integer of 0 to 5, m + 1 is 5 or less, When m is 2 or more, X may be the same or different.) In the presence of an acid, trichlorosilane and the general formula (2)

 N H 2 C O O (2)

 (Wherein, R represents an alkyl group or an aralkyl group)

By reacting with a carpamide ester represented by the general formula (5)

 (In the formula, R represents an alkyl group or an aralkyl group, X represents an alkyl group or a halogen atom, 1 represents an integer of 0 to 5, m represents an integer of 0 to 5, m + 1 represents 5 X is the same or different when m is 2 or more)

An embodiment for obtaining an N-benzylcarbamic acid ester derivative represented by the following formula:

(3) General formula (7)

 (Where n represents an integer of 1 to 5)

In the presence of an acid, trichlorosilane and the trichlorosilane represented by the general formula (2)

 N H 2 C 0 O R (2)

 (Wherein, R represents an alkyl group or an aralkyl group)

By reacting with a carbamide ester represented by the general formula (8)

(In the formula, R represents an alkyl group or an aralkyl group, and n represents an integer of 1 to 5.)

After producing an N-benzylcarbamic acid ester derivative represented by the formula

 (Where n represents an integer of 1 to 5)

Obtaining a trifluoromethylben- derivative represented by the following formula, [4] a general formula (10)

 (In the formula, 'R' represents an alkyl group, and n represents an integer of 1 to 5.) An N-benzylcarbamic acid ester derivative represented by the following formula:

 Hereinafter, description will be made mainly on an embodiment of the present invention for obtaining a benzylamine derivative.

 (First aspect)

First, the first embodiment will be described. In the first embodiment, the benzaldehyde derivative represented by the general formula (4) is combined with trichlorosilane and a carbamide acid ester represented by the general formula (2) in the presence of an acid. To produce an N-benzylcarbamic acid ester derivative represented by the general formula (5) (B = COOR) (hereinafter, this reaction is referred to as “reductive amination reaction”). Sometimes) . Then Of the N-benzylcarbamic acid ester derivative of the present invention (hereinafter referred to as the urethane structure in the N-benzylcarbamic acid ester derivative represented by the general formula (5)). The reaction that forms a primary amino group by decomposition may be simply referred to as “deprotection reaction”) to obtain a benzylamine derivative represented by the general formula (6). .

 (Benzaldehyde derivative)

 The benzaldehyde derivative represented by the general formula (4) to be used as a raw material in one embodiment of the present invention will be described.

In the above formula (4), X represents an alkyl group or a halogen atom. When X is an alkyl group, the alkyl group has 1 to 6 carbon atoms (hereinafter referred to as “C i to C ₆ ” Abbreviated as such) is preferred. More specifically, as such a ~ C ₆ alkyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a s-ec-butyl group, a tert-butyl group Examples thereof include a tyl group, an n-pentyl group, and an n-hexyl group.

 When X is a halogen atom in the general formula (4), examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

 In the general formula (4), 1 represents an integer of 0 to 5 (more preferably an integer of 0 to 2), in represents an integer of 0 to 5 (more preferably an integer of 0 to 3), and Π1 + 1 Is 5 or less, and when m is 2 or more, Xs may be the same or different.

 (Example of benzaldehyde derivative)

Benz represented by the general formula (4) having X, 1, and m as described above. Examples of the aldehyde derivative include benzaldehyde, 4-methylbenzaldehyde, 2-fluorobenzaldehyde, 31-fluorobenzanolide, 4-benzoaldehyde, 2-benzobenzene, and 3-benzobenzene. Black mouth Benzaldehyde, 4-black Benzaldehyde, 2,4-cyclobenzaldehyde, 3,4-cyclobenzaldehyde, 2-trifluoromethylbenzaldehyde, 3-toh 4-Fluoromethylbenzaldehyde, 4-trifluoromethylbenzoaldehyde, 3-funoleol 4-Trifluoromethylbenzaldehyde, 2-fluoro-5—trifunolelomethinolevens Acre Dehide, 2 — Black mouth 3 — Trifluorometinorebenzanoledehide, 2 — Krollo 5 — Tri-funoleolomethinolebenzanolede ide, 41-port _ 3 — Tri-funolelomethylbenzanoledede, 2, 3 —Bis (trifluoromethyl) benzaldehyde, 2 , 4_Bis (trifluoromethyl) benzaldehyde, 2,5-bis (trifluoromethyl) benzaldehyde, 2,6-bis (trifluoromethyl) benzaldehyde, 3,4-bis (trifluoromethyl) Benzaldehyde, 3,5—bis (trifluoromethyl) Benzaldehyde, 41-mouth _ 3,5—bis (trifluoromethyl) Benzaldehyde, 2,3,6—tris (trifluorenemethyl) Benzaldehyde, 2, 4, 6—tris (trifluoromethyl) Benzaldehyde, 2, 3, 4, 6—tetrakis (trifluoromethyl) Benzaldehyde and the like can be mentioned.

The method for obtaining the benzaldehyde derivative represented by the general formula (4) is not particularly limited. For example, Chem. Berchte (Chem. Ber.), Vol. It can be easily produced by, for example, the method of formylation of the corresponding halogenobenzene derivative by Grignard reaction described in the above. (Carpamide ester)

 Next, the carbamide ester represented by the general formula (2) will be described. In the present invention, the carpamide ester usually functions as an N source for reductive amination of the starting material benzaldehyde derivative.

R in the general formula (2) represents an alkyl group or an aralkyl group. The alkyl group for R is preferably a C i -C ₆ linear or branched alkyl group from the viewpoint of availability. Such C丄is a linear or branched alkyl group of ~ C _6, yo Ri specifically methylation group, Echiru group, n- propyl group, i an isopropyl group, n- heptyl group, sec —Butynole group, tert —butynole group, n-pentynole group, and n-hexyl group.

 On the other hand, examples of the aralkyl group for R include a benzyl group, a 2-chlorophenylaminomethyl group, a 41-chlorophenylmethyl group, and a 41-methylphenylaminomethyl group.

 Examples of the carpamide esters represented by the general formula (2) having R as described above include methyl carpamide, ethyl carpamide, n-propyl canolepamide, and carpamide acid Examples thereof include n-butyl, tert-butyl carbamidate, and benzyl carnomidate.

 The amount of the carbamide acid ester represented by the general formula (2) is determined based on 1 mole of the aromatic aldehyde (eg, benzaldehyde) derivative represented by the general formula (1). The amount of the carbamide ester represented by the general formula (2) is usually preferably in the range of 1 to 3 mol, more preferably in the range of 1.0 to 1.5 mol.

 (Reductive amination reaction)

Aromatic aldehyde represented by the general formula (1) (for example, Benz aldehyde) The aralkyl represented by the general formula (3) (B = COOR) (for example, the aralkyl) is obtained by reacting the derivative with a carbamide ester represented by the general formula (2) and trichlorosilane. The reaction (reductive amination reaction) for obtaining an N-benzyl) carpamide ester derivative will be described. Usually, this reductive amination reaction is preferably carried out in the presence of an acid.

 Acids used in this reductive amination reaction include, for example, mineral acids such as sulfuric acid; and organic sulfonic acids such as methanesnolefonic acid, paratonolenesnolefonic acid, trifluorophenolsulfonic acid, and trifluoroacetic acid. Organic acids, including carboxylic acids, can be mentioned. From the viewpoint of reaction yield and selectivity, it is preferable to use an organic acid, and particularly preferable to use trifluoroacetic acid.

 Two or more of the above-mentioned acids can be mixed (combined or mixed) as necessary. The amount of the acid used is usually in the range of 1.0 to 10.0 mol per 1 mol of the derivative of the aromatic aldehyde (for example, benzaldehyde) represented by the general formula (1). And more preferably in the range of 2.0 to 7.0 moles.

 (Reducing agent)

 The reducing agent used in the reductive amination reaction in the present invention is trichlorosilane. The amount used is preferably in the range of 1.0 to 5.0 mol per 1 mol of the aromatic aldehyde (for example, benzaldehyde) derivative represented by the general formula (1). It is preferably in the range of 1.2 to 3.0 mol.

In the present invention, the use of this trichlorosilane makes it easy to suppress the generation of by-products (for example, alcohol derivatives in which the aldehyde group of the raw material is simply reduced). In the present invention, The production of such an alcohol derivative can be suppressed to 1% or less (further, 0.5% or less) in a yield based on the aldehyde derivative as a raw material. The amount of the alcohol derivative as a by-product is defined as a mole, and the desired product, an aralkyl (for example, benzyl) amine derivative (B = H in the general formula (3)) and a no or carbamide ester ( In the production method of the present invention, when the total production amount of B = COR in the general formula (3) is b mol, the ratio (a Z b) of the crude product is not more than 0.01. (Further, 0.05 or less).

 (Dehydrating agent)

 Since water is generated in the reductive amination reaction of the present invention, it is preferable to coexist a dehydrating agent in the reaction system. Trichlorosilane itself, which is a reducing agent, can also function as this dehydrating agent. When the dehydrating agent is also used as the trichlorosilane, the amount of the trichlorosilane used is based on 1 mole of the aromatic aldehyde (e.g., benzaldehyde) derivative represented by the general formula (1). It is preferably in the range of 2.0 to 4.0 mol (more preferably, 2.0 to 3.0 mol).

In this reductive amination reaction, a method in which trichlorosilane itself, which is a reducing agent, also functions as a dehydrating agent, as described above, or a method in which a dehydrating agent different from trichlorosilane is used, may be employed. Wear. The “another dehydrating agent” in such an embodiment is not particularly limited as long as the target reaction is not substantially inhibited, but acid chlorides such as acetyl chloride, acetic anhydride, and trihydric anhydride. It is preferable to use an acid anhydride such as fluoracetic acid or the like, or a trialkyl halide silane such as trimethylchlorosilane as a dehydrating agent. The amount of this “another dehydrating agent” used is 1.0 to 5.0 with respect to 1 mole of the aromatic aldehyde (for example, benzaldehyde) derivative represented by the general formula (1). It is preferably in the range of moles, more preferably in the range of 1.0 to 2.0 moles.

 (Solvent)

 The reductive amination reaction in the present invention can be carried out without a solvent, but a solvent can be used if necessary. When a solvent is used, the solvent can be used alone or as a mixed solvent having an arbitrary mixing ratio. As a solvent to be used, a solvent which is substantially inert to the reductive amination reaction can be used without particular limitation. Examples of such a solvent include an aromatic hydrocarbon solvent and a specific solvent. Specific examples include tonolen, xylene, benzene, benzene, etc .; aliphatic hydrocarbon solvents, specifically, n-hexane, n-heptane, n-decane, etc. can do. It is preferable to use an aromatic hydrocarbon solvent such as toluene, which can be easily recovered or reused and is usually relatively safe in practice on an industrial scale.

 The amount of the solvent to be used is not particularly limited as long as the reaction system can be sufficiently stirred. One mole of the aromatic aldehyde (for example, benzaldehyde) derivative represented by the general formula (1) is used. In contrast, it is preferably in the range of 100 ml or less, and more preferably in the range of 500 ml or less. On the other hand, from the viewpoint of container efficiency, reactivity, and ease of stirring, the amount of the solvent used is preferably in the range of 100 ml or more, and more preferably 200 ml or more. Is preferred.

The reaction temperature of the reductive amination reaction is preferably in the range of 110 to 100 ° C, more preferably in the range of 0 to 60 ° C. The reaction time is preferably in the range of 0.1 to 8 hours. This reductive amination reaction can usually be performed under normal pressure, and usually does not require pressurization. However, pressure may be applied if necessary. (Reaction method)

 The reaction method of the reductive amination reaction is not particularly limited as long as substantial amination can be achieved. From the viewpoint of safety in the practice on an industrial scale, an aromatic aldehyde derivative (for example, benzaldehyde) derivative represented by the general formula (1) and a carpamide ester derivative represented by the general formula (2) A method in which trichlorosilane is added dropwise to a mixed solution of an acid such as trifluoroacetic acid (and a solvent when a solvent is used); or an aromatic aldehyde represented by the general formula (1). A method of dropping an acid such as trichlorosilane and trifluoroacetic acid into a mixed solution of a chlorinated derivative and a carbamide acid ester represented by the general formula (2) (and a solvent, if a solvent is used). Is preferable as a reaction method for the reductive amination reaction.

(N-benzylcarbamide ester derivative)

Examples of the aralkyl (eg, N-benzyl) carbamide derivative represented by the general formula (3) (B = COOR) which can be produced by the method of one embodiment of the present invention include, for example, N-benzylcarpamide Methyl carboxylate, N— (4-methylbenzyl) methyl carpamide, N— (2-phenolyl benzyl) Methinole acid, N— (3-benzyl benzoyl) Methyl carbamide, N— (4 1-Fluorobenzyl) methyl methyl lulfamidate, N— (2-chloro benzyl) Methyl carpamidate, N-mono (3-cyclo benzyl) Methinole canolenomidate, N— (4-cyclo benzyl) ) Methyl carpamide, N— (2,4-dichlorobenzene) Methyl carpamide, N— (3,4-dichlorobenzyl) methyl methyl carbamide, N— (2—trifluo) Lomethylbenzyl) mosquito Methyl lupamidate, N— (3-trifluoromethylbenzyl) Methyl carpamidate, N _ (4—trifluoromethylbenzyl) methinolate carnomidate, N— (3-Funolero 4 1 tri-funoleolomethylbenzyl) Methyl carnomidoate, N— (3-Fluoro-4-tritrifluoromethylbenzyl) Methyl carpamidate, N— (2—Fluoro-5—trifluoromethylbenzyl) Methyl luminomidate, N— (2— Methyl carbamidate 3—Trifluoromethylbenzyl) Carpamidate, N— (2—Chloro 5—Trifluoromethylbenzyl) Methyl carbamidoate, N— (4 Methyl 3- (3-fluoromethylbenzyl) carnomate, N— [2,3-bis (trifluoromethyl) benzyl] methyl methyl rubamidate, N— [2,3-bis (tri-methyl) Fluorometyl) Benzinole] Ethyl carbamidoate, N— [2,4-Bis (trifluoromethyl) benzyl] Methyl canolenomidate, N- [2,4-bis (trifnoroleolomethyl) benzyl] , Ethyl midoate, N- [2,5-Bis (trifluoromethyl) benzyl] methyl carbamidate, N- [2,5—Bis (tri-frenoleolomethinole) benzyl] methyl Ethyl dorate, N- [2,6-Bis (trifluoromethyl) benzyl] carbamidoate, N_ [2,6—Bis (trifluoromethyl) benzyl] carbamidoethyl, N— [3 , 4_Bis (trifnorolelomethinole) benzyl] methyl carpamide, N— [3,4-bis (trifluoromethyl) benzyl] carbethylate, N— [3,5-bis (trifluoromethyl) ) Benzyl] methyl benzoate, N— [3,5-bis (trifnoroleolomethinole) benzyl] canolenomidoethyl,-[3,5-bis (trifluoromethyl) benzyl] Carpamide acid tert-butyl, N [3,5-Bis (trifnorolelomethinole) benzyl] benzyl bermidoate, N— [41-chloro 3,5-Bis (trifluoromethyl) benzyl] bevel / methyl revamidate, N— [4_Cro mouth—3,5—Bis (trifluoromethyl) benzyl] carbamidoethyl, N— [2,3,6—Tris (trifluoromethyl) benzyl] methyl carpamide, N— [ twenty three , 6-tris (trifluoromethyl) benzyl] ethyl ethyl carbamidate, N- [2,4,6—tris (trifluoromethyl) benzyl] force Methyl lupamidoate, N— [2,4,6 — Tris (trifluoromethyl) benzyl] ethyl carbamidoate, N— [2, 3, 4, 6— tetrakis (trifluoromethyl) benzyl] methyl propamate, N- 1, 2, 3 , 4,6-Tetrakis (trifluoromethyl) benzinole] ethyl carpamide and the like.

 The aralkyl (e.g., N-benzyl) carbamide ester derivative represented by the general formula (3) (B = COOR) obtained by the above-mentioned reductive amination reaction is not purified and the next amino acid is obtained. A deprotection reaction of the group may be carried out, and if necessary, a purification step by a conventional method such as recrystallization may be carried out before use in the next step.

 (Deprotection reaction)

Next, the aralkyl (eg, N-benzyl) derivative represented by the above-mentioned general formula (3) is a derivatization reaction of the amino group of the rubamidate derivative (B = COOR), and the general formula (3) ( The reaction for obtaining an aralkyl (eg, benzyl) amine derivative represented by (B = H) will be described. The reagent, reaction method, reaction condition, and the like to be used in such an amino group deprotection reaction are not particularly limited. Examples of the deprotection reaction include a general primary amine carbamide including an amination reaction by deprotection of an amino group protected by a urethane-type protecting group, which is well known in the field of peptide synthesis. Deprotection of the acid ester protecting group is applicable. The term “deprotection reaction” as used herein refers to the formation of a primary amino group by decomposing the urethane structure in the aralkyl carbamide derivative represented by the general formula (3) (B = COOR). This is the reaction that occurs. More specific examples of the reaction included in such a deprotection reaction include a hydrolysis reaction, an alcoholysis reaction, an acid decomposition reaction, and a catalytic hydrogenation reaction. Hereinafter, these reactions will be described. However, the deprotection reaction in the present invention is not limited to the reactions exemplified above, but is a known primary amino acid obtained by decomposing a urethane structure. The group formation reaction can be applied without any particular limitation.

(Hydrolysis reaction)

 The hydrolysis reaction of this deprotection reaction can be carried out under either acidic conditions or alkaline conditions.However, from the viewpoint of reactivity and simplicity of post-treatment, hydrolysis under alkaline conditions is considered. Is common and preferred.

 Bases used in the hydrolysis reaction under alkaline conditions include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline hydroxides such as calcium hydroxide and parium hydroxide. Metal hydroxides can be used. The amount of the base to be used is preferably in the range of 1 to 20 mol, per 1 mol of the aralkylcarbamidate derivative represented by the general formula (3) (B = COOR). It is preferably in the range of 2 to 10 mol.

 On the other hand, the acid used for the hydrolysis reaction under acidic conditions is, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or the like, for example, acetic acid, trifluoroacetic acid, methanesnolefonic acid, trifnoroleromethane Organic acids such as sunolefonic acid, phenol, and toluenesulfonic acid can be used. The amount of the acid used is preferably in the range of 1 to 20 moles, and more preferably 1 to 20 moles, per mole of the aralkyl carbamic acid ester derivative represented by the general formula (3) (B = COOR). It is preferably in the range of 10 to 10 mol.

The amount of water used in the above hydrolysis reaction is not particularly limited, but is, for example, 200 ml or less per mole of the aralkyl force lupamide ester derivative represented by the general formula (3) (B = COOR). Range And more preferably 100 m1 or less. On the other hand, from the viewpoint of vessel efficiency and reactivity, the amount of water is 100 ml per 1 mol of the aralkyl carbamic acid ester derivative represented by the general formula (3) (B = COOR). It is preferably in the above range, and more preferably 200 m 1 or more.

 As a solvent to be used, water as a “reagent” for the hydrolysis reaction can also serve as a solvent, but if necessary, an inert solvent may be used for the reaction. Examples of such “inert” solvents include alcohol solvents, specifically, methanol, ethanol, 2-propanol, ethylene glycol, and the like; aliphatic carboxylic acids, specifically, formic acid and acetic acid. Aromatic hydrocarbon solvents, specifically, tonolen, xylene, black benzene, benzene, and the like. The amount of such an “inert” solvent used is within a range of 200 ml or less per mole of the aralkyl carbamide derivative represented by the general formula (3) (B = COOR). Is more preferable, and more preferably 100 m1 or less. On the other hand, from the viewpoint of vessel efficiency and reactivity, the amount of the “inert” solvent is determined based on 1 mol of the aralkylcarpamide derivative represented by the general formula (3) (B = COOR). It is preferably in the range of 100 ml or more, and more preferably in the range of 200 ml or more. The reaction temperature of the above hydrolysis reaction is preferably in the range of 30 to 180 ° C, more preferably in the range of 50 to 120 ° C. Further, the reaction time is preferably in the range of 1 to 20 hours. This reaction can be carried out under normal pressure, but may be carried out under pressure if necessary.

 (Alcohol decomposition reaction)

Next, the alcoholysis reaction of the deprotection reaction will be described. Prolapse The alcoholysis reaction of the protection reaction is generally and preferably performed under alkaline conditions from the viewpoint of reactivity and simplicity of post-treatment.

 Alkali metal used in the alcoholysis reaction under alkaline conditions includes, for example, alkali metal hydroxides such as sodium hydroxide and sodium hydroxide, calcium hydroxide, barium hydroxide, etc. And alkaline earth metal hydroxides, and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. The amount of the alcohol used is preferably in the range of 1 to 20 mol per 1 mol of the aralkyl carbamide derivative represented by the general formula (3) (B = CO OR), and Is preferably in the range of 2 to 10 mol.

 As the alcohol used in the above alcoholysis reaction, lower alcohols having 1 to 6 carbon atoms, such as methanol, ethanolanol, 2-propanol, tert-butanol, etc., are generally used. 3) The amount is preferably in the range of 2000 ml or less, more preferably 100 ml or less, per 1 mol of the aralkyl carpamide derivative represented by (B = COOR). preferable.

A solvent in this alcoholysis reaction is not always necessary because alcohol usually also serves as a solvent. If necessary, a solvent inert to the reaction may be used as the “other solvent”. Examples of such “other solvents” include, for example, aromatic hydrocarbon solvents, specifically, tonolene, xylene, benzene, and benzodiene chlorobenzene. The amount of the “other solvent” used is within a range of 2000 ml or less per 1 mol of the aralkyl carbamide ester derivative represented by the general formula (3) (B-CO OR). There is Preferably, it is more preferably in the range of 1000 m1 or less. The reaction temperature of the alcoholysis reaction is preferably in the range of 30 to 180 ° C, more preferably in the range of 50 to 120 ° C. The reaction time is in the range of 1 to 20 hours, and the reaction can be carried out under normal pressure. However, if necessary, the reaction may be carried out under pressure.

 (Acid decomposition reaction)

 Next, the acid decomposition reaction of the deprotection reaction will be described. The acid-decomposition reaction of the deprotection reaction is suitably applied when R of the carpamide ester represented by the general formula (3) is a group which can be easily decomposed by an acid such as a tert-butyl group or a benzyl group. it can.

 Examples of the acid used in the acid decomposition reaction include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid; aliphatic carboxylic acids such as formic acid, acetic acid, and trifluoroacetic acid; or methanesnolefonic acid and trifluoromethanesnolefon An organic sulfonic acid such as an acid can be used, but a method using trifluoroacetic acid is generally and preferably used. The amount of the acid used is preferably in the range of 1 to 20 mol per 1 mol of the aralkyl carbamide derivative represented by the general formula (3) (B = COOR). It is preferably in the range of 2 to 10 mol.

As the solvent used in the above-mentioned acid decomposition reaction, the acid used in the acid decomposition reaction (such as trifluoroacetic acid) can also serve as a solvent, but if necessary, it may be used as “another solvent”. A solvent inert to the reaction may be used. Examples of such "other solvents" include alcohol solvents, specifically, methanol, ethanol, 2-propanol, etc .; aliphatic carboxylic acids, specifically, formic acid, acetic acid, Propionic acid and the like; aromatic hydrocarbon solvents, specifically, toluene, xylene, black benzene, and ortho-benzene; "other The solvent is preferably used in an amount of not more than 2000 ml with respect to 1 mol of the aralkyl carbamide derivative represented by the general formula (3) (B = COOR), More preferably, it is within the range of 100 Oml or less.

 The reaction temperature of the acid decomposition reaction is preferably in the range of 30 to 180 ° C, and more preferably in the range of 50 to 100 ° C. The reaction time is in the range of 1 to 20 hours, and the reaction can be carried out under normal pressure. Usually, pressurization is not necessary, but may be performed if necessary.

 (Catalytic hydrogenation reaction)

 Finally, the catalytic hydrogenation reaction of the deprotection reaction will be described. The catalytic hydrogenation reaction of the deprotection reaction can be applied when R of the carbamic acid ester represented by the general formula (3) is an aralkyl group such as a benzyl group.

 Such a catalytic hydrogenation reaction usually uses a metal catalyst. The catalyst to be used is not particularly limited as long as it can be used for the catalytic hydrogenation reaction. For example, a palladium catalyst such as a palladium catalyst supported on activated carbon (PdXC) or a palladium catalyst supported on silica; a platinum catalyst such as a platinum catalyst supported on activated carbon or a platinum catalyst supported on silica; a Raney catalyst such as Raney nickel or Raney cobalt; Can be mentioned. For industrial use, activated carbon-supported palladium (PdZC) is generally preferred in terms of availability. The amount of the metal catalyst used is 0.00.001 to 0.05 gram atom per mole of the N-benzylcarbamic acid ester derivative represented by the general formula (3) (B = COOR). It is preferably in the range of 0.001 to 0.02 gram atom.

The solvent used in the catalytic hydrogenation reaction is inactive in the reaction. An acidic solvent can be used without any particular limitation. Examples of such a solvent include alcohol solvents, specifically, methanol, ethanol, 2-propanol, 1-butanol and the like; aliphatic alkyl ester solvents, specifically, methyl acetate, ethyl acetate , Butyl acetate and the like; aromatic hydrocarbon solvents, specifically, toluene, xylene and the like. The amount of the solvent used may be in the range of not more than 600 ml with respect to 1 mol of the N-benzylcarpamide derivative represented by the general formula (3) (B = CO OR). Preferably, it is more preferably at most 300 Oml.

 The hydrogen used in the catalytic hydrogenation reaction can be usually used alone, but if necessary, it can be diluted with a gas inert to the reaction, such as nitrogen, helium, or argon. . A preferable hydrogen partial pressure during the reaction is usually in the range of 0.01 MPa to 10 MPa.

 The reaction temperature of the above catalytic hydrogenation reaction is preferably in the range of 110 to 180 ° C, more preferably in the range of 0 to 100 ° C. The reaction time is preferably in the range of 1 to 60 hours. (Partial reaction progress)

In the method of the present invention, depending on the structure of the aralkyl (for example, N-benzyl) carbamide derivative represented by the general formula (3) (B = COOR), at the time of completion of the reductive amination reaction, Under the reaction conditions of the reductive amination reaction, the deprotection reaction has already partially proceeded, so that the aralkylamine derivative represented by the general formula (3) (B = H) as the target substance is obtained. May be generated and recovered (for example, when R in the general formula (3) is a tert-butyl group or a benzyl group). In such a case, the remaining general formula (3) (B = C) coexists with the aralkylamine derivative represented by the general formula (3) (B = H). The aralkyl carbamic acid ester derivative represented by the formula (OOR) is further deprotected as described above to lead to the benzylamine derivative represented by the general formula (3) (R = H). The method of producing the desired product by combining with an aralkylamine derivative represented by the general formula (3) (R = H) that has already been formed at the end of the selective amination reaction is also used in the method of the present invention. Is included.

 (Benzylamine derivative)

Examples of the aralkylamine (for example, benzylamine) derivative represented by the general formula (3) (R = H) obtained by the method of the present invention include, for example, penzinoleamine and 4-methinolevene / reamine. , 2 — Fluorobenzinoreamin, 3 — Penolenoamine with phenolic mouth, 4- Benzoreamine with phenolic mouth, 2 — Penzinoleamine with chromium mouth, 3 benzylamine with chromium mouth, 2,4 Penicoleamine with chromium mouth, 3,4 dicyclobenzinoreamin, 4—cyclopentopenialeamine, 2-triphenylolenomethylbenbenoreamine, 3-trifluoromethylbenzylamine, 4_trifluoromethylbenzyamine, 4_trifluorometinoleamine N-zinoleamin, 3—Funoleolo 4 1 Tri-Fnoleolomethinole Benzinoleamine, 2—Fluoro-5—Trifluoromethyl N-diamine, 2—cl-mouth 1- 3—trifnoreolo methinolebenzinoreamin, 2-cl-mouth 5—tri-frenoleo methino-lebenzinoreamin, 4-cl. Rifluoromethyl pentinoleamine, 2,3-bis (trifluoromethyltinole) benzylamine, 2,4—bis (trifluoromethinole) penzinoleamine, 2,5—bis (trifrenoleo) Mouth methinole) Benzinoleamine, 2, 6-bis (trifluoromethyl) benzylamine, 3,4-bis (trifluoromethyl) benzylamine, 3, 5—bis (trifrenoleolome) Tyl) penzinoleamine, 4—chloro 3,5—bis (trifnoroleolomethyl) benzylamine, 2,3,6—tris (trifluoromethyl) benzylamine , 2, 4, 6 — Tris (tris Fluoromethyl) benzylamine, 2,3,4,6-tetrakis (trifluoromethyl) benzylamine, and the like. The obtained aralkylamine derivative represented by the general formula (3) (R = H) may be subjected to a purification step such as rectification or recrystallization if necessary. If necessary, recrystallization can be carried out by deriving an inorganic acid or an organic acid salt which can be easily crystallized.

 (N-benzinolecanolepamide acid estenole derivative)

 Further, among the compounds represented by the general formula (5), which are intermediates in one embodiment of the method of the present invention, compounds wherein m is 0, 1 is an integer of 1 to 5, and R is an alkyl group That is, the N-benzylcarbamic acid ester derivative represented by the general formula (10) is a novel compound. Examples of the N-benzylcarbamic acid ester derivative (compound of the present invention) represented by the general formula (10) include, for example, methyl N_ (2-trifluoromethylbenzyl) carbamidate, N— ( 3— Methyl benzyl benzophenol) Mole canolebamidate, N— (4-Trifluoromethyl benzyl) carbamidate, N— [2,3-Bis (trifluoromethyl) benzyl] carbamido methyl, N— [2,3-bis (trifluoromethyl) benzyl] ethyl carbamidate, N— [

2,4-bis (trifluoromethylinole) benzyl] methyl carbamidate, N— [2,4-bis (triphenylenomethylinole) benzyl] canolenomidine, N-[2,5— Bis (trifluoromethyl) benzyl] kyrupa, methyl medioate, N— [2,5-bis (trifluoromethyl) benzyl] carbyl ethylate, N- [2,6-bis (trif Fluoromethyl) benzyl] methyl carnomate, N— [2,6-bis (trifluoromethyl) benzyl] ethyl ethyl carbamido, N— [

3,4-bis (trifluoromethyl) benzyl] methyl propamate, N— [3,4-bis (trifluoromethyl) benzyl] carpa Ethyl midoate, N— [3,5-bis (trifluoromethyl) benzyl] carbamidate, N— [3,5-bis (trifluoromethyl) benzyl] carnomidyl, N — Tert-butyl [3,5-bis (trifluoromethyl) benzyl] carbamidate, N— [2,3,6—tris (trifluoromethyl) benzyl] methyl carnamide, Ν— [2 , 3,6—tris (trifluoromethyl) benzyl] ethyl olepamidoate, Ν— [2,4,6—tris (trifluoromethinole) benzyl] methinole carbamide, Ν— [ 2,4,61-tris (trifnorolelo methinole) benzyl] ethynole acid ethynoleate, Ν [2,3, 4, 6-tetrakis (trifluoromethyl) benzyl] methyl carbamidate, 酸— [2, 3, 4, 6 Te tetrakis (g Li Furuoro methyl) benzyl] Karupami de acids Echiru like can exemplified child a. Example

 Next, the production method of the compound of the present invention will be specifically described with reference to examples and comparative examples, but the present invention is not limited to these examples.

 The conditions of the instrumental analysis used in the following examples are as follows.

 Melting point: Analyzed using FP-62, trade name, manufactured by METTLLE.

 MS: HEWL ETT—Analysis was performed using a brand name of HP 690, manufactured by PAC KARD.

 I R: Analyzed using FTZIR-420 manufactured by JASCO (JASCO).

GC (Gas Chromatography): manufactured by Shimadzu Corporation, trade name GC17 Analysis was performed using 00. Detailed conditions for GC analysis are as follows.

 <GC analysis conditions>

 Column used: J & W, trade name: DB—17 (inner diameter 0.25 mm, length 25 m, film thickness 0.25 / m)

 Power ram tank temperature: 50 ° C (5 min) → temperature rise (10 ° C / min) → 280 ° C

 Injection volume: 1 μ1

 Inlet temperature: 250 ° C

 Detector: F ID (Detector temperature 280 ° C)

 Data processing: Shimadzu Corporation, trade name C-R8A (quantity ratio was calculated from the ratio of each peak area)

Example 1

 (Production of 3,5-bis (trifluoromethyl) benzylamine) In a reaction vessel (manufactured by Shibata, capacity: 100 milliliters), stirring with a mechanical stirrer (rotational speed: approx. 4 rpm) At 0 rpm), under nitrogen atmosphere, 3.10 g (0.025 mo 1) of 3,5-bis (trifrenoleolomethyl) benzaldehyde, 1.88 g of methyl carpamide 0.025 m 0 1), 5.8 g of trifluoroacetic acid (0.05 mo 1) and 4.6 ml of toluene were added, and trichlorosilane was added to the obtained mixture. g (0.052 5 m 01) was added dropwise at 10 ° C over 20 minutes.

 After the addition of the trichlorosilane, the reaction system is stirred (rotation speed: approx.

(20 rpm) at 20 to 25 ° C for 3 hours, and then 30 ml of toluene was added. Further, 3.5 g of trifluoroacetic acid was recovered from the obtained mixture by distillation under reduced pressure (35 to 42 ° CZ 21.5 KPa). To the residue obtained after the recovery of trifluoroacetic acid was added 30 ml of toluene and 5 ml of water, and a 22.8 g aqueous solution of 23% sodium hydroxide (0.1 g) was added.

3 mO 1) was added dropwise at 30 ° C. After the dropwise addition of the aqueous sodium hydroxide solution, the mixture was aged at 25 ° C. for 30 minutes under stirring (rotational speed: about 400 rpm), and then separated to obtain an organic layer. The aqueous layer obtained by the separation was extracted twice with 30 ml of toluene, and the obtained toluene layer was combined with the previously obtained organic layer, and concentrated under reduced pressure to obtain N— [3, 5-bis (trifluoromethyl) benzyl] methyl carbamidate 7.1 g was obtained in a yield of 94.3% [based on 3,5-bis (trifluoromethyl) benzaldehyde].

 (Physical properties of methyl N- [3,5-bis (trifluoromethyltinole) benzyl] carbamidoate)

 Melting point: 99.8-: L 0 0.2 ° C

 (Confirmation data) MS, m / z: 301 (M +)

^{3 0 0MH z 1 H-NMR} (CDC 1 3) δ values. 3. 7 4 (s, 3 Η), 4. 5 0 (d, 6. 3 Η ζ, 2 Η), 5.] 1 6 ( s, 1Η), 7.74 to 7 · 79 (m, 3Η)

IR (KBr tablets, cm— ¹ ) 3 3 3 1, 1 6 9 3, 1 5 4 3, 1 3 8 6, 1 3 5 8, 1 2 9 8, 1 2 6 1, 1 1 7 0, 2 7 1 0 6 1, 9 0 5, 8 9 1, 7 0 9, 6 8 5

 Subsequently, in a reaction vessel (manufactured by Shibata, capacity: 100 milliliters), the N— [3] obtained above was stirred under a mechanical stirrer (rotational speed: about 400 rpm). , 5—Bis (trifluoromethyl) benzyl] methylsulfate (7.1 g, 0.024 m 01)

4 Add 20.8 g (0.25 m 01) of 8% aqueous sodium hydroxide solution, 10 g of methanol and 14.2 g of water, and ripen for 4.5 hours while heating under reflux. did. After ripening, methanol was collected by an evaporator. Toluene extraction was performed. The obtained toluene layer was analyzed by gas chromatography.

 The desired 3,5-bis (trifluoromethyl) benzylamine is 5.1 g (0.021 mol), yield 84.0% [3,5-bis (trifluoromethyl) benzaldehyde standard ]. Example 2

 (Production of 3,5-bis (trifluoromethyl) benzylamine) Under a nitrogen atmosphere while stirring in a reaction vessel, 3,5-bis (trifluoromethyl) benzaldehyde 0.61 g (0.00.025mo1), tert-butyl carnomidate 0.30g (0.00.025mo1), 0.57g trifluoroacetic acid (0.00.05) mol)) and 1.3 ml of toluene, and 0.71 g (0.00525 m01) of trichlorosilane was added dropwise at 10 ° C over 10 minutes. .

 After completion of the dropwise addition, the mixture was aged at 20 to 25 ° C with stirring for 1 hour. The reaction mixture was analyzed by gas chromatography to find that 3,5-bis (trifluoromethyl) benzylamine was 6%. 9.5%, N- [3,5-bis (triphnolelomethyl) benzyl] hepta, and tert-butyl midate were formed at a composition of 23.8%. Further, the reaction solution was stirred at 20 to 25 ° C. for 12 hours and aged.

 Subsequently, 1.3 g of trifluoroacetic acid and 3 g of water were added to the reaction system, the mixture was aged at 20 to 25 ° C for 5 hours, and a 23% aqueous sodium hydroxide solution was added thereto to adjust the pH. l Toluene extraction was performed. The obtained toluene layer was analyzed by gas chromatography to find that the desired 3,5-bis (trifluoromethyl) benzylamine was 0.55 g (0.00226 mol). ), Yield 90.4% [based on 3,5-bis (trifluoromethyl) benzaldehyde].

Example 3 (Production of 3,5-bis (trifluoromethyl) benzylamine) While stirring in a reaction vessel, under a nitrogen atmosphere, 3,5-bis (trifluoromethyl) benzaldehyde 1.21 g (0.0 0.5 m 0 1), 0.76 g (0.005 mo 1) of benzyl carbamide, and 3.71 g (0.03 25 mo 1) of trifluoroacetic acid, Tri-mouth silane 1.42 g (0.0105 m01) was added dropwise at L 0 ° C over 10 minutes. After completion of the dropwise addition, the mixture was aged at 20 to 25 ° C for 4 hours with stirring, and then the reaction solution was poured into water to precipitate crystals. The obtained crystals were filtered, washed with water and isolated. After the crystals were isolated, a 23% aqueous sodium hydroxide solution was added to the aqueous layer of the filtrate to adjust the pH to 13 or more, followed by extraction with ethyl acetate.The obtained ethyl acetate layer was subjected to gas chromatography. As a result, 3,5-bis (trifluoromethyl) benzylamine was produced in a yield of 22.1% [based on 3,5-bis (trifluoromethyl) benzaldehyde].

 On the other hand, the crystals separated by filtration were dissolved in 10 ml of ethyl acetate, and a pH of 13 or more was added by adding a 23% aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 30 minutes. Separated. After the obtained organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off to obtain 1 g of benzyl N- [3,5-bis (trifluoromethyl) benzyl] canolepamidoate. This was dissolved in 3 ml of ethyl acetate, 10 mg of 5% Pd_ / C (palladium catalyst supported on activated carbon) was added, and the mixture was heated to normal pressure and room temperature in a flask to which a hydrogen-filled parylene was attached. For 48 hours.

After the completion of the reaction, the solvent was distilled off from the filtrate obtained by removing the catalyst (Pd / C) by filtration, and 3,5-bis (trifluoromethyl) benzylamine was obtained in a yield of 53.6%. (3,5-bis (trifluoromethyl) benzaldehyde standard). Combined with the product contained in the aqueous layer obtained when the crystals were filtered off earlier, 3,5-bis was obtained in a total yield of 75.7%. (Trifluoromethyl) benzylamine was obtained [based on 3,5-bis (trifluoromethyl) benzaldehyde].

Example 4

 (Preparation of methyl N- [3,5-bis (trifluoromethyl) benzyl] carbamidate)

 While stirring in a reaction vessel, under a nitrogen atmosphere, 3,5-bis (trifluoromethyl) benzaldehyde 6.10 g (0.025 mo 1), methyl carbamidate 1.88 g (0.025mo1), 1.96g of acetyl chloride (0.025mo1) and 18.2g of trifluoroacetic acid (0.16mo1) were added. 4.4 g (0.03225 mo1) of chlorosilane was added dropwise at 10 ° C over 20 minutes. After completion of the dropwise addition, the mixture was aged at 20 to 25 ° C for 1 hour with stirring, followed by the same post-treatment as in Example 1 to obtain N— [3,5-bis (trifluoromethyl) benzyl). 7.18 g of methyl carpamide was obtained in a yield of 95.4% [based on 3,5-bis (trifluoromethyl) benzaldehyde]. This product can be converted to 3,5-bis (trifnoroleolomethyl) benzylamine by performing a deprotection reaction according to Example 1.

Example 5

 (Preparation of methyl N_ [3,5-bis (trif-leorometinole) benzyl] -propamidate)

While stirring in a reaction vessel, under a nitrogen atmosphere, 3,5-bis (trifluoromethyl) benzaldehyde 6.10 g (0.025 m 01), methyl carbamide 1.88 g (0.025 mol) and 18.2 g (0.16 mo 1) of trifluoroacetic acid were added, and 7.11 g (0.05 25 mo 1 ) Was added dropwise at 10 ° C. over 20 minutes. After completion of the dropwise addition, the mixture was aged at 20 to 25 ° C for 1 hour with stirring, followed by the same post-treatment as in Example 1 to obtain N— [3,5—bis Fluoromethyl) benzyl] Methyl carpamide 7.16 g was obtained in a yield of 95.2% [based on 3,5-bis (trifluoromethyl) benzaldehyde]. This can be converted to 3,5-bis (trifluoromethyl) benzylamine by deprotection according to Example 1.

Example 6

 (Preparation of methyl N- (3-fluorobenzyl) carbamidate) In a reaction vessel, under a nitrogen atmosphere, under a nitrogen atmosphere, 3.1 g (0.025 mol) of 3-fluorobenzaldehyde, potassium chloride To the mixture were added 1.88 g (0.025 mol) of methyl dorate and 18.2 g (0.16 mo1) of trifluoroacetic acid, and 7.11 g of trichlorosilane (0.11 g) was added. 0.05

25 m o 1) was added dropwise at 10 ° C. over 20 minutes. After completion of the dropwise addition, the mixture was aged at 20 to 25 ° C for 1 hour with stirring, and then subjected to the same post-treatment as in Example 1 to obtain methyl N- (3-fluorobenzinole) canolenomidoate 4 4 g was obtained in a yield of 97.0% [3-fluorobenzaldehyde standard].

 The thus obtained methyl N- (3-fluorobenzyl) carbamidate can be converted to 3-fluorobenzylamine by performing a deprotection reaction according to Example 1.

Example 7

 (Production of methyl N- (4-cyclobenzyl) carbamide) While stirring in a reaction vessel, under a nitrogen atmosphere, 0.70 g of 4-benzylbenzaldehyde (0.0.05) mo 1), methyl carpamide 0.

38 g (0.005 mol) and 3.7 g (0.032 25 m01) of trifluoroacetic acid were added, and the mixture was cooled in an ice bath, and trichlorosilane 1 was added.

.42 g (0.0105m01) was added dropwise over 5 minutes. After completion of the dropwise addition, the mixture was aged at 20 to 25 ° C for 1 hour with stirring. After the same post-treatment, 0.98 g of methyl N- (4-cyclobenzyl) carbamidoate was obtained in a yield of 98.6% [based on 4-cyclomethylbenzaldehyde].

 Methyl N- (4-cyclobenzyl) carbamate thus obtained can be converted into 4-neck benzylamine by a deprotection reaction according to Example 1.

Example 8

 (Production of methyl N-benzylcarbamidate)

 While stirring in a reaction vessel, under a nitrogen atmosphere, 0.53 g (0.05 mol) of benzaldehyde, 0.38 g (0.005 mol) of methyl carpamide, and 3.7 g (0.0325 mol) of fluoracetic acid was added, the mixture was cooled in an ice bath, and 1.42 g (0.0105 mol) of trichlorosilane was added dropwise over 5 minutes. . After completion of the dropwise addition, the mixture was aged at 20 to 25 ° C for 2.5 hours, and then subjected to the same post-treatment as in Example 1 to yield 0.80 g of methyl N-benzylcanolenomidoate. 97.4% obtained [Benzaldehyde standard].

 The thus obtained methyl N-benzylcarbamidate can be converted to benzylamine by a deprotection reaction according to Example 1.

Example 9

(Production of methyl N- (4-methylbenzyl) carbamidate) While stirring in a reaction vessel, under a nitrogen atmosphere, 0.70 g of 4-methylbenzaldehyde (0.005mo1) , 0.38 g (0.005 mol) of methyl carpamide and 3.7 g (0.0325 mol) of trifluoroacetic acid were added thereto, and the mixture was cooled in an ice bath. Chlorosilane 1.42 g (0.0105 m01) was added dropwise over 5 minutes. After completion of the dropwise addition, the mixture was aged at 20 to 25 under stirring for 1 hour, and then the same as in Example 1. After similar post-treatments, 0.74 g of methyl N- (4-methylbenzyl) carbamidate was obtained in a yield of 82.8% [based on 4-methylbenzaldehyde].

 Methyl N- (4-methylbenzyl) carbamate thus obtained can be converted to 4-methylbenzylamine by performing a deprotection reaction according to Example 1.

Example 10

 (Production of methyl N- [3,5-bis (trifluoromethyl) benzyl] carbamidate)

 While stirring in a reaction vessel, under nitrogen atmosphere, 3,5-bis (trifluoromethyl) benzaldehyde 0.48 g (0.002 mo1), methyl carpamide 0.1 Add 5 g (0.002 mo 1), 0.77 g (0.008 mol) of methanesulfonic acid and 1 ml of tonoleene, cool in an ice bath, and add 0.557 g (0.0042 mol) of silane was added dropwise over 5 minutes. After completion of the dropwise addition, the mixture was aged at 20 to 25 ° C for 1 hour with stirring. After the reaction was completed, the reaction mixture was analyzed by gas chromatography, and it was found that methyl N- [3,5-bis (trifluoromethyl) benzyl] butaluminate was obtained in a yield of 81.8% [3 , 5-bis (trifluoromethyl) benzaldehyde standard].

 Methyl N- [3,5-bis (trifluoromethyl) benzyl] carbamidate obtained in this manner is subjected to a deprotection reaction according to Example 1 to give 3,5-bis (trimethyl) bis. (Richleolomethyl) Can be converted to benzinoreamine.

Example 1 1

 (Manufacture of 3,4-dichloro benzylamine)

While stirring in the reaction vessel, under a nitrogen atmosphere, 1.75 g (0.01 mo 1) of Zualdehyde, 0.75 g (0.01 mol) of methyl carpamide, 2.28 g (0.02 mo 1) of trifluoroacetic acid , And toluene were added, and the mixture was cooled in an ice bath, and 2.84 g (0.021 mol) of trichlorosilane was added dropwise at 10 ° C over 5 minutes. After completion of the dropwise addition, the mixture was aged at 20 to 25 ° C. for 3 hours while stirring, and then the reaction solution was cooled in an ice bath, and 20 ml of water was added dropwise over 10 minutes. Thereafter, a 23% aqueous sodium hydroxide solution was added to adjust the pH to 13 or more, and toluene extraction was performed three times. The obtained toluene layer was concentrated under reduced pressure to obtain 2.31 g of methyl N- (3,4-dichlorobenzyl) propamate in a yield of 98.6% [3,4-dichloromouth benzene] Rudehid standard].

 Subsequently, 2.31 g (0.099 mol) of N- (3,4-dioctylbenzyl) carpamide methinolate obtained above, 23% aqueous sodium hydroxide solution 17.4 g (0.10 m 0 1) and 16 g of methanol were added, and the mixture was aged for 10 hours with heating under reflux and stirring. After aging, methanol was recovered and extracted with toluene. The obtained toluene layer was analyzed by gas chromatography. The desired 3,4-diclo-pentopenoleamine was produced in a yield of 1.70 g (0.0977 mol) and a yield of 96.6% [based on 3,4-dichloro-opened benzyl aldehyde]. Was

Industrial applicability

As described above, according to the present invention, there is provided a novel method for producing an aralkylamine derivative which can be easily carried out even on an industrial scale. According to the method of the present invention, the aralkylamine derivative can be produced by a simple process that is safe, does not require special equipment, and can be manufactured on an industrial scale. Useful value Very high. Further, according to the method of the present invention, an N-benzyl carbamide ester derivative which is a useful intermediate is provided.

Claims

The scope of the claims

1. General formula (1)

 A r-C H O (1)

 (Wherein, Ar represents an aromatic group) to an aromatic aldehyde derivative represented by the general formula (2) in the presence of trichlorosilane.

 N H 2 C O O R (2)

 (Wherein, R represents an alkyl group or an aralkyl group) by reacting a sulfamic acid ester represented by the general formula (3)

A r-CH ₂ NH- B (3)

 Wherein Ar represents an aromatic group, B represents a hydrogen atom or a COOR group, and R represents an alkyl group or an aralkyl group. Production method.

 2. The method for producing an aralkylamine derivative according to claim 1, wherein the Ar force is a polycyclic aromatic group.

 3. The method for producing an aralkylamine derivative according to claim 1, wherein Ar is a monocyclic aromatic group.

 4. General formula (4)

(In the formula, X represents an alkyl group or a halogen atom, 1 represents an integer of 0 to 5, m represents an integer of 0 to 5, m + 1 is 5 or less, and when m is 2 or more, X may be the same or different), and in the presence of trichlorosilane, a compound of the general formula (2) NH 2 COOR (2) (Wherein, R represents an alkyl group or an aralkyl group) by reacting a sulfamic acid ester represented by the general formula (5)

 (Wherein, B represents a hydrogen atom or —COOR group, R represents an alkyl group or an aralkyl group, X represents an alkyl group or a halogen atom, 1 represents an integer of 0 to 5, m represents 0 Wherein m + 1 is 5 or less, and when m is 2 or more, X may be the same or different. 4. A benzylamine derivative represented by the following formula: A method for producing a ruquilamine derivative.

 5. The aralkylamine derivative according to any one of claims 1 to 4, wherein the carbamide ester (B = CO OR) obtained as an intermediate is deprotected to obtain an aralkylamine derivative (B = H). Production method.

 6. The method according to claim 1, wherein the aromatic aldehyde derivative at least partially provides an aralkylamine derivative (B = H) by reductive amination and deprotection under the conditions of the amination reaction. 5. The method for producing an aralkylamine derivative according to any one of the above items 5.

 7. The method for producing an aralkylamine derivative according to claim 1, wherein the amination is performed in the presence of an acid.

 8. General formula (4)

(In the formula, X represents an alkyl group or a halogen atom, and 1 represents 0 to 5 Represents an integer, m represents an integer of 0 to 5, m + 1 is 5 or less, and when m is 2 or more, X may be the same or different), a benzaldehyde derivative represented by the following formula: Trichlorosilane and general formula (2)

NH ₂ COOR (2)

 (Wherein, R represents an alkyl group or an aralkyl group).

 (In the formula, R represents an alkyl group or an aralkyl group; X represents an alkyl group or a halogen atom; 1 represents an integer of 0 to 5; m represents an integer of ◦ to 5; and m + 1 represents 5 or less, and when m is 2 or more, X may be the same or different.) A process for producing an N-benzylcarbamide ester derivative represented by the formula: .

9. General formula (Ί)

(Wherein n represents an integer of 1 to 5), and trichlorosilane and a general formula (2)

NH ₂ CO〇 R (2)

(Wherein, R represents an alkyl group or an aralkyl group) by reacting with a sulfamide ester represented by the following general formula (8): (8)

(Wherein, R represents an alkyl group or an aralkyl group, and n represents an integer of 15), and then subjected to a deprotection reaction to obtain a compound represented by the general formula (9)

 (Where n represents an integer of 15) A method for producing a trifluoromethylbenzylamine derivative represented by the following formula:

 1 0. General formula (10)

( Ten )

 (Wherein, R and R represent an alkyl group, and n represents an integer of 15). N-benzylcarbamide ester derivative represented by the following formula: