WO2007007828A1

WO2007007828A1 - Ethylenediamine derivative and method for producing same

Info

Publication number: WO2007007828A1
Application number: PCT/JP2006/313933
Authority: WO
Inventors: Masaaki Nagasawa; Nobuo Kawase; Takeshi Watanabe; Minoru Kobayashi
Original assignee: Zeria Pharmaceutical Co., Ltd.
Priority date: 2005-07-14
Filing date: 2006-07-13
Publication date: 2007-01-18
Also published as: TW200744990A; JP2008273841A

Abstract

Disclosed is a novel compound useful as a production intermediate for benzylamine derivatives. Also disclosed is a method for producing such a compound. Specifically disclosed is a method for producing an ethylenediamine derivative represented by the general formula (6) below or a salt thereof. (6) (In the formula, R1 represents a lower alkyl group, an aryl group or an aralkyl group; R2 represents a lower alkyl group or an alkenyl group; R3 represents a lower alkyl group, an optionally substituted aryl group or an aralkyl group; and Ar represents an optionally substituted aryl group.)

Description

Ethylenediamine derivative and method for producing the same

Technical field

[0001] The present invention relates to a novel compound useful as an intermediate for the production of benzylamine derivatives and a method for producing the same.

Background art

[0002] The benzylamine derivative represented by the following general formula (A) has excellent tachycun antagonism, particularly substance P antagonism, antagonism against neurocun A and B, and irritable bowel syndrome (IBS: Irritable Bowel Syndrome), known to be useful for the treatment of diseases such as pain, anxiety, obstructive bronchial disease, headache, vomiting (see Patent Document 1)

) o

[0003] [Chemical 1]

[0004] (Numbers in the formula and symbols in the formula are according to Patent Document 1)

As a method for synthesizing a benzylamine derivative, Patent Document 1 discloses a process for producing a benzaldehyde derivative from a commercially available benzaldehyde via a 2-methylaminopentenol derivative. However, the synthesis method described in Patent Document 1 requires many steps, and the development of a manufacturing method that is industrially superior has been demanded.

Patent Document 1: International Publication No. 2005Z012248 Pamphlet

Disclosure of the invention

Problems to be solved by the invention

[0005] Therefore, an object of the present invention is to provide a novel intermediate useful for the production of the benzylamine derivative represented by the general formula (A) and a method for producing the same. Means for solving the problem

[0006] As a result of diligent studies to solve the above-mentioned problems, the present inventors have found that the ethylenediamine derivative power represented by the following general formula (6) is extremely useful as an intermediate for producing benzylamine derivatives. The present invention has been completed.

That is, the present invention provides the following formula (5)

[0008] [Chemical 2]

[Wherein, R ¹ represents a lower alkyl group, an aryl group or an aralkyl group, R ² represents a lower alkyl group or an alkenyl group, and Ar may have a substituent, which may be an aryl group; A primary amin (NH R ³ ) is reacted with the aziridine compound represented by

2

Formula (6)

[0010] [Chemical 3]

(Wherein R ³ represents a lower alkyl group, an aryl group or an aralkyl group which may have a substituent,

R ² and Ar are as defined above)

The manufacturing method of the ethylenediamine derivative represented by these, or its salt is provided.

[0012] Further, the present invention provides an optically resolved formula (7) characterized by optically resolving an ethylenediamine derivative represented by the formula (6) obtained by the above method or a salt thereof.

[0013] [Chemical 4]

(Wherein * represents an asymmetric carbon atom,! ^ To and Ar are as defined above), and a method for producing an optically active ethylenediamine derivative or a salt thereof.

[0015] Further, the present invention provides the following formula (1)

[0016] [Chemical 5]

O

(1)

Ar

[Wherein X ¹ represents a halogen atom, and Ar is as defined above]

The compound represented by the formula (4) is characterized by reacting a Grignard reagent (R ² MgX ² ) with a haloacetyl aryl compound represented by formula (4), and further reacting with a primary amine (NH R ¹ ).

[0018] [Chemical 6]

OH

R N (4)

Ar

[0019] (where

R ² and Ar are as defined above)

The manufacturing method of the compound or its salt represented by these is provided.

[0020] Further, the present invention provides the following formula (4)

[0021] [Chemical 7]

OH

R ¹ straight (4)

Ar

[0022] (wherein, RR ² and Ar are as defined above)

A compound represented by formula (5) is characterized by reacting triarylphosphine and halogen in the presence of a tertiary amine.

[0023] [Chemical 8] [0024] (where

And Ar is as defined above)

[0025] During the production process of the compound of the present invention, the following formulas (2-1), (3-1), (4-1), (5-1), (6-1) and (7-1) The intermediate compound represented by) is novel. Accordingly, the present invention provides the following general formula (2-1)

[0026] [Chemical 9]

(2-1)

[0027] (wherein, X ¹ and X ² represent a halogen atom, and X ³ and X ⁴ represent a hydrogen atom or a halogen atom)

Or a salt thereof.

Further, the present invention provides the following general formula (3-1)

[0028] [Chemical 10]

(3-1)

[Wherein X ³ and X ⁴ are as defined above]

Or a salt thereof.

Further, the present invention provides the following general formula (4-1)

[0030] [Chemical 11]

[0031] (where

X ³ and X ⁴ are as defined above)

Or a salt thereof.

Further, the present invention provides the following general formula (5-1)

[0032] [Chemical 12]

(5-1)

[0033] (where

X ³ and X ⁴ are as defined above)

Or a salt thereof.

[0034] Further, the present invention provides the following general formula (6-1)

[0035] [Chemical 13]

[0036] (wherein R \ R ³ , X ³ and X ⁴ are as defined above)

In addition, the present invention provides the following general formula (7-1):

[0037] [Chemical 14] [0038] (where

And * are as defined above)

The optically active ethylenediamine derivative represented by these, or its salt is provided. The invention's effect

[0039] According to the present invention, by using an ethylenediamine derivative or a salt thereof as a production intermediate, the benzylamine derivative can be efficiently produced with few steps, and is suitable for industrial production. In addition, the ethylenediamine derivative which is the compound of the present invention is useful as a pharmaceutical production intermediate because it can be isolated and purified as an optically active ethylenediamine derivative by optically resolving and crystallizing it. .

BEST MODE FOR CARRYING OUT THE INVENTION

[0040] In the formula, examples of the lower alkyl represented by R ¹ R ² and R ³ include a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, Examples include isopropyl group, butyl group, t-butyl group, pentyl group, hexyl group and the like. Of these, a methyl group is particularly preferred.

[0041] The aryl group represented by R ¹ includes an aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group.

[0042] The aralkyl group represented by R ¹ and R ³ includes C 1 -C 6 -aryl-C 1 -C 4 alkyl.

6 14 1 6 group, such as ferro-C alkyl group, naphthyl C—C alkyl group

1-6 1 6

Groups and the like. Of these, a benzyl group and a phenethyl group are particularly preferable.

In the formula, R ¹ is preferably a lower alkyl group, and particularly preferably a methyl group.

[0043] The alkenyl group represented by R ² includes a C-C linear or branched alkenyl group.

2 6

Examples thereof include a vinyl group, a aryl group, a butyr group, a pentyl group, and a hexenyl group. Of these, an aryl group is particularly preferable.

In the formula, R ² is preferably an alkenyl group, particularly preferably an aryl group. [0044] Examples of the aryl group having the substituent represented by R ³ include aryl groups having 6 to 14 carbon atoms as described above. Examples of the group that can be substituted on the aryl group include 1 to 3 groups such as a halogen atom, a nitro group, a lower alkyl group, and a lower alkoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms as described above. Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, n propoxy group, isopropyl group, n-butoxy group, isobutoxy group, sec butoxy group, tert butoxy group, n pentyloxy group, isopentyloxy group, n-hexyloxy group, and the like. In the formula, R ³ is preferably a lower alkyl group, and a methyl group is particularly preferable.

[0045] The aryl group optionally having a substituent represented by Ar has the same carbon number as described above.

Examples thereof include 6 to 14 aryl groups, preferably a phenol group. Here, examples of the group that can be substituted on the aryl group include the same halogen atoms as described above, and preferably a chlorine atom. The number of substituents is 1 to 3, but preferably 2. The substitution positions are preferably the 3rd and 4th positions.

[0046] Examples of the halogen atom represented by X ¹ , X ² , X ³ and X ⁴ include the same halogen atoms as described above, preferably a chlorine atom and a bromine atom.

[0047] In the formula, * indicates that the attached carbon atom is an asymmetric carbon atom. In the present invention, the configuration of the asymmetric carbon may be either the R configuration or the S configuration, but the S configuration is preferred.

[0048] The salt of the ethylenediamine derivative is not particularly limited as long as it is a pharmaceutically acceptable salt. However, acid addition salts such as hydrochloride, sulfate, nitrate, hydrobromide, p-toluenesulfonic acid, etc. Salts, methanesulfonate, fumarate, hibenzate, succinate, tartaric acid, lactate and the like. The ethylenediamine derivative or salt thereof of the present invention includes those solvates. Further, both optically active substances and mixtures thereof are included.

[0049] The method for producing an ethylenediamine derivative or a salt thereof of the present invention is represented by the following reaction formula. You can.

[0050] [Chemical 15]

(6) (7)

(Wherein R ¹ represents a lower alkyl group, an aryl group or an aralkyl group, R ² represents a lower alkyl group or an alkyl group, and R ³ has a lower alkyl group or a substituent. Ar may be an aryl group or an aralkyl group, Ar may have a substituent, may represent an aryl group, X ¹ and X ² represent a halogen atom, and * represents an asymmetric carbon atom. Show)

[0052] That is, after reacting the haloacetyl aryl compound (1) with a Grignard reagent, further reacting with a primary ammine, a compound (4) is obtained. Next, the compound (4) is reacted with a triarylphosphine and a halogen atom in the presence of a tertiary amine to give an aziridine compound (5), and the compound (5) is ring-opened with the primary amine. Compound (6) is obtained. Furthermore, compound (6) is optically resolved to separate a desired diastereomeric salt, and the resulting diastereomeric salt is treated with a base to obtain optically active substance (7). Therefore, the compounds (2) to (5) are useful as production intermediates of the compound (6) of the present invention. The compound represented by the general formula (1) which is the starting material of the present invention is a known compound. For example, it can be easily synthesized by reacting a commercially available acetophenone derivative with a halogen atom according to the method described in the fourth edition, Experimental Chemistry Course 19 (Maruzen).

Hereinafter, each reaction step will be described.

[0053] The reaction of the haloacetyl aryl compound (1) and the Grignard reagent is carried out in an ether solvent such as jetyl ether, tetrahydrofuran or dioxane.

The Grignard reagent is preferably used in an equimolar amount with respect to compound (1). The reaction temperature is not particularly limited, but is usually −110 ° C. to −10 ° C., preferably −80 ° C. to 40 ° C.

The reaction time is not particularly limited, but is usually from the end of dropping to 48 hours, preferably from 0.5 to 12 hours. In this reaction, the compound (2) proceeds to the derivative (3). In the reaction solution, it may be a mixture of compounds (2) and (3), but it can be used in the next reaction without changing the reaction system.

[0054] The compound (4) is obtained by reacting the mixture of the compounds (2) and (3) obtained by the above reaction with a primary amine.

Examples of the primary amine used in the reaction include lower alkylamines such as methylamine and ethylamine; aralkylamines such as benzylamine; and arylamines such as aline and naphthylamine. . The amount of amine used is preferably 1 to 3 moles, more preferably 2 to 2.5 moles per mole of the mixture of compounds (2) and (3).

The solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include alcohols such as methanol and ethanol; ethers such as jetyl ether, tetrahydrofuran and dioxane; water and the like. These may be used in combination. The reaction temperature is not particularly limited, but is preferably room temperature to 80 ° C, particularly preferably 30 ° C to 60 ° C.

The reaction time is not particularly limited, but is usually 0.5 to 24 hours, preferably 0.5 to 12 hours.

[0055] The synthesis of the aziridine compound (5) involves the intramolecular cyclization reaction proceeding by reacting the compound represented by the formula (4) with triarylphosphine and halogen in the presence of a tertiary amine. An aziridine ring is formed.

Examples of the tertiary amine used in the reaction include trimethylamine, triethylamine, tri-n-butyramine, N, N-dimethylamine, and preferably triethylamine. The amount of the base used is preferably 2 to 6 mol, particularly preferably 3 to 4 mol, based on 1 mol of the compound (4)! /.

Examples of the triarylphosphine used in the reaction include triphenylphosphine. In addition, examples of the halogen include fluorine, chlorine, bromine and iodine, and bromine is preferable. The amount of triarylphosphine and halogen used is preferably 1 to 3 mol, particularly preferably 1.3 to 2 mol, per 1 mol of compound (4).

The solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, but alcohols such as methanol and ethanol; ethers such as jetyl ether, tetrahydrofuran and dioxane; ethyl acetate, butyl acetate Esters such as: Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane and chloroform; Aprotics such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, etc. Polar solvents may be mentioned, and these may be used in combination. Preferably

, Ethyl acetate, acetonitrile, or a mixed solvent thereof.

This reaction may be carried out at 30-60 ° C by first adding halogen to triarylphosphine to prepare a triarylphosphine monohalogen adduct, then adding compound (4) and tertiary amine. preferable.

The reaction time is not particularly limited, but is usually 10 minutes to 12 hours, preferably 0.5 to 8 hours.

The reaction between compound (5) and primary amine is carried out in the presence of an acid. The reaction is preferably performed under non-aqueous conditions.

Although this reaction is a reaction that opens the aziridine ring, the group attached to the aziridine ring was conventionally considered to be an electron-withdrawing group (J. Org. Chem. 68, 5160, 2003). ), This reaction can be ring-opened even when an electron donating group such as an alkyl group such as a methyl group or an aralkyl group such as a benzyl group is bonded to a nitrogen atom.

As the acid used in the reaction, known acids can be used, for example, hydrochloric acid, hydrobromic acid, sulfuric acid And inorganic acids such as nitric acid; organic acids such as formic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, and trifluoroacetic acid. Preferred are sulfonic acid acids, Particularly preferred is methanesulfonic acid. The amount of acid used is not particularly limited, but is preferably 1 to: especially preferably 4 to 6 moles per mole of compound (5)!

Examples of primary amines include lower alkylamines such as methylamine and ethylamine; aralkylamines such as benzylamine; aralkylamines such as aline and naphthylamine; Methylamine is preferred. The amount of primary amine used is preferably 3 to 20 mol, and more preferably 5 to 7 mol, per 1 mol of compound (5).

The solvent used in the reaction is not particularly limited as long as it does not adversely influence the reaction, but amides such as N-methylpyrrolidone, N, N dimethylformamide, N, N dimethylacetamide; alcohols such as methanol and ethanol These solvents may be used, and these may be used in combination.

Although reaction temperature is not specifically limited, Preferably it is 50 to 200 degreeC, Most preferably, it is 100. C ~ 120. C.

The reaction time is not particularly limited, but is usually 0.5 to 40 hours, preferably 1 to 12 hours.

The racemic compound (6) can be led to the optically active substance (7) by a general optical resolution method. For example, compound (6) is reacted with an optical resolving agent such as (+)-di-p-toluoyl D tartaric acid (hereinafter referred to as “(+)-DTTA”) to obtain a mixture of diastereomeric salts, and then the desired mixture. The diastereomeric salt of is precipitated and separated. The optical resolution is carried out in a solvent, but the solvent used is not limited as long as it is inert to diastereomeric salts. For example, alcohols such as methanol, ethanol and isopropanol; hydrocarbons such as hexane, benzene and toluene; halogeno hydrocarbons such as methylene chloride and chloroform; ketones such as acetone and methyl ethyl ketone; water Etc.

Examples of the optical resolution agent used in the reaction include (+) DTTA, dibenzoyltartaric acid, etc. Examples thereof include active tartaric acid and derivatives thereof, preferably (+)-DTTA. The amount of the optical resolving agent used is preferably 0.5 to 1.2 mol, particularly preferably 1 mol, relative to compound (6).

[0058] The obtained diastereomeric salt can be isolated by a known method such as filtration or centrifugation, and optical purity can be increased by recrystallization. For example, an ester type such as ethyl acetate; a halogen type solvent such as methylene chloride, preferably dissolved in ethyl acetate, and dissolved once by heating and stirring at a temperature between room temperature and the boiling point of the solvent for 0.5 to 9 hours. After that, crystals can be precipitated, purified by cooling and drying. The diastereomeric salt obtained is treated with a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., and then extracted with a solvent using toluene or the like to make an optically active substance. Can do.

The benzylamine derivative or a salt thereof can be produced, for example, according to the following method using the optically active form (7) of the ethylenediamine derivative as a production intermediate.

[0059] [Chemical 16]

R ⁴ .

0 ^0H (8)

(Wherein R ¹ represents a lower alkyl group, an aryl group or an aralkyl group, R ³ represents a lower alkyl group or an optionally substituted aryl group or aralkyl group, and R ⁴ represents R ⁵ represents an optionally substituted lower alkyl group, R ⁵ represents a lower alkyl group, an aryl group, an aralkyl group, or an optionally substituted amino group, and X ³ and X ⁴ represent Represents a hydrogen atom or a halogen atom, and X ⁵ represents a halogen atom)

[0061] That is, the optically active substance (7) is reacted with an acid and a ride (9) in the presence of a base such as sodium hydroxide and the like to obtain a compound (10), and further to the compound (10), The acid halide (11) is reacted in the presence of a tertiary amine such as triethylamine to give an amidy compound (12). Next, the compound (12) is oxidized with an oxidizing agent such as sodium periodate in the presence of a ruthenium catalyst to obtain a mixture of the compounds (13) and (14), and the resulting mixture is further oxidized. Aldehyde ( 14). Next, by reacting the compound (14) with the compound (19) by acting a reducing agent such as sodium triacetoxyborohydride in the presence of an acid, the benzylamine derivative represented by the general formula (20) or Can lead to its salt.

2H-spiro [isoquinoline 1,4, -piperidine] -3 (4H) -one (19) reacts with 1 benzylpiperidin-4-one (15) and 2 ferroacetamide (16) in the presence of acid. To obtain the compound (17), which is isolated and then closed to obtain the spiro compound (18), which is then obtained by catalytic reduction under hydrogen.

[0062] In the formula, having a substituent represented by R ⁴ ! /, May be! /, And the lower alkyl group of the lower alkyl group is the same straight chain having 1 to 6 carbon atoms as described above Or a branched alkyl group is mentioned, Preferably they are a methyl group and an ethyl group. Examples of the group that can be substituted with a lower alkyl group include 1 to 3 halogen atoms similar to those described above, and preferably a fluorine atom. Specific examples of the lower alkyl group which may have a substituent include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a 2,2,2-trifluoroethyl group.

[0063] As the lower alkyl group represented by R ^5, the same linear or branched alkyl group having 1 to 6 carbon atoms, or a cycloalkyl group having a carbon number of 3 to 7. Examples of the cycloalkyl group include a cyclopropyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

[0064] The aryl group represented by R ⁵ includes the same aryl group having 6 to 14 carbon atoms as described above, and is preferably a phenol group. The aralkyl group is the same as C as described above. —C

6-aryl-C—C alkyl group.

14 1 6

[0065] The amino group may have a substituent represented by R ⁵ , and examples of the amino group include an amino group, a lower alkylamino group, a di-lower alkylamino group, and a phenolamino group. Here, examples of the lower alkyl group that can be substituted for the amino group include a linear or branched alkyl group having 1 to 6 carbon atoms, and a cycloalkyl group having 3 to 7 carbon atoms. Specific examples of the alkyl-substituted amino group include a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, an n pentylamino group, a cyclopropylamino group, a dimethylamino group, and a diamino group. Examples include an ethylamino group and a di-n-propylamino group.

In the formula, R ⁵ is preferably an aryl group, particularly a phenyl group.

[0066] Examples of the halogen atom represented by X ^{3 to} X ⁵ include the same halogen atoms as described above, and a chlorine atom is preferable.

[0067] The salt of the benzylamine derivative is not particularly limited as long as it is a pharmaceutically acceptable salt, but an acid addition salt such as hydrochloride, sulfate, nitrate, hydrobromide, p-toluenesulfonic acid, and the like. Examples thereof include salts, methanesulfonate, fumarate, hibenzate, succinate, tartrate, lactate and the like, and hibenzate and tartrate are preferred. The benzylamine derivative or a salt thereof includes a solvate thereof. Further, both optically active substances and mixtures thereof are included.

[0068] The benzylamine derivative (20) obtained as described above can be isolated and purified by known methods such as concentration, concentration under reduced pressure, solvent extraction, filtration, crystallization, recrystallization, and various chromatography. Can do. Further, for example, a desired acid is added after being dissolved in an organic solvent such as a chlorine type such as methylene chloride or black form; an ether type such as ether, tetrahydrofuran or dioxane, or an ester type such as ethyl acetate, preferably ethyl acetate. It can be isolated as an acid addition salt. Examples of the acid used in the reaction include hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, ρ-toluenesulfonic acid, methanesulfonic acid, fumaric acid, hibenzic acid, succinic acid, tartaric acid, and lactic acid. is there. The acid is preferably used in an amount of 1 to 1.5 mol with respect to 1 mol of the compound (20).

[0069] Further, the obtained acid addition salt is alkalinized with a base in the presence of an organic solvent such as ethyl acetate, and then subjected to salt exchange by adding a desired acid to the organic layer, so that the optical addition salt has a higher optical purity. High acid addition salts can be obtained. Here, examples of the acid used for the reaction include the same acids as described above, and tartaric acid is preferable. Examples of the base used in the reaction include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide and potassium hydroxide; organic bases such as triethylamine and diisopropylethylamine. Of these, potassium carbonate is preferred.

In addition, although the property of the acid for acid salt formation is not specifically limited, it is desirable to use it, dissolving in alcoholic solvents, such as methanol and ethanol. Also, the temperature during acid addition salt formation Depending on the solvent used, the temperature is preferably from 0 ° C. to the boiling point of the solvent for 0.5 to 72 hours.

Example

[0070] Next, the power of examples to further explain the present invention. The present invention is not limited to the following examples.

[0071] Reference Example 1 Synthesis of 2-bromo-1- (3, 4-dichloro-phenyl) ethanone (1,)

[0072] [Chemical 17]

[0073] 100 kg of 1- (3,4-dichlorophenol) monoethanone was dissolved in 200 kg of methanol, 85 kg of bromine was added dropwise, and then stirred at 25 to 50 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted by adding ethyl acetate and aqueous sodium sulfate. The organic layer was washed with water, and the organic layer was again concentrated under reduced pressure, and hexane was added to the resulting residue for crystallization. . The crystals were collected by filtration and dried to give 2-promo 1- (3,4-dichlorophenol) ethanone (1, 1) 105.6 kg (74.5%).

Compound (1 ')

'H-NMR (400MHz, CDC13) δ: 4.38 (s, 2H), 7.59 (d, J = 8.5Hz, 1H), 7.81 (dd, J = 2.0, 8.5Hz , 1H), 8. 07 (d, J = 2. OHz, 1H)

[0074] Example 1 (1-Bromo 2— (3, 4—Diclonal Mole) Pento 4 4-Yen 2-ol

Production of (2,) and 2-arylu-2- (3,4-dichlorophenyl) oxysilane (3,)

[0075] [Chemical 18]

[0076] 2 Bromo 1— (3,4 dichlorophenol) ethanone 65. Dissolve Okg in 180 kg of THF and add dropwise an equimolar amount of allylmagnesium bromide in THF at -40 ° C or lower for 3 hours. Stir. Water and concentrated hydrochloric acid were added to the reaction mixture, and the mixture was stirred for 15 minutes and allowed to stand, and the organic layer was taken (1—bromo-2- (3,4 dichlorophenol), pentone, 4-benzene-2-enole (2,) and 2 A mixture of Reru 2- (3,4 dichlorophole) oxysilane (3) was obtained and used as such in the next step.

[0077] Compound (2 ')

'H-NMR (400MHz, CDC13) δ: 2, 59 (s, 1H), 2.69 (d, J = 7.0Hz, 2H), 3.71 (s, 2H), 5.10-5.17 (m, 2H), 5.53 ~ 5.64 (m, 1H), 7.23 (dd, J = 2.5, 8.5Hz, 1H), 7.44 (d, J = 8.5Hz, 1H), 7.55 (d, J = 2.5Hz, 1H) [0078] Compound (3 ')

'H-NMR (400MHz, CDC13) δ: 2.59 (dd, J = 7.0, 15.0Hz, 1H), 2.71 (d, J = 5.5Hz, 1H), 2.87 (ddt, J = 6.5, 15.0, 1.0Hz, 1H), 3.01 (d, J = 5.5Hz, 1H), 5.09 to 5.17 (m, 2H), 5.68 to 5.80 (m, 1H), 7.21 (dd, J = 2.0, 8.5Hz, 1H), 7.40 (d, J = 8.5Hz, 1H), 7.46 (d, J = 2.0Hz, 1H)

Example 2 2— Production of (3, 4 Diclonal Membrane) -1— (Methylamino) pento 4-ene-2-ol Hydrochloride (4,)

[0080] [Chemical 19]

Organic layer obtained in Example 1 (1-bromo-2- (3,4-dichlorophale) pento 4-en-2-ol (2,) and 2-aryl 2- (3,4 dichlorophenol) Mix 77. Okg of methanol and 190 kg of 40% aqueous monomethylamine with a mixture of oxysilane (3,) and stir for 2 hours at about 50 ° C. After concentration under reduced pressure, add 100 kg of toluene to the reaction mixture. Crystals are precipitated to about pH 1 with concentrated hydrochloric acid, collected by filtration, and dried. 69.2 kg (96) of 2- (3, 4 dichlorophenol) — 1 — (methylamino) pento 4-en-2-ol hydrochloride (4,) . 1%) [0082] Compound (4 ')

'H-NMR (400MHz, DMSO-d) δ: 2.47 (t, J = 4.5Hz, 3H), 2.62 (d, J

6

= 7.0Hz, 2H), 3.21 to 3.30 (m, 1H), 3.33 to 3.45 (m, 1H), 4.94 to 5.0 2 (m, 2H), 5.53 to 5.65 (m, 1H), 6.32 (s, 1H) , 7.46 (dd, J = 2.0, 8.5Hz, 1H), 7.64 (d, J = 8.5Hz, 1H), 7.71 (d, J = 2.0Hz, 1H), 8.19 (brs, 1H), 8.68 (brs, 1H)

Example 3 Production of 2 aryl-2- (3, 4 Dichlorophle) -1 methylaziridine (5,)

[0084] [Chemical 20]

[0085] 132 kg of trifluorophosphine and 200 kg of acetonitrile were mixed, 81 kg of bromine was added dropwise at room temperature or lower with stirring, and the mixture was stirred at about 50 ° C for 15 minutes. After concentrating the reaction solution under reduced pressure, 300 kg of ethyl acetate was added to make a triphenylphosphine dibromide-ethyl acetate solution, and then 2— (3,4 dichlorophenyl) — 1— (methylamino) pento 4 — 2—ol 100 kg of hydrochloride (4) and 154 kg of triethylamine 35-50. The mixture was stirred with C for 1 hour. Water was added to the reaction solution at room temperature, and the mixture was stirred for 15 minutes and allowed to stand to take an organic layer. The aqueous layer was extracted with ethyl acetate, combined with the organic layer, and washed with saturated brine. The organic layer was concentrated under reduced pressure, hexane was added to the residue, and the precipitated solid was filtered off. The hexane solution was concentrated to give 7-aryl-2- (3,4-dichlorophenol) -1-methylaziridine (5,) 71.2 kg (purity 92.3%, yield 87.3%) as an oil. This was directly used for the next reaction.

[0086] Compound (5 ')

'H-NMR (400MHz, CDC13) δ: 1.49 (s, 0.35H), 1.60 (s, 0.65H), 1.9 5 (s, 0.35H), 2.05 (s, 1.95H), 2.06 (s, 0.65H ), 2.17 (dd, J = 7.0, 14. OHz, 0.65H), 2.53 (dd, J = 6.5, 16. OHz, 0.35H), 2.62 (s, 1.05H), 2.73 (dd, J = 7.0, 14. OHz, 0.65H), 2.84 ( dd, J = 6.5, 16. OHz, 0.35H), 4.92 to 5.05 (m, 2H), 5.59 to 5.74 (m, 1H), 7.16 (dd, J = 2.0, 8.5Hz, 0.65H), 7.20 (dd , J = 2.0, 8.5Hz, 0.35H), 7.34 (d, J = 8.5Hz, 0.35H), 7.39 (d, J = 2. OHz, 0.65H), 7.42 (d, J = 8.5Hz, 0.65H ), 7.46 (d, J = 2. OHz, 0.35H)

Example 4 2— (3,4-Dichlorophenol) — Production of N ¹ , N ² —Dimethylpentose 4—En—1,2 Diamine (6,)

[0088] [Chemical 21]

[0089] 140 kg of methanesulfonic acid and 230 kg of 40% monomethylamine-methanol solution were added to 280 kg of N-methylpyrrolidone, and the crude aziridine compound (5 ') obtained earlier was added with stirring, and the temperature was 100 to 115 ° C. And stirred with heating. After cooling, toluene and water were added to the reaction mixture, and the mixture was made alkaline with 25% aqueous sodium hydroxide and extracted. The organic layer is taken and washed with saturated brine, and the organic layer is concentrated under reduced pressure. 2— (3,4-Dichlorophenol) —N ¹ , N ² —Dimethylpent— 4 —En— 1, 2— The residue was obtained as diamin (racemate) (6).

[0090] Compound (6 ')

'H-NMR (400MHz, CDC13) δ: 1.38 (brs, 2H), 2.19 (s, 3H), 2.38 (s, 3H), 2.45 ~ 2.62 (m, 2H), 2, 72 (d, J = 12. OHz, 1H), 2.81 (d, J = 12.OH z, 1H), 7.26 (dd, J = 2.0, 8.5Hz, 1H), 7.41 (d, J = 8.5Hz, 1H), 7.53 (d , J = 2. OHz, 1H)

Example 5 (s) — 2— (3, 4-dichlorophenyl) 1 N ¹ , N ² — dimethylpent 4—

— 1, 2—Diamine (+) — Manufacture of ditoluoyl tartrate (7,)

[0092] [Chemical 22]

[0093] (1) Add 840 kg of isopropanol to the resulting residue, add 115 kg of (+)-ditoluoyltartaric acid at about 45 ° C, stir for 1 hour, and collect the precipitated crystals by filtration. 2- (3, 4-Jikurorofu E - Le) - N ^1, N ² - dimethyl pentose 4 E down - 1, 2- Jiamin (+) - ditoluoyltartaric acid salt, 1 type crystal 156.2Kg (purity 93.4% )

[0094] Type 1 crystal

'H-NMR (400MHz, DMSO-d) δ: 2.02 (s, 3Η), 2.35 (s, 6H), 2.43〜

6

2.56 (m, 5H), 3.19 (d, J = 13.0Hz, 1H), 3.33 (d, J = 13.0Hz, 1H), 4.9 4 to 5.01 (m, 2H), 5.36 to 5.48 (m, 1H), 5.60 (s, 2H), 7.28 (d, J = 2. OH z, 4H), 7.35 (dd, J = 2.0, 8.5Hz, 1H), 7.61-7.65 (m, 2H), 7.80 (d, J = (8.0Hz, 4H)

[0095] (2) The obtained crystals were added to 550 kg of ethyl acetate heated to 45 to 55 ° C., stirred at 50 to 55 ° C. for 2 hours, cooled to room temperature, dried, and (s) -2- (3,4-Dichlorophenyl) —N ¹ , N ² —Dimethylpento 4-ene— 1,2-Diamine (+) —Ditoluoyltartaric acid Type 2 crystals 53. lkg (34. 1%) Obtained.

[0096] Type 2 crystal

'H-NMR (400MHz, DMSO-d) δ: 2.02 (s, 3Η), 2.35 (s, 6H), 2.43〜

6

2.56 (m, 5H), 3.19 (d, J = 13.0Hz, 1H), 3.33 (d, J = 13.0Hz, 1H), 4.9 4 to 5.01 (m, 2H), 5.36 to 5.48 (m, 1H), 5.60 (s, 2H), 7.28 (d, J = 8. OH z, 4H), 7.35 (dd, J = 2.0, 8.5Hz, 1H), 7.61-7.65 (m, 2H), 7.80 (d, J = (8.0Hz, 4H)

Claims

The scope of the claims

The following formula (5)

(In the formula, R ¹ represents a lower alkyl group, an aryl group or an aralkyl group, R ² represents a lower alkyl group or an alkenyl group, Ar has a substituent, and may represent an aryl group) A primary amine (NH R ³ ) is reacted with the aziridine compound represented by

2

Formula (6)

[Chemical 2]

(Wherein R ³ represents a lower alkyl group, an aryl group or an aralkyl group which may have a substituent, and R \ R ² and Ar are as defined above)

The manufacturing method of the ethylenediamine derivative represented by these, or its salt.

[2] The production method according to claim 1, wherein R ¹ is a lower alkyl group.

[3] The production method according to claim 1 or 2, wherein R ² is an alkenyl group.

[4] The method according to any one of claims 1 to 3, wherein the primary amine is a lower alkylamine.

[5] The process according to any one of claims 1 to 4, wherein Ar is a full group.

[6] The production method according to any one of claims 1 to 5, wherein the reaction is carried out in the presence of a sulfonic acid acid.

[7] The following general formula (6— 1)

[Chemical 3]

(6-1)

(In the formula, R ¹ represents a lower alkyl group, an aryl group or an aralkyl group, R ³ represents a lower alkyl group, an aryl group or an aralkyl group which may have a substituent, and X ³ and X ⁴ represent (Represents hydrogen atom or halogen atom)

An ethylenediamine derivative represented by the formula:

[8] Represented by the formula (6) obtained by the method according to any one of claims 1 to 6: ^

Formula (7) characterized by optical resolution of amin derivative or its salt

[Chemical 4]

(In the formula, R ¹ represents a lower alkyl group, an aryl group or an aralkyl group, R ² represents a lower alkyl group or an alkyl group, and R ³ may have a lower alkyl group or a substituent. An aryl group or an aralkyl group, Ar may have a substituent, may represent an aryl group, and * represents an asymmetric carbon atom)

The manufacturing method of the optically active ethylenediamine derivative represented by these, or its salt.

[9] The production method according to claim 8, wherein the optical resolution is performed using (+)-di-p-toluoyl D-tartaric acid.

[10] The following general formula (7-1)

[Chemical 5]

(In the formula, R ¹ represents a lower alkyl group, an aryl group or an aralkyl group, R ³ represents a lower alkyl group, an aryl group or an aralkyl group which may have a substituent, and X ³ and X ⁴ represent Represents a hydrogen atom or a halogen atom, and * represents an asymmetric carbon atom)

Or an optically active ethylenediamine derivative or a salt thereof.

11. The salt of an optically active ethylene diamine derivative according to claim 10, which is a diastereomeric salt with tartaric acid or a tartaric acid derivative.

12. The optically active ethylenediamine derivative or a salt thereof according to claim 10 or 11, wherein the steric configuration is the S configuration.

[13] The compound represented by formula (5) is represented by the following formula (4):

[Chemical 6]

OH

(Four)

R '

Ar

(In the formula, R ¹ represents a lower alkyl group, an aryl group or an aralkyl group, R ² represents a lower alkyl group or an alkenyl group, Ar has a substituent, and may represent an aryl group) The production method according to any one of claims 1 to 6, which is obtained by reacting a compound represented by the formula: triarylphosphine and halogen in the presence of a tertiary amine.

[14] The following general formula (5-1)

[Chemical 7]

(5-1)

(Wherein R ¹ represents a lower alkyl group, an aryl group or an aralkyl group, and X ³ and X ⁴ represent a hydrogen atom or a halogen atom)

Or a salt thereof.

[15] Compound power represented by formula (4)

[Chemical 8]

(In the formula, X ¹ represents a halogen atom, Ar represents an aryl group which may have a substituent)

2. A compound obtained by reacting a Grignard reagent (R ² MgX ² ) with a haloacetyl aryl compound represented by the formula ( ¹ ) above, followed by further reacting with a primary amine (NH R ¹ ).

2

3. The production method according to 3.

[16] The following general formula (2-1)

[Chemical 9]

(2-1)

(Wherein X ¹ and X ² represent halogen atoms, and X ³ and X ⁴ represent hydrogen atoms or halogen atoms)

Or a salt thereof.

Or a salt thereof.

[18] The following general formula (4 1)

[Chemical 11]

(4-1)

Or a salt thereof.

[19] The following formula (1)

[Chemical 12]

2

[Chemical 13]

(In the formula, R ¹ represents a lower alkyl group, an aryl group or an aralkyl group, R ² represents a lower alkyl group or an alkenyl group, Ar has a substituent, and may represent an aryl group) The manufacturing method of the compound represented by these, or its salt.

The following formula (4)

[Chemical 14]

(In the formula, R ¹ represents a lower alkyl group, an aryl group or an aralkyl group, R ² represents a lower alkyl group or an alkenyl group, Ar has a substituent, and may represent an aryl group) A compound represented by formula (5) is characterized by reacting triarylphosphine and halogen in the presence of a tertiary amine.

[Chemical 15]

(Wherein, RR ² and Ar are as defined above)

The manufacturing method of the compound represented by these, or its salt.