JP2000053618A - Production of optically active benzylamine compounds - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an optically active benzylamine compound in a high yield by reacting an imine compound with hydrogen in the presence of the complex of a group VIII transition metal, an optically active phosphine and an imide compound. SOLUTION: This method for producing an optically active benzylamine compound of formula II (for example, N-para-chlorobenzyl-phenetylamine) comprises reacting (A) an imine compound of formula I (R1 and R2 are each H, a halogen or the like; R3 is a para-halogenated phenyl) with hydrogen in the presence of (B) the complex of a group VIII transition metal [for example, dichlorotris(triphenylphosphine)ruthenium (II)], (C) an optically active phosphine compound [for example, (R, R)-5,6-bis(diphenylphosphino)-2-norbornene] and (D) an imide compound preferably at 1-200 atm in a temperature range of -40 to 120 deg.C. In the reaction, the component C is used in an amount of 1/10 to 50 times moles that of the component B, and the component D is also used in an amount of 0. 1-20 moles per mole of the component B.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to optically active benzylamines (2) useful as intermediates for the synthesis of pharmaceutical and agricultural chemicals or for synthesis of many general-purpose chemicals, or as optical resolving agents for carboxylic acids. It relates to an advantageous production method.

[0002]

2. Description of the Related Art Conventionally, the following two methods have been generally used to obtain optically active amines as synthetic intermediates. A method for obtaining optically active amines from the corresponding racemic amines by optical resolution using an optically active carboxylic acid. A method of deriving from naturally occurring optically active amines. More recently, many catalytic asymmetric syntheses have been studied, for example, ASYMMETRIC CATALYSIS IN ORGANIC SYNTHESIS By
R. Noyori, (A Wiley-Interscience Publication, John
Wiley & Sons, Inc).

[0003]

However, the above-mentioned conventional method has a limited range of application and is not always sufficient for industrially obtaining a large amount depending on the required optically active amines. In addition, the asymmetric synthesis method using a complex catalyst which has been recently developed has not always been practically satisfactory in yield and enantiomeric excess of the product. Therefore, development of a more excellent asymmetric synthesis of optically active amines by a hydrogenation reaction has been desired.

[0004]

The inventors of the present invention have conducted intensive studies to develop a new route of using a relatively versatile imine as a raw material and subjecting it to an asymmetric hydrogenation reaction. Invented the invention.

That is, the present invention provides a compound represented by the general formula (1) (Wherein, R ₁ and R ₂ represent a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, and an aryl which may have a substituent. Group, an alkenyl group which may have a substituent, an alkoxyl group which may have a substituent, an aryloxy group or an alkyloxycarbonyl group, respectively, or a cyclic compound in which R ₁ and R ₂ are bonded. R ₃ represents a phenyl group having a halogen atom as a substituent at the para-position.)
Reacting with hydrogen in the presence of a complex of a group III transition metal, an optically active phosphine compound and an imide compound; (Wherein, R ₁ , R ₂ and R ₃ have the same meanings as described above).

[0006]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The general formula (1) used in the present invention
In the substituents R ₁ and R ₂ of the imines represented by, a halogen atom is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like, and an alkyl group is, for example, a methyl group, an ethyl group, an n-propyl group, Isopropyl group, n-
Butyl group, isobutyl group, t-butyl group, n-amyl group, neopentyl group, n-hexyl group, cyclohexyl group, n-octyl group, n-nonyl group, menthyl group, 2,
3,4-trimethyl-3-pentyl group, 2,4-dimethyl-3-pentyl group and the like, and aralkyl groups such as benzyl group, 2-phenylethyl group, 2-naphthylethyl group and diphenylmethyl group are aryl. Examples of the group include a phenyl group, a naphthyl group, a biphenyl group, a furyl group, and a thiophenyl group, and examples of the alkenyl group include 2-methyl-
A 1-propenyl group, a 2-butenyl group, a trans-β-styryl group, a 3-phenyl-1-propenyl group, a 1-cyclohexenyl group, and the like, and the alkoxyl group is a methoxy group, an ethoxy group, an n-propoxy group, -Butoxy group and the like, and the aryloxy group is a phenoxy group and the like,
Examples of the alkyloxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a t-butyloxycarbonyl group, a benzyloxycarbonyl group, and a phenyloxycarbonyl group. As a substituent when these groups are further substituted with a substituent,
The same halogen atom as described above, the same alkoxyl group as described above, the same aryloxy group as described above, a methyl group, an ethyl group, an isopropyl group, an n-butyl group, a t-butyl group, a n-amyl group, n Lower alkyl groups such as -hexyl group; lower alkylthio groups such as n-propylthio group and t-butylthio group; arylthio groups such as phenylthio group; nitro groups; and hydroxyl groups.

Examples of the phenyl group having a halogen atom as a substituent at the para position represented by the substituent R ₃ of the imines (1) include p-fluorophenyl group, p-chlorophenyl group, p-chlorophenyl group and p-chlorophenyl group.
Examples thereof include a bromophenyl group and a p-iodophenyl group.

The imines (1) can be easily produced from ketones. Specific examples of the imines (1) in the present invention include, for example, acetophenone, propiophenone, benzaldehyde, benzalacetone, 3-methylcyclohexanone, 3-chlorobenzophenone, methyl isobutyl ketone, cyclohexyl methyl ketone, and 2-naphthophenone And imines which can be synthesized by dehydration condensation from ketones such as, 1-indanone and benzylamine having a substituent of a halogen atom at the para-position by a conventional method (heating to reflux in a solvent such as toluene in the presence of an acid catalyst). Can be mentioned.

As the optically active phosphine compound used in this reaction, a known phosphine compound used for asymmetric synthesis using a transition metal can be used. Specifically, for example, (R) -2,2'-bis (dicyclohexylphosphino) -6,
6'-dimethyl-1,1'-biphenyl, (R) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, (S, S) -2,3-bis (diphenylphosphino ) Butane, (R) -1-cyclohexyl-1,
2-bis (diphenylphosphino) ethane, (R, R) -2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane, (R, R) -1 , 2-Bis [(o-methoxyphenyl) -phenylphosphino] ethane, (R, R) -5,6-bis
(Diphenylphosphino) -2-norbornene, and the like.

The amount of the above-mentioned optically active phosphine compound varies depending on the reaction conditions and economical efficiency, but is usually 1 mol based on the molar ratio of the complex of the Group VIII transition metal coexisting in the reaction system.
/ 10 to 50 times the amount, preferably 9
/ 10 to 5 times the amount.

The complex of the Group VIII transition metal is, for example, a compound represented by the following general formula (3) (Wherein, M ¹ represents a Group VIII transition metal such as rhodium, ruthenium, iridium, platinum, X represents a hydrogen atom, a halogen atom, a carboxyl group, an alkoxy group or a hydroxy group, and L represents an organic ligand. And m and n each represent an integer of 0 to 6). In the above, the organic ligand (L) is
Olefin ligands, including CO, NO, NH ₂ , NH _3, etc.
Examples include acetylene ligands, aromatic compound ligands, organic oxygen-containing compound ligands, organic sulfur-containing compound ligands, and organic nitrogen-containing compound ligands.

The olefin ligands include, for example, ethylene, allyl, butadiene, cyclohexene,
Examples thereof include 1,3-cyclohexadiene, 1,5-cyclooctadiene, cyclooctatriene, norbornadiene, acrylate, methacrylate, cyclopentadienyl, and pentamethylcyclopentadienyl. Also commonly used as a ligand 5
Examples of the five-membered ring compound include a five-membered ring compound represented by the following general formula (4). (Wherein, Ra to Re are the same or different and each have a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, An aryl group which may be substituted, an alkenyl group which may have a substituent, an alkoxyl group which may have a substituent, or an alkyloxycarbonyl group. Atom, bromine atom, iodine atom, etc., as the alkyl group, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-
Amyl group, neopentyl group, n-hexyl group, cyclohexyl group, n-octyl group, n-nonyl group, menthyl group,
2,3,4-trimethyl-3-pentyl group, 2,4-dimethyl-3-pentyl group and the like, and aralkyl groups such as benzyl group, 2-phenylethyl group, 2-naphthylethyl group and diphenylmethyl group. An aryl group includes a phenyl group, a naphthyl group, a biphenyl group, a furyl group, and a thiophenyl group; and an alkenyl group includes a 2-methyl-1-propenyl group, a 2-butenyl group, and a trans-β.
-Styryl group, 3-phenyl-1-propenyl group, 1-
Cyclohexenyl group and the like, alkoxyl group as methoxy group, ethoxy group, n-propoxy group, t-butoxy group and the like, aryloxy group as phenoxy group and the like, and alkyloxycarbonyl group as methoxycarbonyl group and ethoxycarbonyl. Group, t-butyloxycarbonyl group, benzyloxycarbonyl group, phenyloxycarbonyl group and the like. When these groups are further substituted with a substituent, examples of the substituent include the same halogen atom as described above, the same alkoxyl group as described above, the same aryloxy group as described above,
Methyl group, ethyl group, isopropyl group, n-butyl group, t
Lower alkyl groups such as -butyl group, n-amyl group and n-hexyl group, lower alkylthio groups such as n-propylthio group and t-butylthio group, arylthio groups such as phenylthio group, nitro group, hydroxyl group and the like. . The number of the substituents is an arbitrary number of 1 to 5, and the substitution position can be selected at any position.

Examples of the acetylene ligand include acetylene, 1,2-dimethylacetylene, 1,4-pentadiyne, and 1,2-diphenylacetylene.

As the aromatic compound ligand, benzene,
Examples thereof include p-cymene, mesitylene, hexamethylbenzene, naphthalene, and anthracene. Examples of the aromatic compound generally used as a ligand include a cyclic aromatic compound represented by the following general formula (5). Can be (Wherein, Ra ′ to Rf ′ are the same or different, and are a hydrogen atom,
Represents a saturated or unsaturated hydrocarbon group, an allyl group, a functional group containing a heteroatom, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl,
Alkyl groups such as heptyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, groups such as benzyl, vinyl, allyl, phenyl and unsaturated hydrocarbons such as naphthyl, hydroxyl groups, alkoxy groups, alkoxycarbonyl groups and the like Functional groups containing heteroatoms can be indicated. The number of substituents is an arbitrary number of 1 to 6, and the substitution position is arbitrary. )

Examples of the organic oxygen compound ligand include, for example, acetate, benzoate, acetylacetonate and the like. As the organic sulfur-containing compound ligand,
For example, dimethyl sulfoxide, dimethyl sulfide,
Examples thereof include thiophene, carbon disulfide, carbon sulfide, and thiophenol. As the organic nitrogen-containing compound ligand, for example, acetonitrile, benzonitrile, t-butyl isocyanide, pyridine, 1,10-phenanthroline,
2,2′-bipyridyl and the like are exemplified.

The complex of the Group VIII transition metal in the present invention includes, for example, chlorotris (triphenylphosphine) rhodium (I), cyclopentadienylbis (triphenylphosphine) rhodium (I), bis (cyclooctadiene) Diiododirhodium (I), chloro (cyclopentadienyl) bis (triphenylphosphine) ruthenium (II), chloro (pentamethylcyclopentadienyl) (1,3-bis (diphenylphosphino) propane) ruthenium (II) ), Chloro (pentamethylcyclopentadienyl) (1,5-cyclooctadiene)
Ruthenium (II), dichlorotris (triphenylphosphine) ruthenium (II), chlorotris (triphenylphosphine) iridium (I), pentamethylcyclopentadienylbis (ethylene) iridium (I), (ethylene) bis (triphenyl) Phosphine)
Platinum (0), trans- [chloro (ethyl) bis (triethylphosphine) platinum (II)], cis- [diethylbis (triethylphosphine) platinum (II)], dichloro (norbornadiene) platinum (II), tetrakis (triphenyl) Examples thereof include phosphine) platinum (0), and among them, a ruthenium complex has particularly high activity. Of course, the complex used in the present invention is not limited to these.

The amount of the complex of the above-mentioned group VIII transition metal varies depending on the reaction conditions and economical efficiency, but is usually from 1/100 to 1 / molar as the molar ratio to the imine (1) as the reaction substrate.
About 100,000 can be used, preferably 1 /
It is in the range of about 200 to 1 / 10,000.

In this reaction, an imide compound is used to improve the yield and the selectivity (optical purity of the product) in the hydrogenation reduction reaction of the imines (1). Specific examples of the imide compounds include succinimide, α-methyl-α-propylsuccinimide, 2,3,3-trimethylsuccinimide, maleimide, cis-4-cyclohexene-1,2-dicarboximide, phthalimide, Examples include 3,3-dimethylglutarimide, 1,8-naphthalimide and the like. The amount of the additive of the imide compound to be used is 0.1 to 1 molar equivalent of the complex of the Group VIII transition metal.
It is used in an amount of about 1 to 20 mol, preferably about 1 to 5 mol.

In the present invention, a solvent is usually used.
As such a solvent, those that solubilize the reaction raw materials and the catalyst system are preferably used. Specific examples include, for example, aromatic solvents such as toluene and xylene, aliphatic solvents such as pentane and hexane, halogen-containing hydrocarbon solvents such as methylene chloride, ethers, ether solvents such as tetrahydrofuran, methanol, ethanol, and 2-propanol. Alcohol solvents such as butanol and benzyl alcohol, and organic solvents containing heteroatoms such as acetonitrile, DMF, N-methylpyrrolidone, pyridine and DMSO can be used. These solvents can be used alone,
It can also be used as a mixed solvent. The amount of the solvent to be used can be appropriately determined depending on the solubility of the reaction substrate and economic efficiency.

In the present invention, the pressure of hydrogen is usually from 1 to 1.
A range of about 200 atm, preferably a range of about 3 to 100 atm is desirable.

The reaction can be carried out usually at a temperature in the range of about -40 to 120 ° C.
The reaction is carried out at a temperature in the range of from 25 ° C to 100 ° C, preferably from 25 to 40 ° C.

The reaction time varies depending on the reaction conditions such as the concentration of the reaction substrate, the temperature and the pressure, but the reaction is usually completed in a few minutes to about 30 hours.

The reaction in the present invention can be carried out either in a batch system or a continuous system.

As the optically active benzylamines (2) thus obtained, specifically, for example, N-parachlorobenzyl-phenethylamine, N-parabromobenzyl-phenethylamine, N-parachlorobenzyl-2,4- Dichlorophenethylamine, N-parabromobenzyl-2,4-dichlorophenethylamine, N-parachlorobenzyl-1-cyclohexylethylamine, N-parabromobenzyl-1-cyclohexylethylamine, and the like.

[0025]

According to the present invention, benzylamines can be obtained with excellent yield and excellent optical purity. Such optically active benzylamines (2) can be used as optically resolving agents for carboxylic acids, and are also versatile as intermediates for the synthesis of optically active pharmaceutical and agricultural chemicals.

[0026]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 N- [1- (2,4-dichlorophenyl) ethylidene] parachlorobenzylamine (200 mg, 0.64 mmol) was charged into a Schlenk tube (20 ml), and 5 ml of methanol was further added. This solution was degassed and replaced with argon. Thereafter, the imine solution was transferred to an autoclave in which the inside was replaced with argon. on the other hand,
In another Schlenk tube (20 ml), [IrCl (cod)] ₂ complex 21.5 mg (0.
032 mmol), 39.9 mg (0.064 mmol) of (S) -BINAP and 18.8 mg (0.128 mg) of phthalimide, and 5 ml of toluene were further added. This solution was purged with argon, and then stirred for 30 minutes to completely dissolve the solid. Thereafter, the mixture was put into the above-mentioned autoclave. After sufficiently replacing the inside of the autoclave with hydrogen, hydrogen was pressurized to 50 atm. The mixture was stirred at 30 ° C. for 18 hours to cause a hydrogenation reaction. After completion of the reaction, the reaction mixture was concentrated, the solvent was distilled off, dissolved in ether (20 ml), passed through a silica gel column to remove the complex catalyst, etc., concentrated again, and then concentrated to the desired N- [1- (2,4-diamine). Chlorophenyl) ethyl] parachlorobenzylamine (195 mg, 0.62 mmol, 96.9%, 70% ee) was obtained.

Example 2 228 mg (0.64 mmol) of N- [1- (2,4-dichlorophenyl) ethylidene] parabromobedylamine was charged into a Schlenk tube (20 ml), and 5 ml of methanol was further added. This solution was degassed and replaced with argon. Thereafter, the imine solution was transferred to an autoclave in which the inside was replaced with argon. On the other hand, in another Schlenk tube (20 ml), [IrCl (cod)] ₂ complex 21.5 mg (0.032
mmol), 39.9 mg (0.064 mmol) of (S) -BINAP and 18.8 mg (0.128 mg) of phthalimide, and 5 ml of toluene was further added. This solution was purged with argon, and then stirred for 30 minutes to completely dissolve the solid. Thereafter, the mixture was put into the above-mentioned autoclave. After sufficiently replacing the inside of the autoclave with hydrogen, hydrogen was pressurized to 50 atm. The mixture was stirred at 30 ° C. for 18 hours to cause a hydrogenation reaction. After completion of the reaction, the reaction mixture was concentrated, the solvent was distilled off, dissolved in ether (20 ml), passed through a silica gel column to remove the complex catalyst, etc., and concentrated again. Chlorophenyl) ethyl] parabromobedylamine (225 mg, 0.63 mmol, 97.9%, 67% ee) was obtained.

Example 3 189 mg (0.64 mmol) of N- [1- (2,4-dichlorophenyl) ethylidene] parafluorobenzylamine was added to a Schlenk tube (20 ml).
, And 5 ml of methanol was further added. This solution was degassed and replaced with argon. Thereafter, the imine solution was transferred to an autoclave in which the inside was replaced with argon. On the other hand, [IrCl (cod)] ₂ complex 21.5m was placed in another Schlenk tube (20ml).
g (0.032 mmol), 39.9 mg (0.064 mmol) of (S) -BINAP and 18.8 mg (0.128 mg) of phthalimide were added, and 5 ml of toluene was further added. This solution was purged with argon, and then stirred for 30 minutes to completely dissolve the solid. Thereafter, the mixture was put into the above-mentioned autoclave. After sufficiently replacing the inside of the autoclave with hydrogen, hydrogen was pressurized to 50 atm. The mixture was stirred at 30 ° C. for 18 hours to cause a hydrogenation reaction. After completion of the reaction, the reaction mixture was concentrated and the solvent was distilled off.The residue was dissolved in ether (20 ml), passed through a silica gel column to remove the complex catalyst, etc., and concentrated again.The desired 1 N- [1- (2,4- Dichlorophenyl) ethyl] parafluorobenzylamine (65 mg, 0.61 mmol, 95.3%, 68% ee) was obtained.

Example 4 259 mg (0.64 mmol) of N- [1- (2,4-dichlorophenyl) ethylidene] paraiodobenzylamine was charged into a Schlenk tube (20 ml), and 5 ml of methanol was further added. This solution was degassed and replaced with argon. Thereafter, the imine solution was transferred to an autoclave in which the inside was replaced with argon. on the other hand,
In another Schlenk tube (20 ml), [IrCl (cod)] ₂ complex 21.5 mg (0.
032 mmol), 39.9 mg (0.064 mmol) of (S) -BINAP and 18.8 mg (0.128 mg) of phthalimide, and 5 ml of toluene were further added. This solution was purged with argon, and then stirred for 30 minutes to completely dissolve the solid. Thereafter, the mixture was put into the above-mentioned autoclave. After sufficiently replacing the inside of the autoclave with hydrogen, hydrogen was pressurized to 50 atm. The mixture was stirred at 30 ° C. for 18 hours to cause a hydrogenation reaction. After completion of the reaction, the reaction mixture was concentrated, the solvent was distilled off, dissolved in ether (20 ml), passed through a silica gel column to remove the complex catalyst, etc., concentrated again, and then concentrated to the desired N- [1- (2,4-diamine). Chlorphenyl) ethyl] paraiodobenzylamine (252 mg, 0.62 mmol, 97.1%, 62% ee) was obtained.

Comparative Example 1 N- [1- (2,4-dichlorophenyl) ethylidene] benzylamine (178 mg, 0.64 mmol) was charged into a Schlenk tube (20 ml), and 5 ml of methanol was further added. This solution was degassed and replaced with argon. Thereafter, the imine solution was transferred to an autoclave in which the inside was replaced with argon. Meanwhile, 21.5 mg (0.032 mmol) of [IrCl (cod)] ₂ complex was placed in another Schlenk tube (20 ml).
(S) -BINAP 39.9 mg (0.064 mmol) and phthalimide 18.8 m
g (0.128 mg) was added, and 5 ml of toluene was further added.
This solution was purged with argon, and then stirred for 30 minutes to completely dissolve the solid. Thereafter, the mixture was put into the above-mentioned autoclave. After sufficiently replacing the inside of the autoclave with hydrogen, hydrogen was pressurized to 50 atm. The mixture was stirred at 30 ° C. for 18 hours to cause a hydrogenation reaction. After completion of the reaction, the reaction mixture was concentrated, the solvent was distilled off, dissolved in ether (20 ml), passed through a silica gel column to remove the complex catalyst and the like, concentrated again, and then concentrated to the desired N- [1-
(2,4-Dichlorophenyl) ethyl] benzylamine 116mg
(0.42 mmol, 65.0%, 15% ee) was obtained.

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Claims (2)

[Claims] 1. The general formula (1) (Wherein, R ₁ and R ₂ represent a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, and an aryl which may have a substituent. Group, an alkenyl group which may have a substituent, an alkoxyl group which may have a substituent, an aryloxy group or an alkyloxycarbonyl group, respectively, or a cyclic compound in which R ₁ and R ₂ are bonded. R ₃ represents a phenyl group having a halogen atom as a substituent at the para-position.)
Reacting with hydrogen in the presence of a complex of a group III transition metal, an optically active phosphine compound and an imide compound; (Wherein, R ₁ , R ₂ and R ₃ have the same meanings as described above). 2. A complex of a Group VIII transition metal represented by the general formula (3): (Wherein M ¹ represents a Group VIII transition metal of iridium, rhodium, ruthenium or platinum, X represents a hydrogen atom, a halogen atom, a carboxyl group, an alkoxy group or a hydroxy group, and L represents an organic ligand. , M and n each represent an integer of 0 to 6.) The method according to claim 1, which is a complex of a Group VIII transition metal represented by the formula: