JP2003252836A - Method for producing optically active trans-2- aminocycloalkanol or salt thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially producing an optical-active trans-2-aminocycloalkanol or a derivative thereof using easy-to-handle raw materials. <P>SOLUTION: The method comprises carrying out a reaction between a cycloalkene oxide of formula (1) (wherein, ring Z is a 3-8C cycloalkane ring) and an amine of formula (2) (wherein, Ar is an aryl; and R<SP>1</SP>is H or a 1-3C alkyl) in the presence of a Lewis acid and an optically active ligand to form an optically active trans-2-aminocycloalkanol derivative of formula (3a) or (3b) (wherein, ring Z, Ar and R<SP>1</SP>are the same as mentioned above) or a salt thereof, which is then reduced to obtain the objective compound of formula (4a) or (4b) (wherein, ring Z is the same as mentioned above) or a salt thereof. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active trans-2-aminocycloalkanol such as trans-2-aminocyclopentanol or a salt thereof which is useful as an intermediate for fine chemicals such as pharmaceuticals and agricultural chemicals. And a method for purifying an optically active trans-2-aminocycloalkanol derivative.

[0002]

As a method for producing trans-2-aminocycloalkanols, for example, Synth. Commun., 1992,
3003-3012, J. Org. Chem., 1985, 4154-415
Page 5 discloses a method for obtaining trans-2-aminocyclopentanol by reacting cyclopentene oxide with (R) -α-methylbenzylamine in the presence of trimethylaluminum. However, this method is not an industrially advantageous method because it has a low stereoselectivity in the reaction and has a problem in the purification step for obtaining the target compound having high optical purity.

Biosci. Biotechnol. Biochem. 1999,
On pages 2150-2156, a method is disclosed in which cyclopentene oxide is azidated with sodium azide and then an optically active azide compound is obtained with lipase. Also,
J. Org. Chem., 1997, pp. 4197-4199, discloses a method of reacting cyclopentene oxide with trimethylsilyl azide in the presence of an optically active ligand to obtain an optically active azide compound. There is. This azide compound can be converted into an amino compound. However, these methods cannot be said to be industrially advantageous because it is necessary to produce an azide compound that requires careful handling.

Furthermore, Tetrahedron: Asymmetry, 1999.
Pp. 473-486, Tetrahedron, 1991, 4941-4958.
The page contains Mortiere β-ketoamides and β-ketoesters.
A method of obtaining optically active trans-2-aminocyclopentanol by carrying out bioreduction using lla isabellina or Baker's yeast to obtain optically active hydroxyamide and hydroxy acid, and then performing a rearrangement reaction has been reported. However, this method cannot be said to be industrially advantageous since it uses an azide compound or a mercury-based reagent in the rearrangement reaction.

[0005]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a method capable of industrially and efficiently producing an optically active trans-2-aminocycloalkanol or a derivative thereof by using a raw material which is easy to handle. is there. Another object of the present invention is to provide a method for easily producing trans-2-aminocycloalkanol or its derivative having high optical purity.

[0006]

Means for Solving the Problems As a result of intensive studies for solving the above-mentioned problems, the present inventors have found that a cycloalkene oxide (1,2-epoxycycloalkane) and a specific amine are present in the presence of a specific compound. The present invention has been completed by finding that an optically active trans-2-aminocycloalkanol or a salt thereof can be simply and efficiently produced by conducting a reduction reaction after the reaction below.

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

[Chemical 9] (Wherein, ring Z represents a cycloalkane ring having 3 to 8 carbon atoms), and a cycloalkene oxide represented by the following formula (2)

[Chemical 10] (Wherein Ar represents an aryl group, R ¹ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), and reacted with an amine in the presence of a Lewis acid and an optically active ligand. Let the following formula (3a) or (3b)

[Chemical 11] (Wherein ring Z, Ar and R ¹ are the same as above) to obtain an optically active trans-2-aminocycloalkanol derivative or a salt thereof, which is then subjected to a reduction reaction,
Formula (4a) or (4b) below

[Chemical 12] There is provided a method for producing an optically active trans-2-aminocycloalkanol or a salt thereof, which comprises obtaining a compound represented by the formula (ring Z is the same as above) or a salt thereof.

Examples of the amine represented by the above formula (2) include benzylamine and α-phenethylamine. The Lewis acid includes titanium tetraalkoxide and the like. 1,1'-bi-2- as an optically active ligand
Examples include naphthol.

The present invention also provides the above formula (3a) or (3b)
By reacting an optically active trans-2-aminocycloalkanol derivative represented by the following formula (5) HX (5) (wherein H is a hydrogen atom and HX is a protic acid). , The following formula (6a) or (6b)

[Chemical 13] (Wherein ring Z, Ar, R ¹ and HX are the same as above) to form a salt of an optically active trans-2-aminocycloalkanol derivative, and then the salt is recrystallized to improve the optical purity. A method for purifying an optically active trans-2-aminocycloalkanol derivative, which comprises:

The present invention further provides the above formula (3a) or (3
characterized in that an optically active trans-2-aminocycloalkanol derivative represented by b) or a salt thereof is subjected to a reduction reaction to obtain a compound represented by the formula (4a) or (4b) or a salt thereof. The present invention provides a method for producing an optically active trans-2-aminocycloalkanol or a salt thereof.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION In the method of the present invention, the formula (1)
Inside, the ring Z shows a C3-C8 cycloalkane ring. Specifically, ring Z is a cyclopropane ring, a cyclobutane ring,
A cyclopentane ring, a cyclohexane ring, a cycloheptane ring or a cyclooctane ring is shown. Among these, a cyclopentane ring or a cyclohexane ring, particularly a cyclopentane ring is preferable.

Examples of the aryl group represented by Ar in the formula (2) include aromatic hydrocarbon groups such as phenyl group and naphthyl group; and aromatic heterocyclic groups such as pyridyl group. The aromatic ring in the aryl group may have a substituent. The substituent is not particularly limited as long as it does not impair the reaction, and examples thereof include a halogen atom (fluorine, chlorine, bromine atom, etc.), an alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, t-).
Butyl, pentyl, C _1-6 alkyl groups such as hexyl group), aryl groups (eg phenyl, naphthyl group etc.), alkoxy groups (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,
C _1-6 alkoxy groups such as pentyloxy and hexyloxy groups), nitro groups, cyano groups, hydroxyl groups optionally protected with a protecting group, amino groups optionally protected with a protecting group, and protecting groups Examples thereof include a carboxyl group which may be protected (for example, a carboxyl group, an alkoxycarbonyl group and the like), a heterocyclic group and the like. Examples of the protecting group include those commonly used in the field of organic synthesis.

Examples of the alkyl group having 1 to 3 carbon atoms for R ¹ include a methyl group, an ethyl group, a propyl group and an isopropyl group.

As typical examples of the amine represented by the formula (2), for example, benzylamine, α-phenethylamine (= α-methylbenzylamine), (R) -α-phenethylamine, (S) -α- Phenethylamine, 1- (1
Examples include -naphthyl) ethylamine, (R) -1- (1-naphthyl) ethylamine and (S)-(1-naphthyl) ethylamine. Among these, (R) -α-
Optically active amines such as phenethylamine and (S) -α-phenethylamine are preferred. When an optically active amine is used, the compound represented by the formula (3a) and the compound represented by the formula (3b) have a diastereomeric relationship, and therefore the compound represented by the formula (3a) or (3b). Optically active transformer-2-
There is an advantage that the optical purity of the aminocycloalkanol derivative or its salt can be easily increased by recrystallization or the like.

The Lewis acid is a compound having an atom having an electron pair (in the present invention, the epoxy oxygen of the formula (1)) capable of accepting the electron pair, an ion, and an atomic group. It can be appropriately selected and used according to the kind of reaction raw material. Typical examples of Lewis acids include magnesium compounds such as magnesium chloride; titanium tetraalkoxides such as tetraisopropoxy titanium; titanium compounds such as titanium tetrachloride; zirconium tetraalkoxides such as tetrapropoxy zirconium; zirconium chloride; zirconium fluoride; Zirconium compounds such as zirconium sulfide; iron compounds such as iron chloride; copper compounds such as copper chloride; zinc compounds such as zinc chloride, zinc bromide, zinc iodide; boron compounds such as boron bromide, boron chloride, boron fluoride Aluminum compounds such as aluminum chloride, aluminum bromide, alkylaluminum, alkylaluminum chloride and alkoxyaluminum; tin compounds such as tin chloride. Among these, titanium compounds such as titanium tetraalkoxide such as tetraisopropoxy titanium are preferable.

In the formation reaction of the optically active trans-2-aminocycloalkanol derivative represented by the formula (3a) or (3b) or a salt thereof, the amount of Lewis acid used depends on the kind, reaction mode and reaction rate. According to the like, for example, relative to 1 mol of the cycloalkene oxide represented by the formula (1), it can be selected from a wide range of about 0.01 to 1.0 mol, and usually 0.01 to 0.1 mol. Degree, preferably 0.
It is about 025 to 0.1 mol.

The optically active ligand may be any chiral compound containing an atomic group capable of a monodentate or multidentate bond with the central atom of the Lewis acid (which becomes the central atom of the complex), It can be appropriately selected and used according to the kind of the Lewis acid. Preferred ligands include bidentate ligands. Examples of the optically active bidentate ligand include 1,1′-bi-2-
Naphthol, tartaric acid, tartaric acid ester (dimethyl tartarate, diethyl tartarate, dipropyl tartarate, etc.), trans- (2,2-dimethyl-1,
3-dioxolane-4,5-diyl) -bis (diphenylethanol), 1,6-bis (2-chlorophenyl)
-1,6-Diphenyl-2,4-hexadiyne-1,6
-Optically active substances such as diols. Among these, the optically active substance of 1,1′-bi-2-naphthol is particularly preferable.

In the production reaction of the optically active trans-2-aminocyclopentanol derivative represented by the formula (3a) or (3b) or a salt thereof, the ratio of the optically active ligand is Depending on the type, reaction mode, reaction speed, etc.,
For example, cycloalkene oxide 1 represented by the formula (1)
It can be selected from a wide range of about 0.01 to 1.0 mol per mol, and is usually about 0.01 to 0.1 mol, preferably about 0.025 to 0.1 mol.

The Lewis acid and the optically active ligand may be added to the reaction system separately, or a mixture of the Lewis acid and the optically active ligand may be added to the reaction system. When the Lewis acid and the optically active ligand react with each other, a reaction product obtained by previously reacting the two may be added to the reaction system.

The reaction between the cycloalkene oxide represented by the formula (1) and the amine represented by the formula (2) is carried out in the presence or absence of a solvent. The solvent is not particularly limited as long as it does not inhibit the progress of the reaction and dissolves the reaction components. For example, ethers (1,4-dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, t-butyl methyl ether, Cyclic or chain ethers such as dibutyl ether), nitriles (acetonitrile, benzonitrile, etc.), sulfoxides (dimethyl sulfoxide, etc.), sulfur atom-containing solvents such as sulfolane, aliphatic hydrocarbons (pentane, hexane, octane, etc.), Aromatic hydrocarbons (benzene, toluene, etc.),
Alicyclic hydrocarbons (such as cyclohexane), halogen-containing compounds (methylene chloride, chloroform, bromoform,
Halogenated hydrocarbons such as chlorobenzene and bromobenzene, etc., and mixed solvents thereof can be used. The amount of the solvent is not particularly limited as long as it can dissolve a component used in the reaction (for example, an optically active ligand), and is, for example, 1 part by weight with respect to 1 part by weight of the cycloalkene oxide represented by the formula (1). It can be selected from the range of about 1000 parts by weight.

The reaction is usually carried out at atmospheric pressure to 500 atm (0.1
-50 MPa), preferably atmospheric pressure to 100 atm (0.1
10 MPa), and more preferably at atmospheric pressure to 10 atm (0.1 to 1 MPa). Further, if necessary, the reaction may be carried out under reduced pressure from the viewpoint of equipment or operation. The reaction temperature is not particularly limited as long as it is not lower than the melting point and not higher than the boiling point of the system under the reaction conditions, and is, for example, -30 ° C to 2
The temperature is 00 ° C., preferably −10 ° C. to 100 ° C., more preferably 0 to 50 ° C. The reaction is batch type,
It can be carried out by a conventional method such as a semi-batch method or a continuous method.

According to the above method, the by-product of the cis-2-aminocycloalkanol derivative is remarkably suppressed, the trans-2-aminocycloalkanol derivative is preferentially produced, and the Lewis acid and the optically active compound are not activated. Due to the action of the ligand, one of the two stereoisomers of the trans-2-aminocycloalkanol derivative [the compound represented by the formula (3a) and the compound represented by the formula (3b)] Is generated preferentially. Further, a trans-2-aminocycloalkanol derivative having a desired configuration can be prepared depending on the configuration of the ligand.

The produced optically active trans-2-aminocycloalkanol derivative represented by the formula (3a) or (3b) is optionally reacted with an acid to form a salt, and then filtered, concentrated, Distillation, extraction, ion exchange, electrodialysis,
Separation and purification can be carried out by means of separation and purification such as crystallization, recrystallization, adsorption, membrane separation, centrifugation, chromatography (column chromatography, etc.) or a combination thereof. Alternatively, the free trans-2-aminocycloalkanol derivative can be purified and then reacted with an acid to form a salt, which can be further purified. These purification operations can further improve chemical purity and optical purity.

As the acid used to form the salt of the trans-2-aminocycloalkanol derivative, a protic acid such as a mineral acid or an organic acid can be used. As the mineral acid, for example,
Examples thereof include hydrochloric acid, sulfuric acid and phosphoric acid. Examples of the organic acid include carboxylic acids such as formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid and citric acid; sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid. The acid may be an optically active substance. Preferred acids include mineral acids such as hydrochloric acid. Free trans-
The reaction between the aminocycloalkanol derivative and the acid is usually performed in a suitable solvent such as ethanol at a temperature of, for example, about 0 to 50 ° C.

In a preferred embodiment of the present invention, the above formula (3a)
Alternatively, the optically active trans-2-aminocycloalkanol derivative represented by the formula (3b) is reacted with the acid represented by the formula (5) to give the optically active trans represented by the formula (6a) or (6b). A salt of the 2-aminocycloalkanol derivative is obtained, and this salt is then recrystallized. By this method, a salt having a high optical purity [a salt of an optically active trans-2-aminocycloalkanol derivative represented by the formula (6a) or (6b)] can be obtained. Further, by liberating this salt with a basic compound, an optically active trans-2-aminocycloalkanol derivative represented by formula (3a) or (3b) having high optical purity can be obtained. By subjecting such an optically active trans-2-aminocycloalkanol derivative having a high optical purity or a salt thereof to the following reduction reaction, an optically active trans-2-aminocycloalkanol derivative having a high optical purity is obtained.
Aminocycloalkanol or a salt thereof can be obtained.

As the protic acid represented by the above formula (5), the acids exemplified above can be used. As the solvent when recrystallizing the generated salt, depending on the type of the salt, for example,
The solvent can be appropriately selected and used from the solvents exemplified above, alcohols (methanol, ethanol, isopropyl alcohol, propanol, butanol, etc.), esters (ethyl acetate, etc.), water, and mixed solvents thereof. As a preferable recrystallization solvent, alcohol such as methanol and t
-A mixed solvent with an ether such as butyl methyl ether (particularly a chain ether) is included. The recrystallization operation can be performed according to a conventional method.

The reduction (hydrolysis) of the optically active trans-2-aminocycloalkanol derivative represented by the formula (3a) or (3b) or a salt thereof is carried out in the presence or absence of a solvent. As the reaction raw material used for the reduction, an optically active salt of trans-2-aminocycloalkanol derivative is preferable. The solvent can be appropriately selected according to the type of reaction components and the type of reducing agent, and is exemplified as the solvent in the reaction between the cycloalkene oxide represented by the formula (1) and the amine represented by the formula (2). In addition to the above, alcohols (methanol, ethanol, isopropyl alcohol, propanol, butanol, etc.), esters (ethyl acetate, etc.), water, and mixed solvents thereof are included.

The reducing agent may be any reducing agent capable of reductively decomposing a so-called benzyl group bonded to a nitrogen atom, but hydrogen is generally used. The catalytic hydrogenation reaction using hydrogen is carried out in the presence of a transition metal catalyst.

As the metal species of the transition metal catalyst, for example,
Rhodium, ruthenium, platinum, palladium, nickel,
Iron etc. can be used. The transition metal catalyst is usually used as a metal compound or a complex (including a complex salt) composed of the elemental metal or the metal element.

Examples of the metal compound include metal salts [inorganic acid salts,
For example, hydrochloride, sulfate, nitrate, salt with carbonic acid (carbonate, hydrogen carbonate, etc.), salt with phosphoric acid (phosphate, hydrogen phosphate, dihydrogen phosphate, etc.), borate Etc .; organic acid salts such as carboxylates (fatty acid salts such as formate, acetate, lactate, oxalate, naphthenate; thiocyanate, etc.)], halides (chloride, bromide, etc.), etc. Can be illustrated.

Examples of the complex include a complex in which a ligand is coordinated to the above metal element or the above metal compound.
As the ligand, a phosphorus compound such as phosphine (eg, trialkylphosphine such as tri-n-butylphosphine; triarylphosphine such as triphenylphosphine), nitrile, OH (hydroxo), alkoxyl group (methoxy, ethoxy group, etc.) ), Acyl group (acetyl, propionyl group, etc.), alkoxycarbonyl group [methoxycarbonyl (acetato), ethoxycarbonyl group, etc.], acetylacetonato, cyclopentadienyl group, halogen atom (chlorine atom, bromine atom, etc.), C
O, oxygen atom, H ₂ O (acoustic), nitrogen-containing compound (for example, NH ₃ (ammine), NO, NO ₂ (nitro), NO
₃ (nitrato), ethylenediamine, pyridine, phenanthroline, etc.) and the like. In the complex or complex salt, the same or different ligands may be coordinated in one kind or two or more kinds. The metal or metal compound and the ligand may be appropriately combined to form a complex.

The transition metal catalyst may be a homogeneous catalyst or a heterogeneous catalyst. Further, it may be a solid catalyst in which a catalyst component is supported on a carrier. Examples of the carrier include activated carbon, zeolite, silica (such as silica gel), alumina, silica-alumina, and porous carriers such as bentonite.

As the transition metal catalyst, a palladium compound (including palladium alone) is particularly preferable. Examples of the palladium compound include metallic palladium (palladium black, etc.), palladium nitrate, palladium chloride, palladium acetate, acetylacetonatopalladium (II), tetraamminepalladium (II) chloride, bis (ethylenediamine) palladium (II) chloride, tetra Potassium chloropalladium (II), potassium tetranitropalladium (II), dichlorobis (trialkylphosphine) palladium (II), dimethylbis (triethylphosphine)
Palladium (II), biscyclopentadienylpalladium (II), tricarbonylcyclopentadienylpalladium (I), dichloro-μ-bis [bis (dimethylphosphino) methane] dipalladium (I), tetrakis (triphenyl) Phosphine) palladium (0), bis (tricyclohexylphosphine) palladium (0), tetrakis (triethylphosphite) palladium (0), carbonyltris (triphenylphosphine) palladium (0), bis (cycloocta-1.5-diene ) Palladium (0), tris (dibenzylideneacetone) dipalladium (0) and the like. Preferably, metal palladium such as palladium black (including those supported on a carrier such as activated carbon) is used. The valency of palladium constituting the catalyst is not particularly limited and is usually 0 to 4 valence, preferably 0 to 2 valence.

Further, for example, divalent palladium and a suitable reducing agent may be added to the system to generate 0-valent palladium in the system, which is then used in the reaction. Examples of suitable reducing agents include phosphines such as triphenylphosphine and tributylphosphine, hydrazines such as hydrazine, and hydrogen.

In the reduction reaction of the optically active trans-2-aminocycloalkanol derivative represented by the formula (3a) or (3b) or its salt, a combination of palladium-carbon (Pd-C) and hydrogen is preferably used. To be

The amount of the transition metal catalyst used is usually represented by the formula (3a)
Alternatively, relative to 1 mol of the optically active trans-2-aminocycloalkanol derivative represented by (3b) or a salt thereof,
The amount is 0.001 to 1 mol, preferably 0.01 to 0.5 mol, and more preferably 0.01 to 0.2 mol.

The reduction reaction is usually atmospheric pressure to 500 atm (0.1 to 50 MPa), preferably atmospheric pressure to 100 atm (0.1 to 10 MPa), and more preferably atmospheric pressure to 10.
It is performed at atmospheric pressure (0.1 to 1 MPa). Further, if necessary, the reaction may be carried out under reduced pressure from the viewpoint of equipment or operation. The reaction temperature is not particularly limited as long as it is the melting point or higher and the boiling point or lower of the system under the reaction conditions, and for example, -30 ° C
-200 degreeC, Preferably it is -10 degreeC-100 degreeC, More preferably, it is 50 degreeC-80 degreeC.

The reduction reaction can be carried out by a conventional system such as batch system, semi-batch system or continuous system.

Formula (4a) or Formula (4b) generated by the reaction
The optically active trans-2-aminocycloalkanol represented by or a salt thereof is filtered, concentrated, distilled, extracted, ion exchanged, electrodialyzed, crystallized, recrystallized, adsorbed, membrane separated, centrifuged, chromatographed ( Separation and purification can be performed by a separation and purification means such as column chromatography) or a combination thereof. In addition, free optically active trans-2
The aminocycloalkanol and its salts can be converted into each other by conventional methods.

The optically active trans-2-aminocycloalkanol or a salt thereof obtained as described above is useful as a synthetic intermediate for fine chemicals such as pharmaceuticals and agricultural chemicals.

[0041]

According to the method of the present invention, an optically active trans-2-aminocycloalkanol or a derivative thereof can be industrially produced efficiently by using a raw material which is easy to handle. Further, trans-2-aminocycloalkanol or its derivative having high optical purity can be easily produced. The method of the present invention has high versatility and is industrially advantageous.

[0042]

The present invention will be described in more detail based on the following examples, but the invention is not intended to be limited by these examples. Note that "BINOL" is 1,1'-
It is an abbreviation for bi-2-naphthol, and "Pr-i" is an abbreviation for an isopropyl group. In addition, in the following analysis, the salt was analyzed in the form of a free amine.

The NMR spectrum is shown in "BRUKER A
M500 "(device name), 500 MHz ( ¹ H-N
MR) was measured using tetramethylsilane (TMS) as an internal standard.

Cyclopentane oxide and trans-2-
The amount of (α-methylbenzylamino) cyclopentanol was determined by gas chromatography. The analysis conditions are as follows. Column: J & W scientific DB-1 30.0m × 0.25mm × 0.25μm Carrier gas; He Column temperature: 160 ℃ → 200 ℃, Init. 5min, 10 ℃ / min Split Ratio; 1: 100 Flow Rate; 1.1ml / min

(1R, 2R) -trans-2-[(S)
The formation ratio of-(α-methylbenzyl) amino] cyclopentanol and (1S, 2S) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol was determined by liquid chromatography. It was The analysis conditions are as follows. Column: Inertsil SIL 4.6 x 250 mm Mobile phase: Hexane / ethanol = 95/5, 0.1% diethylamine Column temperature: 40 ° C Flow rate: 1.0 ml / min

The chemical purity of (1R, 2R) -trans-2-aminocyclopentanol was determined by gas chromatography. The analysis conditions are as follows. Column; J & W scientific DB-1 30.0m × 0.25mm × 0.25μm Carrier gas; He column temperature; 100 ℃ Split Ratio; 1: 100 Flow Rate; 1ml / min

The optical purity of (1R, 2R) -trans-2-aminocyclopentanol was determined by gas chromatography. The analysis conditions are as follows. Column; CHIRALDEX ^TM G-PN 20m × 0.25mm Carrier gas; He Column temperature; 135 ℃ Split Ratio; 1:50 Flow Rate; 1ml / min

Example 1 Preparation of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol hydrochloride (R) -BIN was placed in a 500 ml three-necked flask under a nitrogen stream.
OL (2.553 g) and Ti (OPr-i) ₄ (2.5
35 g) was added, and the mixture was stirred at room temperature (24 ° C.) for 10 minutes. (S)-(−)-α-phenethylamine (43.22 g) and then 1,2-epoxycyclopentane (= cyclopentene oxide) (30 g) were added to this solution,
The mixture was stirred at room temperature (24 ° C) for 24 hours. Ethanol (30 ml) was added to the obtained mixed solution, 35% by weight aqueous hydrochloric acid solution (55.73 g) was added, and the mixture was stirred for 30 min, and the solvent was evaporated under reduced pressure. Toluene (70 ml) was added to the residue, and the mixture was stirred under reflux for 30 minutes. This was allowed to cool for 2 hours, and the precipitated crystals were filtered off. By drying the obtained crystals, (1R, 2R) -trans-2-[(S)
41.37 g of-(α-methylbenzyl) amino] cyclopentanol hydrochloride was obtained (yield 48%, 86% d
e). ¹ H-NMR (CDCl ₃ ) δ: 1.47-1.57 (1
H, m), 1.62-1.70 (1H, m), 1.78
-1.88 (1H, m), 1.92 (3H, d, J =
6.8 Hz), 1.95-2.12 (3H, m), 2.
79-2.88 (1H, m), 4.23 (1H, br
s. ), 4.64-4.73 (2H, m), 7.40-
7.48 (3H, m), 7.53-7.56 (2H,
m), 9.65 (1H, brs.), 10.16 (1
H, brs. )

Example 2 Preparation of (1S, 2S) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol hydrochloride (S) -BINOL (0. 17
g), Ti (OPr-i) ₄ (0.18 ml) and a hexane-toluene (9/1) mixed solvent (1 ml) were added, and the mixture was stirred at room temperature (24 ° C.) for 10 minutes. (S)-
(−)-Α-Phenethylamine (0.77 ml) and then 1,2-epoxycyclopentane (= cyclopentene oxide) (0.5 g) were added, and the mixture was stirred at a temperature of 40 ° C. for 24 hours. From the obtained mixed solution, according to the method of Example 1, (1S, 2S) -trans-2-[(S)-(α
-Methylbenzyl) amino] cyclopentanol hydrochloride was obtained.

Example 3 Preparation of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol Under a nitrogen stream, (R) -BINOL (0.17) was added to a flask.
g), Ti (OPr-i) ₄ (0.18 ml) and a hexane-toluene (9/1) mixed solvent (2 ml) were added, and the mixture was stirred at room temperature (24 ° C.) for 10 minutes. (S)-
(−)-Α-Phenethylamine (0.77 ml) and then 1,2-epoxycyclopentane (= cyclopentene oxide) (0.5 g) were added, and the mixture was stirred at a temperature of 40 ° C. for 24 hours. The obtained mixed solution was analyzed by GC (gas chromatography) to find that (1R, 2R) -trans-
2-[(S)-(α-methylbenzyl) amino] cyclopentanol was formed at 40% de.

Example 4 Preparation of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol (R) -BINOL (0.17) was added to a flask under a nitrogen stream.
g), Ti (OPr-i) ₄ (0.18 ml) and tetrahydrofuran (1 ml) were added, and the mixture was added at room temperature (24 ° C.) to 1
Stir for 0 minutes. (S)-(-)-α-phenethylamine (0.77 ml) was added to this solution, and then 1,2-epoxycyclopentane (= cyclopentene oxide) (0.
5 g) was added, and the mixture was stirred at a temperature of 24 ° C. for 24 hours. When the obtained mixed solution was analyzed by GC, (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol was found to be produced at 38% de.

Example 5 Preparation of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol Under a nitrogen stream, (R) -BINOL (0.17) was added to a flask.
g), Ti (OPr-i) ₄ (0.18 ml) and tetrahydrofuran (1 ml) were added, and the mixture was added at room temperature (24 ° C.) to 1
Stir for 0 minutes. (S)-(-)-α-phenethylamine (0.77 ml) was added to this solution, and then 1,2-epoxycyclopentane (= cyclopentene oxide) (0.
5 g) was added and the mixture was stirred at a temperature of 40 ° C. for 24 hours. When the obtained mixed solution was analyzed by GC, (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol was found to be produced at 52% de.

Example 6 Preparation of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol Under a nitrogen stream, (R) -BINOL (0.17) was added to a flask.
g), Ti (OPr-i) ₄ (0.18 ml) and tetrahydrofuran (1 ml) were added, and the mixture was added at room temperature (24 ° C.) to 1
Stir for 0 minutes. (S)-(−)-α-phenethylamine (1.16 ml) was added to this solution, and then 1,2-epoxycyclopentane (= cyclopentene oxide) (0.
5 g) was added and the mixture was stirred at a temperature of 15 ° C. for 24 hours. When the obtained mixed solution was analyzed by GC, (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol was produced at 66% de.

Example 7 Preparation of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol (R) -BINOL (0.17) was added to a flask under a nitrogen stream.
g), Ti (OPr-i) ₄ (0.18 ml) and diisopropyl ether (1 ml) were added, and room temperature (24 ° C.)
Stir for 10 minutes below. (S)-(-)-α-
Phenethylamine (0.77 ml), then 1,2-epoxycyclopentane (= cyclopentene oxide)
(0.5 g) was added, and the mixture was stirred at a temperature of 21 ° C. for 24 hours.
When the obtained mixed solution was analyzed by GC, (1R, 2
R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol was formed at 54% de.

Example 8 Preparation of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol Under a nitrogen stream, (R) -BINOL (0.17) was added to a flask.
g) and Ti (OPr-i) ₄ (0.18 ml) were added,
The mixture was stirred at room temperature (24 ° C) for 10 minutes. (S) in this solution
-(-)-Α-Phenethylamine (1.16 ml) and then 1,2-epoxycyclopentane (= cyclopentene oxide) (0.5 g) were added, and the mixture was stirred at a temperature of 24 ° C for 24 hours. When the obtained mixed solution was analyzed by GC,
64% de of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol
Was generated by.

Example 9 Preparation of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol (R) -BINOL (0.68) was added to a flask under a nitrogen stream.
g) and Ti (OPr-i) ₄ (0.72 ml) were added,
The mixture was stirred at room temperature (24 ° C) for 10 minutes. (S) in this solution
-(-)-Α-Phenethylamine (2.45 ml) and then 1,2-epoxycyclopentane (= cyclopentene oxide) (2.0 g) were added, and the mixture was stirred at a temperature of 24 ° C for 24 hours. When the obtained mixed solution was analyzed by GC,
(1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol is 60% de
Was generated by.

Example 10 Production of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol Under a nitrogen stream, (R) -BINOL (0.17) was added to a flask.
g) and Ti (OPr-i) ₄ (0.35 ml) were added,
The mixture was stirred at room temperature (24 ° C) for 10 minutes. (S) in this solution
-(-)-Α-Phenethylamine (0.77 ml) and then 1,2-epoxycyclopentane (= cyclopentene oxide) (0.5 g) were added, and the mixture was stirred at a temperature of 24 ° C for 24 hours. When the obtained mixed solution was analyzed by GC,
38% de of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol
Was generated by.

Example 11 Preparation of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol (R) -BINOL (0.34) was added to a flask under a nitrogen stream.
g) and Ti (OPr-i) ₄ (0.18 ml) were added,
The mixture was stirred at room temperature (24 ° C) for 10 minutes. (S) in this solution
-(-)-Α-Phenethylamine (0.77 ml) and then 1,2-epoxycyclopentane (= cyclopentene oxide) (0.5 g) were added, and the mixture was stirred at a temperature of 24 ° C for 24 hours. When the obtained mixed solution was analyzed by GC,
50% de of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol
Was generated by.

Example 12 Preparation of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol Under a nitrogen stream, (R) -BINOL (0.04) was added to a flask.
3 g) and Ti (OPr-i) ₄ (0.044 ml) were added, and the mixture was stirred at room temperature (24 ° C.) for 10 minutes. (S)-(-)-α-phenethylamine (0.77 m
l), then 1,2-epoxycyclopentane (= cyclopentene oxide) (0.5 g) was added, and the temperature was 24 ° C.
It was stirred for 24 hours. The obtained mixed solution was analyzed by GC and found to be (1R, 2R) -trans-2-[(S)-
(Α-Methylbenzyl) amino] cyclopentanol was produced at 64% de.

Example 13 Preparation of (R) -BINOL-Ti (OPr-i) ₂ (R) -BINOL (1.0 g) was added to dichloromethane (5
ml) and Ti (OPr-i) ₄ (0.9
9 ml) was added and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and the solvent was distilled off to quantitatively obtain reddish brown amorphous (R) -BINOL-Ti (OPr-i) ₂ . In this compound, the hydrogen atoms of the two hydroxyl groups of BINOL are removed and the oxygen atom is bonded to the titanium atom.

Example 14 Preparation of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol (R) -BINO prepared in advance in a flask under a nitrogen stream.
L-Ti (OPr-i) ₂ (0.538 g) was added, to which 1,2-epoxycyclopentane (= cyclopentene oxide) (1.0 g) was added, and then (S)-
(−)-Α-Phenethylamine (1.53 ml) was added dropwise, and the mixture was stirred at a temperature of 23 ° C. for 24 hours. When the obtained mixed solution was analyzed by GC, (1R, 2R) -trans-2
-[(S)-([alpha] -methylbenzyl) amino] cyclopentanol was produced at 44% de.

Example 15 Preparation of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol (R) -BINO prepared in advance in a flask under a nitrogen stream.
L-Ti (OPr-i) ₂ (0.269 g) was added, and (S)-(-)-α-phenethylamine (0.77) was added thereto.
ml), and then 1,2-epoxycyclopentane (= cyclopentene oxide) (0.5 g) was added dropwise,
The mixture was stirred at a temperature of 23 ° C for 24 hours. The obtained mixed solution is G
As a result of C analysis, (1R, 2R) -trans-2-
[(S)-(α-methylbenzyl) amino] cyclopentanol was produced at 64% de.

Example 16 Recrystallization of (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol hydrochloride In a 300 ml two-necked flask under a nitrogen stream, 94% de
(1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol hydrochloride (2
9.11 g), methanol (50 ml) and t-butyl methyl ether (100 ml) were added, and the mixture was stirred under reflux for 30 minutes. The reaction mixture was allowed to cool for 1 hour (up to a solution temperature of 27 ° C.), and the precipitated crystals were separated by filtration. When the crystals were dried, 15.96 g of 99.4% de (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol hydrochloride was obtained (yield). 55%).

Example 17 Preparation of (1R, 2R) -trans-2-aminocyclopentanol Hydrochloride In a 500 ml two-necked flask, the (1R, 2R) -trans-2-[(obtained in Example 16 was obtained. S)-(α-methylbenzyl) amino] cyclopentanol hydrochloride (1
5.96 g, 0.066 mol), ethanol (160
ml) and dry 5 wt% Pd-C (1.596 g), and under a hydrogen atmosphere [1 atm (0.1 MPa)] 60.
The mixture was stirred at ℃ (bath temperature) for 4 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated. Ethanol (100 ml) was added to the obtained crude crystals to dissolve them, and diethyl ether (50 ml) was added for crystallization to give 6.52 g of (1R, 2R) -trans-2-aminocyclopentanol hydrochloride.
Obtained (yield 72%, 99% ee). ¹ H-NMR (MeOD) δ: 1.57-1.64 (2
H, m), 1.73-1.86 (2H, m), 1.97.
-2.05 (1H, m), 2.12-2.19 (1H,
m), 3.24-3.32 (1H, m), 4.07 (1
H, q, J = 6.4 Hz)

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Claims (6)

[Claims] 1. The following formula (1): (Wherein, ring Z represents a cycloalkane ring having 3 to 8 carbon atoms) and a cycloalkene oxide represented by the following formula (2): (Wherein Ar represents an aryl group, R ¹ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), and reacted with an amine in the presence of a Lewis acid and an optically active ligand. Then, the following formula (3a) or (3b) (Wherein ring Z, Ar and R ¹ are the same as above) to obtain an optically active trans-2-aminocycloalkanol derivative or a salt thereof, which is then subjected to a reduction reaction,
Formula (4a) or (4b) below: A method for producing an optically active trans-2-aminocycloalkanol or a salt thereof, which comprises obtaining a compound represented by the formula (wherein ring Z is the same as above) or a salt thereof. 2. The method for producing an optically active trans-2-aminocycloalkanol or a salt thereof according to claim 1, wherein the amine represented by the formula (2) is benzylamine or α-phenethylamine. 3. The optically active trans-2 according to claim 1, wherein the Lewis acid is titanium tetraalkoxide.
-A method for producing an aminocycloalkanol or a salt thereof. 4. The optically active ligand is 1,1′-bi-2-
The method for producing an optically active trans-2-aminocycloalkanol or a salt thereof according to claim 1, which is naphthol. 5. The following formula (3a) or (3b): (In the formula, ring Z represents a cycloalkane ring having 3 to 8 carbon atoms, Ar represents an aryl group, and R ¹ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms). A trans-2-aminocycloalkanol derivative is reacted with an acid represented by the following formula (5) HX (5) (wherein, H is a hydrogen atom and HX is a protic acid), and the following formula (6a) or (6b) [Chemical 6] (Wherein ring Z, Ar, R ¹ and HX are the same as above) to form a salt of an optically active trans-2-aminocycloalkanol derivative, and then the salt is recrystallized to improve the optical purity. A method for purifying an optically active trans-2-aminocycloalkanol derivative, which comprises: 6. The following formula (3a) or (3b): (In the formula, ring Z represents a cycloalkane ring having 3 to 8 carbon atoms, Ar represents an aryl group, and R ¹ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms). A trans-2-aminocycloalkanol derivative or a salt thereof is subjected to a reduction reaction to give the following formula (4a) or (4b): A method for producing an optically active trans-2-aminocycloalkanol or a salt thereof, which comprises obtaining a compound represented by the formula (wherein ring Z is the same as above) or a salt thereof.