WO2007145203A1

WO2007145203A1 - Optically active 2-amino-1-(4-fluorophenyl)ethanol

Info

Publication number: WO2007145203A1
Application number: PCT/JP2007/061799
Authority: WO
Inventors: Takeshi Tachinami; Yoshinori Matsumoto; Takahiro Isobe
Original assignee: Daiichi Fine Chemical Co., Ltd.
Priority date: 2006-06-13
Filing date: 2007-06-12
Publication date: 2007-12-21

Abstract

It is intended to provide a method for producing a compound useful as a production intermediate of a pharmaceutical represented by the following general formula (I): (I) ((R)n represents the same or different halogen atoms in number of (n) present at a substitutable position of the benzene ring; n represents an integer of 0 to 4; R1 represents a hydrogen atom or a protecting group for an amino group; the carbon atom marked with *1 is a carbon atom with either S-configuration or R-configuration), comprising the step of subjecting a corresponding oxo compound to asymmetric hydrogenation using as an asymmetric catalyst, a rhodium complex having a pyrrolidinebisphosphine compound as a ligand.

Description

Specification

Optically active 2-amino 1_ (4_fluorophenyl) ethanol

Technical field

[0001] The present invention relates to an optically active 2-amino-1-mono (4-fluorophenyl) ethanol and a derivative thereof useful as an intermediate for producing a pharmaceutical, and a method for producing them.

Background art

[0002] Various pyrimidone derivatives are known as drugs that enable fundamental prevention and Z or treatment for neurodegenerative diseases such as Alzheimer's disease (International Publication WO03Z27 080), and the pyrimidone ring is modified with substituted morpholine. Proposed composites have been proposed. For example, Compound No. B031 described on page 40 of the above-mentioned International Publication is a compound having an optically active morpholinyl group modified with a 4 fluorophenol group. The above publication does not specifically disclose a method for producing the optically active morpholinyl group modified with the 4 fluorophenyl group. For example, according to the method described on pages 43 to 44 of International Publication WO2005Z87754, It is obvious to those skilled in the art that optically active 2-amino-1- (4-fluorophenyl) ethanol can be produced as a starting material.

Accordingly, optically active 2-amino-1-mono (4-fluorophenol) ethanol and derivatives thereof are expected to be useful as intermediates for the production of pharmaceuticals. The above compounds in which (4 fluorophenyl) ethanol and amino groups are protected, and 2-amino-1- (4 fluorophenyl) ethanol and its derivatives useful as raw materials for production thereof are not known. In addition, compounds having a halogen atom on the benzene ring of those compounds are also known.

[0004] Optically active in which the amino group is protected with a benzyl group 2 Benzylamino 1 Ethanols The production method of 3,1-benzyloxy-2- (N-benzyloxy-N-methyl) aminoacetophenone hydrochloride A method of producing a salt by catalytic reduction in the presence of a complex prepared from (2S, 4S) MCCPM and rhodium (Tetrahedron Lett., 30, 367 (1989)) is known.

[0005] In addition, as a method for producing optically active 2-amino-1-phenylethanol, lipase is used. (R) —Mande-mouth-tolyl is prepared with (R) -oxytrilase and reduced with LiAlH. (J. Chem. Soc. PerkinTrans 1, 1759— 1762 (1992))

4 method (Synthesis, (7), 575-578 (1990)), asymmetric reduction of α-chloroacetophenone in baker's yeast and further amination (Indian J. Chem. Sect. B, 31B ( 1 2), 821-823 (1992)), amino-active optically active styrene oxide (Japanese Patent Laid-Open No. 61-85197), and method of preferentially crystallizing R-form with 3-aminobenzoate (Japan Society for Chemical Research) (5), 910-913 (1985), a method for asymmetric reduction of benzoyl cyanide in the presence of alpine borane to obtain the (R) -isomer (J. Org. Chem., 50, 3237-3239). (1985)), asymmetric reduction in the presence of an alkali metal salt-substituted binaphthylphosphine sulfonate catalyst (Japanese Patent Laid-Open No. 5-170780), a belongs to the genus Morganella for the mixture of aminoketone enantiomers Method of making microorganisms work (WO 01/073100), making decarboxylase in an enantiomeric mixture of DL-threo-3-ferrine And (R) -forms are obtained (JP 2001-46076) and N- (t-butoxycarbol) D-alanine salts are used to preferentially crystallize (R) -forms (Europe) Patent Application Publication No. 294995)) is known.

Non-Patent Document 1: Tetrahedron Lett., 30, 367 (1989)

Non-Patent Document 2: J. Chem. Soc. PerkinTrans 1, 1759-1762 (1992)

Non-Patent Document 3: Synthesis, (7), 575- 578 (1990)

Non-Patent Document 4: Indian J. Chem. Sect. B, 31B (12), 821-823 (1992) Non-Patent Document 5: Journal of the Chemical Society of Japan, (5), 910-913 (1985)

Non-Patent Document 6: J. Org. Chem., 50, 3237-3239 (1985)

Patent Document 1: Japanese Patent Laid-Open No. 61-85197

Patent Document 2: JP-A-5-170780

Patent Document 3: International Publication WO 01/073100

Patent Document 4: Japanese Patent Laid-Open No. 2001-46076

Patent Document 5: European Patent Application Publication No. 294995

Disclosure of the invention

Problems to be solved by the invention [0006] An object of the present invention is to provide optically active 2-amino-1-ethanol (4-fluorophenyl) ethanol and its derivatives, which are useful as intermediates for the production of pharmaceuticals, and methods for producing them.

Means for solving the problem

[0007] Until now, a method for producing an optically active 2-amino-1 phenylethanol compound by asymmetric hydrogenation of 2-amino-1 phenolethanone in which an amino group is protected has not been known. . As a result of intensive studies to solve the above-mentioned problems, the present inventors have used 2-amino-1-fluoroethanone in which the amino group is protected as a catalyst using a rhodium complex compound having a pyrrolidine bisphosphine ligand. It was found that an optically active 2-amino-1-phenyl ethanol having an extremely high optical purity can be produced by carrying out asymmetric hydrogenation and subsequently removing the protecting group. The present invention has been completed based on the above findings.

That is, according to the present invention, the following general formula (I)

[Chemical 1]

(Wherein (R) represents n identical or different nitrogen atoms present at substitutable positions on the benzene ring, n represents an integer of 0 to 4, and R ¹ represents a hydrogen atom or an amino group. a protecting group, the carbon atom marked with * ¹ a compound or a salt thereof represented by a is) carbon atom havingヽdeviation of configuration of S or R configuration, the following General formula (II):

[Chemical 2]

(Wherein (R) _n and n are as defined above, R ¹¹ represents a protecting group for an amino group) or a salt thereof is asymmetrically hydrogenated in the presence of an asymmetric catalyst. Wherein the asymmetric catalyst is represented by the following general formula (III):

[Chemical 3]

(In the formula, R ²¹ is a hydrogen atom, —COOR, —COOR ”, or —CONHR ″ ′ (R ,: R ″, and R ″ ′ are each independently an optionally substituted carbon number. 1 to 10 linear or branched alkyl groups, an aralkyl group which may have a substituent, or an aryl group which may have a substituent), R ²² and R ²³ may independently have a substituent! / ヽ may represent an aryl group, and R ²⁴ and R ²⁵ may each independently have a substituent! / ヽ may be a cycloalkyl group. And carbon atoms marked with * ² and * ³ are both S-configuration carbon atoms or R-configuration carbon atoms) and a rhodium complex having a pyrrolidine bisphosphine compound as a ligand. How is

Is provided.

According to a preferred embodiment of the above invention, the method as described above, wherein R ^{11 is a} benzyl group, R ¹ is a hydrogen atom or a benzyl group, n is 0, and a carbon atom attached with is S configuration; an R ¹¹ Gabe Njiru group, a n is the compound represented by formula (II) is 0, R ¹ is benzyl group, n is 0, the carbon atom marked with is S configuration A compound represented by the general formula (I) is produced, and then the compound is subjected to catalytic reduction so that R ¹ is a hydrogen atom, n is 0, The above method is provided, which comprises the step of producing a compound represented by the general formula (I) in which the carbon atom marked with is S configuration.

More preferably, according to an embodiment, the pyrrolidine bisphosphine compound represented by the above general formula (III) is (2S, 4S) -N-methylaminocarbo-luo 4 dicyclohexylphosphino 2 diphene. -Ruphosphinomethylpyrrolidine, (2S, 4S) — N-phenylamino force, Lol- 4 dicyclohexylphosphino 2 Diphenylphosphinomethylpyrrolidine, (2S, 4S) —N—t-Butyloxycarbo -Lu 4-dicyclohexylphosphino 2 diphenylphosphinomethylpyrrolidine, (2S, 4S) —N—t-butylaminocarbol 4 dicyclohexylphosphino 2 diphenylphosphinomethylpyrrolidine, (2 S, 4S) — N— t-Butylcarbol 4 dicyclohexylphosphino 2 diphenylphosphinomethylpyrrolidine, (2S, 4S) —N—phenoloxyl-roux 4-dichlorophosphine No 2 Diphenylphosphinomethylpyrrolidine, (2S, 4S) — N—Benzyl 4 dicyclohexylphosphino 2 Diphenylphosphinomethylpyrrolidine, (2S, 4S) —N Acetyl-4 dicyclohexylphosphino 2 Diphenylphosphine methylpyrrolidine, and (2S, 4S) —N-methoxycarborulu 4-dicyclohexylphosphino 2-diphenylphosphinomethylpyrrolidine selected from the group consisting of bis-lysine bisphosphines In particular, according to an embodiment, the pyrrolidine bisphosphine compound represented by the general formula (III) is (2S, 4S) —N-methylaminocarbol 4 dicyclohexylphosphino. 2 Diphenylphosphinomethylpyrrolidine or (2S, 4S) —N-phenolaminocarboru 4-dicyclohexyl phosphino 2-diph - The above method is provided which is Le phosphine Ino methylpyrrolidine

[0011] Another aspect of the invention is that, according to the present invention, the above general formula (I) (wherein (R) represents n identical or different halogen atoms present at substitutable positions on the benzene ring). , N represents an integer of 0 to 4, R ¹ represents a hydrogen atom or an amino-protecting group, and a carbon atom attached with is a carbon atom having any configuration of S configuration or R configuration) Or a salt thereof is provided. According to a preferred embodiment of the invention, n is 0, R ¹ is hydrogen atom or a base Njiru group, the compound is carbon atom marked with * ¹ is S or its Of salt is provided.

From another viewpoint, the compound represented by the above general formula (II) (wherein (R) _n and n are as defined above, and R ¹¹ represents a protecting group for an amino group) or The salt is provided. According to a preferred embodiment of the present invention, there is provided the above compound or a salt thereof, wherein n is 0 and R ^{11 is a} benzyl group.

The invention's effect

[0012] The method of the present invention provides optically active 2 amino-1-mono (4-fluorophenyl) ethanol and its derivatives, which are useful as intermediates for the production of pharmaceuticals, and efficient production methods thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

In general formulas (I) and (II), the substitution position of one fluorine atom shown on the benzene ring is not particularly limited, but is preferably 4-position (para-position to the ethanone group or ethanol group). ). (R) represents n (n is 0 to 4) halogen atoms present at substitutable positions on the benzene ring. The type of the hydrogen atom or the rogen atom is not particularly limited, and may be any of a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. . When (R) forces mean more than one halogen atom, the types of halogen atoms may be the same or different. n is a force indicating an integer of 0 to 4, preferably 0 to 2, and more preferably 0 or 1, more preferably 0. When n is 0, there is only one fluorine atom on the benzene ring.

[0014] The type of protecting group for the amino group represented by R ¹ or R ¹¹ is not particularly limited, and is not eliminated during the reduction of the oxo group of the compound represented by the general formula (II). Any material can be used as long as it can be easily detached later. For the types of protecting groups of amino groups, introduction methods, and elimination methods, for example, “Protective Groups in Organic ¾yntheses” (Brother 3rd Edition, Theodora W. Green, John Wiley & Sons, Inc., 1999), "Handbook of Reagents for Organic Synthesis" (4 liters, John Wiley & Sons , Inc., 1999), etc. As a protecting group for an amino group, a substituted group can be used. Or, an unsubstituted benzyl group is particularly preferred, and an unsubstituted benzyl group is preferred. In the compound represented by the general formula (I), a carbon atom marked with * ¹ represents a carbon atom having any configuration in either the S configuration or the R configuration, and preferably the S configuration. .

In the compound represented by the general formula (III), R ²¹ represents a hydrogen atom, COR ′, one COOR ″, or —CONHR ″ ′, and R ′, R ″, and R ″ ′ are each independently A linear or branched alkyl group having 1 to 10 carbon atoms which may have a substituent, an aralkyl group which may have a substituent, or a substituent. A good aryl group is shown. Examples of the alkyl group include methyl group, ethyl group, n propyl group, isopropyl group, n-butyl group, s butyl group, t butyl group, n pentyl group, isopentyl group, s pentyl group, t pentyl group, neopentyl group. Group, hexyl group, heptyl group, octyl group, nonyl group, or decyl group. The same applies to the alkyl part of a substituent having an alkyl part (for example, an aralkyl group or an alkoxy group). Examples of the aralkyl group include benzyl group, 1-phenylethyl group, 2-phenylethyl group, and the like. The aryl group may be either a monocyclic or polycyclic aryl group, and examples thereof include a phenyl group and a naphthyl group.

[0016] When the alkyl group, the aralkyl group, or the aryl group represented by R ', R ", and R" have a substituent, the type, number, and substitution position of the substituent are not particularly limited. Examples of the substituent include a halogen atom (which may be any of a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an alkyl group, an alkoxy group, a hydroxyl group, an aryl group, or an alkoxy group. Forces that are not limited to these. R ²¹ is preferably CON HR "', and R"' is preferably a methyl group or a phenyl group.

R ²² and R ²³ each independently represents an aryl group which may have a substituent. Examples of the aryl group include a phenyl group and a naphthyl group. When the aryl group has a substituent, the type, number, and substitution position of the substituent are not particularly limited. Examples of the substituent include a halogen atom (which may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an alkyl group, an alkoxy group, a hydroxyl group, an aryl group, or an alkoxycarbonyl group. Power It is not limited to these. R ²² and R ²³ are preferably both phenyl groups. [0018] R ²⁴ and R ²⁵ each independently have a substituent and may represent a cycloalkyl group. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. When the cycloalkyl group has a substituent, the type, number, and substitution position of the substituent are not particularly limited. Examples of the substituent include a halogen atom (which may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an alkyl group, an alkoxy group, a hydroxyl group, an aryl group, or an alkoxycarbonyl group. Power It is not limited to these. R ²⁴ and R ²⁵ are preferably both cyclohexyl groups.

[0019] Examples of the pyrrolidine bisphosphine compound include (2S, 4S) -N-methylaminocarbol 4 dicyclohexylphosphino 2 diphenolphosphinomethylpyrrolidine, (2S, 4S) -N-phenolaminocarbo-ru 4 Dicyclohexylphosphino2 2 diphenylphosphinomethylpyrrolidine, (2S, 4S) —N—t Butyloxycarboxyl 4 Dicyclohexylphosphino2 2 diphenylphosphinomethylpyrrolidine, (2S , 4S) — N— t Butylaminocarbol 4 dicyclohexylphosphino 2 diphenylphosphinomethylpyrrolidine, (2S, 4S) —N—t butylcarbolulu 4-dicyclohexylphosphino 2 diphenylphosphine Inomethylpyrrolidine, (2S, 4S) —N-phenoxycarbol 4 dicyclohexylphosphino 2 diphenolphosphinomethylpyrrolidine, (2S, 4S) —N Benzoyl 4 Dicyclohexylphosphino 2—Diphenylphosphinomethylpyrrolidine, (2S, 4S) —N acetyl 4-dicyclohexylphosphino 2 Diphenylphosphinomethylpyrrolidine, or (2S, 4S) — N-methoxycarbonyl 4 dicyclohexylphosphino 2 diphenylphosphinomethyl pyridine lysine, and the like. Particularly preferred pyridolysine bisphosphine compounds include (2S, 4S) -N-methylaminocarbo-luo 4-dicyclohexylphosphino 2-diphenylphosphinomethylpyrrolidine (hereinafter referred to as “(S, S ) —MCCPM ”), (2S, 4S) —N—Phenolaminocarbolulu 4 Dicix Oral hexylphosphino 2-diphenylphosphinomethylpyrrolidine (hereinafter“ (S, S) -P CCPM Etc.)).

[0020] In the method of the present invention, a compound represented by the general formula (II) or a compound thereof used as a raw material is used. The salt of can be easily prepared, for example, by brominating the corresponding substituted acetophenone compound and then reacting the resulting prom compound with an amino compound such as benzylamine. The method for producing the compound represented by (II) is not limited to the above method. The salt of the compound represented by the general formula (II) is not particularly limited as long as it is an acid addition salt that does not inhibit the asymmetric hydrogenation reaction. For example, either an inorganic acid addition salt or an organic acid addition salt can be used. Examples of the inorganic acid addition salt include hydrochloride, bromate, sulfate, nitrate, perchlorate, or phosphate. Examples of the organic acid addition salt include acetate, trifluoroacetate. Oxalate, p-toluenesulfonate, p-toluenesulfonate monohydrate, trifluoromethanesulfonate, or camphorsulfonate. Of these, hydrochloride is particularly preferable. The salts exemplified above can be used as the salt of the compound of the general formula (I), and hydrochloride is particularly preferable.

The asymmetric catalyst used in the method of the present invention is a rhodium complex having an optically active pyrrolidine bisphosphine compound represented by the general formula (III) as a ligand. This rhodium complex can be easily prepared by reacting a pyrrolidine bisphosphine compound represented by the general formula (III) with a rhodium compound, preferably a monovalent rhodium compound. The kind of rhodium compound is not particularly limited, and examples thereof include rhodium compounds having ligands such as ethylene, 1,5-cyclotagen, and 2,5-norbornagen as ligands. More specifically, for example, (acetylylacetonato) (7? -Cycloacta-1,5-gen) rhodium complex, (acetylacetonato) dicarbo-rhodium complex, rhodium-1,5-cyclo Tatagene-chloro complex, rhodium-1,5-cyclooctadiene-tetrafluoroborate complex, rhodium norbornagen-chloro complex, rhodium-norbornagen-tetrafluoroborate complex, rhodium 1,5-cyclotatagene Forces including monotrifluoromethanesulfonic acid complex, rhodium 1,5 cyclooctagen monohexafluorophosphoric acid complex, (acetylylacetonato) bisethylene rhodium complex, or rhodium ethylene chloro complex There is nothing.

[0022] The asymmetric catalyst can be prepared by mixing a pyrrolidine bisphosphine compound and a rhodium compound in a solvent. In general, it can be prepared at the time of use in a reaction system in which an asymmetric hydrogenation reaction is carried out. Between the rhodium compound and the pyrrolidine bisphosphine compound. The ratio is not particularly limited. For example, the amount of the pyrrolidine bisphosphine compound is 0.5 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of the rhodium compound.

[0023] The amount of the asymmetric catalyst in the asymmetric hydrogenation reaction is not particularly limited, but is generally a catalytic amount, for example, 1 mol of the compound represented by the general formula (II) or a salt thereof. The asymmetric catalyst can be used at a ratio of about 1Z2,000 to 1Z100,000 moles, preferably about 1Z5,000 to 1Z50,000 moles.

The asymmetric hydrogenation reaction can be performed in a solvent. The type of the solvent is not particularly limited, and any solvent can be used as long as it is an inert solvent. A mixture of two or more solvents can also be used. For example, alcohols such as methanol, ethanol, and isopropyl alcohol, mixed solvents of organic solvents and alcohols such as toluene, tetrahydrofuran, acetone, methyl isobutyl ketone, and chloroform, or mixed solvents of water and alcohols Etc. The amount of the solvent to be used is not particularly limited, but is about 3 to 50 parts by mass, preferably about 5 to 15 parts by mass with respect to the mass of the compound represented by the general formula (II).

[0024] The hydrogen pressure in the asymmetric hydrogenation reaction is not particularly limited. For example, it may be in the range of about 0.1 to 15 MPa, 0.5 to L0 MPa, and more preferably 0.5 to 5 MPa. The temperature of the asymmetric hydrogenation reaction is not particularly limited, but is, for example, 0 to 150 ° C, preferably 20 to 80 ° C, particularly preferably about 40 to 60 ° C, and the reaction time is about 1 to 100 hours. It is.

In the above asymmetric hydrogenation reaction, it is represented by the hydrogenated general formula (I) according to the steric structure of the 2nd and 4th carbon atoms of the pyrrolidine bisphosphine compound which is a ligand of the rhodium complex. The three-dimensional structure of the carbon atom marked with * ¹ is determined. When the configuration of carbon atoms marked with * ² and * ³ is (2S, 4S) in the pyridolysine bisphosphine compound represented by the general formula (III), the general formula ( The configuration of the carbon atom marked with * ¹ in the compound represented by (I) is changed to the (S) configuration, and compared to the pyrrolidine bisphosphine compound represented by the general formula (III) * ² and * When the configuration of the carbon atom marked with ³ is (2R, 4R), the configuration of the carbon atom marked with * ¹ is (R ) Arrangement.

[0025] After completion of the asymmetric hydrogenation reaction, the compound represented by the general formula (I) is separated and purified by a usual separation and purification means such as filtration, concentration, crystallization, recrystallization or a combination thereof. It can be done.

In the general formula (I), the compound represented by R ¹ is an amino protecting group. By performing deprotection, a compound in which R ¹ is a hydrogen atom in the general formula (I) can be easily obtained. Can be prepared. For example, “Protective Groups in Organic Syntheses” (Third Edition, T heodora W. Green et al., John Wiley & Sons, Inc.) ., 1999).

[0026] For example, in the general formula (I), when the group represented by R ¹ is a benzyl group, the deprotection can generally be easily performed by performing catalytic hydrogenation. . As a catalyst used for debenzylation, a catalyst capable of hydrogenolysis of a benzyl group, such as a palladium-carbon catalyst or a palladium hydroxide catalyst, can be used. However, the catalyst is not limited to these catalysts. Absent. Palladium amount of Norajiumu catalyst 30 wt ^_0/0 approximately, preferably 5 to 2 about 0 wt%. The amount of the catalyst used is about 0.1 to 10 parts by weight, preferably about 0.5 to 5 parts by weight per 1 part by weight of the compound having a protecting group or a salt thereof.

Catalytic hydrogenation for debenzylation can be carried out in a solvent. As the solvent, any solvent can be used as long as it does not inhibit the progress of the reaction, but alcohols are particularly preferable. Examples of alcohols include methanol, ethanol, propanol, and isopropyl alcohol. The solvents may be used alone or in combination of two or more. The amount of the solvent used is not particularly limited, but is about 1 to 50 parts by weight, preferably about 3 to 10 parts by weight, per 1 part by weight of the compound having a protecting group or a salt thereof. The hydrogen pressure in catalytic hydrogenation is, for example, about 1 to 15 MPa, and preferably about 1 to: LOPa. The catalytic hydrogenation is generally carried out at a temperature not higher than the boiling point of the solvent, for example, about 15 to 50 ° C. for 1 to 150 hours.

[0027] After completion of the reaction, the product from which the protecting group for the amino group has been removed can be separated and purified by separation / purification means such as filtration, concentration, crystallization, recrystallization, or a combination of these. The The optical purity of the compound represented by the general formula (I) or a salt thereof obtained by the above production method can be easily measured by, for example, an HPLC method using a chiral column. [0028] Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

Example 1: 2 Benzylamino 1- (4 fluorophenyl) ethanone hydrochloride

4 Bromine (19 mL) was added dropwise to a solution of fluoroacetophenone (50. lg) and toluene (200 mL) at 10 ° C or lower over 1 hour. After confirming the completion of the reaction by thin layer chromatography, 50 mL of water was added to separate the layers. The organic layer was washed with water, saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed, the solvent was distilled off under reduced pressure, and the isopropyl ether power was recrystallized to obtain 63. Og (yield 80%) of 2-bromo-11- (4-fluorophenyl) ethanone as pale yellow crystals.

[0029] The obtained product 50. Og was dissolved in 75 mL of toluene, and this solution was added dropwise to a solution of 61.8 g of benzylamine and 150 mL of toluene at an internal temperature of 10 ° C or lower. The mixture was stirred at the same temperature for 1 hour. After confirming the completion of the reaction by thin layer chromatography, the precipitated benzylamine bromide salt was removed by filtration. To the filtrate, 350 mL of toluene was added and cooled on ice. Into this mixture, 150 mL of 4 mol / L ethyl acetate solution was added dropwise over 1 hour, and the precipitated crystals were collected by filtration. This crystal was recrystallized from 1 L of methanol to obtain 45.4 g of 2 benzylamino-1- (4 fluorophenol) ethanone hydrochloride as colorless scaly crystals.

Melting point: 231.0-233.7. C ヽ

— NMR (CD OD) δ: 4. 31 (2Η, s), 4. 78 (2H, s), 7. 27— 7. 35 (2H, m)

Three

7.44—7.58 (5H, m), 7.27—7.35 (2H, m).

[0030] Example 2: (S) 2 Benzylamino-1 mono (4 fluorophenol) ethanol hydrochloride

2 Benzylamino-1 mono (4 fluorophenol) ethanone hydrochloride 330g, methanol 2.6L and triethylamine 0.8mL into an autoclave, (S, S) —MCCPM 67.8mg and rhodium 1,5 dicrota A catalyst prepared from 29. lmg of the chloro complex was added (molar ratio of reaction substrate (S) to catalyst (C): SZC = 10,000), and the reaction was carried out at 55 ° C under 0.9 MPa of hydrogen pressure. . After 22 hours, the completion of the reaction was confirmed by thin layer chromatography, and then the reaction solution was concentrated under reduced pressure. As a result of analyzing the optical purity of the reaction solution by HPLC (high performance liquid chromatography), it was 93% ee. The concentrated residue was recrystallized from methanol, and the mother liquor was concentrated under reduced pressure. The concentrated residue was recrystallized from isopropyl alcohol to give white crystalline ( 246 g (74% yield) of S) -2 benzylamino 1- (4-fluorophenol) ethanol hydrochloride was obtained. As a result of analyzing the optical purity by HPLC (high performance liquid chromatography), it was 99% ee or higher.

(HPLC analysis conditions)

Column: CHIRALCEL OB— H (4.6 x 250 mm)

Column temperature: 40 ° C

Mobile phase: hexane Z ethanol Z jetylamine = 98/2/0. 01

Flow rate: 0.8mL / min

Detector: UV absorption photometer (254nm)

Retention time: (S) —Body: 32.0 minutes, (R) —Body: 37. 1 minute

Melting point: 217. 6-219.1. C,

Optical rotation [α] ² ° = + 37.7 (c = l. 00, MeOH),

D

— NMR (CD OD) δ: 3. 07 (1H, dd, J = 10. 2, 12. 6Hz) 3. 17 (1H, dd, J

Three

= 3. 3, 12. 6Hz), 4.27 (2H, s), 4.99 (1H, dd, J = 3. 3, 10. 2Hz), 7. 06—7.14 (2H, m) 7.39—7.53 (7H, m).

Example 3: (S) 2 Amino 1 mono (4 fluorophenyl) ethanol hydrochloride

(S) 2 Benzylamino-1 mono (4 fluorophenol) ethanol hydrochloride 3.00 g, methanol 15.0 mL, 5% -palladium-carbon catalyst 7.50 g were added to the reaction vessel and stirred at around 20 ° C. After 24 hours, after the completion of the reaction was confirmed by thin layer chromatography, removed by filtration palladium carbon catalyst, the filtrate was concentrated under reduced pressure (2. 05g) _o Acetone concentrated residue 6. Ka卩E a 15 mL, suspension Purification by turbidity gave 1.95 g (yield 95%) of (S) -2-amino-1-phenolethanol hydrochloride as white crystals. As a result of analyzing the optical purity by HPLC, it was 99% ee or higher.

(HPLC analysis conditions)

Column: CROWNPAK CR (+) (4. O X 150mm)

Column temperature: 10 ° C

Mobile phase: Perchloric acid aqueous solution (pH 2.0) Detector: UV absorptiometer (200nm)

Retention time: (R) —body: 19.1 minutes, (S) —body: 20. 8 minutes

Melting point: 194.5-196.3. C,

Optical rotation [α] ²⁴ · ⁴ = +44.6 (c = l. 00, water),

D

NMR (D O) δ: 3.09 (1Η, dd, J = 8. 7, 13. 2Hz), 3.18 (1H, dd, J = 4.

2

2, 13. 2Hz), 4.88 (1H, dd, J = 4, 2, 8. 7Hz), 7. 01— 7. 09 (2H, m), 7. 28-7. 35 (2H, m ).

[0032] Example 4: (S) — 2 Benzylamino 1- (4 fluorophenol) ethanol

(S) -2 benzylamino 1- (4 fluorophenol) ethanol hydrochloride obtained in Example 2 27.3 g (96.9 mmol) and 545 mL of water were added to the reaction vessel, and lM—NaO HlOOmL at around 20 ° C. Was slowly added dropwise. After stirring at around 20 ° C for 1 hour, filtration and crystals were washed with 1090 mL of water. The obtained crystals were recrystallized from 129 mL of isopropyl alcohol to obtain 20.4 g (yield 86%) of white crystals of) 2-benzylamino-11- (4-fluorophenol) ethanol. The result of measurement under the analysis conditions shown in Example 2 was 99% e.e. or higher. Melting point: 133.5-134.6. C,

Optical rotation [α] ² ° = + 35. l (c = l. 00, MeOH) ゝ

D

— NMR (CDCl) δ: 2.70 (1H, dd, J = 9.0, 12.3Hz), 2.91 (1H, dd, J =

Three

3. 6, 12. 3Hz), 3.80 (1H, d, J = 13.2Hz), 3.86 (1H, d, J = 13.2Hz), 4.69 (1H, dd, J = 3 6, 9. 0Hz), 6. 97— 7. 05 (2H, m), 7. 23— 7. 37 (7H, m)

[0033] Example 5: (S) 2 amino-1 mono (4 fluorophenol) ethanol

(S) -2 Benzylamino 1- (4 fluorophenol) ethanol 2.00 g, methanol 12.0 mL, 5% -palladium-carbon catalyst 5.00 g was added to the reaction vessel and stirred at around 20 ° C. . After 7 hours, after the completion of the reaction was confirmed by thin layer chromatography, Parajiu arm - removing the carbon catalyst by filtration, the filtrate was concentrated under reduced pressure (1. 06g) § _{o The} concentrated residue seton 2. 12 mL Ka卩E Then, suspension purification was carried out to obtain 0.70 g (yield 55%) of (S) -2-amino-1-phenol ethanol as white crystals. As a result of measuring the optical purity under the analysis conditions shown in Example 3, it was 99% ee or higher. Melting point: 172-178 ° C (decomposition point)

Optical rotation [α] ² ° = + 43.4 ° (c = 0. 1, MeOH)

D

NMR (CDCl) δ: 2.76 (1H, dd, J = 7. 8, 12. 6Hz), 2.99 (1H, dd, J = 3

Three

9, 12. 6Hz), 4. 60 (1H, dd, J = 3. 9, 7. 8Hz), 6. 99— 7. 07 (2H, m), 7. 26-7. 35 (2H, m) _Q

[0034] Example 6: (S) 2 Benzylamino-1 mono (2 fluorophenol) ethanol hydrochloride

2 Benzylamino mono 1- (2 fluorophenol) ethanone hydrochloride 5. 59 g, methanol 44.8 mL and triethylamine 14 L in an autoclave, (S, S) —MCCPM 4.3 mg and rhodium 1,5 diclooctadiene chloride Complex 1. The catalyst prepared from 6 mg was caloeed (SZC = 3,000), and the reaction was performed at around 50 ° C under hydrogen pressure 0.85 MPa. After 16 hours, the completion of the reaction was confirmed by thin layer chromatography. The reaction solution was concentrated under reduced pressure. The concentrated residue was recrystallized from methanol, and the mother liquor was concentrated under reduced pressure. The concentrated residue was recrystallized from isopropyl alcohol to obtain 3.20 g (yield 57%) of colorless crystals of (S) -2-benzylamino-11 mono (2-fluorophenyl) ethanol hydrochloride. As a result of measuring the optical purity under the analysis conditions shown in Example 2, it was 99% ee or higher.

Retention time: (S) —body: 44.0 minutes, (R) —body: 20.0 minutes

Melting point 150. 6-153.0. C,

Optical rotation [α] ²⁰ = + 26.8 (c = l. 00, MeOH),

D

'H-NMR S (CD OD): 3.11 (1H, dd, J = 10. 2, 12. 9Hz), 3.23 (1H, dd, J

Three

= 3. 3, 12. 9Hz), 4.29 (2H, s), 5.31 (1H, dd, J = 3. 3, 10. 2Hz), 7.05—7.12 (1H, m) 7.20—7.26 (1H, m), 7.31—7.39 (1H, m), 7.43—7.62 (6H, m).

[0035] Example 7: (S) 2 Benzylamino-1 mono (3 fluorophenol) ethanol hydrochloride

Performed in the same manner as in Example 2 (SZC = 10,000) except that 2 benzylamino-1 mono (3 fluorophenyl) ethanone hydrochloride 2.80 g was used as a raw material. 1.25 g (44% yield) of benzylamino-11 mono (3 fluorophenol) ethanol hydrochloride was obtained. The optical purity was measured under the analysis conditions shown in Example 2 and was 99% ee or higher. Retention time: (S)-body: 32.0 minutes, (R)-body: 29. 9 minutes

Melting point 212.5-21-28.3. C,

Optical rotation [α] ² ° = + 17.7 (c = l.00, MeOH),

D

'H-NMRS (CD OD): 3.07 (1H, dd, J = 10.2, 12.6Hz), 3.22 (1H, dd, J

Three

= 3.0, 12.6Hz), 4.28 (2H, s), 5.03 (1H, dd, J = 3.0, 10.2Hz), 7.00—

7.07 (1H, m), 7.17—7.22 (2H, m), 7.35—7.54 (6H, m).

[0036] Example 8: PCCPM

Other than using (S, S) -PCCPM as the pyrrolidine bisphosphine ligand (SZC = 10

, 000) was carried out in the same manner as in Example 2 to obtain 5.79 g (yield 69%) of colorless crystals of (S) -2-benzylamino-11 mono (4 fluorophenol) ethanol hydrochloride. As a result of measuring the optical purity under the analytical conditions shown in Example 2, it was 99% ee or higher.

[0037] Example 9: (S) 2 Benzylamino-1 mono (4 fluorophenol) ethanol succinate

The reaction was carried out in the same manner as in Example 2 except that 2 benzylamino 1- (4 fluorophenyl) ethanone shinonate was used as a raw material, and colorless crystals of (S) -2-benzylamino-1 (

4. 79 g (yield 69%) of 4 fluorophenyl) ethanol oxalate was obtained. As a result of measuring the optical purity under the analytical conditions shown in Example 2, it was 99% ee or higher.

Melting point 205.7-206.3. C,

Optical rotation [α] ²⁰ = + 30.3 (c = 0. 10, MeOH)

D

[0038] Example 10: (S) 2-Benzylamino-1 mono (2,4 difluorophenol) ethanol hydrochloride 5.95 g of 2-Benzylamino-1 mono (2,4 difluorophenol) ethanone hydrochloride as raw material Except for the above, the reaction was carried out in the same manner as in Example 2 (SZC = 5,000), and colorless crystals of (S) -2-benzylamino-1 mono (2,4 difluorophenyl) ethanol hydrochloride 4.16 g (yield) 69%). As a result of measuring the optical purity under the analytical conditions shown in Example 2, it was 99% ee or higher.

Retention time: (S) -body: 21.4 minutes, (R) -body: 13.8 minutes

Melting point 193.5-59.5. C ヽ

Optical rotation [a] ²⁰ = + 33.6 (c = l.00, MeOH),

D

'H-NMRS (CD OD): 3.07-3.24 (2H, m), 4.29 (2H, s), 5.26 (1H, dd , J = 3.0, 10.2Hz), 6.92-7.06 (2H, m), 7.43—7.54 (5H, m), 7.57—7.65 (1H, m).

[0039] Example 11: (S) 2-Benzylamino-1 mono (3,4 difluorophenol) ethanol hydrochloride As raw material 2-Benzylamino 1-1 mono (3,4 difluorophenol) ethanone hydrochloride 5.95g Except that it was used, the reaction was carried out in the same manner as in Example 2 (SZC = 5,000), and colorless crystals of (S) -2-benzylamino-1 (3,4 difluorophenol) ethanol hydrochloride 4.51 g (yield) 76%).

Melting point 213.4-217.0. C,

Optical rotation [α] ²⁰ = + 32.0 (c = l.00, MeOH),

D

'H-NMRS (CD OD): 2.99-3.22 (2H, m), 4.23 (2H, s), 4.93 (1H, dd

Three

, J = 3.0, 10.2Hz), 7.14-7.35 (3H, m), 7.40—7.49 (5H, m).

[0040] Example 12: 2 Benzylamino-1 mono (3 bromo-4 fluorophenyl) ethanone hydrochloride The reaction was carried out in the same manner as in Example 1 except that 15.2 g of 3 bromo-4 fluoroacetophenone was used as the raw material. As a result, 9-olg (yield 36%) was obtained in the form of gray-white crystals of 2-benzylamino-11- (3-bromo-4-1-fluoro) ethanone hydrochloride.

Melting point 219.0-219.2. C,

'H-NMRS (CD OD): 4.28 (2H, s), 4.78 (2H, s), 7.41—7.57 (6H, m)

Three

, 8.04-8.09 (1H, m), 8.30-8.33 (1H, m).

[0041] Example 13: (S) —2 Benzylamino-1— (3 bromo-4-fluorophenol) ethanolic hydrochloride

2 Benzylamino 1- (3-bromo-4-fluorophenyl) ethanone hydrochloride 7.17 g of the reaction was carried out in the same way as in Example 2 (SZC = 5,000), colorless crystals) Thus, 3.47 g (yield 48%) of benzylamino 1- (3-bromo-4-fluorophenyl) ethanol hydrochloride was obtained.

Melting point 198.5-201.5. C ヽ

Optical rotation [α] ² ° = + 27.8 (c = 0.10, MeOH),

D

'H-NMRS (CD OD): 3.03-3.23 (2H, m), 4.27 (2H, s), 4.99 (1H, dd

Three

, J = 3.0, 10.2Hz), 7.22 (1H, t, J = 8.7Hz), 7.38—7.57 (6H, m), 7.68 -7. 71 (1H, m).

Industrial applicability

According to the method of the present invention, optically active 2 amino-1-mono (4-fluorophenyl) ethanol and its derivatives, which are useful as intermediates for producing pharmaceuticals, and their efficient production methods are provided.

Claims

Claims The following general formula (I)

[Chemical 1]

(In the formula, (R) _n represents n identical or different halogen atoms present at substitutable positions on the benzene ring, n represents an integer of 0 to 4, and R ¹ represents a hydrogen atom or an amino group. Wherein the carbon atom marked with * ¹ is a carbon atom having any configuration of S configuration or R configuration) or a salt thereof, General formula (II):

[Chemical 2]

(Wherein (R) and n are as defined above and R ¹¹ represents a protecting group for an amino group) or a salt thereof is subjected to asymmetric hydrogenation in the presence of an asymmetric catalyst. The asymmetric catalyst is represented by the following general formula (III):

[Chemical 3]

(In the formula, R ²¹ represents a hydrogen atom, COR, —COOR ", or —CONHR"'(R ,,: R ", and R"' each independently has a carbon number 1 which may have a substituent. Represents a linear or branched alkyl group of ˜10, an aralkyl group which may have a substituent, or an aryl group which may have a substituent, and R ²² and R ²³ may independently have a substituent! / ヽ may represent an aryl group, and R ²⁴ and R ²⁵ may each independently have a substituent! / ヽ may represent a cycloalkyl group. , * ² and * ³ are both S-configuration carbon atoms or R-configuration carbon atoms), and a rhodium complex having a pyrrolidine bisphosphine compound as a ligand. There is a way.

[2] The method according to claim 1, wherein R ^{11 is a} benzyl group, R ¹ is a hydrogen atom or a benzyl group, n is 0, and the carbon atom marked with * ¹ is in S configuration.

[3] From the compound represented by the general formula (II) where R ^{11 is a} benzyl group, R ^{1 is a} benzyl group, and n force ^, R ^{1 is a} benzyl group, n Is 0, and the carbon atom with the S configuration is the S configuration, the compound represented by the general formula (I) is produced, and the compound is subsequently catalytically reduced, R ¹ is a hydrogen atom, and n is 2. The method according to claim 1, comprising a step of producing a compound represented by the general formula (I) wherein 0 is a carbon atom with a S configuration.

[4] The method according to claim 2 or 3, wherein one fluorine atom on the benzene ring is bonded to the 4-position.

[5] The pyrrolidine bisphosphine compound represented by the general formula (III) is (2S, 4S) N-methylaminocarbol 4 dicyclohexylphosphino 2 diphenylphosphinomethylpyrrolidine or (2S, 4S) -N phenol. The process according to claim 1, which is -luaminocarbolu 4 dicyclohexylphosphino 2 diphenylphosphinomethylpyrrolidine.

[6] The general formula (I) according to claim 1, wherein (R) represents n identical or different halogen atoms present at substitutable positions on the benzene ring, and n is from 0 to 4 Represents an integer, R ¹ represents a hydrogen atom or an amino-protecting group, and a carbon atom with * ¹ is a carbon atom having either configuration of S configuration or R configuration) Compound or salt thereof.

[7] n is 0, one fluorine atom on the benzene ring is bonded to the 4-position, R ¹ is a hydrogen atom or a benzyl group, and a carbon atom with * ¹ is in S configuration The compound or a salt thereof according to claim 6.

[8] A compound represented by the general formula (II) according to claim 1 (wherein (R) _n and n are as defined above, and R ¹¹ represents a protecting group for an amino group) or a salt thereof .

[9] The compound or a salt thereof according to claim 8, wherein n is 0, one fluorine atom on the benzene ring is bonded to the 4-position, and R ^{11 is a} benzyl group.