JP2004352726A - Method for producing optically active 2-amino-1-phenylethanol derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To simply provide an (R)-2-amino-1-phenylethanol derivative of a high optical purity at a high yield, useful as a synthetic intermediate for antiobestic drugs and the like. <P>SOLUTION: The (R)-2-amino-1-phenylethanol derivative represented by general formula (IIa) (wherein R<SP>1</SP>and R<SP>5</SP>are H or the like; and R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>are a halogen atom or the like), or a salt thereof, can readily be produced by permitting a microorganism belonging to the genus Rhodosporidium, the genus Comamonas or the like to act on a mixture of corresponding (R)-form and (S)-form to asymmetrically utilize, or by permitting a microorganism belonging to the genus Lodderomyces, the genus Pilimelia or the like to act on a corresponding aminoketone derivative to asymmetrically reduce it. An (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative having a high optical purity can easily be obtained from the compound of general formula (IIa) or a salt thereof. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to 2-amino useful as a synthetic intermediate of (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative useful as a medicine or an intermediate thereof. The present invention relates to a method for producing a -1-phenylethanol derivative and an optically active substance thereof, and a method for producing the (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative.

The 1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative has a very low side effect because it selectively acts on the β ₃ receptor in the living body, and is a new type that does not rely on insulin. It is attracting attention as an antiobesity drug and an antidiabetic drug. From the pharmacological study of the 1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative, the above-mentioned β ₃ action was substantially reduced to the (R, R) -enantiomer. [Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 35, pp. 3081 (1992) (Non-Patent Document 1), and US Pat. No. 5,061,727 (Patent Document 1) and the like]. For example, the above-mentioned U.S. Patent discloses that (R, R) -5- [2-[[2- (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1,3-benzodioxole- It has been described that 2,2-dicarboxylic acid disodium salt exhibits an activity 47 times higher than the corresponding (S, S) -enantiomer.

  Conventionally, as a method for producing an optically active (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative, a method by optical resolution of a racemate and a method by asymmetric synthesis are known. Are known.

  For example, JP-A-5-320153 (Patent Document 2), US Pat. No. 5,068,867 (Patent Document 3), and JP-A-58-18340 corresponding to the above-mentioned US Pat. No. 5,061,727 (Patent Document 1). In the gazette (patent document 4), 1-phenyl-2-[(2-phenyl-1-alkyl) is prepared by reacting a racemic phenylethanol derivative, a phenylacetone derivative, and a reducing agent such as sodium cyanoborohydride. A mixture of four kinds of optical isomers of an ethyl) amino] ethanol derivative is obtained, and the (R, R) form and the (S, R) form are separated and removed, and then the (R, R) form is obtained by a diastereomer method. The (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative is obtained by optically resolving the isomer and the (S, S) isomer. How to granulation is disclosed. However, in the above method, it is necessary to separate and purify only one (R, R) isomer, which is one kind of optical isomer, from a complete mixture of four kinds of optical isomers, which complicates the process and lowers the yield. I do. In addition, a large amount of raw material is required, which is economically disadvantageous.

  The U.S. patent specification and the Journal of Medicinal Chemistry disclose a method of reacting an (R) -3-chlorostyrene oxide derivative with an (R) -1-methyl-2-phenylethylamine derivative. However, since the (R) -1-methyl-2-phenylethylamine derivative used as a reaction raw material in this method shows a strong wakefulness effect, special care must be taken in handling, and it is suitable for use on an industrial scale. Not. Further, many steps are required to obtain the (R) -1-methyl-2-phenylethylamine derivative. For example, the (R) -1-methyl-2-phenylethylamine derivative is obtained by introducing a protecting group from L-DOPA (L-DOPA) to an amino group, esterifying, reducing an ester, mesyloxylating a hydroxyl group, It is produced through 6 steps of deprotection and reduction.

  On the other hand, in the present invention, as a method for producing an optically active 2-amino-1-phenylethanol derivative used as a reaction raw material for the 1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative, A method for optically resolving the corresponding racemate using an optical resolving agent is known. For example, Japanese Patent Application Laid-Open No. 64-9979 (Patent Document 5) (Japanese Patent Publication No. 4-48791 (Patent Document 6)) discloses that a racemate of 2-amino-1- (3-chlorophenyl) ethanol is N- ( A method for obtaining an optically active (R) form by optical resolution using (t-butoxycarbonyl) -D-alanine is disclosed.

  Further, Japanese Patent Application Laid-Open No. 2-85247 (Patent Document 7) discloses a method of optically resolving a racemic 2-amino-1- (4-chlorophenyl) ethanol using D-tartaric acid. Further, in the journal of the Chemical Society of Japan, 1985, (5), pp. 910 to 913 (Non-Patent Document 2), a racemate of 2-amino-1-phenylethanol and an optical resolving agent of 3-aminobenzoic acid are described. A method for optical division is disclosed.

  However, it is difficult to obtain a racemic form of the 2-amino-1-phenylethanol derivative to be subjected to optical resolution with a simple operation in a high yield. Therefore, in the above method, the objective optically active 2-amino-1-phenylethanol is used. Derivatives cannot be easily and efficiently produced.

  For example, as a method for producing the 2-amino-1-phenylethanol derivative, a method by reduction of a nitrogen-containing compound and a method utilizing an addition reaction of ammonia are known.

As a method by reduction of the nitrogen-containing compound, (a) a method of reducing mandelonitrile [J. Org. Chem., 45 (14), 2785 (1980) (Non-Patent Document 3), Japanese Patent Application Laid-Open No. Sho. Patent Document 8 (Patent Document 8) and the like], (b) a method for reducing mandelic amide [see J. Appl. Chem., 1 (1951) 469 (Non-patent Document 4)], and (c) reducing a nitro compound [Coll. Czech. Chem. Comm., 43 (7), 1917 (1978) (Non-Patent Document 5)] is known.

However, in the above method (a), since mandelonitrile is unstable, it is necessary to protect the hydroxyl group in order to obtain the desired product in high yield. Further, since the reaction is carried out in the presence of a large amount of a reducing agent such as LiAlH ₄ or NaBH _{4 in} the presence of an activating catalyst, it is not economical and requires careful handling. Furthermore, the purity of the obtained 2-amino-1-phenylethanol derivative is as low as about 95%. Also, the methods (b) and (c) have the same problems as those described above because a large amount of LiAlH ₄ or the like is used as a reducing agent. Further, in the method (c), since nitromethane is used as a solvent, there is a high risk, and sufficient care is required for handling.

As a method utilizing the addition reaction of ammonia, (d) a method of reacting an epoxy compound with ammonia [see Syn. Com., 3 (3), 177, (1973) (Non-Patent Document 6)], and (e) ) A method of reacting ammonia with a halohydrin compound [see Indian. J. Chem., SECT. B, 31B , 821 (1992) (Non-Patent Document 7)] is known. However, in these methods, although the reaction operation is simple, a 1-amino-2-phenylethanol derivative which is a positional isomer of the 2-amino-1-phenylethanol derivative is easily produced as a by-product. This regioisomer is difficult to remove by ordinary separation and purification methods such as distillation, recrystallization, and extraction. In order to obtain a highly pure 2-amino-1-phenylethanol derivative, complicated operations such as column purification are required. I need.

On the other hand, a method for obtaining optically active 2-amino-1-phenylethanol using a microorganism is known. That is, Chemistry Express, Vol. 4, No. 9, pp. 621-624, (1989) (Non-Patent Document 8) includes Staphylococcus, Micrococcus, and Rhodococcus. It is disclosed that microorganisms belonging to the genera Genus and Neisseria generate optically active 2-amino-1-phenylethanol from 2-amino-1-phenylethanol and α-aminoacetophenone, respectively.
U.S. Pat. No. 5,061,727 JP-A-5-320153 U.S. Pat. No. 5,068,867 JP-A-58-18340 JP-A-64-9979 Japanese Patent Publication No. 4-48791 JP-A-2-85247 JP-A-46-27 Journal of Medicinal Chemistry (J. Med. Chem.), 35, 3081 (1992) The Chemical Society of Japan, 1985, (5), pp. 910-913 J. Org. Chem., 45 (14), 2785 (1980) J. Appl. Chem., 1 (1951) 469 Coll. Czech. Chem. Comm., 43 (7), 1917 (1978) Syn.Com., 3 (3), 177, (1973) Indian. J. Chem., SECT. B, 31B, 821 (1992) Chemistry Express, Vol. 4, No. 9, pp. 621-624, (1989)

  Therefore, an object of the present invention is useful for efficiently producing a (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative selectively at a high yield. It is an object of the present invention to provide a method capable of efficiently producing an optically active compound (R) -2-amino-1-phenylethanol derivative with high optical purity.

  Another object of the present invention is to provide a method for producing an optically active compound which is useful in producing the (R, R) form, and which can be easily obtained and handled with high optical purity. is there.

  Another object of the present invention is to provide a method capable of obtaining a 2-amino-1-phenylethanol derivative useful for efficiently obtaining the optically active compound by a simple operation in a high yield and at a high purity. Is to do.

  Still another object of the present invention is to efficiently produce (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative with high optical purity in high yield. It is to provide a method that can be performed.

  Another object of the present invention is to provide a method for efficiently producing the (S) form useful for efficiently producing the optically active compound.

  That is, the present invention provides a compound represented by the general formula (I):

(Wherein, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same or different and are each protected with a hydrogen atom, a halogen atom, a lower alkyl group which may have a substituent, or a protecting group. An optionally substituted hydroxyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, An aryloxy group which may be substituted, a lower alkylthio group which may have a substituent, an acyl group which may have a substituent, a carboxyl group which may be protected by a protecting group, which has a substituent Represents an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group)
Acts on an enantiomeric mixture of a 2-amino-1-phenylethanol compound or a salt thereof represented by the formula (IIa)

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as described above)
(R) represented by the general formula (IIa) produced by reacting a microorganism having a capability of producing a (R) -2-amino-1-phenylethanol compound or a salt thereof represented by the formula (Ia): Provided is a method for producing a (R) -2-amino-1-phenylethanol derivative, which is obtained by collecting a body or a salt thereof.

  In the 2-amino-1-phenylethanol derivative represented by the general formula (I), the hydroxyl group may be protected by a protecting group. Such a derivative, that is, the general formula (VI)

(Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as above; Z represents a hydrogen atom or a protecting group for a hydroxyl group). , The general formula (III)

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as described above)
Or a compound represented by the formula (IV):

(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z are the same as above, and X represents a halogen atom)
And a compound represented by the general formula (V)
Y-NH ₂ (V)
(Wherein, Y represents a hydrogen atom or a group which can be eliminated in the reaction)
And, when Y is a group which can be eliminated in the reaction, Y is eliminated, and an acid is added to the obtained reaction product to obtain a compound represented by the general formula (VI): Can be obtained by precipitating and separating and purifying the compound represented by the formula (1) as a salt.

  Further, the (R) -2-amino-1-phenylethanol derivative represented by the general formula (IIa) or a salt thereof may be, for example, a compound represented by the general formula (VII):

(Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as described above)
Is reacted with a microorganism having a capability of producing the corresponding optically active compound represented by the general formula (IIa) or a salt thereof or a processed product thereof by acting on the compound or a salt thereof. And the resulting optically active compound represented by the general formula (IIa) or a salt thereof is collected.

  The optically active compound represented by the general formula (IIa) and a salt thereof are used as a synthetic intermediate of a (R, R) -1-phenyl-2-[(2-phenyl-1-methylethyl) amino] ethanol derivative. Useful.

  The present invention also provides a compound of the general formula (II)

(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z are the same as described above)
Or a salt thereof, and a compound represented by the general formula (VIII)

(Wherein R ⁷ and R ⁸ are the same or different and are (A) hydrogen atoms, lower alkyl groups which may have a substituent, cycloalkyl groups which may have a substituent, An aralkyl group which may have a substituent, an aryl group which may have a substituent, an acyl group which may have a substituent, a carboxyl group which may be protected by a protecting group, and a group having a substituent. An optionally substituted lower alkoxycarbonyl group, an optionally substituted amino group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group or a protecting group Or (B) R ⁷ is a group represented by the formula (IX): —O—R ^7a , and R ⁸ is a group represented by the formula (X): —O—R a group represented by ^8a, R ^7a and R ^8a together, the adjacent oxygen atom Together may form a ring which may have a ^{substituent, R 6, R 9, R} 10 are the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower Alkyl group, cycloalkyl group which may have a substituent, aralkyl group which may have a substituent, aryl group which may have a substituent, hydroxyl which may be protected by a protecting group Group, an alkoxy group optionally having a substituent, a cycloalkyloxy group optionally having a substituent, an aralkyloxy group optionally having a substituent, optionally having a substituent Aryloxy group, lower alkylthio group optionally having substituent (s), aralkylthio group optionally having substituent (s), acyl group optionally having substituent (s), even if protected with a protecting group Has good carboxyl group and substituent Which may be lower alkoxycarbonyl group, R ¹¹ a nitro group or an optionally substituted amino group, a lower alkyl group)
Including a reaction with a compound represented by the formula: and a reaction of reducing a reaction product of the reaction.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and Z are the same as described above)
And a method for producing (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol or a salt thereof represented by the formula:

  The (S) form corresponding to the (R) form represented by the general formula (IIa) or a salt thereof is, for example, a 2-amino-1-phenylethanol derivative represented by the general formula (I) or a salt thereof. The enantiomeric mixture of the salt acts on the enantiomeric mixture to form the corresponding general formula (XV)

(Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as those described above), or a microorganism having a capability of producing a salt thereof or a salt thereof, or a treated product thereof. Can be obtained by collecting the produced (S) form or a salt thereof.

  The optically active compound represented by the general formula (XV) or a salt thereof also acts on the compound represented by the general formula (VII) or a salt thereof by acting on the compound or a salt thereof to form a compound represented by the corresponding general formula ( XV) can be obtained by reacting a microorganism having a capability of producing an optically active compound represented by XV) or a salt thereof or a processed product thereof, and collecting the produced optically active compound of the general formula (XV) or a salt thereof. it can.

  According to the method for producing the (R) -2-amino-1-phenylethanol derivative and the (S) -2-amino-1-phenylethanol derivative of the present invention, an optically active target compound can be obtained simply and at high cost. It can be obtained with good optical purity and yield.

  According to the method for producing a 2-amino-1-phenylethanol derivative of the present invention, a 2-amino useful for efficiently obtaining an optically active (R) or (S) -2-amino-1-phenylethanol derivative. A -1-phenylethanol derivative can be obtained with a high yield by a simple operation and at a high purity.

  Further, according to the method for producing the (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative of the present invention, (R, R) -1 having high optical purity is obtained. -Phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative can be produced in a high yield by a simple method.

  Hereinafter, the present invention will be described in more detail.

The halogen atom in R ¹ , R ² , R ³ , R ⁴ and R ⁵ in the general formulas (II) and (IIa) includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The lower alkyl group which may have a substituent includes, for example, (a) a C _1-4 alkyl group which may have a substituent (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl group, t-butyl group, etc.). Examples of the substituent which the C _1-4 alkyl group may have include a hydroxyl group, a C _1-4 alkoxy group, a benzoyl group, and a substituent (for example, a C _1-4 alkoxy group). _Preferred examples include a C _6-12 aryl group (eg, a phenyl group), a C _1-4 alkylthio group, a halogen atom and the like. Examples of the alkyl group having such a substituent include (b) an alkyl group having 1 to 4 carbon atoms substituted with a hydroxyl group (for example, hydroxymethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, , 2-dihydroxyethyl, 3,3-dihydroxypropyl group, etc.), (c) C _1-4 alkoxy-C _1-4 alkyl group (for example, methoxymethyl, ethoxymethyl, t-butoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl, etc.), (d) phenacyl, (e) C _1-4 alkylthio-C _1-4 alkyl (for example, C _1-4 such as methylthiomethyl, ethylthiomethyl, etc.) alkylthiomethyl group, etc.), (f) 1 or 2 or more C _1-4 haloalkyl group having halogen atom (e.g., chloromethyl, 2-chloroethyl, 3 Chloropropyl, 4-chlorobutyl, dichloromethyl, trichloromethyl, trifluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl group Etc.) are included.

  Examples of the hydroxyl-protecting group include hydroxyl-protecting groups commonly used in the field of organic synthesis, such as (A) a group forming an ether bond with an oxygen atom, (B) a group forming an ester bond with an oxygen atom, (C) a group that forms a carbonate with an oxygen atom, and (D) a group that forms a sulfonic acid ester with an oxygen atom.

  The group (A) which forms an ether bond together with an oxygen atom includes (1) a lower alkyl group which may have a substituent, (2) an allyl group which may have a substituent, and (3) a substituted allyl group. A cycloalkyl group which may have a group, (4) a heterocyclic group which may have a substituent, (5) an aralkyl group which may have a substituent, and (6) which has a substituent. And an optionally substituted silyl group.

The lower alkyl group (1) which may have a substituent includes (a) a C _1-4 alkyl group which may have a substituent (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) , S-butyl, t-butyl, etc.). As a substituent of the C _1-4 alkyl group, for example, a C _1-4 alkoxy group, a C _1-4 alkoxy-C _1-4 alkoxy group, a C _7-20 aralkyloxy group, a benzoyl group, a C _1-4 alkylthio group And a halogen atom. Examples of the alkyl group having such a substituent include (b) a C _1-4 alkoxy-C _1-4 alkyl group (for example, methoxymethyl, ethoxymethyl, t-butoxymethyl, 1-methoxyethyl, 1-ethoxyethyl A C _1-4 alkoxy-C _1-2 alkyl group such as 2-methoxyethyl), (c) a C _1-4 alkoxy-C _1-4 alkoxy-C _1-4 alkyl group (for example, 2-methoxyethoxy) A C _1-4 alkoxy-C _1-4 alkoxy-C _1-2 alkyl group such as methyl, 2-ethoxymethoxymethyl, etc.), (d) a C _7-20 aralkyloxy-C _1-4 alkyl group (for example, benzyl such as C _7-20 aralkyloxy-methyl groups such as oxymethyl), (e) a phenacyl group, (f) C _1-4 alkylthio -C _1-4 alkyl group (eg, C, such as methylthiomethyl, ethylthiomethyl _{1- 4} alkylthio Etc. butyl group), (g) 1 or 2 or more C _1-4 haloalkyl group having halogen atom (e.g., trichloromethyl, trifluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl Ethyl etc.).

  Examples of the substituent of the allyl group (2) include the substituents exemplified for the lower alkyl group (1).

The optionally substituted cycloalkyl group (3) includes C _3-10 cycloalkyl groups such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. Examples of the substituent of the cycloalkyl group include a halogen atom, a C _1-4 alkyl group, and a hydroxyl group.

The optionally substituted heterocyclic group (4) includes a 5- or 6-membered optionally substituted heterocyclic ring having an oxygen atom or a sulfur atom as a hetero atom in addition to a carbon atom. And the like. The heterocyclic group which may have a substituent is often a non-aromatic heterocyclic group. The 5- to 6-membered heterocyclic group includes, for example, a tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl group and the like. Examples of the substituent of the heterocyclic group include a halogen atom, a C _1-4 alkyl group and a C _1-4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t- Butoxy) and the lower alkyl group (1) include the substituents exemplified above.

  Examples of the heterocyclic group having a substituent include an optionally substituted tetrahydropyranyl group (eg, tetrahydropyranyl, 3-bromotetrahydropyranyl, 4-methoxytetrahydropyranyl, etc.), A tetrahydrothiopyranyl group (e.g., tetrahydrothiopyranyl, 3-bromotetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl, etc.) which may have a tetrahydrothiopyranyl group which may have a substituent ( Examples thereof include a tetrahydrofuranyl group and the like, and a tetrahydrothiofuranyl group which may have a substituent (for example, tetrahydrothiofuranyl and the like).

The aralkyl group (5) which may have a substituent includes a C _7-20 aralkyl group (such as benzyl) which may have a substituent. Examples of the substituent of the aralkyl group include a C _1-4 alkyl group, a C _6-12 aryl group (such as phenyl), a hydroxyl group, a C _1-4 alkoxy group, a nitro group, and a halogen atom. Examples of such substituents include those exemplified in the above (4). Examples of the aralkyl group which may have a substituent include benzyl, o-chlorobenzyl, o-nitrobenzyl, p-chlorobenzyl, p-methoxybenzyl, p-methylbenzyl, p-nitrobenzyl, 2,6 -Dichlorobenzyl, diphenylmethyl, trityl and the like.

The substituent of the silyl group (6) includes a C _7-20 aralkyl group such as benzyl and the substituents described in the aralkyl group (5). Examples of the silyl group (6) which may have a substituent include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tribenzylsilyl, and triphenylsilyl groups.

Examples of the group (B) which forms an ester bond with an oxygen atom include an acyl group which may have a substituent. The acyl group includes (1) a hydroxyl group, a C _1-4 alkoxy group, a C _1-4 alkylthio group, a C _1-6 acyl group optionally substituted with a halogen atom and the like (for example, formyl, acetyl, chloro Acetyl, trifluoroacetyl, propionyl, isopropionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), (2) C _1-4 alkyl group, hydroxyl group, C _1-4 alkoxy group, nitro group, halogen atom, etc. A _C7-16 acyl group having an optionally substituted aromatic ring (e.g., benzoyl, p-phenylbenzoyl, toluoyl, naphthoyl, etc.), (3) _C1-4 alkyl group, hydroxyl group, _C1-4 alkoxy Group, nitro group, acyl group having a heterocyclic ring which may be substituted with a halogen atom (for example, furoyl, tenoyl, nicotine Yl, etc. isonicotinoyl) and the like.

The group (C) which forms a carbonate together with an oxygen atom includes (1) a C _1-4 alkoxy group which may be substituted by a substituent such as a C _1-4 alkoxy group, a C _7-20 aralkyloxy group. , A benzoyl group, a C _1-4 alkylthio group, a C _2-5 alkoxycarbonyl group which may have a substituent such as a halogen atom (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, Isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, etc.), (2) having a substituent such as a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group, a halogen atom, etc. An _optionally substituted C _8-20 aralkyloxycarbonyl group (for example, benzyloxycarbonyl, p-methoxybenzyloxy) Xycarbonyl, p-methylbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, etc.), (3) For example, C _1-4 alkyl group, hydroxyl group, C _1-4 alkoxy group, nitro group And a C _7-20 aryloxycarbonyl group which may have a substituent such as a halogen atom (for example, phenoxycarbonyl, 4-methylphenyloxycarbonyl, 4-nitrophenyloxycarbonyl, 4-chlorophenyloxycarbonyl, naphthyloxy Carbonyl, etc.).

Examples of the group (D) which forms a sulfonic acid ester together with an oxygen atom include (1) a C _1-4 alkoxy group, a C _1-4 alkoxy-C _1-4 alkoxy group, a C _7-20 aralkyloxy group, and benzoyl. group, C _1-4 alkylthio group, a substituted group optionally C _1-4 alkylsulfonyl group which may have a such as a halogen atom (e.g., methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, trichloromethane sulfonyl, trifluoromethanesulfonyl Sulfonyl), (2) C _6-20 arylsulfonyl group which may have a substituent such as C _1-4 alkyl group, hydroxyl group, C _1-4 alkoxy group, nitro group, halogen atom ( For example, benzenesulfonyl, m-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, p-chlorobenzenesulfonyl, p- Romo benzenesulfonyl, p- toluenesulfonyl, naphthalene sulfonyl) and the like.

The optionally substituted alkoxy group includes an optionally substituted alkoxy group having 1 to 4 carbon atoms (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy) , T-butoxy group, etc.). Examples of the substituent of the C _1-4 alkoxy group include a hydroxyl group, a C _1-4 alkoxy group, and a halogen atom. Examples of the alkoxy group having such a substituent include a hydroxy-C _1-4 alkoxy group (for example, hydroxymethoxy, 2-hydroxyethoxy, 1,2-dihydroxyethoxy, 2,2-dihydroxyethoxy, 3,3 -Dihydroxypropoxy group, etc.), C _1-4 alkoxy-C _1-4 alkoxy groups (eg, methoxymethoxy, ethoxymethoxy, 1-ethoxyethoxy group, etc.) and the like.

Examples of the substituent of the cycloalkyloxy group include a halogen atom, a C _1-4 alkyl group, a hydroxyl group and the like. Examples of the cycloalkyloxy group include a C _3-10 cycloalkyloxy group (for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclononyloxy, cyclodecyl) Oxy group etc.).

The aralkyloxy group which may have a substituent includes, for example, a C _1-4 alkyl group, a C _6-12 aryl group (such as phenyl), a hydroxyl group, a C _1-4 alkoxy group, a nitro group, and a halogen atom. And a C _7-20 aralkyloxy group (for example, benzyloxy, m-bromobenzyloxy, m-chlorobenzyloxy group, etc.) which may be substituted with a substituent such as

The aryloxy group which may have a substituent may be substituted with a substituent such as a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group, and a halogen atom. And C _6-16 aryloxy groups (for example, phenoxy groups and the like).

The lower alkylthio group includes, for example, an alkylthio group having 1 to 4 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, and t-butylthio. Examples of the substituent of the lower alkylthio group include a hydroxyl group, a C _1-4 alkoxy group, and a halogen atom.

The acyl group which may have a substituent includes, for example, (1) C _1-6 which may be substituted with a hydroxyl group, a C _1-4 alkoxy group, a C _1-4 alkylthio group, a halogen atom, or the like. Acyl group (for example, formyl, acetyl, chloroacetyl, trifluoroacetyl, propionyl, isopropionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), (2) C _1-4 alkyl group, hydroxyl group, C _1-4 A _C7-16 acyl group having an aromatic ring which may be substituted with an alkoxy group, a nitro group, a halogen atom or the like (for example, benzoyl, p-phenylbenzoyl, toluoyl, naphthoyl, etc.), (3) _C1-4 alkyl group, hydroxyl group, C _1-4 alkoxy group, a nitro group, an acyl group having a heterocyclic ring which may be substituted by a halogen atom (e.g. Furoyl, thenoyl, nicotinoyl, and isonicotinoyl), and the like.

The carboxyl group-protecting group includes, for example, a C _1-4 alkyl group _optionally having a substituent described above, a C _6-16 aryl group _optionally having a substituent, and a substituent. An optionally substituted C _7-20 aralkyl group, an optionally substituted C _1-4 alkoxy group, an optionally substituted C _6-16 aryloxy group, C _7-20 aralkyloxy group which may be substituted, amino group which may have a substituent and the like. As the like optionally C _1-4 alkyl group which may have a substituent, the examples of which may have a substituent group C _1-4 alkyl group or the like is included. Examples of the amino group which may have a substituent include an amino group which may have a substituent and an amino group substituted with a C _7-20 aralkyl group, which are exemplified below.

Specifically, the carboxyl group which may be protected by a protecting group includes, for example, (a) a C _1-4 alkoxy-carbonyl which may have a substituent such as a hydroxyl group and a C _1-4 alkoxy group. Groups (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, methoxymethoxycarbonyl, methoxyethoxycarbonyl, etc.), (b) C _1-4 alkyl, hydroxyl, C _1-4 alkoxy Group, a nitro group, a C _6-16 aryloxy-carbonyl group which may have a substituent such as a halogen atom (for example, phenoxycarbonyl, 4-methylphenyloxycarbonyl, 4-methoxyphenyloxycarbonyl, 4-nitro Phenyloxycarbonyl, 4-chlorophenyloxycarbonyl, naph Such ylcarbonyl group), (c) C _1-4 alkyl group, C _6-12 aryl groups (such as phenyl), hydroxyl group, C _1-4 alkoxy group, a nitro group, have a substituent such as a halogen atom C _7-20 aralkyloxy-carbonyl group (for example, benzyloxycarbonyl, m-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl group and the like), (d) C _1-4 alkyl group, C _7-20 A carbamoyl group (eg, carbamoyl, benzylaminocarbonyl group, etc.) which may be substituted with a substituent such as an aralkyl group, a C _1-6 acyl group, a C _7-16 acyl group having an aromatic ring, and the like are included.

Such carboxyl groups may form salts. Such salts are not particularly limited, and include, for example, alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, magnesium salts, calcium salts, barium salts, etc.), and other metals. Salts with inorganic bases such as salts (eg, zinc salts, aluminum salts, etc.) and ammonium salts; salts with organic bases, such as pyridine, tri-C _1-4 alkylamines (eg, trimethylamine, triethylamine, etc.). .

Examples of the lower alkoxycarbonyl group, e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s- butoxycarbonyl, and the like C _2-5 alkoxycarbonyl group such as t- butoxycarbonyl It is. Examples of the substituent of the lower alkoxycarbonyl group include the substituents exemplified as the substituent of the alkoxy group.

Examples of the substituent of the amino group include, for example, a C _1-4 alkyl group _optionally having the substituent described above, a C _7-20 aralkyl group _optionally having a substituent, and a substituent. Optionally substituted C _1-6 acyl group, _optionally substituted C _7-16 acyl group having an aromatic ring, _optionally substituted hetero ring-containing acyl group, substituted carbonyl group (For example, an acyl group optionally having a substituent described above, a carboxyl group optionally protected by a protecting group, and the like).

Specifically, the amino group which may have a substituent includes (a) an amino group and (b) an amino group substituted with a C _1-4 alkyl group which may have a substituent (for example, , Methylamino, ethylamino, propylamino, t-butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (c) substituted with a C _7-20 aralkyl group which may have a substituent. Amino group (for example, benzylamino group, etc.), and (d) an amino group substituted with an optionally substituted C _1-6 acyl group (for example, formylamino, acetylamino, propionylamino, butyrylamino , isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino group and the like) (e) amino substituted by C _7-16 acyl group having an aromatic ring which may have a substituent (E.g., a benzoylamino group), (f) an amino group substituted with an optionally substituted heterocyclic acyl group (e.g., a nicotinoylamino group), (g) a substituted carbonylamino Groups (eg, acetylaminomethylcarbonylamino, acetylaminoethylcarbonylamino, hydroxymethylcarbonylamino, hydroxyethylcarbonylamino, methoxycarbonylamino, ethoxycarbonylamino, etc.) and the like.

Among them, as R ¹ and R ⁵ , a hydrogen atom, a C _1-4 alkyl group and the like, particularly a hydrogen atom, are preferable.

R ² , R ³ , and R ⁴ are each a hydrogen atom, a halogen atom, a C _1-4 alkyl group _optionally substituted with a halogen atom (for example, a C _1-4 alkyl group, a C _1-4 haloalkyl group). Etc.), a C _1-4 alkoxy group, an amino group optionally having a substituent (especially an amino group optionally substituted with a C _1-6 acyl group, etc.), a nitro group and the like, and particularly a halogen Atoms are preferred.

Examples of the protecting group for the hydroxyl group in Z include a protecting group for a hydroxyl group usually used in the field of organic synthesis, for example, the protecting groups (A) to (D) exemplified in the description of R ^{1 to} R ^6. Can be As Z, a hydrogen atom, particularly a hydrogen atom, a silyl group substituted with a C _1-4 alkyl group, a C _1-6 acyl group, or the like is often used.

  Specific examples of the compound represented by the general formula (II) include (a) (R) -2-amino-1-phenylethanol, and (b) (R) -2 having a protected hydroxyl group. -Amino-1-phenylethanol derivative, (c) a derivative in which a phenyl group is substituted with a hydroxyl group, (d) a derivative in which a phenyl group is substituted with two hydroxyl groups, (e) a phenyl group is substituted with a halogen atom (F) a derivative in which a phenyl group is substituted with two halogen atoms, (g) a derivative in which a phenyl group is substituted with three halogen atoms, and (h) a derivative in which a phenyl group is substituted with four halogen atoms. A substituted derivative, (i) a derivative in which a phenyl group is substituted with 5 halogen atoms, (j) a derivative in which a phenyl group is substituted with a lower alkyl group which may have a substituent, and (k) a phenyl group. A derivative in which a group is substituted with a lower alkoxy group which may have a substituent, (l) a derivative in which a phenyl group is substituted with a nitro group, and (m) an amino in which a phenyl group may have a substituent Group-substituted derivative, (n) phenyl group may be a hydroxyl group optionally protected by a protecting group, a cycloalkyloxy group optionally having a substituent, an aralkyl optionally having a substituent An oxy group, an aryloxy group which may have a substituent, an acyl group which may have a substituent, or a derivative which may be substituted with a carboxyl group which may be protected by a protecting group; No.

  (B) The (R) -2-amino-1-phenylethanol derivative having a protected hydroxyl group includes, for example, (R) -2-amino-1-phenyl-O-trimethylsilylethanol, (R) -2- Amino-1-phenyl-Ot-butyldimethylsilylethanol, (R) -2-amino-1-phenyl-O-tetrahydropyranylethanol, (R) -2-amino-1-phenyl-O-acetylethanol And so on.

  (C) Derivatives in which a phenyl group is substituted with a hydroxyl group include (R) -2-amino-1- (2-hydroxyphenyl) ethanol and (R) -2-amino-1- (3-hydroxyphenyl) Ethanol, (R) -2-amino-1- (4-hydroxyphenyl) ethanol, (R) -2-amino-1- (3-methylthio-4-hydroxyphenyl) ethanol, (R) -2-amino- 1- (3-hydroxymethyl-4-hydroxyphenyl) ethanol, (R) -2-amino-1- (3-methoxycarbonyl-4-hydroxyphenyl) ethanol, (R) -2-amino-1- (3 -Hydroxyethoxy-4-hydroxyphenyl) ethanol, (R) -2-amino-1- (3-ethoxymethyl-4-hydroxyphenyl) ethanol, (R -2-amino-1 - [(3-hydroxy-5- (1,2-dihydroxypropyl) phenyl] ethanol and the like.

  Examples of (d) derivatives in which a phenyl group is substituted with two hydroxyl groups include (R) -2-amino-1- (2,3-dihydroxyphenyl) ethanol and (R) -2-amino-1 -(2,4-dihydroxyphenyl) ethanol, (R) -2-amino-1- (2,5-dihydroxyphenyl) ethanol, (R) -2-amino-1- (2,6-dihydroxyphenyl) ethanol , (R) -2-amino-1- (3,4-dihydroxyphenyl) ethanol, (R) -2-amino-1- (3,5-dihydroxyphenyl) ethanol, (R) -2-amino-1 -(4,5-dihydroxy-3-methylphenyl) ethanol, (R) -2-amino-1- (3,4-dihydroxy-2-methylphenyl) ethanol and the like.

  (E) Derivatives in which a phenyl group is substituted with a halogen atom include (R) -2-amino-1- (2-fluorophenyl) ethanol and (R) -2-amino-1- (2-chlorophenyl) ethanol , (R) -2-amino-1- (2-bromophenyl) ethanol, (R) -2-amino-1- (2-iodophenyl) ethanol, (R) -2-amino-1- (2- Chloro-3-hydroxyphenyl) ethanol, (R) -2-amino-1- (2-chloro-4-hydroxyphenyl) ethanol, (R) -2-amino-1- (2-chloro-4-benzyloxy) (R) -2-amino-1- (2-halophenyl) ethanol derivatives such as phenyl) ethanol; (R) -2-amino-1- (3-chlorophenyl) -O-trimethylsilylethanol; -2-amino-1- (3-chlorophenyl) -O-t-butyldimethylsilylethanol, (R) -2-amino-1- (3-chlorophenyl) -O-acetylethanol, (R) -2-amino -1- (3-fluorophenyl) ethanol, (R) -2-amino-1- (3-chlorophenyl) ethanol, (R) -2-amino-1- (3-bromophenyl) ethanol, (R)- 2-amino-1- (3-iodophenyl) ethanol, (R) -2-amino-1- (3-fluoro-4-methoxyphenyl) ethanol, (R) -2-amino-1- (3-chloro -4-methoxyphenyl) ethanol, (R) -2-amino-1- (4-benzyloxy-3-chloro-5-methoxyphenyl) ethanol, (R) -2-amino-1- (5-ethoxy) (R) -2-amino-1- (3-halophenyl) ethanol such as 4-benzyloxy-3-chlorophenyl) ethanol and (R) -2-amino-1- (3-chloro-4-methylthiophenyl) ethanol Derivatives: (R) -2-amino-1- (4-fluorophenyl) ethanol, (R) -2-amino-1- (4-chlorophenyl) ethanol, (R) -2-amino-1- (4- (R) -2-amino-1- (4-halophenyl) ethanol derivatives such as (bromophenyl) ethanol and (R) -2-amino-1- (4-iodophenyl) ethanol.

  (F) Derivatives in which a phenyl group is substituted by two halogen atoms include, for example, (R) -2-amino-1- (2,3-difluorophenyl) ethanol and (R) -2-amino-1 -(2,3-dichlorophenyl) ethanol, (R) -2-amino-1- (2,3-dibromophenyl) ethanol, (R) -2-amino-1- (2,3-diiodophenyl) ethanol (R) -2-amino-1- (2,3-dihalophenyl) ethanol derivatives such as, (R) -2-amino-1- (2-fluoro-3-chlorophenyl) ethanol; (R) -2-amino -1- (2,4-difluorophenyl) ethanol, (R) -2-amino-1- (2,4-dichlorophenyl) ethanol, (R) -2-amino-1- (2,4-dibromophenyl) ethanol, (R) -2-amino-1- (2,4-dihalophenyl) ethanol derivatives such as (R) -2-amino-1- (2,4-diiodophenyl) ethanol; (R) -2-amino-1 -(2,5-difluorophenyl) ethanol, (R) -2-amino-1- (2,5-dichlorophenyl) ethanol, (R) -2-amino-1- (2,5-dibromophenyl) ethanol, (R) -2-amino-1- (2,5-dihalophenyl) ethanol derivatives such as (R) -2-amino-1- (2,5-diiodophenyl) ethanol; (R) -2-amino- 1- (2,6-difluorophenyl) ethanol, (R) -2-amino-1- (2,6-dichlorophenyl) ethanol, (R) -2-amino-1- (2,6-dibromophenyl) ethanol , (R)- (R) -2-amino-1- (2,6-dihalophenyl) ethanol derivatives such as -amino-1- (2,6-diiodophenyl) ethanol; (R) -2-amino-1- (3,4) -Difluorophenyl) ethanol, (R) -2-amino-1- (3,4-dichlorophenyl) ethanol, (R) -2-amino-1- (3,4-dibromophenyl) ethanol, (R) -2 -Amino-1- (3,4-diiodophenyl) ethanol, (R) -2-amino-1- (3-chloro-4-bromophenyl) ethanol, (R) -2-amino-1- (3 , 4-Dichlorophenyl) -O-trimethylsilylethanol, (R) -2-amino-1- (3,4-) such as (R) -2-amino-1- (3,4-dichlorophenyl) -O-acetylethanol. Dihalofeni C) ethanol derivatives; (R) -2-amino-1- (3,5-difluorophenyl) ethanol, (R) -2-amino-1- (3,5-dichlorophenyl) ethanol, (R) -2- Amino-1- (3,5-dibromophenyl) ethanol, (R) -2-amino-1- (3,5-diiodophenyl) ethanol, (R) -2-amino-1- (3,5- Difluoro-4-methylaminophenyl) ethanol, (R) -2-amino-1- (3,5-dichloro-4-methylaminophenyl) ethanol, (R) -2-amino-1- (3,5- Dibromo-4-methylaminophenyl) ethanol, (R) -2-amino-1- (3,5-dichloro-4-aminophenyl) ethanol, (R) -2-amino-1- (3,5-dichloro) -4-methylphenyl Ethanol, (R) -2-amino-1- (3,5-dichloro-4-ethoxycarbonylaminophenyl) ethanol, (R) -2-amino-1- (4-amino-3-bromo-5-fluoro (R) -2-amino-1- (3,5-dihalophenyl) ethanol derivatives such as phenyl) ethanol and (R) -2-amino-1- (4-amino-3-bromo-5-chlorophenyl) ethanol Is mentioned.

  (G) Derivatives in which a phenyl group is substituted by three halogen atoms include, for example, (R) -2-amino-1- (2,3,4-trifluorophenyl) ethanol and (R) -2- Amino-1- (2,3,4-trichlorophenyl) ethanol, (R) -2-amino-1- (2,3,4-tribromophenyl) ethanol, (R) -2-amino-1- ( (R) -2-amino-1- (2,3,4-trihalophenyl) ethanol derivatives such as 2,3,4-triiodophenyl) ethanol; (R) -2-amino-1- (2,3) , 5-trifluorophenyl) ethanol, (R) -2-amino-1- (2,3,5-trichlorophenyl) ethanol, (R) -2-amino-1- (2,3,5-tribromo Phenyl) ethanol, (R) -2-amino-1 (R) -2-amino-1- (2,3,5-trihalophenyl) ethanol derivatives such as (2,3,5-triiodophenyl) ethanol; (R) -2-amino-1- (2 3,6-trifluorophenyl) ethanol, (R) -2-amino-1- (2,3,6-trichlorophenyl) ethanol, (R) -2-amino-1- (2,3,6-triphenyl) (R) -2-amino-1- (2,3,6-trihalophenyl) ethanol such as bromophenyl) ethanol and (R) -2-amino-1- (2,3,6-triiodophenyl) ethanol Derivatives: (R) -2-amino-1- (2,4,5-trifluorophenyl) ethanol, (R) -2-amino-1- (2,4,5-trichlorophenyl) ethanol, (R) -2-amino-1- (2,4,5- (R) -2-amino-1- (2,4,5-trihalophenyl) such as (ribromophenyl) ethanol and (R) -2-amino-1- (2,4,5-triiodophenyl) ethanol Ethanol derivatives; (R) -2-amino-1- (2,4,6-trifluorophenyl) ethanol, (R) -2-amino-1- (2,4,6-trichlorophenyl) ethanol, (R (R) -2 such as) -2-amino-1- (2,4,6-tribromophenyl) ethanol and (R) -2-amino-1- (2,4,6-triiodophenyl) ethanol -Amino-1- (2,4,6-trihalophenyl) ethanol derivative; (R) -2-amino-1- (3,4,5-trifluorophenyl) ethanol, (R) -2-amino-1 -(3,4,5-trichlorophenyl ) Ethanol, (R) -2-amino-1- (3,4,5-tribromophenyl) ethanol, (R) -2-amino-1- (3,4,5-triiodophenyl) ethanol, ( (R) such as (R) -2-amino-1- (3-chloro-4,5-difluorophenyl) ethanol and (R) -2-amino-1- (3-fluoro-4,5-dichlorophenyl) ethanol -2-amino-1- (3,4,5-trihalophenyl) ethanol derivative and the like.

  (H) Examples of the derivative in which a phenyl group is substituted with four halogen atoms include (R) -2-amino-1- (2,3,4,5-tetrafluorophenyl) ethanol and (R)- 2-amino-1- (2,3,4,5-tetrachlorophenyl) ethanol, (R) -2-amino-1- (2,3,4,5-tetrabromophenyl) ethanol, (R) -2 (R) -2-amino-1- (2,3,4,5-tetrahalophenyl) ethanol derivatives such as -amino-1- (2,3,4,5-tetraiodophenyl) ethanol; (R) -2-amino-1- (2,3,4,6-tetrafluorophenyl) ethanol, (R) -2-amino-1- (2,3,4,6-tetrachlorophenyl) ethanol, (R)- 2-amino-1- (2,3,4,6-tetrab (R) -2-amino-1- (2,3,4,6-tetra) such as (mophenyl) ethanol and (R) -2-amino-1- (2,3,4,6-tetraiodophenyl) ethanol (Halophenyl) ethanol derivative; (R) -2-amino-1- (2,3,5,6-tetrafluorophenyl) ethanol, (R) -2-amino-1- (2,3,5,6- Tetrachlorophenyl) ethanol, (R) -2-amino-1- (2,3,5,6-tetrabromophenyl) ethanol, (R) -2-amino-1- (2,3,5,6-tetra (R) -2-amino-1- (2,3,5,6-tetrahalophenyl) ethanol derivatives such as iodophenyl) ethanol and the like.

  (I) Examples of the derivative in which a phenyl group is substituted with five halogen atoms include (R) -2-amino-1- (2,3,4,5,6-pentafluorophenyl) ethanol and (R ) -2-Amino-1- (2,3,4,5,6-pentachlorophenyl) ethanol, (R) -2-amino-1- (2,3,4,5,6-pentabromophenyl) ethanol , (R) -2-amino-1- (2,3,4,5,6-pentaiodophenyl) and the like.

(J) Derivatives in which a phenyl group is substituted by a lower alkyl group which may have a substituent include (R) -2-amino-1- (2-methylphenyl) ethanol and (R) -2- Amino-1- (2-ethylphenyl) ethanol, (R) -2-amino-1- (2-propylphenyl) ethanol, (R) -2-amino-1- (2-t-butylphenyl) ethanol, (R) -2-amino-1- (2-C _1-4 alkyl-phenyl) ethanol derivatives such as (R) -2-amino-1- (2-methylphenyl) -O-trimethylsilylethanol; (R) -2-amino-1- (3-methylphenyl) ethanol, (R) -2-amino-1- (3-ethylphenyl) ethanol, (R) -2-amino-1- (3-propylphenyl) ) Ethanol, (R) -2- (R) -2-amino-1- (such as amino-1- (3-t-butylphenyl) ethanol, (R) -2-amino-1- (3-methylphenyl) -O-trimethylsilylethanol, 3-C _1-4 alkyl-phenyl) ethanol derivatives; (R) -2-amino-1- (4-methylphenyl) ethanol, (R) -2-amino-1- (4-ethylphenyl) ethanol, ( (R) -2-amino-1- (4-propylphenyl) ethanol, (R) -2-amino-1- (4-t-butylphenyl) ethanol, (R) -2-amino-1- (4- (R) -2-amino-1- (4-C _1-4 alkyl-phenyl) ethanol derivatives such as methylphenyl) -O-trimethylsilylethanol; (R) -2-amino-1- (2-chloro) Methylphenyl) ethanol, R) -2-amino-1- [2- (2-chloroethyl) phenyl] ethanol, (R) -2-amino-1- [2- (3-chloropropyl) phenyl] ethanol, (R) -2- Amino-1- [2- (4-chlorobutyl) phenyl] ethanol, (R) -2-amino-1- (2-trichloromethylphenyl) ethanol, (R) -2-amino-1- (2-trifluoro (R) -2-amino-1- (2-C _1-4 haloalkyl-) such as methylphenyl) ethanol and (R) -2-amino-1- (2-chloromethylphenyl) -O-trimethylsilylethanol. Phenyl) ethanol derivative; (R) -2-amino-1- (3-chloromethylphenyl) ethanol, (R) -2-amino-1- [3- (2-chloroethyl) phenyl] ethanol, (R)- -Amino-1- [3- (3-chloropropyl) phenyl] ethanol, (R) -2-amino-1- [3- (4-chlorobutyl) phenyl] ethanol, (R) -2-amino-1- (3-Trichloromethylphenyl) ethanol, (R) -2-amino-1- (3-trifluoromethylphenyl) ethanol, (R) -2-amino-1- (3-trifluoromethylphenyl) -O- Trimethylsilylethanol, (R) -2-amino-1- (3-trifluoromethylphenyl) -O-acetylethanol, (R) -2-amino-1- [3- (1,1,2,2,2 -Pentafluoroethylphenyl)]-O-acetylethanol, (R) -2-amino such as (R) -2-amino-1- (3-chloromethylphenyl) -O-trimethylsilylethanol No-1- (3-C _1-4 haloalkyl-phenyl) ethanol derivatives; (R) -2-amino-1- (4-chloromethylphenyl) ethanol, (R) -2-amino-1- [4- (2-chloroethyl) phenyl] ethanol, (R) -2-amino-1- [4- (3-chloropropyl) phenyl] ethanol, (R) -2-amino-1- [4- (4-chlorobutyl) Phenyl] ethanol, (R) -2-amino-1- (4-trichloromethylphenyl) ethanol, (R) -2-amino-1- (4-trifluoromethylphenyl) ethanol, (R) -2-amino -1- (4-chloromethyl-phenyl) -O- trimethylsilyl ethanoate - Le etc. (R)-2-amino-1- (3-C _1-4 haloalkyl-phenyl) - ethanol derivatives; (R)-2-amino 1- (3-hydroxymethylphenyl) ethanol such as (R)-2-amino-1- [3- (hydroxymethyl -C _1-4 alkyl - phenyl)] such as ethanol derivatives are included.

  (K) Examples of the derivative in which a phenyl group is substituted with a lower alkoxy group include (R) -2-amino-1- (2-methoxyphenyl) ethanol and (R) -2-amino-1- (3- (Methoxyphenyl) ethanol, (R) -2-amino-1- (4-methoxyphenyl) ethanol, (R) -2-amino-1- (2-ethoxyphenyl) ethanol, (R) -2-amino-1 Derivatives having one lower alkoxy group in the phenyl group, such as-(3-ethoxyphenyl) ethanol and (R) -2-amino-1- (4-ethoxyphenyl) ethanol; (R) -2-amino-1- (2,3-dimethoxyphenyl) ethanol, (R) -2-amino-1- (2,3-diethoxyphenyl) ethanol, (R) -2-amino-1- (2,4-dimethoxyphenyl) Tanol, (R) -2-amino-1- (2,4-diethoxyphenyl) ethanol, (R) -2-amino-1- (2,5-dimethoxyphenyl) ethanol, (R) -2-amino -1- (2,5-diethoxyphenyl) ethanol, (R) -2-amino-1- (2,6-dimethoxyphenyl) ethanol, (R) -2-amino-1- (2,6-di (Ethoxyphenyl) ethanol, (R) -2-amino-1- (3,4-dimethoxyphenyl) ethanol, (R) -2-amino-1- (3,4-diethoxyphenyl) ethanol, (R)- 2-amino-1- (3,5-dimethoxyphenyl) ethanol, (R) -2-amino-1- (3,5-diethoxyphenyl) ethanol, (R) -2-amino-1- (3- Hydroxyethoxy-4-t-butyl Derivatives in which a phenyl group is substituted with two lower alkoxy groups such as (xylphenyl) ethanol: (R) -2-amino-1- (2-hydroxy-3-methoxyphenyl) ethanol, (R) -2-amino- 1- (2-hydroxy-4-methoxyphenyl) ethanol, (R) -2-amino-1- (2-hydroxy-5-methoxyphenyl) ethanol, (R) -2-amino-1- (2-hydroxy -6-methoxyphenyl) ethanol, (R) -2-amino-1- (3-hydroxy-2-methoxyphenyl) ethanol, (R) -2-amino-1- (3-hydroxy-4-methoxyphenyl) Ethanol, (R) -2-amino-1- (3-hydroxy-5-methoxyphenyl) ethanol, (R) -2-amino-1- (3-hydroxy-6-methoxy) (Ciphenyl) ethanol, (R) -2-amino-1- (4-hydroxy-2-methoxyphenyl) ethanol, (R) -2-amino-1- (4-hydroxy-3-methoxyphenyl) ethanol, (R ) -2-Amino-1- (5-hydroxy-2-methoxyphenyl) ethanol, (R) -2-amino-1- (5-hydroxy-3-methoxyphenyl) ethanol, (R) -2-amino- 1- (6-hydroxy-2-methoxyphenyl) ethanol, (R) -2-amino-1- (6-hydroxy-3-methoxyphenyl) ethanol, (R) -2-amino-1- (2-hydroxy -3-ethoxyphenyl) ethanol, (R) -2-amino-1- (2-hydroxy-4-ethoxyphenyl) ethanol, (R) -2-amino-1- (2-hydr) Xy-5-ethoxyphenyl) ethanol, (R) -2-amino-1- (2-hydroxy-6-ethoxyphenyl) ethanol, (R) -2-amino-1- (3-hydroxy-2-ethoxyphenyl) ) Ethanol, (R) -2-amino-1- (3-hydroxy-4-ethoxyphenyl) ethanol, (R) -2-amino-1- (3-hydroxy-5-ethoxyphenyl) ethanol, (R) -2-amino-1- (3-hydroxy-6-ethoxyphenyl) ethanol, (R) -2-amino-1- (4-hydroxy-2-ethoxyphenyl) ethanol, (R) -2-amino-1 -(4-hydroxy-3-ethoxyphenyl) ethanol, (R) -2-amino-1- (5-hydroxy-2-ethoxyphenyl) ethanol, (R) -2-amido -1- (5-hydroxy-3-ethoxyphenyl) ethanol, (R) -2-amino-1- (6-hydroxy-2-ethoxyphenyl) ethanol, (R) -2-amino-1- (6- Derivatives in which a phenyl group is substituted with an alkoxy group and a hydroxyl group, such as (hydroxy-3-ethoxyphenyl) ethanol, are included.

  (L) Examples of the derivative in which a phenyl group is substituted with a nitro group include (R) -2-amino-1- (2-nitrophenyl) ethanol and (R) -2-amino-1- (3-nitro Phenyl) ethanol, (R) -2-amino-1- (2-methyl-3-nitrophenyl) ethanol, (R) -2-amino-1- (4-nitrophenyl) ethanol and the like.

  (M) Derivatives in which a phenyl group is substituted with an amino group which may have a substituent include (R) -2-amino-1- (3-aminophenyl) ethanol and (R) -2-amino -1- (3-amino-4-methoxyphenyl) ethanol, (R) -2-amino-1- (3-acetylaminophenyl) ethanol, (R) -2-amino-1- (4-acetylaminophenyl) ) Ethanol, (R) -2-amino-1- (3-acetylamino-4-hydroxyphenyl) ethanol, (R) -2-amino-1- (3-acetylamino-4-methoxyphenyl) ethanol, ( (R) -2-amino-1- (3-acetylamino-4-benzyloxyphenyl) ethanol, (R) -2-amino-1- (3-acetylaminomethylcarbonylamino-4-hydro (Phenyl) ethanol, (R) -2-amino-1- (3-formylamino-4-hydroxyphenyl) ethanol, (R) -2-amino-1- (3-hydroxymethylcarbonylamino-4-hydroxyphenyl) Ethanol, (R) -2-amino-1- [3-hydroxymethylcarbonylamino-4- (p-methoxyphenyl) methylphenyl) ethanol, (R) -2-amino-1- (3-hydroxy-5 Formylaminophenyl) ethanol, (R) -2-amino-1- (3-carbamoyl-4-hydroxyphenyl) ethanol and the like.

  (N) the phenyl group has a hydroxyl group which may be protected by a protecting group, a cycloalkyloxy group which may have a substituent, an aralkyloxy group which may have a substituent, Examples of the derivative substituted with an optionally substituted aryloxy group, an optionally substituted acyl group, or a carboxyl group optionally protected with a protecting group include (R) -2- Amino-1- (2-benzyloxyphenyl) ethanol, (R) -2-amino-1- (2-benzylcarbonylphenyl) ethanol, (R) -2-amino-1- (2-benzylcarbonyloxyphenyl) Ethanol, (R) -2-amino-1- (3-methoxycarbonyl-4-cyclohexyloxyphenyl) ethanol, (R) -2-amino-1- (3,4-diben (Roxy-2-phenyl) ethanol, (R) -2-amino-1- (3-hydroxymethyl-4-benzyloxyphenyl) ethanol (R) -2-amino-1- (3,5-dibenzyloxyphenyl) ethanol , (R) -2-amino-1- (3,5-di-t-butoxycarbonylphenyl) ethanol and the like.

As preferred compounds among the above exemplified compounds, (R) -2-amino-1-phenylethanol; a derivative in which a phenyl group is substituted with a halogen atom [for example, a derivative in which 1 to 2 halogen atoms are substituted, in particular, Derivatives having 1-2 halogen atoms at positions 2, 3, and 4 of the phenyl group (eg, (R) -2-amino-1- (3-halophenyl) ethanol derivative, (R) -2-amino-1 -(4-halophenyl) ethanol derivative, (R) -2-amino-1- (3,4-dihalophenyl) ethanol derivative and the like)]; a C _1-4 alkyl in which the phenyl group optionally has a substituent. Group, a C _1-4 alkoxy group which may have a substituent, a derivative substituted with an amino group which may have a substituent (for example, (R) -2-amino-1- (3- C _1-4 alkyl - phenylene ) Ethanol derivative, (R)-2-amino -1- (3-C _1-4 haloalkyl-phenyl) - ethanol derivative, (R)-2-amino -1- (3-C _1-4 alkoxy-phenyl) - ethanol Derivatives, (R) -2-amino-1- (3-C _1-6 acylamino-phenyl) ethanol derivatives, (R) -2-amino-1- (4-C _1-4 alkyl-phenyl) ethanol derivatives, (R) -2-amino-1- (4-C _1-4 haloalkyl-phenyl) ethanol derivative, (R) -2-amino-1- (4-C _1-4 alkoxy-phenyl) ethanol derivative, (R ) -2-amino-1- (4-C _1-6 acylamino-phenyl) ethanol and the like).

  Among the (R) -2-amino-1-phenylethanol derivatives represented by the general formula (II), the derivative in which Z is a hydrogen atom, that is, the compound represented by the general formula (IIa) can be obtained by various methods, For example, it can be produced by a chemical synthesis method, but can be advantageously produced by a method utilizing a microorganism or a processed product thereof.

  The (R) -form optically active compound represented by the general formula (IIa) may be, for example, (A) an enantiomer mixture of a 2-amino-1-phenylethanol derivative represented by the general formula (I) or a salt thereof. , A specific microorganism or a processed product thereof, or (B) the compound represented by the general formula (VII) or a salt thereof, and then a specific microorganism or a processed product thereof is reacted with the compound (R). It can be easily obtained by a method of recovering a -2-amino-1-phenylethanol derivative.

  Further, the optically active compound is obtained by reacting (C) an optically active compound represented by the formula (III) or a compound represented by the optically active formula (IV) with an aminating agent, and reacting the reaction product with an acid. The compound represented by the formula (VI) is added as a salt, precipitated as a salt, separated and purified, and when Z in the formula (VI) is a protecting group for a hydroxyl group, the protecting group is removed. Or (D) reacting an aminating agent on the compound represented by the formula (III) or the compound represented by the formula (IV), adding an optically active acid to the reaction product, The compound represented by the formula (VI) is precipitated as a salt, separated and purified, and further, when Z in the formula (VI) is a protecting group for a hydroxyl group, the compound is obtained by removing the protecting group. it can.

  Hereinafter, the method (A) will be described.

The enantiomer mixture of a 2-amino-1-phenylethanol derivative used as a reaction raw material in this method can be prepared, for example, by adding (a) a corresponding benzaldehyde derivative to a trialkyl such as trimethylsilyl cyanide in the presence of a Lewis acid such as anhydrous aluminum chloride; A method of reacting with silyl cyanide to form an O-trialkylsilylmandelonitrile derivative such as an O-trimethylsilylmandelonitrile derivative, treating with a reducing agent such as sodium borohydride, and then hydrolyzing with an acid ( Hereinafter, referred to as a reduction method; see JP-A-56-5445 and U.S. Pat. No. 5,061,727), and (b) a method in which an aminating agent such as NH _{3 is} allowed to act on a corresponding styrene oxide derivative to open the ring. (Hereinafter referred to as styrene oxide-amino addition method), (c) Styrene halohydrin derivative of response, a method for applying a aminating agent such as NH ₃ (hereinafter, halohydrin - that amino addition method) can be obtained in like.

  In these methods, the hydroxyl group of the compound of the general formula (I) may be protected with a suitable protecting group. Such a compound in which the hydroxyl group may be protected by a protecting group is represented by the general formula (VI). After the completion of the reaction, the protecting group is easily removed by a conventional means to give the compound of the general formula (I). Can be converted. As the hydroxyl-protecting group, the hydroxyl-protecting groups exemplified in the description of Z in the general formula (II) can be used.

  According to the (b) styrene oxide-amino addition method and (c) halohydrin-amino addition method, unlike the method (a), it is not necessary to use a large amount of an expensive reducing agent, and the aminating agent is used. Thus, the target compound can be obtained easily.

  (B) In the styrene oxide-amino addition method, a styrene oxide derivative used as a reaction raw material can be obtained by a conventional method, for example, a method of oxidizing a corresponding styrene derivative.

Examples of the aminating agent include a compound represented by the general formula (V):
Y-NH ₂
(Wherein, Y represents a hydrogen atom or a group which can be eliminated in the reaction). Examples of the group capable of leaving in the reaction represented by Y include, for example, a C _1-4 alkyl group which may have a substituent exemplified in the section of the protective group for the hydroxyl group (eg, an allyl group; phenacyl) A C _1-6 acyloxy-C _1-4 alkyl group such as a 3-acetoxypropyl group; an optionally substituted C _1-4 alkoxy-C ₁ group such as a methoxymethyl or 2-chloroethoxymethyl group; _-4 alkyl group; which may have a substituent group C _7-16 aralkyl group (e.g., benzyl, triphenylmethyl;; C _7-16 aralkyloxy -C _1-4 alkyl group such as benzyloxymethyl group 3 , 4-dimethoxybenzyl, di (p- methoxyphenyl) methyl, and the (p- methoxyphenyl) such as C _1-4 alkoxy -C _7-16 aralkyl groups such as diphenylmethyl group). the C _1-4 The like alkyl group, such as a C _1-4 alkyl group exemplified in the description of R ¹ to R ⁵ may be used. Preferred Y include a hydrogen atom or the like.

The reaction may be performed in a solvent inert to the reaction. Examples of the solvent include alcohols such as lower alcohols (eg, C _1-4 alcohols such as methanol, ethanol, propanol, and t-butanol); aromatic hydrocarbons such as benzene, toluene, xylene, and ethylbenzene. Aliphatic hydrocarbons such as pentane, hexane, heptane and octane; alicyclic hydrocarbons such as cyclohexane and methylcyclohexane; halogenated hydrocarbons such as carbon tetrachloride, chloroform, dichloromethane and 1,2-dichloroethane Ethers such as diethyl ether, dibutyl ether, dioxane, and tetrahydrofuran; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate. Alcohols and the like are often used as the solvent.

  The reaction conditions can be selected within a range that does not impair the yield or the like depending on the type of the aminating agent used, and the reaction temperature is, for example, 0 to 80 ° C., preferably about 20 to 60 ° C., and the reaction time Is usually about 5 minutes to 24 hours.

  When Y is a group capable of leaving in the reaction, the compound represented by formula (I) can be easily obtained by removing Y by a conventional method.

  (C) In the halohydrin-amino addition method, the reaction can be carried out in the same manner as in the styrene oxide-amino addition method (b), except that the corresponding styrene halohydrin derivative is used as a reaction raw material. The styrene halohydrin derivative used as a raw material can be obtained by a conventional method, for example, a method of halogenating and reducing the corresponding acetophenone derivative.

  In the methods (b) and (c) by the amino addition, depending on the reaction conditions, for example, the compound represented by the general formula (XVI)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z are the same as those described above), the general formulas (XVII) and (XVII ′)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z are the same as described above) in some cases, such as a dimer. The amount of by-products varies depending on the type of compound, reaction conditions, and the like. The ratio between the positional isomer represented by XVI) and other by-products such as the dimer is often about 7: 1: 2 by weight. The amount of the 2-amino-1-phenylethanol derivative of the general formula (I), its positional isomer and dimer contained in the reaction product can be analyzed by, for example, high performance liquid chromatography.

  The 2-amino-1-phenylethanol derivative can be separated and purified by utilizing the difference in basicity and / or solubility from the by-product. That is, the derivative can be easily separated and purified from a mixture with these by-products by adding an acid to a reaction product containing such by-products to form a salt of the target compound.

  Separation and purification can be performed, for example, in an inert solvent. The solvent is not particularly limited as long as the 2-amino-1-phenylethanol derivative and by-products are dissolved therein and the generated salt of the 2-amino-1-phenylethanol derivative is insoluble. Organic solvents such as alcohols, ketones, aliphatic hydrocarbons, alicyclic hydrocarbons, aromatic hydrocarbons, ethers, esters, and halogenated hydrocarbons. These solvents can be used alone or in combination of two or more.

  The amount of the solvent to be used is generally about 0.5 to 100 times, preferably about 1 to 20 times, more preferably about 5 to 15 times by weight, based on the total amount of the reaction product.

  The salt of the derivative can be formed using any of an inorganic acid and an organic acid. Examples of such a separation and purification method include, for example, a method in which an acid is added to (ia) a 2-amino-1-phenylethanol derivative to selectively precipitate a salt of the derivative, ib) Not only the 2-amino-1-phenylethanol derivative but also the reaction product having another amino group was converted into a corresponding salt by adding an acid, and then a base was added and impurities were liberated by salt exchange. To selectively obtain a salt of a 2-amino-1-phenylethanol derivative.

  In the method (ia), examples of the inorganic acid include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, and carbonic acid. Preferred inorganic acids include hydrochloric acid and the like.

Examples of the organic acid include saturated aliphatic monocarboxylic acids (eg, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, pivalic acid, O-benzoyl glycolic acid, etc.); saturated aliphatic dicarboxylic acids (eg, oxalic acid) , Malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, etc.); unsaturated aliphatic carboxylic acids (eg, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, maleic acid, fumaric acid) Citraconic acid, mesaconic acid, etc.); aliphatic oxycarboxylic acids (eg, glycolic acid, lactic acid, malic acid, tartaric acid, hydroxybutyric acid, hydroxyacrylic acid, glyceric acid, tartronic acid, citric acid, etc.); carbocyclic carboxylic acids (Eg camphoric acid, benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, o Chlorobenzoic acid, m-chlorobenzoic acid, p-chlorobenzoic acid, o-toluic acid, m-toluic acid, p-toluic acid, 2,5-dimethylbenzoic acid, 3,4-dimethylbenzoic acid, 3,5 -Dimethylbenzoic acid, 2,4,6-trimethylbenzoic acid, o-methoxybenzoic acid, m-methoxybenzoic acid, p-methoxybenzoic acid, o-aminobenzoic acid, m-aminobenzoic acid, p-aminobenzoic acid , Vanillic acid, veratric acid, cinnamic acid, 3,4-dihydroxycinnamic acid, 3,4-dimethoxycinnamic acid, benzylic acid, 3-phenylpropionic acid, etc.); aromatic oxycarboxylic acids (for example, salicylic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid, gallic acid, tropic acid, etc.); heterocyclic carboxylic acids (eg, nicotinic acid, isonicotinic acid, etc.); Amino acids that may be protected by protecting groups (eg, glycine, N- (t-butoxycarbonyl) alanine, etc.); sulfonic acids (eg, benzenesulfonic acid, p-toluenesulfonic acid, 2,5-dimethylbenzenesulfonic acid) , 2,4,6-trimethylbenzenesulfonic acid, methanesulfonic acid, etc.). Preferred organic acids include C _1-3 saturated aliphatic monocarboxylic acids such as formic acid and acetic acid; C _1-6 saturated aliphatic dicarboxylic acids such as oxalic acid and succinic acid; C _6-15 carbocyclic acids such as benzoic acid Carboxylic acids and the like are included.

  The amount of the acid to be used can be selected from a wide range according to the kind of the acid and the like. When an inorganic acid is used, it is 1 gram equivalent or less, preferably 0.8 to 1 mol, per 1 mol of the compound of the general formula (VI). It is about one gram equivalent. If the amount of the acid used is too small, the formation of a salt is insufficient, and the yield tends to decrease. If the amount is too large, by-products such as positional isomers form a salt and the purity tends to decrease. When an organic acid is used, the solubility of the organic acid salt of the compound of the general formula (VI) is low, while the solubility of the organic acid salt of a by-product such as the regioisomer is extremely high. Even when an excess acid is used, the organic acid salt of the compound of the general formula (VI) is selectively precipitated. When the organic acid is used, the amount of the acid is, for example, usually 0.8 g equivalent or more (for example, about 0.8 to 8 g equivalent), preferably 1 mol of the compound of the general formula (VI), It is about 1 to 3 gram equivalent, more preferably about 1 to 2 gram equivalent. The reaction temperature at the time of forming a salt is usually 0 ° C to 100 ° C, preferably 10 to 80 ° C, and more preferably about 20 to 70 ° C. The reaction time is not particularly limited, and is usually about 10 minutes to 10 hours.

  After the formation of the salt, the salt of the 2-amino-1-phenylethanol derivative can be recovered from the reaction solution by a known method such as filtration. The filtration temperature is usually 0 to 50C, preferably about 10 to 30C.

  According to the above method (ia), the compound of the general formula (VI) has a higher basicity than by-products such as regioisomers and dimers, and a salt of the compound of the general formula (VI). Is smaller than the solubility of the by-product salt, so that the salt of the 2-amino-1-phenylethanol derivative can be selectively precipitated. Therefore, the 2-amino-1-phenylethanol derivative can be efficiently separated and purified. The salt of the 2-amino-1-phenylethanol derivative thus obtained usually has an impurity content of about 2% by weight or less, and is a target compound in a high yield, for example, 90% or more. In many cases, 2-amino-1-phenylethanol derivatives can be obtained.

  As a method for separating and purifying a 2-amino-1-phenylethanol derivative, (ib) an acid is added to convert a reaction product having an amino group, including a by-product regioisomer, into a corresponding salt. Alternatively, a method of selectively freeing impurities by adding a base and recovering a salt of a 2-amino-1-phenylethanol derivative represented by the general formula (VI) can also be adopted.

  In this method (ib), the salt of the reaction product is formed in the same manner as described above, except that the amount of the acid used is different. The amount of the acid used is, for example, 1 gram equivalent or more, preferably about 1 to 3 gram equivalent, relative to 1 mol of the total amount of the 2-amino-1-phenylethanol derivative and its positional isomer. If the addition amount of the acid is too small, the yield tends to decrease, and if the addition amount is too large, the cost increases and the economic efficiency tends to decrease.

  After the salt is formed by the method (ib) and the salt formed by a conventional method (eg, filtration) is recovered, impurities other than the positional isomer are usually removed, and the obtained salt is obtained by reacting the target compound with the target compound. It is often a mixture of a salt and its regioisomeric salt. In many cases, the ratio between the regioisomer and the compound represented by the general formula (VI) is about the same as before the salt is formed.

  In this method (ib), the compound of the general formula (VI) is separated and purified by utilizing that the basicity of the compound of the general formula (VI) is higher than that of the corresponding regioisomer. That is, the salt obtained by the above-mentioned operation is selectively freed from the positional isomer by allowing a base to act thereon, and the salt of the 2-amino-1-phenylethanol derivative represented by the general formula (VI) is selected. To collect. More specifically, for example, the regioisomer can be selectively freed by dispersing the salt in a solvent and adding a base. The solvent used for dispersing the salt is not particularly limited as long as it has a low solubility for the salt and a high solubility for the free isomer of the regioisomer. For example, the solvents exemplified above can be used.

The base includes an inorganic base and an organic base. Examples of the inorganic base include hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; hydroxides of alkaline earth metals such as magnesium hydroxide, calcium hydroxide, and barium hydroxide; sodium carbonate; Carbonates of alkali metals such as potassium carbonate and lithium carbonate; carbonates of alkaline earth metals such as magnesium carbonate, calcium carbonate and barium carbonate; hydrogen carbonates of alkali metals such as sodium hydrogen carbonate and potassium hydrogen carbonate . Examples of the organic base include alkali metal alkoxides (eg, sodium or potassium C _1-4 alkoxides such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, potassium methoxide, and potassium ethoxide). Metal alkoxides; aliphatic primary amines such as monoalkylamines (eg, C _1-8 alkylamines such as methylamine, ethylamine, propylamine, butylamine, etc.) and aromatic primary amines (eg, aniline, toluidine, Primary amines such as benzylamine and naphthylamine; dialkylamines (eg, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, di-s-butylamine, di- - di -C _1-8 alkyl amines such as butylamine, etc.), aromatic secondary amines (e.g., N- methylaniline, N- ethylaniline, dibenzylamine, diphenylamine and the like), and pipecolic, piperidine, morpholine, pyrrolidine Secondary amines such as cyclic amines, etc .; trialkylamines (eg, tri-C _1-8 alkylamines such as trimethylamine, triethylamine, tripropylamine, tributylamine, etc.), N, N-disubstituted alkanolamines (eg, , N, N-di-C _1-4 alkylalkanolamines such as N, N-dimethylethanolamine), N, N-dimethylaniline, N, N-diethylaniline, 4-dimethylaminopyridine, triphenylamine, Tribenzylamine, N-methyl morpholine, N-methyl piperi Tertiary amines such as gin; basic nitrogen-containing heterocyclic compounds such as pyridine, picoline and quinoline. The base can be used alone or in combination of two or more.

Preferred bases include organic bases, especially amines. In particular, the base preferably has an ionization index pKa value between the pKa value of the 2-amino-1-phenylethanol derivative and the pKa value of impurities such as its positional isomer. By using such a base, impurities can be selectively freed. Preferred bases include bases having a pKa value of about 9.3 to 11.5 [for example, mono-CC _1-8 alkylamine such as ethylamine (pKa = 10.8); and diethylamine (pKa = 10.4). Organic bases such as di-C _1-8 alkylamines; tri-C _1-8 alkylamines such as triethylamine (pKa = 11.0); cyclic amines such as piperidine (pKa = 11.1)]. More preferred bases include bases having a pKa value of 10 to 11.3, especially about 10.5 to 11.2.

  The amount of the base to be used is not particularly limited as long as it is 1 gram equivalent or more relative to 1 mol of the positional isomer. On the other hand, it is about 0.1 to 1.0 gram equivalent, preferably about 0.3 to 0.6 gram equivalent. If the amount of the base is too small, the removal of positional isomers tends to be insufficient, and if the amount of the base is too large, the economic efficiency tends to decrease. The reaction time and the reaction temperature can be selected from the same ranges as the conditions for the salt formation.

  By the addition of such a base, the salt of the regioisomer is salt-exchanged with the added base and becomes free, so that the 2-amino-1-phenylethanol derivative represented by the general formula (I) is converted into a salt. Will remain. The salt of the 2-amino-1-phenylethanol derivative can be easily isolated by performing filtration and the like as described above. The salt of the derivative thus obtained has a high purity and usually has impurities such as by-products of about 2% or less. In some cases, a salt of a salt-exchanged base with the acid used in the salt-forming reaction may be contained, but such a salt can be easily removed at the time of freeing. Further, after the salt is formed, a base can be added without isolating the salt.

  Further, the separation and purification of the 2-amino-1-phenylethanol derivative can be performed by changing the order of adding the acid and the base. That is, an acid may be added to the reaction product after the addition of the base to selectively form a salt of the 2-amino-1-phenylethanol derivative. In this method, the amount of the acid to be added is generally about 0.8 to 2.0 gram equivalent, preferably about 1.0 to 1.5 gram equivalent, per 1 mol of the compound represented by the formula (VI). is there. If the amount of the acid added is less than 0.8 gram equivalent, the yield tends to decrease, and if it exceeds 2.0 gram equivalent, the removal of impurities becomes insufficient and the purity tends to decrease. The amount of the acid to be added is often 1 gram equivalent or more based on 1 mol of the total of the compound represented by the formula (VI) and its positional isomer.

  By the above method, the positional isomer of the 2-amino-1-phenylethanol derivative and other by-products are removed from the reaction product, and the 2-amino-1-phenylethanol derivative represented by the formula (VI) is removed. Salts can be selectively separated and purified.

  The thus obtained salt of the 2-amino-1-phenylethanol derivative is converted into a free form by a conventionally known method, whereby a highly pure 2-amino-1-phenylethanol derivative can be obtained. Freening can be performed by reacting the salt of the 2-amino-1-phenylethanol derivative with a base. For example, by dissolving or dispersing the salt in water or an organic solvent, adding a base, for example, as an aqueous solution, making it free, extracting with an organic solvent, washing with water as necessary, and removing the solvent. Can be.

  As the organic solvent, a hydrophobic organic solvent, for example, an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, or an ester among the solvents exemplified above can be used. These solvents can be used alone or in combination of two or more. Preferred solvents include halogenated hydrocarbons and esters. The amount of the organic solvent used for extracting the freed 2-amino-1-phenylethanol derivative is 0.5 to 40 times, preferably 1 to 20 times, the weight ratio of the total amount of the salt.

  Examples of the base include inorganic bases such as hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; carbonates of alkali metals such as lithium carbonate, sodium carbonate, and potassium carbonate; lithium hydrogen carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; and alkaline earth metal hydroxides such as magnesium hydroxide. The amount of the base is usually about 0.8 to 10 gram equivalent, preferably about 1 to 8 gram equivalent based on 1 mol of the total amount of the salt. The amount of water used for extracting the freed 2-amino-1-phenylethanol derivative is, for example, about 1 to 50 times, preferably about 5 to 20 times by weight, based on the total amount of the salt.

  The compound represented by the general formula (VI) can be easily converted to a 2-amino-1-phenylethanol derivative represented by the general formula (I) by removing a protecting group for a hydroxyl group by a conventional method, For example, it can be used for production of optically active substances using the following microorganisms.

  The microorganism acts on the enantiomer mixture of the 2-amino-1-phenylethanol derivative represented by the general formula (I) or a salt thereof, and reacts with the corresponding (R) -2 represented by the general formula (IIa). Any microorganism may be used as long as it is capable of producing an -amino-1-phenylethanol derivative. Such microorganisms include, among the two enantiomers of the 2-amino-1-phenylethanol derivative, those that selectively assimilate the (S) -form enantiomer and those that selectively utilize the (S) -form enantiomer. (Including the enantiomer of the (R) form).

  Examples of microorganisms having the ability include, for example, Hansenula, Geotrichum, Candida, Cryptococcus, Rhodosporidium, Rhodotorula, Genus Saccharomyces, Genus Sporobolomyces, Genus Kluyveromyces, Genus Issatchenkia, Genus Pichia, Genus Botryoascus, Genus Debaryomyces (Debaryomyces) Lipomyces, Metschnikowia, Saccharomycodes, Schizoblastosporion, Stepahnoascus, Sterigmatomyces, Digosaccharomyces Zygosaccharomyces) genus, The genus Sporidiobolus, the genus Malassezia, the genus Torulaspora, the genus Corynebacterium, the genus Gluconobacter, the genus Promicromonospora, the genus Pseudomonas , Genus Bordetella, genus Acetobacter, genus Bacillus, genus Agrobacterium, genus Arthrobacter, genus Amauroascus, genus Brevibacterium, Micrococcus, Aureobacterium, Azotobacter, Xanthomonas, Klebsiella, Comamonas, Mycobacterium, Terrabacter Genus, Agrocybe, Trichoderma, Alternaria, Hamigera, Moniliella, Pholiota, Podospora, Aegerita , Microorganisms belonging to the genus Streptomyces, genus Saccharomycopsis, genus Leucosporidium or microorganisms belonging to the genus Rhodococcus amidophilis and Rhodococcus equi And microorganisms selected from the group consisting of:

  Specifically, the ability to act on an enantiomeric mixture of a 2-amino-1-phenylethanol derivative represented by the general formula (I) and to produce a corresponding (R) -2-amino-1-phenylethanol derivative Examples of the microorganisms having the following include the following microorganisms.

(1) Genus Hansenula: Hansenula anomala IFO 0707, etc.
(2) The genus Geotrichum: Geotrichum candidum IFO 4601, Geotrichum candidum IFO 4598, etc.
(3) genus Candida: Candida albicans IFO 1594, Candida albicans IFO 1856, Candida parapsilosis IFO 1022, Candida gropengiseri (Candida gropengiesse 65) Candida aaseri IFO 10404, Candida beechii IFO 10229, Candida atmospherica (Candida atmospherica) IFO 1969, Candida natalensis IFO 1981, Candida palida Gena 103a , Candida sake IFO 1149, Candida pintolopesii varity Cinida pintolopesii var. pintolopesii) IFO 0729,
(4) genus Cryptococcus: Cryptococcus neoformans IAM 4788, etc.
(5) genus Rhodosporidium (Rhodosporidium): Rhodosporidium spaerocarpum IFO 1438, Rhodosporidium diobovatum IFO 0688, etc.
(6) genus Rhodotorula: Rhodotorula rubra IFO 0406, Rhodotorula rubra AHU 3948, Rhodotorula glutinis varini dairenensis (Rhodotorula glutinis var. Dairenensis, IFO 04, etc.)
(7) genus Saccharomyces: Saccharomyces montanus IFO 0021, etc.
(8) Genus Sporobolomyces: Sporobolomyces roseus IFO 1040, etc.
(9) genus Kluyveromyces (Kluyveromyces): Kluyveromyces marxianus var. Bulgaricus (Kluyveromyces marxianus var. Bulgaricus) IAM 4829, Kluyveromyces lactis IFO 1267, etc.
(10) genus Issatchenkia: Isatchenkia scutulata var. Scutulata IFO 10069, Isatchenkia scutulata valley scutulata (Issatchenkia scutulata scutulata, etc.).

(11) Pichia genus: Pichia thermotolerans IFO 10024, Pichia farinosa IFO 1163, etc.
(12) genus Botryoascus (Botryoascus): Botryoascus cinnaedendrus (Botryoascus synnaedendrus) IFO 1604, etc.
(13) Genus Debaryomyces: Debaryomyces hansenii IFO 0083, etc.
(14) Genus Lipomyces: Lipomyces starkeyi IFO 1289, etc.
(15) Genus Metschnikowia (Metschnikowia bicuspidata) IFO 1408,
(16) Saccharomycodes (Saccharomycodes) genus: Saccharomycodes ludwigii IFO 0798, etc.
(17) Genus Schizoblastosporion: Schizoblastosporion kobayasii IFO 1644, etc.
(18) Genus Stepahnoascus (Stepahnoascus): Stepahnoascus ciferrii IFO 1854, etc.
(19) genus Sterigmatomyces: Sterigmatomyces halophilus IFO 1488, etc.
(20) Genus Zygosaccharomyces (Zygosaccharomyces rouxii) IFO 0510, Zygosaccharomyces rouxii (Zygosaccharomyces rouxii) IAM 4114, Zygosaccharomyces fermenta acii, etc.

(21) Genus Sporidiobolus: Sporidiobolus salmonicolor IFO 1845, Sporidiobolus pararoseus IFO 1107, etc.
(22) Genus Malassezia: Malassezia furfur IFO 0656, etc.
(23) Genus Torulaspora: Torulaspora delbrueckii IFO 0955, etc.
(24) genus Corynebacterium: Corynebacterium aquaticum IFO 12154, Corynebacterium mediolanum JCM 3346, etc.
(25) Genus Gluconobacter: Gluconobacter asaii IFO 3265, Gluconobacter oxydans IFO 3255, Gluconobacter oxydans IFO 3130, Gluconobacter oxydan Dance (Gluconobacter oxydans) IFO 3289, Gluconobacter frateurii IFO 3271, etc.
(26) Promicromonospora genus: Promicromonospora citrea IFO 12397, etc.
(27) Pseudomonas (Pseudomonas) genus: Pseudomonas aeruginosa IFO 3899, Pseudomonas riboflavina IFO 13584, Pseudomonas fluorescens IFO 3925, Pseudomonas pseudomonas Pseudomonas 12 Pseudomonas Pseudomonas pseudomonas Pseudomonas 12 Pseudomonas syncyanea IFO 3577, Pseudomonas diminuta IFO 12697, Pseudomonas chlororaphis IFO 3522, Pseudomonas fragi IFO 3458, Pseudomonas sp.
(28) Genus Bordetella: Bordetella bronchiseptica IFO 13691,
(29) Acetobacter spp .: Acetobacter sp. IFO 3248, Acetobacter sp. IFO 3297, Acetobacter pasteurianus ATCC 10245, Acetobacter pasteurianus (Acetobacter sp.) Acetobacter pasteurianus) IFO 3259, Acetobacter pasteurianus (Acetobacter pasteurianus) IFO 3277, etc.
(30) Bacillus genus: Bacillus subtilis IFO 3013, Bacillus subtilis IFO 3009, Bacillus cereus AHU 1355, Bacillus cereus cereus cereus cereus AU UH ) IFO 3001, Bacillus coagulans IAM 1115, Bacillus brevis IFO 3331, Bacillus sphaericus IFO 3525 and the like.

(31) Agrobacterium genus: Agrobacterium radiobacter IFO 12664, etc.
(32) Arthrobacter genus: Arthrobacter ureafaciens IFO 12140, etc.
(33) Amauroascus (Amauroascus) genus: Amauroascus reticulatus (Amauroascus reticulatus) IFO 9196, etc.
(34) genus Brevibacterium: Brevibacterium linens IFO 12141, etc.
(35) Micrococcus (Micrococcus) genus: Micrococcus roseus (Micrococcus roseus) IFO 3764, etc.
(36) Aureobacterium genus: Aureobacterium testaceum IFO 12675, etc.
(37) Azotobacter genus: Azotobacter vinelandii IFO 13581, etc.
(38) Xanthomonas genus: Xamthomonas campestris pv oryzae (Xamthomonas campestris pv oryzae) IAM 1657, etc.
(39) genus Klebsiella: Klebsiella pneumoniae IFO 3317, etc.
(40) Genus Comamonas: Comamonas testosteroni IFO 12048, Comamonas testosteroni IAM 1048 and the like.

(41) genus Mycobacterium: Mycobacterium diernhoferi IFO 3707, etc.
(42) genus Terrabacter: Terrabacter tumescens IFO 12960, etc.
(43) Agrocybe genus: Agrocybe cylindracea IFO 30299, etc.
(44) genus Trichoderma: Trichoderma viride IFO 5720, etc.
(45) Genus Alternaria: Alternaria kikuchiana IFO 5778, etc.
(46) Genus Hamigera: Hamigera avellanea IFO 7721, etc.
(47) Moniliella genus: Moniliella acetoabutans IFO 9481, etc.
(48) Genus Pholiota: Pholiota nameko IFO 6141, etc.
(49) genus Podospora: Podospora cardonaria IFO 30294, etc.
(50) Genus Aegerita: Aegerita candida IFO 6988 and the like.

(51) Streptomyces (Streptomyces) genus: Streptomyces cinereoruber (Streptomyces cinereoruber) HUT6142, etc.
(52) Genus Saccharomycopsis: Saccharomycopsis capsularis IFO 0672, etc. (53) Genus Leucosporidium: Leucosporidium scottii IFO (54) Rhodococcus amidophilis: Rhodococcus amidophilis IFO 0144, etc.
(55) Rhodococcus equi (Rhodococcus equi): Rhodococcus equi (Rhodococcus equi) JCM 1313, etc.
At least one of these microorganisms is used. When these microorganisms or processed products thereof are allowed to act on a mixture of enantiomers of the 2-amino-1-phenylethanol derivative represented by the general formula (I), the ratio of the (R) form in both enantiomers is improved. .

  Microorganisms with IFO numbers are described in "List of Cultures, 9th edition (1992)" issued by Fermentation Research Institute (IFO), and can be obtained from the IFO. The microorganisms with JCM numbers are described in "Microorganism strain catalogue, 5th edition (1992)" issued by RIKEN Microorganism Preservation Facility, and can be obtained from the preservation facility. Microorganisms with ATCC numbers are described in "Catalogue of Bacteria and Bacteria Phages, 18th edition (1992)", "Catalogue of Yeasts, 18th edition (1990)" and "Catalogue" issued by American Type Culture Collection (ATCC). of Filamentous Fungi, 18th edition (1990) "and can be obtained from the ATCC. Microorganisms with DSM numbers are described in "Catalogue of Strains (1989)" issued by the German Collection of Microorganisms and Cell Cultures, and can be obtained from the preservation facility. Microorganisms with IAM numbers are described in "Catalogue of Strains" issued by the Institute for Molecular and Cellular Biology, The University of Tokyo, and the Center for Cellular and Functional Polymers, and can be obtained from the preservation facility. Microorganisms with BGSC numbers are described in "Strains and Data" issued by Batillus Genetic Stock Center (BGSC) and can be obtained from the storage facility. Microorganisms with AHU numbers are described in "Catalogue of Cultures, 5th edition (1992)" issued by the Japan Federation of Microbial Strains (JFCC), and can be obtained from the Faculty of Agriculture, Hokkaido University. Microorganisms with IFM numbers can be obtained from Chiba University, and microorganisms with HUT numbers can be obtained from Hiroshima University.

  The microorganism used in the present invention has an ability to act on the enantiomer mixture of the 2-amino-1-phenylethanol derivative represented by the general formula (I) to produce the corresponding enantiomer of the (R) form. As long as it is used, any strain such as a wild strain, a mutant strain, or a recombinant strain derived by a genetic technique such as cell fusion or genetic engineering can be used.

  The microorganism is usually cultured in a medium and subjected to a reaction with an enantiomeric mixture of the compound represented by the general formula (I).

  The medium for culturing the microorganism used in the present invention is not particularly limited as long as the medium can grow the microorganism. As the medium, a liquid medium containing a carbon source, a nitrogen source, and other nutrients is usually used. As the carbon source of the culture medium, any of the above microorganisms can be used, and specifically, for example, sugars such as glucose, fructose, sucrose, dextrin, starch; sorbitol, methanol, ethanol, glycerol, etc. Alcohols; organic acids such as fumaric acid, citric acid, acetic acid and propionic acid and salts thereof; hydrocarbons such as paraffin; mixtures thereof. As the nitrogen source, for example, ammonium salts of inorganic acids such as ammonium chloride, ammonium sulfate and ammonium phosphate; ammonium salts of organic acids such as ammonium fumarate and ammonium citrate; meat extract, yeast extract, malt extract, peptone, corn Inorganic or organic nitrogen-containing compounds such as steep liquor, casein hydrolyzate, and urea; mixtures thereof can be used. To the medium, nutrients such as inorganic salts, trace metal salts, vitamins and the like used for normal culture may be appropriately added. If necessary, the medium may contain a factor that promotes the growth of microorganisms, a buffer substance that is effective in maintaining the pH of the medium, and a factor that enhances the ability to produce the target compound of the present invention. 2-amino-1-phenylethanol derivative or the like may be added.

  The microorganism can be cultured under conditions suitable for growth, for example, at a pH of the medium of 2.0 to 9.5, preferably 3 to 8, and a temperature of 20 to 45 ° C, preferably 25 to 37 ° C. Cultivation of the microorganism can be performed under anaerobic or aerobic conditions. The culturing time is, for example, about 5 to 120 hours, preferably about 12 to 72 hours.

  The ratio of the (R) form to the (S) form in the enantiomer mixture of the 2-amino-1-phenylethanol derivative represented by the general formula (I) is not particularly limited, but is represented by the general formula (I). It is industrially advantageous to use a racemic 2-amino-1-phenylethanol derivative.

  As a method of asymmetric assimilation, a microorganism or a treated product thereof acts on an enantiomeric mixture of a 2-amino-1-phenylethanol derivative represented by the general formula (I) to react with a corresponding general formula (IIa). The method for producing the (R) -2-amino-1-phenylethanol derivative is not particularly limited as long as it is a method for producing the (R) -2-amino-1-phenylethanol derivative. For example, (1) an enantiomer mixture of the 2-amino-1-phenylethanol derivative is added to a culture solution. Method of adding and reacting, (2) The cells isolated from the culture solution by centrifugation, etc., as they are or after washing, resuspended in buffer, water, etc., to obtain a suspension containing the cells A method of adding and reacting an enantiomeric mixture of the 2-amino-1-phenylethanol derivative, and (3) not a living cell but a processed cell, such as a crushed cell, acetone treatment, and freeze-drying. (4) reacting the treated product subjected to the above treatment with the enantiomer mixture of the 2-amino-1-phenylethanol derivative, for example, a polyacrylamide gel method, a sulfur-containing polysaccharide, Examples of the method include immobilization by a conventional method such as a gel method (such as a carrageenan gel method), an alginic acid gel method, and an agar gel method, and a reaction with the enantiomer mixture of the 2-amino-1-phenylethanol derivative. Furthermore, an enzyme obtained from a processed bacterial cell can also be used. The enzyme can be obtained by appropriately combining and purifying conventional methods.

  At the time of the reaction, the addition of a carbon source such as glucose, sucrose, ethanol, methanol, or paraffin as an energy source; phosphoric acid; a nitrogen source such as yeast extract or corn steep liquor can improve the yield of the target optically active compound. May be.

  The enantiomer mixture of the 2-amino-1-phenylethanol derivative may be used as it is, or may be used as a solution, suspension or dispersion containing a solvent. As the solvent, water and an organic solvent that does not adversely affect the reaction can be used. In the suspension or dispersion, a surfactant or the like can be used as necessary. The enantiomer mixture of the 2-amino-1-phenylethanol derivative may be present in the reaction system at one time from the beginning of the reaction, or may be added separately to the reaction system.

  The amount of cells can be appropriately selected within a range where the optical purity and the production rate of the target compound are not reduced. The cell concentration is, for example, about 0.1 to 500 g / L, and preferably about 1 to 300 g / L on a dry cell basis. The concentration of the enantiomer mixture of the 2-amino-1-phenylethanol derivative used as a substrate is not particularly limited, but is, for example, about 0.01 to 20% by weight, preferably about 0.1 to 10% by weight.

  Reaction conditions can be selected within a range that does not impair the production of the target compound. The pH of the reaction system is, for example, pH 2 to 10, preferably about 3 to 8, and the reaction temperature is, for example, 10 to 60 ° C, preferably 20 to 40 ° C, and more preferably about 20 to 35 ° C. The reaction can be performed under stirring or standing for about 1 to 120 hours. If the reaction time is long, the optical purity of the target compound often increases.

  When a specific microorganism or a processed product thereof is allowed to act on the enantiomeric mixture in this way, asymmetric assimilation is carried out smoothly, and the 2-amino-1-phenylethanol derivative having the corresponding absolute configuration of (R) is highly purified. Can be obtained with selectivity.

  The (R) -2-amino-1-phenylethanol derivative of the general formula (IIa) produced by the reaction can be collected by conventional separation and purification means. For example, usually such as membrane separation, extraction with an organic solvent (eg, hexane, chloroform, ethyl acetate, etc.), column chromatography, concentration under reduced pressure, distillation, crystallization, recrystallization, etc., directly or after separating cells from the reaction solution. (R) -2-amino-1-phenylethanol derivative can be easily obtained. The optical purity of the (R) -2-amino-1-phenylethanol derivative can be measured, for example, by high performance liquid chromatography (HPLC) using an optical isomer separation column.

  Next, a method for obtaining the compound represented by the general formula (IIa) from the compound represented by the general formula (VII) using a microorganism will be described.

  In this method, the compound represented by the general formula (VII) is subjected to asymmetric reduction by the action of a specific microorganism or a treated product thereof, and the resulting (R) -form optically active compound is recovered, whereby the compound can be easily obtained. (R) -2-Amino-1-phenylethanol derivative can be obtained.

  The aminoketone derivative represented by the general formula (VII) used as a raw material in this method corresponds to the compound exemplified as a specific example of the (R) -2-amino-1-phenylethanol derivative of the general formula (II). Amino ketone derivatives and the like.

  The aminoketone derivative may be used as a free amine compound, or may be used as a salt of an inorganic acid or an organic acid. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, phosphoric acid and the like. Examples of the organic acid include the aliphatic monocarboxylic acids and aliphatic polycarboxylic acids exemplified in the description of the separation and purification of the 2-amino-1-phenylethanol derivative.

  The compound represented by the general formula (VII) can be produced by a known method, for example, the general formula (XVIII)

(Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as above, and X represents a halogen atom). As the aminating agent, hexamethylenetetramine and the like can be used in addition to the aminating agents exemplified above. Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

  The microorganism used in the method (B) acts on the aminoketone derivative represented by the general formula (VII) to produce the (R) -2-amino-1-phenylethanol derivative represented by the general formula (IIa) Any microorganism that can be used can be used.

  Examples of the microorganisms having the ability include, for example, the genus Candida, the genus Roderomyces, the genus Catenuloplanes, the genus Pilimelia, the genus Saccharothrix, the genus Serratia, and enterococcus. Microorganisms belonging to the genus (Enterococcus), the genus Lactobacillus, the genus Pediococcus, and the genus Lactococcus can be exemplified.

  Specifically, microorganisms having the ability to act on the aminoketone derivative represented by the general formula (VII) and produce the corresponding (R) -2-amino-1-phenylethanol derivative include, for example, the following microorganisms: Such microorganisms can be mentioned.

(56) Candida (Candida) genus: Candida maltosa (Candida maltosa) IFO 1977, Candida maltosa (Candida maltosa) IFO 1978, etc.
(57) genus Roderomyces: Loderomyces elongisporus IFO 1676, etc.
(58) Genus Catenuloplanes (Catenuloplanes): Catenuloplanes japonicus (Catenuloplanes japonicus) IFO 14176, etc.
(59) genus Pilimelia: Pilimelia terevasa IFO 14556, etc.
(60) genus Saccharothrix: Saccharothrix australiensis IFO 14444, etc.
(61) genus Seratia: Serratia marcescens IFO 3735,
(62) genus Enterococcus: Enterococcus faecalis IFO 12964, etc.
(63) Lactobacillus genus: Lactobacillus casei subsp. Casei NRIC 1042, etc.
(64) Genus of Pediococcus: Pediococcus acidilactici NRIC 1089, etc.
(65) Lactococcus genus: Lactococcus lactis subsp. Lactis AHU 1089, etc. At least one of these microorganisms is used. Any of the above microorganisms can be suitably used as long as it has the aforementioned ability, such as a wild strain, a mutant strain, or a recombinant strain derived by a genetic technique such as cell fusion or genetic manipulation.

  Microorganisms with IFO numbers and AHU numbers can be obtained from the above facilities and the like. Microorganisms with NRIC numbers are described in the strain catalog second edition (1992) issued by the Tokyo University of Agriculture Strain Storage Room, and can be obtained from this facility.

  The culturing, reaction, and recovery of the reaction product of the microorganism can be performed in the same manner as in the method (A) using an enantiomeric mixture of a 2-amino-1-phenylethanol derivative represented by the general formula (I). it can.

  Next, the methods (C) and (D) will be described.

  In the method (C), the 2-amino-1-phenylethanol derivative is precipitated as a salt from the reaction product obtained in the method (b) or (c) by the amino addition in the method (A). Can be easily performed by using an optically active (R) form as a compound represented by the formula (III) or a compound represented by the formula (IV) to be used as a reaction component in the separation and purification. .

  According to this method, a (R) -2-amino-1-phenylethanol derivative having high optical purity can be obtained with a simple operation in a good yield.

  In the method (D), the 2-amino-1-phenylethanol derivative is precipitated as a salt from the reaction product obtained in the method (b) or (c) by the amino addition in the method (A). The separation and purification can be easily carried out by using an acid having an optical resolving power, for example, an acid such as an optically active organic acid, as the acid used to form the salt. When an optically active acid is used, it can be separated and purified from by-products such as regioisomers and dimers, and at the same time, the acid acts as an optical resolving agent, and a diastereomer salt is formed by the acid. The (S) form and the (R) form of the 2-amino-1-phenylethanol derivative can be separated.

  Examples of the optically active organic acid include D-lactic acid, L-lactic acid, D-malic acid, L-malic acid, D-tartaric acid, L-tartaric acid, D-di-p-toluoyltartaric acid, and L-di-p. Aliphatic carboxylic acids such as toluoyltartaric acid; (R) -2-phenylpropionic acid, (S) -ibuprofen, (R) -2- (2,5-dimethylphenyl) propionic acid, (S) -2- (2,5-dimethylphenyl) propionic acid, (R)-(-)-2- (2,4,6-trimethylphenyl) propionic acid, (S)-(+)-2- (2,4,6 Carbocyclic carboxylic acids such as -trimethylphenyl) propionic acid; aromatic oxycarboxylic acids such as D-mandelic acid and L-mandelic acid; sulfonic acids such as D-camphorsulfonic acid and L-camphorsulfonic acid; and amino groups But Such optionally protected optically active D or L- amino acid in group.

  Examples of the amino acids include, for example, alanine, valine, leucine, isoleucine, methionine, aliphatic non-polar amino acids such as proline, tryptophan, phenylalanine, amino acids having a non-polar group in the side chain such as aromatic non-polar amino acids such as anthranilic acid A polar uncharged amino acid such as serine, threonine, cysteine, tyrosine, asparagine, and glutamine; a polar positively charged amino acid such as lysine, histidine and arginine; Amino acids having groups.

Examples of the amino-protecting group include a conventional protecting group, for example, an optionally substituted C _1-6 acyl group (formyl, acetyl group, etc.) and an optionally substituted aromatic ring. C _7-16 acyl group (benzoyl, phthaloyl group, etc.), C _1-4 alkoxy-carbonyl group optionally having substituents (t-butoxycarbonyl group, etc.), C _6-16 aryloxy-carbonyl group An _optionally substituted C _7-20 aralkyloxy-carbonyl group (benzyloxycarbonyl, p-nitrobenzyloxycarbonyl group, etc.), an optionally substituted C _7-20 aralkyl group ( Benzyl, triphenylmethyl group, etc.). Preferred amino-protecting groups include optionally substituted C _1-4 alkoxy-carbonyl groups such as t-butoxycarbonyl group and optionally substituted C-substituted groups such as benzyloxycarbonyl group. _7-20 aralkyloxy-carbonyl groups and the like.

  Further, the functional group of the side chain of the amino acid, for example, a hydroxyl group, a mercapto group, a carboxyl group, an amino group and the like may be protected with a conventional protecting group, for example, the above-mentioned protecting group.

  By selecting an appropriate acid from these optically active acids according to the kind of the target compound, the (R) -2-amino-1-phenylethanol derivative can be efficiently obtained.

  Preferred optically active organic acids include an optically active aliphatic or aromatic oxycarboxylic acid in which a hydroxyl group may be protected by a protecting group, an optically active amino acid in which an amino group may be protected by a protecting group, and the like. Is included. Among the above optically active oxycarboxylic acids, optically active tartaric acid whose hydroxy group such as D (or L) -tartaric acid or D (or L) -di-p-toluoyltartaric acid may be protected with a protecting group, etc. Is preferred. In addition, among the optically active amino acids, an optically active aliphatic non-polar amino acid which may be protected with an amino group such as N- (t-butoxycarbonyl) -L (or D) -alanine by a protective group. Besides, N- (t-butoxycarbonyl) -O-benzyl-L (or D) -threonine, N- (t-butoxycarbonyl) -S-benzyl-L (or D) -cysteine, N- (t-butoxy) Amino acid having a polar group in the side chain such as an optically active polar uncharged amino acid in which an amino group such as carbonyl) -L (or D) -tyrosine and / or a functional group of the side chain may be protected by a protecting group; Are preferred.

  The formation and isolation of the salt can be carried out according to the method of the above (A) when forming a salt using an organic acid.

  According to the method (D), for example, an extremely high-purity (R) -2-amino-1-phenylethanol derivative having an impurity content of about 2% or less and an optical purity of about 99% ee or more can be efficiently obtained. .

  The compound of the general formula (IIa) can be easily converted to the compound represented by the general formula (II) by introducing an appropriate protecting group into a hydroxyl group, if necessary. Such a compound represented by the general formula (II) is useful for producing a (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative.

  Next, a method for producing the (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative represented by the general formula (XI) will be described.

In R ⁷ and R ⁸ of the general formula (XI), a lower alkyl group which may have a substituent, a carboxyl group which may be protected by a protecting group, a lower alkoxycarbonyl which may have a substituent Examples of the group, an amino group which may have a substituent, an alkylsulfonyl group which may have a substituent, and an arylsulfonyl group which may have a substituent include those represented by R ^{1 to} R ⁵ , respectively. Examples include the lower alkyl groups exemplified in the description.

The aryl group which may have a substituent, the aralkyl group which may have a substituent, and the acyl group which may have a substituent in R ⁷ and R ⁸ are, respectively, The C _6-16 aryl group which may have a substituent, the C _7-20 aralkyl group which may have a substituent, the acyl group which may have a substituent are the same as those exemplified for the protecting group. Etc. can be used. Examples of the cycloalkyl group which may have a substituent include a C _1-4 alkyl group, a hydroxyl group, and a C _3-10 cycloalkyl group which may be substituted with a halogen atom (for example, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl group, etc.).

Examples of the protecting group for the hydroxyl group in R ⁷ and R ⁸ include a protecting group for a hydroxyl group usually used in the field of organic synthesis, for example, the protecting group for a hydroxyl group (A) exemplified in the description of R ^{1 to} R ^5. To (D) and the like.

R ⁷ and R ⁸ are groups represented by formula (IX): —O—R ^7a and formula (X): —O—R ^8a , respectively, and R ^7a and R ^8a are adjacent to each other. When forming a ring which may have a substituent together with the oxygen atom, the ring is, for example, a 5- to 10-membered ring, preferably a 5- to 8-membered ring, more preferably a 5- or 6-membered ring. Such R ^7a and R ^8a include, for example, an alkylene group, a carbonyl group, and a thiocarbonyl group which may have a substituent.

  Examples of the alkylene group include an alkylene group having 1 to 4 carbon atoms such as methylene, ethylene and trimethylene. Preferred alkylene groups include a methylene group and the like.

  The methylene group which may have a substituent includes, for example, the following formula (XII)

(Wherein, R ^a and R ^b are (i) the same or different, and each represents a hydrogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, or a C _6-20 aryl which may have a substituent; Group, a C _1-4 alkoxy group, an amino group optionally having a substituent, a carboxyl group or a salt thereof, an alkoxycarbonyl group optionally having a substituent, a hydroxymethyl group, or having a substituent Or (ii) R ^a and R ^b together with adjacent carbon atoms may form a C _5-7 cycloalkyl group)
And the like.

The C _1-4 alkyl group, C _1-4 haloalkyl group and C _1-4 alkoxy group for R ^a and R ^b include the groups exemplified for R ^{1 to} R ⁶ . The C _6-20 aryl group which may have a substituent in R ^a and R ^b includes, for example, phenyl, 4-methoxyphenyl, 2-nitrophenyl and the like. Examples of the amino group having a substituent include a mono- or di-C _1-4 alkylamino group such as methylamino, dimethylamino, ethylamino, and diethylamino. As the substituents of the C _6-16 aryl group and amino group, the substituents exemplified as the substituents of the corresponding groups in R ^{1 to} R ⁵ are used.

The salt of the carboxyl group in R ^a and R ^b is not particularly limited, but a physiologically acceptable salt is often used. Examples of the salt include alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, magnesium salt, calcium salt, barium salt, etc.), and other metal salts (eg, zinc salt, aluminum salt, etc.). And salts with inorganic bases such as ammonium salt; salts with organic bases such as pyridine and tri-C _1-3 alkylamine (eg, trimethylamine and triethylamine).

The optionally substituted alkoxycarbonyl group in R ^a and R ^b includes, for example, the optionally substituted C _1-4 alkoxy-carbonyl group exemplified in R ^{1 to} R ⁵ . included.

The optionally substituted alkoxymethyl group in R ^a and R ^b includes a C _1-4 alkoxy-methyl group which may have a substituent in the alkyl portion. Examples of the substituent include a carboxyl group, a C _2-5 alkoxycarbonyl group, a hydroxyl group, and a C _1-4 alkoxy group. Wherein C _1-4 alkoxy - C _1-4 alkoxy in methyl, C _2-5 alkoxycarbonyl group, the C _1-4 alkoxy groups, such as groups exemplified in the can be used. The alkoxymethyl group which may have a substituent includes (a) a C _1-4 alkoxy-methyl group (eg, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, s -Butoxymethyl, t-butoxymethyl, etc.), (b) carboxy-C _1-4 alkoxy-methyl group (for example, carboxymethoxymethyl, carboxyethoxymethyl, carboxypropoxymethyl, carboxybutoxymethyl, etc.), (c) C _{1 -4} alkoxy-carbonyl-C _1-4 alkoxy-methyl group (for example, methoxycarbonylmethoxymethyl, ethoxycarbonylmethoxymethyl, isopropoxycarbonylmethoxymethyl, 2-butoxycarbonylethoxymethyl, etc.), (d) hydroxy-C _{1- 4} alkoxy - menu Le group (e.g., 2-hydroxyethoxy, 3- hydroxypropoxy methyl, etc.), (e) C _1-4 alkoxy -C _1-4 alkoxy - methyl (e.g., 2-methoxyethoxymethyl, 2-ethoxyethoxymethyl , 3-methoxypropoxymethyl, etc.).

The C _5-7 cycloalkyl group includes, for example, cyclopentyl, cyclohexyl, cycloheptyl and the like.

Preferred examples of the optionally substituted methylene group represented by the formula (XII) include (a) in the formula (XII), R ^a and R ^b are the same or different and each are a hydrogen atom, C _{1 -4} alkyl group, or ^a group in which R ^a and R ^b are a C _5-7 cycloalkyl group formed with adjacent carbon atoms (eg, a methylene group; a C _2-4 alkylidene group such as an ethylidene group and an isopropylidene group) A C _5-7 cycloalkylidene group such as cyclopentylidene and cyclohexylidene), (b) In the formula (XII), R ^a and R ^b are the same or different, and a carboxyl group or a salt thereof or a substituent is Examples thereof include an alkoxycarbonyl group, a hydroxymethyl group which may be possessed, and a group which is an alkoxymethyl group which may be possessed by a substituent.

Preferred R ⁷ and R ⁸ include a hydrogen atom, a hydroxyl group which may be protected by a protecting group, and a group in which R ⁷ and R ⁸ are each represented by the formulas —OR ^7a and —OR ^8a. Is included. Particularly preferred R ⁷ and R ⁸ include a hydrogen atom; a hydroxyl group which may be protected with a protecting group selected from a C _1-4 alkyl group, a C _7-20 aralkyl group and a C _1-6 acyl group; ⁷ and R ⁸ are groups represented by the formulas (IX) —O—R ^7a and (X) —O—R ^8a , respectively, wherein R ^7a and R ^8a are integrally formed. In the optionally substituted methylene group represented by (XII), a group in which R ^a and R ^b are the same or different and are a carboxyl group or a salt thereof, or a C _2-5 alkoxycarbonyl group is included. It is.

The halogen atom in ^{R 6, R 9, R 10} , optionally substituted lower alkyl group, which may have a substituent cycloalkyl group, the protecting group of the hydroxyl group, has a substituent May be an alkoxy group, a cycloalkyloxy group optionally having a substituent, an aralkyloxy group optionally having a substituent, an aryloxy group optionally having a substituent, A carbonyloxy group which may have a lower alkylthio group which may have a substituent, an acyl group which may have a substituent, a carboxyl protecting group, and a substituent which may have a substituent; Examples of the lower alkoxycarbonyl group and the amino group which may have a substituent include the halogen atoms exemplified above for R ^{1 to} R ⁵ or R ⁷ and R ⁸ . The aralkylthio group which may have a substituent includes, for example, a C _7- alkyl group which may be substituted with a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group, a halogen atom, or the like. ₂₀ aralkylthio groups (eg, benzylthio, naphthylthio groups, etc.). Examples of the aryl group which may have a substituent and the aralkyl group which may have a substituent include a C group which may have a substituent exemplified in the description of the protecting group for the hydroxyl group. Examples thereof include a _6-16 aryl group and a C _7-20 aralkyl group which may have a substituent.

The substituent of the lower alkyl group and the lower alkoxy group in R ^{6 to} R ¹⁰ includes the amino group which may have a substituent described above.

Preferred R ⁶ , R ⁹ and R ¹⁰ include a hydrogen atom, a C _1-4 alkyl group, particularly a hydrogen atom.

Examples of the lower alkyl group for R ¹¹ include the aforementioned alkyl groups having 1 to 4 carbon atoms. Desirable R ¹¹ includes a methyl group, an ethyl group and the like, particularly a methyl group and the like.

Specific examples of the compound represented by the general formula (VIII) include, for example, methyl phenylmethyl ketone [phenylacetone], ethyl phenylmethyl ketone, propyl phenylmethyl ketone, isopropyl phenylmethyl ketone, Phenylacetone derivatives such as butyl phenylmethyl ketone, isobutyl phenylmethyl ketone, s-butyl phenylmethyl ketone, t-butyl phenylmethyl ketone; methyl 2-methylphenylmethyl ketone, ethyl = 2 -Chlorophenylmethyl = ketone, methyl = 2-ethylphenylmethyl = ketone, ethyl = 2-methylphenylmethyl = ketone, methyl = 2-methoxyphenylmethyl = ketone, methyl = 2-benzyloxyphenylmethyl = ketone, ethyl = 2 -Benzyl Derivatives having a substituent at the 2-position of the phenyl group, such as xylphenylmethyl ketone; methyl 3-methylphenylmethyl ketone, ethyl 3-chlorophenylmethyl ketone, methyl 3-methoxycarbonyl-2-methoxyphenylmethyl = Ketone, ethyl = 3-methoxycarbonyl-2-methoxyphenylmethyl = ketone, methyl = 2-methyl-3-aminoethoxyphenylmethyl = ketone and other derivatives having a substituent at the 3-position of the phenyl group; methyl = 4- Methyl phenyl methyl ketone, ethyl 4-methyl phenyl methyl ketone, methyl 4-ethyl phenyl methyl ketone, ethyl 4-ethyl phenyl methyl ketone, methyl 4-hydroxyphenyl methyl ketone, ethyl 4- Hydroxyphenyl methyl ketone, methyl 4-methoxyphenylmethyl ketone, ethyl 4-methoxyphenylmethyl ketone, methyl 4-benzyloxyphenylmethyl ketone, ethyl 4-benzyloxyphenylmethyl ketone, methyl 4-hydroxyethoxyphenylmethyl ketone Methyl 4- (2-ethoxyethoxy) phenylmethyl ketone, methyl 4- (2-dimethylaminoethoxy) phenylmethyl ketone, methyl 4-methylthiophenylmethyl ketone, methyl 4-benzylthiophenylmethyl = Ketone, methyl = 4-hydroxycarbonylphenylmethyl = ketone, methyl = 4-methoxycarbonylphenylmethyl = ketone, methyl = 4-carbamoylphenylmethyl = ketone, methyl = 4-dimethylaminocarbonylphenylmethyl = ketone Ton, methyl 4-benzylaminocarbonylphenylmethyl ketone, methyl 4-aminophenylmethyl ketone, methyl 4-acetylaminophenylmethyl ketone, methyl 4-acetylaminomethylphenylmethyl ketone, methyl = 4 -Ethoxycarbonylaminophenylmethyl = ketone, methyl = 4-methoxycarbonylmethylaminophenylmethyl = ketone, methyl = 4-acetylphenylmethyl = ketone, methyl = 4- (o-methoxyphenyl) phenylmethyl = ketone, methyl = 4 -(M-methoxycarbonylphenyl) phenylmethyl = ketone, methyl = 4- (p-chlorophenyl) phenylmethyl = ketone, methyl = 4- (p-hydroxyphenyl) phenylmethyl = ketone, methyl = 4- (p-chlorophenyl) Derivatives having a substituent at the 4-position of the phenyl group, such as tyl) phenylmethyl ketone and methyl 4- (p-methoxyphenylmethyl) phenylmethyl ketone; methyl 2-methoxy-4-methoxycarbonylphenylmethyl ketone Methyl 3,4-dimethoxyphenylmethyl ketone, methyl 3,4-dihydroxyphenylmethyl ketone, ethyl 3,4-dihydroxyphenylmethyl ketone, methyl 3,4-dimethoxycarbonylphenylmethyl ketone, Ethyl = 3,4-dimethoxycarbonylphenylmethyl = ketone, methyl = 3-methoxy-4-methoxycarbonylphenylmethyl = ketone, methyl = 3-methyl-4-methoxyphenylmethyl = ketone, methyl = 3-methylamino-4 -Benzyloxyphenylmethyl Ketone, methyl = 3-methoxycarbonyl-4-hydroxyphenylmethyl = ketone, methyl = 3-chloro-4-hydroxyphenylmethyl = ketone, methyl = 3-fluoro-4-methoxycarbonylphenylmethyl = ketone, methyl = 3- Derivatives having a substituent at the 2,4-, 2,5- or 3,4-position of a phenyl group, such as fluoro-4-methylaminoethoxyphenylmethyl ketone and methyl 2-iodo-5-methoxyphenylmethyl ketone A phenyl group such as methyl = 2,3,4-trimethoxyphenylmethyl = ketone, methyl = 3,4,5-trimethoxyphenylmethyl = ketone, methyl = 3,5-difluoro-4-methoxyphenylmethyl = ketone Having a substituent at the 2,3,4 or 2,4,5 position; methyl = (1,3 _C1-4 alkyl = (1,3-benzodioxol-5-yl) methyl = ketone derivatives such as -benzodioxol-5-yl) methyl = ketone; methyl = (2,2-dimethyl-1) C _1-4 alkyl = (2,2-di-C _1-4 alkyl-1,3-benzodioxol-5-yl) methyl such as, 3-benzodioxol-5-yl) methyl ketone = Ketone derivatives; dimethyl 5- (2-oxopropyl) -1,3-benzodioxole-2,2-dicarboxylate, 5- (2-oxopropyl) -1,3-benzodioxole-2, Diethyl 2-dicarboxylate, methyl = [2,2-dimethoxycarbonyl-1,3-benzodioxol-5-yl] methyl = ketone, ethyl = [2,2-dimethoxycarbonyl-1,3-benzodioxy Sole-5-yl] meth = Ketone, methyl = [2,2-bis (ethoxycarbonyl) -1,3-benzodioxol-5-yl] C _1-4 alkyl = [2,2-bis such as methyl = ketone (C _{2- 5} alkoxycarbonyl) -1,3-benzodioxol-5-yl] methyl = ketone derivative; methyl = [2,2-di (hydroxyethoxymethyl) -1,3-benzodioxol-5-yl] C _1-4 alkyl = [2,2-di (hydroxy-C _1-4 alkoxy-C _1-4 alkyl) -1,3-benzodioxol-5-yl] methyl = ketone derivative such as methyl ketone Methyl = [2,2-di (methoxycarbonylmethoxymethyl) -1,3-benzodioxol-5-yl] methyl = ketone, ethyl = [2,2-di (methoxycarbonylmethoxymethyl) -1, 3-benzodioxy Sole-5-yl] C _1-4 alkyl = [2,2-di (C _2-5 alkoxycarbonyl -C _1-4 alkoxy -C _1-4 alkyl) such as methyl = ketone 1,3 Benzojio Xol-5-yl] methyl = ketone derivative; C _1-4 alkyl = (1,4-benzodioxin-6-yl) methyl such as methyl = (1,4-benzodioxin-6-yl) methyl = ketone = Ketone derivatives and the like.

As preferred compounds among the exemplified compounds, C _1-4 alkyl = phenylmethyl = ketone derivatives; C _1-4 alkyl = 3,4-diC _1-4 alkoxyphenylmethyl = ketone derivatives; C _1-4 alkyl = 3 1,4-dihydroxyphenylmethyl = ketone derivative; C _1-4 alkyl = [2,2-bis (C _2-5 alkoxycarbonyl) -1,3-benzodioxol-5-yl] methyl = ketone derivative; C _1-4 alkyl = [2,2-di (C _2-5 alkoxycarbonyl-C _1-4 alkoxy-C _1-4 alkyl) -1,3-benzodioxol-5-yl] methyl = ketone derivative and the like Is mentioned.

The compound represented by the general formula (XI) includes a (R) -2-amino-1-phenylethanol derivative represented by the general formula (II) and a phenylacetone derivative represented by the general formula (VIII). Is a compound obtained by the combination of, for example, (a) (R, R) -1-phenyl-2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] Ethanol derivative, (b) (R, R) -1-phenyl-2-[[2- (2-substituted phenyl) -1-C _1-4 alkyl-ethyl] amino] ethanol derivative, (c) (R, R) -1-phenyl-2-[[2- (3-substituted phenyl) -1-C _1-4 alkyl-ethyl] amino] ethanol derivative, (d) (R, R) -1-phenyl-2- [[2- (4-substituted phenyl) -1-C _1-4 alkyl-ethyl] Amino] ethanol derivatives, (e) (R, R) -1-phenyl-2-[[2- (3,4-disubstituted phenyl) -1-C _1-4 alkyl-ethyl] amino] ethanol derivatives, f) (R, R) -1- (2-halophenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivative, (g) (R, R) -1- (2-substituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivative, (h) (R, R) -1- (3-halophenyl) -2- [ (2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivative, (i) (R, R) -1- (3-substituted phenyl) -2-[(2-phenyl-1-C _{1 -4} alkyl - ethyl) amino] ethanol derivative, (j) (R, R ) -1- (4- halophenyl -2 - [(2-phenyl -1-C _1-4 alkyl - ethyl) amino] ethanol derivative, (k) (R, R ) -1- (4- substituted phenyl) -2 - [(2-phenyl - 1-C _1-4 alkyl-ethyl) amino] ethanol derivative, (l) (R, R) -1- (2,3-disubstituted phenyl) -2-[(2-phenyl-1-C _1-4) Alkyl-ethyl) amino] ethanol derivative, (m) (R, R) -1- (2,4-disubstituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] Ethanol derivative, (n) (R, R) -1- (3,4-dihalophenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivative, (o) (R , R) -1- (3,4-Disubstituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl ) Amino] ethanol derivatives, (p) (R, R) -1- (3,5-disubstituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivatives, (Q) (R, R) -1- (3,4,5-trisubstituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivatives and the like.

(A) (R, R) -1-phenyl-2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivatives include, for example, (R, R) -1-phenyl- 2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1-phenyl-2-[(2-phenyl-1-ethylethyl) amino] ethanol, (R, R) -1 -Phenyl-2-[(2-phenyl-1-propylethyl) amino] ethanol, (R, R) -1-phenyl-2-[(2-phenyl-1-isopropylethyl) amino] ethanol, (R, R) -1-phenyl-2-[(2-phenyl-1-butylethyl) amino] ethanol, (R, R) -1-phenyl-2-[(2-phenyl-1-isobutylethyl) amino] ethanol, (R, R) -1-fe Nyl-2-[(2-phenyl-1-s-butylethyl) amino] ethanol, (R, R) -1-phenyl-2-[(2-phenyl-1-t-butylethyl) amino] ethanol and the like. It is.

(B) Examples of (R, R) -1-phenyl-2-[[2- (2-substituted phenyl) -1-C _1-4 alkyl-ethyl] amino] ethanol derivatives include (R, R) -1-phenyl-2-[[2- (2-chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (2-methylphenyl) -1 -Methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (2-methoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl- 2-[[2- (2-benzyloxyphenyl) -1-methylethyl] amino] ethanol and the like.

(C) (R, R) -1-phenyl-2-[[2- (3-substituted phenyl) -1-C _1-4 alkyl-ethyl) amino] ethanol derivatives include, for example, (R, R) -1-phenyl-2-[[2- (3-methylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (3-methoxyphenyl)- 1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (3-methylaminoethoxyphenyl) -1-methylethyl] amino] ethanol and the like.

(D) (R, R) -1-phenyl-2-[[2- (4-substituted phenyl) -1-C _1-4 alkyl-ethyl] amino] ethanol derivatives include, for example, (R, R) -1-phenyl-2-[[2- (4-biphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (4-methylphenyl) -1 -Methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (4-ethylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl- 2-[[2- (4-hydroxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (4-methoxyphenyl) -1-methylethyl] Amino] ethanol, (R, R) -1-phenyl-2-[[ 2- (4-benzyloxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (4-hydroxyethoxyphenyl) -1-methylethyl] amino] Ethanol, (R, R) -1-phenyl-2-[[2- (4-dimethylaminomethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[ 2- (4-methylthiophenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (4-benzylthiophenyl) -1-methylethyl] amino] ethanol , (R, R) -1-phenyl-2-[[2- (4-hydroxycarbonylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- ( -Methoxycarbonylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (4-carbamoylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (4-dimethylaminocarbonylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (4- (Benzylaminocarbonylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (4-acetylaminocarbonylphenyl) -1-methylethyl] amino] ethanol, ( R, R) -1-phenyl-2-[[2- (4-acetylaminomethylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-fe Le -2 - and the like [[2- (4-acetylphenyl) -1-methylethyl] amino] ethanol.

(E) As the (R, R) -1-phenyl-2-[[2- (3,4-disubstituted phenyl) -1-C _1-4 alkyl-ethyl] amino] ethanol derivative, for example, (R) , R) -1-phenyl-2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (3 , 4-Dimethoxyphenyl) -1-ethylethyl] amino] ethanol, (R, R) -1-phenyl-2-[[2- (3,4-dimethoxyphenyl) -1-propylethyl] amino] ethanol, ( R, R) -1-phenyl-2-[[2- [3,4- (bismethoxycarbonylmethoxy) methylenedioxyphenyl] -1-methylethyl] amino] ethanol and the like.

(F) As the (R, R) -1- (2-halophenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivative, for example, (R, R)- 1- (2-chlorophenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (2-chlorophenyl) -2-[[2- (2-chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-chlorophenyl) -2-[[2- (2-methylphenyl) -1-methylethyl] amino] ethanol, (R, R ) -1- (2-Chlorophenyl) -2-[[2- (2-methoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-chlorophenyl) -2-[[ 2- (3,4-dimethoxyphenyl) -1- Methylethyl] amino] ethanol, (R, R) -1- (2-fluorophenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (2- Fluorophenyl) -2-[[2- (2-chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-fluorophenyl) -2-[[2- (2-methyl Phenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-fluorophenyl) -2-[[2- (2-methoxyphenyl) -1-methylethyl] amino] ethanol, ( R, R) -1- (2-fluorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol and the like.

(G) As the (R, R) -1- (2-substituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivative, for example, (R, R) -1- (2-methylphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (2-methylphenyl) -2-[[2- (2 -Chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-methylphenyl) -2-[[2- (2-methylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-methylphenyl) -2-[[2- (2-methoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-methylphenyl) ) -2-[[2- (3,4-Dimethoxyphenyl) -1- Methylethyl] amino] ethanol, (R, R) -1- (2-hydroxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (2- Hydroxyphenyl) -2-[[2- (2-chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-hydroxyphenyl) -2-[[2- (2-methyl Phenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-hydroxyphenyl) -2-[[2- (2-methoxyphenyl) -1-methylethyl] amino] ethanol, ( R, R) -1- (2-hydroxyphenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-methoxy Phenyl) -2- (2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (2-methoxyphenyl) -2-[[2- (2-chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-methoxyphenyl) -2-[[2- (2-methylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-methoxyphenyl) ) -2-[[2- (2-Methoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-methoxyphenyl) -2-[[2- (3,4- Dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-benzyloxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R ) -1- (2-benzyl) Oxyphenyl) -2-[[2- (2-chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-benzyloxyphenyl) -2-[[2- (2- Methylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-benzyloxyphenyl) -2-[[2- (2-methoxyphenyl) -1-methylethyl] amino] ethanol , (R, R) -1- (2-benzyloxyphenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- ( 2-benzylcarbonylphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol and the like.

(H) (R, R) -1- (3-halophenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivatives include, for example, (R, R)- 1- (3-chlorophenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (2-chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (2-methylphenyl) -1-methylethyl] amino] ethanol, (R, R ) -1- (3-Chlorophenyl) -2-[[2- (2-methoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[ 2- (2-benzyloxyphenyl) -1-methyl [Ethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (3-methylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (3-methoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (3 -Methylaminoethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (4-methylphenyl) -1-methylethyl] amino] Ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (4-ethylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl ) -2-[[2 (4-biphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (4-hydroxyphenyl) -1-methylethyl] amino] ethanol , (R, R) -1- (3-chlorophenyl) -2-[[2- (4-hydroxyphenyl) -1-ethylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl)- 2-[[2- (4-methoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (4-benzyloxyphenyl)- 1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (4-hydroxyethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R ) -1- (3-Chlorophenyl) -2-[[2- (4-dimethylaminomethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2- [[2- (4-methylthiophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (4-benzylthiophenyl) -1- Methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (4-hydroxycarbonylphenyl) -1-methylethyl] amino] ethanol, (R, R)- 1- (3-chlorophenyl) -2-[[2- (4-methoxycarbonylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2 − (4-carbamoylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (4-dimethylaminocarbonylphenyl) -1-methylethyl] Amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (4-benzylaminocarbonylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (4-acetylaminocarbonylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (4-acetylaminomethylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2- (4-acetylphenyl -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl-) 2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R , R) -1- (3-Chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-ethylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2 -[[2- [3,4- (Bismethoxycarbonylmethoxy) methylenedioxyphenyl] -1-methylethyl] amino] ethanol, (R, R) -1- (3-chlorophenyl) -2-[[2 -[3,4- (bismethoxycarbonylmethoxy) methylenedioxyphenyl] -1-ethylethyl] amino] ethanol, (R, R) -1- (3-fluorophenyl) -2-[[2-f -1-methyl ethyl] amino] ethanol and the like.

(I) Examples of (R, R) -1- (3-substituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivatives include (R, R) -1- (3-methylphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3-methylphenyl) -2-[[2- (2 -Chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-methylphenyl) -2-[[2- (2-methoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-methylphenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3- (Hydroxyphenyl) -2-[[2-phenyl-1-methylethyl [Amino] ethanol, (R, R) -1- (3-trifluoromethylphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3 -Trifluoromethylphenyl) -2-[[2- (2-chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-trifluoromethylphenyl) -2-[[2 -(2-methylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-trifluoromethylphenyl) -2-[[2- (2-methoxyphenyl) -1-methyl Ethyl] amino] ethanol, (R, R) -1- (3-trifluoromethylphenyl) -2-[[2- (4-benzylphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3- Trifluoromethylphenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-trifluoromethylphenyl) -2- [ [2- (3,4-dimethoxyphenyl) -1-ethylethyl] amino] ethanol and the like are exemplified.

(J) (R, R) -1- (4-halophenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivatives include, for example, (R, R)- 1- (4-chlorophenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (4-chlorophenyl) -2-[[2- (2-chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (4-chlorophenyl) -2-[[2- (2-methylphenyl) -1-methylethyl] amino] ethanol, (R, R ) -1- (4-Chlorophenyl) -2-[[2- (2-methoxyphenyl-1-methylethyl] amino] ethanol, (R, R) -1- (4-chlorophenyl) -2-[[2 -(3,4-dimethoxyphenyl) -1-methyl Ethyl] amino] ethanol and the like.

(K) As the (R, R) -1- (4-substituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivative, for example, (R, R) -1- (4-methylphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (4-methylphenyl) -2-[[2- (2 -Chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (4-methylphenyl) -2-[[2- (2-methoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (4-methylphenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (4- Hydroxyphenyl) -2-[(2-phenyl-1-methylethyl L) amino] ethanol, (R, R) -1- (4-hydroxyphenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (4-trifluoromethylphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (4-trifluoromethylphenyl) -2-[[ 2- (2-chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (4-trifluoromethylphenyl) -2-[[2- (2-methylphenyl) -1-methyl Ethyl] amino] ethanol, (R, R) -1- (4-trifluoromethylphenyl) -2-[[2- (2-methoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (4-g Fluoromethylphenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (4-methoxyphenyl) -2-[[2- (4-methoxyphenyl-1-methylethyl] amino] ethanol and the like.

(L) (R, R) -1- (2,3-disubstituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivatives include, for example, (R , R) -1- (2-Fluoro-3-chlorophenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (2-fluoro-3-chlorophenyl) -2-[[2- (2-chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-fluoro-3-chlorophenyl) -2-[[2- (2-methyl Phenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-fluoro-3-chlorophenyl) -2-[[2- (2-methoxyphenyl) -1-methylethyl] amino] Ethanol, (R, R) -1- (2-fluoro -3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (2-fluoro-3-chlorophenyl) -2- [[2- [3,4- (Bismethoxycarbonylmethoxy) methylenedioxyphenyl] -1-methylethyl] amino] ethanol, (R, R) -1- (2-chloro-3-hydroxyphenyl) -2 -[(2-phenyl-1-methylethyl) amino] ethanol and the like.

(M) Examples of (R, R) -1- (2,4-disubstituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivatives include, for example, (R , R) -1- (2-Chloro-4-hydroxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (2-chloro-4-benzyl) Oxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol and the like.

(N) Examples of (R, R) -1- (3,4-dihalophenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivatives include (R, R ) -1- (3,4-Dichlorophenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3,4-dichlorophenyl) -2-[[2 -(2-chlorophenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3,4-dichlorophenyl) -2-[[2- (2-methylphenyl-1-methylethyl] amino ] Ethanol, (R, R) -1- (3,4-dichlorophenyl) -2-[[2- (2-methoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- ( 3,4-dichlorophenyl) -2-[[2- ( 3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3,4-dichlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1- Ethylethyl] amino] ethanol, (R, R) -1- (3,4-dichlorophenyl) -2-[[2- [3,4- (bismethoxycarbonylmethoxy) methylenedioxyphenyl] -1-methylethyl] Amino] ethanol and the like.

(O) (R, R) -1- (3,4-disubstituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivatives include (R, R ) -1- (3,4-Dihydroxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3,4-dihydroxyphenyl) -2- [ [2- (3,4-dihydroxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3,4-dihydroxyphenyl) -2-[(2-phenyl-1-ethylethyl) Amino] ethanol, (R, R) -1- (3,4-dimethoxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3-fluoro -4-methoxyphenyl) -2-[(2-phenyl -1-methylethyl) amino] ethanol, (R, R) -1- [3- (2-hydroxyethoxy) -4- (t-butoxy) phenyl] -2-[(2-phenyl-1-methylethyl ) Amino] ethanol, (R, R) -1- (3-acetylamino-4-hydroxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3-acetylamino-4-methoxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3-methylthio-4-hydroxyphenyl) -2- [(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3-hydroxymethyl-4-hydroxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] Eta , (R, R) -1- (3-methoxycarbonyl-4-hydroxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3 -Methoxycarbonyl-4-cyclohexyloxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3-carbamoyl-4-hydroxyphenyl) -2- [ (2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- [3-hydroxymethylcarbonylamino-4- (4-methoxyphenylmethyl) phenyl] -2-[(2-phenyl- 1-methylethyl) amino] ethanol and the like.

(P) Examples of (R, R) -1- (3,5-disubstituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivatives include (R) , R) -1- (3,5-Dihydroxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3,5-dibenzyloxyphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3,5-di-tert-butoxycarbonylphenyl) -2-[(2-phenyl-1- Methylethyl) amino] ethanol and the like.

(Q) As the (R, R) -1- (3,4,5-trisubstituted phenyl) -2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivative, for example, (R, R) -1- (3,5-dichloro-4-methylaminophenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (4- Amino-3-bromo-5-fluorophenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (4-benzyloxy-3-chloro-5-methoxy) Phenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (4,5-dihydroxy-3-methylphenyl) -2-[(2-phenyl-1 -Methylethyl) amino] ethanol and the like. .

Preferred compounds among the exemplified compounds are (R, R) -1-phenyl-2-[(2-phenyl-1-methylethyl) amino] ethanol and (R, R) -1-phenyl-2-[( (R, R) -1-phenyl-2-[(2-phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivatives such as 2-phenyl-1-ethylethyl) amino] ethanol; (R, R ) -1-phenyl-2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol and the like (R, R) -1-phenyl-2-[[2- [3, 4-di-substituted (e.g. 3,4-di-C _1-4 alkoxy) phenyl] -1-C _1-4 alkyl - ethyl] amino] ethanol derivative; (R, R) -1- ( 3- chlorophenyl) -2 -[(2-phenyl-1-methylethyl) a Roh] ethanol and the like of the (R, R) -1- (3- halophenyl) -2 - [(2-phenyl -1-C _1-4 alkyl - ethyl) amino] ethanol derivative; (R, R) -1- (R, R) -1- (3-halophenyl) -2-[[2, such as (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol -[3,4-disubstituted (for example, 3,4-diC _1-4 alkoxy) phenyl] -1-C _1-4 alkyl-ethyl] amino] ethanol derivative; (R, R) -1- (3- Methylphenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol, (R, R) -1- (3-trifluoromethylphenyl) -2-[(2-phenyl-1-methylethyl) ) Amino] ethanol and the like (R, R) -1- (3-position Phenyl) -2 - [(2-phenyl -1-C _1-4 alkyl - ethyl) amino] ethanol derivative; (R, R) -1- ( 3- methylphenyl) -2 - [[2- (3, 4-dimethoxyphenyl) -1-methylethyl] amino] ethanol, (R, R) -1- (3-trifluoromethylphenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methyl (R, R) -1- (3-substituted phenyl) -2-[[2- [3,4-disubstituted (eg 3,4-diC _1-4 alkoxy) phenyl] such as ethyl] amino] ethanol -1-C _1-4 alkyl-ethyl] amino] ethanol derivatives; (R, R) -1- (4-chlorophenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol and other (R , R) -1- (4-Halophenyl) -2-[(2- Phenyl-1-C _1-4 alkyl-ethyl) amino] ethanol derivative; (R, R) -1- (4-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl ] [Amino] ethanol and the like, (R, R) -1- (4-halophenyl) -2-[[2- [3,4-disubstituted (e.g. 3,4-diC _1-4 alkoxy) phenyl] -1 -C _1-4 alkyl-ethyl] amino] ethanol derivatives; such as (R, R) -1- (3,4-dichlorophenyl) -2-[(2-phenyl-1-methylethyl) amino] ethanol (R, R) -1- (3,4-dichlorophenyl) -2-[(2-phenyl-1-C _1-4 alkylethyl) amino] ethanol derivative; (R, R) -1- (3,4-dichlorophenyl) ) -2-[[2- (3,4-dimethoxyphenyl) ) -1-methylethyl] amino] ethanol and the like of the (R, R) -1- (3,4-dihalophenyl) -2 - [[2- [3,4-di-substituted (e.g. 3,4-di C _{1 -4} alkoxy) phenyl] -1-C _1-4 alkyl-ethyl] amino] ethanol derivative.

  In this method, the phenylacetone derivative represented by the general formula (VIII) used as a reaction raw material may be obtained by a conventional method, for example, acetic acid such as an alkaline earth metal salt of acetic acid (for example, calcium acetate, barium acetate, etc.). Easily produced by a method of dry-distilling a mixture of a salt and a phenylacetate such as an alkaline earth metal salt of phenylacetic acid (eg, calcium phenylacetate, barium phenylacetate, etc.) corresponding to the compound of general formula (VIII) [Organic Synthesis Collective Volume II (Org. Synth., Coll. Vol. II), p. 389 (1943), etc.].

  In the method of the present invention, a (R) -2-amino-1-phenylethanol compound represented by the general formula (II) or a salt thereof and a compound (phenylacetone derivative) represented by the general formula (VIII) are used. And the reaction of reducing the reaction product of the above reaction. The (R, R) -1-phenyl-2-[(2-phenyl-1-methylethyl) amino] ethanol derivative represented by the general formula (XI) obtained by this method includes a corresponding salt. It is.

  The reduction reaction can be performed using, for example, a reducing agent. This reaction can also be performed in the presence of a catalytic reduction catalyst. In the reaction, for example, (1) the (R) -2-amino-1-phenylethanol compound represented by the general formula (II) or a salt thereof and the compound represented by the general formula (VIII) are dehydrated. (2) a (R) -2-amino-1-phenylethanol compound represented by the general formula (II) in the presence of a catalytic reduction catalyst; Alternatively, the reaction can be performed by a method of reacting a salt thereof, a compound represented by the general formula (VIII), and hydrogen (hereinafter, referred to as a one-pot method).

  As described above, in the reductive amination method using the optically active 2-amino-1-phenylethanol compound or a salt thereof and the phenylacetone derivative as raw materials, the products are only two kinds of optical isomers. . Moreover, when subjected to a hydrogenation reaction with hydrogen in the presence of a catalytic reduction catalyst, the diastereomer ratio is significantly improved, and the desired optical isomer can be preferentially obtained. Further, in the method using such a catalytic reduction catalyst, the target product can be isolated only by distilling off the solvent after filtering the catalytic reduction catalyst, so that post-treatment is easy and industrially suitable.

  Hereinafter, (1) the stepwise method will be described.

  In this method (1), by performing dehydration condensation before the hydrogenation action is performed, an imine form or enamine form, which is a dehydration condensate, is surely obtained, the conversion rate of the raw material to the target substance is improved, and purification is performed. There is a feature that it becomes easier.

  The dehydration condensation of the (R) -2-amino-1-phenylethanol compound represented by the general formula (II) or a salt thereof with the phenylacetone derivative represented by the general formula (VIII) is performed by a conventional method, for example, Using a solvent inert to the reaction and azeotropic with water, a method such as a method of removing azeotropic water from the system using a trap such as a Dean-Stark trap can be used. The solvent is not particularly limited as long as it is a solvent inert to the reaction and azeotropic with water. For example, among the solvents exemplified in the method for producing the compound of the general formula (IIa), aromatic hydrocarbons ( For example, organic solvents such as benzene, toluene, xylene, ligroin, petroleum ether, and aliphatic hydrocarbons (pentane, hexane, heptane, octane, etc.) can be used.

The dehydration-condensation reaction can also be carried out by using a solvent inert to the reaction and azeotropic with water, and removing water from the system while distilling off the solvent. Examples of such a solvent include lower alcohols (for example, C _1-4 alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol and t-butanol) and the aromatic hydrocarbons exemplified above. And organic solvents such as aliphatic hydrocarbons.

  The reaction may be performed in the presence of an acid catalyst. As the acid, an acid used in the following (2) one-pot method can be used.

  In this reaction, the ratio of the (R) -2-amino-1-phenylethanol compound represented by the general formula (II) or a salt thereof to the phenylacetone derivative represented by the general formula (VIII) is usually The former / latter = 0.5 to 2.0 (molar ratio), preferably about 0.8 to 1.2 (molar ratio).

  As the reducing agent, hydrogen and the like can be used in addition to metal hydrides such as sodium borohydride and sodium cyanoborohydride. Hydrogen is usually used with a catalytic reduction catalyst. When hydrogen is used as the reducing agent, the desired compound (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino is selected from the two diastereomers by asymmetric induction. ] An ethanol derivative is preferentially produced. Examples of the catalytic reduction catalyst include a nickel catalyst (eg, Raney nickel catalyst); a platinum catalyst (eg, platinum carbon, platinum black, platinum oxide (Adams catalyst), etc.), a palladium catalyst, a rhodium catalyst, a ruthenium catalyst (ruthenium carbon, Platinum group catalysts such as ruthenium oxide and ruthenium black; and rhenium catalysts. These catalysts can be used alone or in combination of two or more. Preferred catalysts include platinum and ruthenium catalysts. Of these, a platinum catalyst, particularly platinum oxide, is preferred.

  The amount of the catalytic reduction catalyst to be used can be appropriately selected in consideration of the reaction rate and economy, but is usually 0.01 to 20 parts by weight based on 100 parts by weight of the compound represented by the general formula (II) or its salt. Parts, preferably 0.01 to 10 parts by weight, more preferably 0.01 to 5 parts by weight (for example, 0.5 to 5 parts by weight), and particularly about 0.5 to 3 parts by weight.

  The reaction temperature varies depending on the type and amount of the starting compound, the type of catalyst, the pressure conditions, and the like, but is usually 0 to 100 ° C, preferably 10 to 80 ° C, more preferably 10 to 60 ° C. The reaction may be performed at normal pressure or under pressure. The reaction pressure is usually about 1 to 100 atm, preferably about 1 to 20 atm. The reaction time is relatively short under pressure (for example, about 10 minutes to 10 hours), and is usually about 1 to 48 hours under normal pressure.

The hydrogenation reaction can be performed in a solvent inert to the reaction. Examples of the solvent include alcohols (for example, C _1-4 alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol, and t-butanol); and aromatic hydrocarbons (for example, benzene, toluene, and xylene). , Ethylbenzene, petroleum ether, etc.); aliphatic hydrocarbons (pentane, hexane, heptane, octane, etc.); alicyclic hydrocarbons (cyclohexane, methylcyclohexane, cycloheptane, etc.); halogenated hydrocarbons (chloroform, dichloromethane). , 1,2-dichloroethane, etc.); organic solvents such as ethers (diethyl ether, diisopropyl ether, dibutyl ether, dioxane, tetrahydrofuran, etc.); esters (methyl acetate, ethyl acetate, isopropyl acetate, etc.). No. The solvents may be used alone or in combination of two or more.

  Next, (2) the one-pot method will be described.

  In the one-pot method (2), the (R) -2-amino-1-phenylethanol compound represented by the general formula (II) or a salt thereof, a phenylacetone derivative represented by the general formula (VIII) and hydrogen are used. By reacting in the presence of a catalytic reduction catalyst, an (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative represented by the general formula (XI) is obtained. Obtainable.

  The reaction may be performed in the absence of an acid, but is preferably performed in the presence of an acid. When hydrogenation is carried out in the presence of an acid, the acid acts as a catalyst and the conversion of the raw material to the target compound is improved, so that the purification of the target compound is facilitated. The acid used here may be any of an inorganic acid and an organic acid. As the inorganic acid and organic acid, the inorganic acids and organic acids (including optically active organic acids) exemplified in the description of the method for producing the compound of the general formula (IIa) can be used.

As the acid, among the above, depending on the type of the solvent to be used, an acid which produces an adduct having high solubility in the solvent used during the reaction may be appropriately selected, but usually an inorganic acid is preferably used. Are hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid, particularly preferably, hydrochloric acid, sulfuric acid and nitric acid, and more preferably hydrochloric acid. In the case of an organic acid, a saturated aliphatic monocarboxylic acid, a saturated aliphatic dicarboxylic acid, an unsaturated aliphatic carboxylic acid, a sulfonic acid and the like are preferable, and particularly, a saturated aliphatic monocarboxylic acid, a saturated aliphatic dicarboxylic acid, and an unsaturated aliphatic Carboxylic acids and the like are preferred. Further, saturated aliphatic monocarboxylic acids are preferred, and among them, C _1-4 carboxylic acids such as formic acid, acetic acid and propionic acid are particularly preferred.

  The amount of the acid to be used can be selected from a wide range in consideration of the reaction rate and the like, and is usually 0.1 to 80 parts by weight, preferably 0.1 to 80 parts by weight, per 100 parts by weight of the compound represented by the general formula (II). It is 1 to 50 parts by weight (for example, about 0.1 to 10 parts by weight), more preferably 0.5 to 10 parts by weight (for example, about 0.5 to 5 parts by weight).

  The reaction of the one-pot method (2) can be carried out under the same reaction conditions using the same reducing agent, catalytic reduction catalyst, reaction solvent and the like as the hydrogenation reaction in the above (1) stepwise method.

  According to the method including the reaction of the compound of the general formula (II) or a salt thereof with the compound of the general formula (VIII), and the reaction of reducing the reaction product of the reaction, the compound (R) , R) -1-Phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative can be selectively produced with high yield. Moreover, the (R) -2-amino-1-phenylethanol compound represented by the general formula (II) and the phenylacetone derivative represented by the general formula (VIII) used as raw materials are both easy to handle. And can be obtained easily. Furthermore, the phenylacetone derivative used as one of the two reaction raw materials does not need to be an optically active substance, and can be produced by a simple process.

  The (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative represented by the general formula (XI) produced by the above reaction can be used, for example, if necessary. After adjusting the liquid properties of the reaction solution, the solution is subjected to purification means such as extraction with an organic solvent, concentration under reduced pressure, column chromatography, distillation, crystallization, and recrystallization, so that (R, R) -1- A phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative can be easily obtained.

  In the above reaction, the corresponding general formula (XIII)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and Z are the same as described above) When the (S) form is by-produced, the (R, R) form as the target compound can be selectively and efficiently recovered by adding an acid to the reaction product and fractionating and crystallizing the generated salt.

  The acid may be any of an inorganic acid and an organic acid, and includes the inorganic acids and organic acids (including optically active organic acids) exemplified in the description of the method for producing the compound of the general formula (IIa). Can be used. These acids can be used alone or in combination of two or more.

  Preferred inorganic acids include hydrochloric acid, and preferred organic acids include carbocyclic carboxylic acids, amino acids whose amino group may be protected by a protecting group, sulfonic acids, and the like. When these acids are used, the content of impurities can be remarkably reduced, and a more pure (R, R) form can be obtained.

In particular, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ are hydrogen atoms, R ¹¹ is a methyl group, and R ⁴ is a chlorine atom And a mixture of a (R, R) form represented by the general formula (XI) in which R ⁷ and R ⁸ are methoxy groups and a corresponding (R, S) form represented by the general formula (XIII) In the above case, among the above-mentioned acids, organic acids, especially (R) or (S) -2- (2,5-dimethylphenyl) propionic acid or a mixture of these enantiomers, (R)-(-)-or (S) 2-alkylphenylpropionic acid derivatives which may have a substituent such as)-(+)-2- (2,4,6-trimethylphenyl) propionic acid or a mixture of these enantiomers are preferably used. . When these acids are used, the (R, R) form can be selectively and efficiently recovered.

  The amount of the acid to be used can be selected from a wide range according to the kind of the acid and the like, and is usually represented by the (R, R) form represented by the general formula (XI) and the formula (XIII) ( R, S) and usually 0.5 to 2 gram equivalents, preferably 0.5 to 1.5 gram equivalents, and particularly preferably about 0.5 to 1.3 gram equivalents, per 1 mol of the total amount with the (R, S) form. is there. The acid is usually used in an amount of about 0.8 to 1.2 gram equivalent, preferably about 0.9 to 1.1 gram equivalent, per 1 mol of the mixture.

After the formation of the salt, a base may be added, if necessary. As the base, the bases and the like exemplified in the description of the separation and purification of the 2-amino-1-phenylethanol derivative represented by the general formula (I) can be used. Preferred bases include tertiary amines, especially aliphatic tertiary amines. Among them, tri-C _1-8 alkylamine is preferably used.

  The amount of the base to be added can be appropriately selected depending on the amount of the (R, R) form represented by the general formula (XI) and the like, and the (R, R) form represented by the general formula (XI) and the general formula (XI) 0.05-0.8 gram equivalent, preferably 0.05-0.6 gram equivalent (e.g., 0.05-0.6 gram equivalent), relative to 1 mol of the total amount of the (R, S) form represented by (XIII) About 0.5 gram equivalent), more preferably about 0.1 to 0.5 gram equivalent.

  When the base is added, the (R, S) form is selectively freed because the (R, R) form is more basic than the (R, S) form, and the (R, R) form having high optical purity is obtained. ) The body can be obtained efficiently.

  The reaction temperature varies depending on the type of the (R, R) form and the (R, S) form and the type of the solvent used. For example, the mixture is heated to near the boiling point of the solvent to dissolve the mixture, and then allowed to cool naturally. To obtain room temperature, or to room temperature or about −10 ° C. while preventing generation of oil, whereby crystals of the target compound can be obtained. However, when the melting point of the compound is lower than the boiling point of the solvent used, salt formation is desirably performed at a temperature lower than the melting point of the compound.

  Salt formation and fractional crystallization can be performed in a solvent inert to the reaction. Examples of the solvent include lower alcohols, aromatic hydrocarbons, aliphatic hydrocarbons, cycloaliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters and the like exemplified in the hydrogenation reaction. . These solvents can be used alone or in combination of two or more. Preferred solvents include esters (e.g., ethyl acetate and the like), lower alcohols (e.g., methanol, ethanol, isopropyl alcohol, and the like), and mixed solvents of esters and lower alcohols (e.g., an ethyl acetate-methanol mixed solvent, A mixed solvent of a lower alcohol and an ether (for example, a mixed solvent of isopropyl alcohol and diisopropyl ether). Among them, ethyl acetate, isopropyl alcohol, a mixed solvent of isopropyl alcohol-diisopropyl ether and the like can be preferably used.

The thus-obtained (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative and a salt thereof selectively act on the β ₃ receptor in the living body and produce blood glucose. It significantly reduces the value and significantly suppresses obesity. This pharmacological activity found in the (R, R) form is significantly higher than other optical isomers. For example, disodium (R, R) -5- [2-[[2- (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1,3-benzodioxole-2,2-dicarboxylate The salt shows a 47-fold higher activity compared to the corresponding (S, S) -enantiomer (see the above-mentioned US patent specification).

  In the above reaction, when the corresponding (S) form is used instead of the (R) -2-amino-1-phenylethanol derivative, the target compound (R, R) -1-phenyl The 2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative is hardly formed. In addition, when a racemic 2-amino-1-phenylethanol derivative is used, the yield of the target compound is low and four kinds of optical isomers are generated, so that the separation and purification steps become complicated.

  Thus, the (R) -2-amino-1-phenylethanol derivative represented by the general formula (II) used in the present invention is (R, R) -1-phenyl-2-[(2-phenyl- It is an extremely effective synthetic intermediate for selectively and easily obtaining a 1-alkylethyl) amino] ethanol derivative in a high yield and its usefulness is remarkably higher than the corresponding (S) -form and racemic-form. high.

  Further, the (R) -2-amino-1-phenylethanol derivative does not show awakening effect unlike the (R) -1-methyl-2-phenylethylamine derivative which is a conventional synthetic intermediate, and therefore, is not handled. Easy and suitable for industrial scale production.

R ⁷ and R ⁸ of the compound represented by the general formula (XI) can be converted from one substituent to another by a conventional method. For example, according to the method of the following formula, an (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative in which R ⁷ and R ⁸ are both methoxy groups is converted to R ^7a And R ^8a together can easily be derived into a derivative having a group represented by the formula (XII). In the following formula, for simplicity, only the portion of the phenyl group substituted by R ⁷ and R ⁸ is shown.

In the above formula, R ¹² , R ¹³ and R ¹⁴ each represent an alkyl group which may have a substituent, X ^a and X ^b each represent a halogen atom, and R ⁶ , R ⁹ , R ¹⁰ , R ¹¹ is as defined above.

That is, a compound of formula (XI′a) in which R ⁷ and R ⁸ are both methoxy groups is demethylated by reacting with a demethylating agent such as BBr ₃ , and then, in the presence of a base such as potassium carbonate, When a dihalomalonate (XIX) such as diethyl dibromomalonate is reacted, a compound having a group represented by the formula (XII) in which R ^a and R ^b are an alkoxycarbonyl group which may have a substituent is obtained. can get. This compound, with a reducing agent such as lithium borohydride, can be derived to the compound having a group represented by the formula R ^a, R ^b is a hydroxy methyl group (XI'd). Further, when the obtained compound is reacted with an alkyl halide represented by the formula (XX) in the presence of a base such as sodium hydride, R ^a and R ^b may have an optionally substituted alkoxymethyl group. It can be converted to a compound having a group represented by the formula (XII). Further, the compound (XI′c) having a group represented by the formula (XII) wherein R ^a and R ^b are an alkoxycarbonyl group which may have a substituent may be subjected to a conventional hydrolysis method, When subjected to alkaline hydrolysis using an alkali such as a metal hydroxide (eg, sodium hydroxide), R ^a and R ^b have a carboxyl group or a group represented by the above formula (XII), which is a salt thereof. A compound can be obtained. Regarding this method, reference can be made to the above-mentioned US Pat. No. 5,061,727 and J. Med. Chem., 35 , 3081 (1992).

  The thus obtained (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative or a salt thereof may be subjected to appropriate chemical modification as it is or as necessary. Thus, it can be suitably used as a medicament such as an antiobesity drug and a drug for treating diabetes. The chemical modification method is described in, for example, the aforementioned Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 35, p. 3081 (1992), U.S. Pat. (TWGreen, "Protective groups in Organic Synthesis" A. Wiley Intersience Publication, John Wiley & Sons (1981)).

  Next, a method for producing the (S) -2-amino-1-phenylethanol derivative represented by the general formula (XV) will be described.

Preferred examples of R ^{1 to} R ^{5 in} the general formula (XV) include the substituents exemplified for the general formula (IIa).

  Specific examples of the compound represented by the general formula (XV) and preferable examples thereof include enantiomers of the compounds exemplified for the corresponding (R) -form represented by the general formula (IIa).

  The (S) -2-amino-1-phenylethanol derivative represented by the general formula (XV) can be obtained by various methods, for example, (R) -2-amino-1 represented by the general formula (IIa). -Can be produced by a method according to the method for producing a phenylethanol derivative.

  For example, the (S) -2-amino-1-phenylethanol derivative represented by the general formula (XV) can be produced by a chemical synthesis method or the like, but is advantageously produced by a method using a microorganism or a processed product thereof. it can. That is, the (S) form represented by the general formula (XV) is obtained by adding (E) a 2-amino-1-phenylethanol derivative represented by the general formula (I) or an enantiomer mixture of a salt thereof to a specific microorganism or The treated product is allowed to act, and then the produced (S) -2-amino-1-phenylethanol derivative is recovered (hereinafter referred to as asymmetric assimilation method), or (F) the compound represented by the general formula (VII) ), A specific microorganism or a treated product thereof is allowed to act on the compound or a salt thereof, and the resulting compound is asymmetrically reduced, and the resulting optically active compound (S) is recovered (hereinafter, referred to as asymmetric reduction method). ) Can be obtained easily and easily.

  Hereinafter, (E) the asymmetric assimilation method will be described.

  The microorganism used in this method acts on an enantiomer mixture of a 2-amino-1-phenylethanol derivative represented by the general formula (I) or a salt thereof, and can generate a corresponding (S) -form optically active form. Any microorganism can be used as long as it has the ability. Such microorganisms include a microorganism that selectively assimilates the (R) form and a microorganism that selectively converts the (R) form into another compound (including the (S) form), of the two enantiomers. Etc. are included.

  Examples of microorganisms having the above-mentioned ability include, for example, Saccharomyces, Pichia, Schizosaccharomyces, Candida, Hansenula, Yarrowia, and Geotricum. (Geotrichum), Micrococcus luteus, Brevibacterium, Corynebacterim, Xanthomonas, Actinomaqura, Enterobacter, Pseudomonas (Pseudomonas) genus, Hafnia (Hafnia) genus, Actinoplanes (Actinoplanes) genus, Escherichia (Escherichia) genus, Bacillus genus, Listonella genus, Nosardioides (Nosardioides) genus, Amycolata genus , Aspergillus s), Penicillium, Corynespora, Fusarium, Gerasinospora, Helminthosporium, Mortierelia, Neosartory sola, Neosartory la Microorganisms selected from the group of microorganisms belonging to the genera (Phytophthora), Talaromyces, Scolecobasidium and Rhodococcus are included.

  Specifically, examples of microorganisms having the ability to act on an enantiomeric mixture of the compound represented by the general formula (I) and produce the corresponding (S) form include the following microorganisms.

(66) Saccharomyces genus: Saccharomyces cerevisiae IFO 0718, Saccharomyces cerevisiae IFO 0735, Saccharomyces cerevisiae, Saccharomyces cerevisiae 206, etc.
(67) genus Pichia: Pichia fabianii IFO 1254, etc.
(68) genus Schizosaccharomyces: Schizosaccharomyces pombe IAM 4890, etc.
(69) Candida genus: Candida guilliermondii IFO 0566, Candida melibiosica IFO 10238, etc.
(70) Genus Hansenula: Hansenula polymorpha DSM 70277 and the like.

(71) Genus Yarrowia: Yarrowia lipolytica IFO 0746, etc.
(72) genus Geotrichum: Geotrichum capitatum IFO 0743, Geotrichum capitatum IFO 1197, etc.
(73) Micrococcus luteus: Micrococcus luteus IAM 12009, Micrococcus luteus IAM 12144, Micrococcus luteus IAM 1157, Micrococcus luteus 33us Micrococcus luteus 33us Such,
(74) genus Brevibacterium: Brevibacterium iodinum IFO 3558, etc.
(75) Corynebacterium genus: Corynebacterim sepedonicum IFO 3306, etc.
(76) Genus Xanthomonas: Xanthomonas sp. IFO 12997, etc.
(77) Actinomacula (Actinomaqura) genus: Actinomaqura cremea subspecies cremea (Actinomaqura cremea subsp. Cremea) IFO 14182, etc.
(78) genus Enterobacter: Enterobacter aerogenes IFO 12010, etc.
(79) Pseudomonas genus: Pseudomonas aeruginosa IFO 3445, etc.
(80) Genus Hafnia: Hafnia alvei IFO 3731 and the like.

(81) Actinoplanes (Actinoplanes) genus: Actinoplanes lobatus (Actinoplanes lobatus) IFO 12513, etc.
(82) genus Escherichia: Escherichia coli IAM 1239, etc.
(83) genus Bacillus: Bacillus licheniformis (Bacillus licheniformis) BGSC 5A18, etc.
(84) Listonella genus: Listonella anguillarum IFO 12710, etc.
(85) Genus Nosardioides: Nosardioides flavus IFO 14396, etc.
(86) genus Amycolata: Amycolata autotrophica IFO 12743, etc.
(87) Aspergillus genus: Aspergillus niger IFO 4415, Aspergillus niger AHU 7115, Aspergillus ficuum IFO 4318, Aspergillus peridis casperidas gers peridis caversidas ) IFO 4390, Aspergillus oryzae var. Brunneus JCM 2240, Aspergillus tamarii IAM 2138, etc.
(88) Genus Penicillium: Penicillium chrysogenum IAM 7142, etc.
(89) Genus Corynespora: Corynespora cassiicola IFO 6724, etc.
(90) genus Fusarium: Fusarium solani IFO 5232 and the like.

(91) Genus Gelasinospora (Gelasinospora cerealis) IFO 6759, etc.
(92) genus Helminthosporium: Helminthosporium sigmoideum valitii irreavl (Helminthosporium sigmoideum var. Irreavl) IFO 5273, etc.
(93) genus Mortierelia (Mortierelia): Mortierelia isabellina IFO 6336, Mortierelia ramaniana variti ramaniana (Mortierelia ramanniana var. Ramanniana) IFO 7825, etc.
(94) Genus Neosartorya (Neosartorya): Neosartorya fischeri varity spinosa (Neosartorya fischeri var. Spinosa) IFO 5955, etc.
(95) Phytophthora (Phytophthora) genus: Phytophthora capsici (Phytophthora capsici) IFO 8386, etc.
(96) genus Talaromyces: Talaromyces flavus varity flavus (Talaromyces flavus var. Flavus) IFO 7231,
(97) Scolecobasidium (Scolecobasidium) genus: Scolecobasidium terreum (Scolecobasidium terreum) IFO 8854, etc.
(98) Rhodococcus genus: Rhodococcus luteus JCM 6162, Rhodococcus erythropolis JCM6821, Rhodococcus erythropolis (Rhodococcus erythropolis) JCM 6827 such as Rhodococcus erythropolis, JCM 6827, Rhodococcus erythropolis, etc. Is used at least one type. When these microorganisms or their processed products act on an enantiomeric mixture of the 2-amino-1-phenylethanol derivative represented by the general formula (I), the abundance ratio of the (S) form of both enantiomers is improved. .

  Microorganisms with IFO, JCM, ATCC, DSM, IAM, BGSC, and AHU numbers can be obtained from the above facilities.

  Any of the above microorganisms can be suitably used as long as it has the above-mentioned ability, such as a wild strain, a mutant strain, or a recombinant strain derived by a genetic technique such as cell fusion or genetic engineering.

  The culturing, reaction, and collection of the reaction product of the microorganism can be performed in the same manner as in the method for producing the (R) -2-amino-1-phenylethanol derivative represented by the general formula (IIa). .

  Next, (F) the asymmetric reduction method will be described.

  In this method, any microorganism capable of asymmetrically reducing the compound represented by the general formula (VII) to produce the corresponding optically active compound represented by the general formula (XV) can be used. Can also be used.

  Examples of microorganisms having such abilities include the genus Botryaoascus, the genus Brettanomyces, the genus Candida, the genus Citeromyces, the genus Clavispora, the genus Debaryomyces, and the dipodascus (Dipodascus). ), Genus Eremascus (Eremascus), genus Galacttomyces (Galactomyces), genus Geotrichum (Geotrichum), genus Isachenkia (Issatchenkia), genus Kluyveromyces (Kluyveromyces), genus Kondoa (Kondoa), genus Lipomyces (Lipomyces), Malassezia Malassezia), Oosporidium, Pachysolen, Pichia, Rhodosporidium, Rhodotorula, Saccharomyces, Saccharomyces code Saccharomycopsis, Schizoblastosporio n) genus, genus Schizosaccharomyces, genus Sporidiobolus, genus Sporobolomyces, genus Wickerhamiella, genus Wingea, genus Zygosacchary (Zygosacchary) Bacillus genus, Comamonas genus, Rhodobacter genus, Enterococcus genus, Lactobacillus genus, Pediococcus genus, Leuconostoc genus and Streptoccus genus Streptoccus The microorganisms to which the gene belongs are exemplified.

  Specifically, a microorganism capable of acting on an aminoketone derivative represented by the general formula (VII) to produce a corresponding (S) -2-amino-1-phenylethanol derivative represented by the general formula (XV) Examples include the following microorganisms.

(99) Genus Botryoascus (Botryoascus): Botryoascus synnaedendrus (Botryoascus synnaedendrus) IFO 1604, etc.
(100) Genus Brettanomyces (Brettanomyces anomalus) IFO 0642, etc.
(101) Genus Candida: Candida albicans IFO 1856, Candida beechii IFO 10229, Candida ergatensis IFO 10233; Candida guilliermondii) IFO 0566, Candida halonitratophila IFO 1595, Candida oregonensis IFO 1980, Candida pelta oxy sida and Candida porsida Cropida psylo psi palodi pal Chopida psi ropi psi ropi sida Chopida para Cirda psi ropi sida Chopida para Cirda psi ropi sida Chopida para Cirida psi C rops pal C sir p s s s O p s d a p s s s s s s s s s s s i p o d a p s i p a d i s a p s. ) IFO 1578 etc.
(102) Genus Citeromyces: Citeromyces matritensis IFO 0954, etc.
(103) genus Clavispora: Clavispora lusitaniae IFO 1019, etc.
(104) genus Debaryomyces: Debaryomyces hansenii var. Hansenii (Debaryomyces hansenii var. Hansenii) IFO 0083, etc.
(105) Genus Dipodascus (Dipodascus): Dipodascus ovetensis IFO 1201, etc.
(106) Genus Eremascus: Eremascus fertilis IFO 0691 and the like,
(107) genus Galacttomyces (Galactomyces reessii) IFO 1112, etc.
(108) Genus Geotrichum: Geotrichum fermentans CBS 452.83, Geotrichum candidum IFO 4601, Geotrichum capitatum IFO 1197, Geotrichum capitatum IFO 1197
(109) Genus Issatchenkia (Issatchenkia scutulata var. Scutulata) IFO 10069, etc.
(110) genus Kluyveromyces (Kluyveromyces lactis) IFO 1267, Kluyveromyces marxianus varati bulgaricus (Kluyveromyces marxianus var. Bulgaricus) IAM 4829 and the like.

(111) Genus Kondoa: Kondoa malvinella IFO 1935, etc.
(112) Genus Lipomyces: Lipomyces starkeyi IFO 1289, etc.
(113) Malassezia genus: Malassezia furfur IFO 0656, etc.
(114) Genus Oosporidium: Oosporidium margaritiferum IFO 1208, etc.
(115) Pachysolen genus: Pachysolen tannophilus IFO 1007, etc.
(116) Genus Pichia: Pichia farinosa IFO 1163, Pichia holstii IFO 0986, Pichia subpelliculosa (Pichia subpelliculosa) IFO 0808, Pichia toletana 50, etc.
(117) Rhodosporidium (Rhodosporidium) genus: Rhodosporidium diobovatum (Rhodosporidium diobovatum) IFO 0688, etc.
(118) genus Rhodotorula (Rhodotorula glutinis) IFO 0389, Rhodotorula glutinis varity dairenensis (Rhodotorula glutinis var. Dairenensis) IFO 0415, etc.
(119) Genus of Saccharomyces: Saccharomyces kluyveri IFO 1894, Saccharomyces paradoxus IFO 0259, etc.
(120) Genus of Saccharomycodes (Saccharomycodes): Saccharomycodes ludwigii IFO 0798 and the like.

(121) Saccharomycopsis (Saccharomycopsis) genus: Saccharomycopsis capsularis (Saccharomycopsis capsularis) IFO 0672, etc.
(122) Genus Schizoblastosporion: Schizoblastosporion kobayasii IFO 1644 and the like
(123) genus: Schizosaccharomyces pombe (Schizosaccharomyces pombe) IFO 0358,
(124) Genus Sporidiobolus: Sporidiobolus pararoseus JCM 5350, etc.
(125) Genus Sporobolomyces: Sporobolomyces pararoseus IFO 0471, Sporobolomyces salmonicolor AHU 3982, etc.
(126) Genus Wickerhamiella: Wickerhamiella domercquii IFO 1857, etc.
(127) Genus Wingea: Wingea robertsii IFO 1277, etc.
(128) Genus Zygosaccharomyces (Zygosaccharomyces bailii) DSM 70492, Zygosaccharomyces fermentati IFO 0021, etc.
(129) genus Bacillus: Bacillus subtilis IFO 3037,
(130) Genus Comamonas: Comamonas terrigena IFO 13299 and the like.

(131) genus Rhodobacter: Rhodobacter sphaeroides IFO 12203, etc.
(132) Genus Enterococcus: Enterococcus faecalis NRIC 1142, etc.
(133) Lactobacillus genus: Lactobacillus lactis AHU 1059, etc.
(134) Genus of Pediococcus: Pediococcus acidilactici IFO 3076, etc.
(135) genus Leuconostoc: Leuconostoc mesenteroides subsp. Dextranicum NRIC 1085, Leuconostoc mesenteroides AHU 1072, eosinoL, etc.
(136) Genus Streptococcus: Streptococcus uberis NRIC 1153 and the like.

  In this method, any strain, such as a wild strain, a mutant strain, or a recombinant strain derived by a genetic technique such as cell fusion or genetic manipulation, can be suitably used as long as it has the above ability.

  Microorganisms with IFO, AHU, DSM, and JCM numbers can be obtained from the above facilities. Microorganisms with an IAM number are described in the IAM Catalog of strains, 1st edition (1993) issued by the Japan Society for Applied Microbiology, and are available from the Microalgae Center, Institute for Applied Microbiology, The University of Tokyo.

  Microorganisms with CBS numbers are described in List of cultures FUNGI and YEAST 32nd edition (1990) issued by CENTRAALBUREAU VOOR SCHIMMELCULTURES (CBS) and can be obtained from the institution.

  Microorganisms with NRIC numbers are described in the strain catalog second edition (1992) issued by the Tokyo University of Agriculture Strain Storage Room, and can be obtained from this facility.

  The culturing of the microorganism, the asymmetric reduction reaction, and the collection of the reaction product are performed in the same manner as in the case of producing the (R) -2-amino-1-phenylethanol derivative represented by the general formula (IIa). Can be.

  Further, the (S) -2-amino-1-phenylethanol derivative represented by the general formula (XV) is a derivative of the (R) -2-amino-1-phenylethanol derivative represented by the general formula (IIa). It can also be manufactured according to the manufacturing methods (C) and (D). That is, the (S) form represented by the general formula (XV) is a compound represented by the formula (III) or a compound represented by the formula (IV) used as a reaction component in the production method (C), respectively. It can be easily obtained by using the optically active (S) form. The (S) form can be easily separated from the corresponding (R) form by fractional crystallization or the like in the production method (D).

  The (S) -2-amino-1-phenylethanol derivative represented by the general formula (XV) is subjected to, for example, a nucleophilic substitution reaction accompanied by steric inversion, whereby the (R) represented by the general formula (IIa) is obtained. It can be converted to a 2-amino-1-phenylethanol derivative. This reaction can be performed by using a nucleophile.

  For example, the (S) -2-amino-1-phenylethanol derivative represented by the general formula (XV) can be prepared according to the following formula by selecting a reagent, a catalyst, a reaction condition, and the like that cause the reaction to proceed by steric inversion. It can be easily converted to the (R) -2-amino-1-phenylethanol derivative represented by the general formula (IIa).

In the general formula (XV), R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as described above.

  The conversion from the compound represented by the general formula (XV) to the compound represented by the general formula (IIa) can be performed more specifically, for example, by the following method utilizing the Mitsunobu reaction.

  That is, a compound of the general formula (XV) is reacted with an organic acid in the presence of a triarylphosphine (for example, triphenylphosphine or the like) and an azodicarboxylic acid ester such as ethyl azodicarboxylate, and the corresponding organic acid ester is stereo-inverted. After that, the compound represented by the general formula (IIa) can be obtained by hydrolysis. Examples of the organic acid include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, and benzoic acid. The above-mentioned organic acid ester formation reaction can be performed, for example, at a temperature of about −60 to 60 ° C. The reaction can also be performed in a solvent inert to the reaction, for example, an aromatic hydrocarbon such as benzene or toluene, or an ether such as tetrahydrofuran.

The amounts of the triarylphosphine, organic acid, and azodicarboxylic acid ester to be used are about 0.7 to 2.0 mol, respectively, per 1 mol of the compound represented by the general formula (XV). The organic acid ester can be hydrolyzed by a conventional acid or alkali hydrolysis method (Synthesis, 1 (1981); Tetrahedron Lett., 1619 (1973); Bull. Chem. Soc. Jpn. , 44 , 3427 (1971)).

The following method can also be applied to the present invention as a method for converting an optically active alcohol into a corresponding stereoisomeric enantiomer. That is, the optically active alcohol is converted into a carboxylic acid ester such as trichloroacetic acid ester, and then hydrolyzed in a water-ether solvent such as 75% water-dioxane to obtain a corresponding stereoactively inverted optically active alcohol. (See Chem. Lett., 1976 , 893). Further, the optically active alcohol was converted to a sulfonic acid ester such as p-toluenesulfonic acid ester, and the sulfonic acid ester was reacted with an organic acid salt such as tetraethylammonium acetate and sodium acetate (and acetic acid) to be sterically inverted. The corresponding inverted optically active alcohol can also be obtained by conversion to the corresponding organic acid ester followed by hydrolysis (J. Am. Chem. Soc., 87 , 3682, (1965); J. Chem. Soc., 1954 , 965).

  The (R) -2-amino-1-phenylethanol derivative represented by the general formula (IIa) thus obtained is, as described above, (R, R) -1-phenyl-2-[(2-phenyl-1 -Alkylethyl) amino] ethanol derivatives. Therefore, the (S) -2-amino-1-phenylethanol derivative represented by the general formula (XV) is very useful as an intermediate material for the above synthetic intermediate.

  In addition, from the (S) -2-amino-1-phenylethanol derivative represented by the general formula (XV) to the (R) -2-amino-1-phenylethanol derivative represented by the general formula (IIa) Can also be applied to the conversion from the corresponding (R) -form enantiomer to the (S) -form enantiomer.

  In addition, when the raw material compound has a hydroxyl group or an amino group in each of the above-mentioned production and separation production methods, if necessary, these hydroxyl groups and the like may be protected with an appropriate protecting group before the reaction. As such a protecting group, for example, the protecting group for a hydroxyl group and the protecting group for an amino group described above can be appropriately used.

  The (R) -2-amino-1-phenylethanol derivative can be obtained by efficiently converting the (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative with a good yield. It is extremely useful as a synthetic intermediate for good production, and is easy to obtain and handle. In addition, the (S) -2-amino-1-phenylethanol derivative can be suitably used as an intermediate material of the (R) -2-amino-1-phenylethanol derivative.

  Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to only these Examples.

  In the following Examples, the quantification of the 2-amino-1-phenylethanol derivative and the measurement of the optical purity were performed by high performance liquid chromatography using an optical resolution column [column: Daicel Chemical Industries, Ltd.] unless otherwise specified. Co., Ltd., trade name Crown Pack CR, mobile phase: perchlorate buffer (pH 2.0), wavelength: 220 nm, flow rate: 1 ml / min, column temperature: 40 ° C.]. In the above measurement conditions, for example, the retention time of (R) -2-amino-1- (3-chlorophenyl) ethanol is 16.8 minutes, and the retention time of (S) -2-amino-1- (3-chlorophenyl) ethanol is The time is 18.5 minutes.

Examples 1 to 100 [Production of (R) -2-amino- (3-chlorophenyl) ethanol]
Cell culture media (1) and (2) having the following composition were prepared.

[Cell culture medium (1): for yeast and filamentous fungi]
Glucose 2.0% by weight
Yeast extract 0.3% by weight
Malt extract 0.3% by weight
Polypeptone 0.5% by weight
96.9% by weight of deionized water
(PH 6.0)
[Cell culture medium (2): for bacteria and actinomycetes]
Glucose 2.0% by weight
Yeast extract 0.5% by weight
0.3% by weight of meat extract
0.3% by weight of polypeptone
Ammonium sulfate 0.2% by weight
0.1% by weight monopotassium dihydrogen phosphate
96.6% by weight of deionized water
(PH 7.0)
5 ml of the above-mentioned cell preparation medium is placed in a test tube having an inner diameter of 21 mmφ, and after sterilization, the following microorganisms are added to the medium (1) for yeasts and filamentous fungi and to the medium (2) for bacteria and actinomycetes, respectively. The cells were inoculated and cultured with shaking at 30 ° C. for 48 hours. Subsequently, the cells were separated by centrifugation to obtain live cells.

[yeast]
Example 1: Hansenula anomala IFO 0707
Example 2: Geotrichum candidum IFO 4601
Example 3: Geotrichum candidum IFO 4598
Example 4: Candida albicans IFO 1594
Example 5: Candida albicans IFO 1856
Example 6: Candida parapsilosis IFO 1022
Example 7: Candida gropengiesseri IFO 0659
Example 8: Candida aaseri IFO 10404
Example 9: Candida beechii IFO 10229
Example 10: Candida atmospherica IFO 1969.

Example 11: Candida natalensis IFO 1981
Example 12: Candida paludigena IFO 10330
Example 13: Candida sake IFO 1149
Example 14: Candida pintolopesii Variety Pintropesii (Candida pintolopesii var. Pintolopesii) IFO 0729
Example 15: Cryptococcus neoformans IAM 4788
Example 16: Rhodosporidium spaerocarpum IFO 1438
Example 17: Rhodosporidium diobovatum IFO 0688
Example 18: Rhodotorula rubra IFO 0406
Example 19: Rhodotorula rubra AHU 3948
Example 20: Rhodotorula glutinis var. Dairenensis IFO 0415
Example 21: Sporobolomyces roseus IFO 1040
Example 22: Kluyveromyces marxianus var. Bulgaricus IAM 4829
Example 23: Kluyveromyces lactis IFO 1267
Example 24: Isatchenkia scutulata var. Scutulata IFO 10069
Example 25: Isatchenkia scutulata var. Scutulata IFO 10070
Example 26: Pichia thermotolerans IFO 10024
Example 27: Pichia farinosa IFO 1163
Example 28: Botryoascus synnaedendrus IFO 1604
Example 29: Debaryomyces hansenii IFO 0083
Example 30: Lipomyces starkeyi IFO 1289.

Example 31: Metschnikowia bicuspidata IFO 1408
Example 32: Saccharomycodes ludwigii IFO 0798
Example 33: Schizoblastosporion kobayasii IFO 1644
Example 34: Stepahnoascus ciferrii IFO 1854
Example 35: Sterigmatomyces halophilus IFO 1488
Example 36: Zygosaccharomyces rouxii IFO 0510
Example 37: Zygosaccharomyces rouxii IAM 4114
Example 38: Zygosaccharomyces fermentati IFO 0021
Example 39: Sporidiobolus salmonicolor IFO 1845
Example 40: Sporidiobolus pararoseus IFO 1107
Example 41: Malassezia furfur IFO 0656
Example 42: Torulaspora delbrueckii IFO 0955
Example 43: Saccharomycopsis capsularis IFO 0672
Example 44: Leucosporidium scottii IFO 1923
Example 45: Leucosporidium scottii IFO 1924.

[Filamentous fungi]
Example 46: Agrocybe cylindracea IFO 30299
Example 47: Trichoderma viride IFO 5720
Example 48: Alternaria kikuchiana IFO 5778
Example 49: Hamigera avellanea IFO 7721
Example 50: Moniliella acetoabutans IFO 9481
Example 51: Pholiota nameko IFO 6141
Example 52: Podospora cardonaria IFO 30294
Example 53: Aegerita candida IFO 6988
[Bacteria and actinomycetes]
Example 54: Corynebacterium aquaticum IFO 12154
Example 55: Corynebacterium mediolanum JCM 3346
Example 56: Gluconobacter asaii IFO 3265
Example 57: Gluconobacter oxydans IFO 3255
Example 58: Gluconobacter oxydans IFO 3130
Example 59: Gluconobacter oxydans IFO 3289
Example 60: Gluconobacter frateurii IFO 3271.

Example 61: Promicromonospora citrea IFO 12397
Example 62: Pseudomonas aeruginosa IFO 3899
Example 63: Pseudomonas riboflavina IFO 13584
Example 64: Pseudomonas fluorescens IFO 3925
Example 65: Pseudomonas putida IFO 12996
Example 66: Pseudomonas syncyanea IFO 3775
Example 67: Pseudomonas diminuta IFO 12697
Example 68: Pseudomonas chlororaphis IFO 3522
Example 69: Pseudomonas fragi IFO 3458
Example 70: Pseudomonas sp. ATCC 14676.

Example 71: Bordetella bronchiseptica IFO 13691
Example 72: Acetobacter sp. IFO 3248
Example 73: Acetobacter sp. IFO 3297
Example 74: Acetobacter pasteurianus ATCC 10245
Example 75: Acetobacter pasteurianus IFO 3259
Example 76: Acetobacter pasteurianus IFO 3277
Example 77: Bacillus subtilis IFO 3013
Example 78: Bacillus subtilis IFO 3009
Example 79: Bacillus cereus AHU 1355
Example 80: Bacillus cereus AHU 1707
Example 81: Bacillus cereus IFO 3001
Example 82: Bacillus coagulans IAM 1115
Example 83: Bacillus brevis IFO 3331
Example 84: Bacillus sphaericus IFO 3525
Example 85: Agrobacterium radiobacter IFO 12664
Example 86: Arthrobacter ureafaciens IFO 12140
Example 87: Amauroascus reticulatus IFO 9196
Example 88: Brevibacterium linens IFO 12141
Example 89: Micrococcus roseus IFO 3764
Example 90: Aureobacterium testaceum IFO 12675.

Example 91: Azotobacter vinelandii IFO 13581
Example 92: Xanthomonas campestris pv oryzae IAM 1657
Example 93: Klebsiella pneumoniae IFO 3317
Example 94: Comamonas testosteroni IFO 12048
Example 95: Comamonas testosteroni IAM 1048
Example 96: Mycobacterium diernhoferi IFO 3707
Example 97: Terrabacter tumescens IFO 12960
Example 98: Streptomyces cinereoruber HUT6142
Example 99: Rhodococcus amidophilis IFO 0144
Example 100: Rhodococcus equi JCM 1313.

  Next, 1 ml of a 0.1 M potassium phosphate buffer (pH 7.0) was placed in a test tube having an inner diameter of 21 mmφ, and the viable cells obtained above were suspended therein. 5 μl of racemic 3-chlorophenyl) ethanol was added, and the mixture was allowed to react at 30 ° C. by reciprocal shaking for 48 hours.

  After completion of the reaction, the reaction solution was sterilized by a centrifuge, and the supernatant was subjected to high performance liquid chromatography to obtain the amount, absolute configuration, and amount of the obtained optically active 2-amino-1- (3-chlorophenyl) ethanol. Optical purity was measured. The results are shown in Tables 1 to 5. In the table, “amount” indicates the amount (mg / ml) of optically active 2-amino-1- (3-chlorophenyl) ethanol contained in the reaction solution.

Examples 101 to 111 [Production of (R) -2-amino-1-phenylethanol]
A culture medium (3) having the following composition was prepared. In addition, about yeast and filamentous fungi, the culture medium for cell preparation (1) used in Examples 1 to 100 was used.

[Cell culture medium (3): for bacteria]
Glucose 2.0% by weight
Yeast extract 0.5% by weight
0.3% by weight of meat extract
0.3% by weight of polypeptone
Ammonium sulfate 0.2% by weight
0.1% by weight of monopotassium phosphate
Magnesium sulfate 0.05% by weight
96.55% by weight of deionized water
(PH 7.0)
5 ml of the above-mentioned cell preparation medium is placed in a test tube having an inner diameter of 21 mm, and after sterilization, the following microorganisms are planted in the above-mentioned medium (1) for yeast filamentous fungi and in the above-mentioned medium (3) for bacteria. The cells were cultured and shaking culture was performed at 30 ° C. for 48 hours.

Example 101: Candida maltosa IFO 1977
Example 102: Candida maltosa IFO 1978
Example 103: Lodderomyces elongisporus IFO 1676
Example 104: Catenuloplanes japonicus IFO 14176
Example 105: Pilimelia terevasa IFO 14556
Example 106: Saccharothrix australiensis IFO 14444
Example 107: Seratia marcescens IFO 3735
Example 108: Enterococcus faecalis IFO 12964
Example 109: Lactobacillus casei subsp. Casei NRIC 1042
Example 110: Pediococcus acidilactici NRIC 1089
Example 111: Streptcoccus lactis AHU 1089.

  Next, the cells were collected by centrifugation, suspended in 1 ml of a 0.1 M phosphate buffer (pH 7.0) containing 0.5% aminomethyl phenyl ketone hydrochloride and 5% curcose, and had a diameter of 21 mm. In a test tube at 30 ° C. for 48 hours for reaction. After completion of the reaction, the reaction solution was centrifuged to remove bacteria, and the supernatant was analyzed by high performance liquid chromatography to measure the amount, absolute configuration and optical purity of (R) -2-amino-1-phenylethanol produced. . Table 6 shows the results. In the table, “amount” indicates the amount (mg / ml) of (R) -2-amino-1-phenylethanol contained in the reaction solution.

Examples 112 to 115 [Production of (R) -2-amino-1- (3-chlorophenyl) ethanol]
Culture, reaction, and analysis were carried out in the same manner as in Example 101, except that aminomethyl phenyl ketone hydrochloride was replaced with aminomethyl phenyl ketone hydrochloride using the microorganisms shown below to produce The amount, absolute configuration and optical purity of (R) -2-amino-1- (3-chlorophenyl) ethanol were measured. Table 7 shows the results. In the table, “amount” indicates the amount (mg / ml) of (R) -2-amino-1- (3-chlorophenyl) ethanol in the reaction solution.

Example 112: Lodderomyces elongisporus IFO 1676
Example 113: Candida maltosa IFO 1978
Example 114: Candida maltosa IFO 1977
Example 115: Pilimelia terevasa IFO 14556

Examples 116 to 118 [Production of (R) -2-amino-1- (3,4-dihydroxyphenyl) ethanol]
Using the microorganisms shown below, culture, reaction, and analysis were carried out in the same manner as in Example 101, except that aminomethyl phenyl ketone hydrochloride was replaced with aminomethyl 3,4-dihydroxyphenyl ketone hydrochloride. The amount, absolute configuration and optical purity of (R) -2-amino-1- (3,4-dihydroxyphenyl) ethanol produced were measured. Table 8 shows the results. In Table 8, "amount" indicates the amount (mg / ml) of (R) -2-amino-1- (3,4-dihydroxyphenyl) ethanol in the reaction solution.

Example 116: Lodderomyces elongisporus IFO 1676
Example 117: Candida maltosa IFO 1977
Example 118: Candida maltosa IFO 1978

Example 119 [Production of (R) -2-amino-1- (3-chlorophenyl) ethanol]
GY medium (glucose 2.4% by weight, yeast extract 1.8% by weight, ammonium sulfate 0.2% by weight, monopotassium phosphate 0.1% by weight, ferrous sulfate 7) 1.5 liters of water salt (15 ppm, zinc sulfate heptahydrate 15 ppm) was added, and sterilized using an autoclave. Candida maltosa (Candida maltosa) IFO 1978 was inoculated, pH 6, 30 ° C., aeration 1 vvm, stirring speed 400 rpm. For 24 hours.

  After completion of the culture, the cells were collected, suspended in 1 liter of a 0.1 M phosphate buffer (pH 6.5), and 20 g of aminomethyl-3-chlorophenyl ketone hydrochloride and 50 g of glucose were added. The reaction was performed for 48 hours under the conditions of aeration and a stirring speed of 200 rpm. During the reaction, the pH of the reaction solution was controlled at 6.5 using a 20% aqueous sodium hydroxide solution. When the reaction solution was analyzed during the reaction, (R) -2-amino-1- (3-chlorophenyl) ethanol was produced at a concentration of 13.2 g / l.

  After completion of the reaction, the mixture was acidified to pH 2 or less with concentrated hydrochloric acid, and then the cells were removed by centrifugation. The resulting supernatant was dehydrated and concentrated at a bath temperature of 50 ° C. using a vacuum rotary evaporator. To the obtained concentrate, a 20% aqueous sodium hydroxide solution was added to adjust the pH to 9.0, then 50 g of sodium chloride was added, and the mixture was extracted three times with 300 ml of methylene chloride. After drying the methylene chloride layer over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain 9.8 g of an oily substance. (R) -2-amino-1- (3) was obtained as a result of analysis by high-performance liquid chromatography using an optical resolution column [column: Crownpack CR (+), manufactured by Daicel Chemical Industries, Ltd.]. The optical purity of (-chlorophenyl) ethanol was 100% ee.

  In the following Examples 120 to 172, the optical purity of the obtained (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative or a salt thereof was measured by optical resolution. High-performance liquid chromatography using a column [Column: Chiralpak AD (trade name) manufactured by Daicel Chemical Industries, Ltd., Solvent: n-hexane / 2-propanol / diethylamine = 90/10 / 0.1, flow rate: 0. 5 ml / min, temperature: 25 ° C., detection wavelength: 230 nm].

Example 120 [Production of (R, R) -1- (3-chlorophenyl) -2-[[(2- (3,4-dimethoxyphenyl) -1-methylethyl) amino] ethanol]
Methyl = 3,4-dimethoxyphenylmethyl = ketone (5.83 g), (R) -2-amino-1- (3-chlorophenyl) ethanol (5.15 g) and platinum oxide (50 mg) in isopropyl alcohol (15 ml) And diisopropyl ether (30 ml) and 2 drops of acetic acid, and subjected to a reduction reaction in a hydrogen atmosphere at room temperature and normal pressure for 24 hours. After filtering the platinum oxide, the solvent was distilled off under reduced pressure to give (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl]. 8.43 g (yield: 80.3%) of a white oil of [amino] ethanol was obtained. The optical purity of the obtained (R, R) form was 80%.

Examples 121 to 128 [Production of ((R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol]
Methyl = 3,4-dimethoxyphenylmethyl = ketone (0.344 g), (R) -2-amino-1- (3-chlorophenyl) ethanol (0.304 g), platinum oxide (50 mg), using 10 ml of solvent In the same manner as in Example 120, (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol was obtained. Table 9 shows the solvent used, the yield, and the optical purity of the (R, R) form. In Tables 9 to 13, "OMe" represents a methoxy group, "Me" represents a methyl group, "NHAc" represents an amino group substituted with an acetyl group, and "PTsOH" represents p-toluenesulfonic acid. The "optical purity" indicates the optical purity of the obtained (R, R) form.

Examples 129 to 141 [Production of 1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative]
The procedure of Example 120 was repeated except that platinum oxide was used as a catalytic reduction catalyst, isopropyl alcohol-diisopropyl ether (1: 2) was used as a solvent, acetic acid was used as an acid, and the compounds shown in Table 10 were used as reaction raw materials. , R) -1-Phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative was prepared. Table 10 shows the raw materials, the yields, and the optical purity of the obtained (R, R) form.

Example 142 [Production of (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol]
Methyl 3,4-dimethoxyphenylmethyl ketone (0.344 g) was added to a solution of (R) -2-amino-1- (3-chlorophenyl) ethanol (0.304 g) in benzene (40 ml), and water- The mixture was refluxed for 1 hour in a device equipped with a trap, and the generated water was removed from the system. The reaction solution was cooled, the solvent was distilled off under reduced pressure, the residue was dissolved in methanol (10 ml), platinum oxide was added, and the mixture was subjected to a reduction reaction in a hydrogen atmosphere at room temperature and normal pressure for 24 hours. After filtering the platinum oxide, the solvent was distilled off under reduced pressure to give (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl]. 0.501 g (yield 81.0%) of a white oil of [amino] ethanol was obtained. The optical purity of the obtained (R, R) form was 80%.

Examples 143 to 150 [Production of (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative]
Except that isopropyl alcohol-diisopropyl ether (1: 2) was used as the solvent, and the raw materials and the catalytic reduction catalyst shown in Table 11 were used, the procedure of Example 142 was repeated, except that 1-phenyl-2-[(2-phenyl- A 1-alkylethyl) amino] ethanol derivative was prepared. Table 11 shows the raw materials, the catalytic reduction catalyst, the yield, and the optical purity of the obtained (R, R) form.

Example 151 [Production of (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol]
(R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol (12.36 g) having an optical purity of 89% was hydrogen chloride Was dissolved in toluene to form a hydrochloride, and the solvent was distilled off under reduced pressure. When the obtained oil was recrystallized with a mixed solution of isopropyl alcohol and diisopropyl ether, 7.57 g of a white powder was obtained. 10% NaOH / ethyl acetate was added to the powder, and the solvent was distilled off to give (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl)- 1-methylethyl] amino] ethanol (7.58 g, optical purity 98%) was obtained.

Example 152 [Production of (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol]
(R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol (0.103 g) having an optical purity of 64% was dissolved in isopropyl alcohol Dissolve it in 1 mL, add (R)-(-)-2- (2,4,6-trimethylphenyl) propionic acid (0.057 g), and then add 2 mL of diisopropyl ether to obtain 0.102 g of a white powder. Was. 10% NaOH / ethyl acetate was added to the powder, and the solvent was distilled off to give (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl)- 1-Methylethyl] amino] ethanol (0.065 g, optical purity 92%) was obtained.

Example 153 [Production of (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol]
(R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol (0.107 g) having an optical purity of 64% was dissolved in isopropyl alcohol It was dissolved in 1 mL, (S) -2- (2,5-dimethylphenyl) propionic acid (0.056 g) was added, and then 4 mL of diisopropyl ether was added to obtain a white powder (0.046 g). 10% NaOH / ethyl acetate was added to the obtained powder, and the solvent was distilled off to obtain (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl). ) -1-Methylethyl] amino] ethanol (0.030 g, optical purity 99.4%) was obtained.

Examples 154 to 168 [Production of (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative]
(R, R) -1-phenyl-2-[(2) was prepared in the same manner as in Example 153 except that isopropyl alcohol-diisopropyl ether (1: 2) was used as a solvent, and the raw materials and acids shown in Table 12 were used. -Phenyl-1-alkylethyl) amino] ethanol derivative was prepared. Incidentally, the optical purity of the (R, R) body in the raw material was 65%. Table 12 shows the optical purity of the obtained (R, R) form.

Example 169 [Production of (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol]
(R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol (1.05 g) having an optical purity of 65% was hydrogen chloride Was dissolved in toluene to form a hydrochloride, and the solvent was distilled off under reduced pressure to obtain an oily substance. Triethylamine (0.15 g) was added to the obtained oily substance, and the mixture was recrystallized with a mixed solution of isopropyl alcohol and isopropyl ether to obtain 0.80 g of a white powder. 10% NaOH / ethyl acetate was added thereto, and the solvent was distilled off to give (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1 -Methylethyl] amino] ethanol (0.70 g, optical purity 90%) was obtained.

Examples 170 to 171 [Production of (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative]
The procedure of Example 169 was repeated, except that isopropyl alcohol-diisopropyl ether (1: 2) was used as the solvent and the acid and base shown in Table 13 were used as the acid and base, respectively. A 2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative was produced. Table 13 shows the raw materials, the acid, the base, and the optical purity of the obtained (R, R) form. Incidentally, the optical purity of the (R, R) form in the raw material was 65%.

Example 172 [Production of (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol]
Methyl = 3,4-dimethoxyphenylmethyl = ketone (5.83 g), (R) -2-amino-1- (3-chlorophenyl) ethanol (5.15 g) and platinum oxide (50 mg) were added to isopropyl alcohol (15 ml). ) And diisopropyl ether (30 ml) were added, and subjected to a reduction reaction in a hydrogen atmosphere at room temperature and normal pressure for 24 hours. After filtering the platinum oxide, the solvent was distilled off under reduced pressure to give (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl]. 6.51 g (yield 62%) of a white oil of [amino] ethanol was obtained. The optical purity of the obtained (R, R) form was 65%.

Examples 173 to 222 [Production of (S) -2-amino- (3-chlorophenyl) ethanol]
(S) -2-Amino- (3-chlorophenyl) ethanol was produced in the same manner as in Examples 1 to 100 except that the following microorganisms were used. Tables 14 to 16 show the results of measuring the amount, absolute configuration and optical purity of the optically active 2-amino-1- (3-chlorophenyl) ethanol of the (S) form. In the table, "amount" indicates the amount (mg / ml) of (S) -2-amino- (3-chlorophenyl) ethanol in the reaction solution.
[Filamentous fungi]
Example 173: Saccharomyces cerevisiae IFO 0718
Example 174: Saccharomyces cerevisiae IFO 0735
Example 175: Saccharomyces cerevisiae IFO 0206
Example 176: Pichia fabianii IFO 1254
Example 177: Schizosaccharomyces pombe IAM 4890
Example 178: Candida guilliermondii IFO 0566
Example 179: Candida melibiosica IFO 10238
Example 180: Hansenula polymorpha DSM 70277.

Example 181: Yarrowia lipolytica IFO 0746
Example 182: Geotrichum capitatum IFO 0743
Example 183: Geotrichum capitatum IFO 1197
[Filamentous fungi]
Example 184: Aspergillus niger IFO 4415
Example 185: Aspergillus niger AHU 7115
Example 186: Aspergillus ficuum IFO 4318
Example 187: Aspergillus cavdidus IFO 4389
Example 188: Aspergillus oryzae IFO 4390
Example 189: Aspergillus oryzae var. Brunneus JCM 2240
Example 190: Aspergillus tamarii IAM 2138.

Example 191: Penicillium chrysogenum IAM 7142
Example 192: Corynespora cassiicola IFO 6724
Example 193: Fusarium solani IFO 5232
Example 194: Gelasinospora cerealis IFO 6759
Example 195: Helminthosporium sigmoideum var. Irreavl IFO 5273
Example 196: Mortierelia isabellina IFO 6336
Example 197: Mortierelia ramaniana var. Ramanniana (Mortierelia ramanniana var. Ramanniana) IFO 7825
Example 198: Neosartorya fischeri var. Spinosa IFO 5955
Example 199: Phytophthora capsici IFO 8386
Example 200: Talaromyces flavus var. Flavus IFO 7231
Example 201: Scolecobasidium terreum IFO 8854.
[Bacteria and actinomycetes]
Example 202: Micrococcus luteus IAM 12009
Example 203: Micrococcus luteus IAM 12144
Example 204: Micrococcus luteus IAM 1157
Example 205: Micrococcus luteus IFO 3333
Example 206: Brevibacterium iodinum IFO 3558
Example 207: Corynebacterim sepedonicum IFO 3306
Example 208: Xanthomonas sp. IFO 12997
Example 209: Actinomaqura cremea subspecies cremea (Actinomaqura cremea subsp. Cremea) IFO 14182
Example 210: Enterobacter aerogenes IFO 12010.

Example 211: Pseudomonas aeruginosa IFO 3445
Example 212: Hafnia alvei IFO 3731
Example 213: Actinoplanes lobatus IFO 12513
Example 214: Escherichia coli IAM 1239
Example 215: Bacillus licheniformis BGSC 5A18
Example 216: Listonella anguillarum IFO 12710
Example 217: Nosardioides flavus IFO 14396
Example 218: Amycolata autotrophica IFO 12743
Example 219: Rhodococcus luteus JCM 6162
Example 220: Rhodococcus erythropolis JCM6821
Example 221: Rhodococcus erythropolis JCM 6827
Example 222: Rhodococcus globerrulus IFO 14531

Examples 223 to 282 [Production of (S) -2-amino-1-phenylethanol]
5 ml of YM medium (2.0% by weight of glucose, 0.3% by weight of yeast extract, 0.3% by weight of malt extract, 0.5% by weight of polypeptone, pH 6.0) for yeast and filamentous fungi, and PM for bacteria. Medium (glucose 2.0% by weight, yeast extract 0.5% by weight, meat extract 0.3% by weight, polypeptone 0.3% by weight, ammonium sulfate 0.2% by weight, potassium phosphate 0.1% by weight, magnesium sulfate 5 ml each of 0.05% by weight (pH 7.0) was placed in a test tube having an inner diameter of 21 mm, sterilized, inoculated with the following strain, and cultured with shaking at 30 ° C. for 48 hours.
[Yeast and filamentous fungi]
Example 223: Botryoascus synnaedendrus IFO 1604
Example 224: Brettanomyces anomalus IFO 0642
Example 225: Candida albicans IFO 1856
Example 226: Candida beechii IFO 10229
Example 227: Candida ergatensis IFO 10233
Example 228: Candida fusiformata IFO 10225
Example 229: Candida guilliermondii IFO 0566
Example 230: Candida halonitratophila IFO 1595.

Example 231: Candida oregonensis IFO 1980
Example 232: Candida peltata IFO 1853
Example 233: Candida parapsilosis IFO 10305
Example 234: Candida sorboxylosa IFO 1578
Example 235: Citeromyces matritensis IFO 0954
Example 236: Clavispora lusitaniae IFO 1019
Example 237: Debaryomyces hansenii var. Hansenii IFO 0083
Example 238: Dipodascus ovetensis IFO 1201
Example 239: Eremascus fertilis IFO 0691
Example 240: Galacttomyces reessii IFO 1112.

Example 241: Geotrichum fermentans CBS 452.83
Example 242: Geotrichum candidum IFO 4601
Example 243: Geotrichum capitatum IFO 1197
Example 244: Geotrichum klebahnii JCM 2171
Example 245: Isatchenkia scutulata var. Scutulata IFO 10069
Example 246: Kluyveromyces lactis IFO 1267
Example 247: Kluyveromyces marxianus var. Bulgaricus IAM 4829
Example 248: Kondoa malvinella IFO 1935
Example 249: Lipomyces starkeyi IFO 1289
Example 250: Malassezia furfur IFO 0656.

Example 251: Oosporidium margaritiferum IFO 1208
Example 252: Pachysolen tannophilus IFO 1007
Example 253: Pichia farinosa IFO 1163
Example 254: Pichia holstii IFO 0986
Example 255: Pichia subpelliculosa IFO 0808
Example 256: Pichia toletana IFO 0950
Example 257: Rhodosporidium diobovatum IFO 0688
Example 258: Rhodotorula glutinis IFO 0389
Example 259: Rhodotorula glutinis var. Dairenensis IFO 0415
Example 260: Saccharomyces kluyveri IFO 1894.

Example 261: Saccharomyces paradoxus IFO 0259
Example 262: Saccharomycodes ludwigii IFO 0798
Example 263: Saccharomycopsis capsularis IFO 0672
Example 264: Schizoblastosporion kobayasii IFO 1644
Example 265: Schizosaccharomyces pombe IFO 0358
Example 266: Sporidiobolus pararoseus JCM 5350
Example 267: Sporobolomyces pararoseus IFO 0471
Example 268: Sporobolomyces salmonicolor AHU 3982
Example 269: Wickerhamiella domercquii IFO 1857
Example 270: Wingea robertsii IFO 1277.

Example 271: Zygosaccharomyces bailii DSM 70492
Example 272: Zygosaccharomyces fermentati IFO 0021
[Bacteria]
Example 273: Bacillus subtilis IFO 3037
Example 274: Comamonas terrigena IFO 13299
Example 275: Rhodobacter sphaeroides IFO 12203
Example 276: Enterococcus faecalis NRIC 1142
Example 277: Lactobacillus lactis AHU 1059
Example 278: Pediococcus acidilactici IFO 3076
Example 279: Leuconostoc mesenteroides subsp. Dextranicum NRIC 1085
Example 280: Leuconostoc mesenteroides AHU 1071.

Example 281: Leuconostoc oenos DSM 20252
Example 282: Streptococcus uberis NRIC 1153
Next, the cells were collected by centrifugation, suspended in 1 ml of 0.1 M phosphate buffer (pH 7.0) containing 0.5% aminomethyl phenyl ketone hydrochloride and 5% glucose, and tested in an inner diameter of 2 mm. The mixture was shaken in a tube at 30 ° C. for 48 hours to react.

  After completion of the reaction, the reaction solution was removed by centrifugation, the supernatant was analyzed by high performance liquid chromatography, and the amount, absolute configuration and optical purity of (S) -2-amino-1-phenylethanol produced were measured. . The results are shown in Tables 17 to 19. In Tables 17 to 19, "amount" indicates the amount (mg / ml) of (S) -2-amino-1-aminophenylethanol in the reaction solution.

  In Examples 283 to 303 below, the measurement of chemical purity and optical purity was performed by high performance liquid chromatography using the following column. Unless otherwise specified, "%" indicates% by weight.

Chemical Purity: Column; Inertsil ODS-2 (trade name) manufactured by GL Sciences Inc.
Optical purity: Column; Crown Pack CR (trade name) manufactured by Daicel Corporation
Example 283 [Production of 2-amino-1-phenylethanol]
A mixture of 3 kg (44 mol) of a 25% NH ³ aqueous solution and 1 kg of methanol was heated to 40 ° C., and 120 g (1.0 mol) of styrene oxide was added dropwise to the mixture over 30 minutes. After completion of the dropwise addition, the mixture was aged at 40 ° C. for 3.5 hours, then subjected to NH ₃ removal at 20 ° C. under reduced pressure, and subsequently heated to 40 ° C. to 60 ° C. to remove low boiling, thereby obtaining 135 g of a concentrate. Was. The composition of the concentrate was 67% by weight of 2-amino-1-phenylethanol (0.66 mol), 19% by weight of the corresponding regioisomer and 14% by weight of other by-products.

  13.5 g of the obtained concentrate was dissolved in 135 g of dichloroethane, and 3.8 g (0.038 mol) of triethylamine was added. The solution was heated to 50 ° C., and 1.67 NL (0.075 mol) of hydrochloric acid gas was blown in for 1 hour. After completion of the blowing, the mixture was aged for 30 minutes, cooled to 20 ° C., and separated by filtration under reduced pressure. The obtained wet crystals were dried under reduced pressure to obtain 11.4 g of hydrochloride. The composition of the crystals was 93.4% by weight of 2-amino-1-phenylethanol hydrochloride, 0.7% by weight of the corresponding regioisomer, 6% by weight of triethylamine hydrochloride, and no other by-products were detected. Was. At this time, the yield from the reaction concentrate was 93.5%.

  The crystals were dispersed in 10 g of water, and 11 g (0.068 mol) of a 25% aqueous solution of NaOH was added thereto at 25 ° C. over 20 minutes to remove impurities. After extracting this mixture with 120 g of dichloroethane, the dichloroethane layer was washed twice with 20 g of a saturated saline solution, and the solvent was removed at 40 ° C. under reduced pressure to give 2-amino-1-phenylethanol having a purity of 99.1%. 87 g of crystals were obtained. At this time, the yield from the reaction concentrate was 86%.

Example 284 [Production of 2-amino-1-phenylethanol]
13.5 g of the concentrate obtained by the reaction of styrene oxide in Example 283 (67% of 2-amino-1-phenylethanol (0.066 mol), consisting of 19% of the corresponding regioisomer and 14% of the dimer) The mixture was dissolved in 100 g of ethyl acetate, and hydrochloric acid gas, 1.46 NL (0.065 mol) was blown into the solution at 60 ° C over 20 minutes, cooled to 20 ° C, and the crystals were filtered and dried under reduced pressure. 10.5 g of crystals of the hydrochloride were obtained. The crystal composition was 98% of 2-amino-1-phenylethanol hydrochloride, 1.9% of the corresponding regioisomer, and no other by-product was detected. At this time, the yield from the reaction concentrate is 90%.

  Further, it was freed in the same manner as in Example 283 to obtain 7.65 g of 2-amino-1-phenylethanol having a purity of 98.1%. At this time, the yield from the reaction concentrate was 83%.

Example 285 [Production of 2-amino-1-phenylethanol]
13.5 g of the concentrate obtained by the reaction of styrene oxide in Example 283 was dissolved in 135 g of dichloromethane, and 2.24 NL (0.1 mol) of hydrochloric acid gas was blown into this solution at 30 ° C. over 30 minutes to give 20 g. After cooling to 0 ° C., the crystals were filtered and dried under reduced pressure to obtain 14.0 g of hydrochloride crystals. At this time, the crystal composition was 78% of 2-amino-1-phenylethanol hydrochloride, 21.5% of the corresponding regioisomer, and no other by-product was detected.

  The crystals were dispersed in 80 g of dichloromethane, and 4.1 g (0.04 mol) of triethylamine was added at 40 ° C., and the mixture was aged for 30 minutes, cooled to 20 ° C., and the obtained crystals were filtered and dried under reduced pressure. This gave 10.6 g of hydrochloride crystals. The composition of the hydrochloride was 99.2% of 2-amino-1-phenylethanol hydrochloride and 0.6% of the corresponding regioisomer, and no other by-product was detected. The yield from the reaction concentrate was 92.6%.

  The hydrochloride was freed in the same manner as in Example 283 to obtain 7.78 g of crystals of 2-amino-1-phenylethanol having a purity of 99.3%. At this time, the yield from the reaction concentrate was 85.4%.

Examples 286 to 293 [Production of 2-amino-1-phenylethanol derivative]
A corresponding 2-amino-1-phenylethanol derivative was produced in the same manner as in Example 283 except that the following compound was used instead of styrene oxide.

Example 286: 3-chlorostyrene oxide Example 287: 3,4-dichlorostyrene oxide Example 288: 2-methoxystyrene oxide Example 289: 3,4-dimethoxystyrene oxide Example 290: 4-hydroxystyrene oxide Example 291: 3-chloro-4,5-dihydroxystyrene oxide Example 292: 2-benzylcarbonylstyrene oxide Example 293: 3-hydroxymethyl-4-benzyloxystyrene oxide The composition ratio and yield in each step were determined. Table 20 shows the measurement results. In Table 20, "A" indicates a 2-amino-1-phenylethanol derivative, "B" indicates a corresponding positional isomer, "C" indicates another by-product, and the numbers in the table indicate their composition ratios ( Weight ratio). The yield is represented by the yield (%) from the reaction concentrate.

Example 294 [Production of 2-amino-1-phenylethanol]
A mixture of 265 g (3.9 mol) of a 25% aqueous NH ₃ solution and 90 g of methanol was heated to 40 ° C., and 13.4 g (0.086 mol) of styrene chlorohydrin was added dropwise over 30 minutes. After completion of the dropwise addition, the mixture was aged for 4 hours, cooled to 20 ° C., and subjected to NH ₃ removal under reduced pressure, followed by raising the temperature and removing the solvent until the concentration of the concentrate became 50 g. The concentrate was extracted twice with 100 g of ethyl acetate to transfer 2-amino-1-phenylethanol and the corresponding by-products to the organic layer. At this time, the total amount of the ethyl acetate layer was 210 g, 3.53% (0.054 mol) of 2-amino-1-phenylethanol, the corresponding regioisomer 0.3%, and other by-products 0.7% Met.

  After the ethyl acetate layer was dehydrated using 10 g of sodium sulfate, the temperature was raised to 50 ° C., 1.12 NL (0.05 mol) of hydrochloric acid gas was blown in for 1 hour, and the mixture was cooled to 20 ° C. and filtered. After drying, 8.4 g of hydrochloride was obtained. The composition of this salt was 98.5% of the salt of 2-amino-1-phenylethanol, 1.3% of the salt of the corresponding regioisomer, no other by-products were detected, and The rate was 89%.

  This hydrochloride was freed in the same manner as in Example 283 to obtain 6.2 g of 2-amino-1-phenylethanol having a purity of 98.6%. At this time, the yield from the reaction extraction organic layer was 83%.

Example 295 [Production of (R) -2-amino-1- (3-chlorophenyl) ethanol]
After heating a mixture of 712 g (10.47 mol) of a 25% aqueous NH ₃ solution and 242 g of methanol to 40 ° C., 36 g (0.23 mol) of m-chlorostyrene oxide was added dropwise over 1 hour. After completion of the dropwise addition, the mixture was aged for 3.5 hours, cooled to 20 ° C., subjected to NH ₃ removal under reduced pressure, and subsequently heated to remove the solvent to obtain 40 g of a concentrate. The composition at this time was 76% (0.175 mol) of 2-amino-1- (3-chlorophenyl) ethanol, 11% of the corresponding regioisomer, and 13% of other by-products.

  This concentrate was dissolved in 65 g of ethyl acetate and heated to 70 ° C., and then 67 g (0.35 mol) of Nt-butoxycarbonyl-D-alanine (hereinafter referred to as Boc-D-alanine) was added to 320 g of ethyl acetate. The solution dissolved in was dropped over 30 minutes. After completion of the dropwise addition, the mixture was aged for 30 minutes, gradually cooled to 5 ° C., and the crystals were separated by filtration. The composition ratio of this wet crystal is (R) -2-amino-1- (3-chlorophenyl) ethanol salt 99.9%, the corresponding regioisomer is 0.1% or less, and other by-products are Not detected.

  The wet crystals were dispersed in 620 g of dichloroethane, and 272 g (0.54 mol) of an 8% aqueous NaOH solution was added dropwise over 30 minutes to make the crystals free. After the aqueous layer was separated by liquid separation, the solution was washed twice with 247 g of a saturated saline solution. Furthermore, dehydration was performed with 10 g of sodium sulfate, and the solvent was removed under reduced pressure to obtain 11 g of (R) -2-amino-1- (3-chlorophenyl) ethanol. This composition had a chemical purity of 99.5% and an optical purity of 100% e e, no corresponding regioisomer was detected, and no other impurities were detected.

Example 296 [Production of (R) -2-amino-1-phenylethanol]
(R) -2- having a chemical purity of 99.2% and an optical purity of 100% ee in the same manner as in Example 295 except that 3-chlorostyrene oxide was changed to 27.7 g (0.23 mol) of styrene oxide. 7.3 g of amino-1-phenylethanol were obtained. In addition, regio isomers and other by-products were not detected.

Example 297 [Production of 2-amino-1-phenylethanol]
In the same manner as in Example 295, except that 67 g (0.35 mol) of Boc-D-alanine was replaced by 30.4 g (0.2 mol) of D, L-mandelic acid, 2-amino-amino acid having a chemical purity of 99% was used. 26.8 g of 1- (3-chlorophenyl) ethanol was obtained. The yield of the corresponding regioisomer was 0.9% based on the total amount of the product, and no other by-product was detected.

Example 298 [Production of (R) -2-amino-1- (3-chlorophenyl) ethanol]
3.38 g of a concentrate of the reaction mixture obtained in the same manner as in Example 295 (2.57 g of 2-amino-1- (3-chlorophenyl) ethanol, containing 15.0 mmol) was added to 20 ml of n-butanol. And dissolved at 50 ° C. While gently stirring the solution, 20 ml of n-butanol in which 2.10 g (7.5 mmol) of Nt-butoxycarbonyl-L-tyrosine (hereinafter abbreviated as Boc-L-Tyr) was added, and crystals were added. Was precipitated. After cooling to room temperature, the crystals were filtered to obtain 1.95 g (4.31 mmol) of (R) -2-amino-1- (3-chlorophenyl) ethanol / Boc-L-Tyr salt. The yield based on (R) -2-amino-1- (3-chlorophenyl) ethanol in the mixture used was 58.2%.

  Its physical properties were as follows.

188.8 ° C
Specific rotation [α] D ²⁵ +12.95 (c = 0.926, methanol)
To this salt, 5 ml of 1 N sodium hydroxide was added, and extracted with 10 ml of 1,2-dichloroethane. The solvent was distilled off from the organic layer under reduced pressure to obtain 0.73 g (4.25 mmol) of (R) -2-amino-1- (3-chlorophenyl) ethanol. This was analyzed using an optical resolution column “crown pack CR (+)” manufactured by Daicel Chemical Industries, Ltd., and as a result, the optical purity was 87.2% ee.

Example 299 [Production of (R) -2-amino-1- (3-chlorophenyl) ethanol]
3.38 g of a concentrate of the reaction product obtained in the same manner as in Example 295 (containing 2.57 g (15.0 mmol) of 2-amino-1- (3-chlorophenyl) ethanol) was treated with 1N Dissolve in 15 ml of aqueous hydrochloric acid and add, to the resulting solution, a solution of 2.10 g (7.5 mmol) of Boc-L-Tyr dissolved in 7.5 ml of 1 N aqueous sodium hydroxide while stirring gently. As a result, crystals were precipitated. This was filtered to obtain 2.49 g (5.5 mmol) of (R) -2-amino-1- (3-chlorophenyl) ethanol / Boc-L-Tyr salt. The yield based on (R) -2-amino-1- (3-chlorophenyl) ethanol in the concentrate used was 73.4%.

  Its physical properties were as follows.

187.2 ° C
Specific rotation [α] D ²⁵ +14.28 (c = 0.805, methanol)
To this salt was added 5 ml of a 1 N aqueous solution of sodium hydroxide, and the mixture was extracted with 10 ml of 1,2-dichloroethane. The solvent was distilled off from the organic layer under reduced pressure to obtain 0.92 g (5.37 mmol) of (R) -2-amino-1- (3-chlorophenyl) ethanol. This was analyzed in the same manner as in Example 298. As a result, the optical purity was 81.9% ee.

Example 300 [Production of (R) -2-amino-1- (3-chlorophenyl) ethanol]
To 40 ml of 4-methyl-2-pentanone, 3.38 g (2.57 g (15.0 mmol) of 2-amino-1- (3-chlorophenyl) ethanol) of the reaction concentrate obtained in the same manner as in Example 295 was added. ) And 4.67 g (15.0 mmol) of Nt-butoxycarbonyl-O-benzyl-L-threonine [hereinafter abbreviated as Boc-L-Thr (Bzl)], and after heating and dissolution, cooling to room temperature. And left overnight. The precipitated crystals were filtered to obtain 3.06 g (6.34 mmol) of (R) -2-amino-1- (3-chlorophenyl) ethanol · Boc-L-Thr (Bzl) salt. The yield based on (R) -2-amino-1- (3-chlorophenyl) ethanol in the concentrate used was 83.9%.

  Its physical properties were as follows.

144.6 ° C
Specific rotation [α] D ²⁵ +9.04 (c = 0.962, methanol)
To the salt was added 7 ml of a 1 N aqueous solution of sodium hydroxide, and the mixture was extracted with 10 ml of 1,2-dichloroethane. The solvent was distilled off from the organic layer under reduced pressure to obtain 1.05 g (6.15 mmol) of (R) -2-amino-1- (3-chlorophenyl) ethanol. This was analyzed in the same manner as in Example 298. As a result, the optical purity was 81.6% ee.

Example 301 [Production of (S) -2-amino-1- (3-chlorophenyl) ethanol]
To a mixed solution of 15 ml of ethyl acetate and 10 ml of ethanol, 1.69 g (1.29 g (7.50 mmol) of 2-amino-1- (3-chlorophenyl) ethanol) obtained in the same manner as in Example 295 was added. ) And 1.16 g (3.75 mmol) of Nt-butoxycarbonyl-O-benzyl-L-cysteine [hereinafter abbreviated as Boc-L-Cys (Bzl)], dissolved by heating and cooled to room temperature. After that, it was left overnight. The precipitated crystals were filtered to obtain 1.30 g (2.69 mmol) of (S) -2-amino-1- (3-chlorophenyl) ethanol / Boc-L-Cys (Bzl) salt. The yield based on (S) -2-amino-1- (3-chlorophenyl) ethanol in the reaction concentrate used was 71.6%.

  To this salt was added 1N sodium hydroxide (5 ml), and the mixture was extracted with 1,2-dichloroethane (5 ml). The solvent was distilled off from the organic layer under reduced pressure to obtain 0.69 g (2.69 mmol) of (S) -2-amino-1- (3-chlorophenyl) ethanol. As a result of analyzing this in the same manner as in Example 298, the optical purity was 95.1% ee.

Example 302 [Production of (R) -2-amino-1- (3-chlorophenyl) ethanol]
In 20 ml of methanol, 1.70 g of a concentrate of the reaction product obtained in the same manner as in Example 295 (containing 1.29 g (7.50 mmol) of 2-amino-1- (3-chlorophenyl) ethanol) and L Add 2.88 g (7.50 mmol) of di-p-toluoyltartaric acid (hereinafter abbreviated as L-PTTA), dissolve by heating, add 20 ml of 4-methyl-2-pentanone, cool to room temperature, and overnight I left it. The precipitated crystals were filtered to obtain 1.69 g (2.63 mmol) of (R) -2-amino-1- (3-chlorophenyl) ethanol / L-PTTA salt. The yield of the compound relative to (R) -2-amino-1- (3-chlorophenyl) ethanol in the concentrate was 70.1%.

  To the salt obtained above, 3 ml of 1N sodium hydroxide was added, and the mixture was extracted with 5 ml of 1,2-dichloroethane. The solvent was distilled off from the organic layer under reduced pressure to obtain 0.64 g (2.50 mmol) of (R) -2-amino-1- (3-chlorophenyl) ethanol. As a result of analyzing this in the same manner as in Example 298, the optical purity was 75.7% ee.

Example 303 [Production of (R) -2-amino-1-phenylethanol]
In 20 ml of n-butanol, 2.19 g of a concentrate of the reaction product obtained in the same manner as in Example 296 [containing 1.67 g (7.50 mmol) of 2-amino-1-phenylethanol] and And 2.11 g (7.50 mmol) of Boc-L-Tyr were added and dissolved by heating. The precipitated crystals were filtered to obtain 1.06 g (2.10 mmol) of (R) -2-amino-1-phenylethanol / Boc-L-Tyr salt. The yield based on (R) -2-amino-1-phenylethanol in the concentrate used was 56.0%.

  Further, 3 ml of 1N sodium hydroxide was added to this salt, and the mixture was extracted with 5 ml of 1,2-dichloroethane. The solvent was distilled off from the organic layer under reduced pressure to obtain 0.46 g (2.08 mmol) of (R) -2-amino-1-phenylethanol. This was analyzed in the same manner as in Example 298. As a result, the optical purity was 81.7% ee.

Example 304 [Production of (R, R) -1- (3-chlorophenyl) -2-[[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino] ethanol]
Methyl = 3,4-dimethoxyphenylmethyl ketone (0.58 g) was added to a solution of (R) -2-amino-1- (3-chlorophenyl) ethanol (0.52 g) in benzene (10 ml), and water- The mixture was refluxed for 1 hour in a device equipped with a trap, and the generated water was removed from the system. The reaction solution was cooled, the solvent was distilled off under reduced pressure, the residue was dissolved in methanol (10 ml), cooled to a temperature lower than 10 ° C., and slightly stirred with sodium borohydride (0.14 g) for 30 minutes. Each was processed. Further, the mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated to dryness to obtain 1.09 g of a yellow oil. A part of this was subjected to silica gel thin-layer chromatography, and the obtained compound was analyzed by high-performance liquid chromatography using an optical resolution column [column: Chiralpak AD manufactured by Daicel Chemical Industries, Ltd.]. The (R, R) :( R, S) ratio obtained by mer splitting and recrystallization was 48:52.

Claims (12)

General formula (II)

(Wherein, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same or different and are each protected with a hydrogen atom, a halogen atom, a lower alkyl group which may have a substituent, or a protecting group. An optionally substituted hydroxyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, An aryloxy group which may be substituted, a lower alkylthio group which may have a substituent, an acyl group which may have a substituent, a carboxyl group which may be protected by a protecting group, which has a substituent Represents an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group, and Z represents a hydrogen atom or a protecting group for a hydroxyl group.)
(R) -2-amino-1-phenylethanol compound or a salt thereof represented by the formula:

(Wherein R ⁷ and R ⁸ are the same or different and are (A) hydrogen atoms, lower alkyl groups which may have a substituent, cycloalkyl groups which may have a substituent, An aralkyl group which may have a substituent, an aryl group which may have a substituent, an acyl group which may have a substituent, a carboxyl group which may be protected by a protecting group, and a group having a substituent. An optionally substituted lower alkoxycarbonyl group, an optionally substituted amino group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group or a protecting group Or (B) R ⁷ is a group represented by the formula (IX): —O—R ^7a , and R ⁸ is a group represented by the formula (X): —O—R a group represented by ^8a, R ^7a and R ^8a together, the adjacent oxygen atom Together may form a ring which may have a ^{substituent, R 6, R 9, R} 10 are the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower Alkyl group, cycloalkyl group which may have a substituent, aralkyl group which may have a substituent, aryl group which may have a substituent, hydroxyl which may be protected by a protecting group Group, an alkoxy group optionally having a substituent, a cycloalkyloxy group optionally having a substituent, an aralkyloxy group optionally having a substituent, optionally having a substituent Aryloxy group, lower alkylthio group optionally having substituent (s), aralkylthio group optionally having substituent (s), acyl group optionally having substituent (s), even if protected with a protecting group Has good carboxyl group and substituent Which may be lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group, R ¹¹ represents a lower alkyl group)
Including a reaction with a compound represented by the formula: and a reaction of reducing a reaction product of the reaction.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and Z are the same as described above)
(R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative represented by In the general formula (VIII), R ⁷ and R ⁸ are (A) the same or different:
(1) a hydrogen atom;
(2) a hydroxyl group, a C _1-4 alkoxy group, a benzoyl group, an alkylthio group, a halogen atom, and an amino group which may have a substituent; A good C _1-4 alkyl group;
(3) a C _3-10 cycloalkyl group _optionally having a substituent selected from the group consisting of a C _1-4 alkyl group, a hydroxyl group and a halogen atom;
(4) C ₇ which may be substituted with a substituent selected from the group consisting of a C _1-4 alkyl group, a C _6-12 aryl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group and a halogen atom. _-20 aralkyl groups;
(5) C ₆ which may be substituted with a substituent selected from the group consisting of a C _1-4 alkyl group, a C _6-12 aryl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group and a halogen atom. _-16 aryl group;
(6) (a) a C _1-6 acyl group optionally substituted with a substituent selected from the group consisting of a hydroxyl group, a C _1-4 alkoxy group, a C _1-4 alkylthio group and a halogen atom, (b A) an acyl group selected from the group consisting of a _C7-20 acyl group having an aromatic ring _optionally substituted with a substituent, and (c) an acyl group having a heterocyclic ring _optionally substituted with a substituent;
(7) a carboxyl group which may be protected by a protecting group;
(8) an optionally substituted C _2-5 alkoxycarbonyl group;
(9) (a) a C _1-4 alkyl group which may be substituted with a substituent selected from the group consisting of a hydroxyl group, a C _1-4 alkoxy group, a benzoyl group, a C _1-4 alkylthio group, and a halogen atom (B) a C _7-20 aralkyl group which may be substituted with a substituent selected from the group consisting of a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group and a halogen atom; c) a C _1-6 acyl group which may be substituted with a substituent selected from the group consisting of a hydroxyl group, a C _1-4 alkoxy group, a C _1-4 alkylthio group and a halogen atom, and (d) a substituent. A C _7-20 acyl group having an aromatic ring which may be substituted, (e) an acyl group having a heterocyclic ring which may be substituted with a substituent, and (f) a carboxyl which may be protected with a protecting group A substituent selected from the group consisting of And an amino group which may be;
(10) hydroxyl group, C _1-4 alkoxy group, a benzoyl group, C _1-4 alkylthio groups, which may C _1-4 alkyl sulfonyl group substituted with substituent selected from the group consisting of halogen atoms;
(11) a C _6-20 arylsulfonyl group optionally substituted with a substituent selected from the group consisting of a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group and a halogen atom; (12) a hydroxyl group which may be protected with a protecting group;
A group selected from the group consisting of
(B) R ⁷ is the formula (IX): - O-R 7a, R 8a has the formula (X): - a group represented by O-R ^8a, and R ^7a and R ^8a together Forming a C _1-4 alkylene group which may have a substituent, a carbonyl group or a thiocarbonyl group,
R ⁶ , R ⁹ and R ¹⁰ are each
(1) a hydrogen atom;
(2) a halogen atom;
(3) substituted with a substituent selected from the group consisting of a hydroxyl group, a C _1-4 alkoxy group, a benzoyl group, a C _1-4 alkylthio group, a halogen atom, and an amino group which may have a substituent. An _optionally substituted C _1-4 alkyl group;
(4) a C _3-10 cycloalkyl group _optionally having a substituent selected from the group consisting of a C _1-4 alkyl group, a hydroxyl group and a halogen atom;
(5) C ₇ which may be substituted with a substituent selected from the group consisting of a C _1-4 alkyl group, a C _6-12 aryl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group and a halogen atom. _-20 aralkyl groups;
(6) CC ₆ which may be substituted with a substituent selected from the group consisting of a C _1-4 alkyl group, a C _6-12 aryl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group and a halogen atom. _-16 aryl group;
(7) a hydroxyl group which may be protected with a protecting group;
(8) a hydroxyl group, a C _1-4 alkoxy group, a halogen atom and optionally having a substituent may be substituted with substituents also selected from the group consisting of an amino C _1-4 alkoxy group;
(9) a C _3-10 cycloalkyloxy group _optionally having a substituent selected from the group consisting of a C _1-4 alkyl group, a hydroxyl group and a halogen atom;
(10) C ₇ which may be substituted with a substituent selected from the group consisting of a C _1-4 alkyl group, a C _6-12 aryl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group and a halogen atom. _-20 aralkyloxy group;
(11) It may have a substituent which may be substituted with a substituent selected from the group consisting of a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group and a halogen atom. A C _6-16 aryloxy group;
(12) a C _1-4 alkylthio group which may be substituted with a substituent selected from the group consisting of a hydroxyl group, a C _1-4 alkoxy group and a halogen atom;
(13) C _7-20 which may be substituted with a substituent selected from the group consisting of a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group and a halogen atom.
(14) (a) a C _1-6 acyl group which may be substituted with a substituent selected from the group consisting of a hydroxyl group, a C _1-4 alkoxy group, a C _1-4 alkylthio group and a halogen atom, (b A) an acyl group selected from the group consisting of a _C7-20 acyl group having an aromatic ring _optionally substituted with a substituent and (c) an acyl group having a heterocyclic ring _optionally substituted with a substituent;
(15) a carboxyl group which may be protected with a protecting group;
(16) a C _2-5 alkoxycarbonyl group which may have a substituent;
(17) a nitro group; and (18) (a) even when substituted with a substituent selected from the group consisting of a hydroxyl group, a C _1-4 alkoxy group, a benzoyl group, a C _1-4 alkylthio group, and a halogen atom. A C _1-4 alkyl group which may be substituted with a substituent selected from the group consisting of a good C _1-4 alkyl group, (b) a C _1-4 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a nitro group and a halogen atom. _7-20 aralkyl group, (c) hydroxyl group, C _1-4 alkoxy group, C _1-4 alkylthio group and C _1-6 acyl group optionally substituted with a substituent selected from the group consisting of halogen atoms And (d) a C _7-20 acyl group having an aromatic ring _optionally substituted with a substituent, (e) an acyl group having a heterocyclic ring _optionally substituted with a substituent, and (f) a protecting group. A carboxyl group which may be protected; Amino group which may have a selected substituents from the group that;
A group selected from the group consisting of
R ¹¹ represents a C _1-4 alkyl group,
In the formula (II), Z is (A) a hydrogen atom, or (B) a C _1-4 alkyl group _optionally substituted with (a) a substituent, or (b) optionally substituted with a substituent. An allyl group, (c) a C _3-10 cycloalkyl group _optionally substituted with a substituent, (d) an oxygen atom or a sulfur atom as a hetero atom other than a carbon atom, which may be substituted with a substituent. A 5- or 6-membered heterocyclic group, (e) a C _7-20 aralkyl group _optionally substituted with a substituent, (f) a silyl group optionally substituted with a substituent, and (g) a substituent. A C _1-6 acyl group _optionally substituted with (h) a C _7-20 acyl group having an aromatic ring _optionally substituted with a substituent, (i) a heterocyclic group _optionally substituted with a substituent acyl group having a ring, (j) optionally substituted with a substituent C _2-5 alkoxycarbonyl group, (k) substituent Optionally substituted C _8-20 aralkyloxycarbonyl group, (l) optionally substituted with a substituent C _7-20 aryloxycarbonyl group, (m) optionally substituted with a substituent C _{1 The} compound according to claim 1, wherein the compound is a protecting group for a hydroxyl group selected from the group consisting of a _-4 alkylsulfonyl group and (n) a _C6-20 arylsulfonyl group optionally substituted with a substituent. A method for producing an (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative. The ^optionally substituted C _1-4 alkylene group formed by R ^7a and R ^8a has the following formula (XII)

(Wherein R ^a and R ^b are the same or different in (A)
(1) a hydrogen atom;
(2) a C _1-4 alkyl group;
(3) a C _1-4 haloalkyl group;
(4) C ₆ which may be substituted with a substituent selected from the group consisting of a halogen atom, a C _1-4 alkyl group, a C _6-12 aryl group, a hydroxyl group, a C _1-4 alkoxy group and a nitro group. _-20 aryl group;
(5) a C _1-4 alkoxy group;
(6) an amino group which may have a substituent;
(7) a carboxyl group or a salt thereof;
(8) selected from the group consisting of C _1-4 alkoxy groups, C _1-4 alkoxy-C _1-4 alkoxy groups, C _7-20 aralkyloxy groups, benzoyl groups, C _1-4 alkylthio groups and halogen atoms. A C _2-5 alkoxycarbonyl group which may have a substituent;
(9) a hydroxymethyl group; and (10) a carboxyl group, C _2-5 alkoxycarbonyl group, a hydroxyl group, and C _1-4 optionally C ₁ optionally substituted with a substituent selected from the group consisting of an alkoxy group _-4 alkoxy-methyl group, or (B) R ^a and R ^b may form a C _5-7 cycloalkyl group together with adjacent carbon atoms)
3. A (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative according to claim 2, which is a methylene group which may have a substituent represented by the formula: Production method. In the formula (VIII), R ⁷ and R ⁸ are
(A) the same or different, a hydrogen atom, or a hydroxyl group which may be protected by a protecting group selected from the group consisting of a C _1-4 alkyl group, a C _7-20 aralkyl group and a C _1-6 acyl group; Or (B) R ⁷ is a group represented by the formula (IX): —O—R ^7a , R ^8a is a group represented by the formula (X): —O—R ^8a , and R ^7a and R ^8a Are formed together with the methylene group represented by the general formula (XII), R ^a and R ^b are (i) respectively (a) a hydrogen atom, (b) a C _1-4 alkyl group, (c) A) a carboxyl group or a salt thereof, (d) a C _2-5 alkoxycarbonyl group optionally substituted with a substituent, (e) a hydroxymethyl group, or (f) a C _1- optionally substituted with a substituent. ₄ alkoxy - or a methyl group, or (ii) C _5-7 together with the carbon atom to which the R ^a and R ^b are adjacent cycloalk It may form a group,
R ⁶ , R ⁹ and R ¹⁰ are the same or different and are a hydrogen atom or a C _1-4 alkyl group, R ¹¹ is a methyl group or an ethyl group,
3. The method for producing a (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative according to claim 2, wherein in the formula (II), Z is a hydrogen atom. The (R, R) -1 according to claim 1, wherein the optically active compound represented by the general formula (II), the compound represented by the general formula (VIII), and hydrogen are reacted in the presence of a catalytic reduction catalyst. A method for producing a phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative. The (R, R) -1-phenyl-2 according to claim 1, wherein the optically active compound represented by the general formula (II) is reacted with the compound represented by the general formula (VIII), and then hydrogenated. -A process for producing [(2-phenyl-1-alkylethyl) amino] ethanol derivatives. The method for producing a (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative according to claim 5, wherein the reaction is carried out in the presence of an acid catalyst. The (R, R) -1- compound according to claim 1, wherein an (R, R) -form represented by the general formula (XI) is separated and purified by adding an acid to the reaction product and separating and crystallizing a generated salt. A method for producing a phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative. A salt of the (R, R) form represented by the general formula (XI) and a salt of the general formula (XIII)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and Z are the same as described above)
The base is added in an amount of 0.05 to 0.9 gram equivalent to 1 mol of the total amount of the salt of the (R, S) form represented by the formula (1) to liberate the (R, S) form, The method for producing a (R, R) -1-phenyl-2-[(2-phenyl-1-methylethyl) amino] ethanol derivative according to claim 8, wherein the (R) form is precipitated as a salt. Furthermore, (1) general formula (I)

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as described above)
Acting on an enantiomeric mixture of a 2-amino-1-phenylethanol compound or a salt thereof represented by the general formula (IIa)

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as described above)
(R) -2-amino-1-phenylethanol compound represented by the formula (II) or a treated product thereof, which is capable of producing a (R) -2-amino-1-phenylethanol compound or a salt thereof, is reacted with an optically active compound represented by the general formula (II) ( Wherein Z represents a hydrogen atom) or a salt thereof, or (2) an optical activity represented by the general formula (II) generated in the step (1) in addition to the step (1). An optically active compound represented by the general formula (II) wherein a protecting group is introduced into a hydroxyl group of a compound (provided that Z represents a hydrogen atom) or a salt thereof (wherein Z represents a protecting group for a hydroxyl group) or The method for producing a (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) amino] ethanol derivative according to claim 1, comprising a step of forming a salt thereof. Further, (1) general formula (VII)

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as described above)
Or a salt thereof, acting on the compound to form the corresponding compound represented by the general formula (IIa):

Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as described above, and a (R) -2-amino-1-phenylethanol compound or a microorganism capable of producing a salt thereof. Or a step of reacting the treated product to form an optically active compound represented by the general formula (II) (wherein Z represents a hydrogen atom) or a salt thereof, or (2) adding to the step (1) In addition, a protecting group is introduced into the hydroxyl group of the optically active compound represented by the general formula (II) (where Z represents a hydrogen atom) or a salt thereof formed in the step (1) to form a compound represented by the general formula (II) (R, R) -1-phenyl-2-[(2) according to claim 1, which comprises a step of producing an optically active compound represented by the formula (1), wherein Z represents a protecting group for a hydroxyl group, or a salt thereof. -Phenyl-1-alkylethyl) amino] ethano Manufacturing method of Le derivative. Further, the formula (III)

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as described above)
Or a compound represented by the formula (IV):

(Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as above, Z represents a hydrogen atom or a hydroxyl-protecting group, and X represents a halogen atom)
And a compound represented by the general formula (V)
Y-NH ₂
(Wherein, Y represents a hydrogen atom or a group which can be eliminated in the reaction)
And, when Y is a group which can be eliminated in the reaction, Y is eliminated, and an acid is added to a reaction product containing the compound represented by the general formula (VI). And the general formula (VI)

(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z are the same as above)
The 2-amino-1-phenylethanol compound represented by the following formula is separated by precipitation as a salt, and when Z is a protecting group for a hydroxyl group, the protecting group is eliminated to give a compound represented by the general formula (I). (R, R) -1-phenyl-2-[(2-phenyl-1-alkylethyl) according to claim 10, which comprises a step of producing an enantiomer mixture of a 2-amino-1-phenylethanol compound or a salt thereof to be used. A) Method for producing amino] ethanol derivatives.