Processes for producing optically active 2-amino-1-phenylethanol derivatives

Abstract

An (R)-2-amino-1-phenylethanol derivative shown by the general formula (IIa) wherein R 1 and R 5 represent a hydrogen atom, etc.; R 2 , R 3 and R 4 independently represent a halogen atom, etc., or a salt thereof, can readily be produced (1) 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 (2) 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. 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 the formula (IIa) or a salt thereof. Said derivative is useful as an intermediate for producing an anti-obesity agent and so on.

What is claimed is:  
     
         1 . A process for producing an (R)-2-amino-1-phenylethanol derivative which comprises: 
 permitting a microorganism or a preparation thereof which is capable of acting on a mixture of enantiomers of a 2-amino-1-phenylethanol compound of the general formula (I)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  represent, the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group, or a salt thereof, to produce a corresponding (R)-2-amino-1-phenylethanol shown by the general formula (IIa)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above, or a salt thereof, to act on said mixture of enantiomers, and    harvesting or recovering the product (R)-form shown by the general formula (IIa) or a salt thereof.    
     
     
         2 . A process for producing an (R)-2-amino-1-phenylethanol derivative according to  claim 1 , wherein R 1 , R 2 , R 3 , R 4  and R 5  respectively represent a group selected from the group consisting of: 
 (1) a hydrogen atom;    (2) a halogen atom;    (3) 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, benzoyl group, an optionally substituted C 6-12  aryl group, a C 1-4  alkylthio group and a halogen atom;    (4) a hydroxyl group which may be protected with a protective group;    (5) a C 1-4  alkoxy group which may be substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group and a C 1-4  alkoxy group;    (6) a C 3-10  cycloalkyloxy group which may be substituted with a substituent selected from the group consisting of a C 1-4  alkyl group, a hydroxyl group and a halogen atom;    (7) a C 7-20  aralkyloxy group 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;    (8) a C 6-16  aryloxy 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;    (9) a C 1-4  alkylthio group which may be substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group and a C 1-4  alkoxy group;    (10) an acyl group selected from the group consisting of (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 C 7-20  acyl group having an aromatic ring which may be substituted with a substituent and (c) an acyl group having a heterocyclic ring which may be substituted with a substituent;    (11) a carboxyl group which may be protected with a protective group;    (12) an optionally substituted C 2-5  alkoxycarbonyl group;    (13) a nitro group; and    (14) an amino group which may be substituted with a substituent selected from the group consisting of (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, 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, (d) a C 7-20  acyl group having an aromatic ring 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, (e) an acyl group having a heterocyclic ring 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, and (f) a carboxyl group which may be protected with a protective group.    
     
     
         3 . A process for producing an (R)-2-amino-1-phenylethanol derivative according to  claim 1 , wherein R 1  and R 5  independently represent a hydrogen atom or a C 1-4  alkyl group; R 2 , R 3  and R 4  respectively represent a hydrogen atom, a halogen atom, a C 1-4  alkyl group which may be substituted with a halogen atom or a hydroxyl group, a hydroxyl group, a C 1-4  alkoxy group, a C 7-20  aralkyloxy group, a C 7-20  acyl group having an aromatic ring, a nitro group or an amino group which may be substituted with a C 1-6  acyl group.  
     
     
         4 . A process for producing an (R)-2-amino-1-phenylethanol derivative according to  claim 1 , wherein said microorganism is a strain of microorganism selected from the group consisting of microorganisms belonging to the genus Hansenula, the genus Geotrichum, the genus Candida, the genus Cryptococcus, the genus Rhodosporidium, the genus Rhodotorula, the genus Saccharomyces, the genus Sporobolomyces, the genus Kluyveromyces, the genus Issatchenkia, the genus Pichia, the genus Botryoascus, the genus Debaryomyces, the genus Lipomyces, the genus Metschnikowia, the genus Saccharomycodes, the genus Schizoblastosporion, the genus Stepahnoascus, the genus Sterigmatomyces, the genus Zygosaccharomyces, the genus Sporidiobolus, the genus Malassezia, the genus Torulaspora, the genus Corynebacterium, the genus Gluconobacter, the genus Promicromonospora, the genus Pseudomonas, the genus Bordetella, the genus Acetobacter, the genus Bacillus, the genus Agrobacterium, the genus Arthrobacter, the genus Amauroascus, the genus Brevibacterium, the genus Micrococcus, the genus Aureobacterium, the genus Azotobacter, the genus Xanthomonas, the genus Klebsiella, the genus Comamonas, the genus Mycobacterium, the genus Terrabacter, the genus Agrocybe, the genus Trichoderma, the genus Alternaria, the genus Hamigera, the genus Moniliella, the genus Pholiota, the genus Podospola, the genus Aegerita, the genus Streptomyces, the genus Saccharomycopsis and the genus Leucosporidium.  
     
     
         5 . A process for producing (R)-2-amino-1-phenylethanol derivative according to  claim 1 , wherein said microorganism is a strain of microorganism selected from the group consisting of microorganisms belonging to  Hansenula anomala, Geotrichum candidum, Candida albicans, Candida parapsilosis, Candida gropengiesseri, Candida aaseri, Candida beechii, Candida atmospherica, Candida natalensis, Candida paludigena, Candida sake, Candida pintolopesii  var.  pintolopesii, Cryptococcus neoformans, Rhodosporidium spaerocarpum, Rhodosporidium diobovatum, Rhodotorula rubra, Rhodotorula glutinis  var.  dairenensis, Saccharomyces montanus, Sporobolomyces roseus, Kluyveromyces marxianus  var.  bulgaricus, Kluyveromyces lactis, Issatchenkia scutulata  var.  scutulata, Pichia thermotolerans, Pichia farinosa, Botryoascus synnaedendrus, Debaryomyces hansenii, Lipomyces starkeyi, Metschnikowia bicuspidata, Saccharomycodes ludwigii, Schizoblastosporion kobayashii, Stepahnoascus ciferrii, Sterigmatomyces halophilus, Zygosaccharomyces rouxii, Zygosaccharomyces fermentati, Sporidiobolus salmonicolor, Sporidiobolus pararoseus, Malassezia furfur, Torulaspora delbrueckii, Corynebacterium aquaticum, Corynebacterium mediolanum, Gluconobacter asaii, Gluconobacter oxydans, Gluconobacter frateurii, Promicromonospora citrea, Pseudomonas aeruginosa, Pseudomonas riboflavina, Pseudomonas fluorescens, Pseudomonas putida, Pseudomonas syncyanea, Pseudomonas diminuta, Pseudomonas chlororaphis, Pseudomonas fragi , Pseudomonas sp. ATCC 14676,  Bordetella bronchiseptica , Acetobacter sp. IFO 3248, Acetobacter sp. IFO 3297,  Acetobacter pasteurianus, Bacillus subtilis, Bacillus cereus, Bacillus coagulans, Bacillus brevis, Bacillus sphaericus, Agrobacterium radiobacter, Arthrobacter ureafaciens, Amauroascus reticulatus, Brevibacterium linens, Micrococcus roseus, Aureobacterium testaceum, Azotobacter vinelandii, Xanthomonas campestris  pv  oryzae, Klebsiella pneumoniae, Comamonas testosteroni, Mycobacterium diernhoferi, Terrabacter tumescens, Agrocybe cylindracea, Trichoderma viride, Alternaria kikuchiana, Hamigera avellanea, Moniliella acetoabutans, Pholiota nameko, Podospola cardonaria, Aegerita candida, Streptomyces cinereoruber, Rhodococcus amidophilis, Rhodococcus equi, Saccharomycopsis capsularis  and  Leucosporidium scottii.    
     
     
         6 . A process for producing a 2-amino-1-phenylethanol derivative comprising; 
 allowing (a) a compound shown by the general formula (III)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  represent, the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group; or    (b) a compound shown by the general formula (IV)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above; Z represents a hydrogen atom or a protective group for hydroxyl group; and X represents a halogen atom; to react with a compound shown by the general formula (V)   Y—NH 2   (V)   wherein Y represents a hydrogen atom or a group which can be left in the reaction, further, when Y is the group which can be left in the reaction, allowing Y to be left,    to obtain the compound shown by the general formula (VI)                          wherein R 1 , R 2 , R 3 , R 4 , R 5  and Z have the same meanings as defined above;    which comprises adding an acid to the reaction products containing the compound of the general formula (VI) to precipitate or crystallize said compound as a salt and, thereby, isolating the compound of the general formula (VI).    
     
     
         7 . A process for producing a 2-amino-1-phenylethanol derivative according to  claim 6 , wherein the salt is formed in an organic solvent.  
     
     
         8 . A process for producing a 2-amino-1-phenylethanol derivative according to  claim 6 , wherein an optically active organic acid is used as the acid to obtain the optically active compound of the formula (VI).  
     
     
         9 . A process for producing a 2-amino-1-phenylethanol derivative according to  claim 8 , wherein an optically active hydroxycarboxylic acid or an optically active amino acid, which may protected with a protective group on the amino acid, having a side chain possessing a polar group is employed as the optically active organic acid.  
     
     
         10 . A process for producing a 2-amino-1-phenylethanol derivative according to  claim 6 , wherein 1 gram equivalent or less of an inorganic acid relative to 1 mole of the 2-amino-1-phenylethanol derivative shown by the formula (VI) is added to the reaction products.  
     
     
         11 . A process for producing a 2-amino-1-phenylethanol derivative according to  claim 6 , wherein 0.8 gram equivalent or more of an organic acid relative to 1 mole of the compound of the formula (VI) is added to the reaction products.  
     
     
         12 . A process for producing a 2-amino-1-phenylethanol derivative according to  claim 6 , 
 wherein 1 gram equivalent or more of the acid relative to 1 mole of the total amount of the 2-amino-1-phenylethanol compound of the general formula (VI) and a position-isomer thereof, and a base are added to the reaction products to liberate the position-isomer, and the compound of the general formula (VI) is precipitated or crystallized as a salt to isolate said compound.    
     
     
         13 . A process for producing a 2-amino-1-phenylethanol derivative according to  claim 12 , wherein an organic base is employed as the base.  
     
     
         14 . A process for producing a 2-amino-1-phenylethanol derivative according to  claim 13 , wherein an organic base having an electrolytic dissociation exponent pKa value of 9.3 to 11.5 is used.  
     
     
         15 . A process for producing a 2-amino-1-phenylethanol derivative according to  claim 6 , wherein an optically active compound of the general formula (III) or an optically active compound of the general formula (IV) is used to obtain an optically active compound of the general formula (VI).  
     
     
         16 . A process for producing an (R)-2-amino-1-phenylethanol derivative which comprises: 
 permitting a microorganism or a preparation thereof which is capable of acting on a compound shown by the general formula (VII)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  represent, the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group, or a salt thereof, to produce a corresponding (R)-2-amino-1-phenylethanol compound shown by the general formula (IIa)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above, or a salt thereof, to act on said compound or a salt thereof and    harvesting or recovering the product optically active compound or a salt thereof.    
     
     
         17 . A process for producing an (R)-2-amino-1-phenylethanol derivative according to  claim 16 , wherein said microorganism is a strain of microorganism selected from the group consisting of microorganisms belonging to the genus Candida, the genus Lodderomyces, the genus Catenuloplanes, the genus Pilimelia, the genus Saccharothrix, the genus Seratia, the genus Enterococcus, the genus Lactobacillus, the genus Pediococcus and the genus Lactococcus.  
     
     
         18 . A process for producing an (R)-2-amino-1-phenylethanol derivative according to  claim 16 , wherein said microorganism is a strain of microorganism selected from the group consisting of microorganisms belonging to  Candida maltosa, Lodderomyces elongisporus, Catenuloplanes japonicus, Pilimelia terevasa, Saccharothrix australiensis, Seratia marcescens, Enterococcus faecalis, Lactobacillus casei  subsp.  casei, Pediococcus acidilactici  and  Lactococcus lactis  subsp.  lactis.    
     
     
         19 . A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative shown by the general formula (XI)  
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4  and R 5  represent, the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group; and Z represents a hydrogen atom or a protective group for hydroxyl group;  
         R 7  and R 8  represent,  
         (A) respectively, a group selected from the group consisting of a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted amino group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group and a hydroxyl group which may be protected with a protective group, or  
         (B) R 7  represents a group shown by the formula (IX): —O—R 7a , and R 8  represents a group shown by the formula (X): —O—R 8a , wherein R 7a  and R 8a  may form an optionally substituted ring with the adjacent oxygen atoms;  
         R 6 , R 9  and R 10  independently represent a group selected from a group consisting of a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, a hydroxyl group which may be substituted with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted aralkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group and an optionally substituted amino group; and R 11  represents a lower alkyl group, which comprises:  
         a reaction of an (R)-2-amino-1-phenylethanol compound shown by the general formula (II)  
         
           
             
             
                 
                 
             
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5  and Z have the same meanings as defined above, or a salt thereof, with a compound shown by the general formula (VIII)  
         
           
             
             
                 
                 
             
           
         
         wherein R 6 , R 7 , R 8 , R 9 , R 10  and R 11  have the same meanings as defined above, and  
         a reducing reaction of the reaction product of said reaction.  
       
     
     
         20 . A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative according to  claim 19 , wherein, in the formula (VIII), R 7  and R 8  represent; (A) the same or different, a group selected from the group consisting of: 
 (1) a hydrogen atom;    (2) 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, benzoyl group, a C 1-4  alkylthio group, a halogen atom and an amino group which may be substituted with a substituent;    (3) a C 3-10  cycloalkyl group which may be substituted with a substituent selected from the group consisting of a C 1-4  alkyl group, a hydroxyl group and a halogen atom;    (4) 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 C 6-12  aryl group, a hydroxyl group, a C 1-4  alkoxy group, a nitro group and a halogen atom;    (5) a C 6-16  aryl group 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;    (6) an acyl group selected from the group consisting of (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 C 7-20  acyl group having an aromatic ring which may be substituted with a substituent and (c) an acyl group having a heterocyclic ring which may be substituted with a substituent;    (7) a carboxyl group which may be protected with a protective group;    (8) an optionally substituted C 2-5  alkoxycarbonyl group;    (9) an amino group which may be substituted with a substituent selected from the group consisting of (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, 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, (d) a C 7-20  acyl group having an aromatic ring which may be substituted with a substituent, (e) an acyl group having a heterocyclic ring which may be substituted with a substituent and (f) a carboxyl group which may be protected with a protective group;    (10) a C 1-4  alkylsulfonyl group which may be substituted with a substituent selected from the group consisting of a hydroxyl group, a C 1-4  alkoxy group, benzoyl group, a C 1-4  alkylthio group and a halogen atom;    (11) a C 6-20  arylsulfonyl 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; and    (12) a hydroxyl group which may be protected with a protective group; or    (B) R 7  is a group of the formula (IX): —O—R 7a , and R 8  is a group of the formula (X): —O—R 8a , where R 7a  and R 8a  may form an optionally substituted C 1-4  alkylene group, a carbonyl group or a thiocarbonyl group;    R 6 , R 9  and R 10  independently represent a group selected from the group consisting of: 
 (1) a hydrogen atom;  
 (2) a halogen atom;  
 (3) 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, benzoyl group, a C 1-4  alkylthio group, a halogen atom and an amino group which may be substituted with a substituent;  
 (4) a C 3-10  cycloalkyl group which may be substituted with a substituent selected from the group consisting of a C 1-4  alkyl group, a hydroxyl group and a halogen atom;  
 (5) 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 C 6-12  aryl group, a hydroxyl group, a C 1-4  alkoxy group, a nitro group and a halogen atom;  
 (6) a C 6-16  aryl group 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;  
 (7) a hydroxyl group which may be protected with a protective group;  
 (8) a C 1-4  alkoxy group which may be substituted with a substituent selected from the group consisting of a hydroxyl group, a C 1-4  alkoxy group, a halogen atom and an amino group which may be substituted with a substituent;  
 (9) a C 3-10  cycloalkyloxy group which may be substituted with a substituent selected from the group consisting of a C 1-4  alkyl group, a hydroxyl group and a halogen atom;  
 (10) a C 7-20  aralkyloxy group 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;  
 (11) a C 6-16  aryloxy 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;  
 (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) a C 7-20  aralkylthio 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;  
 (14) an acyl group selected from the group consisting of (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 C 7-20  acyl group having an aromatic ring which may be substituted with a substituent and (c) an acyl group having a heterocyclic ring which may be substituted with a substituent;  
 (15) a carboxyl group which may be protected with a protective group;  
 (16) an optionally substituted C 2-5  alkoxycarbonyl group;  
 (17) a nitro group; and  
 (18) an amino group which may be substituted with a substituent selected from the group consisting of (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, 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, (d) a C 7-20  acyl group having an aromatic ring which may be substituted with a substituent, (e) an acyl group having a heterocyclic ring which may be substituted with a substituent, (f) a carboxyl group which may be protected with a protective group;  
   R 11  represents a C 1-4  alkyl group; and    in the formula (II), Z represents (A) a hydrogen atom or (B) a protective group for hydroxyl group selected from the group consisting of (a) a C 1-4  alkyl group which may be substituted with a substituent, (b) an allyl group which may be substituted with a substituent, (c) a C 3-10  cycloalkyl group which may be substituted with a substituent, (d) a 5- or 6-membered heterocyclic group, which may be substituted with a substituent, having an oxygen atom or a sulfur atom as a hetero atom other than carbon atoms, (e) a C 7-20  aralkyl group which may be substituted with a substituent, (f) a silyl group which may be substituted with a substituent, (g) a C 1-6  acyl group which may be substituted with a substituent, (h) a C 7-20  acyl group having an aromatic ring which may be substituted with a substituent, (i) an acyl group having a heterocyclic ring which may be substituted with a substituent, (j) a C 2-5  alkoxycarbonyl group which may be substituted with a substituent, (k) a C 8-20  aralkyloxycarbonyl group which may be substituted with a substituent, (l) a C 7-20  aryloxycarbonyl group which may be substituted with a substituent, (m) a C 1-4  alkylsulfonyl group which may be substituted with a substituent and (n) a C 6-20  arylsulfonyl group which may be substituted with a substituent.    
     
     
         21 . A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative according to  claim 20 , wherein said optionally substituted C 1-4  alkylene group formed by R 7a  and R 8a  is an optionally substituted methylene group shown by the following formula (XII)  
       
         
           
           
               
               
           
         
         wherein R a  and R b  (A) independently represent: 
 (1) a hydrogen atom;  
 (2) a C 1-4  alkyl group;  
 (3) a C 1-4  haloalkyl group;  
 (4) a C 6-20  aryl group 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;  
 (5) a C 1-4  alkoxy group;  
 (6) an amino group which may be substituted with a substituent;  
 (7) a carboxyl group or a salt thereof;  
 (8) a C 2-5  alkoxycarbonyl group which may be substituted with a substituent selected from the group consisting of 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;  
 (9) a hydroxymethyl group; and  
 (10) a C 1-4  alkoxy-methyl group which may be substituted on the alkoxy group with a substituent selected from the group consisting of a carboxyl group, a C 2-5  alkoxycarbonyl group, a hydroxyl group and a C 1-4  alkoxy group; or  
 (B) R a  and R b  may form a C 5-7  cycloalkyl group with the adjacent carbon atom.  
 
       
     
     
         22 . A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative according to  claim 20 , where, in the general formula (VIII), R 7  and R 8  (A) respectively represent a hydrogen atom or a hydroxyl group which may be protected with a protective group selected from the group consisting of a C 1-4  alkyl group, a C 7-20  aralkyl group and C 1-6  acyl group, or (B) R 7  is the group of the formula (IX): —O—R 7a , and R 8  is the group of the formula (X): —O—R 8a , where, in the methylene group shown by the general formula (XII) formed together by R 7a  and R 8a , R a  and R b  (i) independently represent a group selected from the group consisting of (a) a hydrogen atom; (b) a C 1-4  alkyl group; (c) a carboxyl group or a salt thereof; (d) a C 2-5  alkoxycarbonyl group which may be substituted with a substituent; (e) a hydroxymethyl group; and (f) a C 1-4  alkoxy-methyl group which may be substituted on the alkoxy group with a substituent; or (ii) R a  and R b  may form a C 5-7  cycloalkyl group together with the adjacent carbon atom; R 6 , R 9  and R 10  respectively represent a hydrogen atom or a C 1-4  alkyl group; R 11  represents a methyl group or an ethyl group; and in the formula (II), Z represents a hydrogen atom.  
     
     
         23 . A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative according to  claim 19 , wherein the optically active compound of the general formula (II) is allowed to react with the compound of the general formula (VIII) and hydrogen in the presence of a catalyst for catalytic reduction.  
     
     
         24 . A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative according to  claim 19 , wherein the optically active compound shown by the general formula (II) is allowed to react with the compound shown by the general formula (VIII), and the resultant product is hydrogenated.  
     
     
         25 . A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative according to  claim 23 , wherein the reaction is conducted in the presence of an acid catalyst.  
     
     
         26 . A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative according to  claim 19 , which further comprises: 
 adding an acid to the reaction products and    fractionally crystallizing from the resultant mixture to isolate the (R,R)-isomer of the general formula (XI).    
     
     
         27 . A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative according to  claim 26 , wherein a base in an amount of 0.05 to 0.9 gram equivalent relative to 1 mole of the total amount of the salt of the (R,R)-isomer of the general formula (XI) and the salt of an (R,S)-isomer 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 have the same meanings as defined above, is added to liberate the (R,S)-isomer and the (R,R)-isomer is precipitated or crystallized as the salt.  
     
     
         28 . A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative according to  claim 19 , which further comprises: 
 (1) a step of permitting a microorganism or a preparation thereof which is capable of acting on a mixture of enantiomers of a 2-amino-1-phenylethanol compound shown by the general formula (I)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above, or a salt thereof to produce an (R)-2-amino-1-phenylethanol compound shown by the general formula (IIa)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above, or a salt thereof, to act on said mixture of enantiomers,    to produce the optically active compound shown by the general formula (II) where Z represents a hydrogen atom or a salt thereof, or    (2) further to said step (1), a step of introducing a protective group to the hydroxyl group of the optically active compound of the general formula (II) wherein Z represents a hydrogen atom or a salt thereof produced in said step (1), to produce the optically active compound of the general formula (II) where Z represents a protective group for hydroxyl group, or a salt thereof.    
     
     
         29 . A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative according to  claim 19 , which further comprises: 
 (1) a step of permitting a microorganism or a preparation thereof which is capable of acting on a compound shown by the general formula (VII)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above, or a salt thereof to produce a corresponding (R)-2-amino-1-phenylethanol compound shown by the general formula (IIa)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above, or a salt thereof, to act on said compound or a salt thereof,    to produce the product optically active compound of the general formula (II) where Z represent a hydrogen atom, or a salt thereof or    (2) further to said step (1), a step of introducing a protective group to the hydroxyl group of the optically active compound of the general formula (II) wherein Z represents a hydrogen atom or a salt thereof produced in said step (1), to produce the optically active compound of the general formula (II) where Z represents a protective group for hydroxyl group, or a salt thereof.    
     
     
         30 . A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative according to  claim 28 , which further comprises: 
 step(s) of allowing (a) a compound shown by the general formula (III)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above, or (b) a compound shown by the general formula (IV)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above; Z represents a hydrogen atom or a protective group for hydroxyl group; and X represents a halogen atom,    to react with a compound shown by the general formula (V)   Y—NH 2   (V)   wherein Y represents a hydrogen atom or a group which can be left in the reaction,    further allowing Y to be left when Y is the group which can be left in the reaction, and    adding an acid to the reaction products containing the compound shown by the general formula (VI)                          wherein R 1 , R 2 , R 3 , R 4 , R 5  and Z have the same meanings as defined above, to isolate the compound of the general formula (VI) by precipitating or crystallizing said compound as a salt, and further, when Z is the protective group for hydroxyl group, cleaving the protective group, to produce a mixture of enantiomers of 2-amino-1-phenylethanol compound shown by the general formula (I) or a salt thereof.    
     
     
         31 . A process for producing an (S)-2-amino-1-phenylethanol derivative, which comprises: 
 permitting a microorganism or a preparation thereof which is capable of acting on a mixture of enantiomers of a 2-amino-1-phenylethanol compound of the general formula (I)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  represent, the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group, or a salt thereof to produce a corresponding (S)-form shown by the general formula (XV)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above, or a salt thereof to act on said mixture of enantiomers, and    harvesting or recovering the product optically active compound shown by the general formula (XV) or a salt thereof.    
     
     
         32 . A process for producing an (S)-2-amino-1-phenylethanol derivative according to  claim 31 , wherein said microorganism is a strain of microorganism selected from the group consisting of the microorganisms belonging to the genus Saccharomyces, the genus Pichia, the genus Schizosaccharomyces, the genus Candida, the genus Hansenula, the genus Yarrowia, the genus Geotrichum, the genus Brevibacterium, the genus Corynebacterium, the genus Xanthomonas, the genus Actinomaqura, the genus Enterobacter, the genus Pseudomonas, the genus Hafnia, the genus Actinoplanes, the genus Escherichia, the genus Bacillus, the genus Listonella, the genus Nosardioides, the genus Amycolata, the genus Aspergillus, the genus Penicillium, the genus Corynespora, the genus Fusarium, the genus Gelasinospora, the genus Helminthosporium, the genus Mortierelia, the genus Neosartorya, the genus Phytophthora, the genus Talaromyces, the genus Scolecobasidium and the genus Rhodococcus.  
     
     
         33 . A process for producing an (S)-2-amino-1-phenylethanol derivative according to  claim 31 , wherein said microorganism is a strain of microorganism selected from the group consisting of the microorganisms belonging to  Saccharomyces cerevisiae, Pichia fabianii, Schizosaccharomyces pombe, Candida guilliermondii, Candida melibiosica, Hansenula polymorpha, Yarrowia lipolytica, Geotrichum capitatum, Micrococcus luteus, Brevibacterium iodinum, Corynebacterium sepedonicum , Xanthomonas sp. IFO 12997,  Actinomaqura cremea  subsp.  cremea, Enterobacter aerogenes, Pseudomonas aeruginosa, Hafnia alvei, Actinoplanes lobatus, Escherichia coli, Bacillus licheniformis, Listonella anguillarum, Nosardioides flavus, Amycolata autotrophica, Aspergillus niger, Aspergillus ficuum, Aspergillus cavdidus, Aspergillus oryzae, Aspergillus oryzae  var.  brunneus, Aspergillus tamarii, Penicillium chrysogenum, Corynespora cassiicola, Fusarium solani, Gelasinospora cerealis, Helminthosporium sigmoideum  var.  irreavl, Mortierelia isabellina, Mortierelia ramanniana  var.  ramanniana, Neosartorya fischeri  var.  spinosa, Phytophthora capsici, Talaromyces flavus  var.  flavus, Scolecobasidium terreum, Rhodococcus luteus, Rhodococcus erythropolis  and  Rhodococcus globerrulus.    
     
     
         34 . A process for producing an (S)-2-amino-1-phenylethanol derivative which comprises: 
 permitting a microorganism or a preparation thereof which is capable of acting on a compound shown by the general formula (VII)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  represent, the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group, or a salt thereof, to produce a corresponding optically active compound shown by the general formula (XV)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above, or a salt thereof, to act on said compound or a salt thereof, and    harvesting or recovering the product optically active compound shown by the general formula (XV) or a salt thereof.    
     
     
         35 . A process for producing an (S)-2-amino-1-phenylethanol derivative according to  claim 34 , wherein said microorganism is a strain of microorganism selected from the group consisting of the microorganisms belonging to the genus Botryoascus, the genus Brettanomyces, the genus Candida, the genus Citeromyces, the genus Clavispora, the genus Debaryomyces, the genus Dipodascus, the genus Eremascus, the genus Galactomyces, the genus Geotrichum, the genus Issatchenkia, the genus Kluyveromyces, the genus Kondoa, the genus Lipomyces, the genus Malassezia, the genus Oosporidium, the genus Pachysolen, the genus Pichia, the genus Rhodosporidium, the genus Rhodotorula, the genus Saccharomyces, the genus Saccharomycodes, the genus Saccharomycopsis, the genus Schizoblastosporion, the genus Schizosaccharomyces, the genus Sporidiobolus, the genus Sporobolomyces, the genus Wickerhamiella, the genus Wingea, the genus Zygosaccharomyces, the genus Bacillus, the genus Comamonas, the genus Rhodobacter, the genus Enterococcus, the genus Lactobacillus, the genus Pediococcus, the genus Leuconostoc and the genus Streptococcus.  
     
     
         36 . A process for producing an (S)-2-amino-1-phenylethanol derivative according to  claim 34 , wherein said microorganism is a strain of microorganism selected from the group consisting of the microorganisms belonging to  Botryoascus synnaedendrus, Brettanomyces anomalus, Candida albicans, Candida beechii, Candida ergatensis, Candida fusiformata, Candida guilliermondii, Candida halonitratophila, Candida oregonensis, Candida peltata, Candida parapsilosis, Candida sorboxylosa, Citeromyces matritensis, Clavispora lusitaniae, Debaryomyces hansenii  var.  hansenii, Dipodascus ovetensis, Eremascus fertilis, Galactomyces reessii, Geotrichum fermentans, Geotrichum candidum, Geotrichum capitatum, Geotrichum klebahnii, Issatchenkia scutulata  var.  scutulata, Kluyveromyces lactis, Kluyveromyces marxianus  var.  bulgaricus, Kondoa malvinella, Lipomyces starkeyi, Malassezia furfur, Oosporidium margaritiferum, Pachysolen tannophilus, Pichia farinosa, Pichia holstii, Pichia subpelliculosa, Pichia toletana, Rhodosporidium diobovatum, Rhodotorula glutinis, Rhodotorula glutinis  var.  dairenensis, Saccharomyces kluyveri, Saccharomyces paradoxus, Saccharomycodes ludwigii, Saccharomycopsis capsularis, Schizoblastosporion kobayasii, Schizosaccharomyces pombe, Sporidiobolus pararoseus, Sporobolomyces pararoseus, Sporobolomyces salmonicolor, Wickerhamiella domercquii, Wingea robertsii, Zygosaccharomyces bailii, Zygosaccharomyces fermentati, Bacilus subtilis, Comamonas terrigena, Rhodobacter sphaeroides, Enterococcus faecalis, Lactobacillus lactis, Pediococcus acidilactici, Leuconostoc mesenteroides  subsp.  dextranicum, Leuconostoc mesenteroides, Leuconostoc oenos  and  Streptpcoccus uberis.    
     
     
         37 . A process for separating an optically active 2-amino-1-phenylethanol derivative from a mixture of enantiomers of said derivative which comprises: 
 (1) subjecting a mixture of enantiomers of 2-amino-1-phenylethanol compound shown by the general formula (I)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  represent, the same or different, a group selected from the group consisting of a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group and an optionally substituted amino group, or a salt thereof    to a treatment with a microorganism or a preparation derived therefrom which is capable of selectively utilizing a corresponding (S)-form of said compound or a salt thereof,    allowing the microorganism or a preparation derived therefrom to selectively utilize the (S)-form of said compound or a salt thereof, and    recovering the (R)-form of said compound or a salt thereof; or    (2) subjecting said mixture of enantiomers to a treatment with a microorganism or a preparation derived therefrom which is capable of selectively utilizing the corresponding (R)-form of said compound or a salt thereof,    allowing the microorganism or a preparation derived therefrom to selectively utilize the (R)-form or a salt thereof, and    recovering the (S)-form of said compound or a salt thereof.    
     
     
         38 . A process for asymmetrically reducing an aminoketone derivative to a corresponding optically active 2-amino-1-phenylethanol derivative which comprises: 
 (1) subjecting a compound shown by the general formula (VII)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  represent, the same or different, a group selected from the group consisting of a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group and an optionally substituted amino group, or a salt thereof    to a treatment with a microorganism or a preparation derived therefrom which is capable of asymmetrically reducing said compound or a salt thereof to a corresponding (R)-2-amino-1-phenylethanol derivative shown by the general formula (IIa)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above, or a salt thereof, and    recovering the product optically active compound or a salt thereof; or    (2) subjecting said compound or a salt thereof to a treatment with a microorganism or a preparation derived therefrom which is capable of asymmetrically reducing said compound or a salt thereof to a corresponding (S)-2-phenylethanol derivative shown by the general formula (XV)                          wherein R 1 , R 2 , R 3 , R 4  and R 5  have the same meanings as defined above, or a salt thereof, and    recovering the product optically active compound or a salt thereof.