US2005272797A1PendingUtilityA1

Processes for preparation of bicyclic compounds and intermediates therefor

Assignee: DAIICHI SEIYAKU COPriority: Aug 8, 2000Filed: Aug 5, 2005Published: Dec 8, 2005
Est. expiryAug 8, 2020(expired)· nominal 20-yr term from priority
C07D 209/54
52
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Claims

Abstract

A process for preparing intermediate compound (VII), compound (VIII) and compound (XIV) which will be raw materials for the synthesis of a synthetic antibactrial compound, via compound (I) or compound (X) and then, compound (II), the compounds each being shown below; and novel compounds useful for the preparation.

Claims

exact text as granted — not AI-modified
1 . A process for preparing a compound represented by formula (VIII):  
     
       
         
         
             
             
         
       
     
     , or salt thereof, or a hydrate of the compound or salt, which comprises obtaining a compound represented by formula (II):  
     
       
         
         
             
             
         
       
     
     by either one of Process A or B described below, reducing the cyano group of the resulting compound to prepare a compound represented by formula (III):  
     
       
         
         
             
             
         
       
     
     , hydrolyzing the resulting compound in the presence of an acid catalyst to prepare a compound represented by formula (III-ALD):  
     
       
         
         
             
             
         
       
     
     , subjecting the resulting compound to intramolecular ring-closure under neutral or basic conditions to prepare a compound represented by formula (IV):  
     
       
         
         
             
             
         
       
     
     , reducing the resulting compound into a compound represented by formula (VII):  
     
       
         
         
             
             
         
       
     
     and, converting R 1  of the resulting compound into a hydrogen atom when R 1  is not a hydrogen atom;  
     Process A: 
 a process of reacting a compound represented by the following formula:  
                     
 with an acetalization agent in the presence of an acid catalyst, and, if desired, in the presence of an additive, to prepare a compound represented by formula (I):  
                     
 and reacting the resulting compound with a compound represented by the formula (VI):  
   H 2 N—R 1   VI  
 or salt thereof, and a cyanation agent; and  
 Process B:  
 a process of reacting a compound represented by formula (X):  
                     
 with a compound represented by formula (VI):  
   H 2 N—R 1   VI  
 or salt thereof and a cyanation agent to prepare a compound represented by formula (XI):  
                     
 , oxidizing the resulting compound into a compound represented by formula (II-ALD):  
                     
 , and reacting the resulting compound with an acetalization agent in the presence of an acid catalyst, and if desired in the presence of an additive;  
 {in each of said formulas, n stands for an integer of from 2 to 5,  
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of C 1-4  alkyl groups, C 1-4  alkoxy groups, halogen atoms and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], and  
 R 2  and R 3  each independently represents a C 1-4  alkoxy group or may be integrated together to form a group represented by formula:  
   —O—(CH 2 ) m —O— 
 (wherein, m stands for an integer of from 1 to 4)}.  
 
   
   
       2 . A preparation process of  claim 1 , wherein the compound of the formula (II) is prepared by Process A.  
   
   
       3 . A preparation process of  claim 1 , wherein the compound of the formula (II) is prepared by Process B.  
   
   
       4 . A preparation process of any one of  claims 1  to  3 , wherein the cyano group is reduced using catalytic hydrogenation reaction or a metal hydride.  
   
   
       5 . A preparation process of any one of  claims 1  to  3 , wherein the cyano group is reduced using catalytic hydrogenation reaction.  
   
   
       6 . A preparation process of any one of  claims 1  to  5 , wherein the acid catalyst is hydrochloric acid.  
   
   
       7 . A preparation process of any one of  claims 1  to  6 , wherein the ring-closure reaction is conducted under neutral or basic conditions.  
   
   
       8 . A preparation process of any one of  claims 1  to  7 , wherein R 2  and R 3  each represents a C 1-4  alkoxy group.  
   
   
       9 . A preparation process of  claim 8 , wherein R 2  and R 3  each represents an ethoxy group.  
   
   
       10 . A preparation process of any one of  claims 1  to  9 , wherein the compound of the formula (IV) is reduced using catalytic hydrogenation reaction or a metal hydride.  
   
   
       11 . A preparation process of any one of  claims 1  to  9 , wherein the compound of the formula (IV) is reduced using catalytic hydrogenation reaction.  
   
   
       12 . A preparation process of  claim 11 , wherein the catalyst is Raney nickel or Raney cobalt.  
   
   
       13 . A process for preparing a compound represented by formula (VIII):  
     
       
         
         
             
             
         
       
     
     or salt thereof, which comprises: 
 reacting a compound represented by formula (I):  
                     
 with a compound represented by formula (VI):  
   H 2 N—R 1   VI  
 or salt thereof and a cyanation agent to prepare a compound represented by formula (II):  
                     
 , reducing the cyano group of the resulting compound to prepare a compound represented by formula (III):  
                     
 , hydrolyzing the resulting compound in the presence of an acid catalyst to prepare a compound represented by formula (III-ALD):  
                     
 , subjecting the resulting compound to intramolecular  
 ring-closure under neutral or basic conditions to prepare a compound represented by formula (IV):  
                     
 , reducing the resulting compound into a compound represented by formula (VII):  
                     
 and converting R 1  of the resulting compound into a hydrogen atom when the R 1  is not a hydrogen atom {in each of said formulas, n stands for an integer of from 2 to 5,  
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], and  
 R 2  and R 3  each independently represents a C 1-4  alkoxy group or may be integrated together to form a group represented by formula:  
   —O—(CH 2 ) m —O— 
 (wherein, m stands for an integer of from 1 to 4)}.  
 
   
   
       14 . A preparation process of  claim 13 , wherein the compound represented by the formula (I) is a compound represented by formula (I-R):  
     
       
         
         
             
             
         
       
     
     (wherein, R represents a C 1-4  alkoxy group and n stands for an integer of from 2 to 5).  
   
   
       15 . A preparation process of  claim 14 , wherein the compound represented by the formula (I-R) is available by reacting a compound represented by formula:  
     
       
         
         
             
             
         
       
     
     (wherein, n stands for an integer of from 2 to 5) with an acetalization agent in the presence of an acid catalyst and if desired, in the presence of an additive.  
   
   
       16 . A preparation process of  claim 15 , wherein the compound represented by the formula (I-R) is available by reacting a compound represented by formula:  
     
       
         
         
             
             
         
       
     
     (wherein, n stands for an integer of from 2 to 5) with a compound represented by formula:  
       HC(R) 3    
     (wherein, R represents a C 1-4  alkoxy group) in the presence of an acid catalyst.  
   
   
       17 . A preparation process of  claim 15 , wherein the additive is a compound represented by formula:  
       HC(R) 3    
     (wherein, R represents a C 1-4  alkoxy group) or a dehydrating agent.  
   
   
       18 . A preparation process of  claim 15  or  17 , wherein the compound represented by the formula (I-R) is available by reacting a compound represented by formula:  
     
       
         
         
             
             
         
       
     
     (wherein, n stands for an integer of from 2 to 5) with a compound represented by formula:  
       HR  
     (wherein, R represents a C 1-4  alkoxy group) in the presence of an acid catalyst and a dehydrating agent serving as the additive.  
   
   
       19 . A preparation process of  claim 17  or  18 , wherein the dehydrating agent is an anhydride of an inorganic salt.  
   
   
       20 . A preparation process of any one of  claims 17  to  19 , wherein the dehydrating agent is anhydrous magnesium sulfate or anhydrous sodium sulfate.  
   
   
       21 . A preparation process of  claim 15  or  17 , wherein the compound represented by the formula (I-R) is available by reacting a compound represented by formula:  
     
       
         
         
             
             
         
       
     
     with a compound represented by formula:  
       HR  
     (wherein, R represents a C 1-4  alkoxy group) in the presence of an acid catalyst and a catalytic amount of a compound represented by formula:  
       HC(R) 3    
     (wherein, R represents a C 1-4  alkoxy group) which compound serves as the additive.  
   
   
       22 . A preparation process of any one of  claims 14  to  21 , wherein the acid catalyst is a sulfonic acid compound.  
   
   
       23 . A preparation process of any one of  claims 14  to  22 , wherein R represents an ethoxy group.  
   
   
       24 . A preparation process of any one of  claims 13  to  23 , wherein the cyanation agent is hydrogen cyanide or acetone cyanhydrin.  
   
   
       25 . A preparation process of any one of  claims 13  to  23 , wherein the cyanation agent is hydrogen cyanide.  
   
   
       26 . A preparation process of any one of  claims 13  to  23 , wherein the cyanation agent is acetone cyanhydrin.  
   
   
       27 . A preparation process of any one of  claims 13  to  26 , wherein the cyano group of the compound represented by the formula (II) is reduced by catalytic hydrogenation.  
   
   
       28 . A preparation process of any one of  claims 13  to  27 , wherein the compound represented by the formula (IV) is reduced by a metal hydride compound or catalytic hydrogenation.  
   
   
       29 . A process for preparing a compound represented by formula (I):  
     
       
         
         
             
             
         
       
     
     {wherein, n stands for an integer of from 2 to 5, 
 R 2  and R 3  each independently represents a C 1-4  alkoxy group or may be integrated together to form a group represented by formula:  
   —O—(CH 2 ) m —O— 
 (wherein, m stands for an integer of from 1 to 4)}, which comprises reacting a compound represented by formula:  
                     
 (wherein, n stands for an integer of from 2 to 5) with an acetalization agent in the presence of an acid catalyst and, if desired, in the presence of an additive.  
 
   
   
       30 . A preparation process of  claim 29 , wherein R 2  and R 3  each independently represents a C 1-4  alkoxy group.  
   
   
       31 . A preparation process of  claim 29  or  30 , wherein the compound of the formula (I) is available by reacting a compound represented by formula:  
     
       
         
         
             
             
         
       
     
     (wherein, n stands for an integer of from 2 to 5) with a compound represented by the formula:  
       HC(R) 3    
     (wherein, R represents a C 1-4  alkoxy group) in the presence of an acid catalyst.  
   
   
       32 . A preparation process of  claim 29  or  30 , wherein the additive is a compound represented by formula:  
       HC(R) 3    
     (wherein, R represents a C 1-4  alkoxy group) or a dehydrating agent.  
   
   
       33 . A preparation process of  claim 29 ,  30  or  32 , wherein the compound represented by the formula (I) is available by reacting a compound represented by formula:  
     
       
         
         
             
             
         
       
     
     (wherein, n stands for an integer of from 2 to 5) with a compound represented by formula:  
       HR  
     (wherein, R represents a C 1-4  alkoxy group) in the presence of an acid catalyst and a dehydrating agent serving as an additive.  
   
   
       34 . A preparation process of  claim 29 ,  30 ,  32  or  33 , wherein the dehydrating agent is an anhydride of an inorganic salt.  
   
   
       35 . A preparation process of  claim 32 ,  33  or  34 , wherein the dehydrating agent is anhydrous magnesium sulfate or anhydrous sodium sulfate.  
   
   
       36 . A preparation process of  claim 29  or  30 , wherein the compound represented by the formula (I) is available by reacting a compound represented by formula:  
     
       
         
         
             
             
         
       
     
     with a compound represented by formula:  
       HR  
     (wherein, R represents a C 1-4  alkoxy group) in the presence of an acid catalyst and a catalytic amount of a compound represented by formula:  
       HC(R) 3    
     (wherein, R represents a C 1-4  alkoxy group) which compound serves as the additive.  
   
   
       37 . A preparation process of any one of  claims 29  to  36 , wherein the acid catalyst is a sulfonic acid compound.  
   
   
       38 . A preparation process of any one of  claims 31  to  37 , wherein R represents an ethoxy group.  
   
   
       39 . A process for preparing a compound represented by formula (II):  
     
       
         
         
             
             
         
       
     
     [wherein, n stands for an integer of from 2 to 5, 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], and R 2  and R 3  each independently represents a C 1-4  alkoxy group or may be integrated together to form a group represented by formula:  
   —O—(CH 2 ) m —O— 
 (wherein, m stands for an integer of from 1 to 4)], which comprises reacting a compound represented by formula (I):  
                     
 [wherein, n, R 2  and R 3  have the same meanings as defined above] with a compound represented by formula (VI):  
   H 2 N—R 1   VI  
 {wherein, R 1  has the same meaning as defined above}, or salt thereof, and a cyanation agent.  
 
   
   
       40 . A preparation process of  claim 39 , wherein the cyanation agent is hydrogen cyanide or acetone cyanhydrin.  
   
   
       41 . A preparation process of  claim 39 , wherein the cyanation agent is hydrogen cyanide.  
   
   
       42 . A preparation process of  claim 39 , wherein the cyanation agent is acetone cyanhydrin.  
   
   
       43 . A process for preparing a compound represented by formula (II):  
     
       
         
         
             
             
         
       
     
     {wherein, n stands for an integer of from 2 to 5, 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], and  
 R 2  and R 3  each independently represents a C 1-4  alkoxy group or may be integrated together to form a group represented by formula:  
   —O—(CH 2 ) m —O— 
 (wherein, m stands for an integer of from 1 to 4))}, which comprises reacting a compound represented by formula (X):  
                     
 with a compound represented by formula (VI):  
   H 2 N—R 1   VI  
 or salt thereof, and a cyanation agent to prepare a compound represented by formula (XI):  
                     
 , oxidizing the resulting compound into a compound represented by the formula (II-ALD):  
                     
 , and reacting the resulting compound with an acetalization agent in the presence of an acid catalyst and if desired, in the presence of an additive.  
 
   
   
       44 . A preparation process of  claim 43 , wherein the oxidant is a Collins reagent, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin, or Periodinane.  
   
   
       45 . A preparation process of  claim 43 , wherein the oxidant is pyridinium chlorochromate.  
   
   
       46 . A preparation process of any one of  claims 43  to  45 , wherein the compound represented by the formula (II) is a compound represented by formula (II-R):  
     
       
         
         
             
             
         
       
     
     {wherein, n stands for an integer of from 2 to 5, 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], and  
 R represents a C 1-4  alkoxy group}.  
 
   
   
       47 . A preparation process of any one of  claims 43  to  46 , wherein the compound represented by the formula (II-R) is a compound available by reacting a compound represented by formula (II-ALD):  
     
       
         
         
             
             
         
       
     
     with a compound represented by formula:  
       HC(R) 3  
     (wherein, R represents a C 1-4  alkoxy group) in the presence of an acid catalyst.  
   
   
       48 . A preparation process of  claim 46  or  47 , wherein R is an ethoxy group.  
   
   
       49 . A preparation process of any one of  claims 43  to  48 , wherein the acid catalyst is a sulfonic acid compound.  
   
   
       50 . A preparation process of any one of  claims 43  to  49 , wherein the cyanation agent is hydrogen cyanide or acetone cyanhydrin.  
   
   
       51 . A preparation process of any one of  claims 43  to  49 , wherein the cyanation agent is hydrogen cyanide.  
   
   
       52 . A preparation process of any one of  claims 43  to  51 , wherein R 1  is a group represented by formula:  
     
       
         
         
             
             
         
       
     
     [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group].  
   
   
       53 . A process for preparing a compound represented by formula (III):  
     
       
         
         
             
             
         
       
     
     [wherein, n stands for an integer of from 2 to 5, 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], and  
 R 2  and R 3  each independently represents a C 1-4  alkoxy group or may be integrated together to form a group represented by formula:  
   —O—(CH 2 ) m —O— 
 (wherein, m stands for an integer of from 1 to 4)}, which comprises reducing the cyano group of a compound represented by formula (II):  
                     
 {n, R 1 , R 2  and R 3  have the same meanings as defined above) or salt thereof.  
 
   
   
       54 . A preparation process of  claim 53 , wherein the reduction is conducted using catalytic hydrogenation reaction or a metal hydride.  
   
   
       55 . A preparation process of  claim 53 , wherein the reduction is conducted using catalytic hydrogenation reaction.  
   
   
       56 . A preparation process of any one of  claims 53  to  55 , wherein the compound represented by the formula (III) is a stereochemically single compound;  
   
   
       57 . A preparation process of any one of  claims 53  to  56 , wherein the compound represented by the formula (III) is a compound having a configuration of the following formula:  
     
       
         
         
             
             
         
       
     
     (wherein, n, R 1 , R 2  and R 3  have the same meanings as defined above).  
   
   
       58 . A process for preparing a compound represented by formula (IV):  
     
       
         
         
             
             
         
       
     
     [wherein, n stands for an integer of from 2 to 5, and R 1  represents a hydrogen atom or a group represented by formula:  
     
       
         
         
             
             
         
       
     
     [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], which comprises subjecting, to ring-closure, a compound represented by formula (III):  
     
       
         
         
             
             
         
       
     
     (wherein, n and R 1  have the same meanings as defined above, and 
 R 2  and R 3  each independently represents a C 1-4  alkoxy group or may be integrated together to form a group represented by formula:  
   —O—(CH 2 ) m —O— 
 (wherein, m stands for an integer of from 1 to 4)}, or salt thereof.  
 
   
   
       59 . A preparation process of  claim 58 , wherein the compound represented by the formula (III) is hydrolyzed in the presence of an acid catalyst, followed by ring closure of the resulting hydrolyzate.  
   
   
       60 . A preparation process of  claim 59 , wherein the hydrolyzate is a compound represented by formula (III-ALD):  
     
       
         
         
             
             
         
       
     
     {wherein, n stands for an integer of from 2 to 5, and 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group]).  
 
   
   
       61 . A preparation process of  claim 60 , wherein the acid catalyst is hydrochloric acid.  
   
   
       62 . A preparation process of any one of  claims 58  to  61 , wherein the ring-closure reaction is conducted under neutral or basic conditions.  
   
   
       63 . A preparation process of any one of  claims 58  to  62 , wherein the compound represented by the formula (IV) is a stereochemically single compound.  
   
   
       64 . A preparation process of any one of  claims 58  to  63 , wherein the compound represented by the formula (IV) has a configuration of the following formula:  
     
       
         
         
             
             
         
       
     
     (wherein, n and R 1  have the same meanings as defined above).  
   
   
       65 . A preparation process of any one of  claims 53  to  64 , wherein R 2  and R 3  each represents a C 1-4  alkoxy group.  
   
   
       66 . A preparation process of any one of  claims 53  to  64 , wherein R 2  and R 3  each represents an ethoxy group.  
   
   
       67 . A process for preparing a compound represented by formula (VII):  
     
       
         
         
             
             
         
       
     
     {wherein, n stands for an integer of from 2 to 5, 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], and R 2  and R 3  have the same meanings as defined above}, which comprises reducing a compound represented by formula (IV):  
                     
 [wherein, n and R 1  have the same meanings as defined above].  
 
   
   
       68 . A preparation process of  claim 67 , wherein the reduction is conducted using catalytic hydrogenation reaction or a metal hydride.  
   
   
       69 . A preparation process o  claim 67 , wherein the reduction is conducted using catalytic hydrogenation reaction.  
   
   
       70 . A preparation process, wherein the catalyst is Raney nickel.  
   
   
       71 . A preparation process of any one of  claims 67  to  70 , wherein the compound represented by the formula (VII) is a stereochemically single compound.  
   
   
       72 . A preparation process of any one of  claims 67  to  71 , wherein the compound represented by the formula (VII) is a compound having a configuration of the following formula:  
     
       
         
         
             
             
         
       
     
     (wherein, n and R 1  have the same meanings as defined above).  
   
   
       73 . A process for preparing an isomer mixture, which comprises treating a mixture of isomers which are based on asymmetry of a carbon atom to which bonded is the cyano group of a compound represented by formula (II):  
     
       
         
         
             
             
         
       
     
     {wherein, n stands for an integer of from 2 to 5, 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], and  
 R 2  and R 3  each independently represents a C 1-4  alkoxy group or may be integrated together to form a group represented by formula:  
   —O—(CH 2 ) m —O— 
 (wherein, m stands for an integer of from 1 to 4)}, the content of one of the isomers represented by formula:  
                     
 (wherein, n, R 1 , R 2  and R 3  have the same meanings as defined above) being smaller than the content of another isomer, thereby making the content of said one of the isomers greater than the content of said another isomer.  
 
   
   
       74 . A preparation process of  claim 73 , wherein the treatment is conducted by heating.  
   
   
       75 . A preparation process of  claim 73  or  74 , wherein the treatment is heating in a polar solvent.  
   
   
       76 . A preparation process of  claim 75 , wherein the polar solvent is an alcohol.  
   
   
       77 . A preparation process of  claim 76 , wherein the alcohol is ethanol.  
   
   
       78 . A process for preparing an isomer compound represented by formula:  
     
       
         
         
             
             
         
       
     
     {wherein, n stands for an integer of from 2 to 5, 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], and  
 R 2  and R 3  each independently represents a C 1-4  alkoxy group or may be integrated together to form a group represented by formula:  
   —O—(CH 2 ) m —O— 
 (wherein, m stands for an integer of from 1 to 4)}, which comprises reacting a compound represented by formula (I):  
                     
 [wherein, n, R 2  and R 3  have the same meanings as defined above] with a compound represented by the formula (VI):  
   H 2 N—R 1   VI  
 (wherein, R 1  has the same meaning as defined above) or salt thereof, and a cyanation agent, separating, from the resulting compound represented by formula (II):  
                     
 (wherein, n, R 1 , R 2  and R 3  have the same meanings as defined above), an isomer compound represented by formula:  
                     
 [wherein, n, R 1 , R 2  and R 3  have the same meanings as defined above], and isomerizing another isomer compound which is represented by the following formula:  
                     
 [wherein, n, R 1 , R 2  and R 3  have the same meanings as defined above] and has remained after separation.  
 
   
   
       79 . A preparation process of  claim 78 , wherein the reaction is effected in an alcohol.  
   
   
       80 . A preparation process of  claim 78  or  79 , wherein the cyanation agent is hydrogen cyanide or acetone cyanhydrin.  
   
   
       81 . A preparation process of  claim 78  or  79 , wherein the cyanation agent is hydrogen cyanide.  
   
   
       82 . A preparation process of  claim 78  or  79 , wherein the cyanation agent is acetone cyanhydrin.  
   
   
       83 . A preparation process of any one of  claims 78  to  82 , wherein the isomer compound represented by formula:  
     
       
         
         
             
             
         
       
     
     [wherein n, R 1 , R 2  and R 3  have the same meanings as defined above] is separated from the compound represented by formula (II):  
     
       
         
         
             
             
         
       
     
     [wherein n, R 1 , R 2  and R 3  have the same meanings as described above] by adding water to the reaction mixture, thereby precipitating said isomer.  
   
   
       84 . A preparation process of any one of  claims 78  to  83 , wherein the isomerization of the remaining isomer compound represented by formula:  
     
       
         
         
             
             
         
       
     
     [wherein n, R 1 , R 2  and R 3  have the same meanings as defined above] is effected by heating.  
   
   
       85 . A preparation process of any one of  claims 13  to  84 , wherein n stands for 2.  
   
   
       86 . A preparation process of any one of claims  13  and  39  to  85 , wherein R a , R b  and R c  each represents a group selected from the class consisting of methyl, ethyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-nitrophenyl, 2,4-dichlorophenyl, 2,4-dinitrophenyl, 3,5-dichlorophenyl, 3,5-dinitrophenyl and naphthyl groups.  
   
   
       87 . A preparation process of any one of claims  13  and  39  to  86 , wherein R a , R b  and R c  represent different groups each other.  
   
   
       88 . A preparation process of any one of claims  13  and  39  to  87 , wherein substituent R 1  is a group selected from the class consisting of (R)-1-phenylethyl, (S)-1-phenylethyl, (R)-1-phenylpropyl, (S)-1-phenylpropyl, (R)-1-phenyl-2-(p-tolyl)ethyl, (S)-1-phenyl-2-(p-tolyl)ethyl, (R)-1-(1-naphthyl)ethyl, (S)-1-(1-naphthyl)ethyl, (R)-1-(4-methoxyphenyl)ethyl, (S)-1-(4-methoxyphenyl)ethyl, (R)-1-(4-chlorophenyl)ethyl, (S)-1-(4-chlorophenyl)ethyl, (R)-1-(4-nitrophenyl)ethyl, (S)-1-(4-nitrophenyl)ethyl, (R)-1-(2,4-dichlorophenyl)ethyl, (S)-1-(2,4-dichlorophenyl)ethyl, (R)-1-(2,4-dinitrophenyl)ethyl, (S)-1-(2,4-dinitrophenyl)ethyl, (R)-1-(3,5-dichlorophenyl)ethyl, (S)-1-(3,5-dichlorophenyl)ethyl, (R)-1-(3,5-dinitrophenyl)ethyl, and (S)-1-(3,5-dinitrophenyl)ethyl groups.  
   
   
       89 . A preparation process of any one of claims  13 , and  39  to  87 , wherein the substituent R 1  is an (R)-1-phenylethyl or (S)-1-phenylethyl group.  
   
   
       90 . A compound represented by the formula (II):  
     
       
         
         
             
             
         
       
     
     [wherein, n stands for an integer of from 2 to 5, 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], and  
 R 2  and R 3  each independently represents a C 1-4  alkoxy group or may be integrated together to form a group represented by formula:  
   —O—(CH 2 ) m —O— 
 (wherein, m stands for an integer of from 1 to 4)}, or salt thereof, or a hydrate of the compound or salt.  
 
   
   
       91 . A compound of  claim 90 , wherein the compound represented by the formula (II) has a configuration of the following formula:  
     
       
         
         
             
             
         
       
       (wherein, n, R 1 , R 2  and R 3  have the same meanings as defined above); or salt thereof, or a hydrate of the compound or salt.  
     
   
   
       92 . A compound represented by the formula (II-ALD):  
     
       
         
         
             
             
         
       
     
     [wherein, n stands for an integer of from 2 to 5, and 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group]}, of salt thereof, or a hydrate of the compound or salt.  
 
   
   
       93 . A compound of  claim 92 , wherein the compound represented by the formula (II-ALD) has a configuration of the following formula:  
     
       
         
         
             
             
         
       
     
     (wherein, n and R 1  have the same meanings as described above); or salt thereof, or a hydrate of the compound or salt.  
   
   
       94 . A compound represented by formula (III):  
     
       
         
         
             
             
         
       
     
     [wherein, n stands for an integer of from 2 to 5, 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 (wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], and  
 R 2  and R 3  each independently represents a C 1-4  alkoxy group or may be integrated together to form a group represented by formula:  
   —O—(CH 2 ) m —O— 
 (wherein, m stands for an integer of from 1 to 4)}, or salt), or salt thereof, or a hydrate of the compound or salt.  
 
   
   
       95 . A compound of  claim 94 , wherein the compound represented by the formula (III) has a configuration of the following formula:  
     
       
         
         
             
             
         
       
     
     (wherein, n, R 1 , R 2  and R 3  have the same meanings as defined above); or salt thereof, or a hydrate of the compound or salt.  
   
   
       96 . A compound of  claim 90 ,  91 ,  94  or  95 , wherein R 2  and R 3  each represents an a C 1-4  alkoxy group; or salt thereof.  
   
   
       97 . A compound of  claim 90 ,  91 ,  94  or  95 , wherein R 2  and R 3  each represents an ethoxy group; or salt thereof.  
   
   
       98 . A compound represented by the formula (III-ALD):  
     
       
         
         
             
             
         
       
     
     [wherein, n stands for an integer of from 2 to 5, and 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], or salt thereof, or a hydrate of the compound or salt.  
 
   
   
       99 . A compound of  claim 98 , wherein the compound represented by the formula (III-ALD) has a configuration of the following formula:  
     
       
         
         
             
             
         
       
     
     (wherein, n and R 1  have the same meanings as defined above); or salt thereof, or a hydrate of the compound or salt.  
   
   
       100 . A compound represented by the formula (IV):  
     
       
         
         
             
             
         
       
     
     [wherein, n stands for an integer of from 2 to 5, and 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], or salt thereof, or a hydrate of the compound or salt.  
 
   
   
       101 . A compound of  claim 100 , wherein the compound represented by the formula (IV) has a configuration of the following formula:  
     
       
         
         
             
             
         
       
     
     (wherein, n and R 1  have the same meanings as defined above); or salt thereof, or a hydrate of the compound or salt.  
   
   
       102 . A compound represented by the formula (XI):  
     
       
         
         
             
             
         
       
     
     [wherein, n stands for an integer of from 2 to 5, and 
 R 1  represents a hydrogen atom or a group represented by formula:  
                     
 [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group], or salt thereof, or a hydrate of the compound or salt.  
 
   
   
       103 . A compound of any one of  claims 90  to  102 , wherein n stands for 2; or salt thereof, or a hydrate of the compound or salt.  
   
   
       104 . A compound of any one of  claims 90  to  103 , wherein R 1  represents a group represented by formula:  
     
       
         
         
             
             
         
       
     
     [wherein, R a , R b  and R c  each independently represents a phenyl group, a benzyl group, a naphthyl group (the aryl portion of said groups may have one or more substituents, which may be the same or different in kind, selected from the class consisting of a C 1-4  alkyl group, a C 1-4  alkoxy group, a halogen atom and a nitro group), a hydrogen atom, or a C 1-4  alkyl group]; or salt thereof, or a hydrate of the compound or salt.  
   
   
       105 . A compound of  claim 104 , wherein R a , R b  and R c  represent different groups each other; or salt thereof, or a hydrate of the compound or salt.  
   
   
       106 . A compound of  claim 104  or  105 , wherein R a , R b  and R c  are each a substituent selected from the class consisting of a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 4-chlorophenyl group, a 4-nitrophenyl group, a 2,4-dichlorophenyl group, a 2,4-dinitrophenyl group, a 3,5-dichlorophenyl group, a 3,5-dinitrophenyl group and a naphthyl group; or salt thereof, or a hydrate of the compound or salt.  
   
   
       107 . A compound of any one of  claims 104  to  106 , wherein the substituent R 1  is a group selected from the class consisting of (R)-1-phenylethyl, (S)-1-phenylethyl, (R)-1-phenylpropyl, (S)-1-phenylpropyl, (R)-1-phenyl-2-(p-tolyl)ethyl, (S)-1-phenyl-2-(p-tolyl)ethyl, (R)-1-(1-naphthyl)ethyl, (S)-1-(1-naphthyl)ethyl, (R)-1-(4-methoxyphenyl)ethyl, (S)-1-(4-methoxyphenyl)ethyl, (R)-1-(4-chlorophenyl)ethyl, (S)-1-(4-chlorophenyl)ethyl, (R)-1-(4-nitrophenyl)ethyl, (S)-1-(4-nitrophenyl)ethyl, (R)-1-(2,4-dichlorophenyl)ethyl, (S)-1-(2,4-dichlorophenyl)ethyl, (R)-1-(2,4-dinitrophenyl)ethyl, (S)-1-(2,4-dinitrophenyl)ethyl, (R)-1-(3,5-dichlorophenyl)ethyl, (S)-1-(3,5-dichlorophenyl)ethyl, (R)-1-(3,5-dinitrophenyl)ethyl, and (S)-1-(3,5-dinitrophenyl)ethyl groups; or salt thereof, or a hydrate of the compound or salt.  
   
   
       108 . A compound of any one of  claims 104  to  106 , wherein the substituent R 1  is an (R)-1-phenylethyl or (S)-1-phenylethyl group; or salt thereof, or a hydrate of the compound or salt.

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