Optically active nitro alcohol derivatives, optically active amino alcohol derivatives, and process for producing thereof

Abstract

Optically active 1-substituted phenyl-2-nitro alcohol derivatives having the formula (1) and the process for producing thereof, and 1-substituted phenyl-2-amino alcohol derivatives having the formula (2) and the process for producing thereof from the optically active 1-substituted phenyl-2-nitro alcohol derivatives. From these nitro alcohols, pharmaceuticals such as (R)-albutamin and (R)-sarmeterol useful as a bronchodilator is obtained via optically active amino alcohols which are useful pharmaceutical intermediates.

1 . Optically active 1-substituted phenyl-2-nitro alcohol derivatives characterized by the following formula (1)  
       
         
           
           
               
               
           
         
       
       in which n and m represent the positive integers satisfying 0<n+m≦5; R 1  and R 2  represent a hydrogen atom or a hydroxyl-protective group, respectively, and when n+m is 2 or more, R 1  and R 2  are independent of each other or form a ring among R 1 s, among R 2 s, and among R 1  (s) and R 2  (s); R 3  represents —(CH 2 ) 1 — in which 1 is 0, 1, 2 or 3; R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group; and * represents an optically active site, and when R 4  is a hydrogen atom, optical activity at the site to which R 4  is added is lost and * is omitted.  
     
     
         2 . Optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives characterized by the following formula (1-1)  
       
         
           
           
               
               
           
         
       
       in which R 5  and R 6  represent a hydrogen atom or a hydroxyl-protective group, respectively, and they are independent of each other or form a ring; R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group; and * represents an optically active site, and when R 4  is a hydrogen atom, optical activity at the site to which R 4  is added is lost and * is omitted.  
     
     
         3 . Optically active 1-(3-hydroxymethyl-4-hydroxyphenyl)-2-nitro alcohol derivatives characterized by the following formula (1-2)  
       
         
           
           
               
               
           
         
       
       in which R 1  and R 2  represent a hydrogen atom or a hydroxyl-protective group, respectively, and they are independent of each other or form a ring; R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group; and * represents an optically active site, and when R 4  is a hydrogen atom, optical activity at the site to which R 4  is added is lost and * is omitted.  
     
     
         4 . Optically active 1-(3,5-dihydroxyphenyl)-2-nitro alcohol derivatives characterized by the following formula (1-3)  
       
         
           
           
               
               
           
         
       
       in which R 1  and R 2  represent a hydrogen atom or a hydroxyl-protective group, respectively, and they are independent of each other or form a ring; R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group; and * represents an optically active site, and when R 4  is a hydrogen atom, optical activity at the site to which R 4  is added is lost and * is omitted.  
     
     
         5 . Optically active 1-(4-hydroxyphenyl)-2-nitro alcohol derivatives characterized by the following formula (1-4)  
       
         
           
           
               
               
           
         
       
       in which R 1  represents a hydrogen atom or a hydroxyl-protective group; R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group; and * represents an optically active site, and when R 4  is a hydrogen atom, optical activity at the site to which R 4  is added is lost and * is omitted.  
     
     
         6 . The optically active 1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol according to  claim 2 , characterized in that R 4  represents a hydrogen atom, and both R 5  and R 6  represent a t-butyldimethylsiloxy group.  
     
     
         7 . The optically active 1-(3,4-dimethoxyphenyl)-2-nitroethanol according to  claim 2 , characterized in that R 4  represents a hydrogen atom, and both R 5  and R 6  represent a methyl group.  
     
     
         8 . The optically active 1-(3,4-dibenzyloxyphenyl)-2-nitroethanol according to  claim 2 , characterized in that R 4  represents a hydrogen atom, and both R 5  and R 6  represent a benzyl group.  
     
     
         9 . The optically active 1-(3,4-diacetoxyphenyl)-2-nitroethanol according to  claim 2 , characterized in that R 4  represents a hydrogen atom, and both R 5  and R 6  represent a acetyl group.  
     
     
         10 . The optically active α-nitromethyl-piperonyl alcohol according to  claim 2 , characterized in that R 4  represents a hydrogen atom, and R 5  and R 6  are cyclized with a methylene group.  
     
     
         11 . The optically active 2,2-dimethyl-α-nitromethyl-1,3-benzodioxane-6-methanol according to  claim 3 , characterized in that R 4  represents a hydrogen atom, and R 1  and R 2  are cyclized.  
     
     
         12 . The optically active 1-(3,5-dibenzyloxyphenyl)-2-nitroethanol according to  claim 4 , characterized in that R 4  represents a hydrogen atom, and both R 1  and R 2  represent a bezyl group.  
     
     
         13 . Optically active 1-(4-benzoyloxyphenyl)-2-nitroethanol according to  claim 5 , characterized in that R 4  represents a hydrogen atom and R 1  represents a bezoyl group.  
     
     
         14 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that an aldehyde of the following formula (2)  
       
         
           
           
               
               
           
         
       
       in which n and m represent the positive integers satisfying 0<n+m≦5; R 1  and R 2  represent a hydrogen atom or a hydroxyl-protective group, respectively, and when n+m is 2 or more, R 1  and R 2  are independent of each other or form a ring among R 1 s, among R 2 s, and among R 1  (s) and R 2  (s); R 3  represents —(CH 2 ) 1 — in which 1 is 0, 1, 2 or 3; R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group; is reacted with a nitro alkane derivative of the following formula (3) 
       R 4 —CH 2 —NO 2   (3) 
       in which R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         15 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that an aldehyde of the following formula (2-1)  
       
         
           
           
               
               
           
         
       
       in which R 5  and R 6  represent a hydrogen atom or a hydroxyl-protective group, respectively, and they are independent of each other or form a ring, is reacted with a nitro alkane derivative of the following formula (3) 
       R 4 —CH 2 —NO 2   (3) 
       in which R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         16 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that an aldehyde of the following formula (2-2)  
       
         
           
           
               
               
           
         
       
       in which R 1  and R 2  represent a hydrogen atom or a hydroxyl-protective group, respectively, and they are independent of each other or form a ring, is reacted with a nitro alkane derivative of the following formula (3) 
       R 4 —CH 2 —NO 2   (3) 
       in which R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         17 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that an aldehyde of the following formula (2-3)  
       
         
           
           
               
               
           
         
       
       in which R 1  and R 2  represent a hydrogen atom or a hydroxyl-protective group, respectively, and they are independent of each other or form a ring, is reacted with a nitro alkane derivative of the following formula (3) 
       R 4 —CH 2 —NO 2   (3) 
       in which R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         18 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that an aldehyde of the following formula (2-4)  
       
         
           
           
               
               
           
         
       
       in which R 1  represents a hydrogen atom or a hydroxyl-protective group, is reacted with a nitro alkane derivative of the following formula (3) 
       R 4 —CH 2 —NO 2   (3) 
       in which R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         19 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that, when producing the optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative according to  claim 6 , an aldehyde of the following formula (4)  
       
         
           
           
               
               
           
         
       
       is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         20 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that, when producing the optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative according to  claim 7 , an aldehyde of the following formula (5)  
       
         
           
           
               
               
           
         
       
       is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         21 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that, when producing the optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative according to  claim 8 , an aldehyde of the following formula (6)  
       
         
           
           
               
               
           
         
       
       is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         22 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that, when producing the optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative according to  claim 9 , an aldehyde of the following formula (7)  
       
         
           
           
               
               
           
         
       
       is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         23 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that, when producing the optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative according to  claim 10 , an aldehyde of the following formula (8)  
       
         
           
           
               
               
           
         
       
       is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         24 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that, when producing the optically active 1-(3-hydroxymethyl-4-hydroxyphenyl)-2-nitro alcohol derivative according to  claim 11 , an aldehyde Of the following formula (9)  
       
         
           
           
               
               
           
         
       
       is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         25 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that, when producing the optically active 1-(3,5-dihydroxyphenyl)-2-nitro alcohol derivative according to  claim 12 , an aldehyde of the following formula (10)  
       
         
           
           
               
               
           
         
       
       is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         26 . A process for stereoselectively producing optically active nitro alcohol derivatives, characterized in that, when producing the optically active 1-(4-hydroxyphenyl)-2-nitro alcohol derivative according to  claim 13 , an aldehyde of the following formula (11)  
       
         
           
           
               
               
           
         
       
       is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.  
     
     
         27 . The process according to any one of  claims 14  to  26 , characterized in that said rare earth metal complex is a rare earth metal complex having an optically active ligand prepared from an alkoxide of Y, La, Nd, Sm, Eu, Gd, Tb, Dy, Pr or Yb or a trichloride of this rare earth metal, an optically active 1,1′-bi-2-naphthol derivative of the following formula (12)  
       
         
           
           
               
               
           
         
       
       or the following formula (13)  
       
         
           
           
               
               
           
         
       
       in which R 7  and R 8  independently represent a hydrogen atom, an alkyl group of C 1 -C 4 , an ethynyl group, a trialkylsilylethynyl group, or a phenyl group, and R 7  can be at any one of 4, 5, 6, and 7 positions and R 8  at any one of 4′, 5′, 6′, and 7′ positions, and an alkaline metal compound of lithium, sodium or potassium.  
     
     
         28 . The process for stereoselectively producing optically active nitro alcohols according to any one of  claims 14  to  26 , characterized in that a rare earth metal complex is used which is prepared in such a way that the composition ratio of an alkoxide or a trichloride of the above rare earth metal: an optically active 1,1′-bi-2-naphthol compound: an alkaline metal is 1:1-3:0-10.  
     
     
         29 . The optically active 1-substituted phenyl-2-amino alcohol derivatives characterized by the following formula (14)  
       
         
           
           
               
               
           
         
       
       in which n and m represent the positive integers satisfying 0<n+m <5; R 1  and R 2  represent a hydrogen atom or a hydroxyl-protective group, respectively, and when n+m is 2 or more, R 1  and R 2  are independent of each other or form a ring among R 1  s, among R 2 s, and among R 1  (s) and R 2 (s); R 3  presents —(CH 2 ) 1 — in which 1 is 0, 1, 2 or 3; R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group.  
     
     
         30 . The optically active 1-(3,4-dihydroxyphenyl)-2-amino alcohol derivatives characterized by the following formula (14-1)  
       
         
           
           
               
               
           
         
       
       in which R 5  and R 6  represent a hydrogen atom or a hydroxyl-protective group, respectively, and they are independent of each other or form a ring; R 4  represents a hydrogen atom, an alkyl group, or a hydroxymethyl group.  
     
     
         31 . A process for producing optically active amino alcohols, characterized in that, when producing the optically active 1-substituted phenyl-2-amino alcohol derivative according to  claim 29 , the optically active 1-substituted phenyl-2-nitro alcohol derivative according to  claim 1  is reduced stereoselectively.  
     
     
         32 . A process for producing optically active amino alcohols, characterized in that, when producing the optically active 1-(3,4-dihydroxyphenyl)-2-amino alcohol derivative according to  claim 30 , the optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative according to  claim 2  is reduced stereoselectively.  
     
     
         33 . A process for producing (R)-albutamin having the following formula (15),  
       
         
           
           
               
               
           
         
       
       characterized in that the (R)-1-(3,4-dihydroxyphenyl)-2-amino alcohol derivative of the following formula (14-2)  
       
         
           
           
               
               
           
         
       
       is used as a raw material which is obtained by reducing the (R)-1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the following formula (1-5).  
       
         
           
           
               
               
           
         
       
     
     
         34 . A process for producing (R)-sarmeterol having the following formula (16),  
       
         
           
           
               
               
           
         
       
       characterized in that the (R)-1-(3-hydroxymethyl-4-hydroxyphenyl)-2-amino alcohol derivative of the following formula (14-3)  
       
         
           
           
               
               
           
         
       
       is used as a raw material which is obtained by reducing the (R)-1-(3-hydroxymethyl-4-hydroxyphenyl)-2-nitro alcohol derivative of the following formula (1-6).