Process for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives

Abstract

This invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid, a useful pharmaceutical intermediate, easily from a readily available, inexpensive starting material without using any extraordinary production equipment such as a very-low-temperature reactor. Thus, this invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises permitting a lithium amide to act upon a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative at not below −20° C. Further, this invention also provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises treating a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative with a Grignard reagent to prepare a mixture of a compound and an acetic acid ester of the above formula (I), and permitting a lithium amide to act upon the mixture at a temperature not below −20° C. This invention provides a process for producing a 5- hydroxy - 3 - oxopentanoic acid, a useful pharmaceutical intermediate, easily from a readily available, inexpensive starting material without using any extraordinary production equipment such as a very - low temperature reactor. Thus, this invention provides a process for producing a 5 - hydroxy - 3 - oxopentanoic acid which comprises permitting a lithium amide to act upon a mixture of an acetic acid ester and a 3 - hydroxypropionic acid derivative at not below −20° C. Further, this invention also provides a process for producing a 5 - hydroxy - 3 - oxopentanoic acid which comprises treating a mixture of an acetic acid ester and a 3 - hydroxypropionic acid derivative with a Grignard reagent to prepare a mixture of a compound and an acetic acid ester of the above formula ( I ) , and permitting a lithium amide to act upon the mixture at a temperature not below −20° C.

1. A process for producing a 5-hydroxy-3-oxopentanoic acid derivative of the following formula (IV): 
                 
 
       wherein R 1  represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 1:2 carbon atoms; and R 2  represents any of hydrogen, an alky, group of 1 to 12 carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxy group and an alkoxycarbonyl group,
 which comprises permitting adding a lithium amide of the following formula (III): 
                 
 
 
       wherein R 4  and R 5  may be the same or different and each represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms and a silyl group,
 to act upon a mixture of an acetic acid ester of the following formula (I) and a 3-hydroxypropionic acid derivative of the following formula (II) at a temperature not below −20° C. to conduct reaction: 
   CH 3 CO 2 R 1   (I)  
 
 
       wherein R 1  represents any of an alkyl group of 1 to 12 carbon atoms, an aryl croup of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms: 
                 
 
       wherein R 2  represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxyl group and an alkoxycarbonyl group; R 3  represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms; and R 2  and R 3  may be joined to each other to form a ring, in the presence of a magnesium halide. 
     
     
       2. The process according to  claim 1 
 wherein, referring to the lithium amide, R 4  and R 5  each represents an isopropyl group.  
 
     
     
       3. The process according to  claim 1 
 wherein, referring to the acetic acid ester, R 1  represents a tert-butyl group.  
 
     
     
       4. The process according to  claim 1 ,
 wherein a magnesium halide is added in permitting the lithium amide to act.    
     
     
       5. The process according to claim  4   1  
 wherein magnesium chloride is used as the magnesium halide.  
 
     
     
       6. A process for producing a 5-hydroxy-3-oxopentanoic acid derivative of the following formula (IV): 
                 
 
       wherein R 1  represents any off an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms; and R 2  represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxyl group and an alkoxycarbonyl group,
 which comprises treating a mixture of an acetic acid ester of the following formula (I) and a 3-hydroxypropionic acid derivative of the following formula (II): 
   CH 3 CO 2 R 1   (I)  
 
 
       wherein R 1  represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms: 
                 
 
       wherein R 2  represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxyl group and an alkoxycarbonyl group; R 3  represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms; and R 2  and R 3  may be joined to each other to form a ring,
 with a Grignard reagent of the, following formula (V): 
   R 6 —Mg—X  (V)  
 
 
       wherein R 6  represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms; and X represents halogen,
 to prepare a mixture of a compound off the following formula (VI) and an acetic acid ester of the above formula (I): 
                 
 
 
       wherein R 2  represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon t atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxyl group and an alkoxycarbonyl group; R 3  represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms; R 2  and R 3  may be joined to each other to form a ring; and X represents a halogen atom,
 and permitting adding a lithium amide of the following formula (III): 
                 
 
 
       wherein R 4  and R 5  may be the same or different and each represents any of an alkyl group of 1to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms and a silyl group
 to act upon the mixture at a temperature not below −20° C. to conduct reaction.  
 
     
     
       7. The process according to  claim 6 
 wherein, referring to the lithium amide, R 4  and R 5  each is an isopropyl group.  
 
     
     
       8. The process aces riling to  claim 6 
 wherein, referring to the acetic acid ester, R 1  represents a tert-butyl group.  
 
     
     
       9. The process according to  claim 6 ,
 wherein, referring to the Grignard reagent, R 6  represents a tert-butyl group and X represents a chlorine atom.  
 
     
     
       10. A process for producing a 5-hydroxy-3-oxopentanoic acid derivative of the following formula (IV): 
                 
 
       wherein R 1  represent any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms; and R 2  represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxyl group and an alkoxycarbonyl group,
 which comprises permitting adding a lithium amide of the following formula (III): 
                 
 
 
       wherein R 4  and R 5  may be the same or different and each represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms and a silyl group,
 to act upon a mixture of an acetic acid ester of the following formula (I) and a compound of the following formula (VI) at a temperature not below −20° C. to conduct reaction: 
   CH 3 CO 2 R 1   (I)  
 
 
       wherein R 1  represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms: 
                 
 
       wherein R 2  represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may (have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxyl group and an alkoxycarbonyl group; R 3  represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms; R 2  and R 3  may be joined to each other to form a ring; and X represents a halogen atom. 
     
     
       11. The process according to  claim 10 
 wherein, referring to the lithium amide, R 4  and R 5  each represents an iso propyl group.  
 
     
     
       12. The process according to  claim 10 
 wherein, referring to the acetic acid ester, R 1  represents a tert-butyl group.  
 
     
     
       13. The process according to  claim 10 ,
 wherein, referring to the compound (VI), X represents a chlorine atom.  
 
     
     
       14. The process according to  claim 1 
 wherein R 3  is a methyl group or an ethyl group.  
 
     
     
       15. The process according to  claim 1 
 wherein R 2  is a chloromethyl group, a cyanomethyl group or a benzyloxymethyl group.  
 
     
     
       16. The process according to  claim 1 
 wherein R 2  and R 3  are joined to each other to form a methylene group.  
 
     
     
       17. The process according to  claim 1 
 wherein the compound (II) or (VI) , the  3 - hydroxypropionic acid derivative of the formula  ( II )  or the  5   - hydroxy -   3   - oxopentanoic acid derivative of the formula  ( IV ) is optically active.  
 
     
     
       18. The process according to  claim 2 
 wherein, referring to the acetic acid ester of the formula ( I ), R 1  represents a tert-butyl group.  
 
     
     
       19. The process according to  claim 2   wherein a magnesium halide is added in permitting the lithium amide to act.    
     
     
       20. The process according to  claim 3   wherein a magnesium halide is added in permitting the lithium amide to act.