Process for producing 3-amino-2-oxo-1-halogenopropane derivatives

Abstract

Compounds formed by reacting a protected amino acid with an alkali metal enolate of an alkyl acetate are reacted with a halogenating agent for halogenation of the 2-position, or a protected amino acid is reacted with an alkali metal enolate of an alkyl halogenoacetate, to form a 4-amino-3-oxo-2-halogenobutanoic acid ester derivative, and hydrolysis and decarboxylation are conducted to produce a 3-amino-2-oxo-1-halogenopropane derivative or its salt. The present method is a useful process for producing a 3-amino-2-oxo-1-halogenopropane derivatives which can easily be converted to a 3-amino-1,2-epoxypropane.

1. A process for producing a 3-amino-2-oxo-1-halogenopropane derivative represented by formula (V) 
                 
 
       wherein
 R s  represents hydrogen, an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, or the above-mentioned groups containing a hetero atom in the carbon skeleton; P 1  and P 2 , independently from each other, represent hydrogen or an amino-protecting group, or P 1  and P 2  together form a difunctional amino-protecting group, and at least one of P 1  and P 2  is not hydrogen; and X represents a halogen atom other than fluorine  
 
       or its salt,
 which comprises:  
 (i) reacting a compound represented by formula (I) 
                 
 
 
       wherein
 R s , P 1 , and P 2  are as defined above, and E 1  represents an alkoxy ester residue having from 1 to 10 carbon atoms, a phenoxy or benzyloxy group, which may have a substituent in the ring, an ester residue of N-oxysuccinimide or 1-oxybenzotriazole, an active thioester residue, an imidazolyl group or a residue capable of forming an acid halide, an acid anhydride or an acid azido,  
 with an alkali metal enolate of an acetate to obtain a compound represented by formula (II) 
                 
 
 
       wherein
 R s , P 1 , and P 2  are as defined above, and R 1  represents an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, a trialkylsilyl group having from 4 to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10 carbon atoms or a diphenylalkylsilyl group having 13 to 15 carbon atoms;  
 (ii) reacting the compound of formula (II) with a halogenating agent for halogenation of the 2-position to form a 4-amino-3-oxo-2-halogenobutanoic acid ester derivative represented by formula (III) 
                 
 
 
       wherein R s , P 1 , P 2 , R 1  and X are as defined above;
 (iii) further hydrolyzing the resulting compound of formula (III), to obtain a hydrolyzate; and  
 (iv) decarboxylating said hydrolyzate, to obtain said compound of formula (V).  
 
     
     
       2. The process of  claim 1 , wherein the carbon atom to which R s  is bonded in the compound of formula (I) has a S-configuration except for a case where R s  in formula (I) is hydrogen. 
     
     
       3. The process of  claim 1 , wherein the carbon atom to which R s  is bonded in the compound of formula (I) has an R-configuration except for a case where R s  in formula (I) is hydrogen. 
     
     
       4. A process for producing a 3-amino-2-oxo-1-halogenopropane derivative represented by formula (V) 
                 
 
       wherein
 R s  represents hydrogen, an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, or the above-mentioned groups containing a hetero atom in the carbon skeleton; P 1  and P 2 , independently from each other, represent hydrogen or an amino-protecting group, or P 1  and P 2  together form a difunctional amino-protecting group, and at least one of P 1  and P 2  is not hydrogen; and X represents a halogen atom other than fluorine  
 
       or its salt,
 which comprises:  
 (i) reacting a compound represented by formula (I) 
                 
 
 
       wherein
 R s , P 1 , and P 2  are as defined above, and E 1  represents an alkoxy ester residue having from 1 to 10 carbon atoms, a phenoxy or benzyloxy group, which may have a substituent in the ring, an ester residue of N-oxysuccinimide or 1-oxybenzotriazole, an active thioester residue, an imidazolyl group or a residue capable of forming an acid halide, an acid anhydride or an acid azido  
 with an alkali metal enolate or dianion of a compound represented by formula (IV) 
                 
 
 
       wherein X is as defined above, and R 2  represents hydrogen, an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, a trialkylsilyl group having from 3 to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10 carbon atoms or a diphenylalkylsilyl group having 13 to 15 carbon atoms, 
       to form a 4-amino-3-oxo-2-halogenobutanoic acid ester or salt derivative represented by formula (III′) 
                 
 
       wherein R s , P 1 , P 2 , and X are as defined above, and R 3  represents alkali metal, an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, a trialkylsilyl group having from 3 to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10 carbon atoms or a diphenylalkylsilyl group having 13 to 15 carbon atoms;
 (ii) further hydrolyzing said compound of formula (III′), to obtain a hydrolyzate; and  
 (iii) decarboxylating said hydrolyzate, to obtain said compound of formula (V).  
 
     
     
       5. The process of  claim 4 , wherein the carbon atom to which R s  is bonded in the compound of formula (I) has a S-configuration except for a case where R s  in formula (I) is hydrogen. 
     
     
       6. The process of  claim 4 , wherein the carbon atom to which R s  is bonded in the compound of formula (I) has an R-configuration except for a case where R s  in formula (I) is hydrogen. 
     
     
       7. A process for preparing a compound of formula (VI) 
                 
 
       wherein
 R s  represents hydrogen, an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, or the above-mentioned groups containing a hetero atom in the carbon skeleton; P 1  and P 2 , independently from each other, represent hydrogen or an amino-protecting group, or P 1  and P 2  together form a difunctional amino-protecting group, and at least one of P 1  and P 2  is not hydrogen; and X represents a halogen atom other than fluorine  
 
       or its salt,
 which comprises:  
 (i) reacting a compound represented by formula (I) 
                 
 
 
       wherein
 R s , P 1 , and P 2  are as defined, and E 1  represents an alkoxy ester residue having from 1 to 10 carbon atoms, a phenoxy or benzyloxy group, which may have a substituent in the ring, an ester residue of N-oxysuccinimide or 1-oxybenzotriazole, an active thioester residue, an imidazolyl group or a residue capable of forming an acid halide, an acid anhydride or an acid azido,  
 with an alkali metal enolate of an acetate to obtain a compound represented by formula (II) 
                 
 
 
       wherein
 R s , P 1 , and P 2  are as defined above, and R 1  represents an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, a trialkylsilyl group having from 4 to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10 carbon atoms or a diphenylalkylsilyl group having 13 to 15 carbon atoms;  
 (ii) reacting the compound of formula (II) with a halogenating agent for halogenation of the 2-position to form a 4-amino-3oxo-2-halogenobutanoic acid ester derivative represented by formula (III) 
                 
 
 
       wherein R s , P 1 , P 2 , R 1 , and X are as defined above;
 (iii) further hydrolyzing the resulting compound of formula (III), to obtain a hydrolyzate;  
 (iv) decarboxylating said hydrolyzate, to obtain a compound of formula (V) 
                 
 
 
       wherein:
 R s , P 1 , P 2 , and X are as defined above; and  
 (v) reducing said compound of formula (V), to obtain said compound of formula (VI).  
 
     
     
       8. The process of  claim 7 , wherein the carbon atom to which R s  is bonded in the compound of formula (I) has a S-configuration except for a case where R s  in formula (I) is hydrogen. 
     
     
       9. The process of  claim 7 , wherein the carbon atom to which R s  is bonded in the compound of formula (I) has an R-configuration except for a case where R s  in formula (I) is hydrogen. 
     
     
       10. A process for producing a compound represented by formula (VI) 
                 
 
       wherein
 R s  represents hydrogen, an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, or the above-mentioned groups containing a hetero atom in the carbon skeleton; P 1  and P 2 , independently from each other, represent hydrogen or an amino-protecting group, or P 1  and P 2  together form a difunctional amino-protecting group, and at least one of P 1  and P 2  is not hydrogen; and X represents a halogen atom other than fluorine  
 
       or its salt,
 which comprises:  
 (i) reacting a compound represented by formula (I) 
                 
 
 
       wherein
 R 1 , P 1 , and P 2  are as defined above, and E 1  represents an alkoxy ester residue having from 1 to 10 carbon atoms, a phenoxy or benzyloxy group, which may have a substituent in the ring, an ester residue of N-oxysuccinimide or 1-oxybenzotriazole, an active thioester residue, an imidazolyl group or a residue capable of forming an acid halide, an acid anhydride or an acid azido,  
 with an alkali metal enolate or dianion of a compound represented by formula (IV) 
                 
 
 
       wherein
 X is as defined above; and R 2  represents hydrogen, an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, a trialkylsilyl group having from 3 to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10 carbon atoms or a  
 diphenylalkylsilyl group having 13 to 15 carbon atoms; to form a 4-amino-3oxo-2-halogenobutanoic acid ester derivative represented by formula (III′) 
                 
 
 
       wherein R s , P 1 , P 2 , and X are as defined above; and R 3  represents alkali metal, an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, a trialkylsilyl group having from 3 to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10 carbon atoms or a diphenylalkylsilyl group having 13 to 15 carbon atoms;
 (iii) further hydrolyzing said compound of formula (III′), to obtain a hydrolyzate;  
 (iv) decarboxylating said hydrolyzate, to obtain a compound of formula (V): 
                 
 
 
       wherein:
 R s , P 1 , P 2 , and X are as defined above; and  
 (v) reducing said compound of formula (V), to obtain said compound of formula (VI).  
 
     
     
       11. The process of  claim 13    claim 10 , wherein the carbon atom to which R s  is bonded in the compound of formula (I) has a S-configuration except for a case where R s  in formula (I) is hydrogen. 
     
     
       12. The process of  claim 13    claim 10 , wherein the carbon atom to which R s  is bonded in the compound of formula (I) has an R-configuration except for a case where R s  in formula (I) is hydrogen. 
     
     
       13. A process for preparing a compound of formula (VII) 
                 
 
       wherein
 R s  represents hydrogen, an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, or the above-mentioned groups containing a hetero atom in the carbon skeleton; and P 1  and P 2 , independently from each other, represent hydrogen or an amino-protecting group, or P 1  and P 2  together form a difunctional amino-protecting group, and at least one of  
 P 1  and P 2  is not hydrogen;  
 
       or its salt,
 which comprises:  
 (i) reacting a compound represented by formula (I) 
                 
 
 
       wherein
 R s , P 1  and P 2  are as defined above, and E 1  represents an alkoxy ester residue having from 1 to 10 carbon atoms, a phenoxy or benzyloxy group, which may have a substituent in the ring, an ester residue of N-oxysuccinimide or 1-oxybenzotriazole, an active thioester residue, an imidazolyl group or a residue capable of forming an acid halide, an acid anhydride or an acid azido,  
 with an alkali metal enolate of an acetate to obtain a compound represented by formula (II) 
                 
 
 
       wherein
 R s , P 1 , and P 2  are as defined above, and R 1  represents an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, a trialkylsilyl group having from 4 to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10 carbon atoms or a diphenylalkylsilyl group having 13 to 15 carbon atoms;  
 (ii) reacting the compound of formula (II) with a halogenating agent for halogenation of the 2-position to form a 4-amino-3oxo-2-halogenobutanoic acid ester derivative represented by formula (III) 
                 
 
 
       wherein R s , P 1 , P 2 , and R 1  are as defined above; and X is a halogen atom other than fluorine;
 (iii) further hydrolyzing the resulting compound of formula (III), to obtain a hydrolyzate;  
 (iv) decarboxylating said hydrolyzate, to obtain a compound of formula (V) 
                 
 
 
       wherein:
 R s , P 1 , P 2 , and X are as defined above;  
 (v) reducing said compound of formula (V), to obtain a compound of formula (VI) 
                 
 
 
       wherein
 R s , P 1 , P 2 , and X are as defined above; and  
 (vi) epoxidizing said compound of formula (VI), to obtain said compound of formula (VII).  
 
     
     
       14. The process of  claim 13 , wherein the carbon atom to which R s  is bonded in the compound of formula (I) has a S-configuration except for a case where R s  in formula (I) is hydrogen. 
     
     
       15. The process of  claim 13 , wherein the carbon atom to which R s  is bonded in the compound of formula (I) has an R-configuration except for a case where R s  in formula (I) is hydrogen. 
     
     
       16. A process for producing a compound represented by formula (VII) 
                 
 
       wherein
 R s  represents hydrogen, an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, or the above-mentioned groups containing a hetero atom in the carbon skeleton; P 1  and P 2 , independently from each other, represent hydrogen or an amino-protecting group, or P 1  and P 2  together form a difunctional amino-protecting group, and at least one of P 1 , and P 2  is not hydrogen;  
 
       or its salt,
 which comprises:  
 (i) reacting a compound represented by formula (I) 
                 
 
 
       wherein
 R s , P 1 , and P 2  are as defined above, and E 1  represents an alkoxy ester residue having from 1 to 10 carbon atoms, a phenoxy or benzyloxy group, which may have a substituent in the ring, an ester residue of N-oxysuccinimide or 1-oxybenzotriazole, an active thioester residue, an imidazolyl group or a residue capable of forming an acid halide, an acid anhydride or an acid azido,  
 with an alkali metal enolate of an acetate to obtain a compound represented by formula (IV) 
                 
 
 
       wherein
 X is a halogen atom other than fluorine; and R 2  represents hydrogen, an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, a trialkylsilyl group having from 3 to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10 carbon atoms or a diphenylalkylsilyl group having 13 to 15 carbon atoms;  
 
       to form a 4-amino-3oxo-2-halogenobutanoic acid ester derivative represented by formula (III′) 
                 
 
       wherein R s , P 1 , P 2 , and X are as defined above; and R 3  represents alkali metal, an optionally substituted alkyl group having from 1 to 10 carbon atoms, an optionally substituted aryl group having from 6 to 15 carbon atoms, an optionally substituted aralkyl group having from 7 to 20 carbon atoms, a trialkylsilyl group having from 3 to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10 carbon atoms or a diphenylalkylsilyl group having 13 to 15 carbon atoms;
 (iii) further hydrolyzing said compound of formula (III′), to obtain a hydrolyzate;  
 (iv) decarboxylating said hydrolyzate, to obtain a compound of formula (V): 
                 
 
 
       wherein:
 R s , P 1 , P 2 , and X are as defined above;  
 (v) reducing said compound of formula (V), to obtain a compound of formula (VI) 
                 
 
 
       wherein
 R s , P 1 , P 2 , and X are as defined above; and  
 (vi) epoxidizing said compound of formula (VI), to obtain said compound of formula (VII).  
 
     
     
       17. The process of  claim 16 , wherein the carbon atom to which R s  is bonded in the compound of formula (I) has a S-configuration except for a case where R s  in formula (I) is hydrogen. 
     
     
       18. The process of  claim 16 , wherein the carbon atom to which R s  is bonded in the compound of formula (I) has an R-configuration except for a case where R s  in formula (I) is hydrogen. 
     
     
       19. A process for producing a compound represented by formula ( II ): 
                   
       
         wherein  
           R   s    represents hydrogen, an optionally substituted alkyl group having from  1  to  10  carbon atoms, an optionally substituted aryl group having from  6  to  15  carbon atoms, an optionally substituted aralkyl group having from  7  to  20  carbon atoms, or the above - mentioned groups containing a hetero atom in the carbon skeleton;    
           P   1    and P   2   , independently from each other, represent hydrogen or an amino - protecting group, or P   1    and P   2    together form a difunctional amino - protecting group, and at least one of P   1    and P   2    is not hydrogen; and    
         
           R 
           1  
           represents an optionally substituted alkyl group having from  1  to  10  carbon atoms, an optionally substituted aryl group having from  6  to  15  carbon atoms, an optionally substituted aralkyl group having from  7  to  20  carbon atoms, a trialkylsilyl group having from  4  to  10  carbon atoms, a phenyldialkylsilyl group having  8  to  10  carbon atoms or a diphenylalkylsilyl group having  13  to  15  carbon atoms;  
         
           which process comprises reacting a compound represented by formula  ( I ): 
                   
       
       
         wherein  
         
           R 
           s 
           , P 
           1 
           , and P 
           2  
           are as defined above; and  
         
         
           E 
           1  
           represents an alkoxy ester residue having from  1  to  10  carbon atoms, a phenoxy or benzyloxy group which may have a substituent in the ring;  
         
         
           with an alkali metal enolate of an acetate. 
         
       
     
     
       20. The process of  claim 19 , wherein the carbon atom to which R s    is bonded in the compound of formula  ( I )  has an S - configuration except for a case where R   s    in formula  ( I )  is hydrogen.   
     
     
       21. The process of  claim 19 , wherein the carbon atom to which R s    is bonded in the compound of formula  ( I )  has an R - configuration except for a case where R   s    in formula  ( I )  is hydrogen.   
     
     
       22. The process of  claim 19 , wherein R 1    represents an optionally substituted alkyl group having from  1  to  10  carbon atoms, an optionally substituted aryl group having from  6  to  15  carbon atoms, or an optionally substituted aralkyl group having from  7  to  20  carbon atoms.