Method for manufacturing neuraminic acid derivatives

Abstract

A method for manufacturing a compound represented by the formula (13): wherein R 2 represents a C 1 -C 4 alkyl group and Ac represents an acetyl group, including reacting a compound represented by the following formula (12): wherein R 2 represents a C 1 -C 4 alkyl group, Ac represents an acetyl group and Boc represents a tert-butoxycarbonyl group, with water.

1 . A method for manufacturing a compound represented by the following formula (13): 
       
         
           
           
               
               
           
         
       
       wherein R 2  represents a C 1 -C 4  alkyl group and Ac represents an acetyl group, comprising:
 reacting a compound represented by the following formula (12): 
 
       
         
           
           
               
               
           
         
       
       wherein R 2  represents a C 1 -C 4  alkyl group, Ac represents an acetyl group and Boc represents a tert-butoxycarbonyl group, with water. 
     
     
         2 . The manufacturing method according to  claim 1 , wherein R 2  is a methyl group. 
     
     
         3 . A compound represented by the following formula (13): 
       
         
           
           
               
               
           
         
       
       wherein R 2  represents a C 1 -C 4  alkyl group and Ac represents an acetyl group. 
     
     
         4 . The compound according to  claim 3 , wherein R 2  is a methyl group. 
     
     
         5 . A method for manufacturing a compound represented by the following formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a C 1 -C 19  alkyl group, R 2  represents a C 1 -C 4  alkyl group, and Ac represents an acetyl group, wherein the compound represented by the formula (I) is optionally contained with up to 10 wt. % of a compound represented by the following formula (II): 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and Ac have the same meanings as in the formula (I), or a pharmacologically acceptable salt thereof, comprising:
 reacting a compound represented by the following formula (13): 
 
       
         
           
           
               
               
           
         
       
       wherein R 2  represents a C 1 -C 4  alkyl group and Ac represents an acetyl group, with a compound represented by the formula R 1 C(OR 7 ) 3 , wherein R 1  represents a C 1 -C 19  alkyl group and R 7  represents a C 1 -C 6  alkyl group, or a pharmacologically acceptable salt thereof. 
     
     
         6 . The manufacturing method according to  claim 5 , wherein R 1  is a 1-heptyl group, R 2  is a methyl group and R 7  is a methyl group. 
     
     
         7 . A method for manufacturing a compound represented by the following formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a C 1 -C 19  alkyl group, R 2  represents a C 1 -C 4  alkyl group and Ac represents an acetyl group, wherein the compound represented by the formula (I) is optionally contained with up to 10 wt. % of a compound represented by the following formula (II): 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and Ac have the same meanings as in the formula (I), or a pharmacologically acceptable salt thereof, comprising:
 reacting a compound represented by the following formula (13): 
 
       
         
           
           
               
               
           
         
       
       wherein R 2  represents a C 1 -C 4  alkyl group and Ac represents an acetyl group, with a compound represented by the following formula (15): 
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a C 1 -C 19  alkyl group, R 7  represents a C 1 -C 6  alkyl group and X represents Cl, Br, I, HSO 4  or NO 3 , and with a compound represented by the formula R 7 —OH, wherein R 7  represents a C 1 -C 6  alkyl group. 
     
     
         8 . The manufacturing method according to  claim 7 , wherein R 1  is a 1-heptyl group, R 2  is a methyl group, R 7  is a methyl group and X is Cl. 
     
     
         9 . A method for manufacturing a compound represented by the formula (Ib): 
       
         
           
           
               
               
           
         
       
       wherein Ac represents an acetyl group and Me represents a methyl group, and the compound represented by the formula (Ib) is optionally contained with a compound represented by the following formula (IIb): 
       
         
           
           
               
               
           
         
       
       wherein in the formula (IIb), Ac and Me have the same meanings as in the formula (Ib), or a pharmacologically acceptable salt thereof, wherein the method comprises:
 reacting the following compound (4) with the following compound (5) to produce the following compound (7) as follows: 
 
       
         
           
           
               
               
           
         
         wherein R 3  is a methyl group and R 4  and R 5  together form an oxo group; 
         reacting compound (7) with a compound represented by the formula (R 2 O) 2 SO 2 , wherein R 2  is a methyl group, in the presence of a base to produce the following compound (8): 
       
       
         
           
           
               
               
           
         
         reacting compound (8) with trimethylsilyl azide in the presence of a Lewis acid to produce the following compound (9): 
       
       
         
           
           
               
               
           
         
         treating compound (9) with triphenylphosphine and treating the compound thus obtained with a base and water to produce the following compound (10): 
       
       
         
           
           
               
               
           
         
         reacting compound (10) with the following compound (11) 
       
       
         
           
           
               
               
           
         
       
       to produce the following compound (12): 
       
         
           
           
               
               
           
         
         wherein Boc is a tert-butoxycarbonyl group; 
         reacting compound (12) with water to produce the following compound (13): 
       
       
         
           
           
               
               
           
         
       
       and
 reacting compound (13) with the following compound (14):
   R 1 C(OR 7 ) 3   (14),
 
 
 
       wherein R 1  is a C 1 -C 19  alkyl group and R 7  is a C 1 -C 6  alkyl group, in the presence of an acid to produce the compound of formula (Ib), which is optionally contained with the compound of the formula (IIb). 
     
     
         10 . A compound represented by the following formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a C 1 -C 19  alkyl group, R 2  represents a C 1 -C 4  alkyl group and Ac represents an acetyl group, the compound represented by the formula (I) is optionally contained with up to 10 wt. % of a compound represented by the following formula (II): 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and Ac have the same meanings as in the formula (I), having a chemical purity of 97 wt. % or higher, wherein in the case where the compound represented by the formula (II) is contained with the compound represented by formula (I), the chemical purity of the mixture of the compound represented by the formula (I) and the compound represented by the formula (II) is 97 wt. % or higher, or a pharmacologically acceptable salt thereof. 
     
     
         11 . A composition comprising the compound represented by the formula (I) and up to 10 wt. % of the compound represented by the formula (II), or a pharmacologically acceptable salt thereof according to  claim 10 , wherein the chemical purity of the compound represented by the formula (I) is 99 wt. % or higher. 
     
     
         12 . A composition comprising the compound represented by the formula (I) and up to 10 wt. % of the compound represented by the formula (II), or a pharmacologically acceptable salt thereof according to  claim 10 , wherein the chemical purity of the compound represented by the formula (I) is 99.5 wt. % or higher. 
     
     
         13 . A composition comprising the compound represented by the formula (I) and up to 10 wt. % of the compound represented by the formula (II), according to  claim 10 , wherein R 1  is a 1-heptyl group and R 2  is a methyl group. 
     
     
         14 . A compound represented by the following formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a C 1 -C 19  alkyl group, R 2  represents a C 1 -C 4  alkyl group, and Ac represents an acetyl group, wherein the compound represented by the formula (I) is optionally contained with up to 10 wt. % of a compound represented by the following formula (II): 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and Ac have the same meanings as in the formula (I), or a pharmacologically acceptable salt thereof, containing 0.5 wt. % or less of a compound represented by the following formula (VII): 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and Ac have the same meanings as in the formula (I). 
     
     
         15 . A composition comprising the compound represented by the formula (I) and the compound represented by the formula (II), or a pharmacologically acceptable salt thereof according to  claim 14 , containing 0.3 wt. % or less of the compound represented by the formula (VIII). 
     
     
         16 . A composition comprising the compound represented by the formula (I) and the compound represented by the formula (II), or a pharmacologically acceptable salt thereof according to  claim 14 , containing 0.1 wt. % or less of the compound represented by the formula (VIII). 
     
     
         17 . A composition comprising the compound represented by the formula (I) and up to 10 wt. % of the compound represented by the formula (II), according to  claim 14 , wherein R 1  is a 1-heptyl group and R 2  is a methyl group. 
     
     
         18 . A compound represented by the following formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a C 1 -C 19  alkyl group, R 2  represents a C 1 -C 4  alkyl group, and Ac represents an acetyl group, the compound represented by the formula (I) is optionally contained with up to 10 wt. % of a compound represented by the following formula (II): 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and Ac have the same meanings as in the formula (I), or a pharmacologically acceptable salt thereof, containing 0.5 wt. % or less of a compound represented by the following formula (VIII): 
       
         
           
           
               
               
           
         
       
       wherein R 1  and Ac have the same meanings as the formula (I). 
     
     
         19 . The compound according to  claim 18 , wherein the compound represented by the formula (VIII) is in an amount of 0.3 wt. % or less. 
     
     
         20 . The compound according to  claim 18 , wherein the compound represented by the formula (VIII) is in an amount of 0.1 wt. % or less. 
     
     
         21 . The compound according to  claim 18 , wherein R 1  is a 1-heptyl group and R 2  is a methyl group. 
     
     
         22 . A compound represented by the following formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a C 1 -C 19  alkyl group, R 2  represents a C 1 -C 4  alkyl group, and Ac represents an acetyl group, the compound represented by the formula (I) is optionally contained with up to 10 wt. % of a compound represented by the following formula (II): 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and Ac have the same meanings as in the formula (I), or a pharmacologically acceptable salt thereof, containing 0.5 wt. % or less of a compound represented by the following formula (13): 
       
         
           
           
               
               
           
         
       
       wherein R 2  and Ac have the same meanings as in the formula (I). 
     
     
         23 . A composition comprising the compound represented by the formula (I) and the compound represented by the formula (II), or a pharmacologically acceptable salt thereof according to  claim 22 , containing the compound represented by the formula (13) in the amount of 0.3 wt. % or less. 
     
     
         24 . A composition comprising the compound represented by the formula (I) and the compound represented by the formula (II), or a pharmacologically acceptable salt thereof according to  claim 22 , containing the compound represented by the formula (13) in an amount of 0.1 wt. % or less. 
     
     
         25 . A composition comprising the compound represented by the formula (I) and the compound represented by the formula (II), according to  claim 22 , wherein R 1  is a 1-heptyl group and R 2  is a methyl group. 
     
     
         26 . A composition comprising the compound represented by the formula (I) and the compound represented by the formula (II), according to  claim 10 , wherein the composition ratio of the compound represented by the formula (I) and the compound represented by the formula (II) is 90:10 to 100:0 by weight. 
     
     
         27 . A composition comprising the compound represented by the formula (I) and the compound represented by the formula (II), according to  claim 10 , wherein the composition ratio of the compound represented by the formula (I) and the compound represented by the formula (II) is 92:8 to 100:0 by weight. 
     
     
         28 . A composition comprising the compound represented by the formula (I) and the compound represented by the formula (II), according to  claim 10 , wherein the composition ratio of the compound represented by the formula (I) and the compound represented by the formula (II) is 95:5 to 100:0 by weight. 
     
     
         29 . A method of manufacturing a compound represented by the formula R 1 C(OR 7 ) 3 , wherein R 1  represents a C 1 -C 19  alkyl group and R 7  represents a C 1 -C 6  alkyl group, comprising:
 reacting a compound represented by the following formula (15):   
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a C 1 -C 19  alkyl group, R 7  represents a C 1 -C 6  alkyl group and X represents Cl, Br, I, HSO 4  or NO 3 , with a compound represented by the formula R 7 —OH, wherein R 7  represents a C 1 -C 6  alkyl group, in a solvent which forms a bilayer system. 
     
     
         30 . The manufacturing method according to  claim 29 , wherein the solvent which forms the bilayer system is cyclohexane or methylcyclohexane. 
     
     
         31 . The manufacturing method according to  claim 29 , wherein R 1  is a 1-heptyl group, R 7  is a methyl group and X is Cl. 
     
     
         32 . The manufacturing method according to  claim 30 , wherein R 1  is a 1-heptyl group, R 7  is a methyl group and X is Cl. 
     
     
         33 . A composition for treating or preventing influenza comprising a pharmacologically effective amount of the compound or pharmacologically acceptable salt thereof according to  claim 10  in combination with a pharmacologically acceptable carrier. 
     
     
         34 . A method for treating or preventing influenza comprising administering to a human in need thereof a pharmacologically effective amount of the compound or pharmacologically acceptable salt thereof according to  claim 10 .