Process for Preparing Compound Having HIV Integrase Inhibitory Activity

Abstract

A process for preparing a compound represented by formula (Y1) or (Y2) [wherein R x is an optionally substituted carbocyclyl lower alkyl, or the like] or a salt thereof, using a novel process for preparing a pyridone derivative represented by formula (X4) [wherein R 1d is hydrogen, halogen, or the like; R 2d is hydrogen, a lower alkyl optionally substituted with substituent E, or the like; R 4d is a lower alkyl optionally substituted with substituent E, or the like; and R 6d is a lower alkyl group optionally substituted with substituent group E, or the like].

What is claimed is: 
     
         1 . A method of producing a compound shown by formula (Y1) or formula (Y2) or a salt thereof: 
       
         
           
           
               
               
           
         
         (wherein R x  is carbocyclyl optionally substituted by substituent E, heterocyclyl optionally substituted by substituent E, carbocyclyl lower alkyl optionally substituted by substituent E, or heterocyclyl lower alkyl optionally substituted by substituent E, and substituent E is as defined below) 
         comprising a step of: 
         (Step B) 
         reacting a compound shown by formula (X2): 
       
       
         
           
           
               
               
           
         
         (wherein, 
         R 1d  is hydrogen, halogen, lower alkyloxy optionally substituted by substituent E, carbocyclyl lower alkyloxy optionally substituted by substituent E, heterocyclyl lower alkyloxy optionally substituted by substituent E, or —OSi(R 1e ) 3 , 
         R 1e s are each independently lower alkyl optionally substituted by substituent E, carbocyclyl optionally substituted by substituent E, heterocyclyl optionally substituted by substituent E, carbocyclyl lower alkyl optionally substituted by substituent E, or heterocyclyl lower alkyl optionally substituted by substituent E, 
         R 2d  is hydrogen, lower alkyl optionally substituted by substituent E, carbocyclyl lower alkyl optionally substituted by substituent E, or heterocyclyl lower alkyl optionally substituted by substituent E, 
         R 3d  is hydrogen, lower alkyloxy optionally substituted by substituent E, —N(R 3e ) 2 , or —OR 3e , 
         R 3e s are each independently lower alkyl optionally substituted by substituent E, or two R 3e s in —N(R 3e ) 2  together with the adjacent nitrogen atom may form a heterocycle, and 
         a wavy line means E form and/or Z form or a mixture thereof. 
         Substituent E: halogen, cyano, hydroxyl, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogen, lower alkyl, lower alkyloxy, carbocyclyl optionally substituted by substituent F, heterocyclyl optionally substituted by substituent F, carbocyclyl lower alkyloxy optionally substituted by substituent F, heterocyclyl lower alkyloxy optionally substituted by substituent F, carbocyclyl lower alkylthio optionally substituted by substituent F, heterocyclyl lower alkylthio substituted by substituent F, carbocyclyl lower alkylamino optionally substituted by substituent F, heterocyclyl lower alkylamino optionally substituted by substituent F, carbocyclyloxy optionally substituted by substituent F, heterocyclyloxy optionally substituted by substituent F, carbocyclylcarbonyl optionally substituted by substituent F, heterocyclylcarbonyl optionally substituted by substituent F, carbocyclylaminocarbonyl optionally substituted by substituent F, heterocyclylaminocarbonyl optionally substituted by substituent F, halogen, lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkyloxy carbonylamino, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, and lower alkylsulformylamino; Substituent F: halogen, hydroxyl, carboxy, amino, oxo, nitro, lower alkyl, halogen lower alkyl, lower alkyloxy, and amino protecting group) 
         with a compound shown by formula (V2): 
       
       
         
           
           
               
               
           
         
         (wherein, 
         R 4d  is lower alkyl optionally substituted by substituent E, carbocyclyl lower alkyl optionally substituted by substituent E, or heterocyclyl lower alkyl optionally substituted by substituent E, 
         R 5d  is hydrogen, halogen, lower alkyloxy optionally substituted by substituent E, or —O—SO 2 —R 5e , 
         R 5e  is lower alkyl optionally substituted by substituent E, carbocyclyl optionally substituted by substituent E, heterocyclyl optionally substituted by substituent E, carbocyclyl lower alkyl optionally substituted by substituent E, or 
         heterocyclyl lower alkyl substituted by substituent E, and 
         Substituent E is as defined above) 
         to obtain a compound shown by formula (X3) or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined above). 
       
     
     
         2 . A method of producing a compound shown by formula (Y1) or formula (Y2), or a salt thereof: 
       
         
           
           
               
               
           
         
         (wherein R x  is as defined in  claim 1 ) 
         comprising a step of: 
         (Step C) 
         reacting a compound shown by formula (X3), or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ). 
         with a compound shown by formula (V3), or a salt thereof:
   [Chemical formula 7] 
   H 2 N—R 6d   (V3)
 
 
         (wherein R 6d  is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E, and substituent E is as defined in  claim 1 ). 
         to obtain a compound shown by formula (X4), or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (wherein R 1d , R 2d , and R 4d  are as defined in  claim 1  and R 6d  is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E and substituent E is as defined in  claim 1 ). 
       
     
     
         3 . A method of producing of a compound shown by formula (Y1) or formula (Y2), or a salt thereof: 
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ) 
         comprising a step of: 
         (Step D) 
         reacting a compound shown by formula (X4), or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (wherein R 1d , R 2d , R 4d  are as defined in  claim 1  and R 6d  is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E and substituent E is as defined in  claim 1 ). 
         with (R)-3-amino-butan-1-ol, or (S)-2-amino-propan-1-ol to obtain a compound shown by formula (X5) or formula (X5′): 
       
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ). 
       
     
     
         4 . A method according to  claim 1  comprising a step of:
 (Step C) 
 reacting a compound shown by formula (X3), or a salt thereof: 
 
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ) 
         with a compound shown by formula (V3), or a salt thereof:
   [Chemical formula 13] 
   H 2 N—R 6d   (V3)
 
 
         (wherein R 6d  is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E and substituent E is as defined in  claim 1 ) 
         to obtain a compound shown by formula (X4), or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (wherein R 1d , R 2d , and R 4d  are as defined in  claim 1  and R 6d  is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E and substituent E is as defined in  claim 1 ). 
       
     
     
         5 . A method according to  claim 4  comprising a step of:
 (Step D) 
 reacting a compound shown by formula (X4), or a salt thereof: 
 
       
         
           
           
               
               
           
         
         (wherein R 1d , R 2d , and R 4d  are as defined in  claim 1  and R 6d  is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E and substituent E is as defined in  claim 1 ). 
         with (R)-3-amino-butan-1-ol, or (S)-2-amino-propan-1-ol to obtain a compound shown by formula (X5) or formula (X5′), or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ). 
       
     
     
         6 . A method according to  claim 3  comprising a step of:
 (Step E) 
 reacting a compound shown by formula (X5) or formula (X5′), or a salt thereof: 
 
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ) 
         with a compound shown by formula (V6), or a salt thereof:
   [Chemical formula 18] 
   R X —NH 2   (V6)
 
 
         (wherein R x  is as defined in  claim 1 ) 
         to obtain a compound shown by formula (X6) or formula (X6′), or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ). 
       
     
     
         7 . A method according to  claim 4 , wherein Step B and Step C are continuously performed. 
     
     
         8 . A method of producing of a compound shown by formula (Y1) or formula (Y2), or a salt thereof: 
       
         
           
           
               
               
           
         
         (wherein R x  is as defined in  claim 1 ) 
         comprising a step of: 
         (Step B′) 
         reacting a compound shown by formula (X2): 
       
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ) 
         with a compound shown by formula (V2): 
       
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ) 
         and a compound shown by formula (V2′):
   [Chemical formula 23] 
   NH 4 +X d−   (V2′)
 
 
         (wherein X d−  is a counter anion of ammonium cation) 
         to obtain a compound shown by formula (X4′), or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ). 
       
     
     
         9 . A method according to  claim 8  comprising a step of:
 (Step C′) 
 reacting a compound shown by formula (X4′): 
 
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ) 
         with a compound shown by formula (V3′):
   [Chemical formula 26] 
   R 6d -L d   (V3′)
 
 
         (wherein R 6d  is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E, and substituent E is as defined in  claim 1 , L d  is a leaving group) 
         to obtain a compound shown by formula (X4), or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (wherein R 1d , R 2d , and R 4d  are as defined in  claim 1  and R 6d  is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E and substituent E is as defined in  claim 1 ). 
       
     
     
         10 . A method according to  claim 9  comprising a step of:
 (Step D) 
 reacting a compound shown by formula (X4): 
 
       
         
           
           
               
               
           
         
         (wherein R 1d , R 2d , and R 4d  are as defined in  claim 1  and R 6d  is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E and substituent E is as defined in  claim 1 ). 
         with (R)-3-amino-butan-1-ol or (S)-2-amino-propan-1-ol to obtain a compound shown by formula (X5) or formula (X5′), or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ). 
       
     
     
         11 . A method according to  claim 10  comprising a step of:
 (Step E) 
 reacting a compound shown by formula (X5) or formula (X5′): 
 
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ) 
         with a compound shown by formula (V6), or a salt thereof:
   [Chemical formula 31] 
   R X —NH 2   (V6)
 
 
         (wherein R x  is as defined in  claim 1 ) 
         to obtain a compound shown by formula (X6) or formula (X6′), or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ). 
       
     
     
         12 . A method according to  claim 1 , wherein the compound shown by formula (X2) is obtained by reacting a compound shown by formula (X1): 
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ) 
         with a compound shown by formula (V1): 
       
       
         
           
           
               
               
           
         
         (wherein P d  is lower alkyl optionally substituted by substituent E, and R 3d  and substituent E are as defined in  claim 1 ). 
       
     
     
         13 . A method according to  claim 1 , wherein the compound shown by formula (X2) is obtained by reacting a compound shown by formula (Z1): 
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ) 
         with a compound shown by formula (Z2): 
       
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined in  claim 1 ). 
       
     
     
         14 . A method according to  claim 1 , wherein R x  is carbocyclyl lower alkyl optionally substituted by substituent E. 
     
     
         15 . A method according to  claim 1 , wherein R x  is 2,4-difluorobenzyl. 
     
     
         16 . A method of producing a compound shown by formula (Y1) or formula (Y2), or a salt thereof: 
       
         
           
           
               
               
           
         
         (wherein R x  is as defined in  claim 1 ) 
         comprising steps of: 
         (Step C″) 
         reacting a compound shown by formula (W1): 
       
       
         
           
           
               
               
           
         
         with a compound shown by formula (V3), or a salt thereof:
   [Chemical formula 39] 
   H 2 N—R 6d   (V3)
 
 
       
       (wherein R 6d  is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E and substituent E is as defined in  claim 1 )
 to obtain a compound shown by formula (W2), or a salt thereof: 
 
       
         
           
           
               
               
           
         
         (wherein R 6d  is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E and substituent E is as defined in  claim 1 ), and 
         (Step D″) 
         reacting a compound shown by formula (W2) with (R)-3-amino-burane-1-ol or (S)-2-amino-propan-1-ol to obtain a compound shown by formula (W3) or formula (W4), or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (Step F) 
         reacting a compound shown by formula (W3) or formula (W4) with a halogenating agent to obtain a compound shown by formula (W5) or formula (W6), or a salt thereof; 
       
       
         
           
           
               
               
           
         
         (wherein Hal is a halogen atom). 
       
     
     
         17 . A crystal of a compound shown by formula (U1) or a solvate thereof: 
       
         
           
           
               
               
           
         
         (wherein Me is methyl, and Bn is benzyl) 
         which has peaks in a powder X-ray diffraction spectrum at diffraction angle (2θ): 11.2°±0.2°, 17.2°±0.2°, 17.7°±0.2°, 20.5°±0.2°, 22.0°±0.2° and 26.1°±0.2°. 
       
     
     
         18 . A crystal of a compound shown by formula (U2) or a solvate thereof: 
       
         
           
           
               
               
           
         
         (wherein Me is methyl, and Bn is benzyl) 
         which has peaks in a powder X-ray diffraction spectrum at diffraction angle (2θ): 7.3°±0.2°, 14.4°±0.2°, 16.1°±0.2°, 18.4°±0.2°, 22.3°±0.2° and 23.1°±0.2°. 
       
     
     
         19 . A crystal of a compound shown by formula (U3) or a solvate thereof: 
       
         
           
           
               
               
           
         
         (wherein Me is methyl, and Bn is benzyl) 
         which has peaks in a powder X-ray diffraction spectrum at diffraction angle (2θ): 7.2°±0.2°, 16.1°±0.2°, 18.3°±0.2°, 20.6°±0.2°, 22.6°±0.2°, 23.1°±0.2° and 23.7°±0.2°.