Process for the manufacture of organic compounds

Abstract

A method for preparing an alkali metal salt comprising: (a) condensing a disilyloxydiene with an aldehyde in the presence of a titanium (IV) catalyst in an inert solvent to form a 5(S)-hydroxy-3-ketoester; (b) reducing the 5(S)-hydroxy-3-ketoester to a 3(R),5(S)-dihydroxyester in the presence of a di(lower alkyl)methoxyborane; and (c) hydrolyzing the 3(R),5(S)-dihydroxyester in the presence of an aqueous base to form an alkali metal salt.

1 . A method for preparing compounds having Formula (S 1 ), (S 2 ), or (S 3 ) as follows: 
     
       
         
         
             
             
         
       
     
     said method comprising condensing a disilyloxydiene having Formula (II) 
     
       
         
         
             
             
         
       
     
     with an aldehyde having Formula (Q 1 ), (Q 2 ), or (Q 3 ) as follows: 
     
       
         
         
             
             
         
       
     
     in the presence of a titanium (IV) catalyst of the Formula (IV) 
     
       
         
         
             
             
         
       
     
     in an inert solvent to obtain a 5(S)-hydroxy-3-ketoester having Formula (S 1 ), (S 2 ), or (S 3 ),
 wherein
 R 1  is, independently, an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; 
 R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are, independently, hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy; 
 R 8  is a lower alkyl; the binaphthyl moiety is in the S-configuration; 
 R and R′ are, independently, a lower alkyl; and 
 M is sodium, lithium or potassium. 
 
 
   
   
       2 . The method according to  claim 1 , wherein the molar ratio of a disilyloxydiene of Formula (II) to an aldehyde of Formula (Q 1 ), (Q 2 ), or (Q 3 ) initially present in the reaction mixture ranges from 1:1 to 6:1. 
   
   
       3 . The method according to  claim 1 , wherein the disilyloxydiene of Formula (II) is prepared by
 (a) reacting an acetoacetate of the Formula (VI)   
     
       
         
         
             
             
         
       
     
     with a silylating agent in the presence of a base and an organic solvent to form a silylenolether having Formula (VII) 
     
       
         
         
             
             
         
       
       (b) treating the silylenolether having Formula (VII) with a base and a silylating agent in an inert solvent to form the disilyloxydiene of Formula (II), 
       wherein
 R 1  is, independently, an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; and 
 R is a lower alkyl. 
 
     
   
   
       4 . The method according to  claim 3 , wherein the organic solvent in step (a) is hexane, and the inert solvent in step (b) is diethylether or tetrahydrofuran. 
   
   
       5 . The method according to  claim 3 , wherein the base in step (a) is triethylamine. 
   
   
       6 . The method according to  claim 3 , wherein the base in step (b) is selected from the group consisting of lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide. 
   
   
       7 . The method according to  claim 3 , wherein the silylating agent is trimethylsilyl chloride or triethylsilyl chloride. 
   
   
       8 . The method according to  claim 1  wherein the titanium (IV) catalyst of Formula (IV) is prepared in situ by reacting titanium (IV) tetraisopropoxide with (S)-2,2′-binaphthol of the Formula (VIII) 
     
       
         
         
             
             
         
       
     
   
   
       9 . The method according to  claim 8 , wherein the molar ratio of the titanium (IV) catalyst of Formula (IV) to an aldehyde of Formula (II) initially present in the reaction mixture ranges from 0.01:1 to 0.15:1. 
   
   
       10 . The method according to  claim 1 , wherein R 1  is lower alkyl, R 2  is halogen; and R 3 , R 4 , R 5 , R 6  and R 7  are hydrogen. 
   
   
       11 . The method according to  claim 10 , wherein R 1  is ethyl; and R 2  is fluorine. 
   
   
       12 . A method for preparing syn-3(R),5(S)-dihydroxyesters having Formula (V 1 ), (V 2 ), or (V 3 ) as follows: 
     
       
         
         
             
             
         
       
     
     said method comprising reducing compounds of Formula (S 1 ), (S 2 ), or (S 3 ) in the presence of a di(lower alkyl)methoxyborane, a reducing agent, and a polar solvent, wherein compounds of Formula (S 1 ), (S 2 ), or (S 3 ) as follows: 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is, independently, an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; and 
 R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are, independently, hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy. 
 
   
   
       13 . The method according to  claim 12 , wherein the di(lower alkyl)methoxyborane is diethylmethoxyborane or dibutyl-methoxyborane. 
   
   
       14 . The method according to  claim 12 , wherein the polar solvent is selected from the group consisting of tetrahydrofuran, methanol, ethanol, isopropanol, butanol, and mixtures thereof. 
   
   
       15 . The method according to  claim 12 , wherein the reducing agent is sodium borohydride or lithium borohydride. 
   
   
       16 . A method for preparing calcium salts having Formula (W 1 ), (W 2 ), or (W 3 ) as follows: 
     
       
         
         
             
             
         
       
     
     said method comprising:
 (a) condensing a disilyloxydiene of the Formula (II) 
 
     
       
         
         
             
             
         
       
     
     with an aldehyde having Formula (Q 1 ), (Q 2 ), or (Q 3 ) as follows: 
     
       
         
         
             
             
         
       
     
     in the presence of a titanium (IV) catalyst having Formula (IV) 
     
       
         
         
             
             
         
       
     
     in an inert solvent to form a 5(S)-hydroxy-3-ketoester having Formula (S 1 ), (S 2 ), or (S 3 ) as follows: 
     
       
         
         
             
             
         
       
       (b) reducing the 5(S)hydroxy-3-ketoester having Formula (S 1 ), (S 2 ), or (S 3 ) to a 3(R),5(S)-dihydroxyester in the presence of a di(lower alkyl)methoxyborane, wherein the 3(R),5(S)-dihydroxyester has Formula (V 1 ), (V 2 ), or (V 3 ) as follows: 
     
     
       
         
         
             
             
         
       
       (c) hydrolyzing the 3(R),5(S)-dihydroxyester having Formula (V 1 ), (V 2 ), or (V 3 ) in the presence of an aqueous base to form an alkali metal salt having Formula (X 1 ), (X 2 ), or (X 3 ) as follows: 
     
     
       
         
         
             
             
         
       
       (d) converting the alkali metal salt of Formula (X 1 ), (X 2 ), or (X 3 ) to a calcium salt of Formula (W 1 ), (W 2 ), or (W 3 ), in the presence of a calcium source, 
       wherein
 R 1  is, independently, an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; 
 R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are, independently, hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy; 
 R 8  is a lower alkyl; the binaphthyl moiety is in the S-configuration, 
 R and R′ are, independently, a lower alkyl; and M is sodium, lithium or potassium. 
 
     
   
   
       17 . The method according to  claim 16 , wherein the calcium source in step (d) is calcium chloride. 
   
   
       18 . A method for preparing calcium salts having Formula (We), (W 2 ), or (W 3 ) as follows: 
     
       
         
         
             
             
         
       
     
     said method comprising:
 (a) condensing a disilyloxydiene of the Formula (II) 
 
     
       
         
         
             
             
         
       
     
     with an aldehyde having Formula (Q 1 ), (Q 2 ), or (Q 3 ) as follows: 
     
       
         
         
             
             
         
       
     
     in the presence of a titanium (IV) catalyst having Formula (IV) 
     
       
         
         
             
             
         
       
     
     in an inert solvent to form a 5(S)-hydroxy-3-ketoester having Formula (S 1 ), (S 2 ), or (S 3 ) as follows: 
     
       
         
         
             
             
         
       
       (b) reducing the 5(S)-hydroxy-3-ketoester having Formula (S 1 ), (S 2 ), or (S 3 ) to form a 3(R),5(S)-dihydroxyester having Formula (V 1 ), (V 2 ), or (V 3 ) as follows: 
     
     
       
         
         
             
             
         
       
     
     in the presence of a di(lower alkyl)methoxyborane;
 (c) cyclizing the 3(R),5(S)-dihydroxyester having Formula (V 1 ), (V 2 ), or (V 3 ) to form a lactone having Formula (Y 1 ), (Y 2 ), or (Y 3 ) as follows: 
 
     
       
         
         
             
             
         
       
     
     and acid addition salts thereof, 
     in the presence of an acid and an aprotic water-miscible solvent;
 (d) hydrolyzing the lactone having Formula (Y 1 ), (Y 2 ), or (Y 3 ) or acid addition salts thereof, in the presence of an aqueous base to form an alkali metal salt having Formula (X 1 ), (X 2 ), or (X 3 ) as follows: 
 
     
       
         
         
             
             
         
       
     
     and
 (e) converting the alkali metal salt of Formula (X 1 ), (X 2 ), or (X 3 ) to a calcium salt of Formula (W 1 ), (W 2 ), or (W 3 ), in the presence of a calcium source, 
 wherein
 R 1  is, independently, an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; 
 R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are, independently, hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy; 
 R 8  is a lower alkyl; the binaphthyl moiety is in the S-configuration, 
 R and R′ are, independently, a lower alkyl; and 
 M is sodium, lithium or potassium. 
 
 
   
   
       19 . The method according to  claim 18 , wherein the acid in step (c) is concentrated hydrochloric acid, the aprotic water-miscible solvent is acetonitrile, and the acid addition salt thereof is the hydrochloric acid salt. 
   
   
       20 . A method for preparing an alkali metal salt having Formula (X 1 ), (X 2 ), or (X 3 ) as follows: 
     
       
         
         
             
             
         
       
     
     said method comprising:
 (a) condensing a disilyloxydiene of the Formula (II) 
 
     
       
         
         
             
             
         
       
     
     with an aldehyde having Formula (Q 1 ), (Q 2 ), or (Q 3 ) as follows: 
     
       
         
         
             
             
         
       
     
     in the presence of a titanium (IV) catalyst having Formula (IV) 
     
       
         
         
             
             
         
       
     
     in an inert solvent to form a 5(S)-hydroxy-3-ketoester having Formula (S 1 ), (S 2 ), or (S 3 ) as follows: 
     
       
         
         
             
             
         
       
       (b) reducing the 5(S)-hydroxy-3-ketoester having Formula (S 1 ), (S 2 ), or (S 3 ) to a 3(R),5(S)-dihydroxyester in the presence of a di(lower alkyl)methoxyborane, wherein the 3(R),5(S)-dihydroxyester has Formula (V 1 ), (V 2 ), or (V 3 ) as follows: 
     
     
       
         
         
             
             
         
       
       (c) hydrolyzing the 3(R),5(S)-dihydroxyester having Formula (V 1 ), (V 2 ), or (V 3 ) in the presence of an aqueous base to form an alkali metal salt having Formula (X 1 ), (X 2 ), or (X 3 ); 
       wherein
 R 1  is, independently, an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; 
 R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are, independently, hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy; 
 R 8  is a lower alkyl; the binaphthyl moiety is in the S-configuration, 
 R and R′ are, independently, a lower alkyl; and 
 M is sodium, lithium or potassium. 
 
     
   
   
       21 . The method according to  claim 20 , wherein the aqueous base in step (c) is sodium hydroxide and M represents sodium. 
   
   
       22 . The method according to  claim 20  which additionally comprises a molecular sieve in step (a). 
   
   
       23 . The method according to  claim 22 , wherein water is added to the molecular sieve prior to using the molecular sieve in step (a). 
   
   
       24 . The method according to  claim 23 , wherein the water content of the molecular sieve is from about 1 wt % to about 15 wt %, based on the total weight of the titanium (IV) catalyst. 
   
   
       25 . The method according to  claim 24 , wherein the water content of the molecular sieve is from about 2.6 wt % to about 10 wt %. 
   
   
       26 . The method according to  claim 22  wherein the molecular sieve is situated in a fixed bed external to a reaction vessel in which step (a) is conducted, and the reaction mixture in step (a) is passed through the fixed bed. 
   
   
       27 . The method according to  claim 26  wherein the molecular sieve is reused.