PROCESSES AND INTERMEDIATES FOR PREPARING alpha,omega-DICARBOXYLIC ACID-TERMINATED DIALKANE ETHERS

Abstract

The present disclosure provides a process for the preparation of compounds of formula (III), compounds of formula (V), and corresponding salts of formula (IV). The compounds made by the methods and processes of the invention are particularly useful for administration in humans and animals.

What is claimed is: 
     
         1 . A process for preparing a compound of formula (III): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is alkyl; 
 R 2  and R 3  are each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; and 
 n and m are each independently 0-4; 
 
         comprising:
 (a) reacting a solution comprising a substituted acetic acid ester of formula (I): 
 
       
       
         
           
           
               
               
           
         
         
           with a deprotonating reagent to produce an intermediate of formula (Ia): 
         
       
       
         
           
           
               
               
           
         
         
           wherein M 2  is Li or Zn; and 
           (b) reacting the intermediate of formula (Ia) with a solution comprising a α,ω-halo-terminated dialkane ether of formula (II): 
         
       
       
         
           
           
               
               
           
         
         
           wherein X is halo; 
           to produce a compound of formula (III). 
         
       
     
     
         2 . The process of  claim 1 , further comprising the step of performing an aqueous work-up of the solution of step (b) to isolate an organic solution of the compound of formula (III). 
     
     
         3 . The process of  claim 1 , further comprising the step of treating the crude compound of formula (III) with an aqueous solution of a hydroxide or oxide of an alkali or earth alkaline metal. 
     
     
         4 . The process of  claim 1 , further comprising the step of precipitating the salt of the α,ω-dicarboxylic acid-terminated dialkane ether of formula (IV): 
       
         
           
           
               
               
           
         
         in the presence of an organic solvent, wherein M 1  is Ca or K and x is 1 or 2. 
       
     
     
         5 . The process of  claim 1 , further comprising the step of removing the organic layer by evaporation to afford crude crystalline α,ω-dicarboxylic acid-terminated dialkane ether salt of formula (IV) in the form of an alcohol solvate or hydrate, wherein the alcohol solvate or hydrate is stirred with tetrahydrofuran with subsequent addition of one or more anti-solvents to obtain the crystalline form of the α,ω-dicarboxylic acid-terminated dialkane ether salt of formula (IV). 
     
     
         6 . The process of  claim 1 , further comprising the step of adding one or more anti-solvents so that the salt of the α,ω-dicarboxylic acid-terminated dialkane ether of formula (IV) is insoluble. 
     
     
         7 . The process of  claim 1 , further comprising the step of humidifying the precipitate to obtain a crystalline salt of a α,ω-dicarboxylic acid-terminated dialkane ether of formula (IV). 
     
     
         8 . The process of  claim 1 , further comprising the step of hydrolyzing the compound of formula (III) to produce a compound of formula (V). 
       
         
           
           
               
               
           
         
       
     
     
         9 . The process of  claim 1 , comprising treating a solution of a compound of formula (III) in a water-miscible solvent with an aqueous solution of a base, wherein the water-miscible solvent is selected from DMSO, DMF, methanol, isopropyl alcohol, and ethanol; or treating a solution of a compound of formula (III) in a water-immiscible solvent with an aqueous solution of a base, wherein the water-immiscible solvent is selected from toluene, xylene, methyl ethyl ketone, and methyl isobutyl ketone. 
     
     
         10 . The process of  claim 1 , wherein the compound of formula (III) is 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid). 
       
         
           
           
               
               
           
         
       
     
     
         11 . A process for preparing 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid): 
       
         
           
           
               
               
           
         
         comprising:
 (a) reacting a solution comprising a substituted acetic acid ester: 
 
       
       
         
           
           
               
               
           
         
         
           with a deprotonating reagent to produce an intermediate: 
         
       
       
         
           
           
               
               
           
         
         
           wherein M 2  is Li or Zn; 
           (b) reacting the intermediate of step (a) with a solution comprising a α,ω-halo-terminated dialkane ether: 
         
       
       
         
           
           
               
               
           
         
         
           wherein X is halo; and 
           (c) hydrolyzing the crude diethyl 6,6′-oxybis(2,2-dimethyl-4-hexanoate) 
         
         to produce 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid). 
       
     
     
         12 . A process for preparing crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium: 
       
         
           
           
               
               
           
         
         wherein the process comprises:
 (a) reacting a solution of ethyl isobutyrate: 
 
       
       
         
           
           
               
               
           
         
         
           with a deprotonating reagent to produce a compound: 
         
       
       
         
           
           
               
               
           
         
         
           wherein M 2  is Li or Zn; 
           (b) reacting the ethyl lithiobutyrate of step (a) with a solution of bis(4-chlorobutylether): 
         
       
       
         
           
           
               
               
           
         
         
           (c) performing an aqueous work-up of the solution of step (b) in order to isolate an organic solution of crude diethyl 6,6′-oxybis(2,2-dimethyl-4-hexanoate): 
         
       
       
         
           
           
               
               
           
         
         
           (d) treating the crude diethyl 6,6′-oxybis(2,2-dimethyl-4-hexanoate) of step (c) with a calcium hydroxide or calcium oxide of an alkali or earth alkaline metal in a suitable solvent to produce 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium; 
           (e) precipitating the 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of step (d): 
         
       
       
         
           
           
               
               
           
         
         
            in the presence of an organic solvent; or, alternatively, removing the organic layer by evaporation to afford crude crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) salt as an alcohol solvate or hydrate; 
           (f) adding one or more anti-solvents to the solid of step (e) in which 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium is insoluble; and 
           (g) humidifying the precipitate resultant from step (f) to obtain crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium. 
         
       
     
     
         13 . A process for preparing a compound of formula (48): 
       
         
           
           
               
               
           
         
         wherein:
 R 21  is alkyl; 
 R 22  and R 23  are each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; and 
 m is 0-4; 
 
         comprising:
 (a) reacting a first solution of a compound of formula (46): 
 
       
       
         
           
           
               
               
           
         
         
            with a halogen source to produce a compound of formula (47): 
         
       
       
         
           
           
               
               
           
         
         
            wherein X 24  is F, Cl, or I; and 
           (b) reacting a second solution of a compound of formula (46) with the intermediate of formula (47) in the presence of base to form a compound of formula (48). 
         
       
     
     
         14 . The process of  claim 13 , further comprising the step of reacting the solution of a compound of formula (45): 
       
         
           
           
               
               
           
         
         with potassium tert-butoxide to produce an intermediate of formula (46). 
       
     
     
         15 . The process of  claim 13 , further comprising the step of reacting an intermediate of formula (43a): 
       
         
           
           
               
               
           
         
         wherein M 23  is Li or Zn; 
         with a solution of an alkylhalide of formula (44):
   R 23 —X 23   44
 
 wherein X 23  is halo 
 to produce a compound of formula (45). 
 
       
     
     
         16 . The process of  claim 13 , further comprising the step of reacting the solution of a compound of formula (43): 
       
         
           
           
               
               
           
         
         with a deprotonating reagent to produce an intermediate of formula (43a). 
       
     
     
         17 . The process of  claim 13 , further comprising the step of reacting the intermediate of formula (41a): 
       
         
           
           
               
               
           
         
         wherein M 22  is Li or Zn; 
         with a solution of an alkylhalide of formula (42):
   R 22 —X 22   42
 
 
         wherein X 22  is halo 
         to produce a compound of formula (43). 
       
     
     
         18 . The process of  claim 13 , further comprising the step of reacting a solution of a cyclic lactone of formula (41): 
       
         
           
           
               
               
           
         
         with a deprotonating reagent to produce an intermediate of formula (41a). 
       
     
     
         19 . The process of  claim 13 , further comprising the step of hydrolyzing the compound of formula (48) to produce a compound of formula (49). 
       
         
           
           
               
               
           
         
       
     
     
         20 . The process of  claim 13 , wherein the compound of formula (48) is the di-tert-butyl ester of 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid). 
       
         
           
           
               
               
           
         
       
     
     
         21 . A process for preparing a compound of formula (48): 
       
         
           
           
               
               
           
         
         wherein:
 R 21  is alkyl; 
 R 22  and R 23  are each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; and 
 m is 0-4; 
 
         comprising:
 (a) reacting a solution of a cyclic lactone of formula (41): 
 
       
       
         
           
           
               
               
           
         
         
           with a deprotonating reagent to produce an intermediate of formula (41a): 
         
       
       
         
           
           
               
               
           
         
         
           wherein M 22  is Li or Zn; 
           (b) reacting the intermediate of formula (41a) with a solution of an alkylhalide of formula (42):
   R 22 —X 22   42
 
 
           wherein X 22  is halo; 
           to produce a compound of formula (43): 
         
       
       
         
           
           
               
               
           
         
         
           (c) reacting the solution of a compound of formula (43) with a deprotonating reagent to produce an intermediate of formula (43a): 
         
       
       
         
           
           
               
               
           
         
         
           wherein M 23  is Li or Zn; 
           (d) reacting the intermediate of formula (43a) with a solution of an alkylhalide of formula (44):
   R 23 —X 23   44
 
 
           wherein X 23  is halo; 
           to produce a compound of formula (45): 
         
       
       
         
           
           
               
               
           
         
         
           (e) reacting the solution of a compound of formula (45) with potassium tert-butoxide to produce an intermediate of formula (46): 
         
       
       
         
           
           
               
               
           
         
         
           (f) reacting the solution of a compound of formula (46) with a halogen source to produce an intermediate of formula (47): 
         
       
       
         
           
           
               
               
           
         
         
           wherein X 24  is F, Cl, or I; 
           (g) reacting the solution of a compound of formula (46) with the intermediate of formula (47) in the presence of base to form a compound of formula (48): 
         
       
       
         
           
           
               
               
           
         
         
           (h) reacting the solution of a compound of formula (48) with dilute acid to form a compound of formula (49). 
         
       
       
         
           
           
               
               
           
         
       
     
     
         22 . The process of  claim 21 , wherein the compound of formula (48) is: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The process of  claim 21 , further comprising any of the following steps:
 (i) treating the compound of formula (49) of step (h) with a calcium hydroxide or calcium oxide of an alkali or earth alkaline metal in a suitable solvent;   (j) precipitating the compound of formula (50):   
       
         
           
           
               
               
           
         
         wherein M 1  is Ca or K and x is 1 or 2; 
         in the presence of an organic solvent; or, alternatively, removing the organic layer by evaporation to afford a crude crystalline salt of formula (50) as an alcohol solvate or hydrate; 
         (k) adding one or more anti-solvents to the solid of step (j) in which the compound of formula (50) is insoluble; and 
         (l) humidifying the precipitate resultant from step (k) to obtain crystalline compound of formula (50). 
       
     
     
         24 . A process for preparing a compound of formula (45): 
       
         
           
           
               
               
           
         
         wherein:
 R 22  and R 23  are each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; and 
 m is 0-4; 
 
         comprising:
 (a) reacting a solution of a cyclic lactone of formula (41): 
 
       
       
         
           
           
               
               
           
         
         
           with a deprotonating reagent to produce an intermediate of formula (41a): 
         
       
       
         
           
           
               
               
           
         
         
           wherein M 22  is Li or Zn; 
           (b) reacting the intermediate of formula (41a) with a solution of an alkylhalide of formula (42):
   R 22 —X 22   42
 
 
           wherein X 22  is halo; 
           to produce a compound of formula (43): 
         
       
       
         
           
           
               
               
           
         
         
           (c) reacting the solution of a compound of formula (43) with a deprotonating reagent to produce an intermediate of formula (43a): 
         
       
       
         
           
           
               
               
           
         
         
           wherein M 23  is Li or Zn; 
           (d) reacting the intermediate of formula (43a) with a solution of an alkylhalide of formula (44):
   R 23 —X 23   44
 
 
           wherein X 23  is halo; 
           to produce a compound of formula (45).