Process of making cenicriviroc and related analogs

Abstract

The disclosure includes high purity compounds having CCR5 and/or CCR2 antagonism, or a salt thereof, and processes for synthesizing the same.

1 .- 68 . (canceled) 
     
     
         69 . A process for preparing 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-prop yl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH) comprising the steps of:
 a) reacting a compound according to Formula II:   
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of H, OH, Cl, Br, OR 2 , OCOR 2 , and NHR 2 ; 
         wherein R 2  is selected from the group consisting of H, alkyl, substituted alkyl, aryl, and substituted aryl; 
         with 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III) in the presence of a base to form 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide (Compound I); 
         b) quenching step a) with an aqueous solution; 
         c) adding methanesulfonic acid to the aqueous solution to form 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH); and, 
         d) crystallizing Compound I-MsOH; 
         wherein Compounds III, I, I-MsOH are represented by the following structures: 
       
       
         
           
           
               
               
           
         
       
     
     
         70 . The process of  claim 69 , wherein R 1  is Cl in Formula II, and wherein step a) further comprises the steps of:
 i) dissolving 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid (Compound II-OH) in a solvent; and   ii) adding a chlorinating reagent to a mixture of step i), wherein the chlorinating reagent is selected from the group consisting of thionyl chloride, phosphorous trichloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, phosgene, and a combination thereof;   wherein the chlorinating reagent is in an amount of about 1.0 to about 1.2 equivalent of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid (Compound II-OH).   
     
     
         71 . The process of  claim 69 , wherein step a) uses a solvent comprising dichloromethane and wherein the base in step a) comprises pyridine. 
     
     
         72 . The process of  claim 69 , wherein 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III) of step a) is optically pure (S)-Compound III. 
     
     
         73 . The process of  claim 70 , wherein 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III) is in the amount of about 1.0 to about 1.2 equivalent of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid (Compound II-OH). 
     
     
         74 . The process of  claim 71 , wherein the methansulfonic acid in step c) of  claim 69  is in the amount of about 0.97 to about 1.02 equivalent of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid (Compound II-OH). 
     
     
         75 . The process of  claim 70 , wherein step d) further comprises seeding with 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH);
 stirring the mixture at about 0° C. to obtain crystals; and washing collected crystals with chilled ethyl acetate, wherein after step d) the method further comprises the steps of:
 i) dissolving crystals of Compound I-MsOH obtained from step d) in acetonitrile at about 70° C. to form a mixture; 
 ii) reducing the temperature of the mixture of step i) to about 50° C. to about 55° C. for about 1 hour; 
 iii) seeding the mixture of step ii) with Compound I-MsOH; 
 iv) stirring at about 50° C. to about 55° C. for about 6 hours; 
 v) reducing the temperature of the mixture of step iii) to about 20° C.; 
 vi) stirring at about 20° C. for about 8 hours to form crystals of Compound I-MsOH; 
 vii) collecting the crystals by filtration; and then, 
 viii) washing the crystals with cold acetonitrile. 
   
     
     
         76 . A compound of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(2-(1-propyl-1H-imidazol-5-yl)acetyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH) or an enantiomer, a stereoisomer, or a combinations thereof, with a purity of 96.0% or higher. 
     
     
         77 . The compound of  claim 76 , wherein said compound comprises one or more of the following:
 (a) 1.0% or less of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid (Compound II-OH);   (b) 0.20% or less of 8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid) (Compound VIII);   (c) 0.20% or less of 8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid (Compound IX);   (d) 2000 ppm or less of 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III) ;   (e) 0.25% or less of 8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH-A);   (f) 0.25% or less of 1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH-B);   (g) 0.40% or less of 8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH-C);   (h) 2.0% or less of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH-D);   (i) 0.40% or less of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH-E);   (j) 0.30% or less of 8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH-F); and,   (k) 0.25% or less of 8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide) dimethanesulfonate (Compound I-MsOH-G).   
     
     
         78 . The compound of  claim 76 , wherein mesylate ester resulting from MsOH is present in 0.001% or less, or 10 ppm or less. 
     
     
         79 . The compound of  claim 76 , said compound comprises one or more of the following compounds:
 (i) 1300 ppm or less of 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III);   (ii) 0.10% or less of 8-(4-(2-ethoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH-A);   (iii) 0.10% or less of 1-isobutyl-8-(4-(2-propoxyethoxy)phenyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH-B);   (iv) 0.20% or less of 8-(4-butoxyphenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH-C);   (v) 0.8% or less of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfonyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH-D);   (vi) 0.20% or less of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)thio)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH-E);   (vii) 0.15% or less of 8-(4-(2-butoxyethoxy)phenyl)-1-butyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate (Compound I-MsOH-F); and,   (viii) 0.10% or less of 8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide) dimethanesulfonate (Compound I-MsOH-G).   
     
     
         80 . The compound of  claim 76 , wherein Compound I-MsOH is (S)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate ((S)-Compound I-MsOH),
 and (R)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide methanesulfonate ((R)-Compound I-MsOH) is present in 0.5% or less;   and wherein the compound comprises 5.0% w/w or less water content.