Purified cenicriviroc and purified intermediates for making cenicriviroc

Abstract

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

1 - 30 . (canceled) 
     
     
         31 . A composition 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 combination thereof, with a purity of ≥96.0% or ≥98.5% or higher, wherein said compound comprises one or more of the following:
 (a) about ≤0.50% to about ≥0.30% of 8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid) (Compound VIII); 
 (b) about ≤0.50% to about ≥0.30% of 8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid (Compound IX); 
 (c) about 0.50% to about ≥0.30% 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); 
 (d) about ≤0.50% to about ≥0.30% 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); 
 (e) about ≤0.50% to about ≥0.45% 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); 
 (f) about ≤0.50% to about ≥0.45% 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); 
 (g) about ≤0.50% to about ≥0.45% 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 
 (h) about ≤0.50% to about ≥0.45% 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). 
 
     
     
         32 . The composition of  claim 31 , further comprising ≤1.0% of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid (Compound II-OH). 
     
     
         33 . The composition of  claim 32 , wherein ≤0.50% of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid (Compound II-OH) is present. 
     
     
         34 . The composition of  claim 31 , further comprising 2000 ppm or less of 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III). 
     
     
         35 . The composition of  claim 34 , wherein 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III) is present in 1500 ppm or less. 
     
     
         36 . The composition of  claim 31 , further comprising ≤2.0% 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). 
     
     
         37 . The composition of  claim 36 , wherein ≤1.0% 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) is present. 
     
     
         38 . The composition of  claim 31 , wherein ≤0.10% of 8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid) (Compound VIII) is present, provided there is present one or more of compounds (b)-(h). 
     
     
         39 . The composition of  claim 31 , wherein ≤0.10% of 8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid (Compound IX) is present, provided there is present one or more of compounds (a) and (c)-(h). 
     
     
         40 - 45 . (canceled) 
     
     
         46 . The composition of  claim 31 , said compound comprises one or more of the following:
 (i) ≤0.30% of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid (Compound II-OH);   (ii) ≤0.05% of 8,8′-(4-(2-butoxyethoxy)-1,3-phenylene)bis(1-isobutyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid) (Compound VIII); and   (iii) ≤0.05% of 8-(4-(2-butoxyethoxy)phenyl)-1-butyl-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxylic acid (Compound IX), provided there is present one or more of compounds (c)-(h)   
     
     
         47 . The composition of  claim 31 , said compound comprises one or more of the following:
 (i) 1300 ppm or less wherein 4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)aniline (Compound III);   (ii) ≤0.10% 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% 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% 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) ≤0.80% 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% 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% 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% 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), provided there is present one or more of compounds (a)-(b).   
     
     
         48 . The composition of  claim 31 , wherein mesylate ester resulting from MsOH is present in 0.001% or less, or 10 ppm or less. 
     
     
         49 . The composition of  claim 31 , wherein said compound 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). 
     
     
         50 . The composition of  claim 49 , wherein ≤0.5% of (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. 
     
     
         51 . The composition of  claim 50 , wherein ≤0.2% of (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. 
     
     
         52 . The composition of  claim 51 , comprising 5.0% w/w or less or 2.0% w/w or less water content. 
     
     
         53 - 59 . (canceled)