Alkoxylation methods

Abstract

Among other aspects, provided herein is a mixed-acid salt of a water-soluble polymer-drug conjugate, along with related methods of making and using the same. The mixed-salt acid salt is stably formed, and appears to be more resistant to hydrolytic degradation than the corresponding predominantly pure acid salt or free base forms of the polymer-drug conjugate. The mixed acid salt is reproducibly prepared and recovered, and provides surprising advantages over non-mixed acid salt forms of the water-soluble polymer drug conjugate.

1 - 50 . (canceled) 
     
     
         51 . A method comprising the step of alkoxylating in a suitable solvent a previously isolated alkoxylatable oligomer to form an alkoxylated polymeric material, wherein the previously isolated alkoxylatable oligomer has a known and defined weight-average molecular weight of greater than 300 Daltons. 
     
     
         52 . The method of  claim 51 , wherein the previously isolated alkoxylatable oligomer has a known and defined weight-average molecular weight of greater than 500 Daltons. 
     
     
         53 . The method of  claim 51 , wherein both the previously isolated alkoxylatable oligomer and the alkoxylated polymeric product are soluble in the suitable solvent. 
     
     
         54 . The method of  claim 51 , wherein the previously isolated alkoxylatable oligomer is prepared by (a) alkoxylating a precursor molecule having a molecular weight of less than 300 Daltons to form a reaction mixture comprising an alkoxylatable oligomer, and (b) isolating the alkoxylatable oligomer from the reaction mixture. 
     
     
         55 . The method of  claim 51  where the alkoxylation utilizes ethylene oxide as an alkoxylation agent. 
     
     
         56 . The method of  claim 54 , wherein the precursor molecule is selected from the group consisting of glycerol, diglycerol, triglycerol, hexaglycerol, mannitol, sorbitol, pentaerythritol, dipentaerthitol, and tripentaerythritol. 
     
     
         57 . The method of  claim 51 , wherein both the previously isolated alkoxylatable oligomer and the alkoxylated polymeric product each has from one to eight primary hydroxyl groups. 
     
     
         58 . The method of  claim 57 , wherein each of the one to eight primary hydroxyl groups is the result of an alkoxylation reaction. 
     
     
         59 . The method of  claim 57 , wherein the neither the previously isolated alkoxylatable oligomer and the alkoxylated polymeric product has a hydroxyl group of the precursor molecule. 
     
     
         60 . The method of  claim 51 , wherein both the previously isolated alkoxylatable oligomer and the alkoxylated polymeric product each has a branched structure. 
     
     
         61 . The method of  claim 60 , wherein the branched structure is a 4- to 8-arm branched structure. 
     
     
         62 . The method of  claim 61 , wherein the branched structure is a 4-arm branched structure. 
     
     
         63 . The method of  claim 61 , wherein the branched structure is a 5-arm branched structure. 
     
     
         64 . The method of  claim 61 , wherein the branched structure is a 6-arm branched structure. 
     
     
         65 . The method of  claim 61 , wherein the branched structure is an 8-arm branched structure. 
     
     
         66 . The method of  claim 51 , wherein the previously isolated alkoxylatable oligomer has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein the average value of n within the structure is from 2 to 50. 
     
     
         67 . The method of  claim 51 , wherein the alkoxylated polymeric material has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein the average value of all the instances of n within the structure is from 10 to 1000. 
     
     
         68 . The method of  claim 51 , wherein the previously isolated alkoxylatable oligomer has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein the average value of all instances of the value of n within the structure is from 2 to 35. 
     
     
         69 . The method of  claim 51 , wherein the alkoxylated polymeric material has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein the average value of all instances of the value of n within the structure is from 10 to 750. 
     
     
         70 . The method of  claim 51 , wherein the previously isolated alkoxylatable oligomer has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein the average value of all instances of the value of n within the structure is 2 to 35. 
     
     
         71 . The method of  claim 51 , wherein the alkoxylated polymeric material has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein the average value of all instances of the value of n within the structure is 10 to 600. 
     
     
         72 . The method  claim 67 , wherein the average value of all instances of the value of n within the structure is from 50 to 400. 
     
     
         73 . The method  claim 67 , wherein the average value of all instances of the value of n within the structure is from 50 to 300. 
     
     
         74 . The method of  claim 66 , wherein all values of n are within three standard deviations of each other. 
     
     
         75 . The method of  claim 66 , wherein all values of n are within two standard deviations of each other. 
     
     
         76 . The method  claim 66 , wherein all values of n are within one standard deviation of each other. 
     
     
         77 . The method of  claim 51 , wherein the suitable solvent include organic solvents selected from the group consisting of tetrahydrofuran (THF), dimethylformamide (DMF), toluene, benzene, xylenes, mesitylene, tetrachloroethylene, anisole, and mixtures of the foregoing. 
     
     
         78 . The method of  claim 51 , wherein the suitable solvent is selected from the group consisting of toluene, xylene, mesitylene, tetrahydrofuran (THF), and mixtures of foregoing. 
     
     
         79 . The method of  claim 51 , wherein the suitable solvent is toluene used in quantities that after ethoxylation the solvent consists more than 25 wt % and less than 75 wt % of the reaction mixture. 
     
     
         80 . The method of  claim 51 , wherein the step of alkoxylating is carried out under alkoxylating conditions, wherein the alkoxylation conditions include the presence of a strong base. 
     
     
         81 . The method of  claim 80 , wherein the strong base is selected from the group consisting of one or more alkali metals. 
     
     
         82 . The method of  claim 80 , wherein the strong base is selected from the group consisting of metallic potassium, metallic sodium, sodium-potassium alloys, and a hydroxide. 
     
     
         83 . The method of  claim 82 , wherein the hydroxide is NaOH, KOH and mixtures thereof. 
     
     
         84 . The method of  claim 82 , wherein the strong base is a sodium-potassium alloy. 
     
     
         85 . The method of  claim 80 , wherein the strong base is an alkoxide of a previously isolated alkoxylatable oligomer. 
     
     
         86 . The method of  claim 80 , wherein the strong base is present in a catalytic amount. 
     
     
         87 . The method of  claim 86 , wherein the catalytic amount is from 0.001 to 10.0 weight percent strong base based upon the weight of the total reaction mixture. 
     
     
         88 . The method of  claim 86 , wherein the catalytic amount is from 0.01 to about 6.0 weight percent strong base based upon the weight of the total reaction mixture. 
     
     
         89 . The method of  claim 51 , wherein the step of alkoxylating is carried out under alkoxylating conditions wherein the amount of water present is less than 20 ppm. 
     
     
         90 . The method of  claim 89 , wherein the step of alkoxylating is carried out under alkoxylating conditions wherein the amount of water present is less than 14 ppm. 
     
     
         91 . The method of  claim 90 , wherein the alkoxylating step is carried out under alkoxylating conditions wherein the amount of water present is less than 8 ppm. 
     
     
         92 . The method of claim  1 , wherein the alkoxylating step is carried out at a temperature between 80° C. and 140° C. 
     
     
         93 . A composition comprising the alkoxylated polymeric product prepared in accordance with the method  claim 51 . 
     
     
         94 . The composition of  claim 93 , wherein the purity of the alkoxylated polymeric product is greater than 92 wt % and the total content of high molecular weight impurities and diols is less than 8 wt %. 
     
     
         95 . The composition of  claim 94 , wherein the purity is greater than 98 wt % and the total content of high molecular weight impurities and diols is less than 2 wt %. 
     
     
         96 . The method of  claim 51 , further comprising the step of modifying the alkoxylated polymeric material to bear a reactive group to thereby form a water-soluble polymer reagent. 
     
     
         97 . The method of  claim 96 , wherein the water-soluble polymer reagent has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein each n is from about 40 to about 500. 
     
     
         98 - 100 . (canceled)