Preparation of polymer conjugates of therapeutic, agricultural, and food additive compounds

A process for the preparing a conjugate of the formula I:

• B is a bio-compatible polymer moiety optionally covalently attached to a branched-arm hub molecule;
• q is from about 1 to about 100;
• A at each occurrence is independently a compound of formula II
• or a pharmaceutically acceptable salt thereof, wherein
• J is a group of formula:
• wherein
• m is an integer equal to 0, 1 or 2;
• n is an integer equal to 0, 1 or 2;
• R is selected from the group consisting of a covalent bond to the polymer moiety, amino, hydroxyl, substituted amino, alkyl, alkyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, thiol, arylthio, heteroarylthio, heterocyclylthio and substituted alkyl wherein each amino, substituted amino, alkyl and substituted alkyl is optionally covalently bound to the polymer moiety wherein, in each case, the polymer moiety optionally comprises a linker which covalently links the polymer moiety;
• Ar1 is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl wherein each of aryl, substituted aryl, heteroaryl and substituted heteroaryl is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar1;
• X is selected from the group consisting of —NR1—, —O—, —S—, —SO—, —SO2— and optionally substituted —CH2— where R1 is selected from the group consisting of hydrogen and alkyl;
• Ar2 is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl wherein each of aryl, substituted aryl, heteroaryl and substituted heteroaryl is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar2;
• T is a group of formula
• wherein G is an optionally substituted aryl or optionally substituted heteroaryl 5 or 6 membered ring containing 0 to 3 nitrogens, wherein said aryl or heteroary optionally further comprises a covalent bond to a polymer moiety which optionally comprises a linker;
• R6 is a covalent bond to a polymer moiety which optionally comprises a linker, or R6 is —H, alkyl, substituted alkyl, or —CH2C(O)R17, wherein R17 is —OH, —OR18, or —NHR18, wherein R18 is alkyl, substituted alkyl, aryl or substituted aryl;
• and
• R55 is selected from the group consisting of amino, substituted amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy and substituted aryloxy, and —OH;
• provided that:
• A. at least one of J, Ar2, and T contains a covalent bond to the polymer moiety;
• B. when R is covalently bound to the polymer moiety, n is one and X is not —O—, —S—, —SO—, or —SO2—;
• C. when X is —O— or —NR1—, then m is two;
• and
• D. the conjugate of formula I has a molecular weight of no more than 100,000;
• comprising the steps of:
• a) adding a polymeric alcohol of formula Ia
• wherein B and q are as described above, to a nucleophile of formula H-Nu in the presence of a trivalent phosphine and a dialkyl azodicarboxylate to form the compound of formula I, wherein Nu is a radical of formula A described above;
• and
• b) isolating the compound of formula I.