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

A process for preparing a conjugate of formula (I),

• wherein
• q is from 1 to 100;
• A, at each occurrence, is independently an active compound of formula (II),
• or a pharmaceutically acceptable salt thereof, wherein
• Ar1 is aryl or heteroaryl, wherein
• the aryl or heteroaryl is optionally substituted with one or more groups which are each independently —NO2, —CN, -halo, —(Z1)aMb((Z2)cRZ), or -DdEeF—, wherein,
• M is —C(O)—, —C(S)—, —S(O)—, or —S(O)2—, provided when M is —S(O) or —S(O)2, either a or c is zero;
• Z1 is —O—, —S—, or —N(RN)—, wherein
• RN is —H, —(C1-C6)alkyl, —(C1-C6)alkenyl, —(C1-C6)alkynyl, —(C1-C6)haloalkyl, —(C1-C6)alkanoyl, —(C3-C8)cycloalkyl, -heterocycle, -aryl, -heteroaryl, —(C3-C8)cycloalkanoyl, -heterocycloyl, -aroyl, -heteroaroyl, —(C1-C6)alkoxycarbonyl, or -aryl(C1-C6)alkoxycarbonyl, wherein
• the aryl or heteroaryl is optionally substituted with one or more groups which are independently -halo, —NO2, —CN, —(C1-C6)alkyl, —(C1-C6)haloalkyl, —(C1-C6)alkanoyl, or -aroyl;
• Z2 is —O—, —S—, or —N(RN)—;
• a, b and c are independently 0 or 1, provided when b is zero, a is zero, and when b is one, a is 0 or 1;
• RZ is —H, —(C1-C6)alkyl, —(C1-C6)alkenyl, —(C1-C6)alkynyl, —(C1-C6)haloalkyl, —(C3-C8)cycloalkyl, —(C1-C6)alkylaryl, -heterocycle, -aryl, or -heteroaryl;
• D is —CH2—, —OCH2—, —CH2O—, —C(O)—, —O(O)2—, —C(O)(NRN)—, —S(O)2—, —C(S)—, or —C(S)2—;
• E is —CH(Re)—, —CH(Re)CH2—, —(C3-C16)alkyl-, —(C1-C6)alkoxy-, —(C1-C6)alkenyl-, —(C1-C6)alkynyl, —(C1-C6)haloalkyl-, —(C3-C8)cycloalkyl-, -heterocycle-, -aryl-, or -heteroaryl-, wherein
• Re is —H or —N(R″)(RN);
• and
• R″ is —H or together with Rf form a heterocycloalkyl;
• F is a bond, —CH(Rf)—, or —CH2CH(Rf)—, provided that F is covalently bonded to B, wherein
• Rf is —H, —(C1-C6)alkyl, —(C1-C6)haloalkyl, -aryl, —(C1-C6)alkylaryl, —(C3-C8)cycloalkyl, -heterocycloalkyl, -heteroaryl, or together with R″ form a heterocycloalkyl, wherein
• each aryl or heteroaryl is optionally substituted with one or more groups which are each independently —NO2, —CN, -halo, or —(Z)aMb((Z)cRZ);
• d is 0 or 1;
• and
• e is 0 or 1, provided when E is —(C1-C8)alkoxy-, e is 1 to 250;
• J is:
• a) a group of formula (a),
• wherein
• RA is —(Z1)aMb((Z2)cRZ);
• and
• RB is —H, —NO2, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, -aryl, -heteroaryl, —(C1-C6)haloalkyl, or —(N(RA1))Mb((Z2)cRZ), provided that when b is zero, c is also zero, wherein
• each aryl or heteroaryl is optionally substituted with one or more groups which are each independently —CN, —NO2, -halo, or —(Z1)aMb((Z2)cRZ);
• or
• b) a group of formula (b),
• wherein
• Ar2 is Ar1;
• m is 0, 1, or 2;
• n is 0, 1, or 2;
• each R is independently —(Z1)aMb((Z2)cRZ) or -DdEeF—;
• and
• X is —N(RN)—, —O—, —S—, —S(O)—, —S(O)2—, or —C(R)2—;
• T is
• a) a group of formula (c),
• wherein
• Y is —O— or —N(RN)—;
• and
• W is -L1-L2-, wherein
• L1 is NR2R3, wherein
• R2 and R3 are independently —H or —(C1-C6)alkyl, or together with the nitrogen atom bound thereto, form a heterocycle containing 0 to 4 additional heteroatoms independently selected from —O—, —S—, and —N(RN);
• and
• L2 is absent, RN, or -DdEeF—;
• or
• b) a group of formula (d)
• wherein
• G is aryl or a monocyclic heteroaryl containing 1 to 3 nitrogens;
• and
• R6 is RN or -DdEeF—;
• and
• R55 is -M(Z2RZ);
• and
• B is a group of formula Ia, which is a polymer functionalized with nucleophilic active moieties,
• wherein
• P is a polymer;
• q′ is greater than or equal to q, as defined in formula (I);
• L4 is -DdEeF′f—, wherein
• F′ is F or —C(O)—;
• and
• f′ is 0 or 1;
• and
• Nu is —N(SO2R4)—, —[S(O)2]N(RN)—, -aryl-O—, -aryl-S—, —N(C(O)CF3)—, —(NC)C(H)C(O)—, —(NC)C(H)S(O)2—, —[R4S(O)2]C(H)[S(O)2]—, —[R4S(O)2]C(H)C(O)—, or —C(O)O—, wherein
• the aryl is optionally substituted with one or more groups that are each independently —NO2, —ON, —S(O)2R5, —C(O)OR5, or —C(O)R5, wherein
• R5 is each independently —H, —(C1-C6)alkyl, —(C1-C6)alkenyl, —(C1-C6)alkynyl, —(C1-C6)haloalkyl, —(C3-C8)cycloalkyl, -heterocycle, -aryl, -heteroaryl, wherein
• the aryl or heteroaryl is optionally substituted with —(Z1)aMb((Z2)cRZ);
• and
• R4 is —(C1-C6)alkyl, —(C1-C6)alkenyl, —(C1-C6)alkynyl, —(C1-C6)haloalkyl, —(C3-C8)cycloalkyl, -heterocycle, -heteroaryl, or -aryl, wherein
• the aryl or heteroaryl is optionally substituted with 1 to 4 groups which are independently —NO2, —ON, -halo, or —(Z1)aMb((Z2)cRZ);
• provided that when X is —O— or —N(RN)—, then m is two;
• and
• provided that when R is covalently bonded to B, n is one and X is not —O—, —S—, —S(O)—, or —S(O)2—;
• comprising the steps of:
• a) treating, in at least one solvent, at least one active compound of formula (Ib),
• wherein
• A is as defined in formula (I);
• and
• —OH is covalently bonded to F;
• with a trivalentphosphine, an azodicarbonyl compound, and an optional tertiary amine additive;
• and
• b) adding a polymeric nucleophile of formula (Ic),