One pot synthesis of tetrazole derivatives of sirolimus

A method of preparing a molecule of formula V:

• comprising:
• (a) reacting a molecule of formula VI:
• with triflic anhydride to produce a molecule of formula VII:
• and
• (b) reacting the molecule of formula VII with a molecule of formula IV:
• wherein
• R9 and R10 are independently selected from the group consisting of H, alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, and combinations thereof.

A method of preparing a molecule of formula III:

• comprising:
• reacting a molecule of formula II:
• with triflic anhydride,
• wherein R1 is selected from the group consisting of ═O (H, H), and (H, OH);
• R2 and R5 are independently selected from the group consisting of H, —C(═O)R6, —C(═O)OR6, —C(═O)NHR6, and —C(═S)OR6;
• R3 is selected from the group consisting of ═O and OR5;
• or R2 and R3 can be taken together to form moiety of formula A-C(R7)(R8)—O-α, where A is a bond to oxygen bonded to carbon 28 and B is a bonded to carbon 28 as defined above;
• R4 is selected from the group consisting of H and C1-C4 alkyl;
• R6 is selected from the group consisting of C1-C10 alkyl, C3-C6 cycloalkyl, aryl groups, and heterocyclic groups;
• R7 and R8 are independently selected from the group consisting of H, C1-C6 alkyl, or R7 and R8 taken together are ═O

A method of preparing a molecule of formula I:

• comprising:
• reacting a molecule of formula III:
• with a molecule of formula IV:
• wherein R1 is selected from the group consisting of ═O (H, H), and (H, OH);
• R2 and R5 are independently selected from the group consisting of H, —C(═O)R6, —C(═O)OR6, —C(═O)NHR6, and —C(═S)OR6;
• R3 is selected from the group consisting of ═O and OR5;
• or R2 and R3 can be taken together to form moiety of formula A-C(R7)(R8)—O-α, where A is a bond to oxygen bonded to carbon 28 and B is a bonded to carbon 28 as defined above;
• R4 is selected from the group consisting of H and C1-C4 alkyl;
• R6 is selected from the group consisting of C1-C10 alkyl, C3-C6 cycloalkyl, aryl groups, and heterocyclic groups;
• R7 and R8 are independently selected from the group consisting of H, C1-C6 alkyl, or R7 and R8 taken together are ═O;
• R9 and R10 are independently selected from the group consisting of H, alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, and combinations thereof.

A method of preparing a molecule of formula V:

• comprising:
• reacting a molecule of formula VI:
• with a molecule of formula IV:
• wherein R9 and R10 are independently selected from the group consisting of H, alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, and combinations thereof.

A composition comprising a molecule of formula I:

• and an anti-oxidant,
• wherein
• R1 is selected from the group consisting of ═O (H, H), and (H, OH);
• R2 and R5 are independently selected from the group consisting of H, —C(═O)R6, —C(═O)OR6, —C(═O)NHR6, and —C(═S)OR6;
• R3 is selected from the group consisting of ═O and OR5;
• or R2 and R3 can be taken together to form moiety of formula A-C(R7)(R8)—O-α, where A is a bond to oxygen bonded to carbon 28 and B is a bonded to carbon 28 as defined above;
• R4 is selected from the group consisting of H and C1-C4 alkyl;
• R6 is selected from the group consisting of C1-C10 alkyl, C3-C6 cycloalkyl, aryl groups, and heterocyclic groups;
• R7 and R8 are independently selected from the group consisting of H, C1-C6 alkyl, or R7 and R8 taken together are ═O