Methods of making carfilzomib and intermediates thereof
Racemization-free methods are disclosed for the synthesis of carfilzomib. Novel intermediates and methods of making carfilzomib employing fragment condensation using the novel intermediates are disclosed. Amorphous carfilzomib and methods of making same are disclosed.
1. A compound of the formula IA
and active esters or salts thereof
wherein R1 is Cl or
and R2 is
or OY and Y is 1-hydroxybenzotriazole, azabenzotriazole, succinimidyl, pentafluorophenyl, trichlorophenyl, nitrophenyl, pentachlorophenyl, 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt) or fluorenylmethyl.
2. A compound according to claim 1 of the formula II
3. A compound according to claim 1 of the formula III
4. A compound according to claim 1 of the formula IV
5. A compound according to claim 1 obtained from a corresponding hydroxy compound and/or substituted phenol.
6. A method of making an active ester compound according to claim 1 comprising obtaining a free acid of a compound of formula IA and activating a resulting intermediate using a hydroxy and/or phenolic compound.
7. The method according to claim 6 wherein the step of obtaining a free acid is selected from one or more of bis-silylation, using at least one silylating agent and an organic base, and/or hydrolysis of esters by using at least one alkali metal hydroxide selected from NaOH, KOH, LiOH and their corresponding carbonates.
8. The method according to claim 6 comprising isolating a compound of formula IA using an organic solvent.
9. A method of making carfilzomib comprising employing a compound according to claim 1 using a 3+2 fragment condensation.
10. A method of making carfilzomib comprising employing a compound according to claim 2 using a 3+2 fragment condensation.
11. A method of making carfilzomib comprising employing a compound according to claim 3 using a 3+2 fragment condensation.
12. A method of making carfilzomib comprising employing a compound according to claim 4 using a 3+2 fragment condensation.
13. A method of making amorphous form carfilzomib comprising reacting a compound having the formula I
or an ester or salt thereof, wherein Y is 1-hydroxybenzotriazole, azabenzotriazole, succinimidyl, pentafluorophenyl, trichlorophenyl, nitrophenyl, pentachlorophenyl, 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt) or fluorenylmethyl, with a compound of formula XIII
wherein R is H, methyl, ethyl, benzyl, or isopropyl and X is HCl, TFA, HCOOH, TsOH or MsOH to obtain a compound of formula IV
and
reacting a compound of formula IV with a compound of formula 8
14. A method of making amorphous form carfilzomib comprising the synthetic route:
wherein Y is 1-hydroxybenzotriazole, azabenzotriazole, succinimidyl, pentafluorophenyl, trichlorophenyl, nitrophenyl, pentachlorophenyl, 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt), or fluorenylmethyl and X is HCl, TFA, HCOOH, TsOH, MsOH or isopropyl (IPr).
15. The method according to claim 14 comprising isolating amorphous carfilzomib using organic solvent extraction.