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 having the formula I
and active esters or salts thereof, wherein Y is selected from the group consisting of 1-hydroxybenzotriazole (OBt), azabenzotriazole (OAt), O-succinimidyl (OSu), pentafluorophenyl (OPfp), trichlorophenyl (OTcp), nitrophenyl (ONp), pentachlorophenyl (Opcp), 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt), and fluoroenylmethyl (OFm).
2 . A compound according to claim 1 comprising an active ester.
3 . A compound according to claim 2 obtained from a corresponding hydroxy compound and/or substituted phenol.
4 . A method of making an active ester compound according to claim 1 comprising obtaining a free acid of a compound of formula I and activating a resulting intermediate using a hydroxy and/or phenolic compound.
5 . The method according to claim 4 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.
6 . The method according to claim 4 comprising isolating a compound of formula I using an organic solvent.
7 . A compound of the formula IA
and active esters or salts thereof
wherein R1 is Cl or morpholine and R2 is
or OY and Y is selected from the group consisting of 1-hydroxybenzotriazole (OBt), azabenzotriazole (OAt), O-succinimidyl (OSu), pentafluorophenyl (OPfp), trichlorophenyl (OTcp), nitrophenyl (ONp), pentachlorophenyl (Opcp), 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt), and fluoroenylmethyl (OFm).
8 . A compound according to claim 7 of the formula II
9 . A compound according to claim 7 of the formula III
10 . A compound according to claim 7 of the formula IV
11 . A compound according to claim 7 obtained from a corresponding hydroxy compound and/or substituted phenol.
12 . A method of making an active ester compound according to claim 7 comprising obtaining a free acid of a compound of formula IA and activating a resulting intermediate using a hydroxy and/or phenolic compound.
13 . The method according to claim 12 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.
14 . The method according to claim 12 comprising isolating a compound of formula IA using an organic solvent.
15 . A method of making carfilzomib comprising employing a compound according to claim 1 using a 2+2+1 fragment condensation.
16 . A method of making carfilzomib comprising employing a compound according to claim 7 using a 3+2 fragment condensation.
17 . A method of making carfilzomib comprising employing a compound according to claim 8 or derivatives thereof using a 3+2 fragment condensation.
18 . A method of making carfilzomib comprising employing a compound according to claim 9 or derivatives thereof using a 3+2 fragment condensation.
19 . A method of making carfilzomib comprising employing a compound according to claim 10 or derivatives thereof using a 3+2 fragment condensation.
20 . A method of making amorphous form carfilzomib comprising reacting a compound according to claim 1 with a compound of formula XIII
wherein R is H, methyl, ethyl, benzyl, or isopropyl to obtain a compound of formula IV
and
reacting a compound of formula IV with a compound of formula 8
21 . A method of making amorphous form carfilzomib comprising the synthetic route:
wherein Y is selected from the group consisting of 1-hydroxybenzotriazole (OBt), azabenzotriazole (OAt), O-succinimidyl (OSu), pentafluorophenyl (OPfp), trichlorophenyl (OTcp), nitrophenyl (ONp), pentachlorophenyl (Opcp), 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt), and fluoroenylmethyl (OFm) and X is selected from the group consisting of HCl, TFA, HCOOH, TsOH, and MsOH.
22 . The method according to claim 21 comprising isolating amorphous carfilzomib using organic solvent extraction.
23 . Amorphous form of carfilzomib.
24 . Carfilzomib according to claim 23 having an X-ray diffraction (XRD) according to FIG. 1 .