A PROCESS FOR PURIFICATION OF CARFILZOMIB

Abstract

The present invention relates to a process for the purification of Carfiizomib of Formula I that reduces the level of an acetamide impurity of Formula II preferably below 0.10 wt %. Formula I Formula II.

##STR00001##

Claims

1. A process for purification of Carfilzomib of Formula I, ##STR00011## comprising the steps of: (i) dissolving crude Carfilzomib in a first solvent and adding oxalic acid, to form Carfilzomib oxalate; (ii) precipitating said Carfilzomib oxalate; (iii) reacting said Carfilzomib oxalate with a base in a second solvent, to obtain the Carfilzomib.

2. The process according to claim 1, wherein the Carfilzomib obtained in step (iii) having an acetamide impurity of Formula II, ##STR00012## in an amount less than 0.10 wt % of the total wt of Carfilzomib obtained in step (iii).

3. The process according to claim 1, wherein the first solvent used in step (i) is an aprotic solvent or a mixture of aprotic solvents, preferably, wherein the first solvent is a mixture of tetrahydrofuran and acetonitrile.

4. The process according to claim 3, wherein the ratio of tetrahydrofuran acetonitrile is 1:1 to 1:0.5 by volume.

5. The process according to claim 1, wherein the base employed in step (iii) is selected from triethylamine, diethylamine, ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, preferably, wherein the base is sodium bicarbonate.

6. The process according to claim 1, wherein the second solvent used in step (ii) is selected from dichloromethane, ethyl acetate, toluene and chloroform, preferably, wherein the second solvent is dichloromethane.

7. The process according to claim 1, wherein steps (i) to (iii) of the reaction are carried out at a temperature range below 35° C.

8. The process according to claim 1, wherein in step (ii) the Carfilzomib oxalate is precipitated by cooling down the reaction mixture to below 15° C.

9. Oxalate salt of Carfilzomib having a structure of Formula (III), ##STR00013##

10. Oxalate salt of carfilzomib according to claim 9, wherein oxalate salt of Carfilzomib has X-ray powder diffraction pattern (XRPD) with characteristic peaks at (2 theta±0.2 degree): 4.06; 4.66; 6.99; 8.07; 8.46; 9.30; 10.72; 14.84.

Description

DESCRIPTION OF THE ACCOMPANYING DRAWINGS

[0022] FIG. 1: X-ray powder diffraction pattern (XRPD) of Carfilzomib oxalate

DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention provides an improved commercially viable process for the purification of Carfilzomib, the process of present invention is an easy and cost effective process to implement on industrial scale.

[0024] One aspect of the present invention is to provide a process for purification of Carfilzomib of Formula I to reduce an acetamide impurity of Formula II to below 0.10 wt %, comprising the steps of: [0025] (i) dissolving crude Carfilzomib in a first solvent and adding oxalic acid to form Carfilzomib oxalate; [0026] (ii) precipitating said Carfilzomib oxalate; [0027] (iii) reacting said Carfilzomib oxalate with a base in a second solvent to obtain the Carfilzomib

[0028] Crude Carfilzomib contains undesired impurities including acetamide impurity of formula (II).

[0029] The present invention also provides a purified Carfilzomib, wherein an acetamide impurity is present below 0.10% wt of the total weight of Carfilzomib obtained in Step (iii).

[0030] Another aspect of the present invention is to produce oxalate salt of Carfilzomib of formula III, which can be used as an intermediate in the preparation of Carfilzomib to reduce the acetamide impurity of formula II below 0.10% in the final Carfilzomib.

[0031] Carfilzomib oxalate obtained in the present invention is characterized by X-ray powder diffraction pattern (XRPD) as given in FIG. 1.

[0032] Carfilzomib oxalate obtained in the present invention is characterized by X-ray powder diffraction pattern (XRPD) with characteristic peaks at (2 theta±0.2 degree): 4.06, 4.66, 6.99, 8.07, 8.46, 9.30, 10.72 and 14.84.

[0033] The first solvent employed for conversion of Carfilzomib to its oxalate salt, i.e Carfilzomib oxalate in step (i) may be an aprotic solvent or a mixture of aprotic solvents such as acetonitrile, tetrahydrofuran or mixture of tetrahydrofurane and acetonitrile, preferably, wherein the first solvent may be a mixture of tetrahydrofuran and acetonitrile.

[0034] The ratio of tetrahydrofuran: acetonitrile employed for conversion of Carfilzomib to its oxalate salt, i.e Carfilzomib oxalate in step (i) may be 1:1 to 1:0.5, preferably, 1:0.7 by volume.

[0035] The base employed in step (iii) may be selected from triethylamine, diethylamine, ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, preferably, wherein the base may be sodium bicarbonate.

[0036] The second solvent used in step (iii) may be selected from dichloromethane, ethyl acetate, toluene and chloroform, preferably, wherein the second solvent is dichloromethane.

[0037] The reaction temperature of steps (i) to (iii) may be below 35° C.

[0038] The Carfilzomib oxalate thus obtained in step (ii) may be precipitated out by cooling down the reaction mixture to below 15° C.

[0039] The Carfilzomib oxalate thus obtained in step (ii) is desalted by reacting said Carfilzomib oxalate with a base in a second solvent.

[0040] The final Carfilzomib may be isolated by conventional techniques known in the prior art such as crystallization, centrifugation, filtration, precipitation, drying, extraction or combination thereof.

[0041] The invention is further illustrated by way of following examples which should not be construed as limiting to the scope of the invention.

EXAMPLES

[0042] a) Preparation of Carfilzomib Oxalate:

[0043] Carfilzomib crude (10 g) and oxalic acid (1.31 g) were dissolved in mixture of Tetrahydrofuran (70 ml) and Acetonitrile (50 ml) and stirred for one hr at 20-25° C.

[0044] After one hr cool the reaction mixture to 0-10° C. and stirred for three hr followed by filtration of the precipitates so formed give Carfilzomib Oxalate salt.

[0045] Carfilzomib oxalate: X-ray powder diffraction pattern (XRPD) with characteristic peaks at (2 theta±0.2 degree): 4.06, 4.66, 6.99, 8.07, 8.46, 9.30, 10.72 and 14.84

[0046] b) Preparation of Carfilzomib:

[0047] Precipitated carfilzomib oxalate as a wet cake thus obtained in example-1 was dissolved in dichloromethane (100 ml) followed by sodium bicarbonate solution (100 ml) and water (100 ml) washings. Organic layer was concentrated under reduced pressure and product was crystallized in Ethyl Acetate/Methyl tertiary butyl ether mixture (200 ml) (3:7) to afford Carfilzomib (8 g).

[0048] Wt: 8 gm

[0049] Yield: 80%

[0050] Acetamide impurity: 0.04%