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Process for the preparation of Carfilzomib Disclosure Number: IPCOM000239813D
Publication Date: 2014-Dec-03

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The present disclosure relates to a novel process for the preparation of carfilzomib. The present disclosure also relates to a process for the purification of carfilzomib

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Process for the preparation of Carfilzomib

Carfilzomib is a proteasome inhibitor indicated for treatment of multiple myeloma. Carfilzomib is chemically known as (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran­2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methyl

pentanamide and structurally represented as below.

The present disclosure provides several novel processes for the preparation of carfilzomib. The disclosure relates to the preparation of novel intermediates used in the preparation of carfilzomib and process for the preparation thereof.  The present disclosure also provides a method for the purification of carfilzomib. 

The present disclosure is to provide a process for the preparation of carfilzomib, or salt thereof, as shown in schemes-I - V.










The present disclosure is to provide processes for the preparation of intermediates 1E and/or 1L as shown in schemes-A, B, C and D.








The carfilzomib as synthesized and purified by the methods disclosed herein may be useful in generating pharmaceutical dosage forms suitable for administration to patients in need thereof.  The dosage form may be an intravenous dosage form.  Such formulations may be useful in the treatment of multiple myeloma.  Formulations of carfilzomib are particularly useful for patients having multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within sixty days of completion of the last therapy.

EXAMPLE 1: Preparation of Intermediate 1A

Boc-L-H-Phe (200 g, 1 eq) was dissolved in dichloromethane (1000 ml, 5 Vol) at 25-30 oC and 4-dimethylaminopyridine (45.8 g, 0.5 eq) was added followed by benzyl alcohol (73.5 g, 0.95eq).  The mixture was cooled to 0-5 oC and a solution of dichloromethane (161 g, 1.09 eq) in dichloromethane (1000 ml, 5 Vol) was added at 0-5 oC and stirred for 5-8 hrs. at 25-30 oC.  After completion of the reaction, the dichloromethane was distilled at 35 oC under vacuum.  Ethyl acetate (3000 ml, 15 Vol) and water (600 ml, 3 Vol) were added and the mixture was stirred to form a precipitate of an inorganic solid.  The inorganic solid was filtered and ethyl acetate layer was washed with 10% sodium bicarbonate solution (2*2000 ml, 2*10 Vol), water (2000 ml, 10 Vol), and brine solution [NaCl in water](2000 ml, 10 Vol). Ethyl acetate was distilled under vacuum at 40-45 oC to get the product as oil (275 g, w/w= 137.5%). 

EXAMPLE 2: Preparation of Intermediate 1B

The obtained intermediate 1A (275 g, 1eq) was dissolved in dichloromethane (2750 ml, 10 Vol) at 25-30 oC and cooled to 0-5oC.  Trifluoroacetic acid was added (933 g, 11eq) and stirred for 2 hours at 0-5 oC.  Aqueous sodiu...