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Process for the preparation of amorphous Ibrutinib

IP.com Disclosure Number: IPCOM000247130D
Publication Date: 2016-Aug-09
Document File: 2 page(s) / 327K

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Process for the preparation of amorphous Ibrutinib

Ibrutinib is chemically known as 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and is structurally represented in Formula-I below.  Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK).

Ibrutinib is currently marketed in the United States as IMBRUVICA® by Janssen Pharmaceuticals for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy, chronic lymphocytic leukemia who have received at least one prior therapy, chronic lymphocytic leukemia with 17p deletion, and Waldenstrom’s macroglobulinemia.

U.S. Patent No. 7,514,444 discloses inhibitors of Bruton’s tyrosine kinase, including ibrutinib.

PCT Publication No. WO 2013/184572 discloses crystalline ibrutinib Form-A, Form-B, Form-C, Form-D, Form-E, Form-F and amorphous forms of ibrutinib.

Preparation of amorphous Ibrutinib

Example: 1   

Ibrutinib (1 g) was dissolved in a mixture of methanol (9.5ml) and Dimethylsulphoxide (0.5 ml) at 47˚C. The solution was filtered to remove undissolved particulate and the hot solution was added to the pre-cooled water (35 ml) at 0-5˚C. The resulting mixture was stirred at 13-15 ˚C for 30-60 minutes. Precipitated solids are filtered and washed with water (5 ml). The wet cake was dried at 30-35˚C under vacuum for 15h. The resulting product was identified as amorphous form of Ibrutinib. Yield= 0.8 g

PXRD: Amorphous

Example: 2

Ibrutinib (1 g) was dissolved in a mixture of N-methylpyrolidone  (0.5 ml) and methanol (9.5 m...