The present invention provides efficient, economical, and improved methods for synthesizing ibrutinib and intermediates thereof. The invention involves a unique biphasic acylation reaction system which advantageously allows for easy separation of ibrutinib from the reaction mixture without additional extraction and wash steps. The isolated ibrutinib formed using the methods described herein can be useful in the preparation of an amorphous form of ibrutinib. In some embodiments, the isolated ibrutinib produced by the processes described herein is a homogenous solution of ibrutinib and DMSO which may be directly used in the formation of the amorphous polymorph. In some embodiments, the isolated ibrutinib is solid ibrutinib. The solid ibrutinib may also be used in the formation of amorphous ibrutinib.本發明提供用於合成依魯替尼(ibrutinib)之有效、經濟及改良的方法以及其中間體。本發明涉及一種獨特的兩相醯化反應系統,其有利地允許在無額外萃取及洗滌步驟之情況下,易於自反應混合物中分離依魯替尼。使用本文所描述之方法形成的經分離之依魯替尼可適用於製備依魯替尼非晶型式。在一些實施例中,藉由本文所描述之方法產生的經分離之依魯替尼為依魯替尼與DMSO之均勻溶液,其可直接用於形成非晶多晶型物。在一些實施例中,該經分離之依魯替尼為固態依魯替尼。該固態依魯替尼亦可用於形成非晶依魯替尼。
