Optimization Of Synthetic Method And New Routes Of Pacritinib

Pacritinib is a JAK2(Janus kinase 2)and Fms-like tyrosine kinase 3(FLT3)inhibitor.JAK2 is a member of JAK family,which is a non-receptor tyrosine kinase.JAK2 and Signal transducer and activator of transcription(STAT)are involved in the signal transduction of cytokines and regulate the production of downstream signals.FLT3 is a class III receptor tyrosine kinase that plays an important role in the growth of hematopoietic and non-hematopoietic cells.Pacritinib was first reported in 2007 by Singapore Biotechnology(S·BIO).In 2012,Pacritinib continued to be developed after it was acquired by CTI BioPharma.Subsequently,it was awarded to enter fast track in evaluation by the United States Food and Drug Administration(FDA)in August 2014 and its New Drug Application(NDA)was accepted in 2021.In February 2022,it was approved by the FDA in the United States for the treatment of myelofibrosis patients with thrombocytopenia.Pacritinib is a macrocyclic small molecule compound containing a special trans C=C double bond in its structure.During the synthesis process,because the construction of its macrocyclic involves intramolecular reaction,there are intermolecular byproducts,which pose a great challenge to the synthesis of macrocyclic small molecules.Reported on the synthesis methods of Pacritinib mostly use the olefin metathesis reaction to "ring closure",resulting in the presence of cis-trans isomers(E/Z)in the products,which are difficult to separate and purify with similar polarity.Therefore,in this thesis,we hope to carry out in-depth research the synthesis methods of Pacritinib and use a new "ring closure" strategy to implementation the synthesis of Pacritinib,providing a useful reference for the industrial production of Pacritinib.In this thesis,we first investigated the reported synthetic routes of Pacritinib,summarized and analyzed the differences,advantages and possible deficiency."Synthesis route I" reported in 2011 selected as our initial studies.After synthesis of Pacritinib according to "synthesis route I".optimization work was carried out from two aspects:reaction conditions and reaction steps,respectively,for its low yield and long reaction steps.In view of the problem of low reaction yield(actual total yield 5.9%),four reaction types in "synthesis route I"(Suzuki-Miyaura,Williamson ether synthesis,SNAr and olefin metathesis reaction)were optimized to improve the reaction yield from 19.2%.59.7%.39.9%and 42.5%to 88.9%,83.7%,61.3%and 90.8%,respectively,and the total yield of "synthesis route I" was increased to 29.2%;Aiming at the problem of long reaction steps,the total reaction steps is shortened from 9 to 6 by combined the nucleophilic substitution reaction of allyl bromide,simultaneously reducing aldehyde group and nitro group,and simplified the reaction steps using N-(2-chloroethyl)pyrrolidine hydrochloride.Secondly,in view of the problem that there is cis-trans isomer(E/Z)in the products caused by the use of olefin metathesis reaction for "ring closure" in "synthesis route I",we designed "new route I" using the material trans-1,4-dibromo-2-butene containing trans C=C double bond by retrosynthetic analysis method and carried out experiments on the basis of previous optimization to verify its feasibility.After continuous adjustment and improvement,five synthetic routes("new route I"---"new route V")were designed,of which "new route V"could realize the synthesis of Pacritinib.In "new route V",the intermediates LH-9 and trans-1,4-dibromo-2-butene were used for "ring closure" through nucleophilic substitution reaction,with 12 steps and an overall yield of 4.7%.Finally,the "new route V" is optimized for the problem of its long reaction steps.Because the "new route V" used tert-butyldimethylchlorosilane(TBSCl)to protect intermediate 3 and intermediate 7,adding reaction steps.Therefore,we replaced the material 3-hydroxymethylbenzene boric acid with the material 3-formylbenzene boric acid containing aldehyde group,avoiding the use of TBSCl,shortening the reaction step from 12 to 8 steps and from 9 to 8 steps compared with "synthesis route I".In summary,the synthetic routes of Pacritinib was studied in this thesis.The advantages and disadvantages of four synthetic routes were analyzed by investigated the reported literatures."Synthesis route I" was selected to synthesis Pacritinib to find out its existing problems and carry out relevant studies.1)In view of the problem of low reaction yield,relevant parameters were set to optimize the reaction conditions,which greatly improved the reaction yield;2)We designed a new synthetic route to shorten the reaction steps for the problem of long reaction steps;3)A new Pacritinib synthesis method was developed for the problem of cis-trans isomer(E/Z)in the products,which used the material trans-1,4-dibromo-2-butene containing trans C=C double bond to undergo intramolecular nucleophilic substitution reaction with intermediate LH-9 for "ring closure",so that there was free of cis-trans isomer in the products,and the reaction conditions were milder and the reaction steps was shorter.